Neuronal alpha-Synuclein Disease Integrated Staging System performance in PPMI, PASADENA, and SPARK baseline cohorts.

ABSTRACT The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with underlying Lewy body pathology, including Parkinson's disease (PD), Parkinson's disease dementia, and dementia with Lewy bodies (DLB), and stage them based on underlying biology and increasing degree of functional impairment. The objectives of this paper were to 1) develop both biologic and clinical data-informed definitions for the NSD-ISS; 2) apply these definitions across the disease continuum; and 3) evaluate time to onset of key clinical outcomes based on baseline NSD stage. Methods We utilized data from the PPMI, an observational study and PASADENA and SPARK, two independent interventional studies. Individuals currently defined by clinical features as PD, Prodromal, or Healthy Controls were classified based on biological, clinical, and functional anchors and assigned to one of seven NSD-ISS stages at baseline. Biomarker anchors included synuclein (S) assessed by cerebrospinal fluid (CSF) alpha-synuclein seed amplification assay (n-asyn SAA), dopamine (D) assessed by dopamine transporter imaging (DaTscan), and genetic status (G). Clinical and functional anchors were derived from MDS-UPDRS Parts I-III and the Montreal Cognitive Assessment. The onset of key clinical outcomes for each stage was assessed over 12 years of follow-up. Results Across the three studies 1,741 participants had SAA data and of these 1,030 (59%) were S+ consistent with NSD. Among sporadic PD, 683/736 (93%) were NSD and the distribution for Stages 2B, 3, and 4 was 25%, 63%, and 9%, respectively. Among these individuals, median (95% CI) time to developing a clinical outcome was 8.3 (6.2, 10.1), 5.9 (4.1, 6.0), and 2.4 (1.0, 4.0) years for those staged at baseline as 2B, 3, and 4, respectively. Conclusion We propose data driven biologic and clinical anchors for NSD-ISS. Our data highlight baseline heterogeneity of the individuals currently defined as early PD that impacts progression to clinically meaningful milestones. Validation of the anchors in longitudinal cohorts is necessary. ### Competing Interest Statement 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. MB declares travel grants from The Michael J. Fox Foundation. CG declares employment for The Michael J. Fox Foundation. 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 LBD Research Fellowship and the Knight Initiative for Brain Resilience. 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. 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. CC declares grants from The Michael J. Fox Foundation and NIH/NINDS. 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), 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. 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. LC-M declares employment for and employee stock options in Amprion, grants 16712 and 21233 from The Michael J. Fox Foundation to his institution; grant U44NS111672 from NIH to his institution; and patents or patent application numbers US 20210277076A1, US 20210311077A1, US 20190353669A1 and US 20210223268A1. PD has no declarations. TF declares travel grants and grant payments to her institution (Indiana University) from The Michael J. Fox Foundation. MF declares employment for The Michael J. Fox Foundation and an unpaid advisory role at Vaxxinity. DJ declares employment for and employee stock options from Denali Therapeutics. KK declares support to his institution (University of Rochester Medical Center) from The Michael J. Fox Foundation. KMe declares consultancies for The Michael J. Fox Foundation, AcuRx, Caraway, Cerebral Therapeutics, NRG Therapeutics (scientific advisory board), Nitrase Therapeutics (scientific advisory board), Nurabio, Retromer Therapeutics (director on the board, part-time chief scientific officer), Schrodinger, Sinopia Biosciences (scientific advisory board), and Vanqua Biosciences (scientific advisory board); stock ownership for Cognition Therapeutics, Eli Lilly (retiree stock holder), Envisagenics, Nitrase Therapeutics, Sinopia Biosciences and Retromer Therapeutics; honoraria for the University of Utah; patents or patent applications for Retromer Therapeutics (planned patent); research grant from The Michael J. Fox Foundation and travel grants from the University of Utah. BM declares consultancies from Roche and Biogen; grants from The Michael J. Fox Foundation, ASAP and DFG; honoraria for Abbvie and Bial; leadership role for The Michael J. Fox Foundation and travel grants for Abbvie. TM declares support to his institution (Stanford University School of Medicine) from The Michael J. Fox Foundation. KN declares grant to her institution from The Michael J. Fox Foundation. JS declares consultancies from Invicro, Biogen, and Abbvie; and stock ownership from RealmIDX, MNI Holdings, and LikeMinds as well as grants from The Michael J. Fox Foundation. TSh declares employment for The Michael J. Fox Foundation. ASin declares employment for The National Institutes of Health who received grants from The Michael J. Fox Foundation and ASAP. ASin declares Diagnostic for Stroke royalties (unrelated to current work); honoraria from Movement Disorders Society and Nature Publishing Group; travel grants from Chan Zuckerberg Initiative, The Michael J. Fox Foundation and Weill Cornell. ASin's spouse is an employee of GeneDx. DS has no declarations. MS declared consultancies for Mediflix, Inc., Health and Wellness Partners; honoraria from Atria Foundation, International Parkinson and Movement Disorder Society, Neurocrine, Luye Pharma and Acorda. MS serves on advisory board at Neuroderm, Alexza, Alexion and Biogen. CS declares employment for Amprion; stock ownership for Amprion; honoraria (will receive royalties for the sale of seed amplification assay [SAA]) from Amprion; and patents or patent applications, awarded and amplified in conjunction with Amprion for the SAA assay. ET has no declarations. ASid 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. BD declarations are TBD. TSi 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. KMa declares support to his institution (Institute for Neurodegenerative Disorders) from The Michael J. Fox Foundation. KMa 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. ### Funding Statement Funding support for the data analysis was provided by The Michael J. Fox Foundation for Parkinson's Research (MJFF). This report presents data from three studies, including PASADENA, supported by F. Hoffman-La Roche and Prothena Biosciences, SPARK, supported by Biogen, and PPMI. 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. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes 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. Yes 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). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes PPMI data are publicly available 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. Use of Tier 4 data: 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 For PASADENA, qualified researchers may request access to individual patient level clinical data through a data request platform. At the time of writing, this request platform is Vivli. https://vivli.org/ourmember/roche/. Further details on Roche's criteria for eligible trials for data access are available here (https://vivli.org/members/ourmembers/). For up-to-date details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here: https://go.roche.com/data_sharing. Anonymized records for individual patients across more than one data source external to Roche cannot, and should not, be linked due to a potential increase in risk of patient re-identification. For SPARK, to request access to data, please visits http://www.biogenclinicaldatarequest.com. The individual participant data collected during the trial, which supports the research proposal, will be available to qualified researchers after anonymization and upon approval of the research proposal. Anonymization of the datasets is necessary to allow data to be shared ethically and legally, and to maximize their significant social, environmental, and economic value, whilst preserving confidentiality of the individuals who participated in studies conducted by Biogen.