Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease

Autor: Martin Niethammer, Marilyn S. Albert, Megan Smith, Jennifer G. Goldman, David Eidelberg, Thomas J. Montine, Daniel Weintraub, Ted M. Dawson, John Q. Trojanowski, Zbigniew K. Wszolek, Marie Y. Davis, Amie L. Peterson-Hiller, Joseph F. Quinn, Karen L. Edwards, Alice Chen-Plotkin, James B. Leverenz, Glenn T. Stebbins, Brenna Cholerton, Paul J. Mattis, Shu Ching Hu, Cyrus P. Zabetian, Dennis W. Dickson, Ignacio F. Mata, Dora Yearout, Catherine O. Johnson, Liana S. Rosenthal, Vivianna M. Van Deerlin, Bryan Bernard, Kathryn A. Chung, Owen A. Ross
Rok vydání: 2016
Předmět:
0301 basic medicine
Male
Aging
Movement disorders
Unified Parkinson's disease rating scale
Disease
Neurodegenerative
Logistic regression
0302 clinical medicine
Genotype
2.1 Biological and endogenous factors
Longitudinal Studies
Aetiology
Parkinson's Disease
Cognition
Parkinson Disease
Middle Aged
Neurological
Disease Progression
Glucosylceramidase
Female
Cognitive Sciences
medicine.symptom
Psychology
medicine.drug
medicine.medical_specialty
Levodopa
Clinical Sciences
Article
03 medical and health sciences
Genetic
Clinical Research
Internal medicine
medicine
Acquired Cognitive Impairment
Genetics
Dementia
Humans
Cognitive Dysfunction
Polymorphism
Aged
Polymorphism
Genetic
Neurology & Neurosurgery
Neurosciences
medicine.disease
Brain Disorders
030104 developmental biology
Mutation
Physical therapy
Neurology (clinical)
030217 neurology & neurosurgery
Zdroj: JAMA neurology, vol 73, iss 10
Popis: Importance 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. Design, Setting, and Participants 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. Main Outcomes and Measures 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 and Relevance 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.
Databáze: OpenAIRE
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