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Five-Year Disease Progression in Synuclein Seeding Positive Sporadic Parkinson's Disease
Journal article   Open access   Peer reviewed

Five-Year Disease Progression in Synuclein Seeding Positive Sporadic Parkinson's Disease

Paulina Gonzalez-Latapi, Caroline Gochanour, Seung Ho Choi, Hyunkeun Cho, Chelsea Caspell-Garcia, Christopher Coffey, Michael Brumm, David Erick Lafontant, Yuge Xiao, Thomas Tropea, …
Annals of clinical and translational neurology
03/10/2026
DOI: 10.1002/acn3.70323
PMID: 41808287
url
https://doi.org/10.1002/acn3.70323View
Published (Version of record) Open Access

Abstract

Objective To provide a comprehensive description of disease progression in synuclein seeding assay (SAA) positive sporadic Parkinson Disease participants, using Neuronal Synuclein Disease integrated biological and functional impairment staging framework. Methods We analyzed 5-year longitudinal data from 345 participants recruited in the Parkinson's Progression Markers Initiative with the diagnosis of early (less than 2 years of clinical diagnosis at baseline and untreated) sporadic Parkinson's Disease, who were synuclein seeding assay positive. We assessed 5-year progression in a spectrum of clinical and biomarker measures. We used Cox proportional hazards models to assess the association between baseline stage and time to survival, postural instability, cognitive impairment, and other meaningful milestones. Biomarker analysis included dopamine transporter binding measures, CSF-SAA, amyloid-beta, phosphorylated tau and total tau, as well as serum urate, and neurofilament light chain. Results At baseline there was clear separation of participants by Neuronal Synuclein Disease Stages (23% Stage 2b, 67% Stage 3, 10% Stage 4). Participants in stage 4 at baseline had a significantly higher rate of reaching disability, postural instability, cognitive decline, and the autonomic dysfunction milestones. There was a stage-dependent increase in dopamine deficit at baseline. There was no difference in fluid biomarkers between the stages at baseline and longitudinally. Interpretation This study highlights the heterogeneity in the early Parkinson's Disease population defined by clinical diagnostic criteria and underscores the importance of shifting from clinical to biologically and functional impairment defined inclusion criteria for clinical trials. Biological drivers of stage heterogeneity must be further explored.

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