Euglycemia Indicates Favorable Motor Outcome in Parkinson's Disease
Ioanna Markaki and Theodora Ntetsika contributed equally to this article.
Relevant conflicts of interest/financial disclosures: Nothing to report.
Funding agencies: I.M. receives funding from Stockholm County Council (20180200), Neuroförbundet Stockholm, and Parkinson Research Foundation, Stockholm. P.S. receives funding from Foundation for Strategic Research, Stockholm County Council, Parkinson Research Foundation, and is a Wallenberg Clinical Scholar.
Abstract
Background
The interplay between glycemic control and Parkinson's disease (PD) has long been recognized but not fully understood.
Objectives
To investigate the association of glycated hemoglobin (HbA1c) levels with motor and cognitive symptom progression in a prospective PD cohort.
Methods
Of 244 PD patients, 17 had low HbA1c (≤30 mmol/mol), 184 were euglycemic (HbA1c 31–41 mmol/mol), 18 had high HbA1c (HbA1 ≥42 mmol/mol), and 25 had diabetes mellitus (DM). Survival analysis was applied on time until Hoehn and Yahr stage ≥3 (motor outcome) and until mild cognitive impairment.
Results
Low HbA1c (HR 2.7; 95% CI 1.3–6; P = 0.01) as well as high HbA1c (HR 3.6; 95% CI 1.5–8.9; P = 0.005) but not DM were independent predictors of unfavorable motor outcome.
Conclusions
Both high and low HbA1c levels may be associated with motor symptom progression in PD; however, further studies are needed to confirm these findings and increase understanding regarding causality. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
The deteriorative effect of diabetes mellitus (DM) on the prognosis of patients with Parkinson's disease (PD) was described decades ago.1 Even though a possible link between the two diseases has attracted increasing interest in recent years, the results of studies aiming to confirm the role of DM in PD risk remain conflicting.2, 3 Nevertheless, the presence of diabetes type 2 is now included in the Movement Disorder Society research criteria for prodromal PD,4 based on large population-based studies.5-7 Moreover, previous relatively small studies have indicated an increased likelihood of developing postural instability and gait disorder in PD patients with comorbid DM,8, 9 as well as a greater degree of cognitive impairment,8 through mechanisms that may be independent of disease-specific neurodegeneration.10 Additionally, in a small substudy of the Parkinson's Progression Markers Initiative cohort, it was shown that the presence of DM may contribute to faster motor symptom progression and cognitive impairment.11 In a larger, case−control, longitudinal cohort of de novo PD patients and healthy controls followed for 48 months, coronary artery disease and arterial hypertension were shown to be predictors of motor symptom progression, whereas DM and deregulated glucose were associated with faster cognitive decline.12 Also, in a secondary analysis of over 1000 patients with PD previously included in a randomized trial of creatine monohydrate, followed 3 years after the end of the study, it was shown that the presence of metabolic syndrome was associated with a greater increase in motor Unified Parkinson's Disease Rating Scale (UPDRS) score over time.13 Finally, insulin resistance has been found to be twice as common in patients with PD and dementia than those with PD and intact cognition,14 while in a case−control study of oral glucose tolerance test, PD patients had significantly poorer adaptive insulin response and higher glucose levels than age-, sex-, and body mass index (BMI)-matched healthy controls, possibly linked to PD-associated dysautonomia.15 Few studies have long follow-up data on the evolution of motor and cognitive impairment in relation to glucose homeostasis.
The aim of this study was to investigate the effect of glycemic status on the acceleration of motor symptom progression and cognitive decline in patients with PD.
1 Patients and Methods
Our study was a retrospective analysis of an ongoing longitudinal observational study comprising patients with parkinsonian syndromes, treated at the Movement Disorders Clinic in Karolinska University Hospital from 2011 until 2017, and in the Center of Neurology, Academic Specialist Center in Stockholm since 2018 (detailed in Supplementary information). The study protocol was approved by the local ethical review board and all participants provided written informed consent. All patients in the cohort underwent clinical evaluation of PD symptom severity by a movement disorders specialist, and laboratory blood tests at baseline and thereafter annually. The Montreal Cognitive Assessment (MoCA) is used to test cognition at baseline and thereafter every 2 to 3 years. Referral to the memory clinic is used when indicated for further investigation and diagnosis of mild cognitive impairment (MCI) and dementia. Follow-up time varied from a minimum of 2 years to a maximum of 26 years, as patients were eligible to enter the study irrespective of time elapsed since PD diagnosis.
Patients' medical records were reviewed retrospectively and all glycated hemoglobin (HbA1c) measurements were extracted. The first available HbA1c measurement was used to categorize patients into three groups: low-HbA1c (≤30 mmol/mol),16 euglycemic (HbA1c 31–41 mmol/mol), high-HbA1c (≥42 mmol/mol),17 and a fourth group of diabetic PD patients was defined by the presence of DM diagnosis (type 2 in 24/25 patients) in the patients' records accompanied by an expert's assessment.
Hoehn and Yahr (H&Y) stage was used to measure motor symptom progression. Evaluation of cognitive decline was based on retrospective review of patients' medical records and three groups were defined: normal cognitive status, MCI, and dementia (detailed in Supplementary information).
2 Statistical Analysis
Group-based trajectory modeling (GBTM) was used to describe the evolution of glycemia in non-diabetic patients who had at least two HbA1c measurements available (n = 132) (detailed in Supplementary Information).
Survival analysis and Kaplan–Meier curves with log-rank test were used to assess the time from PD diagnosis until motor and cognitive outcome. In order to investigate the cognitive outcome from a global perspective, two different models of survival analysis were applied (Supplementary Information). Cox proportional hazards regression analysis was performed to calculate hazard ratios (HRs), with 95% confidence intervals (CIs), for the effect of age, gender, glycemic status, and vascular risk factors (ie, hypertension, atrial fibrillation, hyperlipidemia, and atherosclerotic disease) on motor and cognitive outcome. The assumption of proportional hazards was held for all variables.
3 Results
Of 244 PD patients, 184 (75.4%) were euglycemic, 17 (7%) had low and 18 (7.4%) had high HbA1c, and 25 (10.2%) had DM. HbA1c was measured at a median of 3.1 years (interquartile range [IQR] 6.2 years) from PD diagnosis. Sex and age at diagnosis did not differ significantly between glycemic status groups, whereas vascular risk factors were more common in patients with DM (Table 1). Plasma albumin, studied as an indicator of malnutrition, did not differ between groups, as was the case with BMI, for which missing data make the comparison less robust however (Table 1). GBTM resulted in the formation of four groups (Figure S1), which agreed with our classification in 91.7% of patients (Figure S2), when GBTM groups 2 and 3 were cross-checked with the euglycemic group, thus indicating that HbA1c tends to remain stable and that patients’ initial HbA1c level largely agrees with their trajectories. The level of agreement was lower (70%) in the low-HbA1c group.
| Parameter | Total group (n = 244) | Low-HbA1c group (n = 17) | Euglycemic group (n = 184) | High-HbA1c group (n = 18) | DM group (n = 25) | P value |
|---|---|---|---|---|---|---|
| Female, % (n) | 35 (85) | 23.5 (4) | 36 (67) | 22 (4) | 40 (10) | 0.4 |
| Age at diagnosis, y (IQR) | 64.5 (12) | 66 (12) | 64 (12) | 64.5 (15.5) | 66 (11) | 0.07 |
| Hyperlipidemia, % (n) | 9 (21) | 6 (1) | 5 (10) | 5.5 (1) | 36 (9) | <0.0001 |
| Hypertension, % (n) | 42 (103) | 35 (6) | 39 (71) | 50 (9) | 68 (17) | 0.04 |
| Atherosclerotic disease a, % (n) | 21 (51) | 12 (2) | 16 (30) | 17 (3) | 64 (16) | <0.0001 |
| Sleep apnea, % (n) | 3 (7) | 0 | 3 (6) | 0 | 4 (1) | 0.9 |
| Atrial fibrillation, % (n) | 11.5 (28) | 6 (1) | 10 (19) | 17 (3) | 20 (5) | 0.3 |
| BMI b, kg/m2 (IQR) | 24.9 (5.1) | 24.3 (5.4) | 24.8 (5.3) | 25.3 (4.9) | 25.2 (5.3) | 0.6 |
| Total cholesterol b, mmol/L (IQR) | 4.8 (1.4) | 4.65 (1.2) | 4.9 (1.3) | 4.8 (1.4) | 4.4 (1.6) | 0.4 |
| LDL-cholesterol b, mmol/L (IQR) | 2.8 (1.1) | 2.35 (1.6) | 2.8 (1) | 3 (1.3) | 2.5 (1.6) | 0.4 |
| HDL-cholesterol b, mmol/L (IQR) | 1.5 (0.6) | 1.58 (0.85) | 1.5 (0.5) | 1.3 (0.9) | 1.22 (0.4) | 0.008 |
| Triglycerides b, mmol/L (IQR) | 0.95 (0.6) | 0.94 (0.6) | 0.9 (0.) | 1.1 (0.5) | 1.2 (0.9) | 0.01 |
| AST b, ukat/L (IQR) | 0.39 (0.1) | 0.35 (0.1) | 0.39 (0.1) | 0.42 (0.08) | 0.36 (0.1) | 0.2 |
| ALT b, ukat/L (IQR) | 0.29 (0.2) | 0.32 (0.1) | 0.29 (0.2) | 0.32 (0.2) | 0.25 (0.2) | 0.9 |
| Creatinine b, umol/L (IQR) | 73 (18.5) | 77 (16) | 72 (18) | 76.5 (22) | 74.5 (29) | 0.6 |
| Albumin, g/L (IQR) | 39 (4) | 40 (3) | 39 (4) | 40 (4) | 39 (4.5) | 0.4 |
| WBC, 109/L (IQR) | 6.30(2.10) | 5.7 (1) | 6 (2) | 7 (2.5) | 7 (1.9) | 0.001 |
| RBC, 1012/L (IQR) | 4.6 (0.6) | 4.7 (0.4) | 4.6 (0.6) | 4.75 (0.7) | 4.70 (0.9) | 0.5 |
| Hemoglobin, g/L (IQR) | 140 (18) | 150 (23) | 139 (19) | 141 (18) | 139 (16) | 0.04 |
| EVF (IQR) | 0.42 (0.05) | 0.44 (0.05) | 0.42 (0.05) | 0.44 (0.04) | 0.4 (0.07) | 0.2 |
| MCV, fL (IQR) | 92 (5) | 93 (5) | 92 (5) | 92 (3.5) | 90.5 (7.5) | 0.2 |
| MCH, pg (IQR) | 31 (2) | 32 (2) | 30 (2.00) | 31 (3) | 30 (2.5) | 0.04 |
| Platelets, 109/L (IQR) | 232 (81) | 194 (47) | 231 (80) | 247. (49) | 252 (94) | 0.03 |
- Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index; DM, diabetes mellitus; EVF, erythrocyte volume fraction; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; IQR, interquartile range; LDL, low-density lipoprotein; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume; RBC, red blood cell count; WBC, white blood cell count.
- a History of ischemic stroke and/or peripheral arterial disease and/or ischemic heart disease.
- b BMI was available in 179 patients and cholesterol profile in 174 patients. AST, ALT, and creatinine were available in 210, 218, and 224 patients, respectively.
- Bold type denotes statistical significance.
In survival analysis for motor outcome, 8 low-HbA1c patients (47%), 69 (37.5%) euglycemic, 6 high-HbA1c (33%), and 10 (40%) diabetic patients reached the endpoint H&Y ≥3 during a median follow-up period of 6.8 years (IQR 5.7 years). Median time to unfavorable motor outcome was 8.5, 13.3, 9.6, and 10.1 years, respectively (Fig. 1; P = 0.0015 with the log-rank test).
In Cox proportional hazards regression analysis, compared to the euglycemic group (reference), patients with low HbA1c had HR 2.5 (95% CI 1.2–5.3; P = 0.01) to reach unfavorable motor outcome. Also, high-HbA1c patients (HR 3.4; 95% CI 1.4–8.2; P = 0.006) and DM (HR 2; 95% CI 1.1–4; P = 0.04) were at increased risk of having influence of balance during follow-up. The differences remained significant after adjustment for age >65 years, sex, and vascular risk factors in the low-HbA1c (HR 2.7; 95% CI 1.3–6; P = 0.01) and high-HbA1c groups (HR 3.6; 95% CI 1.5–8.9; P = 0.005) but not in DM (HR 1.5; 95% CI 0.6–3.6; P = 0.4). Also, age >65 years (HR 5; 95% CI 3–8.4; P < 0.0001) and hypertension (HR 2.9; 95% CI 1.7–4.7; P < 0.0001) were independent predictors of unfavorable motor outcome.
In survival analysis for cognitive outcome, 7 low-HbA1c patients (41%), 82 (45%) euglycemic, 7 high-HbA1c (39%), and 14 (56%) diabetic patients reached the endpoint MCI during follow up. Median time to development of MCI was 8, 12, 6.8, and 7.1 years, respectively (Figure S3; P = 0.2 with the log-rank test). Detailed results are provided in Supplementary Information and Figure S4.
4 Discussion
HbA1c levels outside the window of euglycemia (ie, <31 and >41 mmol/mol) were associated with faster motor symptom progression, independent of age and vascular risk factors. Also, time to cognitive decline differed in a similar manner; however, the association was not statistically significant after adjustment for confounders.
Previous studies have shown that DM,8, 9, 11 metabolic syndrome13 and cardiovascular diseases12 are associated with motor symptom progression and impairment of balance in PD. There are few studies on HbA1c, including one showing that higher levels are associated with orthostatic hypotension,18 and a study reporting that almost two-thirds of the non-diabetic individuals in a PD cohort were insulin-resistant, often with normal fasting glucose and HbA1c.19 Few studies have investigated the association of HbA1c with long-term PD outcome.
HbA1c is a hemoglobin form chemically linked to a sugar by glycation, measured mainly to determine the average blood glucose levels during the last 3 months.20 Higher HbA1c levels in DM are associated with cardiovascular disease risk through mechanisms comprising release of free radicals causing increased blood viscosity and thrombosis, and triggering of inflammation and atherosclerotic plaque formation.21 Increasing age correlates with increasing HbA1c levels22, 23 in non-diabetic persons, associated with decreased β-cell function without change in insulin sensitivity.23 In our study, HbA1c levels were rather stable during a 3-year period in a subset of non-diabetic patients, and GBTM divided them into groups that corresponded to those defined by the routinely used cut-off values for euglycemia.16, 17
Regarding PD motor symptoms, central dopaminergic activity has been shown to decline with increasing age, BMI, and HbA1c.24 Also, DM has previously been associated with gait and balance impairment, and insulin resistance in non-diabetic individuals has been correlated with decreased gait speed.25 Interestingly, high as well as low HbA1c levels have previously been reported to predict faster physical functioning decline and were also associated with increased interleukin-6 levels in a community-based longitudinal study.26 Chronic inflammation is a hallmark of biological aging,27 and the cross-talk between glycometabolic derangement and inflammatory response has been suggested to be involved in physical functioning decline.28 Both enhancement of insulin resistance,28 followed by increased HbA1c and muscle mass and function loss, as well as increased glucose uptake by peripheral tissues29, 30 and decreased HbA1c levels, followed also by muscle weakness and loss of function, may be plausible mechanisms of physical deterioration in aging. Our results show that non-diabetic PD patients with low as well as high HbA1c developed balance impairment and reached the endpoint H&Y ≥3 earlier than non-diabetic patients with euglycemia. No sensitive markers of inflammation were available for our sample to assess possible interaction with HbA1c levels, and BMI values were not complete for the assessment of underweight. However, causes of false-low HbA1c levels including liver disease,16 chronic renal failure31 and anemia32 could be excluded, based on the biochemical profile of our patients. Hemoglobin levels were even slightly higher in the low-HbA1c group. Also, plasma albumin, that could serve as an indicator of malnutrition, did not differ in patients with low versus high HbA1c levels. DM was not independently associated with motor outcome, which may be attributed to the small size of the group in combination with higher age, and significantly higher frequency of other vascular comorbidities that when adjusted for may have concealed a lower effect size of diabetes. Hypertension was also an independent predictor of unfavorable motor outcome, in line with previous reports in PD12, 33 and a population-based cohort.34
As regards cognition, we found that age, male gender, and presence of sleep apnea were independent predictors of earlier MCI development, in line with previous studies.35-38 Additionally, diabetes39 and dysglycemia40 have previously been associated with poor cognitive outcome in PD. Also, in a population-based study, younger males with high non-diabetic HbA1c and adults with high stable blood glucose were at increased risk for poorer cognition.41 We could not confirm a similar correlation in our cohort, presumably due to lack of power and insufficient follow-up time for the more gradually developing cognitive endpoints.
4.1 Limitations
HbA1c measurements were available at isolated time points and they may not reflect the whole observation period; however, trajectory curves over a 3-year period showed stable values. MDS-UPDRS part 3 is more sensitive marker of motor symptom progression; however, H&Y stage 3 indicates a significant milestone in advanced disease that is also clinically relevant. The definitions of MCI and dementia were based on retrospective review of medical records, which may influence the accuracy in the exact time to cognitive endpoints. However, all patients are closely followed in a specialized movement disorders center, and all motor and non-motor symptoms are monitored regularly. Follow-up time differed among patients; however, a large number of participants reached the endpoints of interest, which made it possible to apply multivariate models. Also, the size of the non-euglycemic patient groups were much smaller than the euglycemic group, which may reduce the power of our analyses; however, the cohort demographics and our main results seem to agree with the existing literature.
In conclusion, our study adds further knowledge about the possible role of glucose control in PD progression. Further prospective, long-term, follow-up studies and trials on the effect of glucose control modification are needed to better understand this link, and whether glucose homeostasis could serve as a therapeutic target.
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.
I.M.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B
T.N.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B
K.S.:1C, 2C, 3B
P.S.: 1A, 1B, 1C, 2C, 3B
Financial Disclosures of All Authors (for the Preceding 12 Months)
P.S. receives grants from Knut and Alice Wallenberg Foundation, Stockholm County Council, Parkinson Research Foundation, and Foundation for Strategic Research.
I.M. receives grants from Stockholm County Council, grants from Parkinson Research Foundation Stockholm, and grants from Neuroförbundet.
