Longitudinal Proteomic Profiling Defines Robust Molecular Subtypes Underlying the Heterogeneity of Parkinson's Disease

Heterogeneity of Parkinsons disease (PD) pathology is a barrier to developing therapeutics and understanding progression and prognosis. High throughput proteomic measures can be used to better interpret PD pathophysiology and generate clusters to define disease subtypes. Identification of subtypes related to clinical phenotypes will help researchers understand PD progression. We analyzed longitudinal proteomic data from the Tracking Parkinsons Cohort, consisting of recent-onset PD patients across 72 UK sites. 794 patients were measured on the Somalogic platform (7596 proteins) for three time points. Weighted Gene Co-Expression Network Analysis (WGCNA) at each time point revealed consistent protein co-expression modules. Two modules were strongly preserved across all three time points and in validation in the Global Neurodegenerative Proteomics Consortia (GNPC) datasets. The brown module was enriched for metabolite pathways and the blue module with cellular signaling pathways and associated with quality of life scores. Conversely, the smaller red module had distinct cognitive function phenotypes and changed protein expression between visit time points. Using detailed characterization of proteomic clusters we have provided a comprehensive view of PD progression offering deeper insights into the conservation of proteomic expression, suggesting new module subsets and providing candidate target proteins for further study.