Rationale and Objectives
Parkinson disease (PD) is a progressive neurodegenerative disorder affecting motor and cognitive functions. Prior studies showed that patients with PD and diabetes (DM) demonstrate worse clinical outcomes compared to nondiabetic subjects with PD. Our study aimed at defining the relationship between DM, gray matter volume, and cognition in patients with PD.
Materials and Methods
This study included 36 subjects with PD (12 with DM, 24 without DM, mean age = 66). Subjects underwent high-resolution T1-weighted brain magnetic resonance imaging, [ 11 C]dihydrotetrabenazine positron emission tomography imaging to quantify nigrostriatal dopaminergic denervation, clinical, and cognitive assessments. Magnetic resonance images were postprocessed to determine total and lobar cortical gray matter volumes. Cognitive testing scores were converted to z-scores for specific cognitive domains and a composite global cognitive z-score based on normative data computed. Analysis of covariance, accounting for effects of age, gender, intracranial volume, and striatal [ 11 C]dihydrotetrabenazine binding, was used to test the relationship between DM and gray matter volumes.
Results
Impact of DM on total gray matter volume was significant ( P = 0.02). Post hoc analyses of lobar cortical gray matter volumes revealed that DM was more selectively associated with lower gray matter volumes in the frontal regions ( P = 0.01). Cognitive post hoc analyses showed that interaction of total gray matter volume and DM status was significantly associated with composite ( P = 0.007), executive ( P = 0.02), and visuospatial domain cognitive z-scores ( P = 0.005). These associations were also significant for the frontal cortical gray matter.
Conclusion
DM may exacerbate brain atrophy and cognitive functions in PD with greater vulnerability in the frontal lobes. Given the high prevalence of DM in the elderly, delineating its effects on patient outcomes in the PD population is of importance.
Introduction
Numerous epidemiologic studies show increased risk of dementia in diabetic subjects compared to nondiabetic individuals. A recent meta-analysis of 16 prior studies (5706 people with diabetes [DM] and 36,191 without DM) estimated a relative risk of 1.5 for clinically defined Alzheimer disease and 2.5 for vascular dementia in diabetic persons compared to nondiabetic individuals . Furthermore, a recent prospective study showed that elevated blood glucose in the absence of DM increases the risk of dementia .
In patients with Parkinson disease (PD), associations between DM and more severe motor symptoms and increased levodopa requirements are described . More specifically, DM in the setting of PD is associated with more severe postural instability and gait difficulty features of PD .
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Materials and Methods
Subjects and Clinical Test Battery
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Table 1
Clinical Characteristics of Study Subjects
PD without DM ( N = 24, M/F = 21/3) PD with DM ( N = 12, M/F = 10/2) Group Comparison Age (y) 66.8 (5.3) 66.0 (5.2)P = 0.7 Hoehn-Yahr stage 2.3 (0.6) 2.6 (0.9)P = 0.3 PD duration (y) 6.2 (4.4) 5.6 (4.6)P = 0.7 Education (y) 15.1 (2.9) 14.3 (2.8)P = 0.5 MoCa 25.6 (2.3) 25.3 (2.2)P = 0.7 Sex (% male) 86.3 83.3P = 0.8
DM, diabetes; PD, Parkinson disease.
Mean values and standard deviations for age (in years), Hoehn-Yahr stage, disease duration (in years), and years of education, as well as Montreal Cognitive Assessment (MoCA) scores are provided.
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Cognitive Assessment
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Imaging Techniques
DTBZ PET Imaging
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PET Imaging Analysis
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MRI
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MRI Analysis
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Standard Protocol Approvals, Registrations, and Patient Consents
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Statistical Analysis
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Results
Relationship Between Gray Matter Volumes and Presence of DM in PD
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Table 2
Effects of Diabetes on Lobar Gray Matter Volumes
PD without DM PD with DM Striatal DTBZ Age Sex ICV DM Overall Model Total GM 666.8 (58.9) 611.4 (38.3) (−8.3%) 2.50 (0.13) 15.9 (0.0004) 0.88 (0.35) 69.2 (<0.0001) 5.96 (0.02) 32.7 (<0.001)Post hoc lobar analyses Frontal GM 185.8 (19.6) 165.7 (13.6) (−10.8%) 1.14 (0.30) 9.67 (0.004) 0.09 (0.76) 31.05 (<0.0001) 6.65 (0.015) 16.61 (<0.001) Parietal GM 90.5 (9.9) 83.8 (5.0) (−7.4%) 1.74 (0.20) 0.94 (0.34) 1.13 (0.30) 32.12 (<0.0001) 0.32 (0.58) 11.74 (<0.001) Temporal GM 110.2 (11.6) 102.2 (7.9) (−7.2%) 1.74 (0.20) 15.35 (0.0005) 0.17 (0.68) 0.05 (<0.0001) 2.81 (0.10) 13.16 (<0.001) Occipital GM 75.6 (8.3) 69.6 (6.0) (−7.9%) 5.0 (0.03) 1.03 (0.36) 5.65 (0.03) 51.2 (<0.0001) 0.86 (0.36) 21.2 (<0.0001)
ANCOVA, analysis of covariance; DM, diabetes; DTBZ, [ 11 C]dihydrotetrabenazine; GM, gray matter; ICV, intracranial volume; PD, Parkinson disease; SD, standard deviation.
Mean (±SD) total and lobar gray matter volumes in the subjects with PD with and without diabetes. ANCOVA F values (with levels of significance) for the overall models as well as for striatal DTBZ distribution volume ratio (DVR), age, sex, intracranial volume, and diabetes group covariates are also presented. Holm-Bonferroni correction for multiple comparisons was applied for post hoc lobar gray matter analyses.
Table 3
Associations Between Diabetes, Gray Matter Volumes, and Cognitive Scores
Striatal DTBZ Age Sex ICV Total Gray Matter Volume × DM Overall Model Composite cognitive z-score 3.91 (0.06) 0.07 (0.7) 5.19 (0.03) 4.48 (0.04) 5.26 (0.01) 4.10 (0.0047)Post hoc cognitive domain analyses Executive z-score 1.99 (0.17) 0.33 (0.57) 5.13 (0.03) 4.47 (0.04) 4.30 (0.02) 3.79 (0.007) Visuospatial z-score 0.23 (0.63) 2.12 (0.15) 2.54 (0.12) 5.08 (0.03) 6.40 (0.005) 3.10 (0.02) Attention z-score 1.45 (0.24) 0.37 (0.54) 1.53 (0.22) 0.89 (0.35) 1.68 (0.20) 1.55 (0.20) Memory z-score 4.67 (0.04) 0 (0.99) 2.58 (0.12) 2.93 (0.10) 2.16 (0.13) 2.59 (0.04)
ANCOVA, analysis of covariance; DM, diabetes; DTBZ, [ 11 C]dihydrotetrabenazine; DVR, distribution volume ratio; ICV, intracranial volume.
Results for ANCOVA analysis with cognitive z-scores as the outcome variables and explanatory variables of total gray matter volume × DM status interaction, striatal DTBZ DVR, age, sex, and ICV. F values (with levels of significance) for the overall models as well as individual parameters and associated P values are presented. Holm-Bonferroni correction for multiple comparisons was applied for post hoc cognitive domain score analyses.
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Post Hoc Analysis on the Relationship Between Cognitive Test Performance and Gray Matter Loss/Regional Cortical Atrophy ( Table 3 )
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Discussion
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