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

• Type of Material: Article
• Authors: Ignacio F. Mata, Veterans Affairs Puget Sound Health Care System; James B. Leverenz, Cleveland Clinic; Daniel Weintraub, University of Pennsylvania; John Q. Trojanowski, University of Pennsylvania; Alice Chen-Plotkin, University of Pennsylvania; Vivianna M. Van Deerlin, University of Pennsylvania; Beate Ritz, University of California, Los Angeles; Rebecca Rausch, University of California, Los Angeles; Stewart Factor, Emory University; Cathy Wood-Siverio, Emory University; Joseph F. Quinn, Portland Veterans Affairs Medical Center; Kathryn A. Chung, Portland Veterans Affairs Medical Center; Amie L. Peterson-Hiller, Portland Veterans Affairs Medical Center; Jennifer G. Goldman, Rush University; Glenn T. Stebbins, Rush University; Bryan Bernard, Rush University; Alberto J. Espay, University of Cincinnati; Fredy J. Revilla, University of Cincinnati; Johnna Devoto, University of Cincinnati; Liana S. Rosenthal, Johns Hopkins University; Ted M. Dawson, Johns Hopkins University; Marilyn S. Albert, Johns Hopkins University; Debby Tsuang, Veterans Affairs Puget Sound Health Care System; Haley Huston, Veterans Affairs Puget Sound Health Care System; Dora Yearout, Veterans Affairs Puget Sound Health Care System; Shu-Ching Hu, Veterans Affairs Puget Sound Health Care System; Brenna A. Cholerton, Veterans Affairs Puget Sound Health Care System; Thomas J. Montine, University of Washington; Karen L. Edwards, University of California Irvine; Cyrus P. Zabetian, Veterans Affairs Puget Sound Health Care System
• Language: English
• Date: 2016-01-01
• Publisher: Wiley-Blackwell
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 International Parkinson and Movement Disorder Society.
• Final Published Version (URL): http://dx.doi.org/10.1002/mds.26359
• Title of Journal or Parent Work: Movement Disorders
• Volume: 31
• Issue: 1
• Start Page: 95
• End Page: 102
• Grant/Funding Information: For a full list of funding, please see the full publication.
• Keywords: neuropsychological tests; GBA; cognition; APOLIPOPROTEIN-E GENOTYPE; Life Sciences & Biomedicine; DEMENTIA; Clinical Neurology; Neurosciences & Neurology; IMPAIRMENT; ONSET; RISK; GAUCHER-DISEASE; GLUCOCEREBROSIDASE MUTATIONS; working memory; PERFORMANCE; INCIDENT; Science & Technology; visuospatial; GENE
• Research Categories: Health Sciences, Pathology; Health Sciences, Epidemiology; Biology, Neuroscience

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.