Dataset Information

Longitudinal Epigenome-Wide Methylation Study of Cognitive Decline and Motor Progression in Parkinson's Disease.

ABSTRACT: BACKGROUND:DNA methylation studies in Parkinson's disease (PD) thus far have focused on disease susceptibility but not progression. OBJECTIVE:In this epigenome-wide association study (EWAS), we aim to identify methylation markers associated with faster cognitive decline or motor progression in PD. METHODS:We included 232 PD patients from the Parkinson's Environment and Gene follow-up study who provided blood samples at enrolment. Information on cognitive and motor function was collected using the Mini-Mental State Examination (MMSE) and Unified Parkinson's Disease Rating Scale (UPDRS). For EWAS analyses, we used a robust measure of correlation: biweight midcorrelations, t-tests, and Cox proportional hazard models. We also conducted weighted correlation network analysis (WGCNA) to identify CpG modules associated with cognitive decline or motor progression in PD. RESULTS:Among 197 individuals of European ancestry, with our EWAS approach we identified 7 genome-wide significant CpGs associated with a MMSE 4-point decline and 8 CpGs associated with faster motor progression (i.e., rate of UPDRS increase ?5-point/year). The most interesting CpGs for cognitive decline include cg17445913 in KCNB1 (cor?=?0.36, p?=?6.85×10-7) and cg02920897 in DLEU2 (cor?=?0.34, p?=?3.23×10-6), while for motor progression it was cg01754178 in PTPRN2 (cor?=?- 0.34, p?=?2.07×10-6). In WGCNA, motor progression related modules were enriched for genes related to neuronal synaptic functions, Wnt signaling pathway, and mitochondrial apoptosis. CONCLUSIONS:Our study provides the first epigenetic evidence that differential methylation in genes previously identified as being associated with cognitive impairment, neuronal synaptic function, Wnt signaling pathway, and mitochondrial apoptosis is associated with cognitive and motor progression in PD.

SUBMITTER: Chuang YH

PROVIDER: S-EPMC6946688 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Longitudinal Epigenome-Wide Methylation Study of Cognitive Decline and Motor Progression in Parkinson's Disease.

Chuang Yu-Hsuan YH Lu Ake T AT Paul Kimberly C KC Folle Aline D AD Bronstein Jeff M JM Bordelon Yvette Y Horvath Steve S Ritz Beate B

Journal of Parkinson's disease 20190101 2

<h4>Background</h4>DNA methylation studies in Parkinson's disease (PD) thus far have focused on disease susceptibility but not progression.<h4>Objective</h4>In this epigenome-wide association study (EWAS), we aim to identify methylation markers associated with faster cognitive decline or motor progression in PD.<h4>Methods</h4>We included 232 PD patients from the Parkinson's Environment and Gene follow-up study who provided blood samples at enrolment. Information on cognitive and motor function ...[more]

PMID: 30958317

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Project description:BackgroundAsymmetric hemispheric loss of dopaminergic neurons is one of the characteristic features of Parkinson's disease (PD). However, it is still debated if right or left asymmetry differently affects cognitive and motor progression.ObjectivesThe objective of this study was to investigate, for the first time, the relevance of dopamine transporter (DAT) asymmetry on cognitive and motor manifestations at onset and at 4-year progression in drug-naïve PD.MethodsFrom the Parkinson's Progression Markers Initiative multicenter cohort, we identified 249 right-handed patients with PD with baseline asymmetry greater than 20% in putamen DAT binding at single-photon emission computed tomography. A predominant putamen asymmetry was found on the left in 143 patients (PD-left), and on the right side in 106 patients (PD-right); we compared them with 196 healthy controls. Patients were followed longitudinally (2-year and 4-year visits), examining their clinical, cognitive, and imaging data.ResultsAt baseline, the PD-left group showed worse performance on the Symbol Digit Modality Test, an attention and processing-speed test, and lower cerebrospinal fluid β-amyloid levels than the PD-right group. These differences were maintained at follow-up, declining over time in both groups. By contrast, the PD-right group showed greater motor impairment at baseline, which increased over 4 years. Striatal DAT binding decreased over time in both groups, but the PD-right group showed a steeper decline, particularly during the first 2-year follow-up. Putaminal asymmetry assessed at baseline was maintained over time.ConclusionsThese findings suggest that hemispheric asymmetric dopaminergic denervation influences PD cognitive and motor performance as well as progression. Predominant right hemisphere nigrostriatal dopaminergic loss is associated with greater motor severity, whereas more pronounced left hemisphere denervation affects cognitive manifestations at onset and their progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Project description:Importance:Genetic factors have a well-known influence on Parkinson disease (PD) susceptibility. The largest genome-wide association study (GWAS) identified 26 independent single-nucleotide polymorphisms (SNPs) associated with PD risk. Among patients, the course and severity of symptom progression is variable, and little is known about the potential association of genetic factors with phenotypic variance. Objective:To assess whether GWAS-identified PD risk SNPs also have a cumulative association with the progression of cognitive and motor symptoms in patients with PD. Design, Setting, and Participants:This longitudinal population-based cohort study of 285 patients of European ancestry with incident PD genotyped 23 GWAS SNPs. One hundred ninety-nine patients were followed up for a mean (SD) of 5.3 (2.1) years for progression (baseline: June 1, 2001, through November 31, 2007; follow-up: June 1, 2007, through August 31, 2013, with mortality surveillance through December 31, 2016); 57 patients had died or were too ill for follow-up, and 29 withdrew or could not be contacted. Movement disorder specialists repeatedly assessed PD symptom progression. Main Outcomes Measures:The combined association of PD risk loci, after creating a weighted polygenic risk score (PRS), with cognitive decline, motor progression, and survival, relying on Cox proportional hazards regression models and inverse probability weights to account for censoring. Results:Of the 285 patients undergoing genotyping, 160 were men (56.1%) and 125 were women (43.9%); the mean (SD) age at diagnosis was 69.1 (10.4) years. The weighted PRS was associated with significantly faster cognitive decline, measured by change in the Mini-Mental State Examination (hazard ratio [HR] per 1 SD, 1.44; 95% CI, 1.00-2.07). The PRS was also associated with faster motor decline, measured by time to Hoehn & Yahr Scale stage 3 (HR, 1.34; 95% CI, 1.00-1.79) and change in Unified Parkinson's Disease Rating Scale part III score (HR, 1.42; 95% CI, 1.00-2.01). Conclusions and Relevance:Susceptibility SNPs for PD combined with a cumulative PRS were associated with faster motor and cognitive decline in patients. Thus, these genetic markers may be associated with not only PD susceptibility but also disease progression in multiple domains.

Dataset Information

Longitudinal Epigenome-Wide Methylation Study of Cognitive Decline and Motor Progression in Parkinson's Disease.

Publications

Longitudinal Epigenome-Wide Methylation Study of Cognitive Decline and Motor Progression in Parkinson's Disease.

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