Young Eun Huh1, Ming Sum Ruby Chiang1, Joseph J Locascio1, Zhixiang Liao1, Ganqiang Liu1, Karbi Choudhury1, Yuliya I Kuras1, Idil Tuncali1, Aleksandar Videnovic1, Ann L Hunt1, Michael A Schwarzschild1, Albert Y Hung1, Todd M Herrington1, Michael T Hayes1, Bradley T Hyman1, Anne-Marie Wills1, Stephen N Gomperts1, John H Growdon1, Sergio Pablo Sardi1, Clemens R Scherzer2. 1. From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston, MA; Department of Neurology (Y.E.H.), CHA Bundang Medical Center, CHA University, Seongnam, Korea; Rare and Neurological Diseases Therapeutic Area (M.S.R.C., S.P.S.), Sanofi, Framingham, MA; School of Medicine (G.L.), Sun Yat-Sen University, Guangzhou, Guangdong, China; and Department of Neurology (J.J.L., A.V., A.L.H., M.A.S., A.Y.H., T.M.H., B.T.H., A.-M.W., S.N.G., J.H.G., C.R.S.), Massachusetts General Hospital, Boston. 2. From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston, MA; Department of Neurology (Y.E.H.), CHA Bundang Medical Center, CHA University, Seongnam, Korea; Rare and Neurological Diseases Therapeutic Area (M.S.R.C., S.P.S.), Sanofi, Framingham, MA; School of Medicine (G.L.), Sun Yat-Sen University, Guangzhou, Guangdong, China; and Department of Neurology (J.J.L., A.V., A.L.H., M.A.S., A.Y.H., T.M.H., B.T.H., A.-M.W., S.N.G., J.H.G., C.R.S.), Massachusetts General Hospital, Boston. cscherzer@rics.bwh.harvard.edu.
Abstract
OBJECTIVE: To test the relationship between clinically relevant types of GBA mutations (none, risk variants, mild mutations, severe mutations) and β-glucocerebrosidase activity in patients with Parkinson disease (PD) in cross-sectional and longitudinal case-control studies. METHODS: A total of 481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson's Disease Biomarkers Program (PDBP) were analyzed, including 47 patients with PD carrying GBA variants (GBA-PD), 247 without a GBA variant (idiopathic PD), and 187 healthy controls. Longitudinal analysis comprised 195 participants with 548 longitudinal measurements over a median follow-up period of 2.0 years (interquartile range, 1-2 years). RESULTS: β-Glucocerebrosidase activity was low in blood of patients with GBA-PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS (p < 0.001) and PDBP (p < 0.05) in multivariate analyses adjusting for age, sex, blood storage time, and batch. Enzyme activity in patients with idiopathic PD was unchanged. Innovative enzymatic quantitative trait locus (xQTL) analysis revealed a negative linear association between residual β-glucocerebrosidase activity and mutation type with p < 0.0001. For each increment in the severity of mutation type, a reduction of mean β-glucocerebrosidase activity by 0.85 μmol/L/h (95% confidence interval, -1.17, -0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in β-glucocerebrosidase activity during a median 2 years of follow-up (p = 0.02). CONCLUSIONS: Residual activity of the β-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. β-Glucocerebrosidase activity is a quantitative endophenotype that can be monitored noninvasively and targeted therapeutically.
OBJECTIVE: To test the relationship between clinically relevant types of GBA mutations (none, risk variants, mild mutations, severe mutations) and β-glucocerebrosidase activity in patients with Parkinson disease (PD) in cross-sectional and longitudinal case-control studies. METHODS: A total of 481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson's Disease Biomarkers Program (PDBP) were analyzed, including 47 patients with PD carrying GBA variants (GBA-PD), 247 without a GBA variant (idiopathic PD), and 187 healthy controls. Longitudinal analysis comprised 195 participants with 548 longitudinal measurements over a median follow-up period of 2.0 years (interquartile range, 1-2 years). RESULTS: β-Glucocerebrosidase activity was low in blood of patients with GBA-PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS (p < 0.001) and PDBP (p < 0.05) in multivariate analyses adjusting for age, sex, blood storage time, and batch. Enzyme activity in patients with idiopathic PD was unchanged. Innovative enzymatic quantitative trait locus (xQTL) analysis revealed a negative linear association between residual β-glucocerebrosidase activity and mutation type with p < 0.0001. For each increment in the severity of mutation type, a reduction of mean β-glucocerebrosidase activity by 0.85 μmol/L/h (95% confidence interval, -1.17, -0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in β-glucocerebrosidase activity during a median 2 years of follow-up (p = 0.02). CONCLUSIONS: Residual activity of the β-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. β-Glucocerebrosidase activity is a quantitative endophenotype that can be monitored noninvasively and targeted therapeutically.
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