Study Rationale: Variants in the GB1A gene represent the most important genetic risk factor for Parkinson’s disease (PD) across the globe. However, different GBA1 variants are associated with varied pathogenicity and predispose to different clinical trajectories in motor and non-motor impairment such as cognitive decline. With an understanding of the underlying mechanisms, several clinical trials are planned to modify disease progression in participants who carry GBA1 variants. The success of these clinical trials critically depends on our knowledge of the clinical trajectories of motor, and most importantly, the different non-motor symptoms in participants with different GBA1 variants.
Hypothesis: We hypothesize that a world-wide GBA1-specific joint analysis of existing patient cohorts would rapidly enhance our understanding of disease mechanism, and that examination of individuals undergoing deep brain stimulation will allow us to evaluate whether this treatment is associated with an additive negative progression.
Study Design: Our Consortium, which includes 22 sites across the globe, has collected data on 29,176 participants with PD who lack GBA1 variants, 2540 participants with PD who carry GBA1 variants and 691 participants carrying GBA1 variants who are clinically not yet affected by PD. Our analyses will focus on progression of motor and non-motor symptoms (including impaired cognition and sleep dysfunction). This analysis will be complemented by examination of PD-related biofluid markers in blood and cerebrospinal fluid as well as MRI imaging data. Importantly, all our analyses will be stratified by single GBA1variants.
Impact on Diagnosis/Treatment of Parkinson’s disease: A worldwide approach combining different cohorts and expertise (including genetics, clinical phenotyping, fluid biomarkers and imaging) will help establish how future trials for GBA1-associated PD should be conducted (meaningful outcome measures, estimating effect sizes, sample-size estimation and trial duration), with a goal of developing the most effective treatment tested in the right population.
Next Steps for Development: We will learn what information we are still missing in order to design clinical trials in GBA1. Our dataset of 29,176 PD cases without GBA1 variants will also provide a valuable resource for studying non-genetic PD, including cognitive decline, which will be one of the major challenges for future trials.