MRI Signature of α-Synuclein Pathology in Asymptomatic Stages and a Memory Clinic Population
Authors: Laura E. M. Wisse, Nicola Spotorno, Marcello Rossi, Michel J. Grothe, Angela Mammana, Pontus Tideman, Simone Baiardi, Olof Strandberg, Alice Ticca, Danielle van Westen, Niklas Mattsson-Carlgren, Sebastian Palmqvist, Erik Stomrud, Piero Parchi, Oskar Hansson, Michael W. Weiner, Paul Aisen, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John C. Morris, Richard J. Perrin, Leslie M. Shaw, Zaven Khachaturian, Maria Carrillo, William Potter, Lisa Barnes, Marie Bernard, Hector González, Carole Ho, John K. Hsiao, Jonathan Jackson, Eliezer Masliah, Donna Masterman, Ozioma Okonkwo, Laurie Ryan, Nina Silverberg, Adam Fleisher, Diana Truran Sacrey, Juliet Fockler, Cat Conti, Dallas Veitch, John Neuhaus, Chengshi Jin, Rachel Nosheny, Miriam Ashford, Derek Flenniken, Adrienne Kormos, Tom Montine, Michael Rafii, Rema Raman, Gustavo Jimenez, Michael Donohue, Devon Gessert, Jennifer Salazar, Caileigh Zimmerman, Yuliana Cabrera, Sarah Walter, Garrett Miller, Godfrey Coker, Taylor Clanton, Lindsey Hergesheimer, Stephanie Smith, Olusegun Adegoke, Payam Mahboubi, Shelley Moore, Jeremy Pizzola, Elizabeth Shaffer, Brittany Sloan, Danielle Harvey, Arvin Forghanian-
Arani, Bret Borowski, Chad Ward, Christopher Schwarz, David Jones, Jeff Gunter, Kejal Kantarci, Matthew Senjem, Prashanthi Vemuri, Robert Reid, Nick C. Fox, Ian Malone, Paul Thompson, Sophia I. Thomopoulos, Talia M. Nir, Neda Jahanshad, Charles DeCarli, Alexander Knaack, Evan Fletcher, Duygu Tosun-Turgut, Stephanie Rossi Chen, Mark Choe, Karen Crawford, Paul A. Yushkevich, Sandhitsu Das, Robert A. Koeppe, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, Nigel J. Cairns, Erin Householder, Erin Franklin, Haley Bernhardt, Lisa Taylor-
Reinwald, Magdalena Korecka, Michael Figurski, Scott Neu, Kwangsik Nho, Shannon L. Risacher, Liana G. Apostolova, Li Shen, Tatiana M. Foroud, Kelly Nudelman, Kelley Faber, Kristi Wilmes, Leon Thal, Lisa C. Silbert, Betty Lind, Rachel Crissey, Jeffrey A. Kaye, Raina Carter, Sara Dolen, Joseph Quinn, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Karen Dagerman, Bryan M. Spann, James Brewer, Helen Vanderswag, Jaimie Ziolkowski, Judith L. Heidebrink, Lisa Zbizek-Nulph, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Javier Villaneuva-
Meyer, Valory Pavlik, Nathaniel Pacini, Ashley Lamb, Joseph S. Kass, Rachelle S. Doody, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Akiva Mintz, Beau Ances, David Winkfield, Maria Carroll, Georgia Stobbs-Cucchi, Angela Oliver, Mary L. Creech, Mark A. Mintun, Stacy Schneider, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Daniel Marson, Hillel Grossman, Martin A. Goldstein, Jonathan Greenberg, Effie Mitsis, Raj C. Shah, Melissa Lamar, Patricia Samuels, Ranjan Duara, Maria T. Greig-Custo, Rosemarie Rodriguez, Marilyn Albert, Chiadi Onyike, Leonie Farrington, Scott Rudow, Rottislav Brichko, Stephanie Kielb, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Martin Sadowski, Thomas Wisniewski, Melanie Shulman, Arline Faustin, Julia Rao, Karen M. Castro, Anaztasia Ulysse, Shannon Chen, Mohammed O. Sheikh, Jamika Singleton-
Garvin, P. Murali Doraiswamy, Jeffrey R. Petrella, Olga James, Terence Z. Wong, Salvador Borges-Neto, Jason H. Karlawish, David A. Wolk, Sanjeev Vaishnavi, Christopher M. Clark, Steven E. Arnold, Charles D. Smith, Gregory A. Jicha, Riham El Khouli, Flavius D. Raslau, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Kim Martin, Nancy Kowalski, Melanie Keltz, Bonnie S. Goldstein, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Gaby Thai, Aimee Pierce, Beatriz Yanez, Elizabeth Sosa, Megan Witbracht, Brendan Kelley, Trung Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Ihab Hajjar, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Daniel H.S. Silverman, Sarah Kremen, Kathleen Tingus, Po H. Lu, George Bartzokis, Ellen Woo, Edmond Teng, Neill R. Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Adam P. Mecca, Susan P. Good, Martha G. MacAvoy, Richard E. Carson, Pradeep Varma, Howard Chertkow, Susan Vaitekunis, Chris Hosein, Sandra Black, Bojana Stefanovic, Chris (Chinthaka) Heyn, Ging-Yuek Robin Hsiung, Ellen Kim, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternak, Irina Rachinsky, Andrew Kertesz, Dick Drost, John Rogers, Ian Grant, Brittanie Muse, Emily Rogalski, Jordan Robson, M.-Marsel Mesulam, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Howard J. Rosen, Bruce L. Miller, David Perry, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Kelly MCCann, Jessica Poe, Reisa A. Sperling, Keith A. Johnson, Gad A. Marshall, Jerome Yesavage, Joy L. Taylor, Steven Chao, Jaila Coleman, Jessica D. White, Barton Lane, Allyson Rosen, Jared Tinklenberg, Christine M. Belden, Alireza Atri, Kelly A. Clark, Edward Zamrini, Marwan Sabbagh, Ronald Killiany, Robert Stern, Jesse Mez, Neil Kowall, Andrew E. Budson, Thomas O. Obisesan, Oyonumo E. Ntekim, Saba Wolday, Javed I. Khan, Evaristus Nwulia, Sheeba Nadarajah, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Pauline Maillard, John Olichney, Owen Carmichael, Vernice Bates, Horacio Capote, Michelle Rainka, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Allison Perrin, Anna Burke, Douglas W. Scharre, Maria Kataki, Rawan Tarawneh, David Hart, Earl A. Zimmerman, Dzintra Celmins, Delwyn D. Miller, Laura L. Boles Ponto, Karen Ekstam Smith, Hristina Koleva, Hyungsub Shim, Ki Won Nam, Susan K. Schtulz, Jeff D. Williamson, Suzanne Craft, Jo Cleveland, Mia Yang, Kaycee M. Sink, Brian R. Ott, Jonathan Drake, Geoffrey Tremont, Lori A. Daiello, Aaron Ritter, Charles Bernick, Donna Munic, Abigail O'Connell, Jacobo Mintzer, Arthur Wiliams, Joseph Masdeu, Jiong Shi, Angelica Garcia, Paul Newhouse, Steven Potkin, Steven Salloway, Paul Malloy, Stephen Correia, Smita Kittur, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Norman Relkin, Gloria Chiang, Athena Lee, Michael Lin, Lisa Ravdin, Ajay Sood, Kimberly S. Blanchard, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T. Greig, Bonnie Goldstein, Kimberly S. Martin, Christopher Reist, Carl Sadowsky, Walter Martinez, Teresa Villena, Howard Rosen, Gad Marshall, Elaine R. Peskind, Eric C. Petrie, Gail Li
Journal: JAMA Neurology (2024)

Importance The lack of an in vivo measure for α-synuclein (α-syn) pathology until recently has limited thorough characterization of its brain atrophy pattern, especially during early disease stages. Objective To assess the association of state-of-the-art cerebrospinal fluid (CSF) seed amplification assays (SAA) α-syn positivity (SAA α-syn+) with magnetic resonance imaging (MRI) structural measures, across the continuum from clinically unimpaired (CU) to cognitively impaired (CI) individuals, in 3 independent cohorts, and separately in CU and CI individuals, the latter reflecting a memory clinic population. Design, Setting, and Participants Cross-sectional data were used from the Swedish BioFINDER-2 study (inclusion, 2017-2023) as the discovery cohort and the Swedish BioFINDER-1 study (inclusion, 2007-2015) and Alzheimer’s Disease Neuroimaging Initiative (ADNI; inclusion 2005-2022) as replication cohorts. All cohorts are from multicenter studies, but the BioFINDER cohorts used 1 MRI scanner. CU and CI individuals fulfilling inclusion criteria and without missing data points in relevant metrics were included in the study. All analyses were performed from 2023 to 2024. Exposures Presence of α-syn pathology, estimated by baseline CSF SAA α-syn. Main Outcomes and Measures The primary outcomes were cross-sectional structural MRI measures either through voxel-based morphometry (VBM) or regions of interest (ROI) including an automated pipeline for cholinergic basal forebrain nuclei CH4/4p (nucleus basalis of Meynert [NBM]) and CH1/2/3. Secondary outcomes were domain-specific cross-sectional cognitive measures. Analyses were adjusted for CSF biomarkers of Alzheimer pathology. Results A total of 2961 participants were included in this study: 1388 (mean [SD] age, 71 [10] years; 702 female [51%]) from the BioFINDER-2 study, 752 (mean [SD] age, 72 [6] years; 406 female [54%]) from the BioFINDER-1 study, and 821 (mean [SD] age, 75 [8] years; 449 male [55%]) from ADNI. In the BioFINDER-2 study, VBM analyses in the whole cohort revealed a specific association between SAA α-syn+ and the cholinergic NBM, even when adjusting for Alzheimer copathology. ROI-based analyses in the BioFINDER-2 study focused on regions involved in the cholinergic system and confirmed that SAA α-syn+ was indeed independently associated with smaller NBM (β = −0.271; 95% CI, −0.399 to −0.142; P &amp;amp;lt;.001) and CH1/2/3 volumes (β = −0.227; 95% CI, −0.377 to −0.076; P =.02). SAA α-syn+ was also independently associated with smaller NBM volumes in the separate CU (β = −0.360; 95% CI, −0.603 to −0.117; P =.03) and CI (β = −0.251; 95% CI, −0.408 to −0.095; P =.02) groups. Overall, the association between SAA α-syn+ and NBM volume was replicated in the BioFINDER-1 study and ADNI cohort. In CI individuals, NBM volumes partially mediated the association of SAA α-syn+ with attention/executive impairments in all cohorts (BioFINDER-2, β = −0.017; proportion-mediated effect, 7%; P =.04; BioFINDER-1, β = −0.096; proportion-mediated effect, 19%; P =.04; ADNI, β = −0.061; proportion-mediated effect, 20%; P =.007). Conclusions and Relevance In this cohort study, SAA α-syn+ was consistently associated with NBM atrophy already during asymptomatic stages. Further, in memory clinic CI populations, SAA α-syn+ was associated with NBM atrophy, which partially mediated α-syn–induced attention/executive impairment.