Volume 30, Issue S1 p. S1-S567
Abstract
Free Access

Poster Presentations

First published: 15 June 2015
Citations: 21

1

Neurovascular status in idiopathic Parkinson's disease; an MRI study

S. Al-Bachari, H.C.A. Emsley, R. Vidyasagar, L.M. Parkes (Manchester, United Kingdom)

Objective: To determine whether novel magnetic resonance imaging (MRI) techniques can reveal altered neurovascular status (NVS) in idiopathic Parkinson's disease (IPD) phenotypes, comparing findings to established cerebrovascular disease (CVD).

Background: Vascular mechanisms are rapidly emerging as key players in the neurodegenerative process in IPD in preclinical studies, yet results of clinical studies are equivocal. MRI arterial spin labelling (ASL) is rapidly emerging as a suitable, non-invasive tool for quantifying cerebral haemodynamics including measurements of cerebral blood flow (CBF) and arterial arrival time (AAT) and may help to overcome the discrepancies in clinical data.

Methods: Participants were recruited into 4 study groups; the tremor dominant [TD] IPD, postural instability and gait dominant (PIGD) IPD, CVD and control (C) groups. All participants underwent a 3T MRI scan protocol including structural and physiological measures of NVS including ASL.

Results: 12 subjects with CVD (manifesting as minor stroke or TIA within the previous 2 years), 19 TD IPD subjects (mean age 67.2 ± 0.6), 17 PIGD IPD subjects (mean age 70.7 ± 6.6) and 23 C subjects (mean age 65.1 ± 5.7) completed the scanning protocol. The number of cerebrovascular risk factors for the control (mean 1.3± 1.0), TD (mean 1.9 ± 1.6) and PIGD (mean 1.5 ± 1.3) groups were matched, but the CVD group had significantly more (mean 3.6± 1.1). The results revealed a significant widespread increase in baseline AAT in both the IPD phenotypes (TD and PIGD) and the CVD group when compared to controls [figure1]. There were also significant differences in voxel-based analysis of CBF revealing focal hypoperfusion, predominantly posteriorly, in the TD, PIGD and the CVD groups when compared to controls.

Conclusions: Despite significantly fewer CV risk factors, IPD subjects of both the TD and PIGD phenotypes had similar patterns of diffuse, prolonged AAT to that of known CVD. Prolonged AAT has been attributed to increased collateral circulation, chronic vasodilatation and/or increased tortuosity of vessels in other studies. Collectively these results provide evidence in a clinical setting of an alteration in NVS in IPD warranting further investigation.

Details are in the caption following the image

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2

Apathy in Parkinson's disease (PD) as a disconnection syndrome – A resting state fMRI study

S. Appel-Cresswell, A. Liu, S.J. Lin, N. Baradaran, T. Kang, J.Z. Wang, M.J. McKeown (Vancouver, BC, Canada)

Objective: to improve the understanding of network pathology in PD apathy.

Background: Apathy is one of the most debilitating non-motor features in PD yet underlying mechanisms are not entirely elucidated, preventing the development of much needed specific treatments. Changes in limbic and variable other brain regions have been identified to be associated with apathy. Although apathy implies a network malfunction, studies so far have focused on individual brain regions; connectivity and network characteristics of apathy are largely unknown.

Methods: 13 subjects diagnosed with idiopathic PD but without depression (BDI <14) or cognitive impairment (MoCA<=26) were assessed with the Apathy Scale. Other clinical indices collected included the UPDRS motor and H&Y scores, and dopaminergic medication. Resting state fMRI (3T) in the OFF state was performed and connectivity inferred with Bayesian network analysis. Apathy scores were correlated with connection strength between two brain regions and relevant connections were identified to predict apathy scores.

Results: Severity of apathy was positively correlated with the following connections: left (L) sup. frontal cortex (FC) to L middle FC (p=0.01), L sup. parietal cortex (PC) to L inf PC (p<0.05), L middle to L inf. temporal cortex (TC) (p<0.05), L hippocampus to right (R) amygdala (p<0.05), L amygdala to L entorhinal (p<0.05). Negative correlations were found for L to R inf. TC (p<0.01), L caudate to L accumbens (p<0.01), R sup FC to R middle FC (p<0.01), L to R insula (p=0.01), L lat. orbitofrontal cortex (OFC) to L insula (p<0.05), R supramarginal PC to R post cingulate (p<0.05), L to R post central cortex (p<0.05), R ant cingulate cortex (ACC) to R inf FC (p<0.05), and R to L middle FC (p<0.05). Predicted apathy scores based on the connectivity analysis correlated to true apathy scores with 0.91. Apathy correlated with motor severity and bradykinesia subscores but not with disease stage.

Conclusions: Apathy is a network disorder, mainly affecting connections between limbic and cognitive areas, despite the clinical correlation to motor severity and bradykinesia. In apathy, interhemispheric connections appear to be weakened whereas mostly local connections are strengthened, possibly acting as compensation.

3

Cortical metabolic alterations underlying cognitive decline in Parkinson's disease

T. Baba, Y. Hosokai, Y. Nishio, A. Kikuchi, T. Hasegawa, K. Hirayama, K. Suzuki, M. Aoki, Y. Itoyama, S. Takahashi, H. Fukuda, A. Takeda, E. Mori (Sendai, Japan)

Objective: To clarify cortical metabolic pattern underlying longitudinal cognitive decline in Parkinson's disease.

Background: Cognitive impairment is common in patients with Parkinson's disease (PD). Mild cognitive impairment (PD-MCI) is thought as an intermediate stage before PD dementia (PDD). The International Parkinson and Movement Disorders Society (MDS) recently published the criteria for PD-MCI. However, neuroimaging evidence of progressive neuronal dysfunction associated with the proposed neurocognitive stages is still lacking.

Methods: We analyzed the data from a 3-year longitudinal study of patients with Parkinson's disease at Tohoku University. Briefly, data of 46 PD patients who did not have dementia at baseline and completed 3-year follow-up with 18F-fluorodeoxyglucose-PET scans were retrospectively analyzed. In this study, patients were classified as PD-MCI and PDD based on the MDS criterias. We analyzed cortical metabolic alterations associated with longitudinal change in these cognitive status by using SPM8 software (Wellcome Department of Cognitive Neurology).

Results: At baseline, 29 patients were classified as cognitively normal PD, and 17 patients fulfilled PD-MCI level I criteria. At follow-up, 28 patients were classified as cognitively normal group, 12 patients were classified as PD-MCI, and 6 patients were classified as PDD. Dementia converting rate was much higher in the PD-MCI group compared with that in the cognitively normal PD group (17.6% vs 10.3%). All dementia converters showed metabolic abnormalities in bilateral parietal lobe at baseline independently of initial cognitive stage.

Conclusions: Current PD-MCI criteria is useful in predicting dementia in PD, but which yet offers a satisfactory predictive accuracy for PDD. In this study, we demonstrated that cortical metabolic abnormalities in bilateral parietal lobe are associated with dementia conversion within 3 years. A combination of PD-MCI criteria and imaging biomarker can improve predictive accuracy for dementia in PD.

4

Corpus callosal atrophy in Parkinson's disease

I.O. Bledsoe, G.T. Stebbins, B.A. Bernard, J.G. Goldman (Chicago, IL, USA)

Objective: To evaluate the volume of the corpus callosum on structural magnetic resonance imaging (MRI) in Parkinson's disease (PD) subjects with varying degrees of cognitive impairment.

Background: Approximately 80% of PD patients develop dementia (PDD), which is often preceded by a prodromal phase of mild cognitive impairment (PD-MCI). Neuroimaging studies in other forms of cognitive impairment (e.g., Alzheimer's Disease, amnestic MCI) show volume loss of the corpus callosum, but little is known about this structure in PD cognitive impairment. The corpus callosum is of particular interest given its critical role in interhemispheric communication and cognitive function.

Methods: 101 PD subjects and 25 healthy controls (HC) underwent clinical/neuropsychological evaluations and MRI brain scans. PD subjects underwent cognitive classification by The International Parkinson and Movement Disorder Society criteria (cognitively normal (PD-NC), n=29; mild cognitive impairment, n=47; demented, n=25). Z-scores for cognitive domains (attention/working memory, executive function, memory, language, visuospatial function) were calculated. T1-weighted sequences were processed by FreeSurfer, and volumes for total and corpus callosum subsections (anterior, mid-anterior, central, mid-posterior, posterior) were computed and normalized by total intracranial volume. Total callosal and subsection volumes were compared between PD and HC using an independent t-test and among PD cognitive groups using ANOVAs, correcting for multiple comparisons as appropriate. Stepwise regression analyses were performed on cognitive domain scores and callosal segment volumes.

Results: Total corpus callosal volume was smaller in PD subjects than in HCs (p=.008), particularly in central (p=.003) and mid-anterior (p=.008) segments. PDD showed smaller volumes than PD-NC in mid-posterior (p=.025), central (p=.009), mid-anterior (p=.014), and anterior (p=.002) segments. In the regression models, anterior callosal segment volumes showed the highest relationship with the cognitive domains.

Conclusions: The corpus callosum demonstrates atrophy in PD subjects compared to HCs. Among PD cognitive subgroups, smaller callosal volumes were found in more anterior regions and especially those PD with greatest cognitive deficits. Greater anterior callosal atrophy in PD cognitive impairment may suggest abnormalities in connectivity, particularly to frontal cortical regions.

5

The role of the supplementary motor area in freezing of gait - A theta-burst stimulation study in Parkinson's disease

F. Brugger, R. Wegener, S. Bohlhalter, E. Abela, S. Hägele-Link, J. Walch, G. Kägi (St. Gallen, Switzerland)

Objective: To assess the role of the supplementary motor area (SMA) in Parkinson's disease related freezing of gait (FOG) by using a multimodal approach including i) a morphological, ii) an electrophysiological and iii) an interventional part.

Background: The SMA is crucial for the planning and control of complex motor sequences. Previous studies showed that structural and functional abnormalities in this brain region are related to FOG in PD.

Methods: PD patients were categorized into freezers and non-freezers according to the FOG questionnaire and the patients’ history. Gait, FOG and FOG-associated parameters were assessed in the joint gait lab of the Kantonsspital and Children's Hospital St.Gallen. FOG-provoking tasks included starting, passing tight quarter, turning and reaching destinations. i) For morphological assessment grey matter changes (GM) were calculated using voxel-based morphometry by the means of standardized 3T MRI scans. ii) For the electrophysiological assessment of the SMA we recorded the Bereitschaftspotential in the off and on state. iii) For the interventional part we applied bilateral intermittent theta burst stimulation (iTBS), a facilitating rTMS protocol, over the SMA in the off state. Gait was analyzed before and immediately after iTBS. The interventional part was designed as a sham-controlled cross-over study.

Results: 12 PD patients with FOG, 13 without FOG and 13 healthy controls were analyzed. i) PD- and FOG-related gait characteristics correlated with GM changes in the SMA with additional clusters in the frontal and parietal brain regions as well as the pedunculopontine nucleus. ii) the late component of the BP showed smaller amplitudes in PD patients with FOG. The administration of dopaminergics led to group specific changes of early premotor and postmotor components of the BP. iii). Intermittent TBS resulted in significant changes of few gait parameters, particularly on turning tasks.

Conclusions: We conclude that cortical alterations not only in the SMA, but in a widespread network including frontal and parietal brain regions are involved in the pathophysiology of PD-related gait impairment and FOG, respectively. However, specific BP patterns and alteration of FOG-associated gait parameters after iTBS over the SMA supports the notion that this brain region is essentially involved in locomotion.

6

A sensory geste-like movement to stop tremor in Parkinson's disease – A clinical and electrophysiological case report

F. Brugger, B. Balint, R. Erro, F. Gövert, E. Antelmi, J.C. Rothwell, K.P. Bhatia (London, United Kingdom)

Objective: To describe the clinical and electrophysiological features in a patient with Parkinson's disease (PD) who uses a sensory geste-like movement to stop his tremor.

Background:: Resting tremor at a frequency of 4-6 Hz is a common clinical sign in PD. Tremor intensity can be modulated by different factors including stress, expectation, distraction as well as by superimposed voluntary muscle activation (also known as re-emergent tremor). Sensory gestes as they are observed in dystonic conditions, however, have never been described in PD.

Methods: We describe the clinical and electrophysiological findings in a PD patient who uses a geste-like movement to stop his resting tremor. Surface EMG of the biceps and triceps was used to record tremor activity. NeuroSpec 2.0 software was used to analyse time-dependent spectra and coherence.

Results: We report a 58-year old patient who came to medical attention due to a right-sided resting tremor of about 6 Hz. Tremor activity was most prominent in the right biceps and triceps. Interestingly, he was able to stop his tremor by a slight touch of the right hand with the contralateral hand, similar to a sensory geste in dystonic conditions. Auto- and crossspectra revealed maxima in the 6 Hz band at the time when the patient was showing the tremor. Coherence analysis revealed a high synchronisation of muscle activity in the pair of antagonists within one second before he touched the right hand and thus stopped the tremor. The frequency of the muscle activity then shifted from the 6 Hz more towards a 15-25Hz band.

Conclusions: This PD patient shows an intriguing strategy to stop his resting tremor which rather resembles a sensory geste as it is observed in dystonic conditions. As the electrophysiological features change even before the patient touches the shaking hand, expectation can be assumed to play an important role in the control of tremor here. The occurrence of muscle activity in the 15-25 Hz frequency band relates to voluntary muscle activation and is thought to originate from the contralateral motor cortex. These results from the coherence analysis are of interest as they allow insights into the modulation of tremor in PD.

7

Disruption of resting state functional connectivity with Parkinson's disease progression

M.C. Campbell, J.M. Koller, A.Z. Snyder, J.S. Perlmutter (St. Louis, MO, USA)

Objective: The purpose of this study was to examine longitudinal changes in resting state networks in Parkinson's disease (PD).

Background: Previous research on resting-state functional connectivity in Parkinson's disease (PD) has consistently demonstrated disruption of cortico-striatal motor networks. Yet most studies have focused on cross sectional evaluation and not determined whether such alterations change over time.

Methods: Resting-state BOLD scans (Seimens 3T Trio) were obtained from non-demented PD participants (N = 21) while off medication and from controls (N = 10), matched for age and head movement. Follow-up resting-state BOLD scans were obtained within 1-3 years after the initial scans. For each of the primary resting state networks (default mode, dorsal attention, control, salience, somatomotor), composite scores were computed based on the correlations among network nodes and compared across groups and across time points.

Results: PD participants demonstrated significantly lower functional connectivity than the controls in the somatomotor network at baseline (p = .05), as expected, but significantly greater functional connectivity within the dorsal attention network than controls (p < .01). Over time, PD participants showed significant reductions in functional connectivity within the default mode network (p = .03) and the dorsal attention network (p = .01). Interestingly, functional connectivity of the somatomotor network in the PD participants did not change significantly (p = .76), whereas functional connectivity increased in controls (p = .04). Controls had no other significant changes in network connectivity (all ps > .34).

Conclusions: These data demonstrate reduced cortical motor network functional connectivity in PD. Within network functional connectivity longitudinally decreased in the default mode network and the dorsal attention network in PD participants without further loss in the cortical motor network. We speculate that such changes in cortical resting state networks may be sensitive to the non-motor features associated with disease progression in PD.

8

Visual motor control in patients with Parkinson's disease

J. Chen, S.L. Ho, M.C. Lee, S.K. Chang, Y.Y. Pang, L. Li (Hong Kong, Hong Kong)

Objective: To understand how Parkinson's disease(PD) and antiParkinsonian medication affect the perceptual and motor abilities in visual motor control using a control-theoretic approach.

Background: Although previous studies have suggested deteriorated visual motor control in PD is likely due to deficits in both the perceptual and motor systems, none of them has directly separated the effects of deficits in the perceptual and neuromuscular systems on visual motor control. In addition, no study has directly measured the effects of antiParkinsonian medication on the perceptual and neuromuscular systems for visual motor control.

Methods: We tested 20 PD patients ON and OFF mediation and 20 healthy controls with a typical closed-loop compensatory manual control task in which participants used a joystick to keep a red target centered on a CRT display (37°Hx21°V) as its horizontal position was perturbed by the sum of seven harmonically-unrelated sinusoids (0.1-2.19Hz). The time series of target position and joystick displacement were Fourier analyzed and averaged across six trials. The performance data were fit by an extensively validated Crossover Model (McRuer et al., 1965) to evaluate how PD and antiParkinsonian medication affect the perceptual system that processes visual information to generate the control command and the neuromuscular system that executes the control command.

Results: Although antiParkinsonian medication improved visual motor control in PD patients, they still showed significantly less control precision (measured by RMS error) and response amplitude (gain) as well as more response delay (phase) compared with the healthy controls. The Crossover-Model-based analysis showed that PD patients’ impaired visual motor control was due to (1) deteriorated perceptual sensitivity to input visual error signal for online motor control, (2) impaired perceptual ability to anticipate the input error to generate control response ahead of the error signal, and (3) decreased stability of the neuromuscular system. AntiParkinsonian medication improved the former two but not the latter.

Conclusions: PD affects patients’ perceptual ability to process visual information for online motor control and the stability of the neuromuscular system to execute the online motor control. The effect of antiParkinsonian medication on visual motor control appears to be primarily through improving perceptual processing.

9

The impact of amyloid deposition on brain network functional connectivity in Parkinson's disease

L. Christopher, M. Criaud, A. Kucyi, Y. Koshimori, P. Rusjan, N. Lobaugh, A.E. Lang, S. Houle, A.P. Strafella (Toronto, ON, Canada)

Objective: The objective was to measure amyloid-β deposition in the brain with [11C] Pittsburgh compound B (PIB) PET in Parkinson's disease (PD) and whether this is associated with functional connectivity (FC) changes in core neurocognitive brain networks.

Background: The presence of amyloid in the brain has been linked to cognitive decline in PD. There is growing evidence that amyloid deposition contributes to alterations in the FC of brain networks in healthy aging and neurodegenerative diseases. Cognitive decline in PD could be associated with amyloid deposition and the resulting effects on brain network function.

Methods: PD patients (n=8) were recruited and each underwent a [11C] PIB PET scan to measure amyloid retention and resting state MRI scan to measure FC in comparison to a group of healthy controls. [11C] PIB non-displaceable binding potential (BPND) was measured in the cortex and striatum. Regions demonstrating increased binding were used as covariates in a seed-based FC analysis to investigate how amyloid impacts FC within and between our networks of interest.

Results: [11C] PIB BPND was highest in the striatum and the cingulate cortex in PD. [11C] PIB binding in the striatum was associated with reduced FC between the ACC and frontal pole/superior frontal gyrus. [11C] PIB in the striatum was also associated with reduced FC between the right DLPFC and the bilateral lateral occipital cortex/angular gyrus as well as the bilateral precuneus. [11C] PIB in the cingulate cortex was associated with reduced FC between the right DLPFC and the frontal pole, angular gyrus and right ACC.

Conclusions: Our findings demonstrate an association between level of [11C] PIB binding in the striatum and cingulate cortex, and reduced FC between networks, primarily between the executive and salience networks, and between the executive and default mode networks. Striatal [11C] PIB was also associated with reduced FC within the central executive network. [11C] PIB was not associated with any increases in FC. These findings suggest that amyloid deposition contributes to reductions in FC within and between cognitive brain networks in PD.

10

Gray matter changes in Parkinson's disease with freezing of gate

M. Delgado-Alvarado, L. García-Penton, H. Jiménez-Urbieta, B. Gago, C. Caballero, M. Carreiras, M.C. Rodriguez-Oroz (San Sebastián, Spain)

Objective: To investigate differences in white (WM) and gray matter (GM) integrity between patients with Parkinson's disease (PD) with freezing of gate (FOG+) and without FOG (FOG-) with a similar cognitive profile.

Background: FOG is one of the most disabling features of PD whose pathophysiology remains unclear. MRI studies have shown that FOG+ patients have more cerebral GM and WM abnormalities than FOG- patients. However, in these studies FOG+ patients showed more severe cognitive impairment, as they are frequent comorbidities.

Methods: 27 FOG+ patients (age 71.67 ± 8.05), 21 FOG- (age 70 ± 5.81) and 21 healthy controls (age 66.24 ± 7.16) were evaluated. FOG+ was defined as a score ≥1in the item 3 of the FOG questionnaire (Giladi et al. 2000). A MRI study (3-T Magnetom Trio Tim scanner, Siemens AG, Erlangen, Germany) was obtained in each participant. T1-MRI and DW-MRI images were obtained. Results were considered statistically significant at a conservative threshold of p<0.01 corrected.

Results: There were no differences between FOG+ and FOG- in age (p=0.4), years of education (p=0.5), gender (p=0.1) and depression scale (p=0.26). The neuropsychological variables were not different between them, i.e., mean composite z scores for attention and working memory (p=0.551), executive function (p=0.808), memory (p=0.165), visuospatial function (p=0.323) and (language p=0.607). Respect to controls, FOG+ and FOG- separately had a similar pattern of impaired neuropsychological tests. The FOG+ group had longer disease duration (9.93 vs 6.81 years; p=0.02) and higher score in the UPDRS-II (20.93 ± 7.75 vs 12.57 ± 6.39; p=0.000), and UPDRS-III (28.67 ± 11.27 vs 18.43 ±9.60; p=0.02). Compared with controls, FOG+ group had a reduction of GM volume in the in right inferior temporal, fusiform, Heschl's, inferior frontal and superior parietal gyri, in the right temporal pole, superior temporal sulcus and right/left amygdala. No difference between FOG+ and FOG- and between FOG- and controls were observed. TBSS did not reveal any significant difference in WM among groups.

Conclusions: To our knowledge, this is the first study comparing groups of FOG+ and FOG- patients with a similar cognitive profile, showing that there are no differences in GM or WM between them. In contrast, the presence of FOG is associated with GM atrophy mainly in the right hemisphere, in areas involved in cognitive processing such as the temporal areas as well as in amygdala bilaterally.

11

Cerebral mechanisms underlying initiation and propagation of Parkinson's tremor – A dynamic causal modeling study

M.F. Dirkx, H.E. Den Ouden, E. Aarts, M. Timmer, R. Cools, R.A. Esselink, B.R. Bloem, I. Toni, R.C. Helmich (Nijmegen, Netherlands)

Objective: To determine the cerebral mechanisms underlying causation and propagation of Parkinson's resting tremor.

Background: Resting tremor in Parkinson's disease is linked to pathophysiological changes both in the basal ganglia and in the cerebello-thalamo-cortical circuit. We previously showed transient brain activity at the onset of tremor episodes in the internal globus pallidus (GPi), and tremor amplitude-related activity in the cerebello-thalamo-cortical circuit. This led to the hypothesis that pathological activity in the basal ganglia drives the cerebello-thalamo-cortical circuit into producing tremor. This hypothesis remains to be tested, because the presence of tremor-related activity may be the cause or consequence of tremor. Accordingly, here we used dynamic causal modeling (DCM), allowing us to make causal inferences on inter-regional interactions within the tremor circuit.

Methods: Using concurrent functional MRI and electromyography (EMG), we tested two independent cohorts of tremor-dominant Parkinson's patients (n=19 and n=22). We compared four different model families where transient activity at the onset of tremor episodes (assessed using the EMG regressor) influences the tremor circuit either through the GPi, motor cortex, thalamus, or cerebellum. Furthermore, we tested whether the GPi influences the cerebello-thalamo-cortical network through the motor cortex or the cerebellum.

Results: We found that in both cohorts, activity at the onset of tremor episodes causally influenced the tremor circuit through the GPi. The magnitude of the influence was larger in patients with a more dopamine-responsive tremor. Finally, the GPi causally influenced the cerebello-thalamo-cortical circuit through the motor cortex, not the cerebellum.

Conclusions: Our findings indicate that the basal ganglia initiate tremor in the cerebello-thalamo-cortical circuit through the motor cortex. This suggests that tremor may be treated by uncoupling the basal ganglia from the cerebello-thalamo-cortical circuit. The difference between patients with relatively dopamine-resistant and dopamine-responsive tremor suggests that regions outside the basal ganglia may trigger dopamine-resistant tremor.

12

Derivation of a levodopa-related pattern with metabolic imaging in idiopathic Parkinson's disease

C. Dresel, C. Tang, D. Eidelberg (Manhasset, NY, USA)

Objective: To derive a Levodopa-related pattern (LDRP) from metabolic brain images in patients with idiopathic Parkinson's disease (PD).

Background: Principle component analysis (PCA) allows extracting disease-related spatial covariance patterns by comparing [F-18]fluoro-deoxy glucose positron emission tomography (FDG PET) images between patients and healthy subjects. These patterns may serve as biomarkers for better differential diagnosis or prognosis of PD or other neurodegenerative disorders, as well as for objective evaluation of therapeutic interventions. For example, levodopa (LD) modulates the expression of the PD-related pattern (PDRP) associated with motor improvement in PD patients. Ordinal trend canonical variates analysis (OrT/CVA) is a variant of supervised PCA designed for deriving patterns of monotonic changes within subjects across conditions or over time. The goal of the present study is utilizing the OrT/CVA method to derive an LD-related pattern that is less dependent on the underlying PD pathology and more specific for the therapeutic intervention itself.

Methods: We applied OrT/CVA to FDG PET scans of a heterogeneous group of 15 PD patients with moderately advanced disease acquired before and after LD treatment. An LDRP was derived to capture levodopa-specific metabolic changes in the brain of PD patients.

Results: OrT/CVA on this preliminary PD sample revealed a significant LDRP (p<0.005, non-parametric permutation test) characterized by LD-induced metabolic decreases in the bilateral pons, midbrain and posterior putamen, and concurrent metabolic increases in the inferior parts of the primary sensorimotor cortex. Bootstrap re-sampling of the data demonstrated a significant stability of this pattern (inverse coefficient of variation ICV=[-2.50, +2.39], p<0.008).

Conclusions: The LDRP contains regions known to be involved in or linked to nigrostriatal dopaminergic neurotransmission and LD pathology. In the long run, this pattern may allow for direct and putatively more accurate assessment of treatment-associated changes in PD. It may be used as an imaging biomarker for monitoring LD effects or for developing customized treatment plans for individual patients.

13

Differential audiovisual processing in Parkinson's disease

C. Fearon, J. Butler, C. McDonnell, I. Killane, R. Reilly, T. Lynch (Dublin, Ireland)

Objective: To investigate auditory and visual processing in Parkinson's disease using an audiovisual task.

Background: Altered visual processing occurs in PD, as evidenced by both clinical and electrophysiological data, often correlating with disease duration and severity. In addition, multisensory integration becomes enhanced in older adults. In particular, visual reaction times tend to be faster than auditory ones, with the greatest multisensory gain attributed to the visual modality. This is likely a strategy to compensate for loss of peripheral sensory processing but may be maladaptive. We hypothesize that a similar adaptive process occurs in PD to compensate for loss of automaticity of movement.

Methods: We studied PD patients under three stimulus conditions: auditory, visual and audiovisual. Participants were presented with a tone or a red disc or both simultaneously on a laptop. The stimulus conditions were randomized in 3 blocks of 100 trials with random interstimulus interval. Participants were asked to press a button in response to all stimuli. Reaction times were computed for each stimulus condition and the Miller Race model was tested to evaluate the multisensory integration contribution to the audiovisual condition. A regression analysis was performed to assess for correlation of the behavioral measures with clinical/neurocognitive scores.

Results: Mean visual reaction time was slower than for auditory and the audiovisual condition was significantly faster. Testing of the Miller Race model revealed that audiovisual responses were facilitated by enhanced multisensory integration. To account for variability in motor response times, the auditory and visual reaction times were normalized by subtracting the audiovisual reaction time. A regression analysis showed that the normalized visual reaction time correlated with disease duration (r=0.62, p<0.05), whereas the normalized auditory reaction time correlated with multisensory integration measures (r=0.69, p<0.05).

Conclusions: Sensory processing is altered in PD with slower visual reaction times and patients becoming more reliant on the auditory modality for multisensory processing. The changes in visual processing speed correlate with disease duration and contrast with healthy older adults who tend to have faster visual reaction times and visual dominance for multisensory integration. These findings support progressive adaptive sensory processes in PD, which differ from that of normal aging.

14

Transcranial static magnetic field stimulation (tSMS) decreases cortical excitability in Parkinson's disease

G. Foffani, M.C. Carrasco-López, J.C. Segundo-Rodriguez, N. López-Ariztegui, F. Alonso-Frech, M.J. Catalan-Alonso, A. Oliviero (Móstoles, Spain)

Objective: To test the hypothesis that transcranial static magnetic field stimulation (tSMS) reduces motor cortex excitability in patients with Parkinson's disease.

Background: We recently introduced tSMS as a novel non-pharmacological, non-invasive, DBS-compatible, low-cost neuromodulation technique to decrease cortical excitability in humans (Oliviero et al., J Physiol 2011). The present study is the first step of a larger project that aims to test the therapeutic potential of tSMS to manage levodopa-induced dyskinesias, supported by the Michael J. Fox Foundation.

Methods: A randomized double-blind sham-controlled cross-over study was performed to assess cortical excitability before and immediately after 10-min of tSMS or sham applied to the motor cortex in patients with Parkinson's disease. Patients were studied off medication after overnight withdrawal of dopaminergic drugs. Cortical excitability was quantified by the amplitude of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). MEPs were simultaneously measured in two muscles: the first dorsal interosseus (FDI), which was the hot spot, and the abductor pollicis brevis (APB). The EMG background was used to exclude trials with muscle pre-activation, often present in tremulous patients.

Results: In our preliminary data, MEP amplitudes were significantly reduced by 28.7 ± 15.0% in FDI and by 27.9 ± 26.3% in APB in the first 4 min after tSMS compared to sham (FDI, 6.9 ± 16.9%, paired t-test p=0.0415; APB, 0.6 ± 31.1%, p=0.0102).

Conclusions: These preliminary results suggest that tSMS is able to decrease cortical excitability in Parkinson's disease.

15

Comparative study of anatomical connectivity of prelemniscal radiations in healthy subjects and Parkinso's disease patients

M.G. García-Gomar, F. Velasco, L. Concha (Querétaro, Mexico)

Objective: Characterize the anatomic connectivity of prelemniscal radiations (Raprl) and identify differences in the fiber populations that conform the Raprl using probabilistic tractography.

Background: The Raprl have been proposed as a neurosurgical target for deep brain stimulation (DBS) for the treatment of PD since 1970's. Despite its clinical usefulness the anatomic connectivity of the Raprl remains unknown.

Methods: Images from 12 healthy subjects and 6 PD patients were acquired using a 3T Philips Achieva scanner. Diffusion-weighted images were acquired using 120 unique diffusion-gradient directions with b=2000s/mm2 (voxel size of 2x2x2mm3). Constrained spherical deconvolution was performed, followed by the creation of track-density images using MRtrix (Brain Research Institute Australia), resulting in final resolution of 0.2x0.2x0.2mm3; these images were crucial for the accurate manual segmentation of subthalamic structures. We seeded 50000 streamlines at the level of the Raprl, differences of streamlines interconnecting the Raprl between groups were assessed by Student's t-test.

Results: All subjects showed Raprl connectivity with cortical and subcortical structures, when these fiber bundles enter the posterior limb of internal capsule they show a clear spatial organization according to their targets, from anterior to posterior as follows: 1) orbitofrontal cortex, 2) globus pallidus (GP) 3) supplementary motor area and 4) primary motor cortex and cerebellum. In 87.5% of healthy subjects GP showed connectivity with the contralateral dorsal brainstem in a region that corresponds to the location of the contralateral pedunculopontine nucleus (PPN), the same connectivity pattern is present in 83.3% of PD patients. The number of reconstructed streamlines obtained showed differences between groups in the connectivity to pallidum (left p=0.017, right p=0.045) and in thalamus (left p=0.02, right p=0.006).

Conclusions: PD patients that have undergone Raprl-DBS show an improvement on gait that also occurs after unilateral GP-DBS, which could be explained because of the bilateral connections from Raprl to PPN through fibers crossing the midline at lower midbrain. Our findings provide new insights into subthalamic connectivity that allow explaining clinical benefits obtained after Raprl-DBS.

16

Neural correlates underlying turning during a virtual reality task in patients with Parkinson's disease and freezing of gait

M. Gilat, J.M. Shine, J.M. Hall, C.C. Walton, S.J.G. Lewis (Sydney, Australia)

Objective: To investigate the pathophysiology underlying turning as a trigger for freezing of gait in Parkinson's disease.

Background: Difficulty with turning often causes injuring falls in Parkinson's disease patients. More specifically, turning is recognized to be the most provocative trigger for freezing of gait, a debilitating symptom that affects around half of patients with Parkinson's disease. Previous studies have used fMRI in combination with saccade tasks or gait imagery to better understand turning in Parkinson's disease, yet no consensus has been reached regarding its underlying pathophysiology.

Methods: This study therefore utilized a validated virtual reality task in combination with fMRI to explore the neural correlates underlying turning in 17 Parkinson's disease patients with clinically confirmed freezing of gait and 10 non-freezers, both off their dopaminergic medications. During fMRI, patients navigated through a virtual environment as presented on a screen that consisted of a straight corridor with 90 degrees turns in both directions. Forward progression through this corridor was accomplished by depressing left and right foot pedals. This allowed for BOLD responses and behavioral footstep latencies to be compared between groups during periods of straight ‘walking’ and periods of turning. BOLD data was analyzed using a mixed-effects analysis in SPM8.

Results: Patients with freezing of gait were more variable and experienced longer delays in their footstep latencies during the turning task compared to the non-freezers group (p < 0.05). In addition, a significant group x task interaction effect revealed that compared to straight walking, turning was associated with altered BOLD responses in the cohort of freezers in key regions that have previously been associated with turning and freezing of gait, such as frontal regions, even when behavioral freezing episodes were removed (p < 0.001; k > 10). Peak ROI analyses also revealed highly significant functional connectivity between the bilateral mesenchephalic locomotor regions during periods of turning in the group of freezers.

Conclusions: Combining fMRI with a virtual reality task allowed for the investigation of neural correlates underlying turning deficits in patients with Parkinson's disease and freezing of gait.

17

White matter abnormalities as a marker of Parkinson's disease cognitive impairment: A diffusion tensor imaging study

J.G. Goldman, D. Merkitch, B. Bernard, G.T. Stebbins (Chicago, IL, USA)

Objective: To investigate markers of white matter (WM) microstructural integrity across the Parkinson's disease (PD) cognitive spectrum using diffusion tensor imaging (DTI) measures of fractional anisotropy (FA) and mean diffusivity (MD).

Background: Dementia develops in about 80% of PD patients in longitudinal studies. Abnormalities in WM may contribute to PD cognitive impairment and can be identified with neuroimaging techniques. Thus, DTI holds promise as a biomarker for advancing our understanding of the neural substrates of PD cognitive impairment and for identifying those at risk for PD cognitive decline.

Methods: Sixty-three PD patients underwent clinical/neuropsychological evaluations, T1- and diffusion-weighted magnetic resonance imaging brain scans, and cognitive classification by the International Parkinson and Movement Disorder Society criteria (cognitively normal (PD-NC), n=20; mild cognitive impaired (PD-MCI), n=28; demented (PDD), n=15). DTI data were processed with mrDiffusion, and wholebrain comparisons of the resulting smoothed FA and MD maps, controlling for PD duration, were analyzed in SPM8 (p<0.001, uncorrected, k=10).

Results: The groups differed in PD duration (mean [SD]: PD-NC 8.8 [3.6], PD-MCI 9.4 [4.2], PDD 13.4 [5.5] years, p=0.007), but not in gender, age (73.4 [6.2] years) or education (15.3 [3.1] years). The PD-MCI group showed decreased FA in frontal, temporal, parietal, and occipital lobes, including the anterior corona radiata, anterior thalamic radiation, inferior fronto-occipital fasciculus, and uncinate fasciculus, and increased MD in frontal, parietal, and temporal lobes, including the superior longitudinal fasciculus, compared to PD-NCs. The PDD group had decreased FA in similar regions but also the posterior corona radiata, and increased MD in frontal, temporal/parietal, and limbic lobes, including corpus callosum splenium and superior longitudinal fasciculus, compared to PD-NCs. Comparisons of PD-MCI and PDD groups revealed no significant FA/MD differences.

Conclusions: WM microstructural abnormalities occur in cognitively impaired PD patients, particularly in those brain regions underlying attention/working memory, executive function, memory, and visuospatial processing. Furthermore, greater disruption of WM pathways in posterior regions may signify greater PD cognitive impairment and thus, provide a biomarker for impending cognitive decline.

18

Attentional modulation of activity in the nucleus basalis of Meynert in patients undergoing deep brain stimulation for Parkinson's disease dementia and Lewy body dementia

J. Gratwicke, A. Oswal, S. Little, M. Beudel, V. Litvak, L. Zrinzo, M. Hariz, P. Brown, M. Jahanshahi, T. Foltynie (London, United Kingdom)

Objective: To investigate the role of the human nucleus basalis of Meynert (NBM) in mediating different modes of attention by examining in vivo local field potential (LFP) recordings during the resting-state and during two types of attention task.

Background: The NBM is the major source of cholinergic innervation to neocortex, and lies just below the globus pallidus internus (GPi) bilaterally. Lesions to the NBM in animals lead to impaired performance on attention tasks, implicating a key role for the NBM in this cognitive domain. However, how activity in the NBM relates to performance on attention tasks is unknown.

Methods: We recorded bilateral LFPs simultaneously from the human NBM and from the GPi in patients enrolled in two ongoing clinical trials of NBM deep brain simulation for Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). The deepest contact on each electrode was located in NBM, with higher contacts in the GPi directly above. Recordings were obtained during the resting state, and also while the patients performed two tasks; one testing orienting of attention (Posner's covert attention task), and the other testing sustained attention (Sustained attention to response task). Spectral analysis of the data was subsequently performed using MATLAB software and open-source academic toolboxes.

Results: Resting state recordings in all hemispheres demonstrated peaks in delta (0.1-3Hz) and theta (4-7Hz) activity in the NBM, which progressively diminished as contacts moved up into the GPi. During task performance NBM activity was differentially modulated depending on the mode of attention employed and this modulation was distinct from that seen in GPi, which corresponded more with motor components of the task.

Conclusions: Our data indicate that while activity in the human GPi reflects movement, activity in the human NBM is more closely related to the mode of attention employed. Deficits in orienting and sustained attention are characteristic symptoms of both PDD and DLB, and the NBM is known to degenerate severely in both conditions. Therefore, our data support the hypothesis that damage to the NBM is a mechanism underlying attentional impairments in PDD and DLB.

19

Structural and functional neuroimaging analysis of Parkinson's disease

R.P. Guimarães, K. Larcher, L. Campos, L. Piovasana, P.C. Azevedo, Y. Zeighami, A.C.F. D'Abreu, F. Cendes, A. Dagher (Campinas, Brazil)

Objective: Our main purpose was to explore structural and functional abnormalities in Parkinson's disease (PD) patients through resting state fMRI and cortical thickness analysis.

Background: Parkinson's disease (PD) is the second most neurodegenerative disease worldwide. Cortical Thickness (CT) and resting state functional MRI (rs-fMRI) are well defined MRI techniques that assess the brain's structure and functionality. Most studies use a Regions of Interest (ROI) based analysis, however ROI identification is based on a priori hypothesis, and this approach is, to some degree, prone to user-introduced bias. We employed a data driven approach focusing on structural and functional abnormalities.

Methods: 58 patients with PD (60.31, SD 8.99) according to the UK Parkinson's disease Society Brain Bank criteria were compared with 33 healthy controls (HC) (57.77 ± 10.06). T1-weighted MRI and EPI images were obtained on a 3T scanner. All fMRI analyses were implemented with the NIAK software. (Neuroimaging Analysis Kit) release 0.7 (Bellec et al. 2010, NIAK website), and CT data was processed with the CIVET pipeline (version 1.1.10; Montreal Neurological Institute at McGill University, Montreal, Quebec, Canada).

Results: Areas showing lower FC in PD when compared to controls were: cerebellum, basal ganglia, postcentral and precentral gyrus, occipital lobe, SMA and substantia nigra. The results are shown in [figure1]. For the CT analysis we stratified patients into 3 subgroups, early PD (EPD), moderate PD (MPD) and severe PD (SPD).

The comparison between EPD and HC revealed decreased CT in left superior temporal gyrus, left gyrus rectus and left olfactory cortex (p<0.05); MPD group, the areas with lower CT were right postcentral gyrus, right SMA and right inferior frontal gyrus (P<0.05). SPD patients had significant lower CT in left inferior frontal gyrus, left precentral and postcentral gyrus, left SMA, left inferior frontal gyrus, left gyrus rectus, right temporal pole, right fusiform gyrus, right middle temporal gyrus, and right occipital gyrus (P<0.05). There were no areas of increased CT. Results are shown in [figure2].

Conclusions: The structural and functional abnormalities found in corresponding areas demonstrate that PD involves a great number of neuronal circuits, including areas responsible for visual processing. A better understanding of the involved areas may further refine our comprehension of the disease and its clinical subtypes.

Details are in the caption following the image

(19).

Details are in the caption following the image

(19).

20

Population analysis of beta band local field potential (LFP) oscillations as a physiomarker in Parkinson's disease (PD)

R. Gupta, S. Stanslaski, T. Denison, P. Stypulkowski (Minneapolis, MN, USA)

Objective: To investigate in a multi-center population of PD patients the characteristics of the LFP oscillations in the beta band (13-35 Hz) and their relevance as a physiomarker of PD.

Background: Abnormal synchronization in the beta band of LFPs within the basal ganglia has been proposed as a pathophysiological hallmark of PD. A population level analysis of this physiomarker across multiple centers with different surgical workflows is necessary to understand its generalizability and potentially learn best-practices. Through our Activa PC+S® brain sensing program, we have the opportunity to look at a population database of LFP signals from PD patients collected via a number of investigator-sponsored studies.

Methods: We analyzed LFP data recorded from the STN of 17 PD patients (4 centers) while the patients were asked to be awake and at rest. Data were collected using a fully implanted chronic DBS research device (Activa PC+S®) that can record brain activity via the standard stimulation electrodes. This device is not FDA-approved in the United States. Data were inspected for the presence of recording artifacts and then analyzed via power spectral analysis techniques to investigate the frequency content.

Results: A distinct peak in the beta band was detected in 12/17 patients (70.6%). Average amplitude of the peaks was 2.47+/- 1.66 uV RMS (calculated as average over +/-1 Hz around the detected peak). Considerable inter-center variability was observed in the amplitude of the peaks, possibly reflecting different surgical targeting approaches and target placements. Furthermore, the peaks were often, but not always, consistent across different follow-up visits. A subgroup analysis revealed that the contact pair with the highest beta power matched the contact selected as the stimulation cathode to deliver therapy. This is consistent with findings from prior studies. The analysis also revealed that patients with higher beta power were programmed to higher stimulation voltages, contrary to prevailing hypothesis.

Conclusions: Our data suggest the prevalence of a peak in the beta band to be 70.6% across a multi-center population of PD patients. Both inter-patient and intra-patient variability were observed in the characteristics of the beta band power. Such variability needs to be taken into consideration when designing algorithms that use this physiomarker as a feedback signal.

21

Does side onset influence neural reserve in patients with Parkinson's disease?

J.H. Ham, Y. Lee, J.J. Lee, P.H. Lee, Y.H. Sohn (Seoul, Korea)

Objective: Handedness is the most prominent human behavioral asymmetry.9 The dominant motor cortex (M1) has a greater dispersion of elementary movement representations with more profuse horizontal connections than does the non-dominant M1.10-12 Therefore, it is conceivable that the dominant hemisphere could have more efficient motor networks with greater neural reserve to cope with pathological changes in PD. We performed this study to investigate whether dominant-side onset PD has a greater neural reserve, and shows less motor deficits despite of similar pathological changes than non-dominant-side onset PD.

Background: Parkinson's disease (PD) symptoms do not develop until 50-60% of dopaminergic neurons in the substantia nigra are lost, suggesting the presence of a significant neural reserve in the motor system affected by PD. Since neural reserve may depend on the resilience of pre-existing neural networks, the dominant hemisphere with more efficient networks could have more resilience in the face of PD-related changes in the brain, and could attenuate motor deficits despite similar degree of dopamine reduction than the non-dominant hemisphere.

Methods: We included the data of 157 consecutive, de novoPD patients with documented right-handedness(mean age, 64.7 ± 7.7 years; range, 46 – 84 years; 47 men) who underwent dopamine transporter PETscans for an initial diagnostic work-up. Among them, 118 patients who showed significant asymmetry of motor deficits were selected for the analyses.

Results: Dominant-side patients (i.e., greater motor deficits on the right-side) showed significantly less motor deficits than non-dominant-side patients (18.0 ± 8.1 and 22.9 ± 10.1, respectively; p = 0.005). Other variables including symptom duration and striatal dopaminergic activities were comparable between the two groups. A general linear model showed this difference in motor deficits remained statistically significantafter controllingthe patient's age, gender, symptom duration, and striatal dopaminergic activity in the posterior putamen (p = 0.010).

Conclusions: These results suggest that dominant-side PD patients have a greater neural reserve to cope with PD-related pathological changes (i.e., less motor deficits despite of similar dopamine reduction) compared to non-dominant-side patients.

22

The changes of the visual evoked magnetic field using the magnetoencephalography and its connectivity using MRI in aging and Parkinson's disease

M. Hirayama, Y. Fujisawa, S. Goto, J. Uemura, M. Hoshiyama, S. Yamada (Nagoya, Japan)

Objective: To clarify a pathophysiology of visual processes in Parkinson's disease (PD), visual evoked magnetic cortical fields (VEFs) and diffusion weighted MRI were recorded in patients with PD, age-matched healthy control and young subjects.

Background: Patients with PD often complain hallucination, which is one of the non-motor symptoms in PD. Histological degenerative changes in retina and visual tract have been reported in patients with PD. Functional abnormality of the visual processes in PD remains unclear.

Methods: Twenty nine healthy subjects (13 younger and 16 elderly) and 10 PD patients participated in this study. We measured visual evoked magnetic field (VEF) using the magnetoencephalography (MEG). Checker pattern reversal (CPR) and monotonous grating pattern (MGP) stimulation were used. MRI was performed to measure the current source position estimation of VEF component and analyzed brain size and tractogram. Cognitive function test, the smell test and UPDRS were evaluated in the PD.

Results: Four VEF components (1M, 2M, 3M, 4M) were seen until the stimulus after 250ms. In CPR stimulus, the latency of 2M and 3M had significantly delayed in the elderly, which compared to the younger. The current of 1M, 2M and 3M were significantly greater and the latency of 1M was delayed markedly in the PD, which compared to the elderly. In MGP stimulus, no significant difference between elderly and the younger was observed. The current of 1M was significantly greater than elderly. In the PD, 1M latency correlated with UPDRS-1, 3 in both stimuli, and it also correlated with the smell test in CPR stimulus. Brain volume using MRI, no difference was not observed, while diffusion tensor imaging was significantly different between younger and elderly, but no difference was found between PD and elderly.

Conclusions: It was suggested that conduction delay corresponding to the checker stimulus occurred in peripheral than the primary visual cortex. Degeneration of Midget cells might be involved in the retina. It is suggested that degeneration of the retina with aging occurred more in PD.

23

Manifestation of Parkinsonian rest tremor is associated with changes in high frequency oscillation power in the subthalamic nucleus

J. Hirschmann, M. Butz, C.J. Hartmann, N. Hoogenboom, J. Vesper, L. Wojtecki, A. Schnitzler (Düsseldorf, Germany)

Objective: To investigate the potential relationship between Parkinsonian rest tremor and high frequency oscillations (HFOs; 200 to 500Hz) in the subthalamic nucleus (STN).

Background: Neuronal oscillations in the STN are related to motor control and undergo drastic changes in patients with Parkinson's disease. While alterations of oscillatory activity in lower frequency bands are well characterized, the role of HFOs is less clear. Recent findings suggest that HFO power is modulated by voluntary movement and administration of levodopa.

Methods: Local field potentials were recorded from 17 STNs in 12 patients with tremor-dominant Parkinson's disease. Simultaneously acquired forearm EMG allowed for the identification of tremor-containing and tremor-free epochs. Spectral power in the HFO band was computed using a multi-taper approach and normalized by mean band power. For each STN, the channel with the highest HFO peak was selected for further analysis, and power and phase-amplitude coupling were compared between tremor-containing and tremor-free epochs.

Results: The average power spectra revealed a slow HFO rhythm (sHFO) of around 260Hz and fast HFO rhythm of around 340Hz (fHFO). sHFO power was stronger in tremor-containing epochs than in tremor-free epochs, while the opposite was true for fHFO power. Eight of eight peaks above 300Hz decreased during tremor, and seven of nine peaks below 300Hz increased during tremor. Notably, peak frequency was stable in all cases, i.e. the change in relative power was not due to peak shift. In addition, some STNs showed a clear change in beta-HFO PAC. However, this change was not significant on the group level.

Conclusions: These results demonstrate an association between STN HFO power and tremor manifestation. The data further support the existence of two distinct HFO rhythms, which seem to be inversely related. The relationship reported here is strikingly reminiscent of the association between HFO power and medication state (Özkurt et al., Experimental Neurology 2011). Thus, it seems plausible that changes in the sHFO/sHFO power ratio reflect dynamic changes of the endogenous dopamine level, which might influence the likelihood of tremor emergence.

24

GBA variations accelerate degeneration of the nigrostriatal pathway in Parkinson's disease: An [123I]FP-CIT study

I. Huertas-Fernandez, S. Jesus, P. Gomez-Garre, F.J. Garcia-Gomez, I. Bernal-Bernal, M. Bonilla-Toribio, M.T. Caceres-Redondo, F. Carrillo, D. Garcia-Solis, P. Mir (Seville, Spain)

Objective: To compare the [123I]FP-CIT SPECT between Parkinson's disease (PD) patients with variations in glucocerebrosidase gene (GBA) and other sporadic PD cases.

Background: PD patients with mutations in GBA show an ealier onset, a more rapid progression of the motor symptoms and an increased risk of developing cognitive decline and other psychiatric symptoms. We hypothesized that [123I]FP-CIT SPECT would be more affected in PD patients with variations in GBA.

Methods: We included a total of 45 GBA variation carriers PD patients and a control group of 60 non-carriers PD patients. We stratified patients based upon disease durarion when underwent [123I]FP-CIT SPECT and compared age-matched groups in early stages (27 GBA variation carriers and 30 non-carriers, mean 2 years) and mid stages (18 GBA variation carriers and 30 non-carriers, mean 8 years). Images were processed and normalised to the MNI atlas with Statistical Parametric Mapping (SPM) and we calculated mean [123I]FP-CIT BPND in bilateral putamen, caudate, and nucleus accumbens. The inter-group statistics were done with T-test.

Results: We found in the subgroup of PD patients at mid stages a decreased [123I]FP-CIT BPND in GBA variation carriers compared to non-carriers in bilateral putamen, caudate, and nucleus accumbens. Differences were more pronounced in the regions ipsilateral to the most-affected side (p<0.001) than those contralateral (p<0.01). Conversely, no significant differences were found in the early-stage subgroup comparisons.

Conclusions: This study shows that GBA variation carriers PD patients have a more severely affected nigrostriatal pathway in the mid stages. However, a similar affection is found in the early stages. Our results suggest that GBA variation carriers PD patients do not have a more aggressive onset than other sporadic PD but in few years they experience higher rates of degeneration.

25

Impact of datscan on clinical decision making: Diagnosis and management of clinically uncertain Parkinsonian syndromes

J.R. Isaacson, S.H. Isaacson (Boca Raton, FL, USA)

Objective: To assess changes in clinical diagnosis and/or treatment of 100 consecutive patients with clinically uncertain Parkinsonian syndromes who underwent DaTscan imaging with ioflupane for striatal dopamine transporter degeneration.

Background: Clinically, the differentiation of Parkinsonism can be challenging due to numerous factors, including symptom overlap and variable response to treatment. It is not uncommon for patients to be initially treated, but later to have diagnosis revised and treatment changed. Striatal dopamine transporter is a marker of presynaptic dopaminergic neuroterminals. Datscan imaging can identify loss of striatal dopamine transporters, indicative of dopaminergic degeneration. Striatal dopamine transporter imaging can help distinguish between Parkinsonian disorders with (PD, SND, PSP, etc) and without (drug-induced, ET, vascular, etc) dopaminergic degeneration.

Methods: Retrospective ongoing analysis of 100 consecutive patients whose clinical diagnosis was unclear and in whom a Movement Disorder specialist ordered DATscan imaging to clarify diagnosis by determining whether dopaminergic degeneration was present. All patients had assessment of % likely abnormal scan prior to imaging based on clinical examination and prior treatment response. After DaTscan imaging, changes to clinical diagnosis and treatment were assessed.

Results: Overall, approximately half of patients had an uncertain provisional diagnosis confirmed, one-third of patients had clarification between two provisional diagnoses, and one-fifth of imaged patients had a provional diagnosis changed. We identified several clinical scenarios where Datscan imaging seem most useful: drug-induced; prominent action tremor; lower extremity predominant; early subtle signs with nonmotor symptoms; and clinically stable and/or without fluctuations after 5 years. Changes in treatment followed clarification of clinical diagnosis and whether dopaminergic degeneration was identified on Datscan.

Conclusions: In several clinical scenarios in which diagnosis of Parkinsonian syndromes is unclear, visualization of striatal dopamine transporters using DaTscan can differentiate between disorders with and without nigrostriatal dopaminergic degeneration, clarifying diagnosis and impacting treatment.

26

Cortical excitability changes induced by L-dopa mirror the unbalanced nigro-striatal denervation in Parkinson's disease

I.U. Isaias, F. Turco, M. Rosanova, G. Marotta, G. Frazzitta, C. Landi, A. Perretti, L. Giusti del Giardino, M. Canesi, M. Massimini, G. Pezzoli, S. Casarotto (Würzburg, Germany)

Objective: To evaluate the effects of acute administration of L-dopa on cortical excitability in frontal and parietal cortices and to assess the asymmetry of this effect in relation to nigro-striatal dopaminergic denervation.

Background: L-dopa is an effective and established treatment for Parkinson's disease (PD). However, its indirect effects on cortical functions have not been fully uncovered, but could be very important to understand the pathophysiology of some L-dopa-related adverse effects (e.g. dyskinesia).

Methods: Thirteen PD patients were investigated by Single Photon Computed Tomography (SPECT) and [123I]FP-CIT. The brain side (hemisphere H) with lower/higher striatal-specific binding ratio was labeled as H-/H+. Cortical potentials evoked (TEPs) by transcranial magnetic stimulation (TMS) were recorded by means of high-density EEG (hdEEG) from each patient 12 hours after withdrawal of all dopaminergic drugs (meds-off) and at 90 minutes after oral intake of 200 mg of fast-released soluble L-dopa (meds-on). TMS was delivered to the supplementary motor area (SMA) and superior parietal lobule (SPL) bilaterally. Cortical excitability was measured by the immediate response slope (IRS) and immediate response area (IRA) computed from TEPs averaged across region-of-interest neighboring channels. The effects of acute L-dopa intake were measured as the percentage change of IRS and IRA (Δ%) between meds-off and meds-on conditions. Δ%IRS and Δ%IRA were compared between H- and H+ at the group level.

Results: The morphology of TMS-evoked potentials was similar across patients and characterized by an early positive wave between 12-35 ms followed by a negative peak at about 45 ms. Δ%IRS and Δ%IRA on the same side of the stimulation target was significantly higher in H- as compared to H+ only when SMA was targeted (p<0.05 for IRS; p<0.02 for IRA). The same analysis performed on the opposite side of the stimulation target did not reveal any significant difference between H- and H+ for stimulation of either SMA or SPL.

Conclusions: Acute administration of L-dopa specifically increases neuronal excitability of premotor cortex on the brain side with greater nigro-striatal dopaminergic denervation. This study also demonstrates the feasibility of measuring cortical excitability in PD patients by means of TMS together with hdEEG.

27

Differential diagnosis of Parkinsonism using two PD-related metabolic patterns

V.A. Jourdain, C.C. Tang, D. Eidelberg (Manhasset, NY, USA)

Objective: To determine whether individual subjects with idiopathic Parkinson's disease (PD) can be distinguished from atypical Parkinsonian syndromes (APS) based on differences in expression values for established PD metabolic covariance patterns relating to motor and cognitive disease manifestations.

Background: Accurate discrimination of patients with PD vs. APS (represented mainly by progressive supranuclear palsy (PSP) and multiple system atrophy (MSA)) can be clinically challenging. We have found that PD is characterized by increases in PDRP and PDCP expression, with greater expression of the former relative to the latter in individual subjects. However, these network changes are uncommon in APS.

Methods: 167 Parkinsonian patients (96 PD, 41 MSA and 30 PSP) with uncertain clinical diagnosis, in which 55 (30 PD, 11 MSA and 14 PSP) had disease duration of ≤2 years, underwent FDG PET. Final diagnoses for these patients were made after a clinical follow-up of 2.6 years. For each patient, we calculated expression values (subject scores) for the PDRP and PDCP networks, as well as delta PDRP-PDCP, the difference in the two scores. Logistic regression was followed by ROC analysis. Area under the curve (AUC) was used to determine the accuracy of delta PDRP-PDCP as a predictive classifier for PD, MSA, and PSP.

Results: Delta PDRP-PDCP was a significant classifier (AUC=0.82, p<0.0001) that distinguished PD from APS patients. A similar result was obtained (AUC=0.78, p=0.002) in the short duration patients. This measure, however, did not differentiate MSA from PSP (AUC=0.52, p>0.57) in either the whole sample or the short duration subgroup. Classification was overall less accurate with this logistic algorithm than with one based on individual subject scores for previously validated metabolic patterns for PD, MSA, and PSP (Tang et al., 2010).

Conclusions: Delta PDRP-PDCP is a potentially useful network classifier for the differential diagnosis of Parkinsonism. This measure is consistently positive (delta>1) in classical PD, reflecting Braak's pathological timeline. In PD, relatively greater PDRP expression may represent earlier subcortical involvement (analogous to Braak Stage V), while consistently smaller PDCP levels reflect the later development of neocortical pathology (analogous to Braak Stage VI). This network timeline, represented by delta PDRP-PDCP, is specific for classical PD, thereby providing accurate differential diagnosis.

28

Levodopa-induced changes in neurovascular reactivity in Parkinson's disease

V.A. Jourdain, F. Holtbernd, C.C. Tang, V. Dhawan, D. Eidelberg (Manhasset, NY, USA)

Objective: To determine whether the difference in levodopa-induced increase in striatal levels of dopamine between dyskinetic and non-dyskinetic patients depends, at least in part, on functional and structural alterations of the brain microvasculature.

Background: In our original study of 8 subjects without levodopa-induced dyskinesia (LID) and 3 with LID (Hirano et al., J Neurosci 2008;28:4201-9), we demonstrated that blood flow/metabolism dissociation was created by levodopa in dopa-decarboxylase-rich brain regions in putamen and internal globus pallidus (GPi), and in the dorsal pons.

Methods: Eleven LID and 5 non-LID PD subjects, as well as 14 healthy volunteers underwent dual tracer [15O]-H2O and [18F]-FDG PET to measure cerebral blood flow (CBF) and cerebral metabolic rate for glucose (CMR) at baseline (OFF) and during an intravenous levodopa infusion (ON) to replicate the original observations. We also measured the OFF-levodopa CBF under normocapnic and hypercapnic (5% CO2, rebreathing up to 5 minutes) conditions in the current PD cohort to measure whether LID is associated with abnormal hypercapnic response (an index of underlying capillary density) in areas of levodopa-mediated flow metabolism dissociation.

Results: The regions identified in the original voxel-based analysis were highly concordant with those identified in the new PD cohort. As in the original study, significant levodopa-mediated flow metabolism dissociation was also seen at the network level for the PD motor-related pattern (PDRP). When combining both cohorts (14 LID, 13 non-LID, 8 test-retest PD and 14 healthy controls), levodopa-mediated flow metabolism dissociation was greater in LID relative to non-LID subjects in the putamen/GPi, as well as the network level. These results were mainly driven by an increase in CBF in the ON-state. Under normocapnic conditions, no difference was observed between controls and PD or between LID and non-LID subjects. Normal and PD subjects both exhibited increased CBF during hypercapnia with a significantly greater increase in LID patients.

Conclusions: The findings suggest that LID subjects have greater flow metabolism dissociation in response to levodopa treatment than their non-LID counterparts. Moreover, the increase in capillary reserve seen with LID suggests that this side effect is associated with underlying microvascular changes in key brain regions.

29

Alternations of human brain connectome in Parkinson's disease using network based statistics (NBS)

A. Kamalian, M.H. Aarabi (Tehran, Iran)

Objective: To determine impaired interconnecting fibers of patients with Parkinson's disease using Diffusion Tensor Imaging (DTI) and a statistical approach – Network Based Statistics (NBS) – to analyze brain connectivity matrices.

Background: Neuroimaging is an accurate method to examine the areas engaged in PD neurodegeneration. Previous DTI studies had used topological features – e.g. degree and clustering coefficient – to investigate PD-correlated brain network alterations. However, we computed average tract length and fiber volumes as measures of white matter integrity. In addition, we adopted a novel statistical approach to conduct group connectivity analyses between PD patients and healthy controls.

Methods: Data Acquisition:

Data used in the preparation of this abstract were obtained from the Parkinson's Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data) with permission. For up-to-date information on the study, visit www.ppmi-info.org.

Methods:

DWI data were analyzed for 18 patients (73.34 ± 3.94) and 12 controls (71.5 ± 3.45) using ExploreDTI . The diffusion tensors were estimated based on weighted linear least squares and for EPI-distortion and head motion correction, DWI data were rigidly registered with MNI atlas. Deterministic full brain tractography was performed using a stopping criterion of 0.2 FA and 30° curvature threshold. The whole-brain fiber tract reconstructions of the previous step were parcellated using the automated anatomical labeling (AAL) atlas. By applying the ROI masks to the reconstructed fiber tracts using the ExploreDTI, the volume and average tract length that originated in one ROI (i) and terminated in another one (j) was determined, creating a 116 × 116 connectivity matrix . Then, we used NBS for group analysis. NBS is a method to control the family-wise error rate (in the weak sense). The overall workflow is illustrated in Figure 1.T-test statistics were applied and significant results (p-values < 0.05) were reported.

[Figure 1]

Results: The regions exhibiting significantly diminished interconnections – including: cingulum, hippocampus, parahippocampus, olfactory lobe, occipital lobe, cuneus, and basal ganglia – are presented extensively in Tables I,II, and Figure 2.

Table 1. Significant Pathways (Volume of Fibers)
Pathway T stat
Frontal_Sup_Orb_L to Frontal_Mid_R. 2.96
Frontal_Mid_R to Frontal_Inf_Tri_R. 3.07
Frontal_Inf_Oper_R to Frontal_Inf_Tri_R. 3.86
Frontal_Inf_Oper_R to Insula_R. 3.68
Frontal_Inf_Tri_R to Insula_R. 2.92
Cingulum_Post_L to Cingulum_Post_R. 3.13
Cingulum_Post_L to Hippocampus_L. 3.10
Cingulum_Ant_R to Hippocampus_R. 3.48
Olfactory_R to ParaHippocampal_L. 3.13
Frontal_Inf_Orb_R to Occipital_Sup_L. 2.99
Cuneus_L to Occipital_Mid_R. 3.53
Occipital_Sup_L to Occipital_Mid_R. 3.04
Occipital_Inf_R to Parietal_Sup_R. 3.33
Frontal_Inf_Tri_L to Precuneus_L. 2.91
Cingulum_Post_L to Precuneus_L. 3.06
Cingulum_Post_R to Precuneus_L. 3.00
Cingulum_Post_R to Precuneus_R. 2.99
Hippocampus_R to Precuneus_R. 3.12
Occipital_Mid_R to Precuneus_R. 3.55
Frontal_Inf_Orb_R to Putamen_R. 2.94
Parietal_Sup_R to Pallidum_L. 3.28
Precuneus_L to Pallidum_L. 3.14
Heschl_L to Temporal_Sup_L. 3.15
Olfactory_R to Temporal_Pole_Sup_L. 3.09
Cingulum_Post_R to Temporal_Pole_Sup_L. 2.95
Precuneus_L to Temporal_Pole_Sup_L. 3.00
Pallidum_R to Temporal_Pole_Sup_L. 3.27
Heschl_L to Temporal_Pole_Sup_L. 3.01
Insula_R to Temporal_Pole_Sup_R. 3.13
Putamen_R to Temporal_Pole_Sup_R. 3.18
Table 2. Significant Pathways (Average Tract Length)
Pathway T stat
Supp_Motor_Area_L to Cingulum_Post_L 3.20
Frontal_Sup_L to Hippocampus_L 2.98
Cingulum_Post_L to ParaHippocampal_L 2.96
Frontal_Inf_Orb_R to Occipital_Sup_L 4.06
Occipital_Mid_L to Occipital_Mid_R 2.98
ParaHippocampal_L to Fusiform_L 3.01
Frontal_Inf_Orb_L to Parietal_Sup_L 4.02
Frontal_Inf_Orb_R to Parietal_Sup_R 3.57
Cingulum_Post_R to Parietal_Sup_R 3.63
Occipital_Mid_L to Parietal_Sup_R 3.10
Occipital_Inf_R to Parietal_Sup_R 3.10
Hippocampus_L to Precuneus_L 3.17
ParaHippocampal_L to Precuneus_L 2.92
Fusiform_L to Precuneus_L 2.97
Parietal_Sup_R to Precuneus_L 3.06
Parietal_Sup_R to Putamen_L 4.41
Parietal_Sup_R to Pallidum_L 3.81
Frontal_Inf_Orb_L to Pallidum_R 3.02
Rolandic_Oper_L to Heschl_L 3.64
Hippocampus_L to Temporal_Pole_Sup_L 3.20
ParaHippocampal_L to Temporal_Pole_Sup_L 3.39
Precuneus_L to Temporal_Pole_Sup_L 3.26
Pallidum_R to Temporal_Pole_Sup_L 3.43
Heschl_L to Temporal_Pole_Sup_L 3.37
ParaHippocampal_L to Temporal_Inf_L 2.92
Parietal_Sup_R to Vermis_3 3.05

[Figure 2]

Conclusions: Our results confirm prior studies reporting fibers interconnecting olfactory lobe, occipital lobe, cingulum, hippocampus, parahippocampus, and basal ganglia as major sites of damage in PD.

Details are in the caption following the image

(29).

Details are in the caption following the image

(29).

30

Importance of proper window setting on visual assessment of dopamine transporter image

A. Kim, H.J. Kim, B.S. Jeon (Seoul, Korea)

Objective: To describe a young male patient with Park2 mutation whose FP-CIT PET was misinterpreted as normal initially.

Background: Diagnosis of neurological conditions associated with disturbances of dopaminergic functioning can be challenging, especially in the early stages or atypical manifestation. In those cases, dopamine transporter imaging can assist the early diagnosis. Although there are quantitation methods for dopamine transporter image assessment, they are laborious and generally are not used for routine clinical practice. Therefore, visual assessment is used in routine clinical practice.

Methods: Case report.

Results: A 17 year-old man presented with progressive gait disturbance, cervical dystonia and head tremor. His neurologic examination showed mild rigidity and resting tremor of bilateral legs which was slightly dominant on the left side. 18F-FP-CIT positron emission tomography (PET) was done and interpreted as normal at other hospital, and his diagnosis remained elusive. He visited our hospital several months later, and the FP-CIT PET image was reviewed by the radiologist in our hospital, who also interpreted it as normal. However, we reviewed his FP CIT-PET image because his clinical picture was strongly suggestive of juvenile Parkinsonism. After adjusting the window setting of the PET image, we could appreciate the decreased uptake in the bilateral basal ganglia. Thus he was finally diagnosed as juvenile Parkinsonism. Gene test confirmed that his Parkinsonism was due to Park2 gene mutation.

Conclusions: Proper window setting is important during visual assessment of dopamine transporter imaging.

31

Putaminal dopamine turnover in de novo Parkinson's disease predicts levodopa-induced motor complications

M. Löhle, J. Mende, M. Wolz, B. Beuthien-Baumann, L. Oehme, J. van den Hoff, J. Kotzerke, H. Reichmann, A. Storch (Dresden, Germany)

Objective: To investigate the predictive value of baseline striatal dopamine metabolism in de novo Parkinso's disease for the onset of later motor complications.

Background: Long-term therapy with levodopa is associated with motor complications, such as wearing-off and levodopa-induced dyskinesias (LID), for which treatment options are still limited. Pathological and neuroimaging studies have not completely unravelled the underlying pathogenesis of these complications, which hinders reliable prediction and potential prevention.

Methods: We performed a retrospective, observer-blind, long-term follow-up study in 31 patients with early, drug-naïve Parkinson's disease, who had originally received quantitative 18F-dopa PET imaging to estimate striatal 18F-dopa uptake (Kocc) and effective dopamine distribution volume ratio (EDVR) as the inverse of dopamine turnover prior to treatment allocation. The onset of wearing-off and LID was estimated based on blinded clinical assessments and patient records. The predictive value of baseline PET results of striatal subregions for the development of motor complications (wearing-off, LID and any motor complication) was evaluated using Cox proportional hazard models.

Results: Over a mean observation period of 6.8 years, 18 (58.1%) patients developed wearing-off, 11 (35.5%) LID and 20 (64.5%) any motor complication. Patients with LID and any motor complication showed lower EDVR (higher dopamine turnover) in the putamen than those without LID and any motor complication, with differences most markedly present in the posterior putamen. EDVR in the whole and the posterior putamen predicted development of motor complications with an increasing risk with lower EDVR (higher dopamine turnover), whereas EDVR in other regions and Kocc did not correlate with motor complications. Kaplan-Meier curves showed reduced survival from motor complications in patients with lower baseline EDVR (higher dopamine turnover) in the posterior putamen with ongoing levodopa treatment and disease duration.

Conclusions: Elevated putaminal dopamine turnover in de novo Parkinson's disease is associated with an increased risk for later motor complications. This increase in putaminal dopamine turnover might constitute an early compensatory mechanism and could play an important role in the development of levodopa-related motor complications as a disease-intrinsic predisposing factor.

32

Understanding the effects of subthalamic nucleus (STN) deep brain stimulation (DBS) with preoperative diffusion tensor imaging (DTI)

P.M. Lauro, N. Vanegas, Z. Kareem, L.I. Codrin, S.S. Ziad, H.G. Silvina (Bethesda, MD, USA)

Objective: We aimed to characterize the specific stimulator-neuronal connectivity associated with favorable clinical outcomes using preoperative DTI and stereotactic electrode locations.

Background: DBS is an effective therapy for treating Parkinson's disease (PD). Symptom relief is achieved by targeting specific areas of the STN. Studies have suggested that stimulation of white matter structures adjacent to the main target have similar beneficial effects.

Methods: Twenty patients (9 male, average age: 57.9 ± 9.49, average disease duration: 13.25 ± 6.69) with idiopathic PD who received STN DBS surgery at the NIH were studied. All patients underwent preoperative MRI including diffusion-weighted imaging (b=1000 s/mm2, 32 directions). Postoperative CT images were co-registered to preoperative T1, T2, and DTI for DBS lead localization. Diffusion images were processed with TORTOISE and tensors were estimated non-linearly with AFNI. Grey-matter ROIs were created from preoperative T1 images with Freesurfer and aligned to DTI volumes.

Monopolar screening of DBS contacts was performed one month after implantation to determine voltages for clinical benefit. The contact with the largest therapeutic window was chosen as the stimulating contact. The volume of tissue activated (VTA) was estimated as a sphere whose radius was calculated using contact impedance and voltage. Probabilistic tractography was used to determine the number of streamlines from each VTA to selected gray-matter ROIs using FATCAT. To adjust for differences in conduction volume, the number of streamlines was scaled by VTA size.

Results: Tractography networks were determined for all chronic stimulation contacts and for contacts with side effects and no clinical benefit. The total percentage of connections with three gray matter structures (ventral diencephalon, caudate and thalamus) ipsilateral to the stimulating contacts (left 81.46 ± 14.83%; right 79.03 ± 15.09%) was higher compared with the one obtained for contacts without clinical benefit (left 63.45 ± 17.48%; right 66.45 ± 18.48%).

Conclusions: By co-registering preoperative DTI and postoperative CT, we were able to determine specific connectivity patterns that characterize clinically effective DBS electrodes. This type of network analysis provides a potential targeting and prospective programming approach for DBS therapy.

33

Gender difference in depletion of presynaptic nigrostriatal dopamine in de novo Parkinson's disease

J.J. Lee, J.S. Oh, J.H. Ham, D.H. Lee, I. Lee, P.H. Lee, J.S. Kim, Y.H. Sohn (Seoul, Korea)

Objective: To explore whether a gender difference in presynaptic nigrostriatal dopaminergic density in patients with de novo Parkinson's disease (PD) using a quantitative analysis of 18F-FP-CIT positron emission tomography(PET) scans.

Background: Several antecedent studies have been reported of gender difference in PD including different clinical characteristics of motor and non-motor symptoms, response to deep brain stimulation and even those in plasma α-synuclein concentrations. The neuroprotective influence of estrogen to dopaminergic neurons, and male-female difference of brain morphology and functions are suggested as possible mechanisms of those distinction.

Methods: This study included 307 drug-naïve patients (152 men and 155 women) with de novo PD who completed an 18F-FP-CIT PET scan at initial diagnosis. Quantitative analyses of dopamine transporter (DAT) activities were performed based on volumes of interests, and thus each unilateral striatum was divided into 6 subregions of which comprised with 2 caudate subregions (anterior and posterior), ventral striatum, and 3 putaminal subregions (anterior, posterior, and ventral). Gender difference of DAT activities in each striatal subregion as increase of age at onset was assessed using linear regression analyses.

Results: We found no significant male-female differences in age at onset, disease duration and Unified PD rating scale (UPDRS) part III. In scatter plot of age at onset versus DAT activities, the DAT activities were reduced with increase of the age at onset and those in female were higher than those in male in all striatal subregions. In linear regression analysis adjusting for age at onset, disease duration and UPDRS III, the degree of gap of DAT activities between male-to-female was reduced as increase of age at onset in all striatal subregions, and these gaps were in significance in anterior putamen (Estimated slope [ES], -0.005 vs -0.018; p=0.001), anterior (ES, -0.021 vs -0.039; p<0.001) and posterior (ES, -0.013 vs -0.025; p<0.001) caudate but not in ventral striatum, posterior and ventral putamen.

Conclusions: We found that nigrostriatal dopamine neurons are significantly more preserved in anterior part of the basal ganglia in female with exception of posterior part which is well known susceptible region for Lewy body degeneration. These findings suggest that neuroprotective effect in female may not be associated with PD pathogenesis per se.

34

Evaluation of saccadic eye movements in patients with Parkinson's disease: Effect of levodopa

A. Lenka, K.R. Jhunjhunwala, R. Kotikalapudi, P.K. Pal (Bangalore, India)

Objective: To assess the saccadic eye movements in patients with Parkinson's disease (PD) and to investigate the effect of levodopa on saccadic eye movements.

Background: Cortical and subcortical brain regions which control saccadic eye movements, are known to be involved in PD. Though abnormalities of saccadic eye movement have been reported in PD, the effect of levodopa on saccadic eye movements is not clear.

Methods: Eye movements of 15 patients (10 men) with PD patients and 15 age and gender matched controls were recorded by an IVIEW X HI-SPEED eye tracker (SensoMotoric Instruments GmbH, Germany) using a Visually Guided Stimulus (VGS) task. Various saccadic parameters such as latency, average velocity, peak velocity, average acceleration and peak acceleration were assessed in drug OFF and best ON states in PD patients and compared with healthy controls. ANOVA was used to compare the saccadic parameters between three groups a) OFF state b) ON state c) Controls. Paired t test was used to compare between ON and OFF state in PD patients. Since saccadic latency does not have a normal distribution, median of reciprocals of latencies were taken which showed a Gaussian distribution.

Results: The mean age of the patients was 52.9 ± 11.6 years and that of controls was 51.7 ± 7.4 years. The mean age at disease onset was 48.2 ± 12.1 years and mean duration of illness was 4.1 ± 2.5 years. The mean UPDRS- OFF and ON scores of PD patients were 35.4 ± 8.4 and 20.1 ± 10.4 respectively. On comparison between the three groups (a, b and c) there was no significant difference in all the saccadic parameters except average acceleration, which was significantly lower in OFF state compared to controls (8344.5 ± 2944.2°/sec2, vs 10327.3 ± 2971.1°/sec2, p=0.039). On comparison, though the saccadic parameters improved from OFF to ON state, the differences were not statistically significant: reciprocal latencies (2.9 ± 0.9 sec-1 vs 3.1 ± 0.8sec-1), average velocity (200.8 ± 56.1°/sec vs 207.8 ± 63.8°/sec), peak velocity (389.6 ± 135.1°/sec vs 397.2 ± 157.3°/sec), average acceleration (8344.5 ± 2944.2°/sec2 vs 9546.3 ± 3286.5°/sec2) and peak acceleration (16501.6 ± 5818.1°/sec2 vs 17885.1 ± 6318.6°/sec2).

Conclusions: PD patients during OFF state had reduced average acceleration of the saccades compared to controls. Levodopa did not significantly improve any of the saccadic parameters, though larger cohort need to be studied.

35

Resetting tremor by single and paired transcranial magnetic stimulation in Parkinson's disease and essential tremor

M.K. Lu, S.M. Chiou, U. Ziemann, H.C. Huang, Y.W. Yang, C.H. Tsai (Taichung, Taiwan)

Objective: To investigate whether tremor in Parkinson's disease (PD) and essential tremor (ET) is differentially modulated by perturbation of the motor-related cortices.

Background: The pathogenesis of tremor in PD and ET is not fully understood. This study tested the role of primary motor cortex (M1), supplementary motor area (SMA) and cerebellar cortex on PD and ET tremor by single- and paired-pulse transcranial magnetic stimulation (TMS).

Methods: Ten PD patients with resting tremor, six of them also with postural tremor, and 10 ET patients with postural tremor were studied. Randomized single- and paired-pulse TMS with an interstimulus interval of 100 ms were delivered over M1, SMA and cerebellum. TMS effects were evaluated by calculating a tremor-resetting index (RI).

Results: Single- vs. paired-pulse TMS showed no difference. M1-TMS and SMA-TMS but not by cerebellar TMS induced a significant RI in PD and ET. M1-TMS resulted in a significantly higher RI in PD than ET. Furthermore, M1-TMS in PD but not in ET resulted in a significantly higher RI than SMA-TMS.

Conclusions: Findings suggest a stronger involvement of M1 in resting and postural tremor in PD than postural tremor in ET. RI provides a useful marker to explore the differential functional role of M1, SMA and cerebellum in PD versus ET tremor.

36

White matter microstructure damage in tremor-dominant Parkinson's disease patients

C. Luo, X. Guo, W. Song, H. Shang, Q. Gong (ChengDu, People's Republic of China)

Objective: The current study aims to investigate the differences in white matter integrity in Parkinson's disease (PD) patients with and without tremor and to identify possible structural correlates of rest tremor.

Background: Rest tremor is a hallmark of PD, yet its pathogenesis is incompletely understood. Several lines of evidence suggest tremor may have different underlying pathophysiology processes from those of bradykinesia and rigidity. It is unclear whether PD patients with and without tremor are also different concerning white matter integrity.

Methods: We recruited two carefully matched groups of PD patients that had either absent or prominent resting tremor, but who all displayed similar levels of akinesia and rigidity (30 with tremor-dominant PD and 30 with nontremor-dominant PD), and 26 normal controls. All participants underwent clinical, neuropsychological assessment and diffusion tensor MRI. We used tract-based spatial statistics to investigate white matter integrity across the entire white matter tract skeleton.

Results: Compared with both healthy controls and nontremor-dominant PD patients, tremor-dominant PD patients were characterized by increased MD and AD along multiple white matter tracts within cortico-cerebello-thalamo-cortical (CTC) pathway and some regions of association fibers. Mean MD value in white matter tracts correlated with tremor scores in tremor-dominant PD patients. There was no significant difference between nontremor-dominant PD patients and controls. [figure1]

Conclusions: Our results support the notion that tremor in PD as a distinct condition in which significant microstructural white-matter changes exist and provide evidence for the involvement of CTC in tremor genesis of PD. These findings suggest that objective measures of white matter integrity may be useful in future genotype-phenotype analyses and in targeted therapeutic trials focused on PD subtypes.

Details are in the caption following the image

(36).

37

The trajectory of disturbed resting-state cerebral function in Parkinson's disease at different Hoehn & Yahr stages

C. Luo, W. Song, X. Guo, H. Shang, Q. Gong (Chengdu, People's Republic of China)

Objective: We aim to investigate the disturbance of neural network associated with the different clinical stages of Parkinson's disease (PD).

Background: Studies using advanced methods of time series analysis of oscillatory brain activity have demonstrated that synchronization of neuronal activity within and between distributed neuronal populations is an important mechanism in a variety of cognitive and motor functions, including movement preparation, sensorimotor integration and attention. It has been suggested that PD is characterized by changing patterns of disturbed neural synchrony that appear to be dependent on the stage of disease. Resting-state fMRI (rfMRI) allows the interrogation in vivo of the neural synchrony disturbance. However, few experiments have utilized rfMRI to depict the changing course of abnormal functional integration in PD.

Methods: We recruited 80 patients at different H&Y stage of PD (28 at H&Y stage I, 28 at H&Y stage II, 24 at H&Y stage III) and 30 normal controls. All participants underwent resting-state fMRI scans on a 3-T MR system. The amplitude of low-frequency fluctuation (ALFF) of blood oxygen level-dependent signals was used to characterize regional cerebral function. Functional integration across the brain regions was evaluated by a seed voxel correlation approach.

Results: PD patients had deceased regional activities in left occipital and lingual regions; these regions show decreased functional connection pattern with temporal regions, which is deteriorating as H&Y stage ascending . Functional integrity in occipital-temporal circuits is negatively correlated with UPDRS III score. In addition, PD patients, especially those at stage II, exhibit increased regional activity in the posterior regions of default mode network (DMN), increased anti-correlation between posterior cingulate cortex (PCC) and cortical regions outside DMN, and higher temporal coherence within DMN. Those indicate more highly functioned DMN in PD patients at stage II. [figure1] [figure2]

Conclusions: Our study demonstrated the trajectories of resting-state cerebral function disturbance in PD patients at different H&Y stages. Impairment in functional integration of occipital-temporal cortex might be a promising measurement to evaluate and potentially track functional substrates of disease evolution of PD.

Details are in the caption following the image

(37).

Details are in the caption following the image

(37).

38

Difference between brain activations for self- and cue-initiated movements in people with Parkinson's disease

M.K. Mak, V. Cheung, D. Wang, C. Wong, Z.L. Lu, L. Shi, W. Lou, V. Mok, W.C.W. Chu (Hong Kong, People's Republic of China)

Objective: To compare the brain activation patterns during self- and cue-initiated movements in healthy subjects and people with Parkinson's disease (PD).

Background: It has been reported that people with PD had difficulties in performing self-initiated movements and the application of external cues improved the speed and/or amplitude of the movements. It is hypothesized that, due to dysfunctions of the basal ganglia, PD patients use the dorsal visual pathway, including the parietal cortex, pre-motor cortex and cerebellum, to replace the supplementary motor area-basal ganglia cortical pathways. Previous studies reported that PD patients could perform well-learnt sequential finger movements by activating more brain areas than healthy subjects (Wu et al. 2005). However, no study has compared the brain activation patterns between self- and cue-initiated movements in patients with PD.

Methods: Twelve PD patients and seventeen healthy subjects were instructed to perform finger tapping with their left index finger in 2 conditions while their brain activity was recorded by fMRI. During the self-initiated condition, subjects had to tap their index finger at an interval of 3s to 5s. During the cue-initiated condition, subjects had to make a tap when they saw a “+” on the computer screen. Data were acquired in self-initiated, cue-initiated, and rest conditions using a block design. There were 5 self- and 5 cue-initiated blocks and 10 rest blocks.

Results: During self-initiated movements, PD patients activated the dorsolateral prefrontal cortex, anterior cingulate cortex and the declive of the cerebellum whilst healthy controls activated the supplementary motor area and the declive of the cerebellum (corrected, p<0.05). During cue-initiated movements, PD patients activated the inferior parietal lobe and mid-cingulate cortex and healthy controls activated the supplementary motor area and the culmen and declive of the cerebellum (corrected, p<0.05).

Conclusions: PD patients had hypoactivation of the supplementary motor areas during self-initiated movement. In both self- and cue-initiated movements, PD subjects activated the cingulate cortex, suggesting that they used more attention than healthy subjects to perform both types of movements. The findings suggest that PD patients may activate the attention network to compensate for their disrupted basal ganglia-cortical pathways in generating body movements.

39

18F-FDG PET/CT imaging in the diagnosis of Parkinson's disease

Z. Mao, S. Ji, Q. Yang, H. Ye, Z. Xue (Wuhan, People's Republic of China)

Objective: To investigate imaging characteristics of 18F-FDG PET/CT in patients with Parkinson's disease (PD), exploring its value.

Background: 11C-CFT dopamine transporer (DAT) positron emission tomography (PET) has important value on the diagnosis of Parkinson's disease, but the imaging agent is expensive and scarce, 18F-FDG is the most common imaging agent,and its role in Parkinson's disease is to be developed.

Methods: (1) Using UPDRS-III score, Hoehn-Yahr (HY) score to evaluate disease duration, severity of 30 PD patients, 10 age- and sex-matched without central nervous system disorders patients as controls;

(2) 30 PD patients and 10 controls underwent brain tomography imaging by intravenous injected 18F-FDG to get the respective ratio of radioactive count per unit area of caudate nucleus, putamen, thalamus, frontal lobe, temporal lobe, parietal lobe, occipital lobe and cerebellum (Rcl/cb). According to H-Y score 30 PD patients were divided as the early, middle and late stage, compare if there were difference in ratio of radioactive count between different stages of the caudate nucleus/cerebellum, putamen/cerebellum, thalamus/cerebellum, substantia nigra red nucleus/cerebellum by ANOVA; According to UPDRS-III score 30 PD patients were divided into tremor-predominant (TDT), rigidity and bradykinesia predominant (ART), mixed type (MT), the correlation between UPDRS-III score and radioactivity ratio of substantia nigra and red nucleus in PD patients with different clinical symptoms were analyzed.

Results: (1) Metabolic imaging of each brain lobe, caudate nucleus, putamen, thalamus, cerebellum, cerebral were of symmetrical distribution in control group, while in PD group each lobe of the brain hemispheres, caudate nucleus, putamen, thalamus were asymmetry reduction.

(2)The uptake of 18F-FDG PET/CT in nigrostriatal system of PD patients gradually reduced with increases on the severity of the disease, a negative correlation (r = -0.709, P < 0.05) with UPDRS-IIIscores; the longer the duration, the lower uptake ratios of caudate nucleus/cerebellum, putamen/cerebellum, thalamus/cerebellum, the substantia nigra red nucleus/cerebellum in PD;

(3) The UPDRS-IIIscores in ART, MT, TDT patients had no significant correlation with 18F-FDG uptake ratio.

Conclusions: 18F-FDG PET/CT imaging can be used for early diagnosis and disease stage in PD.

40

F-DOPA PET reveals a rostro-ventral striatal dopaminergic depletion in Parkinson's disease with impulse control disorders

A. Mari, M.C. Rodriguez Oroz, C. Juri, R. Gonzalez-Redondo, J. Arbizu, E. Prieto, J.A. Obeso (Pamplona, Spain)

Objective: To ascertain the striatal pattern of dopaminergic depletion by L-3,4-Dihydroxy-6-[18F] fluorophenylalanine ([18F]FDOPA) Positron Emission Tomography (PET) in Parkinson's disease patients with and without impulse control disorders(ICD).

Background: ICD occur in a significant number of PD partients. While these abnormal behaviours are associated with dopaminergic treatments, a differential pattern of nigro-striatal dopaminergic denervation has been suggested by findings in DAT-scan. However, most studies are confounded by the effect of dopaminergic drugs on the activity and uptake of the dopamine transporter protien.

Methods: Thirty PD-ICD patients with ICD and 30 PD patients without a life history for ICD were matched for age and disease severity and were ascertained with the UPDRS and the Questionnaire for Impulsive-Compulsive Disorders in PD (QUIP), A voxel-based-analysis using automated Anatomical Labeling map and a self-made ventral striatum Volume of Interest were applied to measure 18F-FDOPA uptake (Ki) in all patients.

Results: All PD patients showed a typical striatal denervation pattern with predominance reduction in 18F-FDOPA uptake in the caudal putamen. 18F-FDOPA uptake was significantly reduced in the anterior and ventral striatum in ICD-PD patients compared to those without ICD. (p<0,01). Total Levodopa equivalent dose was higher (p=0,006) in ICD-PD patients (mean 957,2) compared to the non- ICD group (mean 501,27). No significant difference was found in the mean dose of dopaminegic agonist LEDs.

Conclusions: This study confirms previous findings with DAT-scan showing a significant reduction in ventral striatal dopaminergic activity in ICD-PD patients by F-dopa PET which is less influnced by drug treatments. However, the ICD-PD group received higher dose of dopaminergic agents. The interaction between denervation and treatment probably defines in the origin of ICD in PD.

41

Multimodal MRI changes in Parkinson's disease over one year

T.R. Melzer, D.J. Myall, M.R. MacAskill, L. Livinston, T.L. Pitcher, R. Watts, R.J. Keenan, J.C. Dalrymple-Alford, T.J. Anderson (Christchurch, New Zealand)

Objective: To investigate brain changes associated with Parkinson's disease (PD) over one year with structural, diffusion tensor imaging (DTI) and perfusion magnetic resonance imaging (MRI).

Background: Previous studies demonstrate that MRI can effectively stage PD in terms of both motor severity and cognitive status. However, the contribution of MRI parameters to monitor disease progression over short time periods is uncertain.

Methods: Twenty-three non-demented PD (19 with normal cognition and 4 with MCI) and 23 age-matched control participants completed extensive neuropsychological and disease assessment in addition to multimodal 3T MRI scanning at baseline and one year later. Global cognition was expressed as an aggregate z score derived from the entire neuropsychological battery. SPM was used to preprocess structural (grey matter) and perfusion scans, while FSL and TBSS were used to assess DTI metrics along major ‘skeletal’ white matter tracts. A voxel-based approach assessed change over time and any group by time interactions for each modality.

Results: Compared to controls, PD participants showed greater grey matter atrophy over one year in bilateral inferior and right middle temporal, and left orbito-frontal cortices. There was no significant perfusion change over time. While PD and control participants exhibited similar change in DTI metrics and global cognition over time, grey matter atrophy and change in DTI metrics were associated with change in global cognition in the PD group over time.

Conclusions: Our results suggest that disease-specific progression in non-demented PD patients across one year is associated with regional grey matter changes, but not changes in diffusion or perfusion MRI. Larger studies following patients for longer durations, and those with patients showing more severe cognitive decline, may show the utility of multimodal MRI to track progression in PD.

42

Neuroanatomical correlates of cognitive functioning across the Parkinson's disease cognitive spectrum

D.V. Merkitch, G.T. Stebbins, B. Bernard, J.G. Goldman (Chicago, IL, USA)

Objective: To investigate relationships of gray matter atrophy on structural magnetic resonance imaging (MRI) to cognitive domains in Parkinson's disease (PD).

Background: Cognitive dysfunction is a frequent and debilitating consequence of PD. Detecting neuroanatomical correlates of different aspects of cognitive functioning on brain MRI may provide biomarkers that can predict cognitive decline in PD.

Methods: 101 PD subjects underwent clinical/neuropsychological evaluations, T1-weighted MRI brain sequences, and cognitive classification by The International Parkinson and Movement Disorder Society criteria (cognitively normal, n=29; mild cognitive impairment, n=47; demented, n=25). Z-scores for the cognitive domains (attention/working memory, executive function, memory, language, visuospatial function) were calculated. Whole-brain voxel-based morphometry analyses were conducted using SPM8, covarying for age, PD duration, and scan type. Gray matter volume differences between subject groups were identified, and significant clusters were assigned to a priori-proposed neuroanatomically-based cognitive systems: frontostriatal cognitive-control, medial temporal memory, dorsal spatial-based, ventral object-based, and cerebellar. Stepwise multiple regressions were performed adjusting for age and PD duration with the regional gray matter volumes as criterion variables and cognitive domain z-scores as predictor variables.

Results: Multiple regression analyses demonstrated significant brain-behavior correlates: executive function domain scores best predicted atrophy in the frontostriatal cognitive-control (R2=.28, p<0.005) and ventral object-based systems (R2=.37, p<0.005), memory domain scores best predicted atrophy in the medial temporal memory system (R2=.38, p<0.005), language domain scores best predicted atrophy in the dorsal spatial-based system (R2=.06, p=0.02), and attention and working memory domain scores best predicted gray matter atrophy in the cerebellum (R2=.08, p=.01).

Conclusions: These atrophy patterns follow brain-behavior correlates of cognitive dysfunction and thus, may be useful biomarkers for measuring progression of PD cognitive decline and treatment effects. Furthermore, they provide insights on neuroanatomical and neuropathological differences responsible for clinical heterogeneity with some patients having greater attention/executive dysfunction and others, greater memory deficits.

43

Neural correlates of the effect of cueing on writing skills in Parkinson's disease

E. Nackaerts, E. Heremans, R.C. Pineda, B.C.M. Smits-Engelsman, S.P. Swinnen, W. Vandenberghe, A. Nieuwboer (Leuven, Belgium)

Objective: This study investigated for the first time the neural correlates of visual cueing on writing performance in Parkinson's disease (PD).

Background: Patients with PD often experience handwriting difficulties. As the basal ganglia (BG) are important for internally-generated movements, it was hypothesized that patients may benefit from external cueing to enhance motor output via the use of compensatory brain networks.

Methods: Seventeen PD patients and 14 healthy controls (CTRL) performed cued (reference lines) and uncued writing tasks on a touch-sensitive tablet in the MRI scanner. At the behavioral level a 2 (GROUP) x 2 (CUE) ANOVA was used to compare writing size and speed. BOLD responses were analyzed using two-sample t-tests to compare groups while writing either with or without cues and to compare cued and uncued writing in each group separately (p<.001, uncorrected).

Results: Behaviorally, no differences were found between groups. Both groups wrote smaller and slower with cues compared to without. Comparing brain activity during cued and uncued writing, increased activity in bilateral medial and inferior occipital cortex, left superior parietal cortex, including precuneus, and left cerebellum lobule VI in CTRLs was found. Uncued writing by CTRLs led to increased activity in bilateral orbitofrontal (OFC), ventrolateral prefrontal (VLPFC) and anterior cingulate cortex and left postcentral gyrus. A similar pattern of brain activity was present in PD, with additionally increased activation of the right hippocampus during cued writing. When comparing both groups during cued writing, CTRLs showed increased activation of the left OFC and putamen, while in PD there was increased activity in left precuneus compared to CTRLs. During uncued writing, CTRLs presented increased activity in bilateral VLPFC and right precentral gyrus compared to patients, whereas patients showed increased activity in left precuneus.

Conclusions: Contrary to our hypothesis, adding cues imposed extra task difficulty in both groups. Overall, these results suggest that the BG and prefrontal cortex showed less activity during cued writing in PD, consistent with the affected frontostriatal system. Further analysis will reveal whether the strikingly increased BOLD response in the precuneus operates as part of a dorsomedial compensatory network, and not a dorsolateral one as suggested in previous studies.

44

Chronic recordings of subthalamic oscillatory activity using an implanted pulse generator in patients with Parkinson's disease

W.J. Neumann, F. Staub, J. Schanda, A. Horn, G.H. Schneider, P. Brown, A.A. Kühn (Berlin, Germany)

Objective: To investigate the stability of beta oscillatory activity in the subthalamic nucleus (STN) and its modulation by deep brain stimulation (DBS) in patients with Parkinson's disease (PD) over time.

Background: Oscillatory synchronisation recorded from the subthalamic nucleus in the β-band (13-30 Hz) has previously been shown to be a biomarker for PD symptoms. DBS suppresses this activity in parallel with alleviation of motor symptoms. However, most previous studies have only investigated β-band activity directly after the implantation of DBS electrodes before the implantation of the impulse generator (IPG). Hence, little is known about the long term fluctuations of β-band activity and its modulation by DBS.

Methods: Subthalamic recordings from 7 PD patients (age 65.6 years ± 1.8 SEM; disease duration 9.4 ± 1.3 years) after withdrawal of dopaminergic medication were obtained using a new stimulation device (Medtronic Activa PC+S) that allows for chronic recordings of local field potentials (LFP). Rest recordings were conducted directly (baseline) and three months after the IPG implantation (follow-up) with and without DBS, respectively. Bipolar STN LFP recordings from 10 contact pairs (0-2) were visually inspected for artefacts and taken into the frequency domain using FFT. Power spectra were normalized to 7-45 and 55-95 Hz total power after removal of frequency bands prone to stimulation artefacts. β-band activity (13-30 Hz) was averaged and subjected to a 2x2 (STIMULATION x TIMEPOINT) repeated measures ANOVA.

Results: All power-spectra showed discrete peaks in the β-band in the OFF stimulation condition at baseline (mean frequency: 19.7 ± 1.5 Hz) and follow-up (mean frequency: 19.8 ± 1.6 Hz). Statistical analysis of averaged β-band activity revealed a significant main effect for the factor STIMULATION (p = 0.004). No significant results were obtained for the main effect of factor TIMEPOINT (p=0.157) and no significant interaction was found (p=0.268). β-band power was suppressed by 19.2% (post-hoc t-test: p = 0.001).

Conclusions: Our results suggest that subthalamic β-band activity in PD is stable over 3 months after IPG implantation and is continuously suppressed by DBS.

45

A new manual ROI improves diagnostic accuracy for cardiac sympathetic neuronal dysfunction in Parkinson's disease

H. Odagiri, T. Baba, Y. Nishio, O. Iizuka, M. Matsuda, K. Inoue, M. Iwasaki, Y. Taki, E. Mori (Sendai, Japan)

Objective: The purpose of this study was to determine the diagnostic impact of 123I-MIBG cardiac SPECT/CT imaging compared with conventional scintigraphic evaluation in the diagnosis of PD.

Background: 123I-metaiodobenzylguanidine (123I-MIBG) cardiac scintigraphy is now widely used to assess cardiac sympathetic neuronal dysfunction in Parkinson's disease (PD) and dementia with Lewy bodies(DLB). Manually defined regions of interest (ROIs) on planar images are conventionally used to assess myocardial uptake of 123I-MIBG (the heart-to-mediastinum ratio; H/M ratio). However, arbitrary placing of ROIs on planar image leads to decrease the accuracy.

Methods: We studied 28 patients with PD and 19 patients with idiopathic normal pressure hydrocephalus (iNPH), which is a non-neurodegenerative Parkinsonian disorder as controls. We calculated the H/M ratio both from planar images and fused SPECT/CT images obtained with a hybrid SPECT/CT system, then we compared diagnostic accuracy of these two methods.

Results: Difference in the H/M ratio between PD group and iNPH group was significantly higher in the SPECT/CT method(Early p<0.0001, Delayed p<0.0001) compared with conventional planar method(Early p=0.082, Delayed p=0.041). The sensitivity and specificity between PD group and iNPH group was significantly higher in the SPECT/CT method (sensitivity 92.9%, specificity 57.9%) compared with conventional planar method (sensitivity 67.9%, specificity 47.4%).

Conclusions: The SPECT/CT method is useful in differentiation of the neurodegenerative disease.

46

The effect of deep brain stimulation (DBS) on cortico-subthalamic nucleus coupling in Parkinson's disease (PD)

A. Oswal, A. Jha, S. Neal, A. Reid, P. Limousin, T. Foltynie, L. Zrinzo, M. Hariz, V. Litvak, P. Brown (London, United Kingdom)

Objective: To evaluate the effect of DBS on functional connectivity within a network comprising the subthalamic nucleus (STN) and cortical regions in PD.

Background: DBS is an effective treatment for PD, yet it's mechanisms of action and influences on cortico-STN networks are unknown. It has previously been shown that two spectrally and spatially distinct resting STN-cortical networks exist in PD: 1) An STN-temporo-parietal alpha band (7-12Hz) network and 2) An STN-premotor/motor beta (13-30 Hz) band network. We sought to examine the effect of DBS on these networks.

Methods: We performed simultaneous magnetoencephalography (MEG) and bilateral STN local field potential recordings (LFPs) in 15 post-operative PD patients, whose DBS electrodes had been temporarily externalised for recording. Using a purpose built amplifier we were able to simultaneously stimulate the STN and record its electrical activity during concurrent MEG recording. Source reconstruction of cortical signals was performed using beamforming to allow the computation of coherence between cortical regions and the STN signal.

Results: Unilateral monopolar DBS at 130 Hz suppressed low beta power (12-20Hz) locally within the STN and also suppressed low beta (12-15 Hz) coupling between both STNs. Furthermore, low beta coupling (13-22 Hz) between the STN and the premotor peak of resting beta activity was suppressed by 130 Hz DBS, despite coupling in the high beta range (22-35 Hz) remaining unchanged. Figure 1 shows STN power and STN-premotor coherence results averaged across all subjects and hemispheres [figure1]. We are currently correlating the observed spectral changes with clinical parameters on and off DBS.

Conclusions: Our results highlight that DBS preferentially suppresses low rather than high beta activity in cortico-STN motor circuits in PD. This finding suggests that low beta may be an important pathological process in PD, suppressed by both levodopa and DBS.

Details are in the caption following the image

(46).

47

Multimodal MRI markers discriminate Parkinson's disease from multiple system atrophy patients

P. Péran, M. Sierra, A. Pavy-Le Traon, O. Rascol (Toulouse, France)

Objective: Using multimodal MRI, the aims of the study were (i) to compare changes in patients with idiopathic Parkinson's disease (iPD) compared to multiple system atrophy (MSA) patients with Parkinsonian syndrome (MSA-P) and with cerebellar syndrome (MSA-C) (ii) to discriminate iPD patients from MSA patients.

Background: Multimodal MRI approach is based on combination of MRI parameters sensitive to different tissue characteristics (e.g. volume atrophy, iron deposition, microstructural damage). Previous findings revealed that multimodal MRI is able to discriminate iPD patients from healthy control subjects with high accuracy (Péran et al., Brain, 2010). The combination of different MR biomarkers could help to discriminate different pathologies with Parkinsonian syndrome.

Methods: 26 iPD patients with and 29 MSA patients (16 MSA-P, 13 MSA-C) underwent 3-T MRI comprising: T2*-weighted, T1-weighted and diffusion tensor imaging scans. We used the same method as in the previous work (Péran et al., Brain, 2010) to extract MRI markers (volume, R2* value, mean diffusity and fractional anisotropy). Comparisons between groups were performed using statistical region-based (sub-cortical structures) analysis and whole brain voxel-based analysis. Logistic regressions and ROC curves were computed using results from the previous voxel-based analysis.

Results: Concerning region-based analysis, the main results showed significant changes in brainstem and in putamen in MSA patients compared to PD patients. The sub-group of MSA-P showed a loss of microstructural integrity (higher mean diffusity) in putamen compared to iPD or compared to MSA-C. The sub-group of MSA-C showed a loss of microstructural integrity (higher mean diffusivity) in brainstem compared to iPD or compared to MSA-P. Voxel-based analysis confirmed the previous localizations and identified differences for all markers in the cerebellum. Predictive analysis showed that markers for discriminating iPD from MSA-P were mainly the grey density of putamen, the mean diffusivity in the cerebellum and the fractional anisotropy in the superior corona radiata. [figure1]Figure: MSA-P vs iPD (voxel-based). red: ↑ R2* green: ↑ MD blue: ↓ FA yellow: ↓ grey density.

Conclusions: This study demonstrates that multimodal MRI is able to discriminate patients with iPD from MSA with a high accuracy. The combination of different MR biomarkers could be a great tool to follow disease progression.

Details are in the caption following the image

(47).

48

Phase-amplitude coupling heterogeneity in the Parkinsonian sensorimotor cortex

E. Peña, L. Rosedahl, T.M. Mohammed, F. Al-Mohammed, L. Soualmi, M.D. Johnson, J.A. Bajwa (St. Paul, MN, USA)

Objective: To investigate magnetoencephalographic (MEG) measures of phase amplitude coupling in sensorimotor cortex on and off medication in Parkinson's disease (PD) patients.

Background: The phase amplitude coupling (PAC) measure describes the degree to which oscillatory activity in one frequency band phase-locks to oscillatory activity in a lower frequency band. Such coupling is thought to be indicative of information transfer between neuronal populations at different spatiotemporal scales, and has been shown to play a critical role in cognitive processes such as learning. In some cases, this type of coupling may be pathological, and recent intraoperative studies in PD patients have noted strong coupling between the amplitude of gamma/high-frequency oscillatory activity and the phase of beta-band oscillations in primary motor cortex, in subthalamic nucleus, and between both structures. Here, we used MEG recordings in PD patients to investigate (1) the inter-subject variation in such coupling within sensorimotor cortex off and on medication, and (2) whether such coupling is also present in healthy control subjects.

Methods: Resting-state MEG data was acquired on an Elekta Neuromag from 6 healthy controls and 8 PD patients (ages 55-70, disease duration of 2-9 years), both on and off medication. PAC comodulograms were constructed (phase: 12-30Hz, amplitude: 90-300Hz) based on source-space estimations of oscillatory activity in three gyri (precentral, postcentral, superior frontal) and two sulci (central, superior frontal) from both hemispheres. Regression analysis between the PAC comodulogram results and the clinical evaluation scores using the modified Unified Parkinson's disease Rating Scale (UPDRS) were performed.

Results: Significant PAC was found in 2/8 PD patients in the off medication state, and in both cases, Levodopa-Carbidopa reduced the PAC values in conjunction with improvement in Parkinsonian motor signs. Another patient had significant PAC values only after the administration of Levodopa-Carbidopa, but the patient also had worsened tremor after medication. No significant PAC was found in any of the control subjects. Across the cohort, inter-subject regression analysis showed no correlation between PAC and motor signs (R2 < 0.2).

Conclusions: Significant PAC, while present in some PD patients, was not found to be consistent in the sensorimotor cortex for all PD patients in this study.

49

Aberrant cerebral network topology and mild cognitive impairment in early Parkinson's disease

J.B. Pereira, D. Aarsland, C. Ginestet, A. Lebedev, L.O. Wahlund, A. Simmons, G. Volpe, E. Westman (Stockholm, Sweden)

Objective: The aim of the current study was to assess whether mild cognitive impairment (MCI) is associated with disruption in large-scale structural networks in newly diagnosed, drug-naïve patients with Parkinson's disease (PD).

Background: Mild cognitive impairment has a strong impact on quality of life and frequently progresses to dementia in patients with Parkinson's disease. Although the study of network disruption could provide an important insight into the cortical and subcortical patterns underlying cognitive decline in Parkinson's disease, the organization of the brain's structural architecture has not been assessed in these patients to date.

Methods: Graph theoretical analyses were applied to 3T MRI data from 123 PD patients and 56 controls from the Parkinson's Progression Markers Initiative (PPMI). Thirty-three patients were classified as having MCI using the International Parkinson and Movement Disorders Society Task Force criteria, while the remaining ninety patients were classified as cognitively normal. Global measures (clustering coefficient, characteristic path length, global efficiency, small-worldness) and regional measures (local clustering coefficient, local efficiency, hubs) were assessed in the structural networks that were constructed based on cortical thickness and subcortical volume data in each group.

Results: Patients with MCI showed a marked reduction in the average correlation strength between cortical and subcortical regions compared to controls. These patients had larger characteristic path length and reduced global efficiency in addition to a lower local efficiency in frontal and parietal regions compared to cognitively normal patients and controls. A reorganization of the highly connected regions in the network was observed in patients with and without cognitive deficits.

Conclusions: This study shows the earliest stages of cognitive decline in PD are associated with a disruption of the large-scale coordination of the brain network and with a decrease of the efficiency of parallel information processing. These changes are likely to herald further cognitive decline and provide support to the view of PD as a disconnection syndrome capable of spreading along the connections of the cerebral network.

50

Progressive cerebellar atrophy in patients with tremor-predominant Parkinson's disease

C.C. Piccinin, L.G. Piovesana, R.P. Guimaraes, M.C.A. Santos, B.M. Campos, T.J.R. Rezende, L.S. Campos, P.C. Azevedo, F. Torres, M.C. França, A.C. Amato-Filho, I. Lopes-Cendes, F. Cendes, A. D'Abreu (Campinas, Brazil)

Objective: Our aim was to identify whether the cerebellar grey matter (GM) atrophy presented in tremor-predominant Parkinson's disease (PD) patients is associated to disease severity using a specific cerebellar tool for voxel-based morphometry (VBM) analysis.

Background: Recent neuroimaging studies comparing tremor-predominant-PD versus bradykinesia-predominant-PD demonstrated decreased GM in the cerebellum of tremor-predominant-PD patients only, underlying a potential cerebellar role in the physiopathology of PD's tremor.

Methods: We divided our tremor-predominant-PD patients group into three groups in according to the progression of symptoms and level of disability (trough Hoehn and Yahr rating scale – H&Y) and compared each group with an age-gender-matched healthy control (HC) group. Group 1 included 9 early PD patients (mean age 61.89 ± 10.6) with H&Y scores between 1 and 1.5 and 9 HC (mean age 61.33 ± 9.85); group 2 was comprised of 21 patients (58.52 ± 12.46) with H&Y scores between 2 and 2.5 - and 21 HC (58.81 ± 12.24); and group 3 presented 15 patients (58.87 ± 9.16) with H&Y score ≥ 3 and 15 HC (58.80 ± 9.18). We acquired T1 weighted scans at a 3T scanner and compared the paired groups using VBM in SPM8. We used the SUIT tool (Spatial Unbiased Infratentorial Template) for a specific and detailed evaluation of the cerebellar GM. Statistics were done applying p=.001, uncorrected and extent-threshold ≥ 20 voxels.

Results: We detected no changes in the cerebellar GM in patients classified as early and moderate tremor-predominant-PD. The severe group however, demonstrated large GM decreased in the right anterior lobe, in the left crus I and bilaterally in the lobules V, VI (including the vermis) and VIIIa.

Decreased GM areas in the cerebellum demonstrated in the severe group of patients (H&Y score ≥ 3)
AREA LOBULE CLUSTER SIZE*
Right Hemisphere I - IV 61
Left Hemisphere V 98
Right Hemisphere V 536
Left Hemisphere VI 294
Vermis VI 57
Right Hemisphere VI 193
Left Hemisphere Crus I 316
Left Hemisphere VIIIa 51
Right Hemisphere VIIIa 82
  • *in voxels

Conclusions: We concluded that the decreased cerebellar GM observed in tremor-predominant-PD patients using a special tool for cerebellar analysis parallels the progression of the clinical symptomatology and it is possibly only detectable in patients with bilateral disease and some level of postural instability (H&Y≥3).

51

Impact of the disease and medication on resting state functional connectivity in Parkinson's disease

I. Rektorova, N. Elfmarkova, M. Gajdos, M. Mračkova (Brno, Czech Republic)

Objective: We acquired rs-fMRI data in PD patients in the ON and OFF medication conditions and age-matched HC and used the seed Partial Least Squares Correlation (PLSC) analysis to assess impact of the disease and medication on connectivity strength from our seeds of interest.

Background: Resting state functional connectivity within the large-scale brain networks between healthy subjects (HC) and PD patients in the ON (PD_ON) and OFF (PD_OFF) medication conditions has not been systematically studied.

Methods: We inluded 19 non-demented and non-depressed males with PD (age 64.6 ± 7.5 years, disease duration 29 ± 6 months, levodopa-equivalent dose 1092.7 ± 353.8 mg) and 15 matched HC males (age 62.9 ± 8.2 years). PD subjects were scanned before and after administration of their first morning dose of DA medication. fMRI data were preprocessed using SPM8. Based on literature and our previous work we chose 2 coordinates for motor seeds (left primary motor cortex for hand [L hand SM1] and right primary orofacial cortex [R orofacial SM1], and 6 coordinates for non-motor seeds (precuneus, anterior cingulate cortex [ACC], right middle temporal gyrus/middle occipital gyrus [MTG/MOG], right insula [RI], right inferior frontal gyrus [IFG], R caudate). We extracted the BOLD signal as the first eigenvariate from a sphere with radius of 6 mm. These seed signals were used to compute seed correlation matrices.

Results: The PLSC analysis revealed significant impact of the disease (but not medication) on the connectivity strength of spatial correlation maps seeded by R caudate (p = 0.047), ACC (p = 0.006), MTG/MOG (p = 0.045), and R orofacial SM1 (p = 0.025). The RI and L hand SM1 almost reached statistical significance (p = 0.058 and 0.076, respectively). In PD patients the connectivity within all studied networks decreased in most of the brain regions as compared to HC. In motor networks the connectivity differences were most prominent between PD_OFF and HC while in all studied non-motor networks the major connectivity differences were found between PD_ON and HC.

Conclusions: We observed impact of the disease (PD vs. HC status) while the impact of medication (PD_ON vs. PD_OF states) did not reach statistical significance. Connectivity in PD was decreased as compared with HC and was detected in a number of large-scale brain networks including the motor, insular, ventral visual, and the default mode networks.

52

The neural correlates underlying dual tasking in Parkinson's disease

K. Rosenberg-Katz, I. Maidan, Y. Jacob, S. Shema, N. Giladi, T. Hendler, H.M. Jeffrey, A. Mirelman (Tel Aviv, Israel)

Objective: The aim of this study was to use functional MRI (fMRI) to study the neural mechanisms underlying dual tasking (DT) in PD.

Background: The ability to divide attention plays an important role in DT and in the so called “DT decrement”. In the context of gait, this decrement has major negative consequences as it impacts safe ambulation, increases fall risk, and restricts functional independence. The DT decrement is generally exaggerated with ageing and in Parkinson's disease (PD), however, the understandings of its underlying brain mechanisms are still lacking.

Methods: Twenty-two patients with PD (mean age: 72.69 ± 4.17 yrs) and 14 healthy controls (mean age: 71.18 ± 5.97 yrs) were studied using an fMRI paradigm that included three conditions that were presented in a block design: 1) alternating feet movements against foot pedals (single task), 2) subtracting 3s from a predefined number (single task), and 3) performing both tasks simultaneously (DT). DT related brain activations were examined by comparing the DT condition with both of the single tasks conditions. DT related brain activations were further correlated with measures related to attention and task switching, the Trail Making Test (TMT), and with DT gait speed decrement (i.e., usual walking gait speed minus DT speed).

Results: Both groups showed significant increase in DT related activations in the middle frontal gyrus, precentral gyrus, inferior frontal gyrus (Broca's areas), thalamus, and superior parietal lobe (SPL) (p FWEcorr <0.05). Compared to the healthy elderly, patients with PD had significantly lower DT related activations in the occipital cuneus and lingual gyrus (p FWEcorr <0.05), SPL, middle frontal gyrus, medial frontal gyrus/anterior cingulate and right caudate nucleus (p<0.0005, uncorrected). The SPL fMRI beta values of DT related activations were negatively correlated with the time to complete the TMT part b (r=-0.412, p<0.01, corrected for age) but not with TMT part a duration (r=-0.247, p=0.159, corrected for age). In addition, higher SPL beta values were correlated with lower DT gait speed decrement (r= -0.345, p<0.05).

Conclusions: These findings suggest that part of the difficulties that patients with PD have during DT are related to a decreased ability to recruit brain regions including occipital, parietal, frontal and motor regions. Our results support the involvement of the SPL as a principal factor in DT.

53

Evaluation of striatal PDE10 expression in Parkinson's disease (PD) using [18F]MNI-659 PET imaging

D.S. Russell, D.L. Jennings, O. Barret, G.D. Tamagnan, D. Alagille, J.P. Seibyl, K.L. Marek (New Haven, CT, USA)

Objective: To evaluate the feasibility of [18F]MNI-659 PET, a striatal PDE10A imaging tracer, as a biomarker in early PD and PD with motor fluctuations.

Background: PDE10 is highly and specifically expressed in brain in striatal neurons, primarily medium spiny neurons. This enzyme plays a critical role in striatal dopaminergic function via regulation of cyclic nucleotides. [18F]MNI-659 PET is a well-validated, highly specific PET radioligand targeting PDE10A.

Methods: Eight PD subjects participated, de novo (n=2) and treated with dopaminergics (n=6). All subjects were imaged with [18F]MNI-659 for 90 minutes. Standard uptake values were determined for the basal ganglia and component subnuclei. Binding potentials (BPnd) were estimated using SRTM (cerebellum as reference). MRI imaging was also acquired on all subjects and co-aligned with the PET images for anatomical localization.

Results: Participants (7M, 1F) had a mean age of 65.7 y (range 61.6-69.0 y) and mean duration of diagnosis of 8.0 (range 1.5-12.7). Treated subjects all manifest dyskinesia and on-off phenomena. Mean total UPDRS score was 42.3 (range 7-80) and motor subscale 25.9 (range 5-52). The mean striatal BPnd among the PD subjects was 2.29 (S.D. 0.30) compared to mean 2.45 (S.D. 0.21, P=0.34) among older HS (n=5, >40 yrs). No correlation was noted between striatal BPnd and diagnosis duration (R2 = 0.04), total UPDRS score (R2 = 0.02), or motor subscale score (R2 = 0.02). Mean striatal BPnd for untreated did not differ from treated (2.27, S.D. 0.034 vs. 2.30, S.D. 0.32, P=0.91). Comparison between more affected putamen (2.93; S.D. 0.36) and less affected putamen (2.98; S.D. 0.45) did not detect a difference (P=0.66).

Conclusions: In this limited cohort of de novo and treated PD subjects, there is good brain penetration and binding of [18F]MNI-659 in the striatal regions. While this study is limited by its small sample size, no significant difference in [18F]MNI-659 binding was detected when compared to a similarly aged HS.

54

Decreased gray matter volume in the brainstem: A potential biomarker of Parkinson's disease?

C.D. Schroeder, G.T. Stebbins, J.G. Goldman (Chicago, IL, USA)

Objective: To investigate regional brainstem atrophy on structural magnetic resonance imaging (MRI) in Parkinson's disease (PD).

Background: The neuropathology of PD is hypothesized to have early changes in the brainstem, particularly the medulla oblongata, followed by changes in the midbrain and eventually the neocortex. Structural MRI provides an opportunity to examine differences in brainstem volumes between PD patients and healthy controls. Brainstem atrophy detected on MRI scans could potentially be used as a biomarker of PD progression.

Methods: Twenty-nine clinically diagnosed, cognitively normal PD patients and 24 age-matched, healthy controls underwent clinical evaluations and MRI brain scans (1.5T GE Signa, T1-weighted sequences [MPRAGE, IR-FSPGR]). Whole brain voxel-based morphometry analyses were conducted using SPM8. Images were smoothed with a 6mm kernel. Regions of interest for midbrain, pons, and medulla gray matter volumes were extracted from modulated non-linear scans using the Wake Forest University Pickatlas. Gray matter differences between the PD and control groups were examined using a MANCOVA, covarying for scan sequence and gender with significance set at p<0.05. Logistic regression and receiver operating curve (ROC) analyses were used to measure the specificity and sensitivity of brainstem volume for group discrimination.

Results: The PD and healthy control subjects did not differ significantly in age (mean [SD] PD 70.66 [4.65] years, Controls 71.75 [6.07] years). The PD group had a mean PD duration of 8.38 [2.99] years. The PD group exhibited significant voxel-wise differences with decreased gray matter volume in the gray matter of the midbrain (mean [SD] PD 0.16 [0.03] Controls 0.22 [0.04], p<0.0005). There were no significant differences found in the other brainstem regions. Logistic regression with midbrain volume significantly predicted PD/control classification (χ2=34.29, p<0.0005). ROC analyses revealed an area under the curve of 0.84, and a midbrain relative volume threshold of 0.188 optimally differentiated PD from controls with a sensitivity of 79% and specificity of 83%.

Conclusions: Patterns of brainstem atrophy on MRI, particularly in the midbrain, can distinguish cognitively normal PD patients from healthy controls. This finding may reflect underlying PD-related neurodegeneration and thereby, has potential as a biomarker for diagnosing PD and monitoring disease progression.

55

Early diagnosis of multiple system atrophy in patients with Parkinson's disease and orthostatic hypotension by 123I-IBZM SPECT

D.E. Shan, S.J. Wang, K.K. Liao, H.H. Hu (Taipei, Taiwan)

Objective: To evaluate the probability of 123I-IBZM, a ligand for D2-receptor binding, SPECT in make the differential diagnosis between patients with multiple system atrophy (MSA) and patients with Parkinson's disease with orthostatic hypotension (PD+OH).

Background: Some patients with Parkinson's disease have autonomic dysfunction, including orthostatic hypotension. Differential diagnosis between these PD+OH patients and those with MSA is a difficult but important issue.

Methods: Twelve PD+OH patients were recruited into an 123I-IBZM SPECT study and compared with the data from 9 patients with MSA, 6 patients with idiopathic PD (IPD), and 3 normal controls. To make the diagnosis of MSA, the lowest data from normal controls were used as the cut-off values, i.e. the striatum/occipital (S/O) ratio was set at 1.03 and the putamen/occipital (P/O) ratio was set at 0.95. It was assumed that any patients with an S/O or P/O ratio below these cut-off values were likely to be cases with MSA. The data from two patients with PD+OH were excluded from analysis because they had taken pramipexole or antipsychotic within 5 days before SPECT examination.

Results: According to the S/O ratio from the worst side of lesion, one patient with IPD (16.7%), three patients with MSA (33.3%) and four patients with PD+OH (40%) were below the cut-off value. According to the P/O ratio from the worst side of lesion, none with IPD (0%), six patients with MSA (66.7%) and two patients with PD+OH (20%) were below the cut-off value. Although the initial autonomic dysfunction in one of the two PD+OH patients below the cut-off value of the P/O ratio was not severe enough to meet the diagnostic criteria of MSA, her follow-up studies showed poorly levodopa-responsiveness, progressive worsening of orthostatic hypotension and the development of hot cross-bun sign on MR imaging, which made her diagnosis to be revised to MSA.

Conclusions: The P/O ratio of 123I-IBZM SPECT is more sensitive and more specific than the S/O ratio in making the diagnosis of MSA. The diagnosis of PD+OH should be made cautiously, particularly in those patients with a short duration of illness. Our study reveals that one-tenth of them may be an early manifestation of MSA. 123I-IBZM SPECT may help in making the correct diagnosis early in the course. This work was supported by grants (#NSC- 98- 2314- B- 075- 034) from the National Science Council, ROC, grants (#INIBA071213) from the Institute of Nuclear Energy Research, ROC, and grants (#140-V-B-030) from the Taipei Veterans General Hospital - National Yang-Ming University Excellent Physician Scientists Cultivation Program.

56

Fiber tract atrophy in idiopathic Parkinson's disease

F.M. Skidmore, T. Anthony, J. Marstrander, Y. Liu, G. Cutter, D. Standaert (Birmingham, AL, USA)

Objective: To evaluate changes in fiber tract caliber and fractional anisotropy in Parkinson's disease, using diffusion tensor imaging (DTI).

Background: During image registration, fiber tracts are morphed and matched across subjects. This is a necessary process to localize structures in, but information may be lost. We analyzed changes in fiber tract caliber (radial to the primary fiber direction) in idiopathic Parkinson's disease compared to healthy controls, by evaluating morphological changes during image registration to a common template. DTI data was collected from the Parkinson's Progressive Markers Initiative (PPMI) dataset.

Methods: DTI images from the PPMI dataset were downloaded and processed using the NIH Tortoise suite. A visual quality control step was performed, and acceptable images (68 controls, 105 PD) were analyzed using the analysis of functional neuro-imaging (afni) imaging suite. The afni package 3dQwarp is being iteratively recoded to to allow more fine grain registration of images, and we analyze the transformation matrix for evidence of difference in fiber caliber between groups. Fractional anisotropy in the registered images was also analyzed.

Results: At the time of this abstract, adequate registration is available in 37 controls and 77 subjects with PD. Among these subjects, fiber tract caliber differs in PD subjects compared to controls in the fornix, basal forebrain (including the anterior commissure), and adjacent to deep cerebellar nuclei. Fractional anisotropy differed in the midbrain, including in the peri-nigral regions, as well as in the pons and medulla.

Conclusions: Our data suggest that individuals with PD have measurable morphological changes in caliber of white matter structures. Nonlinear image registration protocols, which accurately register structures, can obscure important disease related information in disorders where atrophy of white matter structures is occurring. However, this information can be retrieved by developing measures to analyze individual subject transformation matrices. In PD, we find that in addition to previously described FA changes in peri-nigral regions, individuals with PD show changes in fiber tract caliber in multiple structures, including limbic structures.

57

Increased dopamine turnover: A possible contributor to the increased risk of Parkinson's disease in LRRK2 mutation carriers

V. Sossi, R. Nandhagopal, D. Wile, M. Schulzer, J. McKenzie, K. Dinelle, M. Farrer, Z.K. Wszolek, J. Aasly, A.J. Stoessl (Vancouver, BC, Canada)

Objective: To investigate the role of the impaired dopamine (DA) storage capacity or its inverse, DA turnover in the asymptomatic stage of subjects with LRRK2 mutations, which increase the risk of Parkinson's disease (PD).

Background: An increase in dopamine turnover has been previously demonstrated in asymptomatic LRRK2 mutation carriers [1]. Whether such increase would represent an initial compensatory reaction to incipient disease or be pathogenic by itself is still a matter of speculation.

Methods: 17 asymptomatic subjects with LRRK2 mutations (Y1699C, R1441C, G2019S, N1437H, G2019S and I2020T, age 49 ± 12 yrs) and 4 mutation negative subjects (age 61 ± 8) yrs underwent a positron emission tomography (PET) scan with the dopamine transporter (DAT) marker 11C-methylphenidate (MP), quantified with the tissue input binding potential BPND and a prolonged 18F-fluorodopa (FD) scan to evaluate the effective dopamine distribution volume (EDV), the inverse of DA turnover. The decrease in EDV and DAT binding relative to age matched normal controls were compared.

Results: Unlike previous studies performed in early PD subjects, which showed a very strong positive correlation between DAT binding and EDV[2], no correlation was found for the mutation carriers. EDV was significantly (p< 0.001) more decreased compared to DAT binding (40% vs 19%). The mutation negative subjects had normal values for both tracers (figure 1).

Conclusions: Given the established correlation between DAT density and dopaminergic terminal deficit, these data support the hypotheses that impaired DA storage, which could lead to excess levels of DA in the cytosol, might be an independent mechanism leading to an increased risk of PD, consistent with recent findings in animal models [3]. Further work is required to establish if very recently observed alterations of the serotonergic innervation may influence the measurement of dopamine turnover.

References:
  1. Sossi, V. et al., Mov Disord, 2010. 25(16): p. 2717-23.
  2. Sossi, V. et al., Ann Neurol, 2007. 62(5): p. 468-74.
  3. Shen, J. et al., Neurodegenerative Diseases, 2010. 7(1-3): p. 80-83.
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(57).

58

Motor and nonmotor symptoms in drug-naive de novo Parkinsonian patients and their relationship to dopaminergic and serotonergic lesions

S. Thobois, A. Maillet, E. Météreau, H. Klinger, E. Lhommée, E. Schmidt, A. Bichon, P. Pelissier, C. Caire, V. Fraix, D. Le Bars, E. Broussolle, P. Krack (Bron, France)

Objective: To investigate the respective involvement of DA and 5-HT neurotransmission dysfunction in the pathophysiology of both motor and nonmotor features in drug-naive de novo PD patients, using Positron Emission Tomography (PET) imaging.

Background: Beyond the well-known dopaminergic (DA) depletion, several lines of evidence indicate that serotonergic (5-HT) neurons also degenerate in Parkinson's disease (PD). Previous works have suggested a link between the alteration of the 5-HT system and the occurrence of motor (tremor, dyskinesia) and nonmotor (depression, fatigue) signs in moderate-to-advanced PD. Nevertheless, little is known regarding the role of 5-HT dysfunction in the expression of both motor and nonmotor symptoms at early stages of PD, without the confounding effect of antiParkinsonian treatment.

Methods: Twenty-nine untreated and recently diagnosed (< 2 years disease duration) PD patients, and fifteen age-matched healthy controls, were enrolled. Fourteen de novo PD patients presented apathy (LARS score ≥ -21) with/without depression or anxiety. All subjects underwent two PET-scans using DAT and SERT transporters ligands ([11C]-PE2I and [11C]-DASB, respectively). We used regions-of-interest (focused on caudate, putamen, ventral striatum) approach to explore the causal role of these two systems in PD symptomatology.

Results: Compared to controls, non-apathetic patients exhibited reduced bilateral DAT binding in anterior and posterior parts of putamen, globus pallidus and substantia nigra, but no alteration of SERT binding. Apathetic patients had reduced bilateral DAT and SERT binding in anterior caudate nuclei, anterior putamen, ventral striatum, substantia nigra, as well as a specific decreased DAT binding in posterior caudate nuclei, posterior putamen and globus pallidus. The comparison between apathetic and non-apathetic patients revealed a greater 5-HT and DA denervation in caudate nuclei. Our data also suggest a link between the severity of rigidity and the 5-HT denervation in putamen and anterior caudate nuclei in all patients. The severity of apathy and depression seem to be mainly associated with DA and 5-HT disruption in ventral striatum.

Conclusions: Altogether, these preliminary findings highlight both DA and 5-HT dysfunction in de novo drug-naive PD patients suffering from neuropsychiatric signs with a specific contribution of the caudate nucleus.

59

Transcranial sonography in LRRK2 G2019S mutation carriers

D. Vilas, L. Ispierto, R. Álvarez, C. Pont-Sunyer, M.J. Martí, F. Valldeoriola, Y. Compta, O. De Fàbregues, J. Hernández-Vara, V. Puente, M. Calopa, S. Jaumà, J. Campdelacreu, M. Aguilar, P. Quílez, P. Casquero, F. Lomeña, E. Tolosa (Barcelona, Spain)

Objective: To assess the echogenicity of the substantia nigra (SN) in LRRK2 G2019S mutation carriers.

Background: Hyperechogenicity of the SN has been proposed as a risk marker of Parkinson's disease (PD). Asymptomatic LRRK2 mutation carriers (aLRRK2+) are subjects at high risk for developing PD.

Methods: Transcranial sonography was performed in twenty-six LRRK2 G2019S PD patients and 50 of their first-degree relatives. Twenty-four of them were aLRRK2+. Thirty-one idiopathic PD (IPD) patients and 26 unrelated control subjects age and sex matched with the aLRRK2+ were also studied. Echographic measures were made by an independent investigator blinded to the clinical and genetic status of subjects, who had not been involved in the TCS examinations.

Results: 75% of the LRRK2-PD patients and 95.5% of the IPD patients showed SN+ (p=0.087). The age of the aLRRK2+, first-degree relatives non mutation carriers and controls was similar (45 [38; 50], 45 [38; 51 and 45 [40; 60], respectively]. aLRRK2+ subjects had a higher frequency of SN+ than first-degree relatives non carriers (58.3% vs 25%, p= 0.039) and controls (58.3% vs 12.5%; p= 0.002). aLRRK2+ had a larger area of SN echogenicity than the first-degree relatives non mutation carriers (0.22 cm2 [0.16; 0.25] vs 0.16 cm2 [0.1; 0.2]; p= 0.030) and controls (0.11 cm2 [0.09; 0.15]; p< 0.001).

Conclusions: Hyperechogenicity of the SN is present in most LRRK2-PD patients and in approximately sixty percent of the asymptomatic LRRK2 G2019S mutation carriers. Properly designed prospective studies should clarify whether hyperechogenicity of the SN is a risk marker for development of Parkinsonism in asymptomatic LRRK2 mutation carriers.

60

Cerebral blood oxygenation changes in the frontal lobe caused by deep brain stimulation in Parkinson's disease: A functional near infrared spectroscopy study

K. Vyas, E. Sanchez, D. Smith, F. Vale, T. Malapira, T. Zesiewicz, R. Murtagh, G.A. de Erausquin (Tampa, FL, USA)

Objective: We study the patterns of cerebral blood oxygenation changes in the frontal lobe caused by electrical stimulation of subthalamic nucleus (STN) in patients with Parkinson's disease (PD) using a new imaging method called functional near infrared spectroscopy (fNIRS).

Background: Deep Brain Stimulation (DBS) surgery for idiopathic PD is a well established treatment. Studies with PET scan have shown that electrical stimulation of STN causes changes in cerebral blood flow in various cortical areas. NIRS opticallly measures oxyhemoglobin and deoxyhemoglobin concentration changes in cerebral vessels by means of characteristic absorption spectra of hemoglobin in near infrared range. Previously, NIRS activation studies have shown that neuronal activation causes increases in oxyhemoglobin, decrease in deoxyhemoglobin at the activated cortical area. We attempt to understand the hemodynamic changes in the frontal cortex during STN-DBS using fNIRS.

Methods: Seven patients with Parkinson's disease were evaluated with electrodes implanted in the subthalamic nucleus. We measured changes in oxyhemoglobin and deoxyhemoglobin in the bilateral frontal and prefrontal lobes during 2 stimulation conditions, stimulation-on and stimulation-off. We recorded time locked near infrared optical signals using 24 photoiodide channels arranged bilaterally over frontal and prefrontal lobes for optical detection (NIRx Medical Technologies, Los Angeles) with a sensitivity of <1 pW NEP and a dynamic range of 90 dBopt, using 760nm and 850 nm wavelengths.

Results: High frequency electrical stimulation of STN consistently increased deoxyhemoglobin with decreases in oxyhemoglobin in the frontal lobe in a time dependent manner when the patients were in the optimal electrode setting. There was an immediate increase in deoxyhemoglobin with the onset of stimulation. By contrast, when the stimulation was turned off, there was an increase in oxyhemoglobin.

Conclusions: Our study showed various frontal lobe hemodynamic changes associated with electrical stimulation of subthalamic nucleus. This might be due complex neuronal connections between the frontal lobe and basal ganglia. Thus fNIRS offers a new way to investigate superficial brain activation and neural connectivity.

61

Striatal and cortical elevations in serotonin transporter binding precede motor onset in asymptomatic patients with LRRK2 gene mutations

D.J. Wile, K. Dinelle, J. McKenzie, N. Heffernan, M. Adam, Q. Miao, C. Zabetian, Z. Wszolek, J. Aasly, M. Farrer, V. Sossi, A.J. Stoessl (Vancouver, BC, Canada)

Objective: To compare serotonin (5HT) function using PET imaging in asymptomatic and symptomatic patients with dominantly inherited pathogenic gene mutations for Parkinson's disease (PD) and apparently sporadic PD.

Background: The earliest (premotor) neurochemical changes in subjects who will develop PD are incompletely understood but may involve nondopaminergic systems including the 5HT system. 5HT neurons share monoamine biosynthetic components with dopamine (DA) neurons and are known to contribute to DA processing in the denervated PD striatum (Politis et al. 2014); binding of the 5HT transporter (5HTT) reduces after onset (Politis et al. 2010). Patients at high genetic risk for PD including those with leucine-rich repeat kinase 2 (LRRK2) mutations provide a unique opportunity to compare the presymptomatic and symptomatic state of 5HT function in vivo. We hypothesized that in LRRK2 mutation carriers, changes in 5HTT would precede both phenoconversion to PD and striatal DA denervation.

Methods: 10 subjects with LRRK2 mutations (5 asymptomatic, 5 with manifest PD) and 7 with sporadic PD were compared to 7 healthy controls. 5HTT binding was assessed using PET with [11C] (N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine (DASB), and DA innervation in striatum with (+)[11C]dihydrotetrabenazine (DTBZ). DASB binding potentials were calculated for regions of interest in cortex, striatum, diencephalon and brainstem. Regional binding was compared between presymptomatic mutation carriers, symptomatic carriers and sporadic PD using ANOVA.

Results: Unaffected mutation carriers had widespread increases in DASB binding, significant in anterior cingulate cortex (ACC) compared to affected carriers (p=0.02) and sporadic PD (p=0.04), in amygdala (p=0.003, p=0.008), and putamen (p=0.05, p=0.003). No significant group differences were seen in other cortical, striatal, diencephalic or brainstem sites or between the two affected groups. All affected patients showed reduced striatal DTBZ binding. DASB binding correlated significantly with DTBZ binding in the more denervated putamen (R2 = 0.28, p=0.03).

Conclusions: Compared with patients with LRRK2 PD and sporadic PD, unaffected LRRK2 mutation carriers have elevated 5HTT binding in the putamen, amygdala and ACC. 5HT neurons may provide an alternate means of DA biosynthesis as an early compensatory mechanism before the motor onset of PD.

62

Co-ordinate based meta-analysis of motor activation deficits in people with Parkinson's and its relation to medication and attentive demand

Y. Xing, M. Wongwandee, C.R. Tench, N. Bajaj, D.P. Auer (Nottingham, United Kingdom)

Objective: To investigate (1)changes in motor brain activation pattern(BAP) in people with Parkinson's disease(PwP) relative to elderly healthy controls(HC); (2)the influence of attention and dopaminergic medication on BAP using co-ordinate based meta-analysis(CBMA).

Background: Dopaminergic deficiency in the nigrostriatal pathway is established as the major driver of motor dysfunction in PwP. Previous motor task(MT) studies have identified some consistent areas related to this defect. However, they also yielded numerous divergent results, which might be associated with study-wise differences.

Methods: We undertook a systematic review searching all year Medline, ScienceDirect and Neurosynth databases for functional neuroimaging studies involving PwP and age-matched HC. The search identified 25 articles(110 MT experiments) suitable for aggregation and CBMA[Tench, CR et al., 2013&2014, PLOS one]. The experiments were grouped based on subject feature(HC/PwP), medication status(on/off), and attentional factors(self/external instructions and freely select/conducting fixed movement).

Results: We identified differences between the common BAP during right upper extremity MT in elderly HC(1st row in Fig1) compared with PwP, which was most prominent for PwPoff(2nd row in Fig1). PwPoff showed significantly hypoactivation than HC in the precentral gyrus, postcentral gyrus, putamen, medial frontal gyrus, inferior parietal lobule and thalamus(Fig2). We also confirmed a medication effect as PwPon showed higher BAP in putamen, frontal gyrus and thalamus versus PwPoff, more consistent with a elderly HC's BAP. Furthermore, we found a significant effect of attention in PwP but not HC: significantly hyperactivation in medial frontal gyrus and amygdala when attention was demanded for MT.

[figure1]

Motor-related BAP in HC(1st row) and PwPoff(2nd row).

CBMA results for HC>PwPoff.

[figure2]

Conclusions: CBMA demonstrated a consistent BAP of known motor networks in HC, and the expected cortico-striato-thalamic hypoactivation in PwP. We also found supporting evidence for the consistent role of limbic system and frontal lobes in compensatory mechanism related to motor planning and attention. The less disparate BAP between PwPoff and HC provides proof for the symptomatic effect of dopaminergic drugs at the neural network level, and a caveat for reporting functional BAP for both on- and off-medication in future studies.

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(62).

Details are in the caption following the image

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64

Diagnostic flowchart using FP-CIT and MIBG scintigraphy in differentiating Parkinsonian syndromes in Japan

M. Yogo, S. Omoto, K. Kawasaki, M. Ariizumi, M. Suzuki (Tokyo, Japan)

Objective: The aim of this study was to propose a diagnostic flow chart for differentiating Parkinsonian syndromes (PS) in routine clinical practice.

Background: [123I]FP-CIT SPECT (FP-CIT) was approved in Japan for clinical use for suspected PS in 2014. Thus, in vivo nuclear imaging of presynaptic nigrostriatal neuronal degeneration and sympathetic cardiac innervation with SPECT is now available to distinguish idiopathic Parkinson's disease (PD) from other atypical Parkinsonian disorder (APD). However, the use of these nuclear methods as stand-alone diagnostic means is not adequate for differentiating different types of PS.

Methods: A consecutive series of 49 patients with PS attending our clinic was prospectively recruited between May and November in 2014. First,we performed brain MRI to exclude advanced morphological changes due to APD, and then divided into 4 groups, Group1: cases presenting gross morphological changes on MRI, Group2: cases showing normal findings on MRI and FP-CIT, Group3: cases presenting abnormal findings on FP-CIT and low MIBG uptake, Group4: cases showing abnormal findings on FP-CIT and preserved uptake of MIBG. We proposed PS diagnostic flow chart based on these conditions. (Figure 1).

Results: Among the 49 Parkinsonism patients in whom a final diagnosis could be made, there were 5 patients with advanced APD such as multiple system atrophy, progressive supranuclear palsy, and cortico basal degeneration in group 1, 19 with drug induced Parkinsonism, essential tremor, vascular PD, scan without evidence of dopaminergic deficits in group 2, 17 with Lewy body disease such as PD, dementia with Lewy bodies, and incidental Lewy body disease in group 3, 8 with very early stage of degenerative PS in group 4.

Conclusions: This provisional flow chart including FP-CIT and MIBG SPECT might assist clinicians in making an accurate clinical diagnosis and minimizing costs and radiation exposure. Because the present data are based on a small sample size from 1 center, confirmation of this flow chart in a large population is warranted using a multicenter design.

Details are in the caption following the image

(64).

65

The relative preservation of the nigral dopaminergic neuroal loss of the patients with Parkinson's disease having dopamine-unresponsive resting tremor

S. You, H.W. Kim (Daegu, Korea)

Objective: To evaluate the influenc of dopaminergic neuronal loss to dopa-responsiveness of resting tremor in Parkinson's disease patients.

Background: It has not been reported yet that whether there is a difference of dopaminergic neuronal loss between Parkinson's disease (PD) patients with dopamine-unresponsive and -responsive resting tremor.

Methods: Between September 1st 2012 and April 30th 2014, seven tremor dominant PD cases were obtained from neurology clinic stipulating: no other abnormal neurological signs or exposure to tremor reducing drugs. We defined the dopamine-responsiveness of resting tremor as a reduction of at least two points for more than 3 months in the UPDRS tremor score of the limb with prominent resting tremor. All patients had underwent [18F] FP-CIT PET on OFF state within 1 year after PD diagnosis. We also executed the quantitative analyses of FP-CIT PET in all patients’ cases. FP-CIT PET images were quantitatively analyzed using 12 striatal subregions and two substantia nigra VOI templates. Subregional binding ratio (BR), inter-subregional ratio of BR (ISR) and subregional asymmetry index were compared between patients with dopamine-unresponsive resting tremor and -responsive resting tremor.

Results: There were 3 men and 4 women (Average age=60.9 ± 10.9). The mean age of onset was 59.7 ± 10.2 years. The mean disease duration was 1.29 ± 0.49 years. Five patients’ resting tremor showed an improved performance after the medical therapy, yet the other two patients’ resting tremor remained still. On quantitative analysis of FP-CIT PET, BR for the substantia niagra of the more affected side in patients with dopamine-unresponsive resting tremor was significantly higher than that in patients with dopamine-responsive resting tremor (0.7163 ± 0.08 vs. 0.43 ± 0.02, P < 0.005). The BR for all striatal subregions in patients with dopamine-unresponsive resting tremor were higher than those in patients with dopamine-responsive resting tremor, but those were not significant.

Conclusions: This study suggests that nigral dopaminergic neuronal loss in PD patients having dopamine-unresponsive resting tremor can be less severe. This is a preliminary study, and the further research is needed for sure.

66

L-Dopa effect on power and variability of Parkinson's tremor is influenced by the behavioral setting

H. Zach, M.F. Dirkx, J.W. Pasman, B.R. Bloem, R.C. Helmich (Vienna, Austria)

Objective: To investigate L-Dopa effects on resting tremor (RT) parameters, influenced by behavioral settings.

Background: Parkinson's disease (PD) RT responds variably to dopaminergic treatment.However,the influencing factors on the L-Dopa effect are unclear. In contrast to many other PD symptoms,RT varies depending on behavioral context like cognitively demanding tasks.

Methods: In 42 tremordominant PD patients(RT score>2UPDRS pts.)clinical scores(UPDRS,tremor rating scale) and accelerometry in the 2 contexts:rest(3x60s) and cognitive coactivation(COCO;counting backwards in steps of three;3x60s)were collected in ON and OFF state. RT power at individual RT frequency was estimated in Fieldtrip by calculating time frequency representations between1-20Hz.For the RT variability we calculated the coefficient of variation of the resulting RT amplitude regressor.Using repeated measures ANOVA,we analyzed the effect of factors TREATMENT(OFF vs. ON),CONTEXT (rest vs.counting) and REPETITION(3 episodes)on average RT power and tremor variability.

Results: We found a clear L-Dopa effect:total UPDRS 43vs.26, clinical RT scores 3.2vs.2.4 pts(p<0.001);tremor constancy3.2vs.1.8 pts(p<0.001). L-Dopa reduced RT power(p<0.001), while COCO increased it(p<0.001). The L-Dopa effect was sign.smaller during COCO than during rest(TREATMENTxCONTEXT interaction,p=0.036).In fact, RT power during COCO ON L-Dopa was similar to RT power at rest OFF L-Dopa(p>0.1). RT power correlated significantly with clinical RT scores in both conditions(correlation coefficient>0.5;Spearman's ρ<0.001). RT variability increased after L-Dopa(p<0.001) and was smaller during COCO than rest(p<0.001); there were no sign. interactions. RT variability was inverse related to clinical tremor constancy(correlation coefficient<-0.6;Spearman's ρ<0.001).

Conclusions: A cognitively demanding task reduces the L-Dopa effect on RT(inconsistent with a previous study(Sturman et al.,2007)).This emphasizes the importance of a simple counting task in clinical practice,as measurements at rest will overestimate the treatment effect.L-Dopa increased RT variability, indicating that patients experience more alternations between rest and tremor episodes. Both factors may contribute to the subjective experience of many patients that L-Dopa is ineffective for RT.Future research is aimed to identify clinical, electrophysiological and cerebral factors influencing the L-Dopa effect on RT.

Parkinson's disease: Pathophysiology

67

Auto-antibodies to α-synuclein are present in Parkinson's disease biofluids

R.S. Akhtar, K.C. Luk, J.Q. Trojanowski, V.M.Y. Lee (Philadelphia, PA, USA)

Objective: To develop an assay for auto-antibodies to α-synuclein (α-syn) in biological fluid samples, and to measure auto-antibody titers in CSF and serum from Parkinson's disease (PD) patients and healthy participants as a potential disease biomarker.

Background: Biomarkers hold great promise in allowing early detection of PD and in identifying sub-populations within an otherwise clinically similar cohort of patients. Endogenous auto-antibodies to amyloidogenic proteins like α-syn have been proposed as biomarkers in several neurodegenerative conditions, including PD. We hypothesized that α-syn auto-antibodies could be a biomarker for PD.

Methods: To measure auto-antibodies, we developed an enzyme-linked immunosorbent assay (ELISA) using purified recombinant α-syn as a capture substrate. We optimized this ELISA by systematically testing incubation parameters and blocking reagents to maximize the signal-to-noise ratio. We then assessed serum and CSF samples from PD patients and age-matched healthy controls (HC) for α-syn auto-antibodies. Each sample was analyzed at least three times in independent experiments.

Results: CSF samples from 54 HC and 93 PD patients and serum samples from 8 HC and 22 PD patients were analyzed. Titers of α-syn auto-antibodies were elevated in both PD patient serum and CSF as compared to HC samples. Auto-antibody titers did not correlate with participant sex or age. In 15 serum-CSF sample pairs, there was a significant correlation in auto-antibody titer. Serum auto-antibody titers were significantly higher in participants with at least one APOE ε4 allele as compared to those without this allele. In contrast, CSF titers were not affected by presence of the APOE ε4 allele. In the PD patients, there was no association between CSF auto-antibody titers and cognitive impairment at the time of sample collection. There was also no association between titer and cognitive and motor performance, as measured by the Dementia Rating Scale-2 and Unified Parkinson's disease Rating Scale, respectively.

Conclusions: Auto-antibodies to α-syn are enriched in both serum and CSF of PD patients as compared to age-matched healthy participants. Further studies are necessary to determine if auto-antibodies that bind pathological forms of α-syn can also be detected in PD patient biofluid samples. Furthermore, studies of longitudinally collected samples will determine whether auto-antibodies change with respect to disease progression.

68

Admixing of two mice strains with differential susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) positively modulates the nigral dopaminergic phenotype

P.A. Alladi, D.J. Vidyadhara, H. Yarriephang, T.R. Raju (Bangalore, India)

Objective: Systematic neuroanatomical evaluation of dopaminergic (DA) neurons of Substantia Nigra pars compacta (SNpc) in C57BL/6 mice (MPTP susceptible), CD-1 mice (MPTP resistant) and their crossbreds to delineate the phenomenon of differential susceptibility to MPTP induced neurotoxicity.

Background: An interesting aspect of Parkinson's disease (PD) is that it has differential prevalence among different ethnic groups. For example, PD is less prevalent in Asian-Indians compared to Caucasians. Further, Anglo-Indians the admixed population of European and Asian Indian origin are 5 times lesser vulnerable than Indians. We aim to understand the phenomenon of varying prevalence using mice strains with differential susceptibility to develop MPTP induced Parkinsonian features.

Methods: The DA neurons of the SNpc of adult C57BL/6 mice, CD-1 mice and the first filial generation of the reciprocal crosses (F1X1 & F1X2) were studied (n=6/group). Unbiased stereology of tyrosine hydroxylase (TH) immunostained serial midbrain sections provided the absolute neuronal numbers; densitometry based image analysis and immunoblotting revealed protein expression levels; and morphometry revealed their cellular character.

Results: Stereological quantification showed significantly higher number of nigral DA neurons in CD-1 and the crossbred mice compared to C57BL/6. Further, there were insignificant differences in the neuronal densities except for the F1X2 crossbreds. Both, densitometric analysis and immunoblots revealed significantly higher TH expression in the crossbreds compared to C57BL/6. The neuronal nuclear and soma area of F1X1 and C57BL/6 matched well; while those of FIX2 and CD-1 were similar.

Conclusions: The presence of higher number of nigral neurons in CD-1 mice provides anatomical basis for its resistance to MPTP induced toxicity. The comparability of numbers in crossbreds and CD-1 mice, complemented by higher TH expression, argue for similar neuroprotection in the crossbreds. The morphological differences in dopaminergic neurons of susceptible and resistant strains indicate that neuronal size may be a decisive factor of vulnerability. Thus, our study provides neuroanatomical basis for differential MPTP susceptibility in mice and the admixing provides an interesting experimental paradigm to study the human phenomenon of differential prevalence of PD.

69

Dopaminergic fibers from the substantia nigra to the olfactory bulb in the rat

D. Alvarez-Fischer, O. Arias-Carrion, C. Klein, W.H. Oertel, G.U. Hoeglinger (Luebeck, Germany)

Objective: To elucidate the neuroanatomical basis of hyposmia in the pre-motor stage of Parkinson's disease (PD) and to investigate the impact of the dopaminergic system on olfaction using a rat model.

Background: PD is a neurodegenerative disorder characterized by a marked loss of midbrain dopaminergic neurons. Whereas onset of motor impairments reflects a rather advanced stage of the disorder, hyposmia is considered as a very early non-motor symptom of the disease. Little is known about the role of nigral dopaminergic projection system in olfaction under physiological conditions and about the anatomical basis of hyposmia in PD. Yet, the early occurrence of olfactory dysfunction implies that pathogens such as environmental toxins could incite the disease via the olfactory system.

Methods: We performed axonal tracing studies, retrograde intoxications and behavioral studies in rats.

Results: Anterograde and retrograde tracing studies identified a direct dopaminergic projection from the substantia nigra pars compacta to the core of the olfactory bulb. Ablation of the nigral projection led to impaired olfactory perception, as evidenced in two independent test paradigms (using unconditioned appetitive and conditioned aversive stimuli). Hyposmia following dopaminergic deafferentiation was reversed by means of pharmacological activation of dopamine receptors.

Conclusions: We demonstrate here the existence of a direct dopaminergic projection into the olfactory bulb and identify its origin in the substantia nigra pars compacta of rats. These observations may provide a neural basis for toxin or pathogen invasion into the basal ganglia and for hyposmia as an early and frequent symptom in Parkinson's disease.

70

Gait patterns associated with freezing of gait in patients with Parkinson's disease

M. Amboni, L. Iuppariello, I. Lista, R. Rucco, P. Varriale, M. Picillo, A. Iavarone, G. Sorrentino, P. Barone (Baronissi (Salerno), Italy)

Objective: To investigate gait patterns associated with freezing of gait (FOG) in Parkinson's disease (PD).

Background: FOG is a common and debilitating symptom in patients with PD. FOG refers to paroxysmal events in which a subject is unable either to initiate locomotion and to turn or to walk through a doorway. Beyond freezing episodes, inconsistent walking abnormalities have been reported.

Methods: Thirty PD patients were enrolled. All patients were neither demented nor depressed. The clinical assessment included H&Y stage, MDS-UPDRS I, II and IV at on state, MDS-UPDRS III both at on and off state, Mini Mental State Examination (MMSE) and Frontal Assessment Battery (FAB). Quantitative gait analysis was performed by means of a motion capture system (Qualisys, Sweden). The following conditions were investigated during off state: 1) normal gait (Gait-off); 2) cognitive dual task (Cog-off); 3)motor dual task (Mot-off). Any freezing episode was excluded by the analysis. Statistical analysis was carried out by means of the Mann-Whitney test followed by a logistic regression analysis.

Results: Based on the objective assessment of FOG during gait analysis, fourteen subjects were classified as patients with FOG (FOG+) and sixteen subjects were classified as patients without FOG (FOG-). There were no significant differences on age, gender, disease duration, H&Y stage during on, MDS-UPDRS I, II, III (during on), MMSE and FAB scores between the two groups. The two groups differed on MDS-UPDRS III during off and MDS-UPDRS IV. The following gait parameters significantly differed between the two groups: 1) velocity during all conditions (Gait-off: p=0.02; Cog-off: p=0.0001; Mot-off: p=0.015); 2) step length during all conditions (Gait-off: p=0.016; Cog-off: p=0.001; Mot-off: p=0.005); 3) step length variability during Gait-off (p=0.03); 4) single/double support time ratio during Cog-off (0.04); 5) Symmetry ratio during Gait-off (p=0.026) and Cog-off (p=0.005). The logistic regression analysis showed that reduced velocity during Cog-off represents the best predictor of FOG.

Conclusions: As compared to FOG-, FOG+ PD patients displayed reduced velocity, step length and symmetry and altered dynamic stability as revealed by increased step length variability and reduced single/double support time ratio. Reduced velocity during cognitive dual task would represent the stronger walking parameter associated with FOG, beyond freezing episodes.

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Staining for unphosphorylated alpha-synuclein in the colon mucosa. No difference between patients with Parkinson's disease and healthy controls

L. Antunes, S. Frasquilho, M. Ostaszewski, J. Weber, L. Longhino, P. Antony, A. Baumuratov, P. Derkinderen, R. Balling, N.J. Diederich (Luxembourg City, Luxembourg)

Objective: To search for alpha-Synuclein in the colon mucosa in patients with idiopathic Parkinson's disease (IPD) and in healthy controls (HC).

Background: The gut has been proposed as the starting point of IPD. Due to barrier leakage, a toxin could pass the mucosa and trigger the disease process by misfolding alpha-Synuclein. However, there are only scarce and so far controversial data on the presence of alpha-Synuclein in the mucosa of the gut.

Methods: Twenty IPD patients (age: 66.9 ± 8.4 yrs.; mean disease duration: 6.95 ± 6.8yrs., 50% male) and 8 HC (age: 65.6 ± 3.9yrs., 25% male) were willing to undergo total colonoscopy within the nation-wide colon cancer screening program. In each subject biopsies were obtained separately for the left and right part of the colon. Mucosa was separated from submucosa, immunostaining for unphosphorylated alpha-Synuclein was performed with alpha-Synuclein (Syn204) Mouse mAb. Presence of alpha-Synuclein was evaluated in a semi-quantitative manner (no presence, weak, medium, strong presence). The examiners were blinded for the status of the subject (IPD versus HC).

Results: Sufficient biopsy samples (left and right colon part) and adequate immunostaining were present in 27 subjects: 19 IPD patients and 8 HC. Unphosporylated alpha-Synuclein was present in 18 of 19 IPD patients and in all controls. The difference in intensities was not significant. However, stronger and more frequent immunostaining was present in the right than in the left colon (p=0.04).

Conclusions: Our data support the results of two other recent studies: unphosphorylated alpha-Synuclein is present in the colon mucosa of both IPD patients and HC. However, the staining is more abundant in the proximal part of the gut, suggesting that the risk for disease generation may be segment-dependent. Importantly, these data need confirmation by screening for phosphorylated alpha-Synuclein as well.

Immunostaining with alpha-Synuclein (Syn204) Mouse mAb; x200 in a healthy control subject; Figure 1: medium presence of unphosporylated alpha-Synuclein in the right colon; Figure 2: weak presence of unphosporylated alpha-Synuclein in the left colon.

Details are in the caption following the image

(71).

Details are in the caption following the image

(71).

72

Endemic vitamin D deficiency, impact on incidence and prevalence of Parkinson's disease

J.A. Bajwa, S. Nahrir, T.M. Muhammad, M.S. Bashir, A. Mujtaba, S.R. Siddiqui (Riyadh, Saudi Arabia)

Objective: To evaluate vitamin D (Vit. D) deficiency in Parkinson's disease (PD) cohort of Arab ancestry.

Background: Over the last decade, there is tremendous evidence linking Vit. D and adverse brain outcomes. Studies have looked at the relationship between PD symptoms and Vit. D levels. Generally it appears that 1,25(OH)2D3 can both induce factors involved in dopamine synthesis and storage as well as perhaps induce an anti-oxidant effect to protect dopamine neuron integrity. The prevalence of Vit. D deficiency appears to be higher in patients with PD than other disease populations. Arab population is well known to be Vit. D deficient despite having decent sunlight throughout the year secondary to many causative and contributing factors.

Methods: A single center retrospective observational study was conducted by reviewing patient charts enrolled in the Movement Disorders registry at King Fahad Medical City, Riyadh, Saudi Arabia. Chart review was used to retrieve demographics and Vit. D data. The study was approved by IRB. The Statistical analysis was done on SPSS version 22.

Results: A Total of 71 diagnosed PD patients were identified with 42 males (59.2%) and 29 females (40.8%). 24 (33.8%) had PD onset at age less than 50 y while 44 (62%) had PD onset after age 50 y. There was statistically significant (p = 0.016) association between gender and serum level of Vit. D deficiency however, there was no statistically significant association of Vit. D deficiency with symptoms of PD. There was higher trend for Vit. D deficiency in PD patients with age of onset being less than 50 y.

Conclusions: Vit. D deficiency could be a potential modifiable risk factor in PD. Endemic Vit. D deficiency may have implications on PD incidence and prevalence, progression and treatment. Further controlled studies are required in larger sample size to assess the role of Vit. D in PD pathophysiology and treatment.

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Gait impairment and cholinergic dysfunction in early PD: Does vascular risk play a moderating role?

S.F. Bartlett, B. Galna, R.A. Lawson, S.E. Lord, R.E. Morris, A.J. Yarnall, D.J. Burn, L. Rochester (Newcastle upon Tyne, United Kingdom)

Objective: To compare the relationship between short latency afferent inhibition (SAI) and quantitative gait characteristics in Parkinson's (PD) subjects with high and low vascular risk.

Background: Cholinergic dysfunction contributes to gait impairment in PD. Recently, cardiovascular risk factors have been implicated in higher level gait disorders in PD. We hypothesised that the relationship between gait and SAI would be moderated by cerebrovascular damage to cholinergic pathways.

Methods: Forty one incident PD subjects and 44 age-matched controls were assessed as part of the ongoing ICICLE-GAIT study, a collaborative study with ICICLE-PD. Mean age 69.3 ± 10.1 years in PD, 68.5 ± 8.4 years in controls (p=0.695). Subjects’ past medical history was obtained and relative cardiovascular risk quantified as 10 year risk compared to expected risk for age and sex, using the QRISK2 calculator. This was used as a proxy for risk of cerebrovascular damage. Low risk was defined as a relative risk ratio ≤1 and high risk as a ratio >1, or existing cardiovascular disease. Cholinergic function was quantified by short latency afferent inhibition (SAI). A 7m instrumented walkway (GAITrite) measured 16 gait characteristics, including: gait speed, step length, stance time, gait variability and asymmetry. SPSS 21 was used to perform Pearson's bivariate correlations and linear regression models.

Results: SAI was higher (more impaired) in PD than controls (75.53 ± 23.72 vs. 58.67 ± 22.17, p=0.001). Gait was impaired in PD subjects, who showed reduced velocity (p=0.005), step length (p=0.005), increased step length variability (p=0.017) and stance time asymmetry (p=0.027). There was no difference in SAI or gait characteristics between high (n=17) and low risk (n=24) PD groups (p=0.611) . Despite this, SAI explained 45.7% of variance in step length in high risk PD compared to only 2.6% in low risk PD and 0.2% in high risk controls.

Conclusions: Our findings suggest that vascular burden may underpin gait impairment associated with cholinergic dysfunction in PD. This relationship was only observed in those with PD and high vascular risk and was not observed in high risk control participants so is unlikely to be related to fitness or cerebrovascular burden alone. Rather, it may represent a cumulative burden of cerebrovascular parenchymal damage, dopaminergic loss, and cholinergic dysfunction, with implications for early gait impairment.

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Quantification of beta activity with disease progression in EEG recordings in Parkinson's disease patients

C.E. Behrend, B.E. Mace, L. Gauger, B.J. Kolls, W.M. Grill (Durham, NC, USA)

Objective: To determine how beta frequency oscillatory activity varies with disease progression and severity in human Parkinson's disease (PD) patients using cortical electroencephalogram (EEG).

Background: PD is a progressive disease in which loss of dopaminergic neurons results in increased burst and oscillatory firing in the cortical-basal ganglia loop and symptoms of tremor, bradykinesia, and rigidity. Exaggerated oscillations are observed in PD patients in local field potentials in a 13-30Hz band –termed the beta band– and are correlated with emergence of bradykinesia. However, the relationship between beta band oscillations and symptom progression in PD remains unclear.

Methods: We recorded cortical EEG in fifteen PD patients of varying disease durations (< 3, 5-10, >10yrs) and severities after overnight medication withdrawal. We recorded EEG at rest (eyes open and closed) and during hand motor tasks, which included both unilateral and bilateral isometric grip and rapid movement tasks. We quantified total percent of spectral power (TPSP) in the beta frequency band for each cortical channel with respect to motor state, disease duration, and off-medication Unified PD Rating Scale (UPDRS) part 3 score. UPDRS 3 scores were categorized as mild (0-20), moderate (21-40), and severe (>40). Repeated measures ANOVA and post-hoc Tukey HSD tests were used to assess all outcome measures.

Results: Across all subjects and channels, TPSP in the beta band decreased significantly with eye closure at rest and varied little across motor tasks. Across disease duration cohorts, TPSP in the beta band averaged across tasks and channels was significantly increased in the 5-10yr and >10yr cohorts (p<0.0001) as compared to the < 3yr cohort. No significant difference was found between the 5-10yr and >10yr groups (p=0.365). Across UPDRS 3 categories, TPSP in the beta band averaged across tasks and channels was significantly lower in the ‘moderate’ group as compared to the ‘mild’ group (p<0.0001) and lower in the ‘severe’ group as compared to the ‘moderate’ group (p<0.0001). Regression analysis of average beta band TPSP as a function of UPDRS 3 score revealed a small, significant negative slope (p<0.0001) and an R^2 of 0.054.

Conclusions: Our data suggest that increasing beta band power may be a marker for disease duration but does not appear to be related to degree of motor impairment.

75

Cerebellar theta-burst stimulation for the evaluation of the pathophysiology and the therapeutic potential for rest tremor in Parkinson's disease

D. Benninger, J. McNames, F. Herrmann, F. Medlin, F. Vingerhoets, M. Stephan (Lausanne, Switzerland)

Objective: To investigate whether functional activation or inhibition of the cerebellum by transcranial magnetic stimulation modulates rest tremor in Parkinson's disease.

Background: Rest tremor in Parkinson's disease (PD) is disabling and responds often incompletely to conventional therapy. The pathogenesis remains largely unknown and therapeutic alternatives are needed. Functional imaging, neurophysiology and structural studies, and stereotactic surgery point to an involvement of the cerebellum and the cerebello-thalamo-cortical pathway in generation of Parkinsonian tremor, but the precise nature of the functional disturbance remains unknown.

Methods: In a randomized, double-blind, sham-controlled, cross-over study design, 15 PD patients with rest tremor underwent single sessions of continuous TBS (cTBS, inhibitory), intermittent (iTBS, excitatory) and sham stimulation of both cerebellar hemispheres. Assessment of rest tremor, motor function and neurophysiology were performed before and after each intervention including a 14-day monitoring of tremor and motor activity.

Results: Continuous TBS, intermittent TBS and sham stimulation of the cerebellum had no effects on tremor and motor performance and failed to restore cerebello-cortical inhibition in Parkinson's disease.

Conclusions: The contribution of cerebellar dysfunction in the pathophysiology of Parkinson's disease remains undetermined, but cerebellar stimulation may not offer a therapeutic alternative for tremor.

76

Progressive nigrostriatal neurodegeneration associated with α-synuclein pathology induced by AAV-mediated overexpression of mutant α-synuclein in mice, rats and marmosets

M. Bourdenx, S. Dovero, M. Engeln, S. Bido, C. Piron, M. Bastide, I. Vollenweider, L. Baud, Q. Li, V. Baekelandt, D. Scheller, A. Michel, T. Boraud, P.O. Fernagut, F. Georges, G. Courtine, E. Bezard, B. Dehay (Bordeaux, France)

Objective: Animal models are an essential asset for basic pathophysiological research as well as validation of therapeutic strategies of human diseases.

Background: The absence of adequate in vivo experimental models has severe repercussions for therapeutic intervention success. To date, no mammalian model recapitulates the required age-dependent phenotypes associated with Parkinson's disease (PD). Both the species and age-related differential susceptibility of dopaminergic neurons was assessed by comparing the extent and pattern of neuronal loss, as well as occurrence of age-dependent intracellular inclusions α-synuclein formation, in mice, rats and monkeys.

Methods: We selected a series of models of ascending complexity with three different strains of mice (i.e. C57Bl/6, senescence-accelerated prone mouse (SAMP8), as a model of aging and their littermate controls, senescence-accelerated resistant mouse (SAMR1)), adult rats and young versus aged marmoset monkeys. Each model received a stereotatic injection in the substantia nigra pars compacta (SNpc) of high-titer (1010 vg/g of body weight) bolus of adeno-associated virus serotype 9 carrying mutant human a-synuclein (A53T) under the neuron specific synapsin promoter including a WPRE enhancer element. Sixteen weeks after injection, we systemically investigated both species specifics and age-dependent differential susceptibility of dopamine neurons regarding the extent and pattern of neuronal loss and kinematic analysis for rats. We also assessed a-synuclein expression levels, pathological state (i.e. S129 phosphorylation) and occurrence of intracellular inclusion formation.

Results: We successfully induced dopaminergic degeneration in all species. Mice were less susceptible to a-syn-mediated toxicity compared to rats and monkeys. Both SAMP8 and SAMR1 present a strong α-syn staining which was not correlated with the occurence of degeneration. High-resolution kinematic analyses revealed that rats exhibited the hallmarks of Parkinsonian syndromes during gait, including periods of freezing, postural instability, and reduced speed of motion. In marmosets, old animals were more susceptible to degeneration at both fibers and cell body levels.

Conclusions: According to the species used, we observed differences in the PD-related neurodegeneration progression over time associated with α-synucleinopathy.

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In utero delivery of scAAV9 mediates widespread brain transduction in rats and monkeys: Towards new models of PD

M. Bourdenx, L. Chansel-Debordeaux, S. Dovero, V. Grouthier, J. Uranga, N. Dutheil, S. Brun, A. Espagna, L. Groc, Q. Li, C. Jimenez, E. Bezard, B. Dehay (Bordeaux, France)

Objective: Transgenic mammals allow to study brain function and diseases.

Background: The adeno-associated virus serotype 9 (AAV2/9) crosses the blood brain barrier, is capable of transducing developing cells and neurons after intravenous injection in many species, and mediates a long-term stable transduction. Ability to transduce brain decreases over time, being maximum at P1 and decreasing dramatically by P10 already suggesting a developmental period in which AAV2/9 transduction has maximal efficacy. While P1 is an attractive (and easily accessible) time point, in utero gene delivery has clearly demonstrated that a wide transduction of neurons is possible at embryonic stages compatible with the development of the targeted area.

Methods: To test this hypothesis, we injected intracerebroventricularly (i.c.v.) high-titer bolus of AAV2/9 carrying either mutant human α-synuclein (A53T) or enhanced green fluorescent protein (EGFP) under the synapsin or CMV immediate enhancer/β-actin (CAG) promoter respectively, at embryonic day 16.5 for rat and around 100 days fetal age for monkeys under ultrasound imaging guidance. Animals after birth have then be behaviourally followed-up and were terminated at regular interval to access the brain pathology.

Results: We characterized the regional distribution of GFP immuno-positivity in brain structures and peripheral organs. We observed transduction of neurons in most regions of the brain – i.e. within hippocampus, thalamus, spinal cord, striatum, globus pallidus, substantia nigra, choroid plexus, cerebellum, and cortex- 25 days after injection in rats. Moreover, the efficacy of transduction seems dependent on the brain structure. Transduction of mutated α-synuclein was then characterized as was defined the specific brain lesions in both rats and monkeys.

Conclusions: Overall, these results indicate that an engineered AAV serotype 9 variant (scAAV9) injected in utero in rats or rhesus macaques results in efficient, neuronal and widespread transduction of the brain. Altogether, this proof of concept study could facilitate and offer unique opportunities for modelling brain diseases in rats and rhesus macaques by targeting mutant genes with tissue-specific gene expression, not mentioning future clinical applications for in vivo correction of monogenic diseases or abnormalities in humans.

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Does the side of onset in Parkinson's disease correlate with interleukins levels?

L.S. Campos, F. Pradella, A.S. Farias, G.A.D. Moraes, R.F.O. de Paula, F. Von Glehn, L.G. Piovesana, P.C. Azevedo, A.S. Moraes, M.D. Andrade, A. D'Abreu, L.M.B. Santos (Campinas, Brazil)

Objective: Evaluate interleukins levels- anti- and proinflammatory- in subjects with Parkinson's disease (PD) and correlate those with clinical manifestations.

Background: Several studies showed altered cytokine levels in Parkinson's disease (PD). However, the role of those cytokines in the pathophysiology of PD has not yet been established.

Methods: We evaluated 21 subjects who fulfilled the Brain Bank Criteria for PD diagnosis . All patients answered a structured standardized clinical questionnaire and the following scale: UPDRS, The modified Hoehn and Yahr staging, Schwab and England Scale, SCOPA cognition (SCOPA-COG), SCOPA-Psychiatric complications (SCOPA-PC) and Non-Motor Symptoms Scale (NMSS). We classified subjects into two clinical subtypes: tremor-dominant (TD) and rigid-akinetic (RA) —. We measured the following serum citokines levels: IL-6, TNF-α, TGF-β, IL-10.

Results: Lelves of IL-6 (0.0053411 ± 0.0059566 versus 0.0012878 ± 0.0017099; p=0.0362) and TNF-α (0.0298595 ± 0.0174282 versus 0.0140438 ± .009449; p=0.0102) were significantly higher in subjects with a left-sided onset compared to those with a right-sided onset. There was no significant difference in age, sex distribution, age of onset, prevalence of dementia, depression, and other clinical scale scores between subjects with left-sided onset compared to those with a right-side one. We also observed higher levels of IL-6 in subjects with dementia when compared to those with normal cognition (0.0019666 ± 0.0032651 versus .0064117 ± .0064288, p=0.0496).

Conclusions: We found higher levels of proinflamamtory cytokines in subjects with a left-side onset compared to those with a right-side onset and in those with dementia compared to those with normal cognition. Those cytokines likely mediate neuronal degeneration, and their levels probably correlate with the differential clinical presentation previously observed in clinical studies considering side-of-onset.

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Dyskinesias are associated with a narrowband 70 Hz activity as revealed by chronic cortical and subcortical recordings in Parkinson's disease patients

C. de Hemptinne, N. Swann, S. Miocinovic, S. Qasim, S. Wang, N. Ziman, J. Ostrem, M. San Luciano, N. Galifianakis, P. Starr (San Francisco, CA, USA)

Objective: To investigate the electrophysiological characteristics of cortical and subcortical activity associated with dyskinesias in Parkinson's disease (PD).

Background: Levodopa-induced dyskinesias (LID) are one of the most frequent and disabling motor complications of long-term dopamine replacement in patients with PD. Deep brain stimulation (DBS) can also exacerbate or induce dyskinesia, especially shortly after implantation, limiting the therapeutic efficacy of PD treatments. In order to improve these therapies it is crucial to investigate the pathophysiology underlying these periods of involuntary movements that is still largely unknown.

Methods: Two PD patients with severe motor fluctuations, minimal tremor and experiencing periods of dyskinesias have been implanted with an investigational, totally implanted neural interface capable of both recording and stimulation. This device was connected to a standard quadripolar DBS electrode placed in the subthalamic nucleus (STN) and one subdural quadripolar strip electrode placed over the primary motor cortex (M1). Cortical and subcortical signals were recorded simultaneously in the outpatient clinic over multiple visits, in the on and off medication state and on and of stimulation, during both dyskinetic and non dyskinetic states. Signals were sampled at 800 Hz, stored internally, downloaded noninvasively by radiotelemetry then analyzed.

Results: Periods of dyskinesias were associated with the emergence of a narrow-band peak in spectral power at about 70 Hz in both M1 and STN signals, although most prominent in M1. An increase in coherence between both structures was also observed at the same frequency. This pattern has been reliably observed during periods of levodopa induced dyskinesias over multiple visits. Preliminary results also suggest that stimulation induced dyskinesias is characterized by a similar pattern of activity.

Conclusions: Dyskinesias are characterized by a narrowband 70 Hz rhythm at the cortical and subcortical level. This signal, could be used in a closed loop DBS paradigm that would automatically adjust the DBS settings, based on this biomarker, to reduce stimulation amplitude or active configuration so as to optimize dyskinesia control.

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Neuroprotective effect of incretin in rat model of Parkinsonism with pre-existing diabetes

E.A. Elbassuoni (Minia, Egypt)

Objective: The goal of this work is to study the effect of pre-existing streptozotocin-induced diabetes on the severity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -induced Parkinsonism in male albino rats, and to find out if GLP-1 could improve symptoms of Parkinsonism in the diabetic animals, and work out how it might do this.

Background: Previous studies have suggested associations between midlife diabetes mellitus (DM) and neurodegenerative diseases, DM contributes to cognitive impairment in the elderly, but its effect in Parkinsonism is not well studied. Glucagon-like peptide-1 (GLP-1), as a member of the incretin family, has roles in glycemic control and satiety. In addition, it appears to exert several additional effects on many tissues via the widespread expression of its receptor.

Methods: 40 adult male albino rats were divided into 4 equal groups: control untreated group, MPTP group, diabetic MPTP group, and diabetic MPTP group+ exenatide (a synthetic GLP-1 mimetic). At the end of the experiment striatal dopamine, tumor necrosis factor alpha (TNF-α), glutathione reductase, malondialdehyde, nitric oxide and catalepsy score were measured.

Results: MPTP induced Parkinsonism in all rats proved by the significant increase in catalepsy score and the significant decrease in striatal dopamine level. Pre-existing of diabetes before Parkinsonism induction worse the condition and increase the severity of Parkinsonism. Exenatide administration to diabetic MPTP rats induced significant increase in the striatal dopamine, glutathione reductase with a significant decrease in striatal TNF-α level, nitric oxide and malondialdehyde level with significant improvement in the catalepsy score better than the non-treated diabetic MPTP group, and the MPTP group.

Conclusions: Diabetes mellitus increases the severity of impairment in Parkinsonism disease. The benefits of incretin extend beyond their hypoglycemic effects since it success as a neuroprotective agent in rats with Parkinsonism through multiple mechanisms of action including the anti-inflammatory, antioxidant and anti-apoptotic effect largely independent of its hypoglycemic effects.

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UPDRS asymmetry is higher for the upper extremities compared to the lower extremities in Parkinson's disease

G. Foffani, J.A. Obeso (Móstoles, Spain)

Objective: To test whether left-right clinical asymmetry is different for the upper extremities compared to the lower extremities in Parkinson's disease.

Background: The clinical onset of Parkinson's disease typically affects one body side with progression towards the other side taking place some few years later. Whether this clinical asymmetry differs between upper and lower extremities remains unknown.

Methods: Data were obtained from the Parkinson's Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). We analyzed the UPDRS III scores of the full cohort of patients with Parkinson's disease included in the PPMI database at their baseline screening. Left and right UPDRS scores were separately obtained for the lower and upper extremities by summing the corresponding lateralized UPDRS items for rigidity, bradykinesia and tremor (3.3b-e, 3.4a-b, 3.5a-b, 3.7a-b, 3.8a-b, 3.17a-d). To minimize floor effects, we considered only patients in which the sum of these UDPRS items was ≥10 (n=252). Clinical asymmetry was measured as the absolute value of left-right UPDRS scores, expressed as a percentage of the corresponding left+right scores.

Results: Left+right UPDRS scores were higher for the upper extremities (9.0+/-3.0) compared to the lower extremities (6.1+/-2.7; paired t-test: p<0.0001). As expected, clinical asymmetry decreased from 54.5% to 29.7% as left+right UPDRS scores increased from 6 to 10 (2-way independent-measures ANOVA, factor UPDRS: F(4,286)=6.6, p<0.0001). More importantly, clinical asymmetry was significantly higher for the upper extremities (54.6+/-30.1%) compared to the lower extremities (42.8+/-31.1%; factor EXTREMITIES: F(1,286)=33.8, p<0.0001). In the small subset of patients whose left+right UPDRS scores were identical for the lower and upper extremities (n=17), clinical asymmetry was higher for the upper extremities (47.6+/-35.3%) compared to the lower extremities (37.3+/-28.5%; paired t-test: p=0.0134).

Conclusions: Parkinson's disease seems clinically more asymmetrical in the upper extremities compared to the lower extremities. This clinical observation could reflect a different UPDRS sensitivity between upper and lower limbs, or could suggest that motor progression advances somatotopically in a caudal-to-rostral direction.

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Fixin’ to die: A common death pathway in catecholamine neurons

D.S. Goldstein, C. Holmes, P. Sullivan, Y. Sharabi, I.J. Kopin (Bethesda, MD, USA)

Objective: We tested whether across a variety of diseases, including familial and sporadic Parkinson's disease (PD) and multiple system atrophy (MSA), neuroimaging and neurochemical evidence for a vesicular storage defect and decreased aldehyde dehydrogenase (ALDH) activity accompany catecholaminergic denervation, independently of the initial disease process.

Background: Several neurodegenerative diseases such as PD involve prominent loss of catecholamine neurons. Determinants of vulnerability of catecholamine neurons have been obscure. We hypothesized that decreased vesicular storage and decreased ALDH activity constitute a common final pathway in catecholamine neuronal death. The combination would be expected to build up levels of 3,4-dihydroxyphenylacetaldehyde (DOPAL), the autotoxic metabolite of dopamine. DOPAL and alpha-synuclein may be nodes in a complex homeostatic nexus, in which cumulative abnormalities at multiple sites could induce lethal positive feedback loops. [figure1]

Methods: We analyzed data from catecholaminergic neuroimaging and neurochemistry and post-mortem tissue neurochemistry in patient groups with catecholaminergic denervation in the brain or periphery (e.g., PARK1, PARK4, Gaucher/PD, sporadic PD, MSA, pure autonomic failure, progressive supranuclear palsy) and in groups without catecholaminergic denervation.

Results: Accelerated loss of 18F-dopamine-derived radioactivity was found specifically in groups with cardiac sympathetic denervation, and accelerated loss of putamen 18F-DOPA-derived radioactivity was found specifically in groups with Parkinsonism. Myocardial norepinephrine depletion was associated with decreased vesicular storage in cardiac sympathetic nerves and putamen dopamine depletion with decreased vesicular storage in nigrostriatal terminals. Decreased putamen ALDH activity and low CSF 3,4-dihydroxyphenylacetic acid levels were found in Parkinsonian but not in non-Parkinsonian groups.

Conclusions: Diseases involving catecholaminergic denervation entail a pattern of decreased vesicular storage and decreased ALDH activity, regardless of the disease etiology or initial disease process, consistent with a common “death pathway” in catecholaminergic neurons.

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(82).

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Contribution of striatal interneurons to L-DOPA induced dyskinesia development in an animal model of Parkinson's disease

G. Gomez, I.R. Taravini, M.G. Murer, O.S. Gershanik (Ciudad Autónoma de Buenos Aires, Argentina)

Objective: To determine changes in number and activity of the different populations of striatal interneurons in a mouse model of hemiParkinsonism and L-DOPA induced dyskinesias.

Background: The administration of 3,4-dihydroxyphenyl-l-alanine (L-DOPA) still remains as the preferred treatment for Parkinson's disease (PD) despite its propensity to induce severe motor complications, known as L-DOPA-induced dyskinesias (LID). Maladaptive changes in the striatum, as well as in other brain areas, are thought to underlie the development of LID. Even though interneurons comprise only ∼5% of all striatal neurons, they strongly modulate striatal output. Therefore, changes in striatal microcircuits may contribute to basal ganglia dysfunction in a number of Movement Disorders such as PD and in LID development.

Methods: C57 mice were injected with 6-hydroxydopamine (6-OHDA) or vehicle in the medial forebrain bundle and treated daily with a dyskinetogenic dose of L-DOPA or saline solution. LID and reversal of forelimb asymmetry (a measure of anti-Parkinsonian response) were assessed on days 1, 4, 8, 12 and 14. Fixed tissue sections from the striatum and substantia nigra pars compacta were obtained and the severity of the dopaminergic lesion was analyzed by tyrosine hydroxylase immunohistochemistry. The density of each type of interneuron population was determined in the different experimental groups by performing immunohistochemical stains for specific interneuron markers. The activity of each interneuron type was assessed by colocalization of each interneuron marker with c-fos.

Results: Changes in c-fos and interneuron markers were observed both after dopaminergic depletion and LID development. 6-OHDA lesion led to reduced number of parvalbumin positive interneurons and this change was not reversed by L-DOPA administration. On the other hand, no significant changes were observed in the number of cholinergic interneurons within the different experimental groups.

Conclusions: Our findings suggest that changes in striatal interneurons contribute to the maladaptive state that occur after dopamine depletion. In addition, chronic treatment with L-DOPA fails to reestablish the initial physiological scenario. Further functional studies are required to elucidate if these changes are just an epiphenomenon or if they actually contribute to LID development.

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L-DOPA induced motor changes in alpha-synculein model of Parkinson's disease in C. elegans

D.K. Gupta, X. Hang, Z. Feng (Cleveland, OH, USA)

Objective: To establish a C. elegans model for L-DOPA-induced dyskinesia in Parkinson's disease.

Background: L-DOPA induced dyskinesia (LID) is a disabling complication of dopaminergic therapy in Parkinson's disease (PD). There is a lack of simple animal models of LID that can capture this clinical phenomenon and enable mechanistic study and high-throughput drug screening. C. elegans, which has a short lifecycle (∼ 3 weeks) and rich genetic resource, is a robust animal model to study pathophysiology of PD.

Methods: We used alpha-synuclein expressing C. elegans model of PD, which exhibits progressive degeneration of dopaminergic neurons and loss of motor activity. Day 1 worms from this model and wild type N2 controls were divided into three groups based on their exposure to L-DOPA (1mM): no exposure, continuous exposure (day 2-10) and alternating exposure (starting day 2). Using automated worm behavioral analysis system, we quantified worm's locomotion speed (LS), body bending (BR), physical displacement per body bend (PDBD) of worms (5 minutes per worms, 6 worms per group) on day 2, 4, 6, 8 and 10.

[figure1]

Results: Compared to controls, a progressive, age-related reduction in LS was observed in PD worms, which was alleviated by both continuous and alternating L-DOPA exposure (figure 1a). In contrast, BR was not altered in PD worms. However, BR of PD worms was significantly increased by L-DOPA exposure, with more dramatic effect on alternating exposure (figure 1b). PD worms also exhibited an age-related reduction in PDBD compared to controls. PDBD of PD worms was not changed by continuous L-DOPA exposure but was further reduced by alternating L-DOPA exposure (figure 1c).

Conclusions: PD worms exhibit progressive, age-related loss of motor activity, which is alleviated by L-DOPA treatment. However treatment with L-DOPA leads to dynamic modulation of motor activity depending on continuous versus alternating exposure. These findings are consistent with the current understanding of LID pathophysiology and may potentially represent motor phenotype of LID in C. elegans. These findings need be further validated as such simple animal model of LID in C. elegans may have important implications for discovering molecular mechanisms and performing high-throughput drug screenings for LID.

Details are in the caption following the image

(84).

85

Is handedness correlated to Parkinson's disease side of onset?

S. Hanif, M.S. Hassan, R.A.l. Sharif, Z.G. Aljohani, J.A. Bajwa (Riyadh, Saudi Arabia)

Objective: To describe correlation between handedness and onset of motor symptom's in Parkinson's disease patients at Movement Disorders center, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia.

Background: Parkinson's disease (PD) characteristically presents with asymmetrical motor symptoms. One hypothesis is that motor asymmetry can be an epiphenomenon of underlying anatomical asymmetry. Multiple factors could be involved in asymmetric presentation of disease like age, sex, disease duration and handedness. Published data postulates that PD motor symptoms emerge more often on the dominant hand side. Asymmetric motor symptoms onset correlated to dominant hand side has not been yet investigated in Arab cohort.

Methods: Seventy four PD patients and their charts were reviewed to get demographic details like age, sex, disease related parameters i.e duration of PD, subtype of PD, initial motor symptom of tremor, rigidity, bradykinesia and family history. Patients were also interviewed over the phone to specifically ask about first motor symptom, sidedness and handedness.

Results: The majority (87.8%) of our patients were right handed among who 55 (74.5%) were male and 19 (25.7%) were females. 97% of all patients were above the age of 45 y at the time of diagnosis. Tremor was the first motor symptom in 65%, bradykinesia in 23% and rigidity in 13.5%. There was a significant association between handedness and site of initial symptom. 63.1% of right handed patients experienced their first symptom on the right side and 36% on their left side. Similarly 87.5% of the left handed patients reported their initial symptom on the left side and remaining 12.5% on their right side (P-value 0.009).

Conclusions: Like published data, our cohort also shows strong association between handedness and side of initial symptom (P-value 0.009) even though the sample size was small. Further research is required to determine PD side of onset, symptom at onset and correlation with hand dominance.

86

Identification of novel biomarkers for Parkinson's disease by metabolomics technologies

T. Hatano, S. Saiki, A. Okuzumi, N. Hattori (Tokyo, Japan)

Objective: The pathogenesis of Parkinson's disease (PD) involves complex interactions between environmental and genetic factors. Metabolomics can shed light on alterations in metabolic pathways in many diseases, including neurodegenerative diseases. In the present study, we attempted to elucidate the candidate metabolic pathway(s) associated with PD.

Background: Although the pathomechanisms underlying neuronal degeneration in PD remain unknown, various PD-related genetic-environmental interactions may contribute to the pathogenesis of this disease. Previous studies revealed the diagnostic value of measuring α-synuclein and DJ-1 levels in cerebrospinal fluid; however, useful biomarkers related to genetic and environmental factors have not yet been elucidated. Serum/plasma metabolomics is a useful tool for understanding metabolic pathways and networks in neurodegenerative diseases.

Methods: Serum samples were collected from 35 individuals with idiopathic PD without dementia; 18 males, mean age 69.1 ± 10.8 years; mean Hoehn & Yahr (H-Y) 2.9 ± 1.1 and 15 healthy age-matched and sex-matched control subjects without PD: 7 males, age 70.7 ± 9.7 years. This analysis was based on a combination of three independent platforms: ultrahigh-performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS) optimized for basic species, UHPLC/MS/MS optimized for acidic species, and gas chromatography/mass spectrometry.

Results: The metabolomic profiles of PD were clearly different from normal controls. PD profiles had significantly lower levels of tryptophan, caffeine and its metabolites, bilirubin, ergothioneine, and significantly higher levels of levodopa metabolites and biliverdin than those of normal controls. Alterations in bilirubin/biliverdin ratio and ergothioneine can indicate oxidative stress intensity and may suggest elevated oxidative stress and/or insufficient ability for scavenging free radicals which could contribute to PD pathogenesis. Decreased serum tryptophan level is associated with psychiatric problems in PD. A decrease in serum caffeine levels is consistent with an inverse association of caffeine consumption with development of PD based on past epidemiological studies.

Conclusions: Metabolomics analysis detected biomarkers associated with PD pathogenesis and disease progression.

87

Parkin mediated mitochondrial quality control in nigrosriatal dopamine neurons

H.Y. Hawong, J.R. Patterson, K.J. Lookingland, J.L. Goudreau, Michigan State University (East Lansing, MI, USA)

Objective: Parkin prevents DA neurodegeneration by maintaining mitochondrial homeostasis in central DA neurons.

Background: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a mitochondrial Complex I inhibitor that recapitulates Parkinsonian features in human and various animal models. Increased parkin expression is associated with resistance of tuberoinfundibular dopamine (TIDA) neurons following acute MPTP exposure, whereas parkin expression decreases in susceptible nigrostriatal (NS) DA neurons. Parkin is a 52 kDa cytosolic protein identified by linkage analysis in autosomal recessive early onset PD. Parkin is reported to mediate mitochondrial quality control through autophagy of mitochondria.

Methods: Mitochondrial ultrastructure, mass, membrane potential and respiratory capacities in NSDA neurons were investigated in parkin null mice using Seahorse XF 24 analyzer, flow cytometry, and transmission electron microscopy. Parkin was overexpressed in substantia nigra by introducing rAAV-hParkin stereotaxically in wild-type (WT) mice. Mitochondrial respiratory capacities and mitochondrial protein levels were measured using Seahorse XF 24 analyzer and Western blot in parkin overexpressed WT mice following acute MPTP exposure.

Results: Reduced mitochondrial maximal and spare respirations, mass, number of mitochondria per synaptosome, and disrupted mitochondrial ultra structure were observed in parkin null mice -. In contrast, parkin overexpression via rAAV-hParkin in WT mice did not affect mitochondrial respiratory function.

Mitochondrial bioenergetics with parkin overexpression
Respiration (OCR) Sham (pMoles/min) F-Parkin (pMoles/min)
Basal 151 ± 6.73 134 ± 8.35
Maximum 514 ± 47.2 497 ± 23.4
Spare 362 ± 46.8 361 ± 16.2

However, parkin overexpression prevented inhibition of maximum and spare respirations and loss of mitochondrial protein Cox IV following MPTP exposure - [figure2].

Conclusions: Mitochondria in striatal synaptosomes had impaired function, ultrastructure and lower mass in the absence of parkin. This may be due to loss of parkin-mediated mitochondrial quality control in NSDA neurons. Parkin overexpression maintained functional mitochondria, likely through autophagy of mitochondria following acute neurotoxicant exposure. Therefore, loss of parkin mediated mitochondrial quality control may contribute to loss of NSDA neurons in a neurotoxicant model of DA neuronal degeneration similar to that which occurs in PD.

Details are in the caption following the image

(87).

Details are in the caption following the image

(87).

88

Insights into freezing of gait from wearable sensors

F.B. Horak, J.G. Nutt, M. Mancini (Portland, OR, USA)

Objective: To characterize the muscle activation patterns and leg movements prior and during freezing episodes to better understand the neural mechanisms responsible for Freezing of Gait (FoG).

Background: We hypothesize that FoG is due to lack of release of hip abductor muscle activity for lateral anticipatory postural adjustments (APAs) in preparation for stepping during gait and turning.

Methods: Five subjects with idiopathic PD with FoG (FoG+, UPDRS III: 51 ± 13) and 5 idiopathic PD without FoG (FoG-, UPDRS III: 40 ± 16) walked a course with gait initiation, passes through a doorway, and 180° turns while wearing 3 Opal inertial sensors mounted on the posterior trunk and on each ankle, and 6 wireless EMG sensors on bilateral tibialis anterior (TA), gastrocnemius medialis (GM) and at the hip on the tensor fasciae latae (TFL). Heel-strike (Hs) and toe-off (To) events for right and left steps were extracted from the shank angular velocities. The FoG ratio (power spectral density ratio between high and low frequencies of shank acceleration) and gait speed were calculated. Onset of activity from Hs for the TA, GM, and contralateral TFL, offset of activity for the ipsilateral TFL; as well as duration of EMG activity were calculated for the 5 steps preceding the turn.

Results: All FoG+ subjects showed FoG. The FoG ratio was significantly larger in FoG+ compared to FoG- (1.25 ± 0.3 vs 0.5 ± 0.3, p=0.007) although gait speed, excluding turns, was similar (0.67m/s±0.23 vs 0.88m/s±0.13, p=0.11). In the steps before a turn:, i) the ipsilateral TFL offset and the contralateral TFL onset were similar between groups, whereas the subsequent, ipsilateral TFL onset was later in the FoG+ for the step prior to a freezing episode; ii) the ipsilateral TFL activity was reduced during stance but increased during swing in FoG+; iii) the contralateral TFL activity was larger during stance and reduced during swing in FoG+. The medio-lateral acceleration traces were similar in amplitude, but less variable in FoG+.

Conclusions: We observed increased ipsilateral TFL activity and reduced contralateral TFL activity in FoG+ compared to FoG-, consistent with a lack of release of APA inhibition and inadequate postural preparation for a step. These observations suggest that abnormal temporal muscle activation patterns during FoG episodes may be due to abnormal coupling of anticipatory postural adjustments with stepping rather than a disruption of central pattern generators.

89

AAV1/2 overexpression of A53T α-synuclein in the substantia nigra results in behavioural deficits and degeneration of the nigrostriatal system: A new mouse model of Parkinson's disease

C.W. Ip, L.C. Klaus, V. Maltese, J. Volkmann, J.M. Brotchie, J.B. Koprich (Wuerzburg, Germany)

Objective: To generate and characterize a mouse model of Parkinson's disease (PD) based on AAV1/2 driven expression of human A53T α-synuclein (aSyn) in the substantia nigra (SN).

Background: α-synuclein is a protein implicated in the pathophysiology of PD. To mimic this aspect of the disease it has been shown in rat and monkey models that AAV1/2 mediated overexpression of human A53T aSyn leads to degeneration of SN dopaminergic neurons, decline of striatal dopamine (DA) and tyrosine hydroxylase (TH), elevation of DA turnover and behavioural abnormalities. Knowing the advantages of a species amendable to genetic manipulation, we aimed to translate the AAV1/2 A53T aSyn model to mouse.

Methods: AAV1/2 A53T aSyn or AAV1/2 empty vector (EV) at a concentration of 5.1 x 10exp12 gp/ml were unilaterally injected into the right SN of male adult C57BL/6 mice. Clinical examination in both groups was longitudinally performed by open field and rotarod analysis on a weekly basis for 8 weeks after AAV injection. Paw use asymmetry was examined by cylinder test at weeks 5 and 9 after injection. Post-mortem analysis was performed by immunohistochemistry to analyze aSyn and TH expression in the SN, striatal dopamine transporter (DAT) levels by autoradiography and dopamine metabolism by high performance liquid chromatography.

Results: Significant paw use asymmetry was observed in the A53T aSyn injected group with preference of the right front paw when compared to EV controls at both 5 and 9 weeks post injection (both p<0.05). Neurochemically, a significant reduction in striatal DAT binding (by 23%), DA (by 36%) and DOPAC (by 36%) levels in A53T aSyn mice was shown as well as an increase in DA turnover (HVA/DA; by 60%) compared to controls (all p<0.05). Immunohistochemical double staining for TH and aSyn showed that the A53T injected mice had widespread nigral expression of aSyn and a reduction in SN DA neurons. No significant effects were detected on the open field analysis (velocity or distance moved) or on rotarod performance.

Conclusions: These data show that unilateral injection of AAV1/2 A53T aSyn into the mouse SN leads to persistent behavioral deficits and neurodegeneration of the nigrostriatal DA system similar to that observed in the rat. This aSyn based model of PD is now in a position to conduct investigations using transgenic mice.

90

Motor behaviour and neuronal network activity after lesions of the anterior or posterior pedunculopontine nucleus in a rat model of Parkinson's disease

X. Jin, J.K. Krauss, M. Alam, K. Schwabe (Hannover, Germany)

Objective: We investigated the effect of anterior or posterior cholinergic lesions of the pedunculopontine nucleus (PPN) in rats with 6-hydroxydopamine (6-OHDA) lesions on gait-related motor behavior, and on neuronal network activity of the cuneiform nucleus (CNF) and the basal ganglia (BG) output region, the entopeduncular nucleus (EPN).

Background: Loss of cholinergic neurons in the mesencephalic locomotor region, comprising the PPN and the CNF, are related to gait disturbances in late stage Parkinson's disease (PD).

Methods: Bilateral anterior and posterior PPN lesions were induced by stereotaxic microinjection of the cholinergic toxin AF64A in male Sprague Dawley rats with or without 6-OHDA-induced bilateral retrograde nigrostriatal degeneration of dopamine neurons, a model of PD. Movement impairments were assessed using rotarod and open field test. Thereafter, in vivo electrophysiology recording were carried out in the CNF and the EPN and single unit (SU) activity was analysed.

Results: Bilateral nigrostriatal dopamine depletion significantly decreased the latency in the rotarod test, which was further deteriorated by anterior PPN lesions (P<0.05). In the activity box 6-OHDA lesions had no effect on spontaneous locomotion, but additional posterior PPN lesions reduced this measure (P<0.05). In the EPN nigrostriatal dopamine lesions led to significantly higher coefficient of variation of the inter-spike interval (P<0.001) coupled with more bursting firing pattern (P<0.05), which were reversed after anterior and posterior PPN lesions. In the CNF the neuronal discharge rate was increased after anterior PPN lesions (P<0.001) with no effect of nigrostriatal dopamine lesions. The CNF bursting pattern was reduced after 6-OHDA lesions, additional PPN lesions further reduced this measure (P<0.05).

Conclusions: Combined nigrostriatal and anterior or posterior PPN lesions had different impact on motor behaviour. The complex effects on neuronal activity of the CNF and the BG network may contribute to elucidate the pathophysiology of PD gait disturbances.

91

Development and evaluation of closed-loop deep brain stimulation (DBS) in a primate model of Parkinson's disease (PD)

L.A. Johnson, S.D. Nebeck, C.M. Hendrix, M.D. Johnson, K.B. Baker, J.L. Vitek (Minneapolis, MN, USA)

Objective: To develop a recording and stimulation system that enables closed-loop control of DBS in an animal model of Parkinson's disease (PD) and to evaluate the behavioral and physiological effects of closed-loop DBS (CL-DBS) relative to traditional DBS (tDBS) and off-DBS conditions.

Background: tDBS systems are always on, continuously delivering pulsed stimulation at a high rate (i.e., >100 Hz) regardless of the clinical state. A promising approach to improve DBS therapy for PD is to incorporate feedback control of DBS based on real-time measures of brain activity. In particular, local field potential (LFP) activity in the beta range (∼13-35Hz) has been implicated as a potential biomarker to use for closed-loop control of DBS.

Methods: The rhesus macaque 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD was used. A scaled version of the human DBS lead was implanted in the subthalamic nucleus (STN), and LFPs from the STN were recorded differentially from two DBS contacts, processed in real-time, and used to control the timing of stimulation at an adjacent contact. High frequency stimulation (135 Hz) was delivered whenever the amplitude of beta-band LFP envelope was above a predetermined threshold level. The relative efficacy of CL-DBS, tDBS and off-DBS conditions were compared using blinded rating scales and objective measures of motor performance during a cued reaching task.

Results: CL-DBS was as effective as tDBS at reducing rigidity in the contralateral limbs. However, CL-DBS was not as effective as tDBS in improving performance on the reaching task, as measured by total movement time. Physiology recordings revealed that the beta-band envelope sharply decreased during the cued reach, such that in the CL-DBS condition stimulation was least likely to be delivered during the reach and beginning of the return epoch.

Conclusions: Our results illustrate the importance of using multiple objective measures when comparing new and traditional DBS methods, and also motivate exploration of more robust biomarker sites and signals for closed-loop DBS, such as oscillations in other frequency bands (e.g. gamma) or relationship between frequency bands. The model we developed will be extremely useful to investigate the optimal parameters for feedback control of DBS and to understand the neural mechanisms underlying the therapeutic benefit of DBS.

92

The sex-specific role of biometals in the risk of Parkinson's disease

M.J. Kim, J.Y. Lee, J. Kim, K. Kim, H.S. Ryu, A.I. Bush, S.J. Chung (Seongnam, Korea)

Objective: To investigate the association between biometals and the risk of Parkinson's disease (PD) and clinical characteristics of PD.

Background: There has been growing evidence of the participation of biometals in neurobiological processes, such as the regulation of synaptic transmission and abnormal protein aggregation. However, experimental and clinical evidence for the association of biometals with PD is still limited.

Methods: We studied 325 patients with PD (175 men and 150 women) and age- and sex-matched 304 controls (141 men and 163 women). We collected clinical data of PD patients, including age at onset of PD, disease duration, Hoehn and Yahr stage (H-Y stage), motor fluctuation, dyskinesia, freezing, hallucination, and mini-mental status examination (MMSE) score. The levels of biometals (iron, copper, zinc, cobalt, and strontium) in serum were assayed by inductively coupled plasma-mass spectrometry.

Results: The age at onset of PD was 58.26 ± 9.20 years (mean ± SD) and the duration of PD was 6.95 ± 4.63 years. The mean H-Y stage was 2.3. The serum level of copper was significantly lower in PD patients compared with controls (13.40 ± 2.43 μmol/L vs 13.88 ± 2.62 μmol/L, respectively; P = 0.016), but this difference was not significant in sex-specific analyses (men-only and women-only analyses). The serum levels of cobalt and strontium were not different between PD patients and controls in overall analysis. In women-only analysis, the serum level of cobalt was significantly higher in PD patients compared with controls. In men-only analysis, the serum level of strontium was lower in PD patients compared with controls. The higher serum level of copper (OR = 1.26, 95% CI = 1.04 - 1.53, P = 0.019) and the lower serum level of iron (OR = 0.88, 95% CI = 0.82 - 0.95, P = 0.001) increased the risk of dyskinesia in women-only analysis, with adjustment for age, disease duration and H-Y stage. The serum level of copper was negatively correlated with MMSE score in PD patients (β=-0.151, P = 0.006). The serum level of cobalt was positively correlated with disease duration in women-only analysis and H-Y stage in men-only analysis.

Conclusions: This study showed a sex-specific association between biometals and PD risk and clinical characteristics of PD. Further experimental studies are needed to confirm these findings.

93

Leukocyte β-glucocerebrosidase and β-hexosaminidase activity is not altered in sporadic and genetic Parkinson's disease

H.J. Kim, B.S. Jeon, J.Y. Kim, H. Park, W.W. Lee, C.W. Shin (Seoul, Korea)

Objective: To examine whether the activity of β-glucocerebrosidase and β-hexosaminidase in peripheral blood leukocyte of patients with sporadic and genetic Parkinson's disease is altered compared with healthy subjects.

Background: Mutations in GBA is one of the most common genetic risk factor for Parkinson's disease (PD). The proposed pathomechanisms by which GBA mutation leads to the development of PD is impaired degradation of pathologic α-synuclein and subsequent accumulation of toxic α-synuclein species and formation of Lewy body. In this regard, it is tempting to hypothesize that β-glucocerebrosidase activity is decreased even in patients with sporadic PD without GBA mutation.

Methods: Fifty-one patient with PD or Parkinsonism (36 patients with sporadic PD, 5 patients with PARK2 mutation, and 10 patients with spinocerebellar (SCA) 17 with Parkinsonism) and 20 healthy controls were included. Activity of β-glucocerebrosidase and β-hexosaminidase in peripheral blood leukocyte was measured using standard protocol used in the screening test for Gaucher's disease.

Results: There was no difference in the age between patients and controls. Neither activity of β-glucocerebrosidase nor β-hexosaminidase in peripheral blood leukocyte was different between patients and control. Subgroup analysis also showed that the activity of both enzymes in patients with sporadic PD, PARK2 mutation, and SCA17 with Parkinsonism was not different from that in controls. This was also true when only the patients with sporadic PD with abnormal FP-CIT-PET (n=27) were counted.

Conclusions: The activity of β-glucocerebrosidase and β-hexosaminidase in peripheral blood leukocyte does not differentiate the patients with PD from healthy controls.

94

3D-EM characterisation of ‘axonal swellings’ in the engrailed-1 heterozygous mouse model of Parkinson's disease

Z. Kurowska, G.J. Kidd, E. Benson, P. Brundin, S. Medicetty, B.D. Trapp (Cleveland, OH, USA)

Objective: Our goal was to better characterize swellings of midbrain dopaminergic axons in the Engrailed-1 heterozygous mouse model of Parkinson's disease.

Background: Engrailed-1 (En1) is a transcription factor important for development and maintenance of dopaminergic neurons. Polymorphisms in this gene are associated with sporadic PD. En1+/- mouse model presents slow progressive degeneration of nigro-striatal pathway. Between 2 and 8 weeks of age, before most of other pathologies can be detected, progressive dopaminergic terminal defects (‘axonal swellings’) in En1+/- mice accumulate.

Methods: 3-dimentional electron microscopy (3D-EM) and immunohistochemistry of dopaminergic axons in dorso-medial striatum at 2, 4, and 8 weeks in En1+/- mice.

Results: Several weeks before the cell bodies of nigral dopamine neurons degenerate, their terminals become dystrophic, swollen and filled with electron dense bodies consistent with abnormal autophagic vacuoles. We have measured the size of the swellings and identified three different types of swellings: early, immediate and mature, based on their size and morphology.

Conclusions: Our findings support a progressive retrograde degeneration of En1+/- nigrostriatal neurons, akin to what is suggested to occur in PD. We conclude that using axonal swelling quantification in En1+/- mouse is highly relevant for testing PD-related therapies, as indicated by a pathological progression that closely mimics that in patients.

95

Metabolomic biospecimen analysis for measuring PD progression

P.A. LeWitt, J. Li, M. Lu, L. Guo, P. Auinger (West Bloomfield, MI, USA)

Objective: To determine if untargeted profiling of small-molecule (<1.5 kDa) constituents of CSF and plasma can yield useful state biomarkers of PD.

Background: Since PD is associated with mitochondrial and other metabolic alterations, metabolomic analysis (measuring hundreds of biochemicals present in minute concentrations) has the potential for recognizing disease-specific patterns that might offer correlations to PD severity and insight into the disease process.

Methods: Specimens were collected from 49 unmedicated DATATOP study PD subjects. CSF and plasma was sampled twice using a standardized protocol (at up to 24 months apart) and at times when UPDRS ratings were conducted. Assays used ultrahigh-performance liquid chromatography combined with tandem mass spectrometry. A spectral reference library provided chemical identifications. Data underwent extensive curation and quality-control measures before application of several bioinformatics statistical approaches.

Results: From 1st to 2nd specimen collections, the data provided indications for decreased efficiency in glucose and fatty acid metabolism, elevated oxidative stress, and variation in gut microflora metabolism. To find a panel of biospecimen constituents that predicted changes over time and in UPDRS Parts 2 + 3 scores, marker selection in CSF and plasma samples was conducted using Least Absolute Shrinkage and Selection Operator (LASSO). Compounds chosen by LASSO were fitted into a multiple linear regression. A composite index was created, based on each marker's coefficient (and which was a linear combination of concentrations for each of the markers). We found that, for plasma constituents, the correlation coefficient was highly positively correlated with measured change in UPDRS Parts 2 + 3 scores (0.87 for 15 compounds, p=2.2e-16), while for CSF, the correlation coefficient was only moderately positively correlated (0.58 for 3 compounds, p=1.3e-5). There was no biomarker differentiation of two PD clinical sub-types (postural instability-gait disorder as compared with tremor-dominant Parkinsonism). A metabolomic pathway analysis of the data was not informative.

Conclusions: Metabolomic profiling of PD plasma specimens provided findings that were highly predictive of PD severity. Our data detected a panel of biomarkers that could be useful for gauging PD progression in easily-sampled biospecimens.

96

Freezing of gait early in Parkinson's: Atypical versus typical Parkinson's disorders

A. Lieberman, A. Deep, R. Dhall (Phoenix, AZ, USA)

Objective: Freezing of Gait Early in Parkinson: Atypical versus Typical Parkinson's Disorders.

Background: Freezing of gait (FOG) is an episodic, often dramatic, gait pattern characterized by an abrupt inability to walk, in which the patient's feet appear to be “stuck,” while the upper body often continues to move. The events preceding and during a freezing episode are characterized by a decrease in postural stability, a decrease in step length, a decrease in range of movement of the hips, knees, and ankles, and an increase in fall risk.

Methods: 850 patients were examined at Muhammad Ali Parkinson's Center (MAPC) with a diagnosis of Parkinson's disease (PD) over a period of 18 months.

Results: Among 850 patients, 212 patients (25%), had had PD for < 5 years, and 27 of these (12.7%) had freezing of gait (FOG). Among the 850 patients 40 patients, 4.7% of the total, had atypical Parkinsonism. Among these 40 patients, all of whom had had symptoms for ≤ 5 years, 12 had FOG.

FOG improved with levodopa treatment in 21/27 patients with typical PD, but FOG did not improve with levodopa in the 12 patients with atypical PD. Although FOG appears to be a problem in locomotion, our results suggest that impaired postural stability rather than impaired locomotion is the main problem, and balance training rather than gait training is more likely to be helpful in patients with FOG.

Conclusions: Primary progressive freezing of gait (PPFG) is viewed as arising from a disconnection between the frontal lobes and basal ganglia. In three patients with PPFG, whose FOG did not respond to levodopa, DaTscans revealed an absence of presynaptic dopamine in the basal ganglia.

97

Neuroprotective effects of sodium butyrate against rotenone neurotoxicity in both wild-type and VMAT2 heterozygote knockout mice

L. Liu, N. Xiong, J. Huang, G. Zhang, X. Xu, C. Han, J. Li, H. Jiang, J. Yang, Y. Shen, T. Wang (Wuhan, People's Republic of China)

Objective: To examine whether administration of sodium butyrate can exert significant neuroprotective effects in animal model of Parkinson's disease (PD) induced by chronic rotenone administration in both wild-type and VMAT2 heterozygote knockout mice.

Background: Previous studies indicate that VMAT2-deficient mice display motor deficits and progressive neurodegeneration in the substantia nigra, as observed in PD. Histone deacetylase (HDAC) inhibitors have recently become a promising therapeutic candidate in PD and other neurodegenerative diseases because there is growing evidence that HDAC inhibitors can exert neuroprotective effects by various mechanisms. Sodium butyrate, a HDAC inhibitor, has shown efficacy for neuroprotection in animal models of stroke and Huntington's disease.

Methods: Wild-type and VMAT2 heterozygote knockout male C57BL/6 mice aged 12-months were divided into the following groups: rotenone-administrated (30 mg/kg/d, p.o.) and rotenone-administrated (30 mg/kg/d, p.o.) with sodium butyrate (0.3 g/kg/d, i.p.) for eight weeks. Then, animals were subjected to behavioral (Rotarod and pole test), neurochemical (striatal content of DA, DOPAC and HVA) and immunohistochemical (tyrosine hydroxylase, α-synuclein and ubiquitin) evaluations.

Results: Administration of sodium butyrate significantly attenuated rotenone-induced motor deficits, depletion of striatal dopamine and loss of tyrosine hydroxylase-positive neurons in the substantia nigra in both wild-type and VMAT2 heterozygote knockout mice. Moreover, administration of sodium butyrate significantly reduced accumulation of α-synuclein and ubiquitin in dopaminergic neurons, which was elevated in rotenone-treated mice.

Conclusions: Our study indicates that sodium butyrate, a well-known HDAC inhibitor, exerts neuroprotective effects through modulation of α-synuclein expression in both wild-type and VMAT2 heterozygote knockout mice treated by rotenone. These findings provide further evidence that administration of sodium butyrate may be a promising approach for the treatment of PD.

98

Risk of Parkinson's disease onset in patients with diabetes, hypertension, dyslipidemia and obesity in Mexican population

R. Llorens-Arenas, M. Rodriguez-Violante, A. Cervantes-Arriaga, H. Calderon-Fajardo, G. Neri-Nani, R. Millan-Cepeda, I.E. Estrada-Bellmann, D. Piña-Fuentes, G. Pagano, M. Tagliati (Mexico City, Mexico)

Objective: To describe the prevalence of metabolic comorbidities (hypertension [HT], diabetes [DM], dyslipidemia [DL], and obesity) in Mexican PD patients. To establish associations between these comorbidities and the occurrence of PD and its clinical course.

Background: Previous studies have suggested an association between PD and metabolic comorbidities. However, the evidence is inconclusive and contradictory, with both risk and protective effects reported. The prevalence of these comorbidities in Mexican general population is 9.2% for DM, 13% for DL and 32% for HT.

Methods: Patients from the Mexican PD Registry (ReMePARK) were enrolled from February through October 2014. Demographic data and history of comorbidities were recorded. Blood analysis was performed screening for DM, DL and end organ damage. Results from the National Health and Nutrition Survey 2012 were used as controls. T test and OR were calculated to compare prevalence of comorbidities between PD patients and general population. In the subgroup of patients in which comorbidities were diagnosed at least 1 year prior to the onset of PD a covariate analysis was performed to determine the effect of these comorbidities and the blood results on the clinical course, correlating with LEDD, MDS-UPDRS, Hoehn-Yahr scale, NMSS and SEND-PD.

Results: 452 patients were recruited. Prevalence of comorbidities was 33.6% for HT, 14.2% for DM, 19.5% for DL, 41.6% for overweight, and 20.3% for obesity. Both HT and DM were diagnosed significantly earlier than the onset of PD, at least 1 year prior to its onset. Patients had significantly higher prevalence of HT (OR 2.11, p < 0.0001, CI 95% 0.11-0.53), DM (OR 1.54, p < 0.001, CI 95% 1.33-2.12), DL (OR 1.50, p < 0.001, CI 95% 1.39-2.06), and overweight (OR 1.45, p < 0.0001, CI 95% 1.65-2.12) compared to general population. Covariate analysis did not establish associations between comorbidities or blood test results and clinical course.

Conclusions: DM, HT, DL and overweight are significantly higher in PD patients than in general population. These comorbidities are diagnosed prior to the onset of PD, suggesting altered metabolic pathways as possible risk factors. Nevertheless, the presence and severity of these comorbidities does not seem to influence the clinical presentation of PD. Further studies are warranted to clarify these associations.

99

Measurement of CSF proteins suggested by gene expression studies as potential Parkinson's disease biomarkers

D. Loeffler, P. LeWitt, J. Aasly, L. Smith, M. Coffey (Royal Oak, MI, USA)

Objective: To determine if cerebrospinal fluid (CSF) concentrations of 5 proteins previously identified by gene expression studies as PD biomarker candidates, and/or the concentration of nrf2, a key activator of anti-oxidant mechanisms, might offer potential PD biomarkers.

Background: No reliable biomarkers have been found for early diagnosis of PD or its neuropathological progression. A previous study (Molochnikov et al., 2012) identified 5 genes as “optimal predictors of PD:” aldehyde dehydrogenase family 1 subfamily A1 (ALDH1A1), heat shock 70-kDa protein 8 (HSPA8), p19 S-phase kinase-associated protein 1A (SKP1A), huntingtin interacting protein-2 (HIP-2), and 19S proteasomal protein PSMC4. A sixth protein, nuclear factor (erythroid-derived 2)-like 2 (nrf2), was included in this study because it is a major antioxidant response regulator.

Methods: ELISAs were used to measure SKP1A, ALDH1A1, HSPA8, PSMC4, HIP2, and nrf2 in CSF samples from subjects with idiopathic PD (n = 20), Parkinsonian LRRK2 gene mutation carriers (n = 9), healthy non-Parkinsonian LRRK2 carriers (n = 20), aged subjects with other neurological disorders (n = 16), and healthy aged control subjects (n = 19).

Results: Only HSPA8 and nrf2 were detected; no statistically significant differences between groups were found for concentrations of either protein. HSPA8 and nrf2 levels were weakly associated (rho = -.30) for all subjects. When associations between the two proteins were examined for subgroups formed by diagnostic group or gender, moderate negative associations were detected for women (rho = -.51; p = .001) and for PD of either type (rho = -.42; p = .023).

Conclusions: Our inability to detect SKP1A, ALDH1A1, PSMC4, and HIP2 in CSF underscores obstacles in PD CSF hypothesis-driven biomarker studies: proteins identified as potential biomarkers based on brain or blood studies may not be detectable in CSF, and if they are detectable, their measurements may not reflect their alterations in PD brain. The negative association in PD patients between HSPA8, which binds to newly formed proteins to facilitate correct folding, and nrf2, a regulator of the response to oxidative stress, is intriguing and will be examined in additional CSF samples. Longitudinal CSF measurements of these proteins are planned to evaluate possible PD progression-related changes.

100

Gait outcomes characterize people with Parkinson's disease who transition to falling within the first year

S. Lord, D. Burn, L. Rochester (Newcastle upon Tyne, United Kingdom)

Objective: To compare the clinical features of people with Parkinson's disease (PD) who transition to falling within 12 months from diagnosis with those of non-fallers.

Background: Falls are common in PD and associated with loss of independence and mortality. Understanding the evolution of falls from diagnosis will assist in accurate prediction and effective early management.

Methods: One hundred and twenty-one consecutive incident PD subjects were assessed in Newcastle-upon-Tyne as part of the ongoing ICICLE-GAIT study, a collaborative study with ICICLE-PD. Falls data were collected in newly diagnosed PD prospectively over 12 months via a falls diary and telephone follow-up. A comprehensive battery of motor, cognitive, self-efficacy and gait measures was used to assess performance and Mann-Whitney U test examined differences between new fallers and non-fallers. Participants who self-reported falling at baseline were not included in the analysis.

Results: At 12 months, 70 subjects were non-fallers and 27 were new fallers. Respective age was 67.4 ± 9.3 v 69.4 ± 10.9 years; UPDRS score 24.3 ± 10.5 v 24.4 ± 9.1 and PIGD score .53 ± .33 v .71 ± .36. Time to first fall was positively skewed, with mean (and SD) of 92 days. Significant differences were found for PIGD score (P = 0.019), stance time variability (P = 0.028), and step time and stance time (P = 0.047) and (P = 0.033) respectively.

Conclusions: These (preliminary) results suggest that gait outcomes discern new fallers from non-fallers one year after diagnosis of PD. Cognitive outcomes were not significantly different between groups. This may change as disease advances and non-motor symptoms emerge. Additional analysis will report prospective falls data over 30 months and identify predictors of first fall.

101

Effect of visual cue timing on gait initiation in Parkinson's with freezing of gait

C. Lu, S. Amundsen, P. Tuite, J. Vachon, C.D. MacKinnon (Minneapolis, MN, USA)

Objective: The purpose of this study was to examine the effect of different visual cue timings on anticipatory postural adjustments (APAs) preceding and accompanying gait initiation in Parkinson's disease (PD) patients with and without freezing of gait (FOG).

Background: External cueing can markedly facilitate movement initiation or “unfreeze” the patients with FOG, even when they are off medication. These observations provide compelling evidence that PD patients retain the capacity to initiate movement via non-dopaminergic pathways. However, the utility of using cues is compromised by inconsistency of effects and habituation. Currently there are no guidelines or standardized protocols for how cues should be presented to patients with FOG.

Methods: We studied twenty patients with PD, 11 freezers and 8 non-freezers, in the off medication state. Step initiation was visually cued using three different instructed-delay (warning – go) timing protocols: fixed delay period (3 s), random delay period (4-12 s) and countdown (3-2-1-go, 1 s between cues). Subjects also performed self-initiated stepping trials. The primary dependent APA timing variables were: time to peak amplitude of the stepping foot loading force, and initial excursions of the net center of pressure in both the mediolateral (COPml) and anteroposterior (COPap) directions. Data were analyzed using a 2 x 4 repeated measures analysis of variance with factors of group and cue timing (fixed delay, random delay, countdown and self-initiated).

Results: There was a significant main effect (p<0.005) of cue timing for all APA timing variables. Post-hoc tests showed that the time to peak loading of the stepping leg and peak excursions of the CoP in the lateral and posterior directions were significantly reduced in the countdown and fixed-delay compared with the self-initiated condition (p < 0.009). Loading force and COPap timing were also significantly improved for the countdown compared with the random delay condition (p < 0.024).

Conclusions: The data demonstrate that visual cueing protocols that incorporate predictive timing (countdown and fixed delay) improve the timing of APAs compared to self-initiated steps in both freezers and non-freezers.

102

Reduction of alpha-synuclein in the substantia nigra of the non-human primate results in neurodegeneration

F.P. Manfredsson, D.E. Redmond, Jr., J.W. Lipton, R.M. Malpass, T.J. Collier (Grand Rapids, MI, USA)

Objective: To determine whether loss of functional alpha-synuclein (a-syn) is a causative event in dopaminergic neurodegeneration.

Background: a-syn aggregation and pathology is integral to both idiopathic and familial Parkinson's disease (PD). The correlation between a-syn and PD has led many to describe aggregates as directly toxic, resulting in efforts to eliminate a-syn as a therapy for PD. However, removal of a-syn from rodent nigral neurons via recombinant adeno associated virus (rAAV)-mediated delivery of a-syn shRNA results in neurodegeneration. Thus, we formulated the hypothesis that a-syn aggregates are not directly toxic; rather a-syn aggregation produces toxicity by reducing levels of functional a-syn. This hypothesis was tested by reducing a-syn expression in midbrain neurons of the non-human primate.

Methods: African Green monkeys (n=1) were injected unilaterally in the substantia nigra (SN) with low (5E12 vector genomes (vg)/ml) or high (2E13vg/ml) titer AAV2/5 expressing a shRNA designed against a-syn or scrambled (SCR) shRNA as control. The vectors also contained GFP as a transduction marker. Animals were monitored for behavioral deficits indicative of nigrostriatal denervation for three months until sacrifice. Brains were analyzed for striatal catecholamine content and neuropathology of the SN.

Results: The animal treated with high-dose a-syn shRNA exhibited a progressive deficit in a summary score of healthy behaviors, but no increase in overt Parkinsonian signs. Analysis of tissue indicated that all a-syn shRNA treated animals exhibited reduced striatal dopamine levels. Reductions in TH+ neurons were observed preferentially in the ventral tier of the a-syn shRNA treated SN. No such decrements were observed in animals treated with equivalent doses of a SCR-shRNA. GFP+ neurons were observed throughout the SN of SCR-shRNA treated subjects. In contrast, GFP was only seen in dorsomedial neurons of a-syn shRNA treated animals, ostensibly due to the loss of ventral tier TH+ neurons. Additionally, a loss of TH phenotype as measured by several TH-/neuromelanin+ neurons was observed with a-syn shRNA treatment.

Conclusions: Our findings indicate that non-human primate nigral dopamine (particularly ventral tier) neurons are sensitive to the loss of a-syn. This sensitivity is not due to non-specific shRNA toxicity. Our results suggest that (functional) a-syn is crucial to neuronal survival.

103

Iron and oxidative stress in Parkinson's disease: In search of injury biomarkers

M.S. Medeiros, M.R. Fighera, A.S. Schuh, C.M. Rieder (Porto Alegre, Brazil)

Objective: To determine peripheral levels of iron, ferritin and transferrin in Parkinson's disease (PD) patients and to evaluate whether iron accumulation in the substantial nigra (SN) could be related to serum levels. To determine reliable peripheral biomarkers of oxidative/nitrative stress.

Background: Parkinson's disease pathophysiology is associated with oxidative/nitrosative stress. Iron accumulates in the SN of PD patients and is related to this damage along with oxygen and nitrogen reactive species (ROS, RNS) through Fenton reaction. ROS and RNS are normally produced in cell and inflammatory processes and are controlled by antioxidant systems.

Methods: Forty PD patients and 46 controls were selected to compare serum levels of iron, ferritin, transferrin and oxidative/nitrative stress biomarkers: superoxide dismutase (SOD), catalase, nitric oxide (NOx), thiobarbituric acid reactive substances (TBARS), non-protein thiols, advanced oxidation protein products (AOPP), ferric reducing ability of plasma (FRAP), NTPDases (ATP and ADP), ecto-5’-nucleotidase, adenosine deaminase (ADA), myeloperoxidase, ischemic-modified albumin (IMA) and vitamin C.

Results: Iron levels were decreased in patients with PD, while ferritin and transferrin were not different. Oxidative stress biomarkers such as TBARS, AOPP, NTPDases, IMA and myeloperoxidase were significantly higher in PD patients, while FRAP, vitamin C and non-protein thiols were significantly lower. SOD, catalase, ecto-5’-nucleotidase were not different between the groups and biomarkers NOx and ADA were significantly increased in controls. No correlation was found between biomarkers and sociodemographic and disease characteristic data.

Conclusions: Plasmatic levels of iron are decreased in patients with PD compared to healthy controls. Biomarkers TBARS, AOPP, NTPDases, IMA and myeloperoxidase presented as reliable to measure oxidative/nitrative damage, while non-protein thiols, FRAP and vitamin C show a significant decrease in the antioxidant capacity in PD.

104

Hypochlorite converts dopamine into redox cycling cytotoxic products

N.J. Mehta, K.A. Beningo, D. Njus (Detroit, MI, USA)

Objective: To study the redox cycling of dopamine oxidized metabolites and investigate the mechanism by which they cause oxidative stress and kill nerve cells.

Background: Parkinson's disease is caused by the death of dopaminergic neurons in the substantia nigra, but the reason those neurons die is unknown. Contributing factors are thought to include oxidative stress, mitochondrial dysfunction, dopamine oxidation and microglial inflammation. Specific mechanisms relating these disparate factors have been elusive. The missing piece may be hypochlorite, which we suggest plays a central role linking dopamine oxidation, oxidative stress and microglial activation.

Methods: Redox Cycling Assay – Redox cycling activity was assayed as ascorbate-dependent oxygen consumption, monitored using a Clark-type oxygen electrode.

Superoxide Assay – Superoxide generation in cells was observed using MitoSOX Red, a fluorogenic dye highly selective for detection of superoxide in the mitochondria of live cells.

Trypan Blue Exclusion Assay – Cell viability was determined using 0.4% trypan blue 24 hours after the cells were exposed to the desired concentration of redox cycler.

Results: Hypochlorite reacts with the dopamine oxidation products cysteinyl-dopamine and cysteinyl-DOPAC and converts them into compounds that redox cycle and produce oxidative stress. In fact hypochlorite is unique in its ability to form redox cycling compounds; other oxidants such as hydrogen peroxide and Fe3+ are not effective. These redox cycling compounds are also formed in the presence of myeloperoxidase and its substrates, H2O2 and Cl-, which produces hypochlorite. The product made by hypochlorite treatment of cysteinyl-dopamine is nearly as effective in the mitochondrial redox cycling assay as the synthetic compounds 3-methyl-5-anilino quinone and 9,10-phenanthrenequinone. These compounds all generate superoxide in cells as indicated by Mitosox Red fluorescence. These compounds are also all cytotoxic at micromolar concentrations, and the LD50 correlates with mitochondrial redox cycling activity. Moreover, evidence suggests that cells undergo apoptosis when treated with these dopamine metabolites.

Conclusions: This raises the possibility that hypochlorite, produced by microglial myeloperoxidase, creates redox cycling compounds that lead to oxidative stress and the consequent death of dopaminergic neurons in Parkinson's disease.

105

Association between locus coeruleus pathology and gait dysfunction in Parkinson's disease: A clinical-pathological preliminary analysis

K.A. Mills, Z. Mari, C. Bakker, G.M. Pontone, J.C. Troncoso, L.S. Rosenthal (Baltimore, MD, USA)

Objective: To correlate the degree of Lewy body pathology and neuronal loss in the locus coeruleus (LC) and degree of gait dysfunction seen in patients with Parkinson's disease (PD).

Background: Gait disorders such as freezing of gait (FOG), hypokinetic stride, imbalance, and postural instability all increase the risk for falls in PD. Impaired mobility is the largest factor determining a decline in quality of life and increased health care expenditures. Animal studies suggest that norepinephrine secreted from the locus coeruleus has a significant role in postural tone and locomotion.

Methods: Clinical rating scales and brain pathology have been collected prospectively as part of the Clinical Core of the Morris K. Udall Center of Excellence for Parkinson's disease Research at Johns Hopkins University. PD patients with at least one UPDRS score and a timed up-and-go (TUG) score who participated in the longitudinal brain donation study were included. UPDRS items 14 (freezing), 29 (gait), 30 (postural stability), and 31 (body bradykinesia), as well as the TUG time were analyzed for association with Lewy body scores in the LC and frontal lobe, LC neuronal loss or gliosis, LC pigment loss, LC neurofibrillary tangles (NFT), and LC pallor using either ordinal logistic regression, Chi-square, or ANOVA models.

Results: Of participants with a LC LB score and frontal LB score, 15 subjects had at least one UPDRS Part III score and 14 subjects had at least one TUG time. 46 participants had neuronal loss or gliosis scores and a UPDRS or TUG score. FOG was positively associated with the degree of neuronal loss or gliosis in the LC (LR X2 = 7.17, p = 0.03) and a trend for an association with LC LB score (LR X2 = 7.13, p = 0.07) was found. The presence of any Lewy bodies in the LC was associated with more severe gait impairment on the UPDRS Part III gait item (p = 0.03). Surprisingly, an inverse association between LC Lewy LB load and TUG time was found (F = 4.68, p = 0.03). Neither frontal Lewy body load nor LC NFT score was associated with any of the UPDRS gait measures or TUG time.

Conclusions: Exploratory analysis of a longitudinal clinical-patholological autopsy series indicates that LC Lewy body load and neuronal loss may be associated with freezing of gait. The relationship between LC pathology and gait speed is less clear and may warrant further investigation.

106

Differential effect of 6-OHDA on different regions of rat brain: Oxidative stress and behavioral parameters

N. Mishra, D. Sharma, N. Mishra (New Delhi, India)

Objective: To evaluate (1) behavioral anomalies (motor behavior, spatial cognition, fear, anxiety, emotional state and sociability) and (2) oxidative stress (superoxide dismutase=SOD, glutathione peroxidase=GPx, glutathione reductase=GR, lipid peroxidation=LP, protein oxidation=PO and total thiol content=TT), in different regions of rat brain, in 6-OHDA rat model of Parkinson's disease.

Background: 6-hydroxydopamine (6-OHDA) has been widely used to produce lesions in the rat brain, specially substantia niagra pars compacta, and generate animal models of Parkinson's disease for drug development and understanding the pathophysiology of the disease. There have however, not been any exhaustive studies on the effects of 6-OHDA on motor and non-motor behaviors associated with the disorder as well as the oxidative stress generated in different regions of the brain. This is important to assess the proximity of the animal pathophysiology and the extent to which it can be extrapolated to the human condition.

Methods: 4μl of 6-OHDA (5μg/ml) or saline was stereotaxically administered to six male Wistar rats (6-8months) in the substantia nigra. After two weeks of recovery, righting reflex, open field test, Morris water maze test, light and dark chambered test and three chambered social behavior test were performed. Thereafter, animals were sacrificed; their brains micro-dissected into hippocampus, amygdala, cortex, midbrain, cerebellum and medulla. SOD, GR, GPx, LP, PO and TT were estimated. Data were expressed as mean standard deviation (S.D.) Statistical comparison was performed by Student's t- test followed by Holm-Sidak pairwise analysis.

Results: There was 2fold decline in motor function, 20fold greater mean latency time, 5fold more fear, anxiety and emotional anomaly in the test rats as compared to the controls. All rats were social but the test rats had preference for social novelty as apposed to controls that showed greater inclination towards the familiar rat. Greater oxidative stress was generated in all parts of the rat brain as compared with the controls (SOD=1.5fold, GPx=1.5fold, GR=2fold, LP=2fold, PO=2fold, TT=1.5fold; average of all brain regions).

Conclusions: Our data suggests sustained effects of 6-OHDA in the rat brain and on the behavior of the animal, and this model can be extrapolated to the human Parkinson's disease state.

107

Turning the head red: Intracranial application of near-infrared light improves behaviour and is neuroprotective in a non-human primate model of Parkinson's disease

J. Mitrofanis, C. Moro, F. Darlot, N. El Massri, D.M. Johnstone, C. Chabrol, C.L. Peoples, H.D.T. Anastacio, F. Reinhart, D. Agay, N. Torres, T. Costecalde, V.E. Shaw, J. Stone, A.L. Benabid (Sydney, Australia)

Objective: To examine whether intracranially delivered near-infrared light (NIr) treatment improves the behaviour and neuroprotects midbrain dopaminergic cells in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkey model of Parkinson's disease.

Background: NIr has been shown to be an effective neuroprotective agent in various rodent models of Parkinson's disease (Johnstone et al; ChronoPhysiology & Therapy, 2014:4 1-14). In this study, we show - for the first time - that NIr has positive therapeutic effects in the much larger primate brain. We used an intracranial optical fibre device, one that delivered sufficient NIr signal to the diseased dopaminergic cells located deep in the brain of macaque monkeys.

Methods: A NIr laser (670nm) optical fibre device was implanted surgically into the midline midbrain of macaque monkeys, close to the substantia nigra of both sides. MPTP injections (1.5-2.1kg total) were then made over a five to seven day period, during which time the NIr device was turned on (5sec/60sec; 10mW power; global dose of 25-35J). This was followed by a three week survival period. Monkeys were evaluated clinically for motor activity and their brains were processed subsequently for immunohistochemistry and stereological analysis.

Results: The MPTP-NIr-treated monkeys (n=9), although not quite to control levels, achieved substantially better clinical scores (80%) than the MPTP-treated monkeys (n=11). The NIr was not toxic to the surrounding brain tissue and neuroprotected many dopaminergic cells (30-40%) and their striatal terminations (40%) against MPTP insult. The neuroprotective effect was stronger in the lower MPTP dose regime (1.5mg/kg) than the higher one (2.1mg/kg).

Conclusions: NIr improved behaviour dramatically and was neuroprotective after MPTP insult, particularly at milder doses. Our findings indicate NIr as an effective therapeutic agent in a primate model of the disease and lay the template for translation into clinical trial.

108

The effects of dual task on finger tapping in Parkinson's disease

A. Miyake, T. Yamamoto, T. Furuya, K. Ikeda, K. Takahashi, N. Tamura, N. Araki (Iruma-gun, Japan)

Objective: To evaluate quantitatively repetitive finger tapping (FT) performance during a repetitive pronation-supination of the forearm and to clarify the relationship between the changes of FT motion by dual task and severity of Parkinsonian symptoms.

Background: Decreased performance of FT during dual task has been well known in patients with Parkinson's disease. However, it is not clear what components of FT motion are impaired.

Methods: The subjects consisted of 23 patients with PD and age-matched 13 healthy controls. The motion of finger- to-thumb tapping with the rigid dominant side hand for 10 sec was recorded with high-speed video camera, with and without simultaneous pronation-supination of the opposite side forearm. Key parameters for a cycle of FT were finger separation amplitude, velocity, and duration, as well as the coefficient of variation [CV; (standard deviation)/(mean value) ×100)] of these parameters. To find the relationship between each parameter of the FT motion and severity of Parkinsonian symptoms, PD patients were divided into two groups based on disease duration (≥ 6Y, 6Y >) and UPDRS part III scores (≥ 25, 25 >), and those parameters were compared between the two groups.

Results: I. PD patients:1. Amplitude was decreased and its CV was increased by dual tusk (p<0.05, p<0.05, respectively). 2. Velocity and its CV did not change. 3. Duration showed no change, but its CV was increased (p<0.05). II Controls: 1.Amplitude did not change, but its CV was increased by dual tusk (p<0.05); the change was smaller as compared to that in PD patients. 2. Velocity slowed and its CV was increased (p<0.05, p<0.05). 3.Duraition was increased (p<0.05) and its CV did not change. III There was no relationship between the changes of FT motion by dual task and disease duration or UPDRS part III scores in all parameters.

Conclusions: 1. The differences in the changes of FT performance by dual tusk between PD patients and controls may be caused by dysfunction of the basal ganglia.

2. The Impaired FT performance may have already existed in the earlier stage of PD.

109

Detection and quantification of freezing of gait and falls in Parkinson's disease patients using a wearable motion sensor

Y. Okuma, H. Mitoma, M. Yoneyama (Izunokuni, Japan)

Objective: The aim of the present study is to objectively detect and quantify freezing of gait (FOG) and falls in Parkinson's disease (PD) patients during everyday activities.

Background: FOG and recurrent falls are disabling features of PD and have a significant negative impact on the patients’ quality of life. Recently, we have found that FOG is the most common cause of falls in advanced PD. However, there are few objective methods for detecting FOG and falls outside of the clinic.

Methods: Patients were selected from among 36 patients who participated in our previous prospective study on falls. We developed a motion recorder (body-fixed 3D accelerometer) with a long-lasting battery. First, healthy volunteers simulated FOG and falls, and acceleration signals were analyzed. Then movements of recurrent PD fallers with severe FOG were recorded during their everyday activities and in the outpatient clinic. A newly developed freezing index (cross correlation calculation based on pattern matching) was also calculated and compared with the previous index (ratio of power spectrum).

Results: Characteristic patterns of acceleration signals were recorded for simulated falls. Falls were associated with abrupt changes in trunk angle. Knee trembling was recorded as a rapid oscillation of acceleration, and the freezing index increased during knee trembling. In PD patients, actual falls in everyday life were also detected as abrupt trunk angle changes, and knee trembling was recorded when patients reported FOG-induced falls. The freezing index increased during the start and turning hesitations, similarly to the index calculated using methods proposed by Moore et al.

Conclusions: Motion recording using our wearable sensor is useful for detecting FOG and falls in everyday life in PD fallers, and calculating the freezing index may improve the quantification of FOG.

110

Humoral response against small heat shock proteins in Parkinson's disease

E. Papuć, E. Kurys-Denis, W. Krupski, K. Rejdak (Lublin, Poland)

Objective: The aim of the study was to check whether Parkinson's disease (PD) has the ability to elicit immune response against small heat shock proteins (sHSP), subsequent to their increased expression. Antibodies titers against HSP60 and alpha B-crystallin were assessed.

Background: HSPs are functionally and immunologically highly conserved molecules present in almost all living organisms. Their expression in the cell increases under the circumstances that are potentially harmful to cells, for example, high temperature. This increased HSP expression is present in cells exposed to mild stress and this protects them against subsequent stress. Anti-HSP antibodies are present in different disorders with involvement of inflammatory process. In the light of evidence for the increased heat shock proteins expression in neurodegenerative disorders, the presence of the adaptive humoral response of the immune system can be expected.

Methods: IgG and IgM autoantibodies against alpha B-crystallin were assessed in 26 PD patients 26 healthy subjects. Serum samples from PD patients were collected twice, at baseline and after mean of 13 months follow up. For the assessment of anti-HSP IgG autoantibodies serum samples from 31 Parkinsonian patients and 31 healthy control subjects were collected.

Results: Both IgM and IgG autoantibodies against alpha B-crystallin in PD patients were significantly higher compared to healthy controls (p<0.05). We also found statistically significant increase in antibodies titers against alpha B-crystallin over the time of 13 months, both for IgG (p=0.021) and for IgM (p<0.0001). Additionally, PD patients presented higher levels of anti-HSP IgG autoantibodies than healthy controls (p=0.02).

Conclusions: Anti-HSP IgG autoantibodies belong probably to the natural auto-antibodies, as they are present in healthy people, nevertheless chronic neurodegenerative process may have additional inducing effect on humoral response involving anti-HSP autoantibodies, which is reflected by significantly higher levels of anti-HSP 60 autoantibodies in PD patients compared to healthy controls. Increase in IgG and IgM antibodies titers against alpha B-crystallin over the investigated period of time reflects activation of the immune response, probably secondary to widespreading neurodegenerative process and may suggest the involvement of the immune system in the disease progression.

111

Zinc dyshomeostasis underlies impairment of cellular energy metabolism in ATP13A2 (PARK9)-associated Parkinson's disease

J.S. Park, B. Koentjoro, C.M. Sue (St. Leonards, Australia)

Objective: To investigate the pathophysiological effect of human ATP13A2 deficiency, we assessed the change in Zn2+ levels and its effect on both mitochondrial and glycolytic function in ATP13A2-deficient Kufor-Rakeb syndrome (KRS) patient-derived cell models.

Background: Mutations in ATP13A2 (PARK9) have been associated with KRS, an autosomal recessive early-onset, levodopa-responsive Parkinson's disease (PD). Although ATP13A2 has been shown to regulate Mn2+ metabolism in yeast, its substrates in humans still remain uncharacterised. Recently, we reported mitochondrial dysfunction in KRS patient cells harbouring compound heterozygous ATP13A2 mutations (c.3176T>G/c.3253delC). However, the molecular mechanism by which loss of ATP13A2 cause mitochondrial dysfunction is unknown.

Methods: We tested toxicity of several biometals in KRS patient-derived human olfactory neurosphere cells and examined changes in intracellular Zn2+ levels ([Zn2+]i). Then, we assessed the effect of altered Zn2+ levels on mitochondrial and glycolytic function in these cells.

Results: Among the biometals tested, KRS patient cells showed an increased sensitivity to Zn2+. Subsequently, we identified low [Zn2+]i, altered expression of Zn2+ transporters and impaired sequestration of Zn2+ into LC3-positive vesicles, indicating zinc dyshomeostasis. Pharmacological treatments that increased [Zn2+]i induced the elevated production of H2O2 and aggravation of both functional deficits and morphological changes in mitochondria that resulted in ATP depletion and cell death. In addition, KRS patient cells showed evidence of glycolytic dysfunction as demonstrated by reduced glycolytic capacity and reserve in extracellular flux analysis, reduced pyruvate/lactate production and NAD+/NADH ratio, which were exacerbated by increased [Zn2+]i. The toxic effect of Zn2+ on mitochondrial and glycolytic function was efficiently blocked by ATP13A2 overexpression, Zn2+ chelation, promotion of mitochondrial fusion and treatment of an antioxidant and pyruvate.

Conclusions: Our data indicate that human ATP13A2 deficiency results in zinc dyshomeostasis and impaired cellular energy metabolism. These findings provide valuable insights into the molecular mechanisms underlying zinc dyshomeostasis and its contribution to impaired bioenergetic function in PD with ATP13A2 as a molecular link between these two distinctive aetiological factors.

112

Impact of Levodopa and motor task on beta band coupling of subthalamic nucleus and spinal motoneuron pool in Parkinso's disease

R. Reese, F. Steigerwald, M.M. Reich, C. Matthies, I.U. Isaias, J. Volkmann (Wuerzburg, Germany)

Objective: To describe the impact of movement task and dopaminergic medication on the oscillatory coupling between subthalamic nucleus (STN) and spinal motor neurons in the beta frequency range in Parkinso's disease (PD).

Background: Coupling of neuronal activity in the beta band (10-30Hz) is common but its relevance in health and disease is controversial. The degree and magnitude of beta band activity have been positively correlated with the severity of the akinetic rigid (AR) motor symptoms in PD.

Methods: We recorded local field potentials (LFP) from the STN in six AR-PD patients via telemetry through a fully implanted system for deep brain stimulation (DBS) 14 weeks after implantation. We furthermore assessed the coherence between STN-LFP and contralateral spinal motor neuron activity (EMG of the forearm extensors) in two simple motor tasks: submaximal tonic wrist extension (“tonic”) and self paced alternating wrist flexion and extension (“alternate”) in motor OFF and motor ON (after a levodopa challenge; DBS OFF in all conditions). The brain hemisphere exhibiting most prominent STN beta band activity in the motor OFF resting state was chosen for recordings (right n=3, left n=3). PD patients were selected for STN-DBS by established clinical criteria and gave their written informed consent. They were then asked to additionally participate in the studies related to chronic LFP recordings. The study was approved by the local ethics committee. Medtronic provided all materials and software under a research agreement.

Results: There was no significant modulation of STN beta band power, neither by the motor task nor by Levodopa. STN-EMG coherence in the lower beta band (10-20Hz) was suppressed by alternating movements irrespective of the dopaminergic state (tonic vs. alternate: motor OFF: p<0.0001, motor ON: p=0.0001; Mann-Whitney-Test). In medicated patients there was significantly stronger coupling compared to motor OFF (tonic, motor OFF vs. motor ON: p=0.0123).

Conclusions: Long-range beta band synchronisation between STN and spinal motoneurons may subserve the control of sustained postures and is facilitated by dopamine. This challenges the hypothesis of beta band activity to be a state or disease marker in PD.

113

Mid-life milk consumption and substantia nigra neuron density at death

G.W. Ross, R.D. Abbott, H. Petrovitch, K.H. Masaki, L.J. Launer, L.R. White, J. Nelson, C.M. Tanner (Honolulu, HI, USA)

Objective: The purpose of this report is to examine the association between mid-life milk intake and substantia nigra (SN) neuron density in brains from an unselected series of deceased Honolulu-Asia Aging Study participants.

Background: The bioaccumulation of organochlorine pesticides in milk may partially explain findings of an association between the intake of dairy products and the incidence of Parkinson's disease (PD). Whether this association exists with early nigral degeneration, a pathological hallmark of PD, is unknown.

Methods: Data on milk intake were collected in the Honolulu Heart Program from 1965 to 1968 in 449 men aged 45 to 68 years with later postmortem examinations. Autopsies were performed from 1992 to 2004. Neuron density (count/mm2) was measured in quadrants from a transverse section of the SN. Measures also included brain residues of heptachlor epoxide, an organochlorine pesticide reported to be found at excessive levels in the milk supply in Hawaii.

Results: Neuron density in all quadrants was lowest in nonsmoking decedents who consumed the most amounts of milk (>16 oz/d). After removing cases of PD and dementia with Lewy bodies, adjusted neuron density in all but the dorsomedial quadrant was 41.5% lower for milk intake >16 oz/d versus intake that was less (95% confidence interval: 22.7-55.7%, p<0.001). Among those who drank the most milk, residues of heptachlor epoxide were found in almost all brains (9/10) as compared to 63.4% (26/41) for those who consumed no milk (p=0.017). For past and current smokers, an association between milk intake and neuron density was absent.

Conclusions: Milk intake is associated with neuronal loss in the SN even among brains from participants unaffected by PD. While these results support the idea that contamination of milk with organochlorine pesticides may cause SN degeneration, more study is needed.

114

Exploring Fyn as a novel molecule in levodopa induced dyskinesias

S. Sanz-Blasco, E. Avale, S. Campana, A. Damianich, M.D. Saborido, G. Gomez, I.R. Taravini, O.S. Gershanik, J.E. Ferrario (Buenos Aires Capital Federal, Argentina)

Objective: To determine the role of the kinase Fyn in levodopa induced dyskinesias.

Background: The administration of L-DOPA is the most effective symptomatic pharmacological therapy for Parkinson's disease (PD). Despite its benefits, most patients develop side effects known as L-DOPA induced dyskinesias (LID). One of the current great challenges in PD therapy is to control LID. To reach this goal it is necessary to better understand the multiple cellular and molecular mechanisms that take place during LID. Although some protein and gene changes have been described within the dyskinetic striatum, the functions and/or mechanism in which they are involved are not fully understood. In our laboratory we have shown that Pleiotrophin and its receptor RPTPz/b are upregulated as a consequence of dopaminergic cell loss and L-DOPA treatment. RPTPz/b belongs to the post synaptic density complex, where it interacts with PSD95 and regulates the protein kinase Fyn, a key molecule in postsynaptic signaling and reorganization. Several evidences suggest Fyn as a potential candidate involved in LID.

Methods: We have determined the amount of Pleiotrophin immunopositive neurons and analyzed the amount of Fyn protein and its phosphorylation state by western blot in striata of dyskinetic rats. Also, we have developed the model of LID in both Fyn knock-out (KO) and WT mice, in which we have performed behavioral tests, determined abnormal involuntary movements (AIMs) and performed histological determinations such as tyrosine hydroxylase and FosB/ΔFosB.

Results: We found that the number of PTN positive neurons is increased and that Fyn is highly phosphorylated in the striatum of dyskinetic rats, while Fyn KO mice show a significant reduction in the development of AIMs in comparison to WT controls.

Conclusions: Our data suggest that Fyn might be involved in the development of LID, yet further work is still necessary to determine the mechanism in which it may be involved and if it could be targeted to control LID.

115

Uric acid levels and disease duration in REM sleep behavior disorder and Parkinsonian syndromes

M. Schiess, J. Suescun, B. Copeland, T. Ellmore, E. Furr-Stimming, R. Castriotta (Houston, TX, USA)

Objective: Compare uric acid (UA) levels between presymptomatic REM sleep behavior disorder (RBD) subjects with idiopathic Parkinson's disease (iPD), Parkinson's Syndrome (PS) and age-matched control subjects. Determine the role of UA in disease progression by comparing measures over time between groups.

Background: UA is a recognized risk factor for the development of iPD with clinical evidence supporting its actions as a CNS antioxidant with neuroprotective potential in preventing the progression of motor symptoms. There is little information on how UA behaves in the high risk prodromal idiopathic RBD patient and whether UA levels could be manipulated in order to confer neuroprotective potential in preventing the development of PD.

Methods: Prospective, longitudinal case-control study with intent to follow at 6-month intervals 37-85 year old men and women; 28 early to moderate iPD, 21 RBD, 19 PS and 18 age-matched Control subjects. A single-night video polysomnogram was performed at baseline and all visits included neurological and cognitive exams, Unified Parkinson's Rating Scale, Hoehn & Yahr, PDQ-39 survey and plasma UA levels. The primary outcome was measurement of plasma UA levels with comparison between groups; secondary outcome was measurement of plasma UA levels over time with comparison between groups and correlations between disease duration, rating scales, disease disability and quality of life.

Results: Significantly lower UA levels were observed in male PD subjects,mean 4.54 mg/dl, compared to Controls, PS and RBD. A significant lower prevalence of PD was found in the 3rd and 4th quartiles (higher level of UA) (OR: 0.20, 95%CI: 0.047- 0.837; OR: 0.028, 95% CI: 0.029-0.277, p<0.01). There was a significant negative correlation between UA levels and disease duration in the RBD subjects, PD and PS subjects (p < 0.01), r-values= -0.50, -0.28, -0.3. There were no significant differences between groups for female subjects.

Conclusions: Our study results confirm previous findings of a relationship between low UA and PD in men, and indicate low levels of UA in RBD but not PS subjects. The negative correlation between disease duration and UA levels found in RBD, PS and PD, suggests a risk for RBD subjects to convert to PD based on declining UA levels over time. Our results support targeting UA levels in RBD subjects as a disease risk modifier to develop PD.

116

Beta band oscillatory activity in the subthalamic nucleus is not correlated with levodopa motor improvement in patients with Parkinson's disease

E. Sellaiah, A. Buot, S. Fernandez Vidal, M.L. Welter, C. Karachi, B. Lau (Paris, France)

Objective: To identify correlations between changes in subthalamic nucleus (STN) local field potential (LFP) power in the 8-35 Hz frequency band and motor improvement in Parkinson's disease (PD) patients highly responsive to levodopa.

Background: Recordings in the STN of PD patients during deep brain stimulation (DBS) procedures have revealed excessive oscillatory beta band activity (8-35Hz), which is reduced by levodopa treatment (Brown et al., 2001). One hypothesis is that the degree of reduction in oscillatory beta activity on levodopa is causally related to the degree of improvement in Parkinsonian bradykinesia and rigidity (Eusebio & Brown, 2009). However, the significance of these changes in beta activity remains controversial.

Methods: We included 27 PD patients selected for DBS between 2009 and 2014 (mean age 59 years). Mean preoperative UPDRS III scores were 36.6 OFF levodopa and 9.5 ON levodopa, with a mean improvement ON levodopa of 75.8% (all patients >45%). We recorded STN LFPs OFF and ON levodopa 4 days after DBS surgery. We tested for correlations between clinical change and beta power change by selecting for each side the contact pair with the maximum power between 8-35Hz OFF levodopa and calculating a percentage change using the same frequency ON levodopa. We measured clinical change using hemibody scores for bradykinesia and rigidity contralateral to each selected contact.

Results: We did not find significant correlations between levodopa-induced beta power suppression and clinical change (p>0.05), nor did we find significant correlations when using average power between 8-35Hz to define beta power change. Finally, a direct search for correlations at each frequency in the 8-35Hz range revealed a significant reduction in beta power ON levodopa (10-25Hz, p<0.001), but did not yield any significant correlations between clinical scores and LFP power at any frequency in this band ON or OFF levodopa (p>0.1).

Conclusions: Our results do not support the hypothesis that reductions in STN oscillatory activity in the 8-35 Hz range are causally linked to levodopa motor improvement in PD patients who are highly responsive to levodopa treatment. This highlights the difficulty in understanding the link between STN beta oscillatory activity and levodopa responsiveness, as well as the role of beta oscillations in the pathophysiology of PD.

117

Beneficial effects of histone deacetylase inhibition in 6-OHDA induced behavioral and biochemical abnormalities in rats

S. Sharma, R. Taliyan (Pilani, India)

Objective: To evaluate the therapeutic potential of HDAC inhibitor, Trichostatin A in 6-OHDA induce Parkinson's disease (PD) in rats.

Background: Recent studies have investigated the involvement of epigenetic modifications in PD. Histone acetylation regulates the expression of various neuroprotective genes. Reduced histone acetylation has been reported in PD. Therefore, we hypothesized that elevating histone acetylation by HDAC inhibition could prove to be beneficial in PD.

Methods: To produce motor deficit, 6-OHDA was administered unilaterally in rats. These animals were then treated with HDAC inhibitor, trichostatin A (TSA) for 2 weeks. Motor performance was evaluated using narrow beam walk test, rotarod activity and wire suspension task. Biochemically oxidative stress and neuroinflammatory markers were evaluated. To explore the molecular mechanism and to confirm the involvement of HDACs, we measured the level of histone acetylation.

Results: 6-OHDA administration results in motor deficits along with significant elevation in oxidative stress and neuro-inflammatory markers in rat striatum. Treatment with HDAC inhibitor, TSA, results in significant improvement in motor performance and rotarod activity. Moreover, HDAC inhibition results in attenuation of oxidative stress and neuroinflammation.

Conclusions: Our data suggest that modulation of histone acetylation by HDAC inhibition could be beneficial in attenuation of oxidative stress and neuroinflammation in PD. Thus, we conclude that HDAC inhibition could be a novel approach to treat PD.

118

Patterns of peripheral immune activity in prodromal asymptomatic and symptomatic Parkinsonism

K.C. Smith, J.S. Ocampo, D.L. Bick, M.C. Schiess (Houston, TX, USA)

Objective: To identify and compare cytokines associated with innate and adaptive immune response in idiopathic Parkinson's disease (PD), asymptomatic prodromal REM sleep behavior disorder (RBD) subjects, and age-matched controls, and to determine changes of these cytokines over time and with duration of disease (DOD).

Background: There is evidence that neuroinflammation plays a role in PD pathogenesis. RBD is recognized as a prodromal stage along the PD spectrum, however, neuroinflammatory response in RBD subjects has not been demonstrated.

Methods: PD (N = 16), RBD (N = 14), and age-matched control (N = 13) subjects were enrolled in a longitudinal biomarker study and underwent exams and blood draw every 6 months. Concentrations of 37 different cytokines/chemokines were determined using a Millipore Multiplex MAP kit. Log-rank, linear regression with Spearman's correlation, and multivariant logistic regression analyses were employed to compare trends in cytokine secretions between groups.

Results: Overall plasma concentrations of 11/37 cytokines were increased in RBD subjects; only three of these were also increased in PD subjects compared to controls. IL-6,IL-1α, and IL-1RA, which are associated with inflammation were significantly increased in RBD but not PD subjects. Cytokines associated with Th2 adaptive immune response including IL-4 and IL-5 were most significantly increased in RBD and PD. Evaluation of cytokine secretion by individual subjects over time revealed that ∼50% of PD and RBD subjects expressed consistently high levels of cytokines. [figure1] The monocyte-associated chemokines CCL4 and CCL22 positively correlated with DOD in RBD subjects, while both inflammatory and lymphocyte-associated cytokines decreased over DOD in the PD group. Subject age affected cytokine production in the PD but not the RBD group.

Conclusions: These results provide evidence for increased innate and adaptive immune activation in asymptomatic RBD subjects as well as in symptomatic PD subjects. Inflammation and lymphocyte-associated cytokines as well as monocyte attracting chemokines remained steady or slightly increased with increasing DOD in RBD subjects, in contrast to the decreased secretion of cytokines observed over DOD in PD subjects. These results support the concept of an evolving role for the immune system in the spectrum of the neurodegenerative process that can be detected in peripheral blood.

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(118).

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(118).

119

Isradipine rescues alpha-synuclein toxicity in a zebrafish model of Parkinson's disease by upregulating autophagy

M.C. Stahl, S. Prabhudesai, A. Lulla, J. Bronstein (Hershey, PA, USA)

Objective: To investigate the effect of isradipine, an L-type calcium channel blocker of the dihydropyridine class, on a genetic model of Parkinson's disease pathology in zebrafish.

Background: Epidemiological data support the potential disease-modifying effect of exposure to dihydropyridine calcium channel blockers in Parkinson's disease. Prior studies suggest this effect may be mediated through modulation of calcium toxicity in “pacemaker” dopaminergic neurons, despite the presence of Lewy pathology in other neuron types. Meanwhile, several L-type calcium-channel blockers have also been shown to induce autophagy, the lysosome-dependent process by which cells dispose of damaged organelles and protein aggregates. This process, implicated in a range of neurodegenerative disease, can dispose of toxic oligomers of alpha-synuclein.

Methods: Zebrafish overexpressing human alpha-synuclein were treated with isradipine and the effects on overall survival, induction of autophagy, and synuclein accumulation were measured. These results were also compared to those obtained in zebrafish in which autophagy was inhibited by morpholino knockdown of the autophagy-related protein LC3.

Results: Isradipine treatment upregulated autophagy as assessed by GFP-LC3 and significantly improved the survival of alpha-synuclein overexpressing zebrafish. The rescue was abrogated by knockdown of LC3.

Conclusions: Isradipine treatment rescues neuronal toxicity in an alpha-synuclein overexpression model of Parkinson's pathology in an autophagy-dependent fashion.

120

Alpha-synuclein immunohistochemistry studies in gastrointestinal tissue from preclinical Parkinson's disease patients

M.G. Stokholm, E.H. Danielsen, S.J. Hamilton-Dutoit, P. Borghammer (Aarhus, Denmark)

Objective: (1) To determine the distribution of pathological aggregated α-synuclein (α-syn) and phosphorylated α-synuclein (p- α-syn) in the peripheral nervous system of both PD patient's and preclinical PD patient's. (2) To examine any differences in the distribution between pathological aggregated α-syn and pathological p-α-syn in the peripheral nervous system.

Background: It is hypothesized that α-syn pathology is initiated in the enteric nervous system 10-20 years prior to debut of motor symptoms and enters the CNS through preganglionic fibers originating in the dorsal motor nucleus of the vagus nerve.

Using different immunohistochemistry techniques recent studies showed α-syn in the gastrointestinal tract of preclinical PD patients, PD patients, and healthy controls with variable results.

Methods: Tissue material removed several years prior to PD diagnosis and post diagnosis time was included. We included 120 different tissue blocks from 67 patients diagnosed with PD and 116 tissue blocks from 116 matched control subjects. The tissue included; nasal mucosa, oral mucosa, salivary gland, esophagus, ventricle, small intestine, appendix, and colon. Aggregated α-syn and p-α-synuclein was visualized using immunohistochemistry with Proteinase K pre-treatment and antibodies against p-α-syn. The distribution of α-syn was evaluated on one single slide from each tissue block.

Results: Aggregated α-syn was found in 56,7% of the PD cases compared to 42,2% of the control cases (p=0.0267; Chi-square test).

Cases with tissue material from surgical resection containing submucosal or myenteric ganglia more frequently displayed positive immunoreactivity compared to superficial mucosa biopsies.

In the individual organs, a near-significant between-group difference was seen in the colon (p=0,054; Fisher's Exact Test).

Staining for phosphorylated α-synuclein is pending.

Conclusions: This study demonstrated that significantly more pathological aggregated α-synuclein was present in the gastrointestinal tract of preclinical PD patients compared to matched controls.

121

Premorbid exercise engagement and motor reserve in Parkinson's disease

M.K. Sunwoo, J.E. Lee, J.Y. Hong, B.S. Ye, H.S. Lee, J. Oh, J.S. Kim, P.H. Lee, Y.H. Sohn (Seongnam, Korea)

Objective: We investigated whether the amount of premorbid exercise engagement affects the relationship between striatal dopaminergic depletion and severity of motor deficits in early, drug-naïve, patients with PD.

Background: The concept of the cognitive reserve (CR) explains the differences between individuals in their susceptibility to age-related brain changes or pathologies related to Alzheimer's disease (AD). An enhanced CR may slow cognitive aging, reduce the risk of dementia, and lead to less cognitive deficits despite severe pathological lesions. Parkinson's disease (PD) is mainly characterized by motor dysfunction related to striatal dopaminergic depletion. Similar to the concept of the CR in relation to neurodegenerative disorders, we hypothesize the presence of the motor reserve (MR) in relation to PD; the MR can explain individual differences in motor deficits despite similar pathological changes.

Methods: We assessed the degree of engagement in premorbid leisure exercise in 102 drug naïve PD patients who had been initially diagnosed at our hospital by dopamine transporter scanning. Patients were classified into the tertile groups based on the frequency, duration, and intensity of the exercises engaged.

Clinical characteristics and dopamine transporter activity in the posterior putamen
Lowest tertile (n=34) Middle tertile (n=34) Highest tertile (n=34) p-value
Age (years) 62.2 ± 10.9 62.5 ± 9.0 64.0 ± 8.2 0.714
Gender (% men) 32.4 41.2 73.5 0.002
Symptom duration (years) 1.6 ± 1.9 1.3 ± 1.1 1.1 ± 0.7 0.349
Education duration (years) 9.0 ± 5.8 10.1 ± 5.3 11.8 ± 4.7 0.114
MMSE score 26.9 ± 3.0 27.0 ± 2.3 27.3 ± 2.2 0.763
BDI score 13.7 ± 9.3 14.7 ± 12.9 13.8 ± 9.4 0.920
UPDRS-motor score 22.1 ± 8.4 24.7 ± 10.9 22.3 ± 11.0 0.503
BPnd in the posterior putamen 1.27 ± 0.41 1.15 ± 0.36 1.14 ± 0.40 0.364
  • Data are means ± standard deviations; UPDRS, unified Parkinson's disease rating scale; BPnd, non-displaceable binding potential of dopamine transporter activity.

Results: When the striatal dopaminergic activity reduction was mild to moderate (above the median dopaminergic activity), the highest tertile group showed significantly lower motor scores (15.53 ± 6.25) despite similar degree of dopamine reduction compared to the other groups (21.57 ± 8.34, p = 0.01), but showed a more rapid decline in motor function in relation to the reduction of striatal dopaminergic activities (p = 0.002 with the middle tertile group and p = 0.001 with the lowest tertile group).

Interaction effect between the exercise group and dopamine transporter activity in the posterior putamen
Unadjusted Adjusted‡
B (S.E.) p-value B (S.E) p-value
BPnd -18.99 (4.43) <0.001 -23.78 (5.02) <0.001
Exercise group
Highest tertile Reference Reference
Middle tertile -15.50 (7.86) 0.052 -22.47 (8.13) 0.007
Lowest tertile -19.52 (7.86) 0.015 -26.01 (8.41) 0.002
Interaction effect†
BPnd*Highest tertile Reference Reference
BPnd*Middle tertile 15.34 (6.15) 0.014 21.80 (6.81) 0.002
BPnd*Lowest tertile 14.77 (5.85) 0.013 22.04 (6.59) 0.001
  • B, estimated slope; S.E., standard error; BPnd, non-displaceable binding potential of dopamine transporter activity in the posterior putamen; Model I analysis is a general linear model for UPDRS motor score using BPnd and exercise group as predictors; Model II analysis is a general linear model to investigate the interaction effect between BPnd and exercise group in the Model I analysis; †, interaction effect between the exercise group and BPnd; ‡, adjusted for age, gender, symptom duration, education duration, and MMSE score.

[figure1]

Conclusions: These results suggest that premorbid exercise engagement acts as a proxy for an active reserve in the motor domain (i.e., motor reserve) in patients with PD.

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122

Relationship among degeneration of the cardiac sympathetic nerve, clinical features and neuropathological findings in dementia with Lewy bodies

M. Takahashi, A. Nakamura, T. Uchihara, M. Yoshida, K. Wakabayashi, A. Kakita, H. Takahashi, S. Orimo (Tokyo, Japan)

Objective: To examine the relation among degeneration of the cardiac sympathetic nerve (CSN), clinical features and neuropathological findings in dementia with Lewy bodies (DLB).

Background: Reduced MIBG uptake is a useful diagnostic biomarker to differentiate DLB from other dementia. However, MIBG uptake is occasionally preserved in patients with DLB.

Methods: In this study, we immunohistochemically examined heart tissues from 58 subjects with pathologically-verified DLB (limbic and neocortical type) to see whether there are subjects with preserved CSN. We quantified tyrosine hydroxylase and neurofilament immunoreactive axons in epicardial nerve fascicles and examined the relationship among degeneration of the CSN, clinical features and neuropathological findings.

Results: All the subjects showed degeneration of the CSN. However, 4 subjects showed relatively preserved CSN. Their clinical diagnoses were Alzheimer disease (AD)(2) and DLB (2), and the mean disease duration was 4.9 years (4.5-6). Neuropathologically, Lewy pathology was neocorical type in 3 subjects and limbic type in one subject. In 3 subjects of neocortical type, AD pathology (Braak & Braak stage and senile plaque stage) was strong, but in one subject of limbic type, AD pathology was weak.

Conclusions: These findings suggest degeneration of the CSN occurs in DLB, whereas a few subjects show relatively preserved CSN, who are subjects with short disease duration.

123

Evaluation of neural connectivity between parvalbumin-expressing interneurons and medium spiny neurons in the lesioned striatum of dyskinetic mice

I.R. Taravini, G. Gomez, M.V. Escande, M.G. Murer, O.S. Gershanik (Ciudad Autónoma de Buenos Aires, Argentina)

Objective: To establish whether the development of dyskinesias induced by L-DOPA modifies the connectivity of parvalbumin-expressing interneurons with medium spiny neurons in the lesioned striatum of transgenic mice expressing fluorescent proteins under the control of the D1 and D2 receptor promoter.

Background: Dyskinesias are a debilitating side-effect of chronic L-DOPA administration, despite of which, the drug remains as the gold standard for symptomatic treatment of Parkinson's disease (PD). Abnormal stimulation of dopaminergic receptors by L-DOPA correlates with long-term functional synaptic changes in striatal medium spiny neurons (MSNs) deprived of dopaminergic innervations which may contribute to the development of dyskinesias (LID). Parvalbumin striatal interneurons modulate and control differentially the activity of MSNs expressing either D1 or D2 receptors and therefore contributing to the imbalance between these pathways both in PD and LID. However, the state of the connectivity between these cell populations in the dyskinetic condition remains elusive.

Methods: Transgenic mice expressing red (tomato) or green (EGFP) fluorescent markers in striatal neurons containing either the D1 or D2 receptor promoter were lesioned unilaterally with 6-OHDA in the mfb and treated with L-DOPA to induce severe dyskinesias. Parvalbumin was determined by immunofluorescence on fixed striatal tissue sections using Cy5 as fluorochrome. The number of synaptic contacts of parvalbumin positive terminals on D1 or D2 MSNs was quantified on confocal microphotograph using the ImageJ software (NIH).

Results: Lesioned mice developed severe dyskinesias after L-DOPA administration. Preliminary results show that the number of perisomatic parvalbumin synapses on D1 and D2 MSNs remains unaltered after 6-OHDA lesion. Conversely, a dyskinetogenic dose of L-DOPA reduces the number of parvalbumin contacts onto D2 but not D1 MSNs.

Conclusions: These results suggest that L-DOPA affects the synaptic connectivity of parvalbumin interneurons with both types of MSNs differentially. These are clear evidences that L-DOPA treatment induces alterations at structural and functional levels that lead to a new pathophysiologic condition in the basal ganglia circuits. Further analysis will help to clarify if these structural adaptations are directly related to the development of dyskinesias.

124

Cognitive dysfunction due to over-expression of alpha-synuclein in hippocampus by using viral vector based approach: Modeling cognitive decline in PD

B. Tel, G. Yalcin Cakmakli, E. Cinar, S.U. Mutluay, G. Telli, E. Saka, A. Ulusoy, B. Elibol (Ankara, Turkey)

Objective: In this study, we aimed to reproduce the cognitive decline observed in the majority of PD patients at different stages, in the AAV (adeno-associated virus) mediated alpha-synuclein (a-syn) over-expression model by stereotactic viral injection into the dentate gyrus of hippocampus (DG). This will allow us to better understand the behavioral correlates of PD as in the natural course of the disease.

Background: In PD, pathological intracellular aggregation of a-syn plays a key role in the neurodegenerative process. There is strong evidence showing that non-motor findings including cognitive dysfunction, are related to the spread of a-syn pathology from the lower brainstem to the cortex.

Methods: In female Wistar rats (200-250g), AAV carrying either a-syn or green fluorescent protein (GFP) gene were stereotactically injected into DG either unilaterally (n= 6 a-syn, 3 GFP) or bilaterally (n= 5 a-syn, 3 GFP). The animals were tested with novel object recognition test (NOR) for memory; Morris water maze (MWM) for spatial learning; elevated plus maze (EPM) for anxiety between week 13-16. The intensity of a-syn aggregates/GFP in hippocampi and possible neuronal loss were evaluated by a-syn, GFP and NeuN immunohistochemistry.

Results: The well-known PD model induced by AAV mediated a-syn over-expression in substantia nigra has been successfully realized in our laboratory before. In this study, we have detected marked short-term memory dysfunction in the unilateral DG a-syn group compared to GFP (p<0.05) but this difference did not reach significance in the bilateral DG a-syn group. The results of MWM and EPM did not show any statistical significant difference between groups. We observed a-syn and GFP over-expression at each injection site, the intensity of a-syn staining did not correlate with behavioral test results. NeuN staining showed no significant neuronal loss either in the a-syn or GFP group. Therefore, the functional loss which is prominent in short-term memory is thought to be due to synaptic dysfunction which takes place just before neuronal death.

Conclusions: Hippocampal AAV-mediated a-syn over-expression may be a promising model to study the cognitive dysfunction seen in PD. Our future plans are to increase the number of animals in each group and to study the synaptic changes which are thought to be responsible from the functional loss.

125

Sequence effect (SE) in Parkinson's disease (PD) is dopamine-independent and improves with visual feedback

S. Tinaz, A. Pillai, M. Hallett (Bethesda, MD, USA)

Objective: (1)To better characterize SE, (2) assess its response to dopamine and visual feedback systematically, and (3) examine its relationship to motor impairment, fatigue, and mood.

Background: SE is a feature of bradykinesia and refers to the rapid decrement in speed and amplitude of sequential movements in PD. It impairs many motor functions, e.g., handwriting, voice, and gait. SE does not seem to respond to dopamine, but SE in gait improves with visual feedback. Loss of motor energy, underscaling of movements, and central fatigue are proposed mechanisms.

Methods: We tested 12 right-handed, non-demented PD patients (5 females) with mild-to-moderate bilateral disease (6 left- and 6 right-onset) and 12 right-handed matched healthy volunteers (HV) (6 females) on an isometric motor task using a hand-clench dynamometer. Participants squeezed the dynamometer repetitively to a metronome cue at 1.25 Hz and at 50% of their maximum force (F50) for ∼ 90 s. The initial 30 s segment was analyzed.

All participants performed the task with both hands, first without visual feedback (VF-) relying on perceived effort required for F50, then with VF (VF+) trying to match the F50 target on the computer screen. PDs were tested twice: (1) After at least 12-hr washout of dopaminergic medication (“off”) and (2) at the peak of dopaminergic effect (“on”). We also administered the Beck Depression and Spielberger Anxiety Inventories to all participants, and the Unified PD Rating and Fatigue Severity Scales to PDs.

Results: The mean age was 63 (± 6.4) for PDs, and 62.75 (± 6.9) for HVs. PDs demonstrated significantly higher state anxiety and depression scores compared to HVs. Dopamine significantly improved overall disability and motor functioning in PDs.

Clinical Data
Group BDI STAI-S STAI-T FSS UPDRS total off/on UPDRS motor off/on
HV 1.9 (3.2) 22.2 (2.8) 26.8 (7.3) - - -
PD 7.0 (3.1) 29.3 (9.2) 34 (10.2) 39.8 (11.4) 52.2 (8.5)/39.1 (10.9) 32 (4.8)/23.4 (6.9)
  • Mean and (SD) values. BDI: Beck Depression Inventory, STAI: Spielberger S: State T: Trait Anxiety Inventory, FSS: Fatigue Severity Scale, UPDRS: Unified Parkinson's disease Rating Scale

PDs showed a stronger negative slope in the on/VF- condition for both hands (left > right) compared with HV. [figure1] Higher starting F50 correlated with steeper negative slope in both groups. VF improved the slope in both groups. Medication had no effect on the slope in PDs. Left-hand slopes correlated positively with STAI-T and FSS in the off/VF- and with STAI-T in the on/VF- conditions in PDs.

Conclusions: SE is observed within 30 s in a repetitive isometric task in PD. Medication increases initial motor energy, but does not improve SE. Only VF improves SE. Elevated perception of anxiety and fatigue may lead to overcompensation.

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(125).

126

Connectivity of pedunculopontine and sub-thalamic nuclei in patients with Parkinson's disease

C.H. Tsai, Y.T. Hsu, H.Y. Lai, S.M. Chiou, M.K. Lu, Y.C. Lin, Y.Y. Chen (Taichung, Taiwan)

Objective: To investigate: 1. through which frequency band(s) are the two nuclei bridged? 2. Which nucleus leads the other one if there is functional connectivity between them?

Background: There is anatomical connectivity between sub-thalamic nucleus (STN) and pedunculopontine nucleus (PPN) in humans. However, the functional linkage between the two has not been fully explored.

Methods: Three patients with Parkinson's disease (PD) underwent bilateral STN and left PPN deep brain stimulation (DBS) were recruited for the investigation on the 2nd day after operation. The local field potentials (LFPs) were recorded from the externalized electrodes in resting states during patients’ ‘off’ and ‘on’ states . The coherence and cross-power spectral density estimates were conducted for signal analysis.

Results: There is a strong coherence at alpha frequency between STN and PPN LFP. The analysis of phase spectra over the alpha frequency showed significant coherence between STN and PPN and PPN led STN at this frequency by 5.9, 7.3 and 5.1 ms, respectively, in three subjects were detected. After levodopa treatment, the leading time increased in subject 2 and 3 (13.7 and 9.5 ms).

Conclusions: There is functional connection between PPN and STN with PPN in leading position through alpha frequency band in PD. Levodopa administration lengthened the leading time of PPN. It seems that the increase of dopamine levels may open another route, probable via basal ganglia, for the connection of the two nuclei and this lead to a longer duration for the cross talk to occur.

127

In silico drug discovery for Parkinson's disease by using genome-wide association study (GWAS) data

T. Uenaka, W. Satake, C.P. Chieng, Y. Okada, T. Toda (Kobe, Japan)

Objective: To discover neuroprotective drugs for sporadic Parkinson's disease (PD).

Background: Sporadic Parkinson's disease (PD) is a complex disorder caused by multiple genetic risk factors. Twenty four risk loci for sporadic PD were reported from a meta-analysis of Caucasian genome-wide association studies (GWAS) (Nalls MA et al, Nature Genet 2014). Although those data from GWAS have provided valuable biological insights, the translation of the genetics findings from GWAS into the clinic remains limited. A new method of drug discovery utilizing risk genes and computational database was proposed in rheumatoid arthritis (Okada Y et al, Nature 2014). We applied this method to discovery of drugs for sporadic PD.

Methods: We obtained 871 drug target genes from drug databases (DrugBank and Therapeutic Target Database). Using a protein-protein interaction (PPI) database, we extracted genes which show PPI with PD-risk genes reported by GWAS.

Results: We detected 761 genes as 24 PD-risk genes and its PPI-genes. Among those, using drug databases, we found 77 genes which are targeted by 54 approved-drugs for other diseases.

Neuroprotective effects in vitro or in vivo had been already reported in 16 of those 54 approved-drugs (∼30%), including raloxifene, an approved-drug for osteoporosis. In order to examine whether these drugs have neuroprotective effects, we performed LDH assay and cell viability assay using SH-SY5Y cells with exposure of rotenone. We confirmed a neuroprotective effect of raloxifene in LDH assay. Furthermore, we found that 2 drugs significantly improved LDH release (p=0.01) and cell viability (p=0.01) under the condition of rotenone exposure, which suggests that these 2 drugs have a neuroprotective effect.

Conclusions: In silico drug discovery using GWAS-data is an efficient manner to extract candidates of neuroprotective drugs for PD.

128

Postural instability and gait disorder subtype in early to mid-stage Parkinson's disease: Beyond axial motor control impairment

G. Vervoort, A. Bengevoord, E. Nackaerts, E. Heremans, W. Vandenberghe, A. Nieuwboer (Leuven, Belgium)

Objective: To clarify the validity of PD subtypes by investigating behavioral outcomes at multiple levels.

Background: Clinical subtypes in Parkinson's disease (PD) are founded on the heterogeneity of symptoms and are based on the presence of clustered motor symptoms. The postural instability and gait disorder (PIGD) subtype is associated with rapid disease progression, predominantly axial motor involvement and increased cognitive impairment while the tremor dominant (TD) subtype is characterized by slow disease progression and the presence of significant tremor. It is, however, unclear if subtypes represent distinct underlying pathologies or rather are a reflection of disease progression.

Methods: 73 patients and 20 age-matched controls were recruited for this study. Patients were classified as PIGD (n=43), TD (n=22) or indeterminate (n=8) based on MDS-Unified Parkinson's disease rating scale (UPDRS) III scores. Patients in the indeterminate group were excluded Spatiotemporal kinematics of gait, upper and lower limb repetitive movements in combination with a balance and cognitive assessment were recorded while ‘off’ medication.

Results: Surprisingly, PIGD patients only had gait impairment in few parameters, i.e. reduced step length and gait speed compared to TD patients. In contrast, impairments in postural control and cognition were present across the board as shown by lower scores on the mini-BESTest and the Frontal Assessment Battery (FAB) and trail making test (TMT) B in PIGD patients compared to controls. Motor scaling and coordination of distal movements were impaired in PIGD compared to TD patients during foot and finger tapping. TD patients were not significantly different from controls, except for a greater asymmetry of repetitive movements.

Conclusions: These results indicate a widespread motor impairment within the PIGD group that is not restricted to axial motor control, but also involves distal motor control. These findings suggest refining the PIGD subtype to a more complex motor profile.

129

Salivary alpha-synuclein: A new biomarker for Parkinson's disease?

G. Vivacqua, A. Latorre, M. Nardi, A. Suppa, G. Fabbrini, C. Colosimo, A. Berardelli (Rome, Italy)

Objective: To investigate whether salivary monomeric and oligomeric alpha-synuclein (a-syn) concentration can differentiate Parkinson's disease (PD) patients from healthy controls.

Background: Increasing evidence support the hypothesis that a-syn, a 140 aminoacids protein closely related to the pathogenesis of PD, might be considered a biomarker for the diagnosis and follow-up of PD. In addition to cerebrospinal fluid (CSF), a-syn can be easily detected in several extra-neuronal tissues and biological fluids including saliva.

Methods: We collected salivary samples from 26 PD patients and 26 age- and sex-matched healthy subjects. Patients were recruited from the Movement Disorder clinic of “Sapienza” University of Rome. PD patients were clinically evaluated before starting each experimental session. Motor signs were scored using the motor section of the Unified Parkinson's disease Rating Scale (UPDRS) and the Hoehn & Yahr (H&Y) scale. Non-motor symptoms were evaluated by Non Motor Symptoms Assessment Scale (NMSS) and Hamilton Depression Rating Scale (HDRS). Cognitive functions were tested by Montreal Cognitive Assessment (MOCA) and Frontal Assessment Battery (FAB). Samples of saliva were collected and immediately centrifugated at 5000 x g for 20 minutes, followed by a further centrifugation at 15000 x g for other 20 minutes. Supernatant was pre-treated with a buffer inhibiting protease activity (Sigma Aldrich, St.Luis, MO, USA, Cat # P2714, concentration: 100 μL for 1 ml salive). Samples were subsequently analyzed by specific anti-monomeric and anti-oligomeric a-syn ELISA kits (SensoLyte Anti-alpha-Synuclein Quantitative ELISA and Rabbit a-syn oligomer ELISA kit).

Results: Compared with healthy subjects, PD patients have a significantly reduced concentration of salivary monomeric a-syn (p<0.01). By contrast, oligomeric a-syn concentrations in PD patients resulted similar to those observed in healthy subjects. For each patient correlation between biochemical and clinical evaluation have been performed.

Conclusions: The observation that monomeric a-syn is significantly reduced in salivary samples of patients with PD might be interpreted as a result of a-syn aggregation in PD. Finally, salivary oligomeric a-syn concentration is comparable in PD and healthy subjects probably because in PD, a-syn aggregation is not only due to free a-syn oligomers but also to intracellular aggregation of the protein.

130

Can we predict motor subtype fidelity in patients with tremor-dominant Parkinson's disease?

R. von Coelln, E. Barr, A.L. Gruber-Baldini, S.G. Reich, M.J. Armstrong, B. Hanna-Pladdy, L.M. Shulman (Baltimore, MD, USA)

Objective: To identify predictors of whether Parkinson's disease (PD) patients initially classified as tremor-dominant (TD) later convert to the postural instability/gait difficulty (PIGD) or indeterminate (ID) motor subtype of PD.

Background: TD, PIGD, and ID are commonly-used PD motor subtypes. Stability of these subtypes over time and predictors of subtype fidelity have not been studied systemically. Identifying valid and stable subtypes is important for future biomarker-phenotype correlation studies.

Methods: We performed a longitudinal analysis of 183 PD patients, applying an established PD motor subtype algorithm (Jankovic 1990) at baseline (within 5 yrs of diagnosis) and follow-up (FU) ≥ 5 yrs later. Patients classified as TD at baseline, but re-classified as PIGD or ID at FU, were compared to patients remaining in TD subtype at FU. We also compared the change in TD and PIGD scores from baseline to FU between the two groups. Logistic regression models evaluated predictors of subtype fidelity after controlling for time between study visits.

Results: At baseline, 103 out of 183 patients were classified as TD. At FU, 49% of those 103 TD patients were re-classified as PIGD, and 15% as ID (total of 64% converters). Only 36% of patients remained in the TD subtype (non-converters). Significant baseline predictors of TD subtype fidelity included younger age (57.5 vs. 60.9 yrs., p=0.04), higher TD score (0.75 vs. 0.57, p=0.02), and higher TD/PIGD ratio (3.3 vs. 2.6, p=0.05), but PIGD scores were not predictive (0.11 vs. 0.14, p=0.47). Between baseline and FU, the TD score increased in non-converters, while decreasing in converters (+0.18 vs. -0.21, p=0.0003). Increase in PIGD score (non-converters vs. converters: 0.18 vs. 0.86, p<0.001) and decrease in TD/PIGD ratio (-0.3 vs. -2.1, p=0.003) predicted conversion over time. Gender, disease duration, H&Y, MMSE, depression, anxiety (BSI-18), SF-12 health scores, and ADL/IADL disability (OARS) were not significant predictors of subtype fidelity.

Conclusions: Our data suggest that the TD subtype of PD is not stable over time. Older age and less severe tremor at baseline predicted conversion from TD to PIGD over ≥5 years. Conversely, increase of tremor over time, coupled with minimal progression postural and gait problems, predicted TD subtype fidelity. These results suggest two distinct subgroups of TD patients which might be relevant for biomarker-phenotype correlation studies.

131

Characterization of PINK1 knockin mouse model for Parkinson's disease

T.H. Yeh, C.C. Chiu, H.L. Wang, S.C. Lai, H.C. Chang, C.S. Lu (Taipei, Taiwan)

Objective: To generate PINK1 knockin mouse model to investigate the molecular mechanism of Parkinson's disease.

Background: Parkinson's disease (PD) is the most common neurodegenerative motor disorder. PINK1 is the second most frequent causative gene in early-onset PD, which is believed to regulate mitochondrial functions of dopaminergic neurons in substantia nigra pars compacta (SNpc). Clinical features exhibited by PINK1-mutation carriers are indistinguishable from those observed in sporadic PD patients. Thus investigating PARK6 mutant PINK1-induced Parkinsonism is important to unveil the common pathogenic mechanism of PARK6 and sporadic PD.

Methods: In this study, we generate PINK1-knockin mice expressing common PARK6 mutant (G309D). Homologous recombination was used to replace the exon 4 of Pink1 gene with mutated (G308D) exon 4 in embryonic stem (ES) cells in C57BL/6J genetic background which were injected into the C57BL/6-C2J blastocysts. Then, chimeric mice were mated with wild-type albino C57BL/6-C2J mice and bred to obtain F1 heterozygous mutant mice expressing PARK6 mutant (G308D). The LoxP-flanked neomycin selection cassette was removed by crossing the F1 mice with Pink1 knockin (G308D) allele with Cre deleter (EllA-Cre) transgenic mice to generate Pink1G308D/G308D homozygous mice. The behavior test and histopathology were performed.

Results: We have generated Pink1G308D/G308D homozygous knock-in mice. Similarly to motor signs displayed by PD patients, 12-month-old Pink1G308D/G308D knockin mouse exhibited an impaired motor performance and the phenomenon of bradykinesia. The homozygous Pink1G308D/G308D knockin mouse also exhibited progressive degeneration of SNpc dopaminergic neurons.

Conclusions: This humanized knockin mice expressing PARK6 mutant could be used for investigating the molecular pathogenesis of neurodegeneration caused by PINK1 mutations.

132

Vitamin D deficiency and endothelial dysfunction in Parkinson's disease

J.H. Yoon, S.W. Yong, J.M. Hong, J.S. Lee, I.S. Joo (Suwon, Korea)

Objective: To evaluate the relationship between serum 25-hydroxyvitamin D (25(OH) D) levels and flow mediated dilatation (FMD) in patients with a Parkinson's disease.

Background: In recent years, increasing evidence has shown that individuals with Parkinson's disease (PD) have lower levels of 25(OH) D relative to healthy controls. Vitamin D insufficiency is associated with endothelial dysfunction in human, irrespective of traditional risk burden. Flow mediated dilatation (FMD) is widely used as a clinical marker of endothelial function.

Methods: We enrolled 82 patients with PD patients and 45 healthy controls. Clinical information and disease duration were collected. PD severity was assessed using the motor Unified Parkinson's Disease Rating Stage (UPDRS).

Results: The results indicated that the mean serum 25(OH) D levels were significantly lower in PD patients as compared to controls (21.3 ± 3.2 ng/ml VS 24.3± 5.6 ng/ml) (p<0.05). FMD was significantly lower in PD patients (6.2% ± 2.2%) than in controls (8.6 ± 2.7%, p < 0.05). FMD was significantly associated with serum 25(OH) D independently of BMI, CVD risk factor, motor UPDRS, disease duration and homocysteine (r=0.232, p=0.03).

Conclusions: These findings provide evidence that vitamin D play a role in endothelial dysfunction in patients with PD and identify specific outcome measure for detecting effect of vitamin D.

133

Parkinson's disease-linked mutation in DNAJC13 causes specific trafficking defect in endosomal pathway

S. Yoshida, T. Hasegawa, E. Miura, R. Oshima, N. Sugeno, A. Kikuchi, A. Takeda, M. Aoki (Sendai, Japan)

Objective: The aim of this study is to investigate the effect of mutant DNAJC13 on the vesicle transport machinery using cultured cellular model.

Background: Recently, a missense mutation (p.N855S) in DNAJC13 gene has been identified in patients with autosomal dominant, rare familial forms of Parkinson's disease (PD). DNAJC13 is a Dnaj-domain-containing protein that is tightly associated with endosomal membrane.

Methods: Human wild-type (wt) and Mutant DNAJC13 cDNAs were subcloned into the pEGFP-C1 eukaryotic expression vector. Human Rab5A, Rab7 and Rab11A cDNAs were introduced into pmStrawberry vector. COS7 were transiently transfected with GFP-tagged DNAJC13 as well as mStrawberry-tagged Rab GTPase constructs using the NEPA gene square-wave electroporator. The expression and subcellular localization of DNAJC13 were examined using laser scanning microscopy (LSM) and Western blot analyses in combination with density-gradient centrifugation. To determine how the DNAJC13 mutant affect on the different endosomal pathway, cells overexpressing wt or mutant DNAJC13 were incubated in the culture media containing Alexa555-labeled reference molecules including transferrin, EGF and Shiga Toxin 1B subunit.Time-lapse images of internalized reference molecules were acquired using LSM at 15 sec intervals.

Results: While wt DNAJC13 was exclusively co-localized with rab5A-positive early endosome, part of DNAJC13 p.N855S was mislocalized from Rab5A to Rab11A-positive recycling endosome. Transport assay using reference molecules showed abnormal endosomal trafficking in cells overexpressing DNAJC13 p.N855S.

Conclusions: PD-linked DNAJC13 mutation impairs specific endosomal trafficking and would thereby contribute to the pathogenesis of disease.

134

Relative sparing from the death of serotonergic fibers in ipsilateral striatum is related with development of levodopa-induced dyskinesia in hemi-Parkinsonian rats

J. Youn, M.Y. Jeon, T.O. Son, J.W. Cho (Seoul, Korea)

Objective: To investigate the relationship between serotonergic cell death and development of levodopa-induced dyskinesia (LID).

Background: Although, dopaminergic medication is the most effective therapy in Parkinson's disease (PD), LID presents commonly with chronic treatment, and has great impacts on quality of life. Recently, there are growing evidences about the role of serotonergic system in development of LID. However, the specific molecular mechanisms about the pathogenesis of LID are not clearly elucidated.

Methods: In present study, chronic levodopa treatment (12mg/Kg) was done for 3 weeks after making unilateral mid-forebrain bundle lesion with 6-hydroxydopamine in male F344 SD rats. Levodopa-treated rats were divided into two groups based on the LID development using abnormal involuntary movement scale (AIMS). We compared dopaminergic cell and serotonergic fibers between two groups using immunohistochemistry and western blotting.

Results: There was no difference in dopaminergic cell wipe-out in striatum between hemi-Parkinsonian rat models with and without LID. When we compared the number of 5-HT positive cells in dorsal raphe nucleus, there was no significant difference between two groups. However, rats without LID showed 21.7% reduction of 5-HT transporter (SERT) in striatum compared with those with LID. There were no correlations between AIMS score, and 5-HT positive cell count or SERT.

Conclusions: These findings suggest relative sparing from the death of serotonergic fibers in ipsilateral striatum could be related with development of LID in PD.

135

Withdrawn by Author

 

136

Neuronal oscillatory activity in the ventrolateral thalamus in patients with Parkinsonian tremor and essential tremor

P. Zhuang, M. Hallett, T. Liu, Y. Zhang, J. Li, Y. Li (Beijing, People's Republic of China)

Objective: To characterize oscillatory activity in the ventrolateral thalamus (VL) in patients with Parkinsonian tremor and essential tremor (ET).

Background: The pathophysiology of Parkinson's disease (PD) and ET is unclear.

Methods: 26 patients with PD and 14 patients with ET who underwent thalamic surgery were studied. Microelectrode recordings in the VL and EMG of contralateral limbs were performed. Single unit analysis and interspike interval was used to assess neuronal mean firing rate (MSFR) and pattern. Spectral characteristics were evaluated. Coherence analysis was used to explore the relationship between oscillatory activity and EMG.

Results: Of total neurons (n=224) obtained from 26 tracts of PD patients, 66.4% neurons were oscillatory. Of these neurons, 71.1% neurons (n=109) with bursting activity at mean tremor frequency of 4.5 ± 0.9 Hz were correlated with tremor and defined as TFB oscillatory neurons; 28.8% neurons (n=44) with ß frequency oscillation at 16.6 ± 8.9Hz were defined as ßFB oscillatory neurons. Of total neurons (n=72) obtained from 14 tracts in ET, 63.9% neurons were oscillatory. Of these, 89.1% (n=41) TFB neurons had burst activity frequently correlated with postural tremor at mean frequency of 6.8 ± 4.5 Hz; 10.9% neurons (n=5) had ßFB oscillation at mean of 18.4 ±7.9 Hz. The proportion of ßFB oscillatory neurons in PD were significant higher than that of ßFB oscillatory neurons in ET (p<0.05). Moreover, MSFR of oscillatory neurons in PD were significantly lower than that of oscillatory neurons in ET (26.7 ±6.8 Hz vs. 42.3 ±15.6 Hz, p<0.05).

Conclusions: The proportion of thalamic ßFB oscillatory neurons is higher in PD supporting that ßFB oscillatory neurons are associated with dopaminergic deficits in the basal ganglia circuit. Compared with normal MSFR (estimated to be 30 Hz from recordings in normal monkeys), the MSFR of oscillatory neurons in the VL are likely high in ET suggesting an etiologic role of the thalamus in ET.

Parkinson's disease: Psychiatric manifestations

137

Prevalence study of impulse control disorders and compulsive behaviours in Parkinson's disease in a single – centre: Association with premotor signs and clinical characteristics

A. Acarer, Z. Colakoglu (Izmir, Turkey)

Objective: We aim to determine prevalence of impulse control disorders (ICDs) and compulsive behaviours (CBs) in Parkinson's disease (PD) patient seen in our Movement Disorders outpatient clinic (Department of Neurology, Ege University Medical Faculty, Izmir, Turkey) between years 2005 – 2013 and their associations with premotor signs and clinical characteristics of PD.

Background: Impulse-control disorders and compulsive behaviours occur in patients with Parkinson's disease, especially in younger patients on dopamine therapies. Studies indicate a prevalence of impulse control disorders in Parkinson's disease of 6-16%. ICDs including pathological gambling, compulsive buying, sexual behaviour and eating. CBs are punding, hobbyism, dopamine dysregulation syndrome (DDS) and walkabout.

Methods: In this study, we investigated prevalence of ICDs and CBs among 477 PD patients seen our Movement Disorders outpatient clinic between years 2005 – 2013. 477 patients were questioned using a semi-structured questionnaire directed to patients and their caregivers based on the DSM IV criteria. We directed questions to our patients with PD and their caregivers about premotor signs (REM sleep behaviour disorder, constipation and smell problems). We also investigated 477 patients’ records. There were 40 PD patients with ICDs and CBs. These 40 patients records were again examined to determine premotor signs and clinical characteristics of PD.

Results: Impulse control disorders and compulsive behaviours were identified in 40 patients (prevalence, 8,3%). Some patient have multiple behaviour symptoms of ICDs and CBs. Pathological gambling was observed in 7 patients with PD, hypersexuality in 11, compulsive buying in 14, punding in 11, dopamine dysregulation syndrome in 15, hobbyism in 4, compulsive internet use in 2, walkabout in 2, compulsive eating in 2. We determined risk factors regarding ICDs and CBs. These were male sex, younger age, younger age at PD onset, a pre-PD history of ICDs and gambling problems. There were not any associations between ICDs and premotor signs.

Conclusions: ICDs and CBs are common among Parkinson's patients. These behaviours can possibly lead to serious psychosocial consequences. Therefore, it is extremely important to detect and manage these behaviours.

138

Susceptibility to visual hallucinations in Parkinson's disease: A fMRI study

G. Baille, S. Lefebvre, D. Pins, L. Defebvre, K. Dujardin (Lille, France)

Objective: To assess the propensity to hallucinate in Parkinson's disease (PD) by comparing the access to consciousness of visual inputs between PD patients with and without visual hallucinations (VH) and healthy subjects.

Background: Despite their frequency and their impact, pathophysiology of VH in PD remains unknown. Several studies have reported a disturbance in processing of visual inputs. Nevertheless, the role of more elaborated cognitive processes need to be determined.

Methods: Seventeen healthy subjects, 14 PD patients without VH and 15 PD patients with minor VH participated in the study. None had dementia. During a fMRI session, all participants performed a task of visual detection. A detection threshold was determined, defined as the duration of presentation for which 50% of the stimuli were “seen” and 50% “not seen”. The contrast of the “seen” and “not seen” conditions for a same stimulus presented at threshold allowed the evaluation of BOLD signal variations at time of access to consciousness of visual inputs.

Results: The visual detection threshold was significantly lower for healthy subject in comparison with PD patients with and without VH (57 vs 159 and 173 ms respectively, p<0.05). This threshold did not differ in both groups of PD patients. Compared with PD patients without VH, access to consciousness of visual inputs in PD patients with minor VH was characterized by a higher involvement of the left anterior cingulate gyrus and the left prefrontal dorso-lateral cortex, as well as a lower involvement of the left fusiform gyrus and the left inferior temporal gyrus.

Conclusions: In PD patients with minor VH, access to consciousness of visual inputs is characterized by a hyperactivation of brain areas involved in high level cognitive processes, and by a hypoactivation of regions involved in low level visual processes.

139

Impact of depression on the rate of progression of impairment, disability and quality of life in early Parkinson's disease: NET-PD LS1 cohort

D. Bega, S. Luo, H. Fernandez, K. Chou, M. Aminoff, S. Parashos, H. Walker, D.S. Russell, C. Christine, R. Dhall, C. Singer, I. Bodis-Wollner, A. Nicholas, R. Hamill, D. Truong, Z. Mari, S. Glazman, E. Houston, T. Simuni, On Behalf of the NET-PD LS1 Investigators (Chicago, IL, USA)

Objective: To characterize the relationship between depressive symptoms as measured by the baseline Beck Depression Inventory (BDI) and multiple measures of symptom progression in PD using data from the NINDS Exploratory Trials in PD Long-Term Study 1 (NET-PD LS1) cohort, which involved early, treated PD patients.

Background: Depression is one of the most common non-motor symptoms associated with Parkinson's disease (PD) and the major factor contributing to impairment of disease related quality of life (QOL). Yet limited data exist on the impact of depression on progression of PD disability.

Methods: Using baseline and longitudinal data from LS1, BDI scores from participants were correlated with change in multiple measures of disability, impairment, and QOL over a 5-year period. In order to assess which variables have the greatest contribution to the BDI in a multivariate model the analysis was reversed using change in BDI as the outcome measure.

Results: Of 1741 participants, 746 had completed 5-year assessments and were included in this analysis. Their mean age was 62.00 years (SD 9.22) and mean disease duration was 1.69 years (SD 1.16). Mean baseline BDI score was 6.24 (SD 5.02) and increased to 8.57 (SD 6.60) at 5 year follow-up. At baseline 11.8% (n=206) of subjects had a BDI ≥ 14, and 22.0% of subjects were using antidepressants. Baseline BDI score was strongly associated with the rate of change in all examined measures of disease severity, disability, and QOL. In a multivariate analysis using change in BDI as the outcome measure, baseline BDI was associated with 5-year UPDRS Part I (with depression item removed) (p<0.01) but not UPDRS ADL (p=0.28) or UPDRS motor scores (p=0.19). It was also associated with QOL measures, PDQ-33 (p<0.01) and EQ-5D (p=0.02), but not cognitive measures (p=0.17 for SCOPA-COG). This was a fairly robust model, with these 4 significant variables (Total Functional Capacity, UPDRS part I, PDQ-33, and EQ-5D) explaining about 68.8% of the variance of the BDI score 5-year change.

Conclusions: Worse baseline BDI scores, even in the absence of depression, are associated with a decline in multiple measures of disease severity and symptomatology in PD. Change in the BDI at 5 years was associated with the change in UPDRS Part I and QOL measures, rather than motor and cognitive measures.

140

Psychiatric and psychosocial outcome after bilateral deep brain stimulation of the globus pallidus pars interna and subthalamic nucleus for advanced Parkinson's disease

J.A. Boel, V.J.J. Odekerken, G.J. Geurtsen, B. Schmand, D.C. Cath, M. Figee, R.J. de Haan, P.R. Schuurman, R.M.A. de Bie, The NSTAPS Study Group (Amsterdam, Netherlands)

Objective: To assess psychiatric and psychosocial outcome 12 months after bilateral deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) and subthalamic nucleus (STN) for advanced Parkinson's disease.

Background: Concerns have been raised regarding the psychiatric side-effects of DBS, especially STN DBS. The effects on mood and behaviour could be the deciding factors in the choice between the two targets (GPi vs. STN).

Methods: We randomly assigned patients to receive either GPi DBS (n=65) or STN DBS (n=63). Standardized psychiatric and psychosocial questionnaires were assessed at baseline and after 12 months. Patients and study assessors were masked to treatment allocation. We performed between-group, within-group, and descriptive analyses.

Results: No differences were found between GPi DBS and STN DBS on psychiatric evaluation investigating, mania, mood, personality, and affect. Within-group comparisons showed small, but statistically significant changes on several measures in both groups. Mania scores and positive affect decreased after GPi DBS. Positive affect scores decreased after STN DBS. Descriptive analyses indicated slight changes in work status, social participation, and social relations. Marital satisfaction of patients and partners remained relatively stable after GPi DBS and STN DBS.

Conclusions: We found neither clinically relevant differences in psychiatric and psychosocial outcome between GPi DBS and STN DBS, nor any relevant within-group differences before and after DBS.

141

The Parkinson's active living (PAL) program: A behavioral intervention targeting apathy in Parkinson's disease

L.C. Butterfield, C.R. Cimino, R.D. Salazar, C.S. Lee, W.E. Haley, J. Sanchez-Ramos, M.S. Okun, D. Bowers (Gainesville, FL, USA)

Objective: (1) To develop protocol materials to facilitate treatment delivery, (2) to determine ease of training interventionists, (3) to assess feasibility, acceptability, and estimated effect of a 6-week, primarily telephone-based activity scheduling/monitoring intervention on reducing apathy in non-demented, apathetic Parkinson's (PD) patients.

Background: Apathy, reflecting motivation and self-initiation impairment, is common in PD and associated with a host of negative associates, including reduced cognitive and daily functioning, treatment compliance, and quality of life, and increased caregiver stress. While some studies have evaluated pharmacologic approaches to treating apathy, few have evaluated non-pharmacologic approaches. To our knowledge, this is the first behavioral intervention program designed to target apathy in a PD population.

Methods: 34 non-demented, apathetic PD patients participated. 1) An interventionist manual outlining treatment protocol and a patient workbook were created. 2) Interventionists were trained and evaluated for protocol adherence. 3) A one-arm uncontrolled trial was conducted to estimate treatment effect on self-rated apathy, depression, ADLs, QoL, and caregiver burden. Intervention consisted of one in-person Planning Session to identify and schedule tailored goals, and 6 weekly phone sessions. Outcomes were assessed at baseline, post-test, and 1-month follow-up. Paired t-tests examined differences in outcomes by time point.

Results: Treatment delivery, feasibility, and acceptability data reflected strong interventionist adherence, expected attrition, and high patient satisfaction. Apathy, depression, and QoL significantly improved post-treatment with medium to large effects and clinically meaningful changes. Improvements in apathy and depression were maintained at follow-up. Response to treatment was associated with higher baseline executive function, novelty seeking, and self-awareness.

Conclusions: A promising manualized intervention designed to target self-generational deficits common in PD is presented. Preliminary results showed improved motivation, mood, and QoL in PD through a telehealth intervention. A randomized controlled trial is needed to further investigate the efficacy of the PAL program.

142

Problematic mobile gaming: A previously unreported impulse control disorder

E.A. Byrd, N.B. Galifianakis, C.A. Racine (San Francisco, USA)

Objective: To present a case of dopaminergic medication-induced problematic mobile gaming, a previously unreported impulse control disorder (ICD) behavior.

Background: ICD's are a known side effect of dopaminergic medications used in the treatment of Parkinson's disease (PD), estimated to occur in 10-40% of individuals with PD. Previous studies have largely focused on the following behaviors: pathological gambling, hypersexuality, hobbyism/punding, compulsive eating and excessive spending. Recent reports have also described problematic internet use, but our case extends ICD behavior into excessive gaming on mobile devices.

Methods: Single case report.

Results: A 64-year-old woman with a 5 year history of PD who was taking levodopa and pramipexole presented with an ICD that manifested primarily as playing a video game on her mobile device for 2-4 hours per day. She spent $600/month on within-app purchases, which allowed her to continue playing after running out of “lives”. Playing allowed her to “take her mind off everything” and was an “escape” for her. She was successfully treated with education, deleting the game, and strict monitoring by her daughter who had moved in with her. However, 10 months later on return visit she had started playing another mobile game, spending $800-900/month. She was again treated by deleting the game. Tapering her dopamine agonist was not possible in this case due to painful foot dystonia and truncal dystonia that was minimally responsive to botulinum toxin.

Conclusions: To our knowledge, this is the first report of problematic mobile gaming, an ICD behavior with several unique characteristics which may lead to potentially serious financial consequences. First, mobile games are exquisitely designed with entertaining graphics, music, and sometimes subtle within-app purchasing options to maximize game use and profit. Perhaps more importantly, smart phones and other mobile devices are ubiquitous, which makes problematic mobile gaming readily available in almost any time and place. This ubiquity, combined with the fact that gaming does not usually have the stigma associated with gambling and other ICDs, make this behavior an important new ICD to actively screen with our PD patients. Furthermore, currently available questionnaires and scales do not address this behavior.

143

Relation between farmachological treatment and impulse control disorder in patients with Parkinson's diseases of recent diagnose

H. Durán Meza, D. Santana Vargas, D. Trejo Martínez (México City, Mexico)

Objective: Identify the relation between pharmachological treatment and the presence of Impulse Control Disorder.

Background: Most of drugs being used for Parkinson's disease treatment are being oriented to reestablish the content of dopamine in the striatum. Levodopa and Dopamine Agonists improve motor symptoms. Agonists are related to Impulse Control Disorder (ICD), which has been related its presence between 15% to 20% of patients. This disorder includes pathological gambling, hypersecuality, compulsive buying, and binge eating, compulsive and repetitive behaviors, hobbyist, walkabout, and compulsive use of medication. Regarding time frame where ICD appeared, there is controversy. About gender difference there is not clear an esteaby pattern.

Methods: 31 patients with PD recruited from the outpatients Neurologic department at the General Hospital from Mexico, (15 women and 16 men), without data indicating depression according to the Yesavage scale, or showing severe dementia according to the Minimental test (Folstein, 1975) or specific items from UPDRS. All patients were under stable pharmachological treatment for at least three months before testing and rated at stages 2 and 3 of the Hoenh and Yarh scale. Patients belonged to one of two groups: a)levodopa-carbidopa or b)levodopa with dopaminergic agonist (Pramipexole). Analysis were conducted using the Statistical Package for the Social Sciences (SPSS) for Windows version 17, to find relation between treatment type and the QUIP score and one factor ANOVA for tratment effect. Significant level were set at α≤0.05.

Results: Neither Spearman correlation nor significat effect for ANOVA test were significant for levodopa or levodopa plus dopaminergic teatment effect and QUIP score. However, differences were found when comparisons were performed by sex. Spearman correlation coefficient showed positive high correlation for women (0.701) and significative at 95%IC (p=0.004). One factor ANOVA was also signifficant for women showing higher scores for levodopa plus pramipexole than for levodopa alone (F (13,1) = 4.827, p=0.047).

Conclusions: Based in previous results we have found, for this sample that there is not changes between both groups but when we separate by sex, we found positive correlation that indicates, the Dopaminergic Agonist has a positive relation with the presence of Impulse Control Disorder in women.

144

Improvement of obsessive-compulsive symptoms after bilateral subthalamic stimulation in Parkinson's disease

F.M.C. Fonoff, E.T. Fonoff, E.R. Barbosa, R.B. Machado, R.G. Cury, M.G.G. dos Santos, M.J. Teixeira, D. Fuentes (São Paulo, Brazil)

Objective: To investigate the effects of deep brain stimulation (DBS) over Obsessive-compulsive symptoms (OCS) and other neuropsychiatric changes in patients with Parkinson's disease.

Background: OCSs are fairly common in Parkinson's disease patients. OCSs have been a concern when indicating DBS for Parkinsonian patients.

Methods: Thirty-three Parkinson's disease patients were evaluated before surgery and 12 months after implantation of deep brain stimulation in subthalamic nucleus, using scales and standardized tests.

Results: It was observed improvement in depression (from 11.27 ± 4.32 to 8.24 ± 4.40; 26.88%; p=0.004), anxiety (from 15.39 ± 6.55 to 11.27 ± 6.45; 26.77%; p=0.002), attentional impulsivity (from 18.43 ± 3.16 to 16.84 ± 3.39; 8.61%; p=0.031) and in obsessive-compulsive symptoms (from 4.38 ± 4.78 to 0.90 ± 2.23; 79.34%; p=0.001) 12 months after bilateral stimulation. No significant changes were observed in neuropsychological tests that assess attention, mental flexibility, decision making, planning.

Conclusions: In this series, stimulation of the subthalamic nucleus did not affect the cognitive performance, relieved significantly depression, anxiety, impulsivity but the most significant impact was observed in obsessive-compulsive symptoms.

145

Assessment of current treatment approaches for patients with Parkinson's disease psychosis (PDP)

D. Fredericks, J. Norton, R. Suresh, R. Mills (San Diego, CA, USA)

Objective: To survey physicians who treat PDP and characterize current treatment approaches and drivers.

Background: PDP is a prevalent neuropsychiatric manifestation with a lifetime prevalence of up to 50% in patients who have been diagnosed with Parkinson's disease (PD). Typically, patients characterized as having disruptive psychotic symptoms are more likely to receive treatment. This study aims to provide insight into current treatment approaches.

Methods: 201 physicians (109 neurologists, 46 psychiatrists, and 46 primary care physicians) were surveyed to understand current treatment approach for PDP.

Results: The decision to treat is driven primarily by the perceived disruptiveness of psychotic symptoms. Fifty percent of patients characterized with non-disruptive symptoms of PDP were treated, and the decision to treat was driven mainly by concern that psychotic symptoms would worsen or by patient/family request for treatment.

For PDP patients characterized as disruptive who were treated, adjustment of PD medication was the primary treatment approach (55%) and most common amongst neurologists (63%). These PD medication adjustments were typically made over a period of 2 weeks to 3 months, and were successful in controlling psychosis in less than 25% of cases, at which point almost half (45%) were prescribed an atypical antipsychotic (AP). In cases where an AP was prescribed, quetiapine was the preferred agent (60%). Twenty-eight percent of PDP patients who were prescribed an AP eventually were switched to a second AP, and 19% of those to a third AP. In cases where an AP was not utilized, patients received anti-dementia or anti-depressant agents approximately 20% of the time as it is commonly believed that managing dementia and depression may help resolve psychosis; however, permanent adequate control was achieved in only approximately 15% of these cases.

Conclusions: The main factors that influence whether a PDP patient will receive treatment for psychotic symptoms are the perceived degree of disruption of the symptoms and the level of concern about impact on motor control. The primary method of treatment was reduction of PD medication, followed by the addition of an AP, usually quetiapine, or, less commonly, anti-dementia or anti-depressant agents. The results show that PDP is undertreated, especially in cases considered non-disruptive, and that treatment options are currently limited in their usefulness.

146

Dopamine agonist induced impulse-control behaviors in Parkinson's disease are not dose-dependent

T.J. Gupta, M.E. Gomez, L. Yang, S. Cen, D. Togasaki, J.S. Hui (Los Angeles, CA, USA)

Objective: To prospectively assess Impulse Control Behaviors (ICBs) in PD patients initiating dopamine agonist (DA) therapy, and to examine the association between peak LEDD and cumulative DA exposure and the development of ICBs.

Background: DA are widely used in the management of Parkinson's disease (PD). Recent evidence suggests that DA therapy in PD is associated with the development of one or more impulse-control behaviors (ICBs). While there appears to be a class effect for DA in the development of ICBs, studies have been inconsistent in implicating medication-specific or dose-specific effects with DA use. There have been few prospective, longitudinal studies which examine the effect of peak levodopa-equivalent dose (LEDD) and cumulative lifetime dose of DA on expression of ICBs.

Methods: Participants were recruited from a pool of patients identified as candidates for therapy with a non-ergot DA. Peak LEDD of and cumulative exposures to ropinirole (RPL) or pramipexole (PPX) during the study period were calculated using drug accountability logs and analyzed via independent-samples t-test and ANOVA respectively.

Results: Of 18 subjects starting agonist therapy, 9 received RPL and 9 PPX. 8/18 (44%) subjects developed ICBs. Mean time to develop ICBs was 10.1 months (SD 11.3). There was no difference in either peak or cumulative doses administered between RPL and PPX. The peak LEDD medication was not associated with expression of ICBs (p=0.98). Repeated measures ANOVA showed that there was no statistical interaction between drug type, presence of ICBs, and overall cumulative dose over time (p=0.36). All (100%) subjects who developed ICBs were also taking levodopa, compared to only 10% of subjects who did not develop ICBs.

Conclusions: While ICB expression may be a class effect of non-ergot DA, it does not appear to demonstrate dose-related or medication-specific effects, and may be influenced by polypharmacy of DA with levodopa. Further elucidation of ICB risk factors may provide insight for clinicians who manage patients on DA therapy.

147

Symptoms of depression and anxiety in Parkinson's disease patients and a population based elderly cohort

K. Hückelheim, E.J. Vollstedt, S. Tunc, V. Tadic, A. Lorwin, J. Hagenah, J. Graf, C. Klein, M. Kasten (Luebeck, Germany)

Objective: To address the prevalence, severity, and subtype of depression and anxiety in Parkinson's disease (PD) patients and a population based-control group including controls with other disorders according to different assessment tools.

Background: Depression and anxiety in the context of PD have been established as prominent predictors for quality of life in several studies. However, broad ranges (3-90%) of prevalences are reported partially due to variable assessment methods and different definitions of the terms “depression” and “anxiety”.

Methods: After a postal screening of 10,000 citizens of Luebeck, 729 participants were examined, PD diagnostic criteria checked according to the UK Brain Bank Criteria, medication intake and psychiatric symptoms recorded. We applied the Structured Clinical Interview (SCID) screening questions for anxiety, the Beck Depression Inventory (BDI), the UPDRS I depressive symptoms question, and the State-Trait-Anxiety Inventory (STAI).

Results: The sample comprised 385 men and 344 women (mean age 66+/-8 years), 283 healthy controls, 260 disease controls, 74 persons with mild Parkinsonian signs (MPS), and 112 PD patients. Using antidepressive medication, self-reported prior diagnosis of depression, or BDI (≥9) as indicator of depression, frequency ranged from 5%-42%. A BDI≥9 was present in 35% of healthy controls, 51% of controls with other diseases, and 43% of PD patients. STAI scores were increased in PD patients compared to healthy but not to disease controls. The SCID screening showed similar numbers of anxiety subtypes across groups. Anxiety and depression markers were highly correlated in the BDI and STAI, whereas the SCID screening only mildly correlated with the BDI and STAI results. In binary logistic regression for the outcome BDI≥9 the predictors were history of prior depression, PD diagnosis, and presence of mild Parkinsonian signs.

Conclusions: The question how to measure depression and anxiety in PD is partially unresolved and syndromes not represented in DSM and ICD may be of clinical interest. A prior depression could be a valuable red flag for risk of depression in a clinical setting. Assessment method and cut-off for anxiety and depression need to be specified and harmonized between comparison groups in future studies. Additional data is needed to specify the prevalence of depression and anxiety in PD in comparison to other chronic conditions.

148

Depressive symptoms in Parkinson's disease correlate with brain gray matter thinning over time

A. Hanganu, M.A. Bruneau, C. Degroot, C. Bedetti, B. Mejia-Constain, A.L. Lafontaine, O. Monchi (Calgary, AB, Canada)

Objective: To evaluate the correlation between depressive symptoms and gray matter changes in the brain over time in patients with Parkinson's disease (PD).

Background: Depression is one of the most common non-motor symptoms in PD accounting for up to 40% of patients at the beginning of the disease. However this condition is under-diagnosed in PD with only 25% of patients who will actually receive effective antidepressant treatment.

Methods: 24 non-demented patients with PD were studied twice at 19.8 months apart by receiving a comprehensive neuropsychological assessment and an MRI session at two time points. Using an automated processing and analysis of MRI data, we performed a longitudinal study and measured the rate of change of cortical thickness over time in our group. Additionally, a correlation between depressive symptoms score (Beck Depression Inventory) and the rate of change of gray matter over time has been performed.

Results: Depression was negatively correlated with the rate of change of cortical thickness and subcortical volumes over time after Monte-Carlo correction at p=0.05. More specifically, a higher BDI depression score was associated with a thinner cortical gray matter in the rostral frontal, tempo-parietal and lingual regions. Additionally negative correlations have been revealed with the hippocampus, amygdala and nucleus accumbens volumes. Non-corrected clusters at p=0.001 were revealed in the supplementary motor, primary motor and premotor regions.

Conclusions: Our data suggest a significant effect of depressive symptoms over the cortical gray matter changes over time in PD patients. This specific pattern of brain degradation might serve as a marker for evaluating the treatment effect in PD as well as to prevent further cortical degradation.

149

Long-term effectiveness of pimavanserin in PD psychosis: Data from 2 open-label studies

S. Isaacson, J.P. Azulay, J. Ferreira, D. Kreitzman, T.V. Ilic, K. Chi-Burris, H. Williams, R. Mills (Boca Raton, FL, USA)

Objective: Two open-label studies (OLS) have assessed the long-term safety of pimavanserin in PD Psychosis (PDP); continued effectiveness was also evaluated.

Background: Psychosis is common in PD and increases with disease duration. It is associated with increased morbidity/mortality, complicates management of motor symptoms and often leads to long-term care placement. Pimavanserin is a potent, selective 5-HT2A inverse agonist that has shown antipsychotic benefit with improvements on night/day-time sleep and caregiver burden in 6-week PDP RCTs. Long-term persistence of benefit may confer improved patient and caregiver quality of life and help delay/prevent institutionalization.

Methods: Patients completing a previous RCT could roll into a OLS to receive pimavanserin QD for as long as the Investigator considered it beneficial. In a Phase 2 OLS (N=39), long-term efficacy measures were limited to CGI-Severity (CGI-S), while in a Phase 3 OLS (n=459), the Scale for Assessment of Positive Symptoms (SAPS) was used at Week 4 and CGI-S, CGI-Improvement (CGI-I), and caregiver burden score (CBS) were assessed at all visits.

Results: 498 PDP patients were evaluated for a median period of ∼15 months (longest >8 years). In the Phase 2 OLS, improvement in CGI-S continued through ≥Week 24, then maintained through Week 72 (with >50% subjects still active). At Week 96, with 34% of subjects remaining, further improvement in mean CGI-S was seen. In the larger ongoing Phase 3 OLS, subjects were enrolled from 114 international sites and receive once-daily pimavanserin 40mg. SAPS-PD scores by blinded, independent raters at Week 4 (i.e., 10 weeks total treatment duration from core baseline) suggest that effect is improved among patients previously treated with placebo (or low pimavanserin doses) and maintained in subjects previously treated with pimavanserin 40mg. Discontinuation for lack of efficacy is <20%. Subjects who remain on study at 2 years maintained an average CGI-I score of ∼2.5-2.7 (minimally-much improved) and mean CGI-S showed minimal fluctuation (±0.2). CBS also shows stable benefit over time.

Conclusions: In addition to efficacy in pivotal 6-week RCTs, these two OLS provide support for durability of antipsychotic effect and CBS in PDP. Pimavanserin may offer long-term benefit for patients with PDP with a demonstrated safety/tolerability profile appropriate for chronic use.

150

Improvement of neuropsychiatric symptoms after initiation of dopaminergic treatment in drug-naive patients with Parkinso's disease

S. Isais-Millan, D. Piña-Fuentes, A. Cervantes-Arriaga, M. Rodriguez-Violante, C. Guzman-Astorga, R. Llorens-Arenas, H. Calderon-Fajardo (Mexico, Mexico)

Objective: To determine the prevalence of neuropsychiatric disorders in patients with Parkinson's disease before and after initiation of dopaminergic antiParkinsonian treatment.

Background: Parkinson's disease is accompanied by a wide range of psychiatric disturbances, some of which have been associated to dopamine replacement therapy.

Methods: A prospective study was carried out. Patients with untreated PD were evaluated using Hoehn and Yahr scale (severity), MDS-UPDRS (motor function), MoCA (cognitive impairment), BPRS (psychosis), Dex-sp (dysexecutive), HADS (depression/anxiety), LARS (apathy) and QUIP-RS (impulse control). Patients were re-evaluated 6 months after initiating antiParkinsonian treatment using the same scales. Scores pre-and post-treatment diagnosis and scale score were compared using paired T test.

Results: A total of 63 patients were included in the basal evaluation (61.9% men and 38.1% women). Mean age was 57.8 years (±10.2 SD). Mean disease duration was 21.7 months (±15.8 SD).

Total MDS-UPDRS mean score was 40.52 (±22.6 SD), PDQUALIF-33 score was 40.6% (±12.7 SD), Global HRQoL was 55.3% (±20.9 SD). The mean BPRS score was 25.52 (±5.4 SD), while scores in the HADS anxiety and depression were 5.7 (±4.4 SD) and 5.6 (±4), respectively. Using the MOCA, a total of 41.3% patients resulted in cognitive impairment (MCI in 80% of them). According to the DEX-sp (Dys-executive Questionnaire), 19.5% patients had dysexecutive impairment, 7.9% mild-moderate, 6.3% moderadate-severe, and 4.8% severe. Using the LARS, a total of 20% subjects were diagnosed with apathy. Finally, the QUIP-RS showed an ICD overall prevalence of 12.6%. Comparison of the mean scores of all the scales before and after antiParkinsonian treatment is shown in Table 1.

Comparison of neuropsychiatric scales before and after dopaminergic treatment
SCALE PRE-TREATMENT POST-TREATMENT P VALUE
PDQUALIF-33 41.2 (9.7 SD) 31.6 (7.9 SD) <0.001
MDS-UPDRS 32.3 (13.2 SD) 19.0 (7.6 SD) <0.001
MOCA 26.0 (2.8 SD) 27.0 (1.9 SD) <0.002
BPRS 24.3 (2.8 SD) 24.1 (2.7 SD) 0.486
HASD-A 4.9 (3.7 SD) 4.0 (2.5 SD) 0.006
HADS-D 4.9 (3.3 SD) 3.4 (2.1 SD) <0.001
DEX-sp 13.7 (9.9 SD) 9.4 (7.3SD) <0.001
QUIP-RS 6.81(9.5 SD) 6.83 (6.5 SD) 0.976
LARS -18.7 (9.5 SD) -21.4 (6.3SD) 0.002
  • In 46.8%, pramipexole was started. On the follow up-visit (n=47), improvement was found in quality of life, total MDS-UPDRS, depression, anxiety, dysexecutive funtion, apathy and cognitive function. No significant changes were found in the BPRS and QUIP-RS. Worsening of disease severity, in terms of HY, was also found.

Conclusions: Dopaminergic therapy has a statistically significant effect on neuropsychiatric symptoms, with the exception of psychotic symptoms and impulse control disorders. The latter symptoms are associated with dopaminergic treatment.

151

Clinical implications of psychotic syndrome diagnosis for patients with Parkinson's disease

R.B.G. Kauark, P.C. Gordon, C.D. Miranda, M.O. Okada, F. Godinho, M.S.G. Rocha (São Paulo, Brazil)

Objective: This study aimed to perform a clinical analysis of different subgroups of patients with Parkinson's disease (PD) and psychotic symptoms.

Background: A significant percentage of PD patients show changes of perception and thought characteristic of psychotic syndromes, however only in some cases these phenomena will present any clinical impact, and antipsychotic treatment indication.

Methods: Patients with idiopathic PD were selected. A neurologist evaluated each case for diagnosis confirmation and data collection, including unified Parkinson's disease rating scale (UPDRS), sleep symptoms scales, NIH criteria for psychosis in PD, and cognitive screening. A psychiatrist evaluated subjects using the structured clinical interview for DSM disorders and the brief psychiatric rating scale. Subjects underwent a formal neuropsychological evaluation, with further diagnosis of dementia according with MDS criteria. Subjects were divided into 3 groups: 1) Psychotic: subjects who meet DSM-IV criteria for psychotic disorder; 2) Subsyndromal symptoms: subjects who have psychotic symptoms according to NIH criteria, but not classified as “psychotic”; 3) Non-psychotic: subjects without any perception disturbance. Statistical analysis between groups involved MANOVA and a post hoc analysis.

Results: There were 94 subjects (64.9% men), with a mean age of 64.1 years (± 10.1) and mean duration of PD of 7.7 years (± 4.8). Fourteen (14.9%) subjects met the criteria for psychosis, and 35 (37.2%) had subsyndromal psychotic phenomena. UPDRS, cognitive, sleep and psychopathological symptoms were significantly different between the groups. Post-hoc analysis showed that the group “psychosis” had higher rates of psychopathology, PD symptoms, sleep disorder symptoms, and higher prevalence of dementia than the groups “subsyndromal symptoms” and “non-psychotic”. There was no difference between “subsyndromal symptoms” and “non-psychotic” groups.

Conclusions: Although sleep and cognitive disturbances have been associated with psychotic features in PD, not enough attention has been paid to diagnosis of the psychotic disorder. Results suggest that patients who meet the formal diagnosis of psychotic syndrome make up a separate category with more psychopathological symptoms, sleep disorders and low cognitive performance. This result is clinically important for diagnostic criteria, with therapeutic and prognostic implications.

152

Cognitive and psychometric properties of drug-induced Parkinsonism and Parkinson's disease

J.S. Kim, J.M. Kim (Cheongju-si, Korea)

Objective: To investigate the cognitive and psychiatric aspects of drug-induced Parkinsonism(DIP) and Parkinson's disease(PD).

Background: DIP is the second most common cause of Parkinsonism after PD and can be clinically indistinguishable from idiopathic PD, especially in early stages. Among clinical manifestations, cognitive and psychiatric features that distinguish degenerative from pharmacologic Parkinsonism are needed.

Methods: The sample consisted of consecutive patients who fulfilled the clinical criteria for DIP and PD. General characteristics include medication history were obtained. The clinical severity was evaluated at first visit and after 6 months based on the activities of daily living, score on the Unified Parkinson's disease Rating Scale, and the Hoehn and Yahr scale. The patients’ cognitive state were evaluated with the mini-mental state examination (MMSE), the Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating scale, and mood disorders were screened by Hamilton Depression Rating (HAM-D) scale, Hamilton Anxiety Rating scale, Sheehan disability scale, and Liebowitz Social Anxiety Scale.

Results: Over 12 months, a total of 114 were included. Fifty one patients (44.7%) were DIP patients, and 63 (55.3%) were PD patients. The patients with DIP showed significantly lower educational level. In addition, the number of comorbidities and taking medications were more in DIP patients than PD. The score of MMSE and MoCA were also lower in DIP patients who committed more errors than PD patients on orientation and executive functions. In addition, higher HAM-D scores were associated with DIP patients.

Conclusions: These findings suggested that cognitive impairment and depression are common among DIP patients than PD. In addition, lower educational level and disorientation, various comorbidities and many kinds of medical pills might affect the drug induced medical problems.

153

Neuropsychiatric disorders in idiopathic Parkinson's disease

M.U. Kulsum, A. Dutt, S. Choudhuri, S.S. Anand, C. Sengupta, B. Mondal, P. Chatterjee, H. Kumar (Kolkata, India)

Objective: 1. To study prevalence of various psychiatric disorders in patients with PD.

2. To compare the prevalence of psychiatric disorders in Tremor dominant (TD) variant of PD with that in postural instability gait difficulty (PIGD) variants of PD.

Background: Psychiatric and behavioral symptom associated with Parkinson's disease (PD) is a frequently encountered problem which may affect the quality of life of PD patients. By reason of inadequate accessibility of reports in this ethnic population; we intended to assess the frequency and determinants of PD associated psychiatric disorders.

Methods: In this cross sectional study conducted in a Movement Disorder and psychiatry Out Patient Department, we have evaluated 150 patients with PD (diagnosed by UK Brain Bank Criteria) on socio-demographic and clinical profile. The PD symptoms were objectively quantified using Unified Parkinson's disease Rating Scale (UPDRS), Modified Hoehn and Yahr staging and Schwab and England activities of daily living scale. Cognitive assessment was done by Mini Mental state examination (MMSE). The Mini International Neuropsychiatric Interview was used to screen for psychiatric illness and the National Institute for Neurological disorder and Stroke, National Institute of Health (NIND and NIMH) criteria was used to assess Parkinson's associated psychosis. Psychotic symptoms and depression were rated using Brief psychosis rating scale (BPRS) and Patient Health Questionnaire 9 (PHQ9) score respectively.

Results: 49.3% patients had one or more co morbid psychiatric disorders. Depression (33.3%) was the most common diagnosis followed by psychotic illness (24.7%) and anxiety disorder (20.7%). Patients with psychiatric disorder had significantly higher UPDRS and H&Y score (median score 2.5 Vs 2, p value 0.0001). Daily living was significantly more impaired among patients with psychotic symptoms. These patients had significantly higher daily dose requirement of dopaminergic drugs. Psychotic symptoms were more frequent in Postural Instability/gait difficulty (PIGD) variant of PD patients.

Conclusions: Psychiatric disorders are prevalent among patients with relatively severe PD. Patients with PIGD variant of PD had a higher risk of having psychiatric disorders as compared to tremor dominant (TD) variant.

154

Relationship between cognition and the self-assessment of the psychological symptom in PD

A. Kumon, Y. Kobayashi, M. Saruwatari, N. Kawashima, K. Hasegawa (Sagamihara, Japan)

Objective: Investigate to clarify the relationship between cognition and self-assessment of depression in patients with Parkinson's disease (PD).

Background: In patients with PD, depression is one of the most frequent psychiatric symptoms and examined by several subjective scales. But it is known there were the cases that those patients have difficulty in self-assessment of the symptom or state such as posture and volume of voice. Based on the results of our previous study about apathy, it is likely to indicate a similar tendency in psychiatric symptoms.

Methods: Subjects were 124 patients with PD (male: female=60:64, mean age 68.6 years old, MMSE≥24, HAMD<7), who had been examined frontal lobe function, everyday memory and subjective depression using FAB, RBMT, SDS, BDI-II.

Results: Subjects were divided into two groups according to results tendency of SDS and BDI. 88 subjects whose results showed same tendency were discrepancy (-) group. Other 38 subjects whose results showed different tendency were discrepancy (+) group. Compared with the discrepancy (-) and (+) group there were no significant differences in age, Hoehn and Yahr Scale, HAMD and RBMT. FAB score in discrepancy (-) group (14.5 ± 2.4) was significantly higher than in discrepancy (+) group (13.8 ± 2.3) (p= .032).

Conclusions: In 31% of PD patients maintaining a certain level of cognitive function and without obvious depression, the results of self-assessment of depression differed depending on the scale being used. And the difference related to not everyday memory but frontal lobe function. In PD patients, even though they have no problems with everyday memory, we should carefully evaluate results of subjective scale of depression.

Hereafter we will investigate other factors affecting the difference.

155

Psychotic symptoms in Thai patients with Parkinson's disease: Prevalence and associated factors

P. Lolekha, K. Kulkantrakorn (Pathumthani, Thailand)

Objective: To determine the prevalence and associated factors of neuropsychiatric symptoms in Thai Parkinson's disease (PD) patients.

Background: Hallucinations, Sense of Presence (SoP) and delusions are frequent neuropsychiatric symptoms that reduce quality of life of PD patients. While the pathophysiology of these neuropsychiatric phenomena is not well understood, it is commonly believed as a side-effect of dopaminergic treatment in combination with the underlying brain pathology of PD patients.

Methods: One-hundred and thirty patients with PD were included in the study. Demographic and clinical variables were recorded, including Schwab & England Activity of Daily Living (SE-ADL scale), UPDRS motor score, Hoehn & Yahr stage (H&Y), Levodopa Equivalent Dose (LED), Thai Mental State Examination (TMSE), and Thai Geriatric Depression Scale-15 (TGDS-15). Hallucinations, SoP and delusions were assessed by Thammasat University Non-Motor Symptoms Questionnaire (TU-NMSQuest).

Results: Of 130 PD patients, 33.1% (n=43) had experienced psychotic symptoms: hallucinations (21.5%, n=28), SoP (17.7%, n=23), and delusions (20%, n=26). Among the patients with psychotic symptoms, 21% (n=9) had isolated hallucinations, 7.1% (n=3) had isolated SoP, and 18.6% (n=8) had isolated delusions. Auditory hallucinations were found in 7.7% (n=9) and all were combined with visual hallucinations. The psychotic symptoms in PD patients were significantly associated with poorer SE-ADL scale, lower TMSE score, higher TGDS-15 score, higher TU-NMSQuest score, advanced age, higher H&Y stage, and higher UPDRS motor score. Multiple linear regression analysis showed severe cognitive impairment, depression, anxiety disorder and advanced disease stage were the most significant factors for psychotic symptoms in PD. Duration of PD, type of antiParkinsonian medication and LED were not significantly associated with these symptoms.

Conclusions: Hallucinations, SoP and delusions are common in Thai PD patients and are likely to be multifactorial in origin. Advanced disease stage, cognitive impairment, depression and anxiety disorder are the most significant factors of psychotic symptoms in Thai PD patients, regardless of disease duration, type and dosage of antiParkinsonian medication.

156

Efficacy and tolerability of pimavanserin in PD psychosis: Analysis of an integrated phase 3 placebo-controlled dataset

R. Mills, J.H. Friedman, W. Ondo, R. Pahwa, K. Black, K. Chi-Burris, H. Williams (San Diego, CA, USA)

Objective: Pooling of efficacy data across studies can provide a more precise estimate of overall treatment effect, treatment effect for endpoints measured infrequently, and variation of effect across subgroups of interest. A pooled analysis of two Phase 3, placebo-controlled studies was conducted to further evaluate the efficacy of pimavanserin in PD Psychosis (PDP). The dataset comprised 268 N. American subjects who received once-daily blinded treatment for up to 6 weeks.

Background: Psychosis is common in PD and increases with disease duration. It is associated with increased morbidity/mortality, complicates management of motor symptoms and often leads to long-term care placement. Pimavanserin is a potent, selective 5-HT2A inverse agonist being developed as a first-line treatment for PDP.

Methods: Pooling is appropriate only for homogeneous populations, where the same treatment duration, comparator and treatment regimens were used. These conditions were met for Studies ACP-103-020 and -012 (North America, pimavanserin 40mg and placebo groups). The analysis included 133 placebo- and 135 pimavanserin-treated subjects.

Results: Pimavanserin 40mg demonstrated a 6.21-point improvement in psychosis at Week 6 as measured by blinded, independent raters using the PD-adapted Scale for Assessment of Positive Symptoms (SAPS-PD; primary change from baseline analysis [MMRM]). The treatment difference was 2.87 points over placebo (p<0.001) and was clinically meaningful. Pimavanserin 40mg also showed statistically greater benefit over placebo on all SAPS supportive measures and sensitivity analyses as well as on CGI-Severity, CGI-Improvement (CGI-I), CGI-I responder analysis, SCOPA-nighttime sleep and daytime wakefulness measures, and caregiver burden score. Results were consistent across all subgroups of interest, showing greater improvement with pimavanserin 40mg over placebo, regardless of age, sex, race group, or screening MMSE score. There was no worsening of Parkinsonism as measured by UPDRS II+III, and the adverse event profile was virtually identical to placebo.

Conclusions: Pimavanserin appears effective, safe and well-tolerated for PDP based on individual study data (previously published) and in this pooled analysis of Phase 3 placebo-controlled data.

157

Othello syndrome in a Parkinson's disease patient with dementia initiating Donepezil therapy: A case report

O.A. Molokwu, I.O. Onwuekwe, A.C. Nwabueze (Enugu, Nigeria)

Objective: To report a case of Othello syndrome in a Parkinson's disease patient with dementia following commencement of Donepezil.

Background: Psychiatric presentations such as depression, delusional disorders etc. have been described in patients with Parkinson's disease (PD). Othello syndrome (OS) describes a psychiatric condition characterized by morbid jealousy in which the sufferer holds a strong delusional belief of spousal or sexual partner's infidelity without having any significant proof to back up such claim.The causes of OS cuts across psychiatric illness, alcoholism, drug abuse, neurological illness including PD and/or in association with its drug treatment etc. Few case reports have described the occurrence of OS in PD patients.OS impacts negatively on marital relationship and increases caregiver strain. OS increases the risk for violence and aggression towards spouse which if not tackled may lead to suicide and/or homicide.

Methods: We report a case of Othello syndrome in a PD patient who was initiating treatment with Donepezil for recently diagnosed dementia and to review literature on the condition.

Results: A 62 year old man who was diagnosed of PD with dementia and was commenced on Donepezil. About a week thereafter, he developed morbid jealousy associated with delusional belief that his wife was having an affair with his bosom friend. He engaged in confirmatory behaviors such as checking his wife's phone call list and messages. He was aggressive sometimes, then later became depressed.The temporal association with initiation of Donepezil tended to suggest that the OS was an adverse drug reaction (ADR). However,Naranjo score for ADR probability was 2 which implies a probable ADR.He was admitted into the ward and did haemogram, liver function test, biochemical panel test which were unremarkable. CT scan done showed age related brain atrophy. He was reviewed by the psychiatrist and was tried on some neuroleptics and antidepressants with minimal improvement. He was later discharged on request by the relatives and was lost to follow up.

Conclusions: Prompt recognition and treatment of Othello syndrome is imperative in other to prevent the untoward knock-on negative effect on marital relationship and patient outcome. while checkmating the increased risk of violence against partner, suicide and/or homicide seen in this condition.

158

Effect of dopaminergic medication on BOLD fMRI in Parkinson's disease patients with visual hallucinations during a visuoperceptual task

A.J. Muller, C. O'Callaghan, J.M. Shine, S.J.G. Lewis (Sydney, Australia)

Objective: To investigate neural mechanisms affected by dopaminergic Parkinson's disease (PD) medications during visual misperception events in patients with visual hallucinations (VH).

Background: Although VH are extremely common in PD, their neural mechanisms remain poorly understood. First line of treatment of VH in PD usually involves a reduction of dopaminergic medication dose; however the direct effects of dopaminergic medication on the neurobiology underlying hallucinatory events has yet to be established.

Methods: We performed functional MRI combined with the Bistable Percept Paradigm (BPP), a visuoperceptual task capable of eliciting visual misperceptions in patients with VH. All 15 patients reported VH and were assessed in a randomised order both on their regular treatment and on a separate occasion after overnight withdrawal of their dopaminergic medication. Task-based functional MRI data was analysed to investigate the neural activity patterns associated with correct perceptions on the task versus visual misperceptions, in both the ON and OFF states. Correction for multiple comparisons was performed by controlling FWE<0.05, with 20-voxel extent threshold.

Results: Misperceptions were associated with significantly different neural activity patterns in the ON versus OFF states. These included a significant increase of activation in the right parietal lobe, and left inferior parietal lobe, cuneus, precuneus and dorsal posterior cingulate area. A significant decrease of activation was shown in the left superior frontal gyrus. Behaviourally, there was no difference in the amount of misperceptions experienced in the ON and OFF states, although patients exhibited significantly higher levels of misperceptions on the BPP compared to established performance in healthy age matched controls (p < .01).

Conclusions: Whilst behavioural results did not show significant differences within patients, these results indicate that dopaminergic medication mediates neural activity associated with hallucinatory events. The left-lateralised inferior parietal lobule, precuneus, and dorsal posterior cingulate regions potentially implicate dopaminergic modulation of the default mode network during visual misperceptions in PD with VH; a network normally involved in introspection and self-referential tasks. The present results have implications for the understanding and management of VH in PD.

159

Investigation of factors associated with distinct psychiatric symptoms in patients with advanced Parkinson's disease

K. Nakahara, R. Kurisaki, T. Sakamoto, K. Yi, T. Yamashita, K. Uekawa, Y. Ando (Uki, Japan)

Objective: To investigate factors associated with individual psychiatric symptoms in patients with advanced Parkinson's disease (PD).

Background: Psychiatric symptoms are serious complications in patients with advanced PD.

Methods: Ninety-nine patients with PD who had Hoehn and Yahr (HY) scale scores ≥3 were treated as outpatients or inpatients in our institute between April 1 and November 30, 2013. Among these, seven patients who underwent stereotactic brain surgery or had insufficient data were excluded from the study.

Based on the medical interviews and examinations performed by neurologists, relationships between psychiatric symptoms (hallucination, dementia, depression, delusion) and other clinical parameters were assessed in a retrospective cross-sectional analysis.

Results: Demographic characteristics of patients with PD were: male, 34, female, 58; mean age, 72.7 ± 10.9 years old; mean duration of PD, 9.8 ± 6.3 years; and mean HY stage, 3.9 ± 0.8 (stage 3: 46 patients, stage 4: 25 patients, stage 5: 21 patients). Psychiatric symptoms were diagnosed in 36 patients (39.1%); of these 19 had hallucinations; 18, dementia; 10, depression; and 5, delusion. Univariable logistic regression analysis revealed that the presence of hallucination significantly correlated with the duration of PD, urinary incontinence (UI), and dyskinesia (Dys); presence of dementia significantly correlated with duration of PD, HY stage, and UI; and delusion significantly correlated with Dys. Depression did not correlate with other clinical parameters. Multivariable logistic regression analysis (explanatory variable: every item showing a significant difference by each analysis) revealed that hallucination significantly correlated with UI [Odds ratio (OR), 4.489; 95% confidence interval (CI), 1.432 to 14.617; p = 0.010] and dementia significantly correlated with HY stage 5/3 (OR, 5.304; 95% CI, 1.327 to 22.948; p = 0.018).

Conclusions: Our results suggest that among patients with PD, the presence of hallucination, dementia, and delusions may be related to UI, HY stage, and Dys, respectively.

160

Parkinson's disease psychosis (PDP): Characteristics of the PDP patient in clinical practice

J. Norton, D. Fredericks, R. Suresh, R. Mills (San Diego, CA, USA)

Objective: To characterize the typical PDP patient across a variety of dimensions.

Background: PDP is a prevalent neuropsychiatric manifestation with lifetime prevalence in Parkinson's disease (PD) patients of up to 50%. The PDP patient's care is complex due to the need to not only manage the symptoms of Parkinson's but also a variety of non-motor issues, including psychosis.

Methods: 214 physicians (132 neurologists, 37 psychiatrists, and 45 primary care physicians) were asked to participate in a questionnaire on PDP patients. Patients with Schizophrenia, Schizo-affective disorder or Bipolar disorder were ruled out. Patient records were required to include:

• 2 records for patients currently being treated with an antipsychotic.

• 1 record for patients currently being treated with either an anti-psychotic, anti-depressant or anti-dementia agent.

• 1 record for patients managed through modification of PD medications.

A total of 716 patient records were collected and reviewed.

Results: The chart review revealed that the typical PDP patient was 74 years of age, male (63%), and on Medicare (74%). The majority of PDP patients were living at home and being managed in an office setting (54%), while 19% were in a long term care setting. 89% had some type of caregiver support, typically by an unpaid caregiver. The reported psychotic symptoms varied, with 50% reporting hallucinations, 33% delusions, 33% lack of impulse control, 32% paranoia, and 25% aggressive behavior. In 60% of the PDP patients, the onset of psychotic symptoms developed at an average age of 67 and within 4 years of initial PD diagnosis. The PDP patient typically had more severe PD and a higher incidence of comorbidities, particularly Alzheimer's disease and renal dysfunction. Additionally, 71% of PDP patients suffered from sleep disorders.

Conclusions: The PDP patient is typically older and has a significant number of comorbidities adding to the complexity of their treatment. Current literature suggests that PDP patients suffer primarily from hallucinations within the latter half of the first decade after diagnosis; however, this study found that delusions, impulse control issues, paranoia and aggressive behavior are also common and occur earlier in the course of the disease. Because of the severity of these symptoms treatment should be considered earlier.

161

Risk factors for psychosis in patients with Parkinson's disease

M.S.G. Rocha, R.G. Borges, C.D.M. Costa, M.O. Oliveira, S.M.D. Brucki, F.F. Godinho, P.C. Gordon (Sao Paulo, Brazil)

Objective: The aim of this study is to evaluate risk factors, particularly sleep alterations and dementia, associated with psychosis diagnosis in PD.

Background: Parkinson's disease (PD) patients frequently present psychotic symptoms that have been associated with old age, duration of PD, and cognitive impairment. Depression and sleep abnormalities are also related to these factors.

Methods: This is a cross-sectional evaluation of 94 consecutive patients from a Movement Disorder's clinic. A neurologist performed clinical evaluation. Behavioral questionnaires were applied by a psychiatrist, who used structured interview with both patient and caregiver to define psychosis diagnosis (PC) in accordance with DSM-4 criteria. Clinical evaluation included UPDRS, sleep scales (SCOPA-sleep, Epworth and REM sleep behavior disorder), quality of life (PDQ-39), depression (Beck Inventory), and NINDS criteria for psychosis in PD. Subjects underwent a formal neuropsychological evaluation, with further diagnosis of dementia according with MDS criteria.

Results: Among 94 PD patients (64.5% male, mean age = 64.1 ± 10.1), psychosis was present in 13.8% of cases (13); individuals with PC had significant differences (p<0.01) in relation to patients without PC in relation to diurnal sleep quality (SCOPA-Sleep), more severe diurnal hyper somnolence (Epworth scale), worse quality of life (PDQ39), and more severe depression. Dementia was significantly higher between PC patients (84.6%) than those without psychosis (24.5%). There was no significant difference in severity of REM sleep behavior disorder between groups. Logistic regression analysis, including age, sex, PD duration, UPDRS total score, Hoehn & Yahr stage, daily levodopa equivalent dosage, Beck depression inventory score, sleep scales scores, and postural instability gait disorder score, showed that only dementia and Epworth score were independently associated with PC in PD (p=0.002 for dementia, and p=0.016 for Epworth score).

Conclusions: Our data show that the presence of dementia and diurnal somnolence are strongly associated with PC in PD and reaffirm that, in most patients, psychotic symptoms are probably part of a full spectrum of dementia associated with PD, and not an isolated syndrome.

162

Incidence and severity of impulse control disorders in Parkinson's disease patients treated with dopamine agonists

M.C. Rodríguez-Oroz, R. Ribacoba Montero, A. Rojo-Sebastián, A. Sesar Ignacio, M. Delgado-Alvarado, B. Ares Pensado (San Sebastian, Spain)

Objective: Evaluate the incidence and severity of Impulse Control Disorders (ICDs) among Parkinson's disease (PD) patients treated with dopamine agonists (DAs).

Background: Chronic use of DAs is often associated with side effects among which ICDs are common.

Methods: An observational, descriptive, cross-sectional study was conducted in 4 hospitals in Spain. A total of 159 patients treated with ropinirole, pramipexole or rotigotine were consecutively recruited, 53 patients in each treatment arm. Patients with PD on treatment with a DA for a minimum of 2 years or less if an ICD occurred were eligible to participate. Demographic and clinical data of patients, previous history of DAs and treatment at the time of the study and when an ICD occurred were collected. Clinical features were evaluated using the following scales: Hoenh and Yarh Scale, Unified Parkinson's disease Rating Scale (UPDRS), Questionnaire for Impulsive-Compulsive Disorders (QUIP-PD), QUIP- Rating Scale (QUIP-RS), Barratt Impulsiveness Scale, Novelty Seeking Test, Hospital Anxiety and Depression Scale (HADS) and Parkinson's disease questionnaire (PDQ-8). Patient analysis sets: pramipexole-ropinirole (group A) and rotigotine (group B).

Results: 151 patients were analysed: pramipexole (51), ropinirole (49), rotigotina (51). 64% were male with a mean age of 68 ± 8.8. ICD by clinical criteria occurred in 11% and 14% of patients in groups A and B respectively (p=0.62). QUIP questionnaire showed more gambling and less hobbyism (p<0.05) in group B (gambling A 4% and B14%; hobbyism A 37% and B 20%) without differences in the (QUIP-RS) between the groups. No differences in incidence of ICDs were seen for different cumulative doses of DA Patients in group A were younger and had less years of evolution of the disease (age: A: 67 ± 8.9 and B: 70 ± 8.3; years of disease: A: 8 ± 5.1 and B: 10 ± 5.3). UPRDS and PDQ-8 scores were higher in group B (UPDRS II: A: 12 ± 6.0, B: 16 ± 8.3; UPDRS III: A: 19 ± 9.6, B: 28 ± 13.4; UPDRS IV, A: 2 ±2.3, B: 3.5 ± 2.9; PDQ-8: A: 27 ± 18, B: 35 ± 22). There were no differences in the rest of scales except for HADS (A: 5 ± 3.9, B: 6 ± 4.4), although these scores were below clinical significance.

Conclusions: The incidence of ICD was similar with the different DAs. Rotigotine was more frequently associated with gambling and less with hobbyism than pramipexole and ropinirole but the severity of all ICDs was not different among groups.

163

Left temporal lobe focal EEG abnormalities in Parkinson's disease with visual hallucinations

G.J. Schwartz, M.L. Gordon (Stony Brook, NY, USA)

Objective: To describe electroencephalography (EEG) abnormalities in a cohort of Parkinson's disease (PD) patients with visual hallucinations (VHs).

Background: The cause of VHs in PD remains poorly understood. While dopaminergic medications have been implicated, there is a growing body of evidence suggesting that VHs may be a manifestation of the underlying disease itself. One study has suggested that left hemispheric dysfunction in particular is associated with VHs in PD. Furthermore, the phenomenology of temporal lobe ictal hallucinations resembles those of VHs in PD.

Methods: We conducted a retrospective chart review of PD patients with VHs, who had routine EEGs available for review. This cohort of patients had no clinical evidence of seizures. They underwent routine clinical EEGs to determine whether some of these patients might have electroencephalographic evidence of temporal lobe seizures.

Results: Forty nine EEGs were available for review in 28 patients with PD and VHs. The male:female ratio was 1.5:1, the average age was 79 years, and Parkinsonian motor signs were right-predominant in 70% (p = 0.10 by Chi-square). The mean duration of PD, dopaminergic pharmacotherapy, and VHs was 10, 8 and 3 years, respectively. Formed VHs were present in all patients, although 11% had elementary VHs as well. They were predominantly diurnal, although in 14% of patients they were only hypnopompic. At least one abnormal EEG was found in 85% of patients: generalized background slowing in 79%, intermittent delta activity in 21%, and focal temporal lobe spikes or sharp-waves in 14%. Lateralized focal EEG abnormalities were detected in 17% (n = 5), all of which appeared in the left temporal lobe. The probability of lateralized abnormalities occurring exclusively on the left by chance alone would be less than 4% (p = 0.03).

Conclusions: We found left temporal lobe focal EEG abnormalities in a subset of PD patient with VHs, findings which are consistent with a potential for left temporal lobe epileptogenicity. Furthermore, in this cohort of PD patients with VHs, we found a disproportionate number of those with left hemisphere-predominant Parkinsonism. These findings suggest that left temporal lobe dysfunction may predispose to VHs in PD.

164

Limitations of the BDI-II in PD evaluation: Concordance with the GDS-30

M.J. Sollman, I. Ul Haq, S.S. Kramer, J.F. Cook, J.G. Hesse, M.S. Siddiqui, A.W. Laxton, S.B. Tatter (Winston Salem, NC, USA)

Objective: To evaluate diagnostic utility and operating characteristics of the BDI-II in Parkinson's disease (PD) patients undergoing neuropsychological assessment as part of routine care or Deep Brain Stimulation surgery (DBS) evaluation.

Background: The presence of Depression in PD has relevance to QOL (Jones et al., 2014), suicidal ideation, and DBS planning. A high estimated prevalence of minor or major depression in PD (20-45%) suggests strong need for routine screening. Tremendous research has supported use of the BDI-1a as a screening instrument in this population. Less knowledge is available about the BDI-II, while very similar to its predecessor (see Inoue et al., 2010).

Methods: We examined concordance between the BDI-II and GDS-30, another well-validated measure of depression that places significantly less emphasis on somatic symptoms (Ertan et al., 2015; Schrage et al., 2007). Participants were 204 PD-positive, well-educated older adults (mean education 14 [SD=2.9] years) undergoing full neuropsychological evaluation as a part of routine care or DBS work-up(71%). The International Parkinson and Movement Disorder Society (MDS) Task Force-recommended score of 9/10 (Schrage et al., 2007) was used for the GDS-30, and published cut score of 14/15 was used for the BDI-II.

Results: In the overall sample, 33.0% of patients screened positive with the GDS-30 compared to only 6.7% with the BDI-II, despite its inclusion of somatic symptoms. Concordance in 120 patients administered both screens suggests a BDI-II sensitivity of .71 and a specificity of 1.0 (GDS-30 = 28.3%, BDI-II = 8.3%, hit rate = .80). The rate of detection was not grossly different in the subset of 86 pre-DBS patients (26.7% versus 5.8%). The sample had similar prevalance of apathy (30%) as found in other studies (e.g., Zahodne et al., 2012). Maximizing sensitivity of the BDI-II while maintaining adequate specificity required a cut score of < 4 in this sample (AUC=.915, Sn=1.0, Sp = .826).

Conclusions: Our data suggest the BDI-II grossly underestimates the likelihood of current minor or major Depression in PD patients using validated cut scores. This does not appear to be due to presentation management of pre-DBS patients. Lowering the BDI-II cut score to maximize sensitivity was not a reasonable solution in this sample. The GDS-30 is felt to be additionally beneficial in offering two questions of hopelessness.

165

Brain regions associated with neuropsychiatric symptoms in patients with Parkinson's disease: An analysis of cerebral blood flow using 123I-iodoamphetamineSPECT

H. Tachibana, K. Kawabata, T. Yamanishi, H. Nishimura, T. Tokunaga, T. Nakajima (Nishinomiya, Japan)

Objective: To analyze correlations between rCBF and neuropsychiatric symptoms such as cognitive impairment, depression, apathy, and anxiety.

Background: Mental impairments and neuropsychiatric symptoms can appear in patients with Parkinson's disease (PD), which may affect regional cerebral blood flow (rCBF).Previous human imaging studied failed to achieve a consensus regarding regional changes associated with these symptoms in patients with PD.

Methods: Thirty-three patients with PD (mean age, 71.7 years) underwent brain SPECT using 123I-iodoamphetamine.SPECT images were constructed using the 3D-SSP program. Correlational analyses between rCBF reduction and the degree of neuropsychiatric symptoms were performed using SSPcor.exe program. In voxel-by-voxel correlation between rCBF and clinical parameters, the statistical results were expressed as Z score on surface projections maps. PD patients completed the Beck Depression Inventory 2nd edition (BDI-II),the State-Trait Anxiety Inventory (STAI), and Starkstein's Apathy Scale (AS) . The Hoehn and Yahr (HY) staging, the Unified Parkinson's disease Rating Scale (UPDRS) and Mini-Mental State-Examination (MMSE) were administered on the same day.

Results: The mean scores of MMSE,BDI-II, AS and STAI were 27.4, 17.0, 17.4 and 49.4, respectively. The mean values of duration of illness and HY scale were 7.4 years and 2.9, respectively. Significant correlations between rCBF and MMSE score were found particularly in bilateral frontal cortices. Significant negative correlations between rCBF and BDI-IIscores were noted in bilateral temporal, parietal and occipital cortices, precuneus, posterior cingulated cortex and cerebellum. Correlations in similar areas were observed between rCBF and AS scores. In the STAI score, negative correlations were found in bilateral parieto-temporo-occipital cortices, medial part of frontal cortex and cerebellum.

Conclusions: Present results suggest that there are some differences in associated brain regions among these major neuropsychiatric symptoms and cognitive impairment in PD patients.

166

Dopaminergic medication increases risky choice via decreasing loss aversion in depressed but not in non-depressed Parkinsonian patients

M. Timmer, G. Sescousse, P. Piray, R. Esselink, R. Cools (Nijmegen, Netherlands)

Objective: To investigate dopaminergic drug effects on loss aversion – defined as the relative weighting of gains and losses during risky choice – in depressed and non-depressed patients with Parkinson's disease (PD).

Background: Dopaminergic medication is known to trigger undesirable side effects such as impulse control disorders (ICDs) in patients with PD. However, these side effects only occur in a subgroup of patients, presumably reflecting an underlying vulnerability related to ventral striatal function. Depression, which is associated with ventral striatal dysfunction, is a frequent non-motor symptom of PD. Here we hypothesize that it might constitute a vulnerability factor for developing ICDs following dopaminergic medication, eventually leading to risky behavior.

Methods: Depressed and non-depressed PD patients performed a well-established gambling task designed to measure loss aversion during risky choice. Dopaminergic drug effects on loss aversion were investigated using a within-subject design, in which patients were assessed on two occasions - once after taking their normal dopaminergic medication (ON) and once after withdrawal of their medication (OFF).

Results: Dopaminergic medication induced differential effects on loss aversion in depressed and non-depressed PD patients. While there was no clear drug effect on loss aversion in non-depressed PD patients, dopaminergic medication significantly reduced loss aversion (i.e. increased risky choice) in currently depressed PD patients. Furthermore, the degree to which medication reduced loss aversion correlated with current depression severity and with drug effects on depression scores. Medication-related reductions in loss aversion were greater in more severely depressed patients and in patients who exhibited greater medication-related decreases in depression scores.

Conclusions: Dopaminergic medication increases risky choice via decreasing loss aversion in depressed but not in non-depressed PD patients. These data suggest that side effects of dopaminergic medication in the domain of risky choice might differ between depressed and non-depressed PD patients.

167

Withdrawn by Author

 

Parkinson's disease: Clinical trials, pharmacology and treatment

168

Repeated intravenous amantadine infusions in advanced Parkinsonism: The preliminary Tel-Aviv Medical Center experience

M. Abu Snineh, T. Nussbaum, A. Hindi, A. Rosenberg, J. Knaani, A. Ezra, N. Giladi, T. Gurevich (Tel Aviv, Israel)

Objective: To summarize our experience with repeated intravenous Amantadine in patients with advanced Parkinsonism.

Background: Few studies have examined the effect of intravenous amantadine infusions in advanced Parkinsonism.

Methods: The medical files of 30 patients were reviewed. They received IVAM once every 3-4 weeks in the setting of neurological day care service. Patients and caregivers participated in a structured interview on clinical global impression of changes scale (CGICS) regarding various symptoms. Treatment was initiated by a loading dose of 200/400 mg for 5 days followed by a once every 2-3 weeks dosage of 200/400 mg depending on the duration of treatment effect.

Results: Thirty patients (12 females) participated in the study. Nineteen had PD, 5 had multiple system atrophy (MSA) Parkinsonian type, 3 had MSA cerebellar type, 2 had vascular Parkinsonism, and 1 had diffuse Lewy body disease. Their mean age was 73.27 ± 9.67 years, average disease duration 5.5 ± 4.8 years, and H&Y score 3.16 ± 0.87. The average levodopa dose was 1051 ± 1782 mg. The mean IVAM treatment duration was 22.9 ± 11.26 months. Most (76%) of the patients reported an improvement in tremor and rigidity, and an improvement in stability and falling reduction (79%).

An unexpected significant improvement of constipation was reported by 4 patients (20%, p =0.012). Overall 91% of the patients and 81% of the caregivers reported improvement in general functioning.The main advantages of the treatment according to the patients was gait improvement and decrease in the dosage of antiParkinsonian drugs (8 patients). Three patients reported treatment-related confusion and urinary complaints.

Conclusions: The results of this retrospective open-label study indicated that repeated IVAM were effective and safe in patients with Parkinsonism. Controlled double blind studies for exclusion of a placebo effect are warranted.

169

A randomized controlled trial of telemedicine for Parkinson's disease (Connect.Parkinson) in the United States: Interim assessment of investigator and participant experiences

M.A. Achey, C.A. Beck, D.B. Beran, C.M. Boyd, P.N. Schmidt, A.W. Willis, S.S. Riggare, R.B. Simone, K.M. Biglan, E.R. Dorsey, J. Aldred, J. Ayan, M.T. Bull, J. Carter, K. Duderstadt, B. Dunlop, N.B. Galifianakis, P. Hickey, C.B. Hunter, J. Jimenez-Shahed, H.T. Keenan, R.E. Korn, Z. Mari, N.I. Meijia, J.C. Morgan, M.A. Nance, S.A. Parashos, I.H. Richard, L.C. Shih, M.A. Spindler, C. Wielinski, C. Zadikoff (Rochester, NY, USA)

Objective: The Connect.Parkinson's study aims to assess the feasibility, efficacy, impact on quality of care, and value to patients and families of home telemedicine visits for Parkinson's disease (PD).

Background: This is the first national randomized comparative effectiveness study of telemedicine for PD.

Methods: Participants are recruited via PD community website and social media outreach, e-mails to advocacy groups, and outreach to primary care providers in underserved areas. Participants are randomly assigned to usual care or usual care plus 4 telemedicine visits with a specialist. Primary outcomes include feasibility, measured by percentage of telemedicine visits completed, and efficacy, measured by change in PDQ-39. Secondary outcomes include blinded MDS-UPDRS scores. Here we report preliminary enrollment, retention, and satisfaction.

Results: As of January 2015, 87 people (44% of 200 planned) are enrolled and 61 (70%) have been randomized. Four have withdrawn, due to disappointment at randomization to control (n=1), preference of local provider (n=1), and technology incompatibility (n=2). Participants’ mean age is 65, mean disease duration is 8 years (range 1-22), and 51% are women. The 29 telemedicine participants are younger (mean 63) than the 32 usual care participants (mean 67) (p<0.05), while gender distribution and disease duration are similar (p>0.05).

To date, 27 telemedicine visits have been completed, 93% as scheduled. Median visit duration is 51 minutes, 42 (82%) of which are spent with investigators. Participants report spending 120 minutes (median) away from home for their last in-person appointment, 30 (25%) with a provider. All participants report being “very satisfied” or “satisfied” with the care, comfort, and overall experience of telemedicine. Video quality remains a limitation: for 38% of initial telemedicine visits, investigators were “highly unsatisfied” (14%) or “unsatisfied” (24%) with their ability to perform the MDS-UPDRS motor assessment. However, 21 visits (78%) were rated “highly satisfactory” or “satisfactory” overall by investigators.

Conclusions: Participants are highly satisfied with telemedicine visits. Investigators are modestly satisfied, but connection quality remains a challenge. Future results of participant-reported and blinded outcomes will enable comparison of telemedicine care to usual care.

170

Pharmacokinetics, safety and tolerability of sub-lingually administered APL-130277 compared to subcutaneous apomorphine in healthy volunteers

A. Agro, J. Dubow, L. Toong-Chow, A. Giovinazzo (Toronto, Canada)

Objective: To evaluate the pharmacokinetics, safety and tolerability of 2 doses of Sub-lingually administered APL-130277 (APL) compared to subcutaneous apomorphine (SC Apo) in healthy volunteers.

Background: Parkinson's disease (PD) patients suffer from a variety of “Off” episodes as the disease progresses. These consist of wearing off, delayed-On or dose failures, sudden Offs and morning akinesia. The only acute and effective rescue medication for these “Off” episodes is apomorphine administered subcutaneously. Easier to administer rescue treatments are needed. APL is a soluble film strip of apomorphine delivered sub-lingually, designed to deliver apomorphine rapidly through absorption from the oral cavity.

Methods: This was a single-center, Phase 1 trial in healthy volunteers that assessed the single-dose pharmacokinetics, safety and tolerability of APL administered to two cohorts (10mg and 15 mg) in a cross over design as compared to 2 mg and 3 mg of SC Apo (10 mg APL received 2 mg SC Apo and 15 mg APL received 3 mg of SC Apo). Subjects were dosed with APL film strip on the underside of the tongue with the drug layer facing the bottom of the tongue. Subjects were pre-medicated with 3 days of domperidone, which was continued during treatment.

Results: The mean Cmax, Tmax, T1/2 and AUC for APL 10 mg (N=13), APL 15 mg (N=12), SC Apo 2 mg (N=13) and SC Apo 3 mg (N=12) are outlined in Table 1. Mean plasma levels are presented in Figure 1. The time spent above 3 ng/ml (the typical plasma level for a patient to go from “Off” to “On”) was longer for APL compared to SC Apo and the number of subjects reaching the minimal toxic concentration (8.5 ng/ml) was lower for APL compared to SC Apo.

Table 3. Mean Pharmacokinetics of APL-130277 and SC Apomorphine
Dose Cmax (ng/ml) Tmax (min) T1/2 (min) AUCLast (min*ng/ml) AUCinf (min*ng/ml)
APL-130277 10 mg 5.45 34.2 56.5 509 543
SC apomorphine 2 mg 9.78 20.4 42.1 597 612
APL-130277 15 mg 8.02 39.2 54.7 804 854
SC apomorphine 3 mg 16.2 26.7 40.1 996 1022

[figure1]

APL was safe and well-tolerated. A higher incidence of AEs of nausea and vomiting were reported when subjects crossed over from APL to SC Apo (Table 2). There was a higher incidence of related AEs and moderate AEs with SC APO than with APL and the only severe AE of seizure occurred with SC APO 3 mg. There were no discontinuations due to AE.

Table 4. Number and Percentage of Subjects With Adverse Events On APL-130277 Compared to Subcutaneous Apomorphine
Adverse Event APL 10 mg N(%) N=13 SC Apo 2 mg N(%) N=13 APL 15 mg N(%) N=14 SC Apo 3 mg N(%) N=14
Any AE 5(38) 11(85) 13(93) 12(86)
Related AE 5(38) 9(69) 11(79) 12(86)
Moderate AE 2(15) 5(38) 4(29) 11(79)
Sleepiness 0 3(23) 11(79) 10(71)
Nausea 2(15) 4(31) 3(21) 8(57)
Dizziness 3(23 4(31) 7(50) 7(50)
Vomiting 0 0 2(14) 5(36)
Yawning 0 0 0 3(21)

Conclusions: Sub-lingually administered APL reaches therapeutic blood levels comparable to SC Apo but remains in the therapeutic window for a longer duration of time with less dopaminergic and severe adverse events compared to SC Apo. APL-130277 may offer an easy to administer, rapid, on-demand treatment of “Off” episodes in PD patients.

Details are in the caption following the image

(170).

171

Pharmacokinetics, safety and tolerability of high-dose sub-lingually administered APL-130277 in healthy volunteers

A. Agro, J. Dubow, L. Toong-Chow, A. Giovinazzo (Toronto, Canada)

Objective: To evaluate the pharmacokinetics, safety and tolerability of sub-lingually administered APL-130277 (APL) 25 mg in healthy volunteers.

Background: Parkinson's disease (PD) patients suffer from a variety of “Off” episodes as the disease progresses. These consist of wearing off, delayed-On or dose failures, sudden Offs and morning akinesia. The only acute and effective rescue medication for these “Off” episodes is apomorphine administered subcutaneously. Easier to administer, convenient rescue treatments are needed. APL is a soluble film strip of apomorphine delivered sub-lingually, designed to deliver apomorphine systemically through absorption from the oral cavity. This is the highest dose of APL studied in healthy volunteers.

Methods: This was a single-center, randomized, double-blind, placebo-controlled Phase 1 trial in healthy volunteers assessing the single-dose pharmacokinetics, safety and tolerability of APL 25 mg. Subjects were pre-medicated with 3 days of the anti-emetic domperidone, which was continued during treatment.

Results: Eleven subjects were dosed with APL and two with placebo. The mean Cmax was 11.2 ng/ml, Tmax was 41.5 minutes, t1/2 was 62.2 minutes, AUCLast was 1102 min*ng/ml, and AUCinf was 1204 min*ng/ml. The mean plasma concentration over time is presented in Figure 1. It took approximately 7 minutes to reach the minimum threshold concentration necessary to achieve efficacy in patients (3 ng/ml). A concentration greater than this threshold was maintained for 154 minutes. [figure1]

Incidence of adverse events reported with APL 25 mg are presented in Table 1. The events were mostly mild to moderate in severity, except for dizziness, which was reported to be severe in three subjects. No serious adverse events occurred.

Incidence of Adverse Events with APL 25 mg in 2 or more Subjects
Type of AE N(%) N=11
Any AE 11(100)
Related AE 11(100)
Dizziness 9(82)
Sleepiness 9(82)
Nausea 4(36)
Vomiting 4(36)
Feeling Cold 2(18)
Hypotension 2(18)

Conclusions: APL 25 mg administered sub-lingually demonstrates a favorable PK profile to support a rapid and sustained effect for the relief of “OFF” episodes in Parkinson's disease patients. Time to reach a minimum efficacious concentration was under 10 minutes and apomorphine levels were maintained above this concentration for over 2.5 hours. Although dopaminergic AEs were relatively high in healthy volunteers, these are expected to be lower in PD patients already on dopaminergic medications and with impaired dopamine production. APL-130277 may offer easy to use, rapid, on-demand management of “Off” episodes in PD patients.

Details are in the caption following the image

(171).

172

Therapeutic dancing for people with Parkinson's disease: A systematic review of its effects on mobility and quality of life

L.C. Aguiar, M.E. Morris (Melbourne, Australia)

Objective: This systematic review evaluated studies on the outcomes of different dance genres for mobility and quality of life in PD (1). The emphasis was on walking speed, freezing and participant wellbeing. The feasibility and safety of trials were also examined (2).

Background: Therapeutic dancing has recently been advocated as an effective adjunct to conventional physical therapies for people living with Parkinson's disease (PD).

Methods: Studies were identified through a detailed search of online databases including CINHAL (1982-2014), Medline (1922-2014), Scopus (1996-2014), Web of Science (2002-2014), Embase (2007-2014), PEDro (1999-2014) and the Cochrane Library (1996-2014). Parkinson's disease, Paskinson*, Parkinsonism, dance, dance therapy, dance genres, safety, feasibility, quality of life. Two independent investigators (LA & PR) completed the full text assessment. Only randomized controlled trials (RCTs), quasi-RCTs and case series were included.

Results: We found that therapeutic dancing was beneficial for improving motor performance, mobility and balance in some people living with PD. Dancing also had a positive impact on quality of life and adherence to physical activity over the long term. Dancing may improve freezing of gait, walking speed and participant wellbeing in some individuals However, just a few studies described thoroughly the evaluations of these outcomes. Little was reported on the effects of partnered versus non-partnered dancing, the use of different dance genres in mixed dancing classes, efficacious scheduling of therapy, the frequency of dance therapies, the effects of different music genres, participant satisfaction with therapy, socialisation, or retention of improvements associated with therapeutic dance intervention. Moreover there was little information about the advantages of caregiver participation on the therapy, which may be closely correlated with participant compliance. Therefore, more research is needed to comprehensively evaluate these aspects of dancing programs.

Conclusions: There was emerging evidence that dance therapy is safe and feasible for people with mild to moderately severe PD, with beneficial effects on walking speed, freezing and health related quality of life in some individuals.

173

Efficacy of safinamide in early Parkinson's disease: Results of pooled analysis

R. Anand, R.D. Hartman, V. Lucini, E. Forrest, R. Giuliani, M. McBride (St. Moritz, Switzerland)

Objective: Analyses were performed to determine if the significant benefits noted with safinamide as an add-on to early-stage PD patients in three DA-agonist monotherapy (ESPD) trials extend to multiple measures of clinical relevance in pooled data analyses.

Background: Safinamide (50 and 100mg/day) add-on to DA-agonist monotherapy given in non-fluctuating patients (Studies 009, 015 and MOTION) demonstrated significant benefit on the primary efficacy measure (UPDRS III) and selected secondary measures.

Methods: Analyses of data pooled from ESPD studies were performed on a modified Intent-to-Treat Population (mITT). Patients were assigned to a treatment group based on the randomized targeted dose (placebo; safinamide 50 or 100 mg/day). The difference between treatment groups was compared using Mixed Model Repeated Measures (MMRM) and Analysis of Covariance (ANCOVA) for continuous measures (UPDRS I, II, III, II+III and I+II+III) and logistic regression (chi-square test) for categorical ones (improvements of ≥ 30%, 40%, 50% in UPDRS III, ≥ 20% and 30% in UPDRS II+III, and improvement in CGI-Change [CGI-C]).

Results: The pooled analyses included 649 patients on safinamide and 349 on placebo without significant differences between treatment groups in demographics, disease characteristics (PD duration, Hoehn &Yahr stage, UPDRS scores, CGI-S, dosage/type of DA-agonist). Statistically significant improvements were noted for the MMRM and ANCOVA analyses for safinamide 100mg/day, compared with placebo, for the mean change (LS diff vs. placebo) in UPDRS Sections II (-0.5, p=0.0011), III (-1.2, p=0.0003), II+III (-1.6, p=0.0001) and I+II+III (-2.0, p=0.0035). A significantly (p<0.05) greater proportion of patients in both safinamide group met each of the above responder criteria. The percentages of patients meeting the most stringent responder criteria were: ≥ 50% in UPDRS III [50 mg: 11.4% (p=0.027), 100 mg: 14.4% (p=0.003), Pbo: 7.6%]; ≥ 30% in UPDRS II+III [50 mg: 25.4% (p=0.005), 100 mg: 29.3% (p=0.003), Pbo: 20.1%]; and any improvement in CGI-C [50 mg: 45.5% (p=0.018), 100 mg: 48.2% (p=0.016), Pbo: 39.6%].

Conclusions: Pooled analyses of safinamide studies in patients on DA-agonist monotherapy demonstrated statistically significant and clinically relevant benefits for motor symptoms, activities of daily living, and global evaluation for both the 50 and 100mg/day doses compared with DA-agonist monotherapy.

174

Early onset and duration of effect of safinamide in patients with motor fluctuations

R. Anand, R.D. Hartman, V. Lucini, E. Forrest, R. Giuliani, M. McBride (St. Moritz, Switzerland)

Objective: To determine the onset of efficacy of safinamide on key efficacy measures by analysis of the data at all study visits in both the 016 and SETTLE studies.

Background: Safinamide add-on to levodopa in fluctuating patients demonstrated significant superiority over standard of care in the 24-week studies 016 and SETTLE on the primary (ON Time without troublesome dyskinesia) and secondary (OFF Time, UPDRS III) measures. Study 016/018 also demonstrated persistence of benefit for 2 years.

Methods: The two studies differed in the visit schedules and dosing. In Study 016 patients were randomized to fixed doses of 50 or 100mg/day of safinamide or placebo; in the SETTLE patients were randomized to placebo, or a starting dose of safinamide 50 mg/day that was increased to 100 mg/day not earlier than 2 weeks. Additionally, the first assessment visit for 016 and SETTLE was at Week 4 and Week 2, respectively. These differences precluded data pooling for determining both onset of efficacy and duration of benefit. Analyses (t-tests) were performed to determine the change in ON and OFF Time in safinamide-treated patients compared to placebo (ITT population).

Results: In both studies 016 (n=669) and SETTLE (n=559), the mean ON and OFF Time at baseline were comparable among all treatment groups. Statistically significant differences between safinamide and placebo were evident at all post-baseline visits for ON and OFF Time. The first post-baseline assessment visit at Week 2 for SETTLE showed a highly statistically significant (p=0.0003) increase in median ON Time of 1 hr for safinamide, compared with 30 min for placebo, and a decrease in median OFF time (p<0.0001, 1 hr for safinamide and 30 min for placebo). Similarly, in Study 016 the first post-baseline assessment visit at Week 4 showed a statistically significant (p=0.017) increase in median ON Time [40 min for safinamide (50 and 100 mg/day) compared with 20 min for placebo], and a decrease in median OFF Time (p<0.01, 45 min for safinamide and 15 min for placebo). Onset of efficacy for the UPDRS III was first noted at Week 4.

Conclusions: Safinamide was associated with statistically significant benefit already at the first assessment (Week 2 or 4) for ON and OFF Time. These rapid improvements in patients on standard of care suggest that safinamide's dual mechanism produces benefits that will be appreciated by patients, caregivers and physicians.

175

Efficacy and safety of levodopa-carbidopa intestinal gel in patients with less than 10 years of Parkinson's disease – Interim results from the GLORIA long-term registry

A. Antonini, K.R. Chaudhuri, L. Bergmann, A. Yegin, K. Onuk, W. Poewe (Venice, Italy)

Objective: To evaluate the efficacy of Levodopa-Carbidopa Intestinal Gel (LCIG) in a subgroup of advanced Parkinson's disease (PD) patients of relatively younger age and shorter disease duration.

Background: LCIG is a long-term treatment option for advanced PD patients. The efficacy and safety of LCIG in <60 year-old advanced PD patients with <10 years of disease have not been reported.

Methods: This 24-month prospective, observational study of LCIG included 374 patients with advanced PD at 75 centers in 18 countries. A post-hoc subgroup analysis was conducted on safety and efficacy data collected on/before 3rd January 2014 from patients who were <60 years old with <10 years of disease at baseline. Efficacy and quality of life (QoL) were evaluated by the mean change from baseline to 12 months (12M) on the Unified Parkinson's disease Rating Scale (UPDRS) part II, III, IV (items 32 and 39), Non-Motor Symptoms Scale (NMSS) total score and 8-item Parkinson's disease Questionnaire (PDQ-8) total score. Adverse drug reactions (ADR) were evaluated throughout the study. Baseline was the first visit before the start of LCIG infusion.

Results: There were 28 (8.2%) patients in the subgroup of patients who were <60 years old with <10 years of disease, 15 (53.6%) of which completed ≥12M of the study. At baseline, this subgroup had a mean (SD) age of 52.5 (5.7) years, 6.1 (1.9) years disease duration, and 19 (67.9%) were male. At baseline this subgroup had mean (SD) levodopa dose of 914.0 (396.0) mg and a higher level of ‘off’ time and lower level of UPDRS sections II and III scores relative to the total population (Table 1).[ref1] There were significant decreases from baseline to 12M in hours of ‘off’ time and NMSS total score, and no significant changes in hours of dyskinesia or QoL scores. In this subgroup, there were 12 (42.9%) patients with ≥1 ADR, 5 (17.9%) with ≥1 serious ADR, and 1 (3.6%) who discontinued due to an ADR.

Motor and Non-Motor Efficacy Measures in a Relatively Early Disease Subgroup and Total Population of Advanced Parkinson's disease Patients
Total Population at BL (n=343)(a) Earlier Disease Subgroup(b) at BL (n=26) Earlier Disease Subgroup(b) Change from Baseline at 12M
Efficacy and Quality of Life Assessments Mean ± SD Mean ± SD n Mean ± SD
Unified Parkinson's disease Rating Scale (UPDRS):
Part II (activities of daily living score) 16.3 ± 9.9 11.4 ± 7.5 12 -2.7 ± 6.4
Part III (motor score) 24.5 ± 11.9 18.0 ± 9.8 14 -4.9 ± 9.2
Part IV item 32 (hours of dyskinesia/day) 4.4 ± 3.8 4.3 ± 4.7 11 -1.5 ± 3.1
Part IV item 39 (hours of ‘off’ time/day) 6.0 ± 3.2 8.0 ± 3.3 10 -6.7 ± 2.2***
Non-Motor Symptom Scale (NMSS) total score 69.2 ± 42.1 76.3 ± 40.3 13 -32.9 ± 46.5*
8-item Parkinson's disease Questionnaire (PDQ-8) total score 46.5 ± 18.7 44.2 ± 18.2 12 13.8 ± 32.1
  • a Ref 1; b Defined as advanced PD patients <60 years old and with <10 years of disease; *Two-sided P<0.05, ***Two-sided P≤0.0001; BL = baseline, 12M = month 12; SD = standard deviation.

Conclusions: Although the sample sizes were limited, LCIG reduced ‘off’ time and non-motor symptoms in a subgroup of patients in a relatively early disease stage. The observed ADR profile in this subgroup was consistent with the established safety profile of LCIG.

176

Efficacy of rotigotine at different stages of Parkinson's disease symptom severity and disability: Post hoc analysis according to baseline Hoehn & Yahr staging

M. Asgharnejad, L. Bauer, F. Woltering (Raleigh, NC, USA)

Objective: To investigate the efficacy of rotigotine transdermal patch across different stages of Parkinson's disease (PD) symptom severity and functional disability.

Background: The efficacy of rotigotine has been demonstrated in studies of patients with early-stage PD (defined as not receiving levodopa) and advanced-stage PD (defined as receiving levodopa). Here we aimed to further investigate the benefit of rotigotine throughout the PD patient journey, based on symptom severity and disability according to baseline Hoehn & Yahr (HY) stage. The HY is a descriptive five-point staging scale that provides an estimate of clinical function in PD (motor symptom severity and relative level of disability); it ranges from 1: ‘unilateral involvement, minimal/no functional disability’, to 5: ‘confined to bed/wheelchair unless aided’ [1].

Methods: Post hoc analysis of 7 placebo-controlled studies of rotigotine in patients with early-PD (SP506, SP512, SP513; rotigotine ≤8 mg/24h) or advanced-PD (SP511, SP515, SP650, SP921; rotigotine ≤16 mg/24h), with maintenance phase ≥7 weeks. Data from the studies were pooled, and patients stratified according to HY stage at baseline (HY stage 1, 2, 3, or 4). For each HY stage, change from baseline to end of maintenance is reported for Unified Parkinson's disease Rating Scale (UPDRS) II+III total score, and UPDRS II and III subscores. P-values are exploratory only.

Results: Data were available for 2363 patients: HY stage 1, n=274; HY 2, n=1304; HY 3, n=692; HY 4, n=93. Compared to patients at a lower HY stage, patients at higher HY stages were generally older, had a longer time since PD diagnosis, more likely to be receiving levodopa (and at higher doses), and higher baseline UPDRS II+III total scores (Table 1). Rotigotine improved UPDRS II+III total score vs placebo for each individual HY stage (p<0.01 for all individual HY stages) (Table 2). Similar results were observed for UPDRS II and III subscores (p<0.01 for individual HY stages).

Conclusions: This post hoc analysis suggests that rotigotine transdermal patch is efficacious in patients with PD across the stages of the disease from mild symptoms/minimal functional disability (HY stage 1) to increasing symptom severity and disability (HY stage 4). These data support the use of rotigotine across the progressive stages of PD.

1. Goetz CG, et al. Mov Disord. 2004;19:1020-8.

Mean (±SD) baseline score Mean (±SD) change from baseline
Full analysis set, last observation carried forward Placebo Rotigotine Placebo Rotigotine LS mean [95% CI] treatment difference vs placebo, ANCOVA* p-value
HY stage 1 22.1 ± 7.25 (n=80) 22.5 ± 9.20 (n=194) -2.0 ± 6.88 -5.6 ± 8.85 -3.17 [-5.19,-1.16] 0.002
HY stage 2 32.2 ± 12.60 (n=409) 32.2 ± 12.83 (n=895) -2.2 ± 10.62 -7.3 ± 10.47 -5.03 [-6.19,-3.87] <0.001
HY stage 3 42.0 ± 16.63 (n=211) 42.8 ± 16.70 (n=481) -3.1 ± 13.57 -8.1 ± 11.83 -5.18 [-7.10,-3.26] <0.001
HY stage 4 65.8 ± 18.62 (n=32) 64.7 ± 18.23 (n=61) -3.8 ± 9.74 -15.3 ± 13.93 -11.33 [-16.43,-6.22] <0.001
  • *Analysis of covariance (ANCOVA) model adjusted for baseline UPDRS score and study. All p-values presented are exploratory in nature and do not infer statistical significance. UPDRS, Unified Parkinson's disease Rating Scale; CI, confidence interval; SD, standard deviation; LS, least squares
Table 7. Demographic and baseline characteristics by HY stage at baseline
Full analysis set HY stage 1 (unilateral involvement, minimal/no functional disability) N=274 HY stage 2 (bilateral involvement, no impairment of balance) N=1304 HY stage 3 (mild/moderate disability, impaired postural reflexes) N=692 HY stage 4 (severe disability, but able to walk/stand unaided) N=93
Age, mean ± SD, years 58.9 ± 10.5 62.8 ± 9.6 65.3 ± 10.0 69.0 ± 8.4
Male, n (%) 176 (64.2) 872 (66.9) 417 (60.3) 56 (60.2)
Caucasian 261 (95.3) 1110 (85.1) 601 (86.8) 85 (91.4)
Time since PD diagnosis, mean ± SD, years 1.3 ± 1.72 5.0 ± 4.24 6.8 ± 4.94 10.4 ± 5.43
Receiving levodopa at baseline, n (%) 17 (6) 775 (59) 560 (81) 93 (100)
Levodopa dose at baseline (mg/day), mean ± SD 473.5 ± 256.25 698.6 ± 449.51 724.7 ± 405.04 809.9 ± 418.61
UPDRS II+III total score, mean ± SD 22.4 ± 8.67 32.2 ± 12.76 42.6 ± 16.67 65.0 ± 18.27
  • UPDRS, Unified Parkinson's disease Rating Scale; SD, standard deviation

 

177

Adverse effects of amantadine in patients of Parkinson's disease- A cross sectional study

K. Bahrani, V. Goyal, G. Shukla, M. Vanathi, M. Behari (New Delhi, India)

Objective: To evaluate the adverse effects of amantadine in patients of Parkinson's disease with special reference to corneal endothelial toxicity.

Background: In outpatient door consultation, some patients complain of visual problems on changing dose of amantadine. Anti-cholinergic drugs also cause visual blurring and are usually co-prescribed, which creates problem that which drug is causing visual symptoms. Amantadine can rarely cause corneal endothelial cell degeneration leading to visual loss, which is partially reversible.

Methods: A total of 120 Parkinson's patients with 90 patients on amantadine (≥6 months) & 30 amantadine naïve Parkinson's patients along with 30 age and gender-matched healthy controlswere enrolled. The amantadine treated group was divided into 3 sub-groups according to daily dosage of amantadine, with 30 subjects in each subgroup on 200 mg/300 mg/400 mg of amantadine daily.

Endothelial indices were compared between Parkinson's patients on amantadine (≥6 months), amantadine naïve Parkinson's patients & age-gender matched healthy controls. Other signs & symptoms of amantadine induced pedal edema, livedoreticularis (LR), visual hallucinations were also screened.

Outcome Measures: Endothelial cell density, Coefficient of variation, Hexagonality, proportion of Parkinson's patients with pedal edema/livedoreticularis on amantadine.

Results: The amantadine group had lower ECD (mean ± SD; 2584.78 ± 350.95 vs. 2707.37 ± 220.68, p=0.07), lower hexagonality (mean ± SD; 45.23 ± 6.55 vs. 47.87 ± 7.45, p=0.06) & larger coefficient of variation (mean ± SD; 43.27 ± 9.35 vs. 41.50 ± 6.07, p=0.33) compared with amantadine naïve Parkinson's patients. Subgroup on high dose amantadine (400 mg) had significantly lower ECD (p=0.01)& lower %Hex (p=0.001) as compared to low dose amantadine (200 mg & 300 mg) group. Among the subgroups of Parkinson's patients on amantadine with peripheral adverse effects,all the subgroups had nearly equal number of patients with pedal edema & livedoreticularis.

Conclusions: Amantadine is more likely to have effect on corneal endothelial cells in a dose dependent manner when used long term. Our study is the first of its kind to show dose-dependent toxicity of amantadine in patients of Parkinson's disease from tertiary care hospital in INDIA.

178

The effect of the Lee Silverman voice treatment (LSVT ®) in Filipino Parkinson's disease patients: A pilot study

J.M.P. Bautista, C.K.A. Cuadro, R.D.G. Jamora (Quezon City, Philippines)

Objective: The primary aim is to determine the effect of LSVT® in the Filipino Parkinson's disease (PD) patient based on two measured parameters: vocal intensity and length of time of sustained phonation. Another objective of this study is to correlate the subjects’ clinical PD profile to their response to treatment.

Background: As much as 89% of PD patients develop voice and speech disorders. This is characterized by decreased vocal intensity, monotonous speech, and imprecise articulation, collectively called hypokinetic dysarthria. The Lee Silverman Voice Treatment (LSVT ®) is an intensive therapeutic course focused on improving the voice of PD disease patients. This program is relatively new in the Philippines with very few certified LSVT speech pathologists. No studies have yet been done on LSVT and the Filipino PD patient.

Methods: This is a cross-sectional study of PD patients in a single institution in the Philippines. All records of PD patients independent of disease and speech disorder severity who completed the LSVT course were retrieved. Data on vocal intensity and length of time of sustained phonation at different vocal pitches were measured at baseline and during all 16 sessions of LSVT. Baseline data and the mean of all sixteen sessions were compared and statistically analyzed.

Results: From 9 PD patients referred for LSVT, only 7 patients completed the whole course of 16 sessions. For vocal intensity, 5 out of 7 subjects showed louder vocal intensity compared to baseline on at least 1 vocal pitch. The remaining 2 out of the 7 subjects did not show any improvement in vocal loudness on any of the 3 vocal pitches. For the length of time of sustained phonation, 5 out of 7 subjects were noted to have significantly longer sustained phonation on at least 1 vocal pitch. The remaining 2 subjects failed to show any improvement from their baseline time on any of the three pitch levels.

Conclusions: Among Filipino PD patients who completed the LSVT, majority showed significant improvement in either vocal intensity or in length of time of sustained phonation. Significant improvement was seen more on the patient's habitual pitch compared to lower or higher pitch levels. Most improvement was also seen in patients with mild PD and mild speech disorder. This implies that LSVT may have most benefit in this category of PD patients.

179

A study of the pharmacological chaperones targeting glucocerebrosidase mutations in human fibroblast models of Parkinson's disease

M. Beavan, S.Y. Yang, K.Y. Chau, R. Shahar-Golan, D. Hughes, A. Mehta, A. Schapira (London, United Kingdom)

Objective: We have extended our investigation into the efficacy of existing pharmacological chaperones (PC) for manipulating the activity of glucocerebrosidase enzyme (GCase), and their potential to reverse the underlying molecular events in the pathogenesis of Parkinson's disease (PD).

Background: After aging, the most important risk factor known for the development of PD is certain mutations of the glucocerebrosidase gene (gba).

Methods: Human skin fibroblast cultures from individuals carrying heterozygous N370S (n = 5) or L444P (n=5) gba mutations, with and without PD, and those with mutation-negative idiopathic PD were treated with selected concentrations of PC ambroxol and isofagomine. GCase enzyme activity, levels of glucocerebrosidase protein (GBA) and gene expression, and related lysosomal and autophagic proteins were characterized.

Results: We observed a 50-70% decrease in GCase activity, 50% lower GBA levels and 50% gba expression in fibroblasts obtained from the heterozygous gba mutation carriers, associated with biochemical abnormalities including defective localization of GBA and lysosomal autophagy. Optimised treatment of skin fibroblast cultures with ambroxol and isofagomine resulted in significant restoration of GCase activity, GBA protein and gba gene expression in all cell lines, and correction of GBA localization. Autophagic compromise associated with the pathogenesis of PD was identified and we are in the process of assessing the influence upon drug treatment.

Conclusions: We have demonstrated that the PC ambroxol and isofagomine are able to modulate GCase function. It is unclear whether the treatment alone may be able to overcome all biochemical defects due to mutations in gba, due to the limitation of fibroblasts as a model for interrogating the complete pathway in PD.

180

Yoga versus resistance training in Parkinson's disease: A 12-week pilot feasibility study

D. Bega, D. Corcos, J. Stein, D. Victorson, C. Zadikoff, B. Jovanovic, T. Simuni (Chicago, IL, USA)

Objective: To explore the safety and feasibility of a 12-week biweekly course of gentle Iyengar yoga in patients with PD, and to collect pilot data on efficacy compared to resistance exercise.

Background: Yoga is a mind-body intervention which may address the motor and non-motor needs of patients with Parkinson's disease (PD). Despite the wide utilization of yoga there is little evidence in support of its use.

Methods: Prospective randomized controlled single blinded study in patients with mild to moderate PD (H&Y stage 1-3). Patients selected a site in downtown Chicago or the suburbs and were randomized 1:1 to yoga or resistance classes within each site. Groups were matched for age, gender, and disease severity. Assessments were performed at screening and after the final session. Safety and attendance data was collected by phone every 3 weeks. The main exploratory outcome measures were change in Timed-Up-And-Go (TUG), UPDRS part III, and PDQ-39.

Results: 23 patients were screened and 17 were eligible (11 downtown, 6 suburbs). Demographics of the groups were similar, with mean age of the cohort 67.3 (SD 9.8) years, and mean UPDRS III score of 24.2 (SD 7.0). There were 3 withdrawals (2 yoga, 1 resistance) unrelated to the intervention. There were no major adverse events. 16% of yoga classes were missed compared to 8% of resistance classes (p=0.04). Significantly more classes were missed at the downtown campus compared to the suburbs (14.8% vs 7.5%). Upon completion of the trial both groups improved on mean TUG time, UPDRS score, and PDQ-39 score compared to baseline, although the standard deviations for all values were wide and none of the between-group differences was statistically significant. With the exception of 1 subject in each group, participants stated that they benefited from the intervention, and they would have continued the intervention beyond 12 weeks.

Conclusions: The feasibility of a 12-week group yoga intervention in a cohort with mild-moderate PD was somewhat limited, with better attendance seen for resistance classes. The suburban location was associated with significantly better compliance. Pilot exploratory outcome data suggest comparable improvement in motor and non-motor outcome measures in both groups, but a larger study powered to detect these differences is needed. Feasibility data will need to be taken into account in designing such a study.

181

Clinical predictors of functional decline in early treated Parkinson's disease: NET-PD LS1 cohort

D. Bega, S. Kim, Y. Zhang, J. Elm, J. Schneider, R. Hauser, A. Fraser, T. Simuni, On Behalf of the NET-PD LS1 Investigators (Chicago, IL, USA)

Objective: Current data regarding predictors of functional decline in Parkinson's disease (PD) are largely based on studies of de novo populations at baseline, often limited to the use of motor outcomes which fail to capture the full scope of the disease. We aimed to determine the clinical predictors of decline in early treated PD as defined by a novel multi-domain outcome measure.

Background: Clinical predictors of functional decline in PD are prognostically important in the absence of validated biomarkers of disease progression. Older age at disease onset and PD symptom subtype have been identified as the strongest predictors of more rapid rate of progression.

Methods: We used data from NINDS Exploratory Trials in Parkinson's disease Long-Term Study 1 (NET-PD LS1), a large multicenter cohort of early treated PD patients followed for 5-7 years. Decline was defined by a global outcome metric that consists of the following 5 domains of disability, quality of life, motor and cognitive impairment: Schwab and England ADL scale (S&E), Parkinson's disease Quality of Life Scale (PDQ-39), Unified Parkinson's disease Rating Scale (UPDRS) Ambulatory Capacity Score, Symbol Digit Modalities Test (SDMT), and Modified Rankin Scale (mRS). Linear mixed models were used to test the association of predictors of interest, with a standardized rank-sum of the global outcome (GO) in both univariate and multivariate models.

Results: Of 1700 subjects who entered the study between 2007 and 2012, 765 had 5 year data and were included in the analysis. Older age at disease onset (p<0.0001), higher baseline levodopa equivalent dose (p=0.01), and lower/worse Scales for Outcomes of Parkinson's disease Cognition (SCOPA-COG) score (p=0.001) at baseline were the strongest predictors of functional decline (worsening GO) in multivariate analysis. PD symptom subtype was not a significant predictor of outcome (p=0.42).

Conclusions: This is the largest study to systematically assess predictors of functional decline in early treated PD over a period as long as five years, and the first study to use a multi-domain outcome measure of decline. Older age at disease onset was confirmed as a predictor of decline, but PD symptom subtype was not.

182

Prefrontal repetitive transcranial magnetic stimulation in Parkinson's disease: Pilot study of motor and neurophysiology outcomes

M.C. Biagioni, G.S. Dacpano, S. Agarwal, K.R. Sticklor, W.R. Small, J.N. Chimienti, P. Kumar, A. Loggini, J.Y. Singleton-Garvin, E.R. Friedman, M. Brys, R.M. Gilbert, A. Di Rocco (New York City, NY, USA)

Objective: To explore clinical and electrophysiology outcomes of low frequency repetitive Transcranial Magnetic Stimulation (rTMS) of two prefrontal stimulation targets in patients with PD.

Background: rTMS trials showed promising results improving motor symptoms of PD with a class-I trial reporting motor improvement with low frequency (LF) rTMS over the supplementary motor area (SMA). Neurophysiology (NPh) studies suggest that motor cortex excitability in PD is abnormal and can be modulated with rTMS; particularly LF rTMS over dorsal premotor cortex (PMd) can normalize motor excitability abnormalities. Optimizing rTMS treatment strategies is challenging and NPh may help with understanding the TMS effects and optimizing design of novel rTMS treatment protocols.

Methods: 8 PD patients with H&Y score of 2 or 3 participated in this parallel, double-blind pilot study of four weekly LF rTMS sessions over prefrontal areas and were assessed at 1 and 4 weeks post-treatment. The stimulation targets included either active rTMS over PMd and SMA (PMd+SMA group), or realistic sham on PMd and active rTMS on SMA (SMA group). UPDRS III was used to measure motor outcomes. Cortical silent period (SP), short interval intra-cortical inhibition and intra-cortical facilitation measures were used to asses NPh outcomes.

Results: No significant adverse effects reported. At week 4 post-treatment, UPDRS III decreased in both groups, in PMd+SMA group from 30.25 (sd=12.7) to 24.5 (sd=11.4); in SMA group from 30.0 (sd=6.7) to 24.5 (sd=5.3), both approaching significance [p < 0.1]; magnitude of decrease was greater in PMd+SMA group but did not reach significance. Neurophysiology results revealed a trend towards a significant difference [p < 0.1] between both groups’ SP at week 4 post-treatment (prolongation of SP in the PMd+SMA group and shortening of SP in the SMA group). Other NPh results were not significant. [figure2]

Conclusions: Both rTMS interventions were well tolerated and improved UPDRS motor scores. Improvement was sustained up to four weeks post-treatment. Combined PMd+SMA rTMS prolonging SP may indicate increased activity of inhibitory circuits in this group which may reflect a more effective intra-cortical modulation by LF rTMS (as SP is abnormally shorter in PD patients). Larger studies are needed to better define the effects of prefrontal LF rTMS on NPh measures and potential clinical interactions in PD.

Details are in the caption following the image

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Details are in the caption following the image

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183

Utilizing remote blood pressure monitoring in a phase III clinical drug trial for Parkinson's disease

R.A. Biemiller, K.J. Andrzejewski, M.T. Bull, K. Helles, B. Greco, D. Oakes, T. Simuni, K.M. Biglan (Rochester, NY, USA)

Objective: To determine the feasibility of remote blood pressure monitoring in a phase III clinical trial for Parkinson's disease.

Background: Orthostatic hypotension is common in Parkinson's disease (PD). Clinical trials for PD have used home blood pressure (BP) monitoring for participant safety and enrollment eligibility. Monitoring typically involves patients keeping a home log, which is presented at interim in-person visits to research staff for review. These home logs may be subject to inaccuracies due to errors in transcribing results or non-compliance. This has the potential to impact study validity and participant safety.

Safety, Tolerability, and Efficacy Assessment of Isradipine for Parkinson's disease (SteadyPD3) is a phase III double-blinded study of isradipine, a dihydropiridine calcium channel antagonist, as a potential neuroprotective agent in PD. Given the mechanism of isradipine, STEADYPD3 requires frequent BP monitoring prior to drug initiation and during drug titration to ensure participant eligibility and safety. The use of a BP monitor that can instantly send readings remotely to researchers allows for real time data capture and analysis and has the potential to improve validity and safety of the trial.

Methods: Participants in SteadyPD3 take twice-daily orthostatic BP readings during screening and drug titration. Patients are given a BP monitor (Carematix) and a MiFi unit (Verizon). The unit automatically sends BP readings to an online database, which is remotely monitored by the research team. The database tags all BP readings outside the prespecified safety range for review. We report on our initial findings on the feasibility and challenges of remote BP monitoring.

Results: SteadyPD3 began enrollment in November 2014. It has enrolled 29 and screened 46 patients who have utilized the remote BP units and have successfully transmitted to the online database. The main complications have been: spurious readings due to patient error, extra reported readings from researchers instructing patients on the use of the units and an excessive amount of BP reads that require dedicated personnel to review.

Conclusions: Remote blood pressure monitoring in an ongoing Phase III trial of PD has been feasible. Remote BP monitoring has the potential to increase safety and validity in PD studies but will require further testing.

184

Shared decision making in advanced Parkinson's disease (PD); protocol of a feasibility study

B.R. Bloem, M.J. Faber, F.A.P. Nijhuis, D.L.M. Radder (Nijmegen, Netherlands)

Objective: We developed a shared decision making (SDM) intervention to create equal accessibility to all treatment options for advanced PD patients, and to improve patient involvement in the decision making process (DMP). Here we describe a study where this intervention will be evaluated on feasibility by analyzing 1) the impact on the decision making process; and 2) the barriers and facilitators for uptake of the intervention.

Background: For many PD patients, it eventually becomes difficult to manage motor complications with adjustments in oral medication. For these patients, Deep Brain Stimulation, Continuous Duodenal Levodopa Infusion and Continuous Subcutaneous Apomorphine Infusion are the cornerstones for therapeutic management. A decision aid (DA) aims to improve decision making and should lead to a quality decision. The choice for one of the treatments is an individual decision, based on patients’ personal preferences and values. The notion that the patient's perspective and participation in decision making is needed for a quality decision, was the starting point for us to develop a SDM intervention comprising a DA and a training for professionals.

Methods: The SDM intervention will be tested in clinical practice. The aim is to select 40 patients; 20 after introducing the SDM intervention, and 20 according to usual care. At baseline, the usual DMP is followed and the patient will receive care as usual. After this, professionals will get a theoretical and hands-on training in SDM and use of the online DA. With the next 20 patients, they will work according to the SDM intervention.

Feasibility of this intervention will be measured in both patients and professionals by means of questionnaires, interviews, observations of the DMP and logging behavior of the online decision aid.

Results: Important outcomes will be the level of SDM in the consultations and informed preference as a measure of the quality of decision making.

Conclusions: The results of this project will inform the implementation of the new SDM approach, which could be evaluated in a larger RCT in clinical practice. Our long-term goal is to create equal accessibility to all advanced therapies and offer patients the opportunity to actively participate in this complex medical decision. This should reduce the under treatment of patients with advanced PD and improve treatment compliance.

185

Designing a decision aid for patients in advanced Parkinson's disease (PD): The user test experiences

B.R. Bloem, M.J. Faber, F.A.P. Nijhuis, D.L.M. Radder (Nijmegen, Netherlands)

Objective: To optimize a newly developed decision aid (DA) for patients with PD in the advanced stage, we conducted a user test with PD patients. The aim was to test the DA on 1) quality of the information; and 2) ease of use.

Background: For many PD patients, it eventually becomes difficult to manage motor complications with adjustments in oral medication. For these patients, Deep Brain Stimulation, Continuous Duodenal Levodopa Infusion and Continuous Subcutaneous Apomorphine Infusion are the cornerstones for therapeutic management. The choice for one of the treatments is an individual decision, based on patients’ personal preferences and values. The notion that the patient's perspective and participation in decision making is needed for a quality decision, was the starting point for us to develop a SDM intervention comprising a DA and a training for professionals.

Methods: For testing the DA, 25 patients were approached, of which 19 responded. All participants received a personal login code, testing the DA for one week. Afterwards, the patients received an evaluation questionnaire. Four of them were interviewed at home to obtain more extensive qualitative feedback.

Results: Most patients scored the content of the DA as ‘good’ (overview of treatment options (79%), information on the risks of treatments (68%)). Less than half (47%) rated the information on the effects of the treatments as ‘good’. Patients judged the language as comprehensible (95%) and the length of the DA (68%) and quantity of information (63%) were optimal. Patients felt that the DA offered well-balanced information about the specific treatments (88%). All participants would use the DA if they were faced with the choice (100%). Moreover, patients provided several instructions for improving the DA, particularly to include more experiences of patients that underwent one of the treatments, and to include practical information about how the devices are used at home.

Conclusions: Patients rated the DA as a useful tool in making the decision and as easy to use. Obviously, it differs per patient how much information they wish to receive. Therefore patients have access to the information pages for both patients and professionals, allowing patients in need of more information to read the more extensive scientific knowledge for professionals. We have incorporated the feedback into a new version of the DA, which will be tested in a feasibility study.

186

Short-term benefits of a progressive aerobic exercise and skill acquisition program for people with mild to moderate Parkinson's disease in a community group setting

E.E. Borchers, E. Ferrigni, K. Krauss, B.G. Farley (Tucson, AZ, USA)

Objective: To examine the short-term effects of a progressive aerobic exercise and skill acquisition program conducted at The Parkinson's Wellness Recovery Gym (PWR!Gym®), a community based exercise center devoted to improving quality of life for people with Parkinson's disease (PD).

Background: Progressive aerobic exercise has been shown to improve endurance, gait, balance, and executive function as well as decrease fatigue and depression in people with Parkinson's disease (PD). Prior research suggests that vigorous aerobic exercise in combination with skill acquisition augmented with feedback improves function and can mediate brain health and repair mechanisms in people with PD. Limited research has been done on the effectiveness of this type of exercise program implemented in a community group setting.

Methods: Sixteen members of the PWR!Gym® with mild to moderate PD participated for 7 weeks. Volunteers provided individualized education and feedback regarding perceived effort based on the Modified Borg scale correlated with heart rate. Group 1, which included 8 participants with moderate stage PD, exercised 3 times per week with total cardio times increasing from 30 to 40 minutes. Group 2, which included 8 participants with mild to moderate stage PD, exercised 3 times per week with total cardio times increasing from 40 to 50 minutes. Both groups utilized treadmills and stationary bicycles followed by various PWR!Moves® for skill acquisition for the remaining time to total a one hour class.

Results: Preliminary findings suggest improvements in motor and cognitive assessments as well as non-motor symptoms associated with PD. The majority of participants improved in the 6 Minute Walk Test, 2 Minute Walk Test, Timed Up and Go, and 5 Times Sit to Stand suggesting benefits in the domains of endurance and functional mobility. Improvements were also found in verbal fluency and trailmaking tasks. In addition, subjects reported less fatigue, improved sleep quality, better mood, less pain, and higher quality of life after participating in this program.

Conclusions: These findings suggest that a 7 week progressive aerobic group exercise and skill acquisition program based upon the Modified Borg scale at high-intensity intervals and the PWR!Moves® can benefit motor, cognitive, and non-motor symptoms of PD.

187

Treatment of apomorphine-induced skin reactions: A pilot study

R.W.K. Borgemeester, G.F.H. Diercks, M.F. Jonkman, T. van Laar (Groningen, Netherlands)

Objective: To evaluate the efficacy of four treatment strategies, including massage, dilution of apomorphine, treatment with topical hydrocortisone, and pre-treatment with subcutaneous administration of hydrocortisone, in Parkinson's disease (PD) patients with apomorphine-induced skin reactions.

Background: Apomorphine-induced skin reactions (i.e. erythema, swelling and/or subcutaneous nodule formation) are a common side-effect of continuous subcutaneous apomorphine infusion. However, the pathogenesis of apomorphine-induced skin reactions is poorly understood, which explains the absence of proven treatment strategies.

Methods: An open-label, sequence-fixed, cross-over study with four treatment arms including local massage, dilution of the apomorphine concentration from 0.5% to 0.25%, topical hydrocortisone 1% and pre-treatment with subcutaneous 10 mg hydrocortisone, was designed in 20 patients being treated with subcutaneous infusion of apomorphine. Each treatment arm started after a wash-out period of 2 weeks. The efficacy of each treatment was evaluated after 2 weeks by determining patient satisfaction, local erythema and nodule size, as well as skin tissue characteristics. Two skin biopsies were taken after each treatment modality, at 2 sites, consisting of 1 site 3 days after infusion and another site 14 days after apomorphine infusion.

Results: Massage and dilution of apomorphine seem to have a good effect on the nodule formation of apomorphine, whereas the hydrocortisone creme was less effective as compared with the subcutaneous pre-treatment with hydrocortisone. Several biopsies showed an allergic component as well, consisting of eosinophils.

Conclusions: To our knowledge, this is the first study examining various treatment strategies in apomorphine-induced skin reactions in PD. Local treatment with massage, dilution of apomorphine and pre-treatment with subcutaneous hydrocortisone are effective measures in reducing the skin problems associated with apomorphine. Thereabove, anti-allergic drugs like anti-histamines might play a role in the treatment of apomorphine-induced skin reactions in the future.

188

Long-term evaluation of 24 hour ambulatory blood pressure monitoring in patients with Parkinson's disease and symptomatic neurogenic orthostatic hypotension treated with droxidopa

S. Brillman, S. Husain, S.H. Isaacson (Boca Raton, FL, USA)

Objective: To determine if the effect of droxidopa on clinical symptoms and systolic blood pressure are durable.

Background: Neurogenic Orthostatic Hypotension due to autonomic dysfunction in Parkinson's disease (PD) not uncommonly complicates clinical management. Treatment options are limited, due both to limited symptomatic efficacy in some patients and to increases in supine hypertension (sHTN) in others. Studies using droxidopa to raise standing systolic blood pressure (sSBP) in patients with PD and nOH have identified short term improvement in symptoms and in sSBP, but clinical durability beyond 1-2 weeks has been limited by study design and other factors.

Methods: Droxidopa, a synthetic precursor converted to norepinephrine, was administered to five patients with PD and symptomatic nOH. During routine clinic visits, patients were assessed with 24 hour ambulatory blood pressure monitoring (ABPM) Orthostatic Hypotension Questionnaire Question #1 (OHQ-Q1) before and 3-6 month after beginning treatment with droxidopa.

Results: Retrospective analysis of baseline ABPM demonstrated marked fluctuations in sSBP in all treated patients, and overnight sHTN. After treatment with droxidopa, most patients had a reduction in the number of sSBP lower than 90mmHG measurements on 24 hour ABPM at the post-treatment assessments. Improvement in OHQ-Q1 (lightheadedness/dizziness) was also. However, fluctuations in ABPM sSBP measurements and in OHQ-Q1 persisted among patients at all timepoints.

Conclusions: In this cohort of patients treated with droxidopa for symptomatic NOH, efficacy and imrpoved s-SBP was maintained months after beginning treatment. Variabilty in blood pressure and symptoms persist though, pointing to an underlying difficulty in the clinical assessment of patients with PD and autonomic dysfunction.

189

Chemogenetic inhibition of the subthalamic region of Parkinsonian mice improves motor function

L. Broom, T. Samardzic, A. Worley, C. Joanne, O. Yo, D.K. Simon, C.B. Saper, V. VanderHorst (Boston, MA, USA)

Objective: To test whether chemogenetic inhibition of the subthalamic region improves motor function in a Parkinsonian mouse model.

Background: Deep brain stimulation is an effective treatment of motor symptoms in Parkinson's disease (PD). Chemogenetic approaches provide an alternative without limitations of hardware and unintended stimulation of fiber tracts. One such approach makes use of Ivermectin (IVM) channels, which are mutated nematode glutamate gated chloride channels that can be delivered locally via microinjection of an adeno-associated viral vector (AAV). IVM channels are inert in mammals due to a mutation, but can be specifically and reversibly targeted by the drug IVM, leading to inhibition of transfected neurons. We apply this strategy to the subthalamic region (STN), which is overactive in PD, to assess the feasibility of this approach to ameliorate motor function in an acute Parkinsonian mouse model.

Methods: We placed micro-injections of AAV10-CMV-IVM-GFP into the STN region of male C57Bl6J mice. Following transfection, we injected vehicle or IVM i.p. to assess the effect of inhibition of the STN region on motor function. We did this first in the intact CNS and following injection of 6-hydroxydopamine (6OHDA) into the substantia nigra of the same mice. Motor tests included high speed gait and kinematic analysis, and assessment of complex motor behavior using rotarod, balance beam, horizontal ladder, open field testing, and grip strength. After the behavioral tests, we used immunohistochemistry to visualize GFP+ transfected neurons in the STN region and tyrosine hydroxylase (TH) neurons and fibers. Behavioral test results were correlated with injection sites, and the loss of TH staining.

Results: The results show that chemogenetic inhibition of the STN region in non-lesioned mice induces small enhancements of motor performance such as an increase in gait speed. Following 6OHDA-induced dopaminergic cell loss and worsening of motor performance, inhibition of the STN region results in marked improvements of motor function. The effects are reversible and dose dependent.

Conclusions: These findings represent a proof of concept for this novel technology to ameliorate motor function in a Parkinsonian mouse model. The results demonstrate its potential as a treatment in PD and other neurological conditions that involve an imbalance in neural circuitries.

190

No benefit from multifocal repetitive transcranial magnetic stimulation on motor and mood symptoms of Parkinson's disease compared to sham stimulation: Results of the MASTER-PD study

M. Brys, M. Biagioni, S. Agarwal, G. Dacpano, P. Kumar, E. Pirraglia, Z. Gray, D.K. Simon, A. Wu, H. Fernandez, R. Chen, A. Wagle Shukla, J.S. Lou, A. Di Rocco, A. Pascual-Leone (New York, NY, USA)

Objective: To determine efficacy and duration of benefits of motor and prefrontal cortex high frequency rTMS on motor and mood symptoms of PD.

Background: Several studies suggest that high frequency rTMS (HF rTMS) to the motor cortex improves motor symptoms of PD and HF rTMS to left dorsolateral prefrontal cortex (DLPFC) improves depression. Yet, there are no appropriately powered, sham controlled studies targeting depression and motor dysfunction concurrently despite the frequent co-morbidity.

Methods: 71 PD subjects with motor dysfunction and depression despite optimized medication treatment consented to participation and were randomized in this multicenter, double-blind, sham-controlled, parallel-group study of real or realistic (electrical) sham HF rTMS to primary motor cortex bilaterally, left DLPFC alone or concurrently. Patients received 2000 stimuli (50 x 4-sec trains of 40 stimuli at 10Hz) for 10 days and were evaluated in standard OFF state at baseline, at 1 week and at 1, 3 and 6 months post treatment. Hamilton Depression (HAM-D) scale was used for depression outcome and UPDRS III for motor outcome.

Results: 59 subjects completed the treatment, 46 subjects (78%) completed all study visits (real M1-sham DLPFC n=13, real DLPFC-sham M1 n=10, real M1+DLPFC n=21, double sham n=15). There was a significant, sustained decrease in HAM-D in all study participants regardless of stimulation status (p<0.001), while UPDRS III improved transiently (p=0.03) and reverted to baseline by month 6. As compared to sham stimulation, no change in UPDRS III or HAM-D was found 1 month post treatment completion in participants receiving real TMS (p=ns). Similarly, no study group difference was shown when all study visits were analyzed (rANOVA, p=ns).

Conclusions: Multifocal M1 and/or DLPFC HF rTMS was no better than sham stimulation for motor or mood symptoms of PD. Sustained improvement of depression, regardless of stimulation status, points to universal benefit from study participation or from a perceived intervention. Transient improvement of UPDRS III indicates strong placebo response (perhaps related to salient electrical sham stimulation) precluding further conclusions regarding multi-target rTMS efficacy. Better understanding of sham rTMS response in this particular population may help in the design of future efficacy studies.

191

Effect of antidepressants on the motor symptoms of Parkinson's disease

H. Calderon, R. Llorens-Arenas, D. Piña-Fuentes, A. Cervantes-Arriaga, M. Rodriguez-Violante (Mexico City, Mexico)

Objective: To evaluate the effect of antidepressants in the motor symptoms of Parkinson's disease.

Background: Depressive syndromes occur in an average of 40% of patients with Parkinson's diseaseDepressive. However, they are often not identified.

Depression and anxiety disorders are the most common neuropsychiatric syndromes in people with PD.

To date, few studies have evaluated the effect of antidepressant treatment on motor symptoms in patients with Parkinson's disease (PD) and results have been controversial.

Methods: A longitudinal analytical study was conducted. Patients were evaluated and divided into two groups: non-depressed (controls), and untreated depression. The diagnosis of depression was based on the DSM-IV. Treatment with SSRI was initiated in patients with depression. Patients were assessed 10 weeks after the start of antidepressants; no adjustment was made antiParkinsonian drugs during this time. All patients were evaluated with the MDS-UPDRS. Other scales applied were: NMSS (scale non-motor symptoms of PD) and PDQ8 (scale of quality of life PD), HAM-D (Hamilton depression Scale, HAS (Hamilton anxiety Scale), LARS (scale apathy Lille), MOCA (Montreal Cognitive Assessment) and the NPI (neuropsychiatric Inventory).

Motor and non-motor symptoms scales in depressed patients before and after treatment with antidepressants including controls
Scale Pre-treatment Post-treatment P (Post-treatment vs. pre-treatment) Controls P (Post-treatment vs. controls)
MDS-UPDRS I 17.4 ± 4 14.7 ± 3.6 <0.001* 8.5 ± 6 <0.001*
MDS-UPDRS II 14.5 ± 9 13.4 ± 7 0.294 10.7 ± 9 0.828
MDS-UPDRS III 30.4 ± 13 27.9 ± 11 0.213 25.5 ± 11 0.095
MDS-UPDRS IV 2.5 ± 4 2.6 ± 3.8 0.285 2.1 ± 3.4 0.828
NMSS 109.4 ± 53 100 ± 50 <0.001* 40.3 ± 36 <0.001*
HAM-D 24.4 ± 7 15.8 ± 6 <0.001*
HAS 24.0 ± 11 20.5 ± 9 0.002*
PDQ8 36.6 ± 26 34.9 ± 24 0.079 19.5 ± 18 0.024*
LARS 14.5 ± 11 15 ± 10 0.170
MOCA 24.1 ± 5 24 ± 5 0.846
NPI 26.0 ± 11 19.5 ± 7 <0.001*

Results: A total of 48 patients were included (34% male) with a mean age of 70 ± 9) years for men and a mean age of 64 ± 13 for women. The mean disease duration was 7.3 ± 3.8 years.

The analysis of the results in depressed patients after 10 weeks of treatment with antidepressants showed no statistical significance between groups regarding the MDS-UPDRS motor was found (30.4 ± 13 vs 27.9 ± 11 points respectively, P=0.213). There was no significant difference between the groups in terms of bradykinesia (P=0.083), tremor (P=0.203) or stiffness (P=0.202). In regards to the HAM-D scale, NMSS, HAS and NPI a statistical significant difference was observed between groups (P=<0.001, P=<0.001, P=0.002, and P=<0.001 respectively. Comparison with the controls can be seen in [Table I]

Conclusions: The use of antidepressants was not associated with a beneficial or deleterious effect on the symptoms of Parkinson's motor disease. Furthermore, no change was observed in motor complications assessed by the MDS-UPDRS part IV.

The SSRI antidepressants should be initiated when indicated, as well as improving mood, also improve anxiety without affecting motor symptoms.

192

Outcome quality in iSTEP istradefylline Parkinson's disease trial

M. Cantillon, B. Novak, J. Montero, G. Wilson, R. Smith (Livingston, NJ, USA)

Objective: PD patient diaries have been consistently and reliably used as a clinical outcome measure, contributing to regulatory approval of PD medications. However, estimation of ON and OFF times relies heavily on accurate completion of patient diaries. This investigation focused on the impact of rater training and central data review of the ON and OFF Patient Diary data in the iSTEP Phase III istradefylline trial.

Background: PD diary information and training was prepared.

Methods: A total of 240 raters from 8 countries participated in the ON and OFF Patient Diary rater training program. This included in-person training at Investigator's Meetings (IM) and online training for absentee and new raters. Only trained raters were permitted to conduct diary training and concordance testing with subjects. Findings were categorized and documented by type (e.g. Invalid Diaries, Batched Data Entry, Concordance Error, etc.). Raters received additional training and were asked to retrain subjects on appropriate diary completion conventions.

Results: Of the 292 visits centrally reviewed diaries to date, 64% contained findings, some significant. Findings included batched data entry (57%) defined by more than 5 hours of data entered at one time (excluding Asleep time), followed by prospective data entry (27%). Additionally, invalid diaries were identified, defined as diaries containing more than 4 invalid entries, concordance errors, and missing data findings; these accounted for 16% of all findings.

Conclusions: These results support the use of a stringent training and centralized data review program to monitors diary completion. Such continuous training of users and feedback is effective in ensuring quality data.

193

The freezing of gait (FoG) in Parkinso's disease (PD) could be reduced by a physiotherapy programme with multisensory cues

T.T.C. Capato, N. Agostini, F. Kolozuk, E.R. Barbosa, M.E.P. Piemonte (São Paulo, Brazil)

Objective: Was to check the effectiveness of a MC physiotherapy programme to reduction FoG in PD.

Background: Freezing of gait (FoG) is a disabling clinical phenomenon characterized by brief episodes of inability to step or by extremely short steps that typically occur on initiating gait or on turning while walking. Reduction in step length with frequent trembling of the legs during FoG episodes. Medications and physicaltherapy techniques can alleviate symptoms of FoG in some patients, but these treatments lack efficacy in patients with advanced FoG. A better understanding of the phenomenon is needed to aid the development of effective therapeutic strategies. There are evidences that a physiotherapy treatment with Multisensory Cues (MC) improve functional disturbances of the basal ganglia motor circuit. The mechanisms by which improvement occur in HD remains inexplicable.

Methods: 30 PD, H&Y 3, were assessed by a single blind examiner before and after 10 training sessions (once in a week during 45 min) and after 60 days of the end of the training. Balance was assessed by Berg Balance Scale (BBS) and Mini BESTest, Pull and Release Test (PRT). Gait by Time UP and GO (TUG) and 6 min walk test. FoG was assessed by NFOG-Q and Snijders & Bloem Freezing of Gait test. The Independence to AVDS and motor performance and cognition were assessed by UPDRS. The subjects should have PD history of FoG and falls. They were expected to understand tests and exercises sequences according to inclusion criteria. During the study period there was't medication changing. The patients were divided on 2 groups according criterial rules; aged 66.41. Group (I) done programme comprised exercises with MC (stretching, leg strength exercises; gait and balance training with multisensory cues (visual, auditory and proprioceptive cues) and functional activities/attention strategies; breathing exercises and trunk control). The Group II did the same exercises without cues. Group III receives only orientations. ClinicalTrials.gov Identifier NCT01960985.

Results: The results showed improvement after treatment, according to media score for the Group I e II TUG (p=0,01), 6 min walk (p=0,00) and BBS (p=0,00), Mini BESTest (p=0,00),PRT (p=0,00) NFOG-Q (p= 0,01) only to Group I.

Conclusions: The MC physiotherapy programme proposed in this study connected to medicine was effective to minimize FoG in PD and postural instability.

194

The impact a belt adaptation in walker stabilize on gait measures and falls in Huntington's disease (HD) and Parkinso's disease (PD)

T.T.C. Capato, M.S. Haddad, R. Guimarães, J. Tornai, M.R. Gonçalves, M.E.P. Piemonte, E.R. Barbosa (São Paulo, Brazil)

Objective: Examine the effects a belt Adaptation in Walkers Stabilizer (BAWS) on Gait Measures and falls in HD and PD.

Background: Gait and postural instability disturbs lead to balance loss and falls in individuals with HD e PD. The slowness of motor responses to unexpected balance disturbances and greater variation spatial and temporal are related to disorder processing of sensory feedback. Assistive devices (AD) such as walkers are often prescribed to prevent falls, but their efficacy is unknown. However, there are no evidence-based guidelines available to prescribe and recommendations of adaptations.

Methods: Were assessed 05 subjects with HD moderate and 10 PD (H&Y 3-4) as they walked 3 conditions (without AD, Walker Stabilizer and BAWS). Demographic information, UHDRS and UPDRS motor scores, and fall history (FES-I) data were obtained from ambulatory patients with a diagnosis of HD and PD who were examined by physical therapists at our Movement Disorders Clinic. Gait and Balance parameters was assessed by TUG, 6 min walk, Mini BESTest, Push and Release Test (PRT). We used a BAWS placed in low back region to provide a proprioceptive cue to the patients. It also acts as a security belt.

Results: In AD condition, there were differences in gait velocity and balance parameters between the HD and PD and slowness in both groups. In Walker Stabilizer conditions to HD and PD there were a significant improvement in gait velocity and balance scores in comparison between without AD. The higher differences were shown with BAWS on 6 min walk, TUG and Mini BESTest. These scores shown with BAWS show decreased fall risk in HD and PD.

Conclusions: Walker Stabilizer can be very helpful for moderate HD and PD patients. BAWS can reduce falls when used as a proprioceptive cue. BAWS selection, training and adjustments should be considered and conducted by a physicaltherapist. More researches are necessary to evaluate the effects on freezing in PD.

195

Efficacy of safinamide as adjunct therapy in mid- to late-stage fluctuating Parkinson's disease patients: Post-hoc analyses of 016 and SETTLE trials

C. Cattaneo, E. Bonizzoni, R. La Ferla, M. Sardina (Bresso (Milan), Italy)

Objective: To investigate the clinical effects of safinamide vs. placebo on cardinal symptoms of Parkinson's disease and on motor fluctuations in defined patient subgroups using pooled data from studies 016 and SETTLE.

Background: Safinamide, a unique molecule with a novel mechanism of action (dopaminergic and non-dopaminergic), resulted safe and effective in two double-blind, placebo-controlled, 6-months trials (016 and SETTLE) when used as add-on therapy in patients with idiopathic Parkinson's disease (PD) and motor fluctuations, treated with stable doses of levodopa alone or in combination with other anti-Parkinson's drugs.

Methods: This post-hoc analysis of pooled data from the pivotal Phase III trials 016 and SETTLE evaluated the effects of safinamide vs. placebo on individual cardinal symptoms of PD during the “ON” phase (bradykinesia, rigidity, tremor, postural stability, gait) and the mean change from baseline in daily “OFF” time in subgroups of patients who were receiving levodopa alone or concomitant treatments with dopamine agonists (DA) or catechol-O-methyltransferase inhibitors (COMT-I), or who were considered “mild fluctuators” at baseline (daily “OFF” time ≤ 4 hours, irrespective of concomitant medications).

Results: Compared to placebo, safinamide 100 mg/day significantly improved bradykinesia, rigidity tremor and gait, and significantly reduced mean daily “OFF” time when used as adjunct therapy in all subgroups of patients considered without increasing the rate of adverse events nor the risk to develop troublesome dyskinesia.

Conclusions: Safinamide was an effective and safe drug when used as add-on therapy in mid- to late-stage fluctuating PD patients: improvements were seen in “OFF” time and in almost all cardinal symptoms in subjects with “wearing-off” phenomena, despite they were receiving an optimized dopaminergic treatment regimen, without deteriorating their motor complications.

196

24 hour levodopa-carbidopa intestinal gel may reduce falls from unresponsive freezing of gait in Parkinson's disease

F.C.F. Chang, D.S.Y. Tsui, N. Mahant, N. Wolfe, S.D. Kim, A.D. Ha, J.M. Griffith, M. Drury, V.S.C. Fung (Westmead, Australia)

Objective: We report ongoing data on a prospective, open label study of 24 hour levodopa-carbidopa intestinal gel (LCIG), as treatment for levodopa-unresponsive freezing of gait (u-FOG) and falls in Parkinson's disease (PD).

Background: FOG associated with PD is a challenging phenomenon, in terms of pathophysiology and treatment. “Off” period FOG is treated with increased dopaminergic therapy whereas u-FOG is not responsive to levodopa or deep brain stimulation.

Methods: Patients with u-FOG documented with an oral dose cycle of levodopa were commenced on continuous 24 hour infusion through the LCIG pump with the night-time rate at 50 to 80% of daytime infusion rate. Patients with u-FOG underwent baseline, 3, 6, 9, 12 and 18 month gait assessments, video-taped examination and FOG questionnaire. The change in falls frequency were recorded and Friedman's test was used to test for statistical significance for variables up to 9 months, using SPSS 22.0, defined as p < 0.05.

Results: 7 patients participated, their mean age 67.4 +/- 8.3 with duration of PD 18.2+/-9.1 years. The falls frequency reduced after 24 hour LCIG (p=0.048) at 3, 6 and 9 months compared to baseline. The FOG questionnaire and 360 degree turning time non-significantly improved compared to baseline after follow-up of up to 18 months. The LCIG daytime infusion rate was unchanged relative to baseline and two subjects had transient dyskinesia or postural hypotension. One subject withdrew from the study following persistent visual hallucinations. Otherwise it was well tolerated without side effects.

Conclusions: Our study provides additional evidence that 24 hour LCIG infusion reduces motor complications in PD. We offer a novel therapy that may reduce falls associated with u-FOG due to PD. However, a larger prospective study is needed for confirmation.

197

Antecollis associated with Parkinson's disease improved following apomorphine therapy

F.C.F. Chang, N. Mahant, V.S.C. Fung, D.S.Y. Tsui, Z. Aldaajani, R. Adam, M.A. Hely (Wentworthville, Australia)

Objective: We report improvement in antecollis in a Parkinson's disease (PD) patient following subcutaneous apomorphine therapy.

Background: Antecollis is dystonia of the neck resulting in excessive forward flexion, often associated with dysphagia. It is associated with later stage of PD and is often refractory to medical and botulinum toxin therapy.

Results: We report a 70 year old lady with idiopathic PD diagnosed 12 years ago. She presented with unilateral levodopa responsive hand tremor with akinesia and rigidity. 12 months ago, during treatment with levodopa 600 mg daily, pramipexole ER 3 mg daily, she developed acute antecollis over 24 hours after a fall with minor head injury. Reduction in pramipexole to 2.25 mg daily made no difference. Over 8 months she developed gradual worsening of antecollis with reduced oral intake, weight loss and reduce mobility. She had visual hallucinations with insight. On examination she had normal neck extensor strength. There was no rigidity and minimal bradykinesia in the extremities. Administration of oral medication via nasogastric tube was ineffective. An apomorphine challenge was performed after pre-treatment with domperidone. There was acute improvement in hand function, rigidity and mobility without speech or neck posture improvement. However, neck posture started to improve 4 hours post apomorphine. Apomorphine was commenced regularly at 2mg subcutaneous injections 3 times a day. This was well tolerated with mild generalized dyskinesia and no hallucinations. At 2 and 4 months followup, the patient had significant improvement in swallowing and resolution of antecollis. She was able to feed, transfer herself and play the piano again and gained 8 kilograms. She had presence hallucinations at night with retained insight. At 7 months followup she had recurrence of antecollis and dysphagia which improved following cessation of pramipexole and commencement of an apomorphine 16 hour daytime infusion with nocturnal rotigotine patch therapy.

Conclusions: Apomorphine therapy may be an useful treatment for antecollis in PD.

198

Analysis of daily dose of dopaminergic replacement therapy in patients with Parkinson's disease: Experience of a medical center in Taiwan

Y.Y. Chang, T.K. Lin, Y.F. Chen, C.S. Su, M.Y. Lan, Y.F. Chen (Kaohsiung, Taiwan)

Objective: To study the anti-Parkinsonian medication patterns and investigate the association between the levodopa equivalent daily dose (LEDD) and the various clinical variables in patients with Parkinson's disease (PD).

Background: The pharmacological treatment of PD is individualized based on motor symptom severity, non-motor symptoms, and benefits and side effects of the medications. Here we analysed data on the anti-Parkinsonian treatment and clinical characteristics of PD patients treated by Movement Disorder specialists.

Methods: A territary care medical center cross-sectional survey was conducted over a defined period. Information on patient demographics and clinical features including age, age at PD onset, disease duration, and modified Hoehn and Yahr (H-Y) stage, and LEDD of anti-Parkinsonian medications was obtained from the patients’ medical records.

Results: During the study period, a total of 244 PD patients (156 male, mean age 67.48 ± 10.79 years, range from 30∼92 years) were included. The mean LEDD in the study population was 654.6 ± 412.4 mg/day, which tended to increase depending on the duration of disease and H-Y stage. The LEDD was not significantly affected by gender and the influence of age on the LEDD was variable. The most frequently administered drugs were L-dopa (89.3%), dopamine agonists (DA) (70.9%), entacapone (49.2%), amantadine (27.9%), selegiline (15.6%), and anticholinergics (13.5%). Besides, the most frequent pattern was a combination of L-dopa and DA (66.8%), followed by L-dopa monotherapy (18.4%), DA monotherapy (4.1%), and other dopaminergic drugs (2.0%) respectively. There was no difference in mean LEDD with the use of anticholinergics and selegiline, while the mean LEDD was significantly higher in cases taking amantadine (982.6 ± 453.8 vs. 527.9 ± 315.3 mg/day, p<0.001).

Conclusions: This study provides a systematic analysis of mean LEDD in a large cohort of Taiwanese patients with PD. Moreover, our survey shows that the LEDD is positively correlated with the duration and severity of PD, and is affected by the different pattern of use of anti-Parkinsonian medications. The comparison of mean LEDD between different ethnic populations are worth for the further assessment.

199

Relationship of vitamin B12 status to baseline clinical condition and outcomes in a large, early Parkinson's disease cohort (DATATOP)

C.W. Christine, P. Auinger, A. Joslin, R. Green, PSG DATATOP Investigators (San Francisco, CA, USA)

Objective: To determine the prevalence of low vitamin B12 status and its association with cognitive and motor outcomes in early Parkinson's disease (PD).

Background: Previous studies have identified relationships of low vitamin B12 levels with neurological features including neuropathy and cognitive impairment in moderately advanced PD. We sought to determine the prevalence of low vitamin B12 status in early PD and whether low B12 was associated with greater morbidity.

Methods: We measured vitamin B12 and methylmalonic acid (MMA) levels using 680 of the baseline serum samples from the DATATOP cohort of patients with early, untreated PD. Low B12 status was defined as serum B12 <184 pmol/l (250 pg/ml) and outright B12 deficiency was defined as B12 <157 pmol/l (212 pmol/l) and MMA >400 nM. Outcomes included motor assessments (UPDRS scores) and cognitive assessments (Symbol Digits Modalities Test and Selective Reminding Test) at baseline and follow-up, calculated as an annualized rate of change for those who participated for 9 months to 2 years. T-tests and chi-square tests were used to compare outcomes between subjects who were deficient to those who were non-deficient.

Results: A B12 level <184 pmol/l was present in 12.8% of subjects at baseline and 5% had B12 levels <157 pmol/l (regardless of MMA levels). Fifteen (2%) were B12 deficient. Using either the threshold of B12 <184pmol/l (82 subjects) or MMA >400 nM (27 subjects), we found lower scores in the selective reminding test for these groups at baseline. We also found greater clinical deterioration (measured by the annualized increase in total UPDRS and motor scores) in those with baseline B12 levels <184 pmol/l. No associations were found between baseline B12 status and baseline sensory, gait, or stability outcomes as measured by individual UPDRS items.

Conclusions: In this cohort of early PD subjects, 1 in 8 subjects had low B12 status. Moreover, low B12 status was associated with both baseline cognitive defects and more rapid rate of progression of impairment as measured by the UPDRS. These changes occurred in the absence of sensory or gait changes, suggesting that serum tests may be necessary to detect low B12 status. Our data raise the possibility that prevention or early correction of low B12 status may slow the onset of disability in PD. Supported by MJFOX Foundation, Grant 8646.

200

Do late-stage Parkinson's disease patients still respond to levodopa?

M. Coelho, M. Fabbri, D. Abreu, L. Guedes, N. Gonçalves, M.M. Rosa, J.J. Ferreira (Lisbon, Portugal)

Objective: Our aim was to study the response to a levodopa test in a late stage PD (LSPD) population.

Background: A subgroup of advanced Parkinson's disease (PD) patients reaches a late disease phase, whose phenotype is dominated by complete loss of independence and motor and non-motor levodopa-resistant symptoms. However, it is still open to debate whether the apparent loss of benefit from levodopa is real or the result of downgrading its dosage due to the occurrence or fear of adverse effects (AE).

Methods: 20 LSPD patients, with Schwab and England ADL Scale (SE) < or = 50 or Hoehn Yahr (HY) Stage >3 (MED ON), underwent a levodopa challenge test with a supra-maximal dose. MDS-UPDRS-III and the Abnormal Involuntary Movement Scale were evaluated before and after levodopa.

Results: We included in the study 9 men and 13 women, with median age of 78.8 years (IRQ: 73.5-82), median disease duration of 14 years (IQR: 10-19.75) and median S&E of 40 (IQR:30-40) during MED ON.

Motor outcomes before (MED OFF) and after (MED ON) levodopa challenge test in the LSPD population
MED OFF MED ON p - value
MDS-UPDRS-III 67.5 [60.6-78.2] 57 [49-64] <0.001
Speech 3 [2-4] 3 [2-4] 1
Rigidity 9 [4-14.25] 3.5 [0-11] <0.001
Bradykinesia 36,50 [33-40] 33 [24.2-37.5] 0.001
Rest tremor 0 [0-4] 0 <0.05
Arising from chair 4 [3-4] 3.5 [3-4] 0.157
Freezinf og gait 3 [2-3] 2 [2-2] 0.068
Posture 2 [2-3] 2 [2-3] 1
Postural Stability 3 [3-4] 3 [3-3.75] 0.059
Gait 3 [3-4] 3 [3-3.75] <0.05
Axial Signs 19 [17-22.5] 17 [15-19] 0.053
AIMS 0 [0-0] 1.5 [0-9.5] 0.001
S&E 30 [20-40] 40 [30-40] <0.05
H&Y 4 [4-5] 4 <0.05
  • Values are presented as median [IQR, 25th–75th percentile]. AIMS: Abnormal involuntary movement scale. Statistical significant results are in bold character. Axial Sign: Speech, Freezing, Gait and Postural stability. *: S&E scores during ON and OFF condition were not evaluated before and after the levodopa challenge test but by means of the clinical interview.

Table 1 reports on motor response to levodopa. Levodopa significantly improved the MDS-UPDRS-III score (14.9%), but had no effect on axial signs with exception of gait in a minority of patients. There was not significant improvement in the SE or HY scales. The response to levodopa positively correlated with the acute appearance of dyskinesias and the MDS-UPDRS-IV score. AE occurred in 7 patients during the test, the most frequent being moderate drowsiness (n = 6).

Conclusions: LSPD patients still show a mild response to a supra-maximal levodopa dose but frequently associated to AE. Even in this late disease phase, there is a positive association of levodopa response with motor fluctuations and dyskinesias, A decrease in the response to a levodopa test is a potential marker of disease progression in the later stages.

201

AntiParkinson's drug use in response to practice parameter publication, drug availability, and ‘unofficial’ prescribing forces

J.A.G. Crispo, Y. Fortin, M. Emons, L.M. Bjerre, D.E. Kohen, S. Perez Lloret, D.R. Mattison, A.W. Willis, D. Krewski (Ottawa, ON, Canada)

Objective: To describe patterns of antiParkinson's drug utilization between January 2001 and December 2012 in a national cohort of individuals with Parkinson's disease (PD). We also examined the impact of practice parameter publication, drug introduction/withdrawal, and ‘unofficial’ prescribing forces on prescribing patterns.

Background: Therapeutic options and practice parameters for PD have changed significantly in the past 15 years, yet prescribing practices in the U.S. are unknown.

Methods: Retrospective study of 16,785 individuals receiving pharmacological treatment for PD who were identified in Cerner Health Facts®. Our primary outcome was standardized annual prevalence of antiParkinson's drug use by drug class from 2001 to 2012. We also compared antiParkinson's medication trends and polypharmacy by age and sex.

Results: The most frequently prescribed PD drugs between 2001 and 2012 were levodopa (83%) and dopamine agonists (29%). Dopamine agonist use began to fall in 2007, from 37% to 25% in 2012, but the timing of the decline was more closely associated with adverse event reporting rather than publication of the American Academy of Neurology's (AAN) practice parameter refuting levodopa toxicity. Despite safety concerns for cognitive impairment and falls, individuals ≥80 years had stable rates (20%) of dopamine agonist use. Polypharmacy was most common in younger individuals.

Conclusions: Dopamine agonist use declined from 2007 to 2012, suggesting that increased awareness of safety issues and AAN practice parameters influenced prescribing. However, these events seemed to have little effect on the treatment provided to older adults with PD. Additionally, use of dopamine agonists did not begin to decline until two years after publication of the AAN's practice parameter, showing that the decline in dopamine agonist use was not immediate and may have been impacted by increasing safety concerns.

202

Changes in motor-cortex excitability after different rehabilitation programs in PD patients with freezing of gait: Neurocognitive rehabilitation with motor Iimagery vs treadmill training

A. Cucca, M. Catalan, L. Antonutti, S. Mezzarobba, P. Busan, N. Koscica (Venice, Italy)

Objective: Testing the efficacy of two different rehabilitation programs in improving FoG in PD patients and studying the impact of these treatments on cortical excitability.

Background: Freezing of gait (FoG) is a highly disabling symptom of Parkinson's disease (PD) characterized by brief, episodic absence or marked reduction of forward progression of the feet during walking. FoG pathogenesis is not completely understood and pharmacological treatments generally have a poor outcome. For this reason many rehabilitation treatments have been proposed with contrasting results. We wanted to test the efficacy of Motor Imagery (NR-MI) in reducing FoG, as compared with Treadmill Training (TT).

Methods: 20 PD patients with FoG were enrolled and randomly assigned to treatment groups. Group 1 performed 20 sessions of a Neurocognitive Rehabilitation program based on NR-MI, while Group 2 underwent 20 sessions of TT. At baseline and at the end of the rehabilitation program (T1), patients were evaluated by assessing: disease stage (H&Y and UPDRS III), FoG (FOGQ), cognitive abilities (e.g. attention, executive functions) and indexes of cortical excitability evaluated registering from lower limbs, by means of single and paired-pulse Transcranial Magnetic Stimulation (TMS).

Results: Results at baseline, the groups did not differ for any considered variable. After treatment, Group 1 experienced a significant reduction of FoG (p<0.001) while Group 2 did not show any improvement. TMS mainly suggested a tendency toward an increase in the excitability of the motor cortex after both treatments with respect to baseline indexes of motor thresholds and motor evoked potentials recruitment curves, as well as in intracortical inhibition. On the other hand, a tendency toward a prolongation in the duration of the silent period could be observed in both groups, as well as a tendency toward a diminution in intracortical facilitation in the TT group.

Conclusions: Although both rehabilitation programs mainly induced comparable effects on TMS, only NR-MI showed a significant improvement of FoG, suggesting a different mechanisms of intervention between the two treatments. NR-MI appears to be an interesting suitable rehabilitation strategy to treat FoG in PD patients.

203

Use of tDCS as motor cortex stimulation predictor for gait disorders in advanced Parkinson's disease

E.U. da Silva, L.A. Nilton, Jr., J.C.E. Veiga, J.M.d.A. Silva, H.C. de Souza (Sao Paulo, Brazil)

Objective: To evaluate the benefit of Epidural Motor Cortex Stimulation (MCS) in Parkinsonian patients who presented improvement of freezing of gait (FOG) and balance after transcranial motor cortex stimulation (tDCS).

Background: Gait disturbances such as freezing of gait (FOG), balance and apraxia are challenging symptons in advanced advanced Parkinson's disease (PD), generally resistant to conventional drug and non-drug treatment, can generate loss of autonomy and traumatic complications. Recently, researches have been directed toward these devastating symptoms. Traditional deep brain stimulation have been proved worthless and Pedunculopontinous Nucleus Stimulation, proposed as a new potential target, still havent been widely accepted for its risks and lack of predictors. Few reports suggested improvement of bradykinesia and gait after MCS. Lately, the possibility of cortex modulation with tDCS have leaded to new perspectives and non-invasive approaches. Many authors reported changes in gait and motor skills after these modalities. We report the benefit MCS in 4 patients who presented improvement after tDCS and submitted to MCS.

Methods: We selected 12 PD patients, who presented motor fluctuations, severe gait disturbances, and who showed insufficient improvement after levodopa trial (30%). All patients were submitted tDCS, 4 weekly sessions, with 2mA, during 30.

Patients who presented improvement of Gait, balance and bradykinesia were considered to underwent Surgical Epidural Motor Cortex Stimulation (MCS) of the left hemisphere. Improovement of gait was considered as remission of FOG, step larger than a foot, 5 m walking time, and improove in posture and balance. Patients were assessed preoperatively and 3 months after surgery.

Results: We observed that 33% of patients showed improvement of gait and balance after TDCS. All selected patients showed expressive gait changes following TDCS and MCS, in a follow-up of 4-18 mo. [figure1]The benefit of MCS was similar to the best response observed after TDCS which occurred 1-3hrs after the session and lasted for 3-5 days. There was no change in mean daily medication intake, and no side effects were observes during this period.

Conclusions: This study suggests that MCS improves FOG, balance and apraxia in PD similar to TDCS responses, since this modality provides continuos stimulation, responses are more stable and lasting. TDCS could be an efficient trial.

Details are in the caption following the image

(203).

204

Eight years’ experience with continuous intraduodenal levodopa infusion in Parkinson's disease

O. De Fabregues, J. Dot, A. Abadia, J. Hernandez, M. Ibarria, A. Ferre, C. Puiggros, J.R. Armengol, M. Quintana, J. Alvarez-Sabin (Barcelona, Spain)

Objective: To describe our experience of 8 years in the management of continuous intraduodenal infusion of levodopa (CIDLI) treatment for Parkinson's disease (PD).

Background: CIDLI is a new treatment for advanced PD that has demonstrated to improve motor fluctuations. Long-term therapy complications and their management and its effect on sleep, cognition and behavior and impact in patient's quality of life and caregiver burden are not well established.

Methods: Open and prospective study in patients with advanced PD with disabling motor fluctuations treated with CIDLI. Motor scale and patient diaries were used to evaluate the motor condition. Adverse events and action taken to solve them were collected.

Quality of sleep subgroup (sG): evaluated with Epworth scale, fatigue scale, Pittsburg quality of sleep questionnaire, Beck depression scale, and Hamilton anxiety scale, and overnight polysomnography study.

Neuropsychological assessment sG: evaluated with a specific neuropsychological battery for cognitive assessment by the same neuropsychologist at the same environmental conditions.

Health status, quality of life and caregiver burden sG: evaluated with quality of life questionnaire in PD (PDQ-39), health status questionnaires (EQ-5D and EQ-VAS), global clinical impression scale (CGI) and caregiver burden questionnaire (Zarit Burden index).

Assessments at baseline, week 1, three, six, twelve months and one, two, three, four, five, six, seven and eight years.

Results: Thirty patients were included (17M/13F) with advanced PD. Mean age was 68.5 years (range 54-79) and the mean duration of the disease was of 13.8 years (range 7-23).

Patients showed a significant and sustained motor improvement with increase of time “ON” to more than 80% of their waking time, and a mean decrease of 5.2 h in “OFF” time, without deterioration or with a tendency to an improvement of non-motor disorders studied. With improvement in the quality of life and reduction of the caregiver burden, despite several complications and adverse events most of low and moderate severity, and some serious related to PEG, to the infusion system or to the treatment itself. All the patients selected maintained the treatment except 5. Five patients in CIDLI treatment died by not related cause with the treatment.

Conclusions: We confirm CIDLI as a treatment with sustained efficacy, where the correct management requires the organization of a multidisciplinary team.

205

The efficacy and safety of coenzyme Q10 in preventing the progression of early Parkinson's disease: A meta-analysis

R.C. De Roxas, R.D.G. Jamora (Manila, Philippines)

Objective: The objective of this study is to assess and summarize the available evidence on the efficacy and safety of Coenzyme Q10 administration in the prevention of the progression of early Parkinson's disease.

Background: Coenzyme Q10, also known as Ubiquitone, is a substance now being used as a dietary supplement in many countries including the Philippines. It has also been the focus of several researches as treatment for several diseases including Parkinson's disease. Several studies have shown that Coenzyme Q10 inhibits mitochondrial dysfunction in Parkinson's disease, hence delaying its progression.

Methods: This is meta-analysis of randomized controlled trials on the use of Coenzyme Q10 in Parkinson's disease. A literature search in several databases was conducted for relevant studies. Three randomized controlled trials met the inclusion criteria. The efficacy of Coenzyme Q10 were measured using the total and the component scores of the Unified Parkinson's disease Rating Scale on follow-up. On the other hand, safety were measured using the withdrawal rate and the associated adverse reactions during the therapy of CoQ10. The Review Manager Software was utilized for the meta-analysis.

Results: Compared to Placebo, treatment of CoQ10 did not show any significant difference in the mean scores of the UPDRS mental and ADL scores. Interestingly, the UPDRS motor score showed a significant difference between Coenzyme Q10 and placebo, but no significant difference when a subgroup analysis between high-dose (-4.03 [-15.07-7.01], p-value= 0.47, I2=67%, P for heterogeneity=0.08) and low-dose Coenzyme Q10 (0.53 [-0.89-1.94], p-value= 0.47, I2=34%, P for heterogeneity=0.22) was done. Overall, there was no significant difference in the total UPDRS score (0.68 [-0.61-1.97], p-value= 0.30, I2=0%, P for heterogeneity=0.70). The most common side effects of the use of Coenzyme Q10 are anxiety, back pain, headache, sore throat, nausea, dizziness and constipation.

Conclusions: CoQ10 treatment was found to be safe with only minimal side effects but it did not show any significant difference in the mean scores of the UPDRS total and component scores in patients with Parkinson's disease.

206

The impact of electrical parameters on bradykinesia of Parkinson's disease patients after deep brain stimulation surgery

M. Delrobaei, S. Tran, G. Gilmore, K. Ognjanovic, K. McIsaac, M. Jog (London, ON, Canada)

Objective: (1) To provide an effective approach for monitoring of Parkinson's disease (PD) patients’ bradykinesia, (2) to systematically and objectively identify the clinical effects on the bradykinesia of 15 PD patients undergone Subthalamic deep brain stimulation (STN-DBS) over successive programming sessions.

Background: Clinical scale based follow-up of patients undergoing STN-DBS has shown inconsistent effect on bradykinesia in PD patients. However, quantitative assessment of STN-DBS effects on bradykinesia has not been done.

Methods: Fifteen PD patients and 15 healthy controls are recruited. The study has been approved by the local ethics committee. Each patient is assessed pre-operatively and followed for 6 months post-operatively. At each visit, we test three DBS settings with enough time between the sessions. The settings are pre-defined and cover the whole range of device settings in common practice. The settings are randomized for each patient. The patients are recorded in the lab environment while wearing a motion capture suit. A variety of features are extracted from the data to quantify bradykinesia.

Results: Currently there are 15 patients enrolled in this study and preliminary analysis has been performed for 3 patients who have finished all the 9 lab visits as well as 3 healthy controls. We analyze forearm angular displacement during a hand pronation-supination task. The extracted features are: standard deviation (STD), range of motion (ROM), angular velocity (Vel), and variability in terms of time (Time_Var) and amplitude (Amp_Var). We define a new bradykinesia index which considers all the features: B-Index = sqrt(STD*ROM*Vel/Time_Var*Amp_Var). Our analyses reveal that increasing the frequency of stimulation (voltage and pulse width fixed) generally decreases the B-Index. Increasing the pulse width (voltage and frequency fixed) does not generally cause a consistent effect on the B-Index. Increasing the voltage (frequency and pulse width fixed) increases the B-Index. On average, the B-Index of healthy controls is higher than the patients.

Conclusions: We conclude that our method provides an effective approach to quantify PD patients’ bradykinesia after DBS surgery which overcomes some of the shortcomings of the other studies. We show that our approach form an accurate tool to compare the slowness of movement of PD patients and healthy people.

207

Efficacy of IPX066, an extended-release formulation of carbidopa-levodopa, in advanced Parkinson's disease patients with troublesome dyskinesia

R. Dhall, L. Struck, R. Rubens, V. Shah, S. Gupta (Phoenix, AZ, USA)

Objective: Evaluate the efficacy of IPX066 in advanced Parkinson's disease (PD) patients with troublesome dyskinesia.

Background: IPX066 is an extended-release formulation of carbidopa-levodopa (CD-LD) designed to provide a rapid increase in plasma LD concentrations similar to immediate-release CD-LD, but with sustained stable concentrations to allow a dosing interval of every 6 hours. IPX066 has demonstrated improvements in PD motor symptoms in early and advanced PD.

Methods: IPX066 was administered for 13 weeks in a double-blind, parallel-group study vs. immediate-release CD-LD (IR) in advanced PD patients (randomized N=393). This post-hoc analysis compared the cohort of patients who entered the study with any reported “on” time with troublesome dyskinesia, by patient diary (IPX066, n=44; IR, n=35). Efficacy measures included patient diaries and Unified Parkinson's disease Rating Scale (UPDRS) Parts II (activities of daily living) + III (motor score).

Results: At baseline, these patients had a mean (SD) “on” time with troublesome dyskinesia of 1.7 (1.3) hr and 1.9 (1.6) hr, and mean “off” time of 5.3 (1.8) hr and 5.5 (1.7) hr, for IPX066 and IR groups, respectively. Baseline UPDRS Parts II+III scores were 30.3 (14.9) for IPX066 and 34.1 (14.8) for IR. At the end of the 13-week treatment period, IPX066 treatment produced a significantly greater improvement in UPDRS Parts II+III scores (-4.9 [10.5] points) compared to IR, which worsened by +1.6 (10.4) points (P<.001). IPX066 treatment also produced a greater decrease in “off” time (-1.4 [2.8] hr) compared to the IR group (-0.7 [2.9] hr), although this was not statistically significant (P=.13). Both groups showed less “on” time with troublesome dyskinesia at the end of treatment, -0.4 (1.9) hr for IPX066 and -0.8 (2.2) hr for IR (P=.40).

Conclusions: Advanced PD patients with troublesome dyskinesia at baseline demonstrated significantly greater improvement in UPDRS Parts II+III scores and numerically greater improvement in “off” time after treatment with IPX066 compared to IR. These improvements were not accompanied by increased “on” time with troublesome dyskinesia in either treatment group.

208

Feasibility study of an intensive multi-strategy rehabilitation program for Parkinson's disease

J.M. Domingos, V. Caniça, C. Godinho, A. Pinho, D. Guerreiro, J.J. Ferreira (Torres Vedras, Portugal)

Objective: To assess the feasibility of an intensive multi-strategy rehabilitation program for individuals with Parkinson's disease (PD) and to evaluate the responsiveness of multiple outcome measures that could be candidates to be applied on confirmatory trials.

Background: Increasing research suggests that intensive rehabilitation programs can provide both short and long-term benefits to individuals with PD. Given the variety of rehabilitation programs that exist, the true acceptability to these programs is still limited.

Methods: We conducted an exploratory feasibility study in individuals diagnosed with idiopathic PD. Feasibility was assessed by level of adherence to the program. Participants were recruited from a Movement Disorders Unit (Campus Neurológico Sénior - CNS) based on their balance and gait impairments. Participants were assessed with the MDS -UPDRS (part III), Pull-test, Timed-up and go (TUG) and Balance Berg scale, and Schwab & England Scale. Our intervention consisted of at least 2 hour individual physiotherapy sessions per day, 3 times a week for at least 4 weeks. The program consisted of practicing gait and balance multitask activities with different kinds of motor and cognitive tasks progressively introduced. Focused attention and multitasking was also explored with resistance training using plurisports adapted to PD, such as boxing, dancing and swimming.

Results: The participants included 6 woman and 7 men, mean age of 72.5, Hoehn and Yahr stages 2 to 4 and with a mean disease duration of 7 years. Every participant completed the program with no relevant adverse effects and according to the protocol. The outcomes with larger effect size were the MDS-UPDRS (Part III) (with 0,78 Cohen's effect size); Berg balance scale (0,25 Cohen's effect size); Timed Up and Go (0,25 Cohen's effect size); Pull test (0,07 Cohen's effect size) and Schwab and England (0,03 Cohen's effect size).

Conclusions: Our results suggest that this intensive rehabilitation program had a high adherence level and appears to be feasible for these individuals with moderately severe PD. Our results also suggest that the most responsive outcome measure for an intervention with these characteristics is the MDS-UPDRS (Part III).

209

Onset and duration of clinical effect of IPX066, an extended-release formulation of carbidopa-levodopa, in advanced Parkinson's disease

A. Ellenbogen, R.A. Hauser, N.B. Modi, A. Hsu, S. Khanna, S. Gupta (Bingham Farms, MI, USA)

Objective: Compare the onset and duration of clinical effect of IPX066 to immediate-release (IR) carbidopa-levodopa (CD-LD) and CD-LD + entacapone (CL+E) in patients with advanced Parkinson's disease (PD).

Background: IPX066 is an extended-release, multiparticulate capsule formulation of CD-LD designed to provide a rapid increase in plasma LD concentrations similar to IR CD-LD, but with sustained stable concentrations to allow dosing every 6 hours. IPX066 has demonstrated improvements in PD motor symptoms in early and advanced PD.

Methods: IPX066 and CL+E were compared in a double-blind crossover study; IPX066 and IR CD-LD were compared in an open-label randomized crossover study. The Unified Parkinson's disease Rating Scale (UPDRS) Part III (motor score), Investigator Dyskinesia Assessment (IDA; rating of “off” time and “on” time with or without dyskinesia), and finger tapping (taps/min) were assessed after a single dose of IPX066 or the comparator. Outcomes were assessed pre-dose and at 30 min (tapping, IDA) or hourly (UPDRS) intervals after dosing. The time at which patients crossed a threshold of improvement in finger tapping [10, 15, 20%] and UPDRS Part III [2.5, 5, 7, 11 units] were used to determine the onset and duration of clinical effect. Time to “on” and duration of “on” without troublesome dyskinesia (“on” with no or non-troublesome dyskinesia) were analyzed for the IDA.

Results: For IPX066 vs. CL+E, a subset of 32 patients underwent pharmacodynamic assessment (of 91 randomized in the larger study); 27 patients were enrolled for IPX066 vs. IR CD-LD. Time to “on” and duration of “on” using a threshold of 15% increase from baseline in tapping, and an 11 point improvement in UPDRS were similar to values obtained on the IDA, and are shown in Table 1. The pattern of improvements was similar using other improvement thresholds. [figure1]

Conclusions: The onset of clinical effect for IPX066 was rapid, similar to that for IR CD-LD and CL+E. The duration of effect for IPX066 was substantially longer than that for either IR CD-LD or CL+E.

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(209).

210

TDCS and gait training for hypokinetic gait disorders: A pilot study

T. Emara (Cairo, Egypt)

Objective: Different gait training protocols usually improve gait speed by 0.1 m/sec. Our objective was to test whether applying Transcranial Direct Current Stimulation (TDCS) with gait training may help achieve better gains in walking speed.

Background: Gait problems in patients with Parkinson's disease or vascular Parkinsonism are often resistant to medical treatments.

Methods: Nine patients with PD or vascular Parkinsonism were recruited. 12 20-minute sessions of Anodal TDCS at Cz that were followed by gait training sessions within a period of 4 weeks were applied. 10 mts walking speed at self selected pace was measured at baseline and at the end of the treatment period. Other outcome measures included degree of assistance (1-7 score similar to the functional independence measure grading), number of falls, and functional category according to walking speed (difficult in-home ambulation less than 0.2 m/s; in-home ambulation 0.2-0.4 m/s, limited community ambulation 0.4-0.8 m/s; community ambulation more than 0.8 m/s). No change of medications was allowed during the study period.

Results: Six cases with PD (5 males and one female) and three male patients with vascular Parkinsonism with mean age of 68.1 +/- 4.5 and mean duration of illness of 7.5 +/- 2.3 yrs were recruited. There was a significant change in gait speed (baseline 0.29+/-0.17 m/s, post 0.56+/-0.23 m/s; p=0.0001), and degree of assistance needed (p=0.001) but not in the number of falls (p=0.1). The mean speed gain was 0.27+/-0.14 m/s. 5/9 patients had a 1-2 point change in their functional category of walking speed, all of them had a starting speed of less than 0.4 m/s.

Conclusions: TDCS may augment the effects of gait training in patients with hypokinetic gait disorders. The effect is particularly clear in those with low starting walking speed and results in a functional change of walking ability in those cases. A larger RCT is currently underway to validate these results and to monitor the sustainability of this improvement.

211

The influence of baseline disease severity on the efficacy of IPX066, an extended-release formulation of carbidopa-levodopa, in advanced Parkinson's disease

A.J. Espay, G. Liang, K. Sharma, R. Rubens (Cincinnati, OH, USA)

Objective: Evaluate whether the clinical efficacy of IPX066 is influenced by baseline disease severity in clinical trials of advanced Parkinson's disease (PD), using post hoc subgroup analyses.

Background: IPX066 is an extended-release formulation of carbidopa-levodopa (CD-LD) designed for a rapid increase in plasma LD concentrations (similar to immediate-release [IR] CD-LD), but with sustained stable concentrations to allow dosing every 6 hours. IPX066 has demonstrated improvements in motor symptoms in early and advanced PD.

Methods: IPX066 was tested in advanced PD in two randomized, double-blind, active comparator-controlled Phase 3 studies (ADVANCE-PD: IPX066 vs. IR CD-LD for 13 weeks, N=393; ASCEND-PD: IPX066 vs. CD-LD+entacapone using a 2-week per period crossover, N=91). Subgroups were dichotomized into “more severe” or “less severe” based on median baseline “off” time (5.67 hr, ADVANCE-PD; 5.0 hr, ASCEND-PD) and median UPDRS Part II+III (activities of daily living + motor score: 32, ADVANCE-PD; 30, ASCEND-PD). The changes from baseline in UPDRS II+III scores, “off” time, and “on” time with troublesome dyskinesia by PD diary were analyzed by treatment for each subgroup.

Results: IPX066 significantly improved “off” time (P<.0001) and UPDRS II+III scores (P<.03) compared with the active controls in the overall studies. In both studies, numerical improvements from baseline in UPDRS Parts II+III and “off” time were seen with IPX066 vs. the comparator in each disease severity subgroup. In the larger ADVANCE-PD study, the improvements in “off” time were significantly greater for IPX066 vs. IR CD-LD in the more severe “off” (P<.0001) and in both the more (P=.02) and less severe (P=.0001) UPDRS subgroups. Greater improvements in UPDRS II+III were also seen with IPX066 in the more severe “off” (P=.0002) and UPDRS (P=.0001) subgroups; the approximate 2-fold improvement by IPX066 compared to IR CD-LD in the less severe “off” (P=.13) and UPDRS (P=.18) subgroups did not reach significance, possibly due to a lower score range (floor effect). For both studies, IPX066 did not worsen “on” time with troublesome dyskinesia compared to active controls in any subgroup (P>.11).

Conclusions: Across disease severity subgroups, IPX066 consistently improved UPDRS Part II+III and “off” time vs. the active controls without significantly worsening troublesome dyskinesia.

212

Impact of tDCS in Parkinson's disease on mood, cognition, and motor deficits: A randomized, double-blinded, placebo-controlled trial

R.A. Falconer, S.L. Rogers, Y. Torres-Yaghi, P. Turkeltaub, F. Pagan (Washington, DC, USA)

Objective: Evaluate the potential for bifrontal transcranial direct current stimulation (tDCS) to improve mood, cognitive and motor functioning in patients with Parkinson's disease.

Background: tDCS has demonstrated ability to temporarily enhance cognitive, motor and affective functions of the brain. Prior studies have shown definable improvement in post-stroke patients. This study seeks to examine whether these benefits translate to neurodegenerative conditions. An open-label trail showed potential for improvement. This study examines the validity of those results in a placebo-controlled trial.

Methods: Seven patients with Parkinson's disease were randomized to either a treatment arm or a placebo arm in a double-blinded method. Pre-stimluation testing included the following: UPDRS, Becks Depression Screen (BDS), MOCA, and speech assessments. Participants in the treatment arm were then given tDCS treatments daily for 10 days. These daily treatments involved 2mA current administered in a bifrontal montage for 30 minutes, designed to facilitate frontal lobe integration at the prefrontal cortex. Participants in the placebo-controlled arm received a brief, 15-second stimulation to mimic treatment, but no other therapy. After completion of the 10 days, a post-test battery was completed for comparison. We will complete 1 month post-follow-up with testing and a full delayed intervention to the placebo group.

Results: Regarding mood, the treatment arm experienced a 65% improvement on average in BDS, compared to 22% in the placebo group. For cognition, the treatment group saw a 36% improvement on average in MOCA score, compared to 4% in placebo group. Regarding motor functioning, the treatment group saw a 24% improvement on average in UPDRS, compared to an average decline of 13% in the placebo group. When comparing treatment and placebo, improvement was consistently greater in the treatment arm by a difference of 43% (BDS), 32% (MOCA) and 37% (UPDRS).

Conclusions: With 10 days of tDCS stimulations to the bifrontal regions, we observed a noted improvement in mood, cognitive and motor scoring that was not reflected in the placebo arm. Although low sample size is a limitation to this study, the noted improvement in the treatment arm compared to placebo arm is encouraging for tDCS to be a low-risk, high-yield treatment in the Parkinson's community and should propel further tDCS studies in PD.

213

Leg rest tremor response to acute dopaminergic challenge predicts long term Parkinson's disease diagnosis

S. Fariña, M. Wilken, P. Morisset, D. Cerquetti, M. Rossi, M. Merello (Buenos Aires, Argentina)

Objective: To evaluate leg rest tremor (LRT) response to acute dopaminergic challenge and its relationship to subsequent long term Parkinson's disease (PD) diagnosis.

Background: LRT can be an early sign of PD and other Parkinsonisms, such as multiple system atrophy and vascular Parkinsonism. Its predictive value for PD clinical diagnosis has not been described.

Methods: A retrospective review of medical records from patients with a short-onset Parkinsonism that were submitted to acute levodopa challenge for clinical prediction of sustained long-term dopaminergic response between November 1999 and August 2014. Data was collected on demographics, levodopa response (a modification of UPDRS-III or MDS-UPDRS-III ≥30% was considered a positive test and a reduction in at least one point in LRT subscore was considered a positive response of LRT), clinical manifestations and final clinical diagnosis after at least one-year follow-up.

Results: A total of 778 patients were evaluated, of which 75 (10%) patients presented LRT. Fifty four (72%) had responsive LRT, of which 41 (76%) showed a positive response to levodopa acute challenge and 49 (65%) fulfilled all UKPDSBB criteria at one-year follow-up. Of the 21 (28%) non-responsive LRTs, only one (5%) showed a total positive response to acute levodopa challenge and a final PD diagnosis, whereas 20 (95%) had negative response to acute challenge, of which 6 (30%) received a PD diagnosis at one-year follow-up (false negatives). A responsive LRT to acute levodopa challenge obtained a sensitivity of 88%, a specificity of 74% with a positive and negative likelihood ratio for a final clinical PD diagnosis of 3.3 and 0.2, respectively. Multivariate analysis revealed the presence of limb bradykinesia (p<0.0001) and the total UPDRS/MDS-UPDRS-III response to levodopa acute challenge (p=<0.0001) were independent factors related to LRT response. No PD patient had isolated (without any akineto-rigid feature) LRT, whereas 5 out of 19 (26%) presented LRT without arm or leg rest tremor. LRT magnitude response to levodopa was significantly higher than hand rest tremor (p=0.033).

Conclusions: LRT, although infrequent, can be an early sign of PD. It was frequently accompanied with hand rest tremor, but showed a greater magnitude response to levodopa than the latter. Its positive response to acute levodopa challenge has a high sensitivity and moderate specificity for PD diagnosis.

214

Benefits of task-specific learning-principled practice to improve freezing of gait for individuals with Parkinson's disease in a small group community setting. A case series study

B.G. Farley, K.M. Hamilton, A.B. Messer, K. Greene, L. Rankin (Tucson, AZ, USA)

Objective: To examine the benefits of task-specific learning-principled practice to improve freezing of gait (FOG) for individuals with Parkinson's disease (PD) in a small community setting.

Background: FOG is one of the most disabling symptoms of advanced stage PD and is associated with frequent falls and reduced quality of life (QoL). Researchers and clinicians define FOG as: An episodic inability to generate effective stepping most commonly experienced during turning and step initiation, but also when faced with spatial and time constraints, stress, and distraction. Despite the multifactorial nature of FOG, task-specific training has not yet been applied to counteract the multiple motor/cognitive/emotional triggers that lower threshold for the occurrence of FOG and that may interact and deteriorate synergistically. In addition, learning principles of practice have not been applied to task specific antifreeze exercises. Instead, more general gait and balance training with attentional strategies and external cues are typically used to circumvent freezing episodes.

Methods: In this case series study, we investigated the effects of a task-specific learning principled approach that targeted each person's unique “triggers” directly. In addition to specificity of training, other learning principles were integrated into the program including: feedback, intensity through high effort and dosage (5 days; 3 hours/day), and progressive difficulty by manipulating environment, balance requirements, distractors, and variability of practice. Attentional strategies and external cues were integrated to enhance learning by allowing for greater success during the practice of complex multitasking conditions. The study was held in a community setting with a small group “boot camp” approach to take advantage of social/emotional interactions shown to impact learning and quality of life.

Results: 5/6 subjects showed improvement in the FOG questionnaire and objective measures including dual tasking conditions. These improvements were related to QoL for 4/5 subjects. One subject with mild FOG did not show improvement on any FOG outcomes.

Conclusions: We will report on the trends across 6 individuals and discuss the implication to future studies and real world implementation.

215

Preliminary report investigating the benefits of neuroplasticity-principled community-based exercise programs for people with Parkinson's disease

B.G. Farley, A. Okurily, J. Bazan-Wigle, K. Moynahan (Tucson, AZ, USA)

Objective: Report preliminary short-term benefits on mobility of ongoing community-based group exercise programs that implement progressive aerobic training and Parkinson's disease (PD) specific skill acquisition forms of training for people of varying disease severity.

Background: Progressive aerobic training and skill acquisition have emerged as forms of practice for people with PD that are capable of not only improving function, but capable of mediating brain health and repair mechanisms. Translating neuroplasticity-principled research protocols effectively, thereby counteracting inactivity, is a challenge. The Parkinson's Wellness Recovery Gym (PWR!Gym®) offers ongoing specialty group classes and intensive therapies for people with Parkinson's disease of varying severity in a community center.

Methods: All participants are provided an initial consult with a physical therapist to determine the class that will best meet their fitness/cognitive/mobility goals. Intensity and complexity of training varies across groups from most (HIIT, N=13) to moderate (Circuit, N=12) to least (MOVES, N=10). Measurements are collected at initial intake and ∼6 months thereafter. All classes meet for 1 hour 2-3x/week and target 20’ of progressive aerobic training plus 20’ of a functional amplitude-focused training program called PWR!Moves®.

Results: MOVES/Circuit both improved in 10 m self-selected walking (12%) and stand to floor transfer time (17-24%). All groups improved in backward walking (14-23%) and timed up/go (TUG) in motor dual task conditions (∼14%). MOVES showed greatest change in TUG in both dual task conditions (motor/cognitive) interference. Circuit was the only group to show meaningful improvements in 6’ walk endurance (16%) and 10 m fast walking (12%). HIIT showed least improvement on all measures.

Conclusions: The least challenging class showed the greatest improvement on functional mobility outcomes. Backward walking and dual task TUG were most sensitive across groups. Data may reflect need for more sensitive clinical mobility outcomes, differences in specificity of training across exercise classes, and need for better clinical criteria to predict an individual's response to manipulations of fitness/learning principles of training.

216

Initiating intrajejunal infusion of levodopa/carbidopa intestinal gel: An outpatient model

A. Fasano, L.W.C. Liu, Y.Y. Poon, A.E. Lang (Toronto, ON, Canada)

Objective: To describe our experience with an outpatient-model for levodopa/carbidopa intestinal gel (LCIG) treatment in patients with Parkinson's disease.

Background: Although there are no published procedural guidelines on the best model to deliver intrajejunal infusion of LCIG treatment, patients are generally hospitalized and switched from their conventional pharmacotherapy to LCIG through a percutaneous endoscopic gastrostomy (PEG) with jejunal tube (PEG-J).

Methods: We propose the nasojejunal test phase for patients whose potential clinical benefit is uncertain. Patients undergo endoscopic PEG/PEG-J placement as outpatients, are sent home 1-2 hours after and seen by the gastroenterologist the following day to examine the PEG insertion site and to adjust the bumper position against the abdominal wall as necessary. A minimum of two weeks later, patients return to the clinic off medications and LCIG dose is slowly titrated. Patients are sent home at the end of each day; they are seen again on the following two days, in order to refine the optimal LCIG dosage as well as to taper off oral drugs. [figure1]

Results: To date, five patients (including 1 with levodopa-responsive multiple system atrophy, 1 female, age: 61.8 ± 8.1 years, disease duration: 10.0 ± 2.6 years) have received the treatment successfully and safely with the proposed outpatient model. None needed the nasojejunal test-phase. All patients reported an improvement of motor fluctuations (on average by 59.7 ± 15.3%). One patient suffered from a stoma infection treated with topical antibiotic.

Conclusions: Our model is characterized by a delay between the PEG-J procedure and initiating the LCIG to allow the fistula track to mature, thus possibly reducing PEG site related complications, frequently reported in clinical trials. We believe that there is no urgency to start LCIG following the PEG-J procedure, as is often encouraged in the full inpatient model in order to expedite patient's stay in the hospital.

Avoiding hospitalization has a number of other advantages: 1) it ensures a faster access to LCIG treatment especially in busy hospitals where elective admissions are often extremely limited due to bed shortages; 2) it ensures better patient compliance and reduces complications associated with hospitalization, such as delirium or infections; 3) it is more cost-effective.

Future studies enrolling a larger number of outpatients will likely prove the value of our approach.

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(216).

217

Risk factors and safe dosage of levodopa for wearing-off phenomenon in Chinese patients with Parkinson's disease

T. Feng, H. Chen, J. Fang, F. Li, L. Gao (Beijing, People's Republic of China)

Objective: To investigate risk factors of wearing-off phenomenon in Parkinson's disease (PD) and propose safe dosage of levodopa to reduce wearing-off development based on Chinese cohort.

Background: Risk factors of wearing-off in PD were reported differently and safe dosage to reduce wearing-off has not been indicated via statistic model.

Methods: Patients with PD who had taken levodopa (L-dopa) for at least 1 month were recruited. Wearing-off was diagnosed based on validated Chinese version of a patient self-rated 9-question Wearing-Off Questionnaire (WOQ-9) and clinical definition. Eleven variables (gender, disease duration at L-dopa initiation, disease duration at assessment, age at onset, age at assessment, H-Y stage, UPDRS III, L-dopa daily total dosage and dosage adjusted to weight, duration of L-dopa treatment, initial drug recipe) were included in our analysis. Univariate analysis, multivariate logistic regression analysis and decision tree classification model(DTC) were used to detect risk factors of wearing-off. Receiver operating characteristic (ROC) curve and DTC were used to investigate cut-off value of L-dopa to best predict wearing-off.

Results: Two hundred and thirty four patients were investigated in our study, among whom 111 developed wearing-off. Patients with wearing-off tended to receive higher L-dopa dosage and endure longer duration of L-dopa treatment.

Table 9. univariate analysis of difference between wearing-off and control
Control(n=97) WO(n=111) P p▲
Demographic profile
gender(male:female)Δ 53:44 63:48 0.919 0.530
Age at assessment 62.2 ± 10.5 62.1 ± 10.2 0.986 0.583
Disease profile
H-Y stage(range) 2(1.5—2.5) 2(1.5—3) 0.071 0.097
UPDRS III(range) 23(12—32) 26.25(19—37.63) 0.016* 0.004*
Age at onset 58.0 ± 11.3 57.0 ± 10.8 0.523 0.873
disease duration at assessment(month, range) 54(35—86) 61(48—96) 0.007* 0.053
Treatment profile
disease duration at L-dopa initiation(month, range) 26(9—49) 19(8.25—37.75) 0.150 0.155
L-dopa dosage, mg/kg/day◆(range) 4.2(2.5—5.6) 6.1(4.3—8.9) <0.001* <0.001*
L-dopa dosage, mg/day(range) 300(200—350) 387.5(300—600) <0.001* <0.001*
Duration of L-dopa treatment(range) 21(5—42) 41(23—60) <0.001* <0.001*
Initial therapyΔ 0.597
L-dopa 68 72
DA 3 5
L-dopa+DA 12 10
others 14 22
  • *The significance level of average difference is 0.05. Variables were comparing to control group. ▲ initial therapy matched comparison ◆ variables with abnormal distribution or unequal variances that underwent Mann-Whitney test Δ non-numeric variable underwent chi-square test.
Table 10. multivariate analysis of risk factors for wearing-off
variables P value Hazard ratio (OR)
Duration of L-dopa treatment 0.003* 1.024
Disease Duration at assessment (month) 0.241 0.994
HY stage 0.590 1.168
UPDRS III 0.181 1.024
L-dopa daily dosage adjusted to weight (mg/kg) <0.001* 1.282
L-dopa Daily total dosage (mg)▲ <0.001* 1.004
  • *The significance level of average difference is 0.05. ▲ was tested separately from L-dopa daily dosage adjusted to weight

L-dopa dosage as 281mg/day and 4.2mg/kg/day by ROC[figure 1], as well as 269mg/day and 3.2mg/kg/day by DTC[figure 2] were cut-off values for wearing-off. [figure1] [figure2]

Conclusions: L-dopa dosage and duration of L-dopa treatment were related to increased wearing-off development. Cumulative L-dopa dosage and L-dopa daily dosage were better predictive of wearing-off. Inadequate evidence was present for delayed L-dopa initiation. L-dopa daily dosage no more than 275 mg or 4.2 mg/kg was regarded as safe.

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(217).

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(217).

218

Effect of levodopa-carbidopa intestinal gel on resting tremor in patients with advanced Parkinson's disease

H.H. Fernandez, J. Dubow, W.Z. Robieson, K. Chatamra, S. Eaton, J.A. Benesh, P. Odin (Cleveland, OH, USA)

Objective: To evaluate the effect of levodopa-carbidopa intestinal gel (LCIG) treatment on resting tremor in patients with advanced Parkinson's disease (PD) in a 54-week, open-label Phase 3 study.

Background: Resting tremor is prevalent in advanced PD patients.1 The resting tremor response to dopaminergic therapy is often regarded as insufficient and underpins one of the reasons deep brain stimulation may be chosen over other non-oral therapies in advanced PD.

Methods: 354 patients were enrolled in an open-label study, 286 had both baseline (BL) and post-PEG-J assessment of unified Parkinson's disease rating scale (UPDRS). UPDRS III #20 (resting tremor) total score (5 categories: arms, legs, and face), safety and diary data were analyzed post-hoc in 3 subgroups defined by their max BL tremor score: No BL Tremor, Mild BL Tremor (max score =1 in any category), and Significant (SIG) BL Tremor (max score ≥2 in any category).

Results: .BL demographics were previously described for the intent-to-treat (ITT) population.2 The majority (69%) of patients (n=286) had No BL Tremor, 13% had Mild BL Tremor and 18% had SIG BL Tremor (Table 1). The mean (SD) change from BL to final resting tremor total score was -0.79 (2.4) in the ITT, and reductions in the Mild BL Tremor and SIG BL Tremor groups were substantial. Notably, amantadine use and levodopa dose were consistent across subgroups as all PD medications were initially tapered off and could be added back after 28 days. In the Mild BL Tremor group (n=38), 79% patients had no tremor at final, while only 2 (5%) had an increase max score to 2 at final. In the SIG BL Tremor group (n=52), 88% had a reduction in max tremor score to 0 or 1 at final, while no patients had an increase. Improvements in reducing “off” time and increasing “on” time without troublesome dyskinesia were comparable between subgroups (Figure 1). Treatment-emergent (TE) adverse events (AE) were reported in 91.2% of enrolled patients (n=354), and TE serious AEs reported in 30.5%. The tremor TEAE was reported in 4 (2.0%) No BL Tremor (n=196), 1 (2.6%) Mild BL Tremor (n=38), and 1 (1.9%) SIG BL Tremor (n=52) patient.

Table 11. Mean Change from Baseline to Final UPDRS III #20 Total Score, Levodopa Dose and Amantadine Use in Resting Tremor Subgroups
UPDRS III #20 Total Score Levodopa Dose Amantadine Use
BL Resting Tremor Subgroup n (% of studya BL Mean Score ± SD Mean Change from BL to Final ± SD Mean Change from BL to Final ± SD At BL, n (%) During Study, n (%)
No BL Tremorb 196 (69) 0.00 ± 0.0 0.21 ± 0.7 423.0 ± 646.6 61 (31.1) 20 (10.2)
Mild BL Tremorc 38 (13) 1.69 ± 0.8 -1.29 ± 1.0 336.4 ± 585.4 12 (31.6) 3 (7.9)
SIG BL Tremord 52 (18) 5.25 ± 2.6 -4.17 ± 3.6 441.0 ± 546.0 14 (26.9) 6 (11.5)
  • aN=286; bUPDRS III #20 = 0 at baseline; cMaximum UPDRS III #20 score =1 in any category at baseline; dMaximum UPDRS III #20 score ≥2 in any category at baseline; BL=baseline; UPDRS = unified Parkinson's disease rating scale; SD = standard deviation

Conclusions: Tremor remains prevalent in advanced PD patients. LCIG may alleviate resting tremor that was not well controlled by optimized oral medical treatment in advanced PD patients.

1Baumann CR. Parkinsonisn Relat Disord. 2012. 18:S90-2.

2Fernandez H et al. Mov Disord. 2014 Dec 24.

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219

Efficacy of opicapone in Parkinson's disease patients with motor fluctuations: A phase III, randomized, double-blind, placebo and active-controlled study – BIPARK I

J. Ferreira, A. Lees, A. Santos, R. Pinto, N. Lopes, T. Nunes, J.F. Rocha, P. Soares-da-Silva (Lisbon, Portugal)

Objective: Investigate the efficacy and tolerability of 3 different opicapone (OPC) doses (5, 25 and 50 mg) administered once-daily, compared with entacapone (ENT) and placebo, in levodopa-treated patients with Parkinson's disease (PD) and motor fluctuations.

Background: OPC is a novel once-daily potent and long-acting peripheral COMT-inhibitor under investigation for Parkinson's disease.

Methods: Multinational, multicentre, 14 to 15-week, double-blind, placebo- and active-controlled study. The primary efficacy variable was the change from baseline in absolute OFF-time based on patient diaries. The key secondary efficacy endpoint was the proportion of OFF- and ON-responders (≥ 1 hour improvement). Tolerability was assessed by adverse events (AEs), laboratory, vital-signs, ECG, physical and neurological examinations.

Results: A total of 600 patients were randomized to placebo (N=121), 5mg-OPC (N=122), 25mg-OPC (N=119), 50mg-OPC (N=116) or ENT (N=122). Both 50mg-OPC and ENT significantly reduced the OFF-time (1.95 h [p=0.0015] 50mg-OPC and -1.61 h [p=0.0141] ENT vs. -0.93 h placebo) and increased the ON-time without troublesome dyskinesia (1.82 h [p=0.0016] 50mg-OPC and 1.57 h [p=0.0150] ENT vs. 0.78 h placebo). Significantly more patients receiving 25mg- or 50mg-OPC achieved the OFF-time responder endpoint (60.3% [p=0.0464] 25mg-OPC and 69.6% [p=0.0011] 50mg-OPC vs. 47.5% placebo). Both 5mg-OPC and ENT missed statistical significance for OFF-time responders. A significantly higher proportion of ON-responders was also found for the 50mg-OPC group (65.2% [p=0.0028]). OPC and ENT were generally safe and well tolerated.

Conclusions: Opicapone, particularly 50mg-OPC, was effective in reducing OFF-time in PD patients with a favourable profile compared to ENT.

220

Safety and tolerability of opicapone in the treatment of Parkinson's disease and motor fluctuations: Analysis of pooled phase III studies

J. Ferreira, A. Lees, H. Gama, N. Lopes, A. Santos, R. Costa, C. Oliveira, R. Pinto, T. Nunes, J.F. Rocha, P. Soares-da-Silva (Lisbon, Portugal)

Objective: Evaluate the safety of opicapone (OPC) in patients with Parkinson's disease (PD) and motor fluctuations across phase III studies.

Background: OPC, a novel once-daily peripheral COMT inhibitor, has shown to be effective in reducing OFF-time in PD patients with motor fluctuations.

Methods: Patient-level data of matching treatment arms of BIPARK I and II studies was integrated (placebo, 25mg-OPC and 50mg-OPC). Both were multicentre, 14 to 15-week double-blind, randomised, placebo- and active-controlled studies and had similar designs and measurement instruments. Safety was assessed by incidence of treatment-emergent adverse events (TEAEs), changes in laboratory values, ECGs and vital signs.

Results: The pooled safety set included over 750 patients (N=257, 244 and 265 for placebo, 25mg- and 50mg-OPC). Dopaminergic events and other PD symptoms were the most commonly reported TEAEs: dyskinesia (18.3% OPC vs. 6.2% placebo), constipation (5.7% vs. 1.9%), insomnia (5.1% vs. 1.6%) and dry mouth (4.7% vs. 1.2%). No dose relationship was observed for the majority of TEAEs. Serious AEs were reported for few patients: 4.3% placebo and 3.5% OPC. One death (pneumonia) occurred in the placebo group. There were no reports of severe diarrhea, myocardial infarction, prostate cancer, melanoma or any serious hepatic event in OPC groups. Impulse control disorders were reported by <1% of OPC-treated patients. No relevant differences compared to placebo were observed for laboratory parameters, vital signs or ECG readings.

Conclusions: OPC is safe and well tolerated with no apparent association to known safety concerns of other anti-PD drugs, particularly other COMT inhibitors.

221

Efficacy of opicapone as adjunctive therapy to levodopa in patients with Parkinson's disease and motor fluctuations: Analysis of pooled phase III studies

J. Ferreira, A. Lees, A. Santos, N. Lopes, R. Costa, C. Oliveira, R. Pinto, T. Nunes, J.F. Rocha, P. Soares-da-Silva (S. Mamede do Coronado, Portugal)

Objective: Evaluate the efficacy of opicapone (OPC) in patients with Parkinson's disease (PD) and motor fluctuations across phase III studies.

Background: OPC is a novel once-daily potent and long-acting peripheral COMT inhibitor under investigation for PD.

Methods: Patient-level data of matching treatment arms of BIPARK I and II studies was integrated (placebo, 25mg-OPC and 50mg-OPC). Both were multicentre, 14 to 15-week double-blind, randomised, placebo- and active-controlled studies and had similar designs and measurement instruments. The primary efficacy variable was the change from baseline in absolute OFF-time based on patient's diaries. Key secondary measure was the OFF- and ON-time responder rates (≥ 1 hour).

Results: The pooled efficacy set included over 750 subjects (placebo n=255, 25mg-OPC n=241, 50mg-OPC n=262). Treatment with either 25mg- or 50mg-OPC resulted in a significant reduction of daily OFF-time (1.56 h [p=0.0106] 25mg-OPC and -1.94 h [p<0.0001] 50mg-OPC vs. -0.97 h Placebo) and increase in the ON-time without troublesome dyskinesia (1.43 h [p=0.0083] 25mg-OPC and 1.80 h [p<0.0001] 50mg-OPC vs. 0.72 h placebo). Significantly more patients receiving 25mg- and 50mg-OPC achieved the OFF- and ON-time responders endpoint (60.2% to 64.6% [p<0.005]).

Conclusions: OPC is effective in reducing OFF-time and increasing ON-time without troublesome dyskinesia.

222

Number-needed-to-treat analysis of droxidopa in patients with symptomatic neurogenic orthostatic hypotension

C. François, G.J. Rowse, R.A. Hauser, L.A. Hewitt (Deerfield, IL, USA)

Objective: To evaluate the safety and efficacy of droxidopa vs placebo for the treatment of symptomatic neurogenic orthostatic hypotension (NOH) in terms of the number needed to treat (NNT) and number needed to harm (NNH).

Background: Droxidopa is a norepinephrine prodrug recently approved to treat symptomatic NOH caused by primary autonomic failure (Parkinson's disease, multiple system atrophy, and pure autonomic failure), dopamine β-hydroxylase deficiency, and nondiabetic autonomic neuropathy. To date, safety and efficacy of droxidopa have been studied in 6 multicenter, phase 3 trials ranging from 2 weeks to 2 years in duration and involving >600 patients.

Methods: Safety and efficacy data were pooled from 2 phase 3 trials: NOH301 and NOH306. To calculate the NNT, outcome assessed was the response rate of Item 1 of the Orthostatic Hypotension Symptom Assessment (OHSA) showing improvement ≥50% or ≥2 units at Week 1; to calculate the NNH, outcomes assessed were adverse events (AEs) with >5% frequency, AE rate leading to dropout, and AEs related to falls. NNT and NNH were calculated as the reciprocal of the risk difference for placebo vs droxidopa. Likelihood to be helped or harmed (LHH) was calculated as NNH/NNT.

Results: Based on pooled OHSA Item 1 results, the NNT was significant for improvement ≥50% (5; 95% CI: 3–11) and ≥2 units (5; 95% CI: 4–8). The NNH was dependent on outcome assessed. Of the AEs occurring >5% (headache, dizziness, nausea, fatigue, and hypertension), the NNH ranged from 23 to 302 and was significant only for pooled incidence of hypertension (28; 95% CI: 16–95). For AEs related to falls, the NNH was -17 and -12 (not significant) in NOH301 and NOH306B, respectively, suggesting that placebo was more likely to cause harm compared with droxidopa. For pooled dropouts due to AEs, the NNH was 34 (NOH301: 84; NOH306: 24) and NNT of 5 (responder week 1 OSHA >2 or 50% improvement); therefore, LHH was calculated as 34/5=6.8.

Conclusions: Droxidopa is 6.8 times more likely to achieve response than result in a discontinuation because of an AE compared with placebo.

223

Impact of reduction in falls for patients with PD and NOH: Post hoc economic analyses of phase 3 clinical trial data on droxidopa

C. François, R.A. Hauser, H. Kaufmann, S. Heritier, L.A. Hewitt, R. Owen, B. Rive, G.J. Rowse (Deerfield, IL, USA)

Objective: To estimate the impact of droxidopa therapy on total costs in patients with Parkinson's disease (PD) and neurogenic orthostatic hypotension (NOH) while considering the observed reduction in the number of falls experienced by patients and droxidopa drug cost.

Background: NOH results from inadequate noradrenergic response to postural change. It is known to be a substantial risk factor for falls in patients with PD. Droxidopa is a norepinephrine prodrug recently approved to treat symptomatic NOH caused by primary autonomic failure (PD, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy.

Methods: Cost offset due to a reduction in falls was estimated using a retrospective, piggyback design of randomized controlled trial data and published data. Patients with PD in a phase 3 study underwent double-blind titration up to 2 weeks with droxidopa, followed by 8-week maintenance therapy (100–600 mg TID) or placebo. Falls were recorded daily via electronic diaries. Utilizing probability of falls to be fatal or nonfatal, falls requiring medical care, and costs from a systematic review of falls data in people ≥60 years old living in the community, we calculated the average cost/fall/treatment to estimate the potential cost reduction during 10 weeks of droxidopa therapy vs placebo.

Results: Droxidopa treatment over 10 weeks was associated with significantly fewer falls per patient-week vs placebo and with fewer fall-related injuries. The estimated average costs of falls per patient were $4,573 for droxidopa vs $11,813 for placebo. This results in a cost reduction of $7,239. The average droxidopa drug cost was $10,108. Thus the net cost of droxidopa therapy was $2,869. Sensitivity analyses with more conservative estimates of cost of falls or number of falls increased the net costs to $6,640 and $7,457, respectively.

Conclusions: This simple model indicates that droxidopa could reduce falls for PD patients with symptomatic NOH, limiting the financial impact of droxidopa therapy to $2,869 over 10 weeks of treatment. Inclusion of other potential benefits on functioning, quality of life, and associated costs related to negative consequences of fear of falling may further decrease the overall cost.

224

Cost effectiveness of droxidopa in patients with neurogenic orthostatic hypotension: Post hoc economic analysis of phase 3 trial data

C. François, R.A. Hauser, J. Dorey, E. Kharitonova, S. Aballéa, L.A. Hewitt (Deerfield, IL, USA)

Objective: To develop a cost-effectiveness (CE) model to estimate the impact of droxidopa vs the standard of care (SoC) in terms of US costs and quality-adjusted life-years (QALYs).

Background: Neurogenic orthostatic hypotension (NOH) is caused by autonomic dysfunction in which there is an inadequate noradrenergic response upon standing. Droxidopa is a norepinephrine prodrug that is FDA approved to treat symptomatic NOH. Orthostatic falls in blood pressure can lead to serious injuries, limited daily activities, and decreased quality of life, and represent a significant economic burden on the US healthcare system.

Methods: A Markov model was used to predict risk of falls and impact of NOH symptom improvement. Probabilities of falls and treatment responses were from randomized controlled trials (NOH306A and NOH306B) with Parkinson's disease patients who underwent 2-week, double-blind placebo or droxidopa dose titration, followed by 8 weeks of double-blind maintenance treatment. The placebo arm was assumed to be representative of the SoC since patients could enter the trials on stable nonpharmacologic measures and/or stable dosages of fludrocortisone. Severity of falls, utility values, and injury-related costs were from published studies. Model outcomes included the number of falls (total and by severity), number of QALYs, and costs (total, treatment acquisition, fall-related, and NOH management). The primary CE measures were the incremental CE ratios (ICERs), calculated as the difference in costs between the two treatment groups divided by the differences in falls and number of QALYs. Outcomes were assessed over a 12-month period, based on a treatment duration of 6 months.

Results: Droxidopa patients had fewer falls in each severity category and a higher number of QALYs. Estimated droxidopa costs for 6 months were $30,112, and estimated cost savings due to falls were $14,574 over 12 months. From a payer perspective, droxidopa was cost-effective vs the SoC with an ICER of $47,001 per QALY gained. ICERs per avoided fall with no or minor injury and per avoided fall with moderate or major injury were $1559 and $24,866, respectively. Main drivers were the distribution of falls by severity, fear of fall-related inputs, and costs due to injuries.

Conclusions: Droxidopa is a cost-effective option compared with the SoC in US clinical practice for the treatment of NOH.

225

Medical near-miss events in hospitalized patients with Parkinson's disease, using a nationwide online open database in Japan

T. Furuya, K. Takahashi, A. Miyake, T. Kimura, Y. Ito, T. Sasaki, N. Araki, T. Yamamoto (Saitama-ken, Japan)

Objective: To investigate medical near-miss events in hospitalized patients with Parkinson's disease (PD) in Japan, using a nationwide online open database provided by the Japan Council for Quality Health Care (JCQHC).

Background: Complex medication regimens are often prescribed to manage PD symptoms. For PD inpatients, safety and adherence to a regular PD medication schedule are important in achieving optimal symptom control. Only a few studies have investigated medical near-miss events in hospitalized PD patients.

Methods: A division of JCQHC has undertaken a project to collect medical near-miss/adverse event information in Japan, and the collected information and all anonymous individual reports can be accessed on JCQHC's website (http://www.med-safe.jp). A total of 39,379 medical near-miss events were recorded in this database between January 2010 and November 2014.

Results: We performed a retrospective analysis and identified 131 cases related to PD inpatients, among which 119 incorrect medication administrations (90.8%) were included. We found three major categories associated with inappropriate medications: incorrect time (40 cases), dose omission (30 cases) and preparation errors (12 cases). The causes of incorrect medications were a lack of confirmation by medical staff, and drug regimen complexity/polypharmacy. The medical staff involved in these cases were nurses (113 cases), pharmacists (12 cases) and others (6 cases). The number of cases related to an extra dose of PD medication (with the exception of after each meal) was 21. The incorrect medication time details were as follows: right after waking up (6 cases), at bed time (2 cases) and others (13 cases). The numbers of errors in each PD drug category were 50 cases of L-dopa, 12 cases of dopamine agonists, eight cases of selegiline and four cases each of entacapone/amantadine/anti-cholinergic drugs. In two cases, the daily replacement of a transdermal patch was skipped. Contraindicated medications were ordered for two patients.

Conclusions: Although adherence to complex PD medication schedules during hospitalization entails various challenges, collaboration for the confirmation of medication administration by interdisciplinary medical staff can improve outcomes and help safeguard against the disruption of PD patients’ prescribed medication schedules at home.

226

Pharmacokinetic profile of ND0612L (levodopa/carbidopa for subcutaneous infusion) in patients with moderate to severe Parkinson's disease

N. Giladi, Y. Caraco, T. Gurevich, R. Djaldetti, Y. Cohen, O. Yacobi-Zeevi, S. Oren (Tel Aviv, Israel)

Objective: To characterize the pharmacokinetic profile of ND0612L in PD patients with motor fluctuations.

Background: The symptomatic efficacy of continuous levodopa/carbidopa (LD/CD) delivery in PD patients with motor fluctuations is well known. However, intrajejunal infusion systems are associated with tolerability concerns, and poor LD solubility has prevented development as a subcutaneously deliverable formulation. ND0612L is a proprietary liquid formulation of LD/CD that enables subcutaneous administration of LD/CD to achieve steady levodopa plasma levels.

Methods: This was a Phase II randomized, placebo-controlled, double-blind, two-period study of ND0612L in PD patients with motor response fluctuations. During Period-1 (14 days), 30 patients received their optimized current oral treatment (dose reductions permitted), and were randomized (2:1) to adjunct ND0612L or placebo. During Period-2 (7 days), 16 patients were offered open-label ND0612L and were randomized to ND0612L monotherapy or ND0612L plus oral entacapone.

Results: Patients treated with adjunct ND0612L had their plasma LD concentrations consistently maintained above a mean (±SD) of 800 ±570ng/ml, as well as a lower peak-to-trough ratio and fluctuation index vs. placebo. Exploratory efficacy analysis showed that ND0612L treatment reduced OFF time by a mean±SD of 2.42 ± 2.62h and 2.13 ± 2.24h from baseline according to in-clinic and home diaries, respectively (vs. 0.41 ± 2.62h and 1.39 ± 2.33h with placebo). ND0612L also improved sleep quality (17.1 ± 17.58 improvement in PDSS scores from baseline vs. 0.5 ± 11.35 with placebo), quality of life (6.6 ± 10.52 improvement in PDQ-39 scores from baseline vs 1.78 ±11.10 with placebo), and global impression (90% of the patients had improved CGI-C scores vs. 36% in placebo). All 16 patients chose to continue to Period-2 in which plasma LD levels were maintained at a mean of 550 ± 79ng/ml with ND0612L monotherapy and 800 ±144ng/ml with ND0612L plus oral entacapone. In these patients, the oral LD intake was reduced by a median of 80%, with 3 of 16 patients completely discontinuing oral LD therapy.

Conclusions: These data suggest that subcutaneous continuous delivery of LD/CD with ND0612L, provides relatively stable LD levels with reduced variability compared with oral LD. Efficacy findings are also promising and warrant further study.

227

Deep brain stimulation and the effect on gait in Parkinson's disease

G. Gilmore, M. Delrobaei, S. Tran, K. Ognjanovic, M. Jog (London, ON, Canada)

Objective: To assess the progression of gait changes, following deep brain stimulation (DBS) intervention, over a year long period using objective kinematically based gait measures.

Background: Gait impairments contribute to PD patient falls and reduced quality of life. Specifically, it remains unclear whether PD gait improves or worsens with DBS intervention over a long-term. Currently gait changes are monitored using the UPDRS, which is subjective and qualitative in nature. An objective and quantitative assessment of gait, using kinematic technology, will allow the clinician to more effectively determine whether gait is affected by DBS. Kinematic sensor technologies that are targeted to specifically studying gait are a new avenue being explored to monitor the gait changes with DBS.

Methods: PD patients undergoing bilateral STN-DBS alongside healthy age-matched controls will be used. Patients are assessed one week pre-operatively and then up to one year post-operatively. During each programming visit the patient is monitored by a clinician, and their device is adjusted if required. The patients gait is captured using the PKMAS gait analysis carpet. The carpet assesses various aspects of gait, including: stride length, stride width, gait cycle, center of mass/pressure and single/double support time. The study has been approved by the university ethics committee.

Results: Seven of the total patients (N=15) have completed the 6 month session. Preliminary data has shown an improvement in important areas of gait performance up to 6 months post-operatively. Stride length (Pre-op: M=94.56 cm, 6 months: M=113.32 cm) and step length (Pre-op: M=47.53 cm, 6 months: M=59.89 cm) both increased from pre-operative baseline. Gait cycle is a measure of time from when one foot touches the ground to when the same foot touches the ground again. Gait cycle improved from PD pre-operative baseline (Pre-op: M=1.11 sec, 6 months: M=1.04 sec). Double support time decreased from Pd pre-operative baseline (Pre-op: M=.30 sec, 6 months: .26 sec), which better represents control data (M=.28 sec).

Conclusions: Preliminary data analysis suggests DBS intervention may improve gait over a 6 month period post-operatively. Further analysis, up to 1 year post-operation, will better elucidate the long-term efficacy of DBS intervention on gait. Our method provides the first objective and quantitative measure of long-term gait variances in PD patients undergoing DBS treatment.

228

Switch form immediate release pramipexole to extended release pramipexole: Experience from a tertiary referral center

S.I. Gul, M. Kuzu, O. Herdi, S. Tezcan, N.F. Mercan, C.M. Akbostanci (Ankara, Turkey)

Objective: To evaluate the safety and efficacy of switch from immediate release pramipexole (pex) to extended release pramipexole (pex-ER).

Background: Since the avalibility of pex-ER in our country about a year ago, we could reach satisfactory information from the files of 69 patients (26 females, 38%) who had switched from pex to pexER.

Methods: We documented pre and post switch pramipexole and levodopa-equivalent doses of other antiParkinsonian medication, and analyzed the frequency and nature of reported adverse effects.

Results: Mean age of patients was 63,3 (range 44-88), and mean disease duration was 7,1 years (range 1-27). The other drugs were levodopa (57 patients, 82,6%), entacapone (24 patients, 34,58%), rasagiline (20 patients, 29%), amantadine (18 patients, 26,1%), apomorphine (six patients, 8,7%).

Switch from pex to pexER was uneventful in 59 (92,2%) patients. Adverse events reported in five (7,2%) patients were ankle swelling (two patients), nausea (one patient), dyskinesia (one patient), hypersexuality (one patient), and psychosis (one patient). Problems resolved with further medication change in two patients. Three patients preferred to went back to pex.

Pre and post switch pramipexole and levodopa-equivalent doses of the patients.
Pre-Switch Dose (mg/day) Post-Switch Dose (mg/day) p
Pex to Pex-ER 2,5 (SD 1,3) 3,1 (SD 1,2) ,00
Levodopa-Equivalent Dose 653,2 (SD 498,2) 719,1 (SD 562,9) ,00

Conclusions: Great majority of patients (92,2%) switched from three times daily pex to once daily pex-ER uneventfully. A slight increase in pramipexole daily dose, tailored according to patients’ symptomatic needs, resulted in an increase in post-switch levodopa equivalent doses. Our experience is compatible with previously reported studies.

229

Effect of medical cannabis in Parkinson's disease: Survey of patient experiences

T. Gurevich, L. Bar Lev Chleider, A. Rosenberg, J. Knaani, Y. Baruch, R. Djaldetti (Tel Aviv, Israel)

Objective: To assess the effect of cannabis treatment in patients with Parkinson's disease (PD).

Background: Medical cannabis is now widely used for improving the quality of life of patients with various neurological disorders.

Methods: A telephonic survey was conducted on PD patients granted medical cannabis treatment licenses from the Israel Ministry of Health and who had received at least 2 months of treatment prior to the interview. The structured questionnaire contained epidemiological questions and items about the effects of cannabis on different symptoms.

Results: Thirty-nine patients (31 males, age 63.6 ± 9.6 years, disease duration 11.6 ± 8 years) among 76 patients that met the inclusion criteria participated in the survey. Thirteen did not agree to participate, 20 could not be reached by phone, 4 had passed away.

The mean duration of cannabis treatment was 16.8 ± 18.9 months, the mean daily dose - 1.1 ± 0.9 grams. The consumption methods were smoking (n=24 [61%]), oil (n=6 [15.3%]), smoking +oil (n=4 [10.2%]) and vaporizer (n=1 [3%]). Nine patients (23%) discontinued treatment due to lack of effect or side effects. Thirty patients (76.9%) reported a positive impact of cannbis on their general condition and mood, 25 (64%) reported improvement in pain and rigidity, 22 (59%) reported decrease in tremor and improved quality of sleep. The most common reported side effects were coughing due to smoking (n=9), hallucinations (n=6), restlessness (n=6) and confusion (n=5).

Conclusions: Subjective improvement of motor and non-motor symptoms was reported by most of the survey responders. However, a significant number of patients had no improvement or experienced side effects on short-term treatment. The long-term safety profile of medical cannabis in PD patients is still undetermined. The results of this retrospective open-label study require confirmation in a double blind study to exclude the placebo effect and to assess longer-term safety of cannabis use in PD.

230

LSVT LOUD voice treatment: Training normal healthy loudness with good quality

A.E. Halpern, L.O. Ramig, E. Peterson (Denver, CO, USA)

Objective: The target voice in LSVT LOUD is normal loudness with healthy voice quality, not shouting or vocal hyperfunction. This poster will present a review of a series of data sets which demonstrate healthy vocal loudness Post LSVT LOUD. Group data will include 1) physiological measures of laryngeal videostroboscopic 2) glottographic and aerodynamic tasks, as well as listener perceptual data. 3) A case study of Pre supraglottic hyperfunction that was reduced Post LSVT LOUD will be presented. LSVT LOUD strategies for achieving a normal loudness, good quality voice will be discussed.

Background: LSVT LOUD is a voice and speech treatment that was developed for Parkinson's disease (PD), and has applications to other neurological disorders. Over 20 years of research data have demonstrated the efficacy of this treatment (e.g., Ramig et al, 2001). LSVT LOUD targets the hallmark PD voice symptoms of decreased loudness, hoarseness, and breathiness. A key component of LSVT LOUD is training individuals to achieve normal loudness with a healthy voice quality that is not hyperfunctional. Due to deficits in sensory feedback in PD, a “normal loudness” voice may feel “too loud” to the individual with PD. Sensory re-calibration to normal loudness levels is incorporated into the treatment to address this sensory mismatch.

Methods: Data were collected on individuals with PD, Pre-Post LSVT LOUD. 1) Laryngeal videostroboscopic data were collected on 13 individuals. The randomized studies were rated by 4 judges. 2) Glottographic (EGGW) and aerodynamic measures were collected to investigate the mechanism of change. Blinded listener perceptual ratings of hoarseness and breathiness were used to assess changes in voice quality. 3) Laryngeal videostroboscopic data were collected on an individual with PD pre/post LSVT LOUD who exhibited Pre supraglottic hyperfunction.

Results: Pre-Post LSVT LOUD findings indicated 1) less glottal incompetence and no significant change in supraglottal hyperfunction 2) significant improvements in EGGW, aerodynamic and perceptual measures 3) decreased supraglottic hyperfunction.

Conclusions: The results of these studies and our clinical experience demonstrate that when providing LSVT LOUD treatment correctly, the result is a voice with normal healthy loudness that is not hyperfunctional and is of good quality.

231

Integrated cardiovascular safety profile of droxidopa

R.A. Hauser, W.B. White, G.J. Rowse, L.A. Hewitt (Tampa, FL, USA)

Objective: To evaluate the cardiovascular (CV) safety profile of droxidopa in patients with symptomatic neurogenic orthostatic hypotension (NOH).

Background: Droxidopa is a norepinephrine prodrug recently approved to treat symptomatic NOH caused by primary autonomic failure (PD, multiple system atrophy [MSA], and pure autonomic failure [PAF]), dopamine β-hydroxylase deficiency, and nondiabetic autonomic neuropathy. It is thought that droxidopa raises blood pressure (BP) by causing vasoconstriction.

Methods: CV safety data were integrated from 5 trials (N=666) of patients with symptomatic NOH and diagnoses of PD, MSA, PAF, dopamine β-hydroxylase deficiency, or nondiabetic autonomic neuropathy. Two were short-term, double-blind, randomized, placebo-controlled trials (RCTs) in patients with autonomic failure; a third RCT was in patients with PD randomized to 2-week, double-blind placebo or droxidopa dose titration, followed by 8-week, double-blind maintenance treatment. Two studies were long-term, open-label extensions with patients following completion of one of the short-term studies. Adverse event (AE) rates were adjusted for treatment duration and calculated by the number of events per patient per year of mean exposure.

Results: A total of 307 (46%) patients enrolled in any one of the trials had a preexisting CV disorder at baseline; the most common diagnoses (n [%]) were arrhythmia (235 [35.3%]), coronary artery disease (164 [24.6%]), and hypertension (116 [17.4%]). In the trial in PD patients, over the entire 10 weeks the rates of CV-related AEs were 0.17 and 0.24 for patients randomized to placebo and droxidopa, respectively; the event rates were nominally higher during titration vs maintenance for placebo (0.65 vs 0.07) but similar during titration vs maintenance for droxidopa (0.30 vs 0.29). The rates of cardiac-related treatment-emergent AEs (TEAEs) were nominally higher in droxidopa vs placebo patients who had a preexisting CV disorder (0.34 vs 0.16); similarly, the rates of BP-related TEAEs were nominally higher in droxidopa vs placebo patients with a preexisting CV disorder (1.11 vs 0.62). There were no CV-related AEs during 1 to 2 weeks of double-blind treatment in the short-term trials. In the long-term extensions, the event rate was 0.13.

Conclusions: There were nominal, modest increases in CV-related AE rates with droxidopa vs placebo; event rates in the long-term extension was low.

232

Efficacy of rasagiline in early Parkinson's disease: A meta-analysis of data from the TEMPO and ADAGIO studies

R.A. Hauser, V. Abler, E. Eyal (Tampa, FL, USA)

Objective: To evaluate the efficacy of rasagiline 1 mg/day versus placebo in a pooled population of patients with early Parkinson's disease (PD).

Background: TEMPO and ADAGIO were both Phase III studies that evaluated the symptomatic efficacy of rasagiline versus placebo in patients with early PD.

Methods: Both studies recruited early, untreated patients with early PD who were randomized to placebo, rasagiline 1mg/day or rasagiline 2 mg/day. The placebo-controlled phase was 26 weeks in TEMPO and 36 weeks in ADAGIO. This meta-analysis included UPDRS efficacy observations from weeks 12, 24 and 36 in ADAGIO and from weeks 14 and 26 in TEMPO; TEMPO visits were recoded to weeks 12 and 24 respectively to allow integration with ADAGIO. The analysis includes 1546 patients who had ≥1 post baseline efficacy observations at the selected weeks. Change from baseline in UPDRS Total, UPDRS mentation, ADL and Motor sub-scores were evaluated using mixed models repeated measures (MMRM) analyses with baseline efficacy value, age, gender, treatment, categorical week in study, treatment by week interaction and study, included as fixed effects. The analysis used an unstructured covariance matrix pattern for observations within the same subject. Interactions between study and treatment; and study, treatment and week, were included in the model and removed if they were not significant (p>0.10).

Results: Mean ±SD baseline age was 61.9 ±10.0 years, years since diagnosis was 0.54 ±0.75 and Hoehn and Yahr stage was 1.6 ±0.5. Baseline mean ±SD UPDRS scores were: 21.58 ±9.39 for total, 0.96 ±1.19 for mentation, 5.47 ±3.12 for ADL and 15.15 ±7.12 for motor. Effects on UPDRS total, motor and ADL scores were significantly better for both doses of rasagiline compared with placebo at all time periods.

Variable 1mg/day – placebo Estimate; mean ±SE (p value) 2mg/day – placebo Estimate; mean ±SE (p value)
UPDRS Total
Week 12/14 -2.18 ±0.33 (<0.0001) -1.75 ±0.33 (<0.0001)
Week 24/26 -3.57 ±0.40 (<0.0001) -3.17 ±0.40 (<0.0001)
Week 36 -3.01 ±0.48 (<0.0001) -3.30 ±0.48 (<0.0001)
UPDRS Mentation
Week 12/14 -0.16 ± 0.06 (<0.01) -0.17 ± 0.06 (<0.01)
Week 24/26 -0.23 ± 0.06 (<0.001) -0.32 ± 0.06 (<0.0001)
Week 36 -0.21 ± 0.08 (<0.01) -0.10 ± 0.08 (0.23)
UPDRS ADL
Week 12/14 -0.70 ±0.12 (<0.0001) -0.67 ±0.12 (<0.0001)
Week 24/26 -0.97 ±0.15 (<0.0001) -0.99 ±0.15 (<0.0001)
Week 36 -0.85 ±0.18 (<0.0001) -0.96 ±0.18 (<0.0001)
UPDRS motor
Week 12/14 -1.30 ±0.25 (<0.0001) -0.88 ±0.25 (<0.001)
Week 24/26 -2.35 ±0.30 (<0.0001) -1.82 ±0.30 (<0.0001)
Week 36 -1.90 ±0.36 (<0.0001) -2.15 ±0.36 (<0.0001)

Conclusions: This meta-analysis combines data from two large RCTs and confirms the symptomatic efficacy of rasagiline in early PD over 36 months.

233

Efficacy of sublingual apomorphine (APL-130277) for the treatment of “off” episodes in patients with Parkinson's disease

R.A. Hauser, J. Dubow, B. Dzyngel, T. Bilbault, A. Giovinazzo, A. Agro (Tampa, FL, USA)

Objective: To evaluate the efficacy of single treatments of APL-130277 in patients with Parkinson's disease.

Background: Parkinson's disease (PD) patients suffer from a variety of “Off” episodes as the disease progresses. These consist of wearing off, delayed-On, no-On, unpredictable Offs, and morning akinesia. The only approved, acute medication treatment for these “Off” episodes is apomorphine given subcutaneously. Easier to administer, convenient, on-demand treatments are needed. APL-130277 (APL) is a soluble film strip of apomorphine administered sub-lingually and designed to rapidly deliver apomorphine through absorption from the oral cavity.

Methods: This was a multi-center phase 2, open-label single-arm study. 19 PD patients with at least one “Off” episode per day, ≥ 2 hours of total daily “Off” time, predictable “Off” episodes in the morning on awakening and a Modified Hoehn-Yahr stage I-III in the “On” state were included. Patients presented to the clinic in the morning in the “Off” state and were administered APL 10 mg. If a satisfactory response was not seen, the dose of APL was increased in 5 mg increments until a clinically meaningful “On” was achieved, to a maximum dose of 30 mg. Patients were dosed up to two times on three days. Change in MDS-UPDRS Part III was evaluated from pre-dose morning “Off” state to post-dose at 15, 30, 45, 60 and 90 minutes. Patients were pre-medicated for 3 days with trimethobenzamide, which was continued during the study.

Results: Baseline demographic data are presented in Table 1. Fifteen of 19 patients dosed achieved a satisfactory full “On” following APL administration. Mean change from pre-dose to post-dose MDS-UPDRS Part III at full “On” for responders or last dose for non-responders is presented in Figure 1 and Table 2. Of the 15 responders, all turned fully “On” within 30 minutes of dosing and 6 within 15 minutes. Thirteen of 15 remained fully “On” for at least 30 minutes and 9/15 for at least 60 minutes.

Table 12. Baseline Demographic Data
Mean Age 61.5 (48-79)
Male: Female) 14(73.7%):5(26.3%)
Modified Hoehn-Yahr 2.2 (1-3)
Mean # of Daily “Off” Episodes 3.9 (1-7)
Mean # of PD Medications 3.0 (1-5)
Mean Daily Levodopa Dose (mg) 836.8 (100-1500)
Mean # of Levodopa Doses Per Day 5.3 (1-12)
Table 13. Mean Change from Pre-dose to Post-dose MDS-UPDRS Following APL-130277 Administration
Time (min) 15 30 45 60 90
ITT -11.5 -14.6 -15.1 -13.5 -9.2
Responders -11.9 -16.7 -17.4 -15.9 -11.9
Per Protocol -10.1 -15.5 -15.8 -15.0 -11.2

[figure1]

Conclusions: APL provided rapid, clinically meaningful improvement in MDS-UPDRS Part III scores for PD patients in the “Off” state. Much of the benefit was sustained through 90 minutes. A range of doses were utilized but over half of patients responded to the two lowest doses of APL (10 and 15 mg). APL-130277 may be an effective, easy to administer medication for the on-demand management of “Off” episodes in PD patients.

Details are in the caption following the image

(233).

234

Safety analysis by higher and lower total daily dose of IPX066, an extended-release formulation of carbidopa-levodopa, in advanced Parkinson's disease

V.K. Hinson, N. Stover, P. Agarwal, S. Khanna, S. Kell (Charleston, SC, USA)

Objective: Compare the adverse event (AE) profile in groups taking higher (≥1600 mg/day) or lower (<1600 mg/day) total daily dosages of IPX066 in clinical trials of advanced Parkinson's disease (PD).

Background: IPX066 is an extended-release formulation of carbidopa-levodopa (CD-LD) designed to provide a rapid increase in plasma LD concentrations (similar to immediate-release CD-LD [IR]) and sustained stable LD concentrations to allow dosing every 6 hours. IPX066 has demonstrated improvements in motor symptoms in early and advanced PD.

Methods: AEs were recorded during IPX066 treatment in two phase 3 studies in advanced PD: ADVANCE-PD (IPX066 vs. IR [N=451]); and ASCEND-PD (IPX066 vs. CD-LD+entacapone [N=110]). AEs were compared in patients with a final total daily dose of IPX066 <1600 (lower dose) or ≥1600 (higher dose) mg/day. The most common AEs for each group and AEs with notable differences between groups are reported.

Results: A total of 161/317 (68.9%) patients in the lower, and 132/241 (54.8%) in the higher dosage group had ≥1 AE. The most frequent AEs in the lower dosage group were nausea (6.6%), insomnia (5.0%), and headache (4.4%); the most frequent in the higher dosage group were dyskinesia (10.4%), nausea (6.2%), and dizziness (5.0%). A greater proportion of higher compared to lower dosage patients reported dyskinesia (10.4% vs. 3.2%, respectively) and worsening “off” (4.6% vs. 1.3%, respectively). Five of the reported dyskinesia AEs in the higher and two in the lower dosage group, as well as one of the worsening “off” AEs in each group were rated as severe. Insomnia was more frequent in the lower dosage group (5.0%) than the higher dosage group (2.1%). Nausea (6.2% vs. 6.2%), headache (4.1% vs. 4.4%), and hallucinations (2.5% vs. 2.2%) were similarly reported among higher and lower dosage groups, respectively. Both somnolence (higher: 0.8% vs. lower: 1.8%) and orthostatic hypotension (higher: 0.8% vs. lower: 0.6%) were infrequently reported by both groups. AEs most frequently leading to discontinuation included dyskinesia (n=6) for the higher dosage group and anxiety, nausea, and visual hallucination (n=2 each) for the lower dosage group.

Conclusions: The AE profile of IPX066 was consistent with the known effects of CD-LD in the treatment of PD. No clear patterns emerged between dosage groups in the frequency of the more common dopaminergic AEs.

235

Does cognitive dysfunction affect the efficacy of physiotherapy for Parkinson's disease?

M. Hizume, Y. Hashimoto, T. Hori, Y. Fumimura, K. Kasai, T. Ichikawa (Ageo, Japan)

Objective: To assess the influence of cognitive decline on the effectiveness of physiotherapy in hospitalized patients with Parkinson's disease (PD).

Background: Physiotherapy is effective in patients with PD to maintain their activities of daily living as well as medical therapies and surgical interventions. However it is uncertain about whether patients with cognitive decline benefit from physiotherapy as well as patients without it.

Methods: The participants were 64 patients with PD admitted to our hospital for rehabilitation (34 men and 30 women, age 69.2 ± 7.9 years, Hoehn and Yahr scale 3.8[thinsp]±[thinsp]0.9, length of hospital stay 48.8 ± 29.8 days). They were divided into two groups: patients without cognitive decline (Mini-Mental State Examination (MMSE) score of 24 or more, n = 48) and patients with cognitive decline (MMSE score of 23 or less, n = 16). We assessed range of motion (ROM), manual muscle test (MMT), turning in bed, rising from bed, rising from chair, posture, walking and stair-stepping by scoring their outcomes of physiotherapy (1: improved, 0: unchanged, -1: worsened) and compared the efficacy of physiotherapy for PD between the two groups.

Results: In patients with cognitive decline the effectiveness of physiotherapy was not inferior to that in patients without cognitive decline: ROM (0.31 vs 0.53, p = 0.34); MMT (0.07 vs 0.35, p = 0.06); turning in bed (0.13 vs 0.12, p > 0.99); rising from bed (0.06 vs 0.12, p = 0.67); rising from chair (0.20 vs 0.23, p > 0.99); posture (0.29 vs 0.12, p = 0.15); walking (0.67 vs 0.76, p > 0.99) and stair-stepping (0.50 vs 0.43, p > 0.99).

Conclusions: Patients with PD can receive benefits from physiotherapy even though their cognitive functions decline.

236

Effect of hippotherapy on functional capacity and quality of life in people with Parkinson's disease

R.C.P.P. Homem, Q.J. Almeida, G.P. Tolentino, S. Vidal, R.J. Oliveira (Brasília, Brazil)

Objective: To assess the effects of hippotherapy on functional performance and health-related quality of life in people with Parkinson's disease.

Background: Motor symptoms associated with Parkinson's disease impair one's ability to perform daily activities called functional activities, and consequently decrease quality of life. Hippotherapy is a strategic alternative physical activity for people with disabilities. Hippotherapy has been shown as an effective treatment to increase functional capacity and quality of life in other neurological populations different of people with PD (Lee et al., 2014; Sunwoo et al., 2012). Hippotherapy does not require excessive effort or walking from patients who can no longer coordinate motor actions or exercise in a standing position.

Methods: The study was conducted with eigtheen people, nine participants formed the hippotherapy group (HT) which performed a 10 weeks hippotherapy program (2 familiarization + 8 hippotherapy weeks, each session lasting thirty minutes), and nine indivuduals formed the control group (CG) which attended lectures on PD twice a week for ten weeks, each session lasting thirty minutes. Functional outcome measures included functional strength, functional mobility, gait velocity and health-related quality of life. The study was approved by the Research Ethics Committee of the University of Brasilia by the number CAAE 17329213.7.0000.0030. The intervention was performed at First Regiment of Cavalry Guard of the Brazilian Army, with the partnership of the Solidario Horse Institute.

Results: The hippotherapy group increased gait velocity (p ≤ 0.05) and improved emotional aspects of quality of life (p ≤ 0.01), as shown in Table 1 and Figure 1. The results of functional mobility and functional strength showed tendency but were not significant.

Table 14. Effect of hippotherapy on Parkinson's disease