Association of GBA Genotype with Motor and Functional Decline in Newly Diagnosed Patients with Parkinsons Disease

Abstract

Objectives:To establish the significance of GBA-carrier status on motor impairment in a large cohort of patients with incident Parkinson’s disease (PD).Methods:Three European population-based studies followed 528 patients with PD from diagnosis. 440 with genomic DNA from baseline were assessed for GBA variants. We evaluated motor and functional impairment annually using the Unified PD Rating Scale (UPDRS) motor and Activity of Daily Living (ADL) sections. Differential effects of classes of GBA variants on disease progression were evaluated using mixed random and fixed effects models.Results:387 idiopathic patients (age at baseline 70.3±9.5 years; 60.2% male) and 53 GBA-carriers (age at baseline 66.8±10.1 years; 64.2% male) were included. The motor profile of the groups was clinically indistinguishable at diagnosis. GBA-carriers showed faster annual increase in UPDRS scores measuring ADL (1.5 points per year, 95% CI 1.1 to 2.0) and motor symptoms (2.2 points per year, 95% CI 1.3 to 3.1) compared to non-carriers (ADL, 1.0 points per year, 95% CI 0.9 to 1.1, P = 0.003; motor, 1.3 points per year, 95% CI 1.1 to 1.6, P = 0.007). Simulations of clinical trial designs showed that recruiting only GBA-carriers can reduce trial size by up to 65% compared to a trial recruiting all patients with PD.Conclusion:GBA variants are linked to a more aggressive motor disease course over seven years from diagnosis in patients with PD. A better understanding of PD progression in genetic subpopulations may improve disease management and has direct implications for improving the design of clinical trials.