title: GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease.
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.
authors: Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.|Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
authors: Ignacio F
authors: IF
authors: Mata
authors: Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors: James B
authors: JB
authors: Leverenz
authors: Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA.
authors: Daniel
authors: D
authors: Weintraub
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: John Q
authors: JQ
authors: Trojanowski
authors: Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Alice
authors: A
authors: Chen-Plotkin
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Vivianna M
authors: VM
authors: Van Deerlin
authors: Department of Epidemiology, School of Public Health, University of California Los Angeles, Los Angeles, California, USA.|Department of Environmental Health Sciences, School of Public Health, University of California Los Angeles, Los Angeles, California, USA.|Department of Neurology, University of California Los Angeles, Los Angeles, California, USA.
authors: Beate
authors: B
authors: Ritz
authors: Department of Neurology, University of California Los Angeles, Los Angeles, California, USA.
authors: Rebecca
authors: R
authors: Rausch
authors: Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors: Stewart A
authors: SA
authors: Factor
authors: Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors: Cathy
authors: C
authors: Wood-Siverio
authors: Portland Veterans Affairs Medical Center, Portland, Oregon, USA.|Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA.
authors: Joseph F
authors: JF
authors: Quinn
authors: Portland Veterans Affairs Medical Center, Portland, Oregon, USA.|Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA.
authors: Kathryn A
authors: KA
authors: Chung
authors: Portland Veterans Affairs Medical Center, Portland, Oregon, USA.|Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA.
authors: Amie L
authors: AL
authors: Peterson-Hiller
authors: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
authors: Jennifer G
authors: JG
authors: Goldman
authors: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
authors: Glenn T
authors: GT
authors: Stebbins
authors: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
authors: Bryan
authors: B
authors: Bernard
authors: Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
authors: Alberto J
authors: AJ
authors: Espay
authors: Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio, USA.|Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
authors: Fredy J
authors: FJ
authors: Revilla
authors: Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
authors: Johnna
authors: J
authors: Devoto
authors: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Liana S
authors: LS
authors: Rosenthal
authors: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Solomon H. Snyder Department of Neuroscience and Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Ted M
authors: TM
authors: Dawson
authors: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Marilyn S
authors: MS
authors: Albert
authors: Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.|Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
authors: Debby
authors: D
authors: Tsuang
authors: Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.|Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
authors: Haley
authors: H
authors: Huston
authors: Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.|Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
authors: Dora
authors: D
authors: Yearout
authors: Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.|Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
authors: Shu-Ching
authors: SC
authors: Hu
authors: Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.|Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
authors: Brenna A
authors: BA
authors: Cholerton
authors: Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA.
authors: Thomas J
authors: TJ
authors: Montine
authors: Department of Epidemiology, School of Medicine, University of California Irvine, Irvine, California, USA.
authors: Karen L
authors: KL
authors: Edwards
authors: Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.|Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
authors: Cyrus P
authors: CP
authors: Zabetian
mesh_terms: D000368:Aged; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010300:Parkinson Disease / Q000150:complications*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012720:Severity of Illness Index; D014481:United States
chemical_list: D005962:Glucosylceramidase
keywords: GBA; cognition; neuropsychological tests; visuospatial; working memory