Long-term longitudinal data on outcomes in sporadic Parkinsons Disease are limited, especially from cohorts with extensive biological characterization. Recent advances in biomarkers characterization of Parkinsons Disease necessitate an updated examination of long-term progression within contemporary cohorts like the Parkinsons Progression Markers Initiative, which enrolled individuals within 2 years of clinical diagnosis of Parkinsons Disease. Our study leverages the Neuronal Synuclein Disease framework, which defines the disease based on biomarker assessed presence of neuronal alpha-synuclein and dopamine deficit, rather than based on conventional clinical diagnostic criteria. In this study we aimed to provide a comprehensive long-term description of disease progression using the integrated biological and clinical staging system framework. We analyzed data from 344 participants from the sporadic Parkinsons Disease cohort in the Parkinsons Progression Markers Initiative, who met Neuronal Synuclein Disease criteria. We assessed 11-year progression in a spectrum of clinical measures. We used Cox proportional hazards models to assess the association between baseline stage and time to key outcomes, including survival, postural instability (Hoehn & Yahr >= 3), loss of independence (Schwab & England < 80%), cognitive decline, and domain-based milestones such as walking and balance, motor complications, autonomic dysfunction, and activities of daily living. Additional analyses were completed to account for death and participant dropout. Biomarker analysis included dopamine transporter binding measures, as well as serum urate, neurofilament light chain and CSF amyloid-beta, phosphorylated tau and total tau. At baseline, despite the cohort consisting of individuals within 2 years of clinical diagnosis, there was clear separation of participants in Neuronal Synuclein Disease Stages (23% Stage 2b, 67% Stage 3, 10% Stage 4). At 11 years, data were available for 153 participants; 35 participants had died over the follow up period. Of retained participants, 59% presented normal cognition, 24% had evidence of postural instability and mean Schwab & England score was 78.5. Serum neurofilament light chain consistently increased over time. No other biofluids had a consistent change in trajectory. Of importance, baseline Neuronal Synuclein Disease Stage predicted progression to clinically meaningful milestones. This study provides data on longitudinal, 11-year progression in Neuronal Synuclein Disease participants within 2 years of clinical diagnosis. We observed better long-term outcomes in this contemporary observational study cohort. It highlights the heterogeneity in the early Parkinsons Disease population as defined by clinical diagnostic criteria and underscores the importance of shifting from clinical to biologically and functionally based inclusion criteria in the design of new clinical trials.

PG-L declares grant from PPMI supported by The Michael J. Fox Foundation. She has also received research grants from The Michael J. Fox Foundation and the Parkinsons Foundation . CG declares employment for The Michael J. Fox Foundation. HC declares travel grants from The Michael J. Fox Foundation. SC declares travel grants from The Michael J. Fox Foundation. CC-G reports no disclosures. CC declares grants from The Michael J. Fox Foundation and NIH/NINDS. MB declares travel grants from The Michael J. Fox Foundation. D-EL declares travel grants from The Michael J. Fox Foundation. YX declares employment for and travel grants from The Michael J. Fox Foundation. CT declares consultancies for CNS Ratings, Australian Parkinsons Mission, Biogen, Evidera, Cadent (data safety monitoring board), Adamas (steering committee), Biogen (via the Parkinson Study Group steering committee), Kyowa Kirin (advisory board), Lundbeck (advisory board), Jazz/Cavion (steering committee), Acorda (advisory board), Bial (DMC) and Genentech. CT also declares grant support to her institution from The Michael J. Fox Foundation, National Institute of Health, Gateway LLC, Department of Defense, Roche Genentech, Biogen, Parkinson Foundation and Marcus Program in Precision Medicine. CT declares membership on the npj Parkinsons Disease Editorial Board. CV declares grants from NIH/NINDS. KK is an employee of the University of Rochester, that receives funding from the Michael J Fox Foundation, and is an employee of Clintrex Research LLC, a division of Tox Strategies, who receive funding from commercial clients. KK has equity interests in Tox Strategies, Safe Therapeutics, Inhibikase, Photopharmics, Biohaven and Hoover Brown LLC. LC declares grants to her institution from Biogen (clinical trial funding), MJFF, UPMC Competitive Medical Research Fund, National Institutes of Health, and University of Pittsburgh; grant and travel support from MJFF; royalties from Wolters Kluwel (for authorship); and in-kind donation by Advanced Brain Monitoring of equipment for research study to her institution. KP declares consultancies for Curasen; was on a scientific advisory board for Curasen and Amprion; honoraria from invited scientific presentations to universities and professional societies not exceeding $5000 per year from California Congress of Clinical Neurology, California Neurological Society, and Johns Hopkins University; and patents or patent applications numbers 17/314,979 and 63/377,293. KP also declares grants to her institution (Stanford University School of Medicine) from NIH/NINDS NS115114, NS062684, NS075097, NIH/NIA U19 AG065156, P30 AG066515, The Michael J. Fox Foundation, Lewy Body Dementia Association, Alzheimers Drug Discovery Foundation, Sue Berghoff. AS declares consultancies for SPARC Therapeutics, Capsida Therapeutics and Parkinson Study Group; honoraria from Bial; grants from The Michael J. Fox Foundation (member of PPMI Steering Committee); and participation on board at Wave Life Sciences, Inhibikase, Prevail, Huntington Study Group and Massachusetts General Hospital. KM declares support to his institution (Institute for Neurodegenerative Disorders) from The Michael J. Fox Foundation. KM also declares consultancies for Invicro, The Michael J. Fox Foundation, Roche, Calico, Coave, Neuron23, Orbimed, Biohaven, Anofi, Koneksa, Merck, Lilly, Inhibikase, Neuramedy, IRLabs and Prothena and participates on DSMB at Biohaven. TS declares consultancies for AcureX, Adamas, AskBio, Amneal, Blue Rock Therapeutics, Critical Path for Parkinsons Consortium, Denali, The Michael J. Fox Foundation, Neuroderm, Roche, Sanofi, Sinopia, Takeda, and Vanqua Bio; on advisory boards for AcureX, Adamas, AskBio, Biohaven, Denali, GAIN, Neuron23 and Roche; on scientific advisory boards for Koneksa, Neuroderm, Sanofi and UCB; and received research funding from Amneal, Biogen, Roche, Neuroderm, Sanofi, Prevail and UCB and an investigator for NINDS, MJFF, Parkinsons Foundation.

Dr. Gonzalez-Latapi is supported by an Early Investigator Award from PPMI. Dr. Tanya Simuni is a member of the PPMI Executive Steering Committee.

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Data used in the preparation of this article were obtained on June 24th, 2024 from the PPMI database (www.ppmi-info.org/access-data-specimens/download-data), RRID:SCR 006431. For up-to-date information on the study, visit www.ppmi-info.org. This analysis was conducted by the PPMI Statistics Core and used actual dates of activity for participants, a restricted data element not available to public users of PPMI data. Access can be obtained upon request. Statistical analysis codes used to perform the analyses in this article are shared on Zenodo (10.5281/zenodo.11660808).

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Data used in the preparation of this article were obtained on June 24th, 2024 from the PPMI database (www.ppmi-info.org/access-data-specimens/download-data), RRID:SCR 006431. For up-to-date information on the study, visit www.ppmi-info.org. This analysis was conducted by the PPMI Statistics Core and used actual dates of activity for participants, a restricted data element not available to public users of PPMI data. Access can be obtained upon request. Statistical analysis codes used to perform the analyses in this article are shared on Zenodo (10.5281/zenodo.11660808).