Evaluation of glucocerebrosidase pathway biomarkers in Parkinson's Disease (U01)

Parkinson disease (PD) due to monoallelic glucocerebrosidase (GBA1) gene mutations (GBA-PD) is at the forefront of novel approaches to the treatment of PD. Exciting potential therapeutic agents that target the pathway disrupted in this genetic form of PD are becoming available, and evidence suggests that benefits extend to non-mutation PD, as well. Trial development is at a pivotal stage. Demonstration of effects in trials of potential disease-modifying agents for PD in general has been impeded by uncertainty about disease etiology, heterogeneity of underlying mechanisms, few identified targets, few sensitive and stable outcome measures (especially for non-motor outcomes), and insufficient surrogate markers. This proposal aims to set the stage for clinical trials using GBA-PD as a model to transcend trial design hurdles. GBA1 mutations cause deficiency in the lysosomal glucocerebrosidase enzyme (GCase) and are the most common genetic factor associated with PD. This well-defined pathway allows study of a population with decreased heterogeneity of etiologic mechanism, and a known target for intervention. Evaluation of biochemical markers in this pathway in conjunction with clinical motor and non-motor features will provide outcome measures for clinical trials. Further, disruption of the GCase pathway may be an important representative mechanism for non-mutation, idiopathic PD (IPD), and has been implicated as a possible etiology in at least a subset of IPD. While our cross-sectional preliminary data is promising, validation and longitudinal assessment of these biomarkers are needed to optimize their utility in clinical trials. Unprecedented sharing of biospecimen and clinical data through the Parkinson’s Disease Biomarker Program (PDBP) enables us to leverage our extensive GBA cohort at Mount Sinai Beth Israel (MSBI). Using extant samples from our MSBI cohort, the Harvard Biomarker Study (HBS), and the PDBP, we propose to characterize focused biochemical measures of the GCase pathway, including central and peripheral biomarker assessments of enzyme, lipid and α-synuclein levels and their relation to clinical outcomes and decline. This will not only improve the likelihood of clinical trial success, but will lead to better understanding of the pathophysiologic mechanisms of this prominent etiology of PD. Specifically, we will: (Aim 1) validate findings in the MSBI dataset, associate peripheral and CSF markers, and assess their longitudinal change; (Aim 2) analytically derive a clinical severity score to optimally relate clinical and biological markers; (Aim 3) evaluate markers in IPD to discern whether a subset of IPD shares the same etiologic mechanism.

Goals of this project:

1. Transfer data from 135 subjects enrolled in the MSBI cohort to the PDBP data management resource.  Submit HBS data for subjects analyzed for GBA activity, alpha-synuclein protein levels and sphingolipids.

2. Enroll prospective participants in the PDBP using data entry through the data management resource and collection and deposition of biofluid biosamples with the NINDS BioSEND repository.

3. Compare plasma vs. dried blood spot (DBS) glucocerebrosidase activity assays using MSBI samples, and develop normalization schema if needed.

4. Longitudinal analysis of plasma from approximately 245 individuals for glucocerebrosidase activity, α-synuclein protein, and sphingolipid levels.