Strategies to establish a biologically defined Parkinson's disease cohort prior to the onset of clinically significant motor symptoms

In the PPMI cohort, CSF alpha-synuclein seed amplification assay positivity was enriched by recruitment strategy, reaching 94% in RBD+Hyposmia and 85% in Hyposmia+DEB.

• Why it matters: Trials need biologically defined Parkinson’s disease risk cohorts before clinically significant motor symptoms, but enrollment strategies must reliably enrich for early synucleinopathy.
• What they did: PPMI enrolled polysomnogram-confirmed REM sleep behavior disorder and centrally identified hyposmia, stratifying participants into RBD+Hyposmia, RBD-Hyposmia, Hyposmia+DEB, and Hyposmia-DEB, then tested CSF alpha-synuclein seed amplification assay and imaging/clinical domains.
• The result: All strategies enriched CSFaSynSAA positivity, and CSFaSynSAA+ participants showed multi-domain clinical heterogeneity, with RBD+Hyposmia and Hyposmia+DEB having more mood, autonomic, and cognitive symptoms than Hyposmia-DEB.