Neuronal alpha-Synuclein Disease integrated staging system performance in PPMI, PASADENA, and SPARK baseline cohorts
Tien Dam, Gennaro Pagano, Michael C. Brumm, Caroline Gochanour, Kathleen L. Poston, Daniel Weintraub, Lana M. Chahine, Christopher S. Coffey, Caroline M. Tanner, Catherine Kopil, Yuge Xiao, Sohini Chowdhury, Luis Concha‐Marambio, Peter DiBiaso, Tatiana Foroud, Mark Frasier, Danna Jennings, Karl Kieburtz, Kalpana Merchant, Brit Mollenhauer, Thomas J. Montine, Kelly Nudelman, John Seibyl, Todd Sherer, Andrew Singleton, Diane Stephenson, Matthew Stern, Claudio Soto, Eduardo Tolosa, Andrew Siderowf, Billy Dunn, Tanya Simuni, Kenneth Marek, the Parkinson’s Progression Markers Initiative, Caroline Tanner, Douglas Galasko, Lana Chahine, Kathleen Poston, Roseanne Dobkin, Dan Weintraub, Ethan Brown, Roy Alcalay, Aleksandar Videnovic, Duygu Tosun-Turgut, Werner Poewe, Susan Bressman, Jan Hammer, Raymond James, Ekemini Riley, Leslie Shaw, David Standaert, Sneha Mantri, Nabila Dahodwala, Michael Schwarzschild, Connie Marras, Hubert Fernandez, Ira Shoulson, Helen Rowbotham, Paola Casalin, Claudia Trenkwalder, Jamie Eberling, Katie Kopil, Alyssa O’Grady, Maggie McGuire Kuhl, Leslie Kirsch, Tawny Willson, Project Management Core, Emily Flagg, Site Management Core, Bridget McMahon, Strategy and Technical Operations, Craig Stanley, Kim Fabrizio, Data Management Core, Dixie Ecklund, Trevis Huff, Screening Core, Laura Heathers, Christopher Hobbick, Gena Antonopoulos, Imaging Core, Statistics Core, Chelsea Caspell-Garcia, Michael Brumm, Bioinformatics Core, Arthur Toga, Karen Crawford, Biorepository Core, Jan Hamer, Doug Galasko, Genetics Core, Pathology Core, Thomas Montine, Found, PPMI Online, Carlie Tanner, Roseann Dobkin, Monica Korell, Site Investigators, Charles Adler
Abstract
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.