Strategies to establish a biologically defined Parkinson′s disease cohort prior to the onset of clinically significant motor symptoms
Identifying individuals at risk for neurodegeneration is a priority for clinical trials. Parkinson′s Precision Medicine Initiative (PPMI) deploys strategies to enroll individuals before typical clinical Parkinson′s disease symptoms: recruiting polysomnogram-confirmed REM sleep behavior disorder (RBD) and central identification of hyposmia via smell testing. Groups were divided into RBD with and without hyposmia (RBD+Hyposmia, RBD-Hyposmia) and hyposmia with and without self-reported dream enactment behavior (Hyposmia+DEB, Hyposmia-DEB). Participants underwent clinical and biomarker testing including CSF alpha-synuclein seed amplification assay (CSFaSynSAA) and dopamine transporter imaging. While all enrollment strategies showed robust enrichment for CSFaSynSAA positivity, RBD+Hyposmia and Hyposmia+DEB were more likely CSFaSynSAA+ (94% and 85%) vs RBD-Hyposmia (40%) and Hyposmia-DEB (55%). Among CSFaSynSAA+, RBD+Hyposmia and Hyposmia+DEB had more mood, autonomic, and cognitive symptoms than Hyposmia-DEB. PPMI identified a large biologically-defined early neuronal synucleinopathy cohort and demonstrated biomarker and multi-domain clinical heterogeneity within CSFaSynSAA+ individuals prior to symptom onset.
Authors
- Ethan G. Brown (ORCID: https://orcid.org/0000-0001-9744-8562)
- Lana M. Chahine (ORCID: https://orcid.org/0000-0003-2521-7196)
- Thomas Francis Tropea (ORCID: https://orcid.org/0000-0003-0766-1496)
- Roy N. Alcalay (ORCID: https://orcid.org/0000-0002-5717-4875)
- Daniel A. Weintraub (ORCID: https://orcid.org/0000-0003-0633-7168)
- Tatiana Foroud (ORCID: https://orcid.org/0000-0002-5549-2212)
- Anuprita Nair (ORCID: https://orcid.org/0009-0008-6067-1531)
- Kathleen L. Poston (ORCID: https://orcid.org/0000-0003-3424-7143)
- Kalpana Merchant (ORCID: https://orcid.org/0000-0003-1118-9403)
- Tanya Simuni (ORCID: https://orcid.org/0000-0002-2347-1644)
- Douglas R Galasko (ORCID: https://orcid.org/0000-0001-6195-3241)
- Andrew D. Siderowf (ORCID: https://orcid.org/0000-0002-1750-7698)
- Caroline M. Tanner (ORCID: https://orcid.org/0000-0002-3775-5082)
- David-Erick Lafontant (ORCID: https://orcid.org/0000-0003-2157-7151)
- Brit Mollenhauer (ORCID: https://orcid.org/0000-0001-8437-3645)
- Roseanne D. Dobkin (ORCID: https://orcid.org/0000-0002-2535-5495)
- Helena S. Blumenau (ORCID: https://orcid.org/0000-0003-2835-4305)
- KENNETH L. MAREK (ORCID: https://orcid.org/0000-0002-4197-5627)
- Christopher S. Coffey (ORCID: https://orcid.org/0000-0002-8130-5484)
- Noah Johnson (ORCID: https://orcid.org/0009-0000-4890-5835)
- Parkinson's Precision Medicine Initiative
Institutions
- Northwestern University (US)
- University of Iowa (US)
- University of California, San Francisco (US)
- Columbia University Irving Medical Center (US)
- Tel Aviv Sourasky Medical Center (IL)
- Johnson University (US)
- University of California San Diego (US)
- Institute for Neurodegenerative Disorders (US)
- Universitätsmedizin Göttingen (DE)
- Paracelsus Elena Klinik Kassel (DE)
- Stanford Medicine (US)
- Indiana University Indianapolis (US)
- Indiana University School of Medicine (US)
- University of Pennsylvania (US)
- Stanford University (US)
Publication Details
- Journal
- medRxiv
- Published
- 2026-10-28
- DOI
- https://doi.org/10.64898/2026.10.26.26366535
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- preprint