Neuronal alpha-Synuclein Disease integrated staging system performance in PPMI, PASADENA, and SPARK baseline cohorts
Authors: Dam Tien , Pagano Gennaro , Brumm Michael C. , Gochanour Caroline , Poston Kathleen L. , Weintraub Daniel , Chahine Lana M. , Coffey Christopher , Tanner Caroline M. , Kopil Catherine M. , Xiao Yuge , Chowdhury Sohini , Concha-Marambio Luis , DiBiaso Peter , Foroud Tatiana , Frasier Mark , Jennings Danna , Kieburtz Karl , Merchant Kalpana , Mollenhauer Brit , Montine Thomas J. , Nudelman Kelly , Seibyl John , Sherer Todd , Singleton Andrew , Stephenson Diane , Stern Matthew , Soto Claudio , Tolosa Eduardo , Siderowf Andrew , Dunn Billy , Simuni Tanya , Marek Kenneth ,   the Parkinson’s Progression Markers Initiative,   Executive Steering Committee, Tanner Caroline , Galasko Douglas , Chahine Lana , Poston Kathleen , Dobkin Roseanne , Dan Weintraub  , Brown Ethan , Alcalay Roy , Videnovic Aleksandar ,   Steering Committee, Tosun-Turgut Duygu , Poewe Werner , Bressman Susan , Jan Hammer  , James Raymond , Riley Ekemini , Shaw Leslie , Standaert David , Mantri Sneha , Dahodwala Nabila , Schwarzschild Michael , Marras Connie , Fernandez Hubert , Shoulson Ira , Rowbotham Helen , Casalin Paola , Trenkwalder Claudia ,   Michael J. Fox Foundation (Sponsor), Eberling Jamie , Kopil Katie , O’Grady Alyssa , Kuhl Maggie McGuire , Kirsch Leslie , Willson Tawny ,   Study Cores, Committees, and Related Studies,   Project Management Core, Flagg Emily ,   Site Management Core, McMahon Bridget ,   Strategy and Technical Operations, Stanley Craig , Fabrizio Kim ,   Data Management Core, Ecklund Dixie , Huff Trevis ,   Screening Core, Heathers Laura , Hobbick Christopher , Antonopoulos Gena ,   Imaging Core,   Statistics Core, Caspell-Garcia Chelsea , Brumm Michael ,   Bioinformatics Core, Toga Arthur , Crawford Karen ,   Biorepository Core, Hamer Jan ,   Biologics Review Committee, Galasko Doug ,   Genetics Core,   Pathology Core, Montine Thomas ,   Found,   PPMI Online, Tanner Carlie , Dobkin Roseann , Korell Monica ,   Site Investigators, Adler Charles , Amara Amy , Barone Paolo , Bloem Bastiaan , Bressman Susan , Brockmann Kathrin , Brüggemann Norbert , Chou Kelvin , Espay Alberto , Factor Stewart , Fullard Michelle , Hauser Robert , Hogarth Penelope , Hu Shu-Ching , Hu Michele , Isaacson Stuart , Klein Christine , Krueger Rejko , Lew Mark , Mari Zoltan , Martí Maria Jose , McFarland Nikolaus , Mestre Tiago , Moukheiber Emile , Noyce Alastair , Oertel Wolfgang , Okubadejo Njideka , O’Shea Sarah , Pahwa Rajesh , Pavese Nicola , Postuma Ron , Riboldi Giulietta , Ruffrage Lauren , Martinez Javier Ruiz , Russell David , Saint-Hilaire Marie H. , Santos Neil , Schlett Wesley , Schneider Ruth , Shill Holly , Shprecher David , Stefanis Leonidas , Tai Yen , Tarakad Arjun ,   Coordinators, Ainscough Susan , Blair Courtney , Botting Erica , Chung Isabella , Clark Kelly , Croitoru Ioana , DeLano Kelly , Egner Iris , Esha Fahrial , Eshel May , Ferrari Frank , Foster Victoria Kate , Garrido Alicia , Grümmer Madita , Herrera Bethzaida , Hilt Ella , Huntzinger Chloe , Kausar Farah , Koros Christos , Krasowski Yara , Le Dustin , Liu Ying , Marques Taina M. , Santana Helen Mejia , Mosovsky Sherri , Mule Jennifer , Ng Philip , O’Brien Lauren , Ogunleye Abiola , Ojo Oluwadamilola , Onyinanya Obi , Pennente Lisbeth , Perrotti Romina , Pileggi Michael , Ramachandran Ashwini , Raymond Deborah , Razzaque Jamil , Reddie Shawna , Ribb Kori , Rizer Kyle , Rodriguez Janelle , Roman Stephanie , Sanchez Clarissa , Simonet Cristina , Singh Anisha , Sittig Elisabeth , Sommerfeld Barbara , Stovall Angela , Stubbeman Bobbie , Valenzuela Alejandra , Wandell Catherine , Willeke Diana , Williams Karen , Wubuli Dilinuer 
Published: September 2024

The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA, and SPARK studies, we developed and applied biologic and clinical data-informed definitions for the NSD-ISS across the disease continuum. Individuals enrolled as Parkinson’s disease, Prodromal, or Healthy Controls were defined and staged based on biological, clinical, and functional anchors at baseline. Across the three studies 1741 participants had SAA data and of these 1030 (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. Median (95% CI) time to developing a clinically meaningful outcome was 8.3 (6.2, 10.1), 5.9 (4.1, 6.0), and 2.4 (1.0, 4.0) years for baseline stage 2B, 3, and 4, respectively. We propose pilot biologic and clinical anchors for NSD-ISS. Our results highlight the baseline heterogeneity of individuals currently defined as early PD. Baseline stage predicts time to progression to clinically meaningful milestones. Further research on validation of the anchors in longitudinal cohorts is necessary.