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

作者：Marie Y. Davis, Catherine Owens Johnson, James B. Leverenz, Daniel A. Weintraub, John Q. Trojanowski, Alice S. Chen‐Plotkin, Vivianna M. Van Deerlin, Joseph F. Quinn, Kathryn A. Chung, Amie L. Peterson‐Hiller, Liana S. Rosenthal, Ted M. Dawson, Marilyn S. Albert, Jennifer G. Goldman, Glenn T. Stebbins, Bryan A. Bernard, Zbigniew K. Wszołek, Owen A. Ross, Dennis W. Dickson, David Eidelberg, Paul J. Mattis, Martin Niethammer, Dora Yearout, Shu‐Ching Hu, Brenna Cholerton, Megan Smith, Ignacio Fernandez Mata, Thomas Jude Montine, Karen L. Edwards, Cyrus P. Zabetian · 发表于：JAMA Neurology · 年份：2016 · DOI：10.1001/jamaneurol.2016.2245 · 被引用次数：230 · 研究领域：Lysosomal Storage Disorders Research、Parkinson's Disease Mechanisms and Treatments、Neurological diseases and metabolism

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 progr...