title: Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease.
abstract: OBJECTIVE
  Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets.
  
  
  OBJECTIVE
  To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression.
  
  
  METHODS
  The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state.
  
  
  METHODS
  Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site.
  
  
  RESULTS
  Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (β = 4.65; 95% CI, 1.72-7.58; P = .002), E326K (β = 3.42; 95% CI, 0.66-6.17; P = .02), and GBA variants combined as a single group (β = 4.01; 95% CI, 1.95-6.07; P = 1.5 × 10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (β = 0.38; 95% CI, 0.23-0.53; P = .01) and E326K (β = 0.64; 95% CI, 0.43-0.86; P = .002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P = .01) and GBA variant carriers (15 of 39 [38.5%]; P = .04) progressed to mild cognitive impairment or dementia.
  
  
  CONCLUSIONS
  GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.
authors: Veterans Affairs Puget Sound Health Care System, Seattle, Washington2Department of Neurology, University of Washington School of Medicine, Seattle.
authors: Marie Y
authors: MY
authors: Davis
authors: Department of Neurology, University of Washington School of Medicine, Seattle.
authors: Catherine O
authors: CO
authors: Johnson
authors: Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, Ohio.
authors: James B
authors: JB
authors: Leverenz
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia.
authors: Daniel
authors: D
authors: Weintraub
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia.
authors: John Q
authors: JQ
authors: Trojanowski
authors: Department of Neurology, University of Pennsylvania, Philadelphia.
authors: Alice
authors: A
authors: Chen-Plotkin
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia.
authors: Vivianna M
authors: VM
authors: Van Deerlin
authors: Portland Veterans Affairs Medical Center, Portland, Oregon8Department of Neurology, Oregon Health and Science University, Portland.
authors: Joseph F
authors: JF
authors: Quinn
authors: Portland Veterans Affairs Medical Center, Portland, Oregon8Department of Neurology, Oregon Health and Science University, Portland.
authors: Kathryn A
authors: KA
authors: Chung
authors: Portland Veterans Affairs Medical Center, Portland, Oregon8Department of Neurology, Oregon Health and Science University, Portland.
authors: Amie L
authors: AL
authors: Peterson-Hiller
authors: Neurodegeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland10Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Liana S
authors: LS
authors: Rosenthal
authors: Neurodegeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland10Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland11Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland12Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Ted M
authors: TM
authors: Dawson
authors: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Marilyn S
authors: MS
authors: Albert
authors: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
authors: Jennifer G
authors: JG
authors: Goldman
authors: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
authors: Glenn T
authors: GT
authors: Stebbins
authors: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
authors: Bryan
authors: B
authors: Bernard
authors: Department of Neurology, Mayo Clinic, Jacksonville, Florida.
authors: Zbigniew K
authors: ZK
authors: Wszolek
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.
authors: Owen A
authors: OA
authors: Ross
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.
authors: Dennis W
authors: DW
authors: Dickson
authors: Center for Neurosciences, Feinstein Institute for Medical Research, Manhasset, New York17Department of Neurology, Northwell Health, Manhasset, New York.
authors: David
authors: D
authors: Eidelberg
authors: Center for Neurosciences, Feinstein Institute for Medical Research, Manhasset, New York17Department of Neurology, Northwell Health, Manhasset, New York.
authors: Paul J
authors: PJ
authors: Mattis
authors: Center for Neurosciences, Feinstein Institute for Medical Research, Manhasset, New York.
authors: Martin
authors: M
authors: Niethammer
authors: Veterans Affairs Puget Sound Health Care System, Seattle, Washington2Department of Neurology, University of Washington School of Medicine, Seattle.
authors: Dora
authors: D
authors: Yearout
authors: Veterans Affairs Puget Sound Health Care System, Seattle, Washington2Department of Neurology, University of Washington School of Medicine, Seattle.
authors: Shu-Ching
authors: SC
authors: Hu
authors: Veterans Affairs Puget Sound Health Care System, Seattle, Washington18Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle.
authors: Brenna A
authors: BA
authors: Cholerton
authors: Department of Epidemiology, University of California, Irvine, School of Medicine.
authors: Megan
authors: M
authors: Smith
authors: Veterans Affairs Puget Sound Health Care System, Seattle, Washington2Department of Neurology, University of Washington School of Medicine, Seattle.
authors: Ignacio F
authors: IF
authors: Mata
authors: Department of Pathology, University of Washington School of Medicine, Seattle.
authors: Thomas J
authors: TJ
authors: Montine
authors: Department of Epidemiology, University of California, Irvine, School of Medicine.
authors: Karen L
authors: KL
authors: Edwards
authors: Veterans Affairs Puget Sound Health Care System, Seattle, Washington2Department of Neurology, University of Washington School of Medicine, Seattle.
authors: Cyrus P
authors: CP
authors: Zabetian
mesh_terms: D000368:Aged; D060825:Cognitive Dysfunction; D003704:Dementia; D018450:Disease Progression; D005260:Female; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology*; D011110:Polymorphism, Genetic
chemical_list: D005962:Glucosylceramidase