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Author Notes:

Corresponding Author: Cyrus P. Zabetian, MD, MS; VA Puget Sound Health Care System, GRECC S-182, 1660 S. Columbian Way, Seattle, WA 98108. Phone: (206) 277-6167; fax: (206) 764-2569; Email: zabetian@u.washington.edu

The authors thank all participants for participating in this work. We also thank Jacqueline Rick for technical assistance. [For a full list of contributions and acknowledgments please see the publication.]

Financial Disclosure/Conflict of Interest concerning the research related to the manuscript: None

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Research Funding:

For a full list of funding, please see the full publication.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Clinical Neurology
  • Neurosciences & Neurology
  • cognition
  • GBA
  • neuropsychological tests
  • visuospatial
  • working memory
  • APOLIPOPROTEIN-E GENOTYPE
  • GAUCHER-DISEASE
  • GLUCOCEREBROSIDASE MUTATIONS
  • DEMENTIA
  • RISK
  • PERFORMANCE
  • IMPAIRMENT
  • INCIDENT
  • ONSET
  • GENE

GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease

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Journal Title:

Movement Disorders

Volume:

Volume 31, Number 1

Publisher:

, Pages 95-102

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Background: Loss-of-function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known. Methods: We screened the GBA coding region for mutations and the E326K polymorphism in 1,369 PD patients enrolled at eight sites from the PD Cognitive Genetics Consortium. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised), working memory/executive function (Letter-Number Sequencing Test and Trail Making Test A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation), and global cognitive function (MoCA). We used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates and accounted for multiple testing using Bonferroni's corrections. Results: Mutation carriers (n=60; 4.4%) and E326K carriers (n=65; 4.7%) had a higher prevalence of dementia (mutations, odds ratio=5.1; P=9.7×10-6; E326K, odds ratio=6.4; P=5.7×10-7) and lower performance on Letter-Number Sequencing (mutations, corrected P[Pc]=9.0×10-4; E326K, Pc=0.036), Trail Making B-A (mutations, Pc=0.018; E326K, Pc=0.018), and Benton Judgment of Line Orientation (mutations, Pc=0.0045; E326K, Pc=0.0013). Conclusions: Both GBA mutations and E326K are associated with a distinct cognitive profile characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits.

Copyright information:

© 2016 International Parkinson and Movement Disorder Society.

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