Biologic Frameworks for Synucleinopathies: Contributions of the Parkinson's Progression Markers Initiative.

Abstract

A research biologic definition and staging of neuronal alpha-synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, is critical toward improving clinical trial design and drug development. Neuronal synuclein disease, and the companion Integrated Staging System, are a biologic definition and staging system conceptualized by multiple stakeholders including academia, industry, advocacy organizations, and importantly, people with lived experiences. In large part, this was informed and enabled by the knowledge garnered from the Parkinson's Progression Markers Initiative. This review provides a historical perspective and details contributions from the Parkinson's Progression Markers Initiative, among others, that made this advancement possible. These include the key role it played in validation of an in vivo biomarker of neuronal alpha-synuclein, longitudinal characterization of dopaminergic dysfunction imaging, biospecimen collection and assays, comprehensive genetic characterization, and clinical phenotyping. In addition, the Parkinson's Progression Markers Initiative is generating and sharing data that will be used to address key gaps in knowledge, revisions, and future refinements of a biologic definition and staging of synucleinopathies. ANN NEUROL 2026.