Objective:

To introduce the Harvard Biomarkers Study 2.0 (HBS 2.0), a large-scale, longitudinal, multi-modal resource designed to accelerate biomarker discovery, mechanistic understanding, and precision medicine in Parkinson’s disease (PD) and related synucleinopathies.

Background:

Accurate diagnosis and disease-tracking in PD remain limited by the absence of validated biomarkers. Building on two decades of the Harvard Biomarkers Study (HBS 1.0), HBS 2.0 expands this landmark natural-history cohort under new leadership to integrate comprehensive clinical, genetic, and biochemical data with cutting-edge analytical approaches.

Design/Methods:

HBS 2.0 enrolls 2,500 participants (1,000 PD, 1,000 other neurodegenerative diseases, 500 controls) with baseline and seven annual follow-ups. Data include standardized motor, cognitive, autonomic, and olfactory assessments; blood, saliva, and optional CSF sampling; wearable sensor and telehealth modules; and linkage to other MGB-directed studies (MyTrial, CLIMB, Kneu Health). Integration of legacy HBS 1.0 datasets into a unified REDCap/i2b2 infrastructure enables harmonized querying and cross-study interoperability. Additionally, biochemical pipelines include optimization of quantitative α-synuclein seed amplification assays (SAA) in plasma and neuronal models. Lastly, genomic analyses leverage rare-variant association frameworks (SKAT-O, NERINE) to identify genetic determinants of progression. 

Results:

Harmonization and database development have achieved full alignment of HBS 1.0 and HBS 2.0 variables. This allowed us to conduct slope analyses of UPDRS and MMSE trajectories, delineating fast versus slow progressors, and supporting downstream genotype–phenotype association testing. Biochemically, pilot SAA and immunoprecipitation methods demonstrate improved specificity for α-synuclein seed detection in plasma. While, genomically, preliminary NERINE analyses highlight autophagy and vesicle-trafficking modules as enriched for PD-associated rare variants.

Conclusions:

HBS 2.0 represents one of the world’s most comprehensive PD biorepositories, integrating longitudinal clinical, genetic, and biospecimen data. Its open-science infrastructure and methodological innovations establish a powerful platform for biomarker discovery, mechanistic insight, and future clinical-trial readiness in PD and related disorders.