Abstract
ObjectiveTo establish the significance of glucocerebrosidase gene (GBA) carrier status on motor impairment in a large cohort of patients with incident Parkinson disease (PD).MethodsThree European population-based studies followed 528 patients with PD from diagnosis. A total of 440 with genomic DNA from baseline were assessed for GBA variants. We evaluated motor and functional impairment annually using the Unified Parkinson’s Disease Rating Scale (UPDRS) motor and activities of daily living (ADL) sections. Differential effects of classes of GBA variants on disease progression were evaluated using mixed random and fixed effects models.ResultsA total of 387 patients with idiopathic disease (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 point per year, 95% confidence interval [CI] 1.1–2.0) and motor symptoms (2.2 points per year, 95% CI 1.3–3.1) compared to noncarriers (ADL, 1.0 point per year, 95% CI 0.9–1.1, p = 0.003; motor, 1.3 point per year, 95% CI 1.1–1.6, 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.ConclusionGBA variants are linked to a more aggressive motor disease course over 7 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.
Highlights
Three European population-based studies followed 528 patients with Parkinson disease (PD) from diagnosis
GBA carriers showed faster annual increase in Unified Parkinson’s Disease Rating Scale (UPDRS) scores measuring activities of daily living (ADL) (1.5 point per year, 95% confidence interval [CI] 1.1–2.0) and motor symptoms (2.2 points per year, 95% CI 1.3–3.1) compared to noncarriers (ADL, 1.0 point per year, 95% CI 0.9–1.1, p = 0.003; motor, 1.3 point per year, 95% CI 1.1–1.6, 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
Summary
Three European population-based studies followed 528 patients with PD from diagnosis. Differential effects of classes of GBA variants on disease progression were evaluated using mixed random and fixed effects models. Approvals, and Patient Consents The participants in this study take part in the Norwegian ParkWest study, the Swedish NYPUM study, and the Scottish PINE study, 3 prospective population-based longitudinal incidence studies of PD (recruitment running between 2002 and 2009) with similar study design.[12,13,14,15] A total of 212 patients were enrolled in the ParkWest study, 211 in the PINE study, and 182 in the NYPUM study. The patients are under continued follow-up, and only those with a confirmed clinical or pathologic (if performed postmortem) diagnosis of PD according to the UK Brain Bank criteria at their latest or final clinical visit were included. The remaining 440 patients were eligible for this study and the 7-year clinical visits were complete
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