Background. Neuronal alpha-Synuclein Disease (NSD) is defined by presence of an in vivo biomarker of neuronal alpha-synuclein (n-asyn) pathology, independent of presence of clinical syndrome. The NSD integrated staging system (NSD-ISS) describes progression across the disease continuum as stages 0 to 6. The objective of this analysis was to assess 5-year longitudinal change in the NSD-ISS. Methods. Analysis included a subset of participants from the Parkinson's Progression Markers Initiative (PPMI) enrolled before 2020 as Parkinson's disease, prodromal, or healthy controls who met NSD criteria. Staging was defined based on biomarkers of n-asyn and dopaminergic dysfunction in early stages, clinical features (cognition, other non-motor features, and parkinsonism), and increasing degree of functional impairment in stages 3-6. Stages were examined annually for 5 years, along with the determinants of progression and effects of dopaminergic medication. Findings. 576 participants were n-asyn positive and included in the analysis. Of these, 494 were enrolled as Parkinson's disease, 74 as prodromal and 8 as healthy controls. At baseline 56% of participants were in stage 3, 24% stage 2B, 13% stage 4, 4% stage 2A, and <1% in the other stages. At year 5, the percent of individuals in stage 2B, 3, and 4 were 11%, 50%, and 34% respectively, indicating progression through NSD stages. Median (95% CI) time to next stage increase from baseline was 1.19 (1.07-2.01) for stage 2B, 4.98 (4.07-5.35) for stage 3, and 9.77 (7.04-NA) for stage 4. Progression was driven by functional impairment in predominantly motor domain (95%) for stage 2B to 3, increasing degree of non-motor dysfunction for stage 3 to 4 (46%), and combination of motor, non-motor and cognitive domains for stage 4 to 5. Initiation of dopaminergic medications lead to stage regression in 8% participants in stage 3 and 41% in stage 4. Interpretation. Our analysis supports the validity of the NSD-ISS in defining stages of disease progression and support the utility of the NSD-ISS as a potential tool to identify clinical trial cohorts for drug development. Further validation in interventional studies is a crucial next step.

TS declares consultancies for AcureX, Adamas, AskBio, Amneal, Blue Rock Therapeutics, Critical Path for Parkinson's 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, Parkinson's Foundation. CG- nothing to declare; AN- nothing to declare. MB declares travel grants from The Michael J. Fox Foundation. CG declares employment for The Michael J. Fox Foundation. CG declares research funding to her institution from The Michael J. Fox Foundation. AN declares research funding to her institution from The Michael J. Fox Foundation. MB declares travel grants from The Michael J. Fox Foundation. CC declares grants from The Michael J. Fox Foundation and NIH/NINDS. 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, Alzheimer's Drug Discovery Foundation, Sue Berghoff. 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. DW declares salary support from The Michael J. Fox Foundation for serving on an Executive Steering Committee for the PPMI and consultancies for Roche Pharma. In addtion, he has received research funding or support from Michael J. Fox Foundation for Parkinson's Research, International Parkinson and Movement Disorder Society (IPMDS), National Institute on Health (NIH), The Parkinson's Foundation and the U.S. Department of Veterans Affairs; honoraria for consultancy from AbbVie, Boehringer Ingelheim, Cerevel Therapeutics, CHDI Foundation, Citrus Health Group, Medscape, Modality.AI, Sage Therapeutics, Scion NeuroStim, Signant Health and Vanqua Bio; and license fee payments from the University of Pennsylvania for the QUIP and QUIP-RS.  CT declares consultancies for CNS Ratings, Australian Parkinson's Mission, Biogen, Evidera, Cadent (data safety monitoring board), Adamas (steering committee), Biogen (via the Parkinson Study Group steering committee), Praxis (via the International Parkinsons and Movement Disorder Society), 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 Parkinson's Disease Editorial Board. PG-L decares an early investigator award from the Michael J. Fox Foundation. CK declares employment for The Michael J. Fox Foundation. YX declares employment for and travel grants from The Michael J. Fox Foundation. SC declares employment for and travel grants from The Michael J. Fox Foundation. TD declares former employment for and employee stock options in Biogen. GP declares employment for F. Hoffmann-La Roche Ltd. and stock ownership for F. Hoffmann-La Roche Ltd., Atea, Novartis and Eli Lilly. DS has no declarations. AS declares consultancies for Mitsubishi, GE healtcare, Capsida Therapeutics and Parkinson Study Group; grants from The Michael J. Fox Foundation (member of PPMI Steering Committee); and participation on DSMB boards at Spark Therapeutics, Cerevance. Alerity, Wave Life Sciences, Inhibikase, Prevai (Eli Lilly), Huntington Study Group and Massachusetts General Hospital. BD declarations are TBD. 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. 

https://dx.doi.org/10.17504/protocols.io.n92ldmw6ol5b/v2

Funding support for the data analysis was provided by The Michael J. Fox Foundation for Parkinson's Research (MJFF). PPMI, a public-private partnership, is funded by MJFF and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson's, AskBio, Avid Radiopharmaceuticals, BIAL, BioArctic, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, BristolMyers Squibb, Calico Labs, Capsida Biotherapeutics, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE HealthCare, Genentech, GSK, Golub Capital, Handl Therapeutics, Insitro, Janssen Neuroscience, Jazz Pharmaceuticals, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Neuropore, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, UCB, Vanqua Bio, Verily, Voyager Therapeutics, the Weston Family Foundation and Yumanity Therapeutics.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Data used in the preparation of this article were obtained on February 5, 2024 from the Parkinson's Progression Markers Initiative (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.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Data used in the preparation of this article were obtained on February 5, 2024 from the Parkinson's Progression Markers Initiative (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.

https://www.ppmi-info.org/access-data-specimens/download-data