MRI Signature of α-Synuclein Pathology in Asymptomatic Stages and a Memory Clinic Population
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Published:2024-07-28
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ISSN:2168-6149
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Container-title:JAMA Neurology
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language:en
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Short-container-title:JAMA Neurol
Author:
Wisse Laura E. M.1, Spotorno Nicola2, Rossi Marcello3, Grothe Michel J.45, Mammana Angela3, Tideman Pontus26, Baiardi Simone7, Strandberg Olof2, Ticca Alice7, van Westen Danielle89, Mattsson-Carlgren Niklas21011, Palmqvist Sebastian26, Stomrud Erik26, Parchi Piero37, Hansson Oskar26, Weiner Michael W.12, Aisen Paul12, Petersen Ronald12, Jack Clifford R.12, Jagust William12, Trojanowki John Q.12, Toga Arthur W.12, Beckett Laurel12, Green Robert C.12, Saykin Andrew J.12, Morris John C.12, Perrin Richard J.12, Shaw Leslie M.12, Khachaturian Zaven12, Carrillo Maria12, Potter William12, Barnes Lisa12, Bernard Marie12, González Hector12, Ho Carole12, Hsiao John K.12, Jackson Jonathan12, Masliah Eliezer12, Masterman Donna12, Okonkwo Ozioma12, Ryan Laurie12, Silverberg Nina12, Fleisher Adam12, Sacrey Diana Truran12, Fockler Juliet12, Conti Cat12, Veitch Dallas12, Neuhaus John12, Jin Chengshi12, Nosheny Rachel12, Ashford Miriam12, Flenniken Derek12, Kormos Adrienne12, Montine Tom12, Rafii Michael12, Raman Rema12, Jimenez Gustavo12, Donohue Michael12, Gessert Devon12, Salazar Jennifer12, Zimmerman Caileigh12, Cabrera Yuliana12, Walter Sarah12, Miller Garrett12, Coker Godfrey12, Clanton Taylor12, Hergesheimer Lindsey12, Smith Stephanie12, Adegoke Olusegun12, Mahboubi Payam12, Moore Shelley12, Pizzola Jeremy12, Shaffer Elizabeth12, Sloan Brittany12, Harvey Danielle12, Forghanian-
Arani Arvin12, Borowski Bret12, Ward Chad12, Schwarz Christopher12, Jones David12, Gunter Jeff12, Kantarci Kejal12, Senjem Matthew12, Vemuri Prashanthi12, Reid Robert12, Fox Nick C.12, Malone Ian12, Thompson Paul12, Thomopoulos Sophia I.12, Nir Talia M.12, Jahanshad Neda12, DeCarli Charles12, Knaack Alexander12, Fletcher Evan12, Tosun-Turgut Duygu12, Chen Stephanie Rossi12, Choe Mark12, Crawford Karen12, Yushkevich Paul A.12, Das Sandhitsu12, Koeppe Robert A.12, Reiman Eric M.12, Chen Kewei12, Mathis Chet12, Landau Susan12, Cairns Nigel J.12, Householder Erin12, Franklin Erin12, Bernhardt Haley12, Taylor-
Reinwald Lisa12, Korecka Magdalena12, Figurski Michael12, Neu Scott12, Nho Kwangsik12, Risacher Shannon L.12, Apostolova Liana G.12, Shen Li12, Foroud Tatiana M.12, Nudelman Kelly12, Faber Kelley12, Wilmes Kristi12, Thal Leon12, Silbert Lisa C.12, Lind Betty12, Crissey Rachel12, Kaye Jeffrey A.12, Carter Raina12, Dolen Sara12, Quinn Joseph12, Schneider Lon S.12, Pawluczyk Sonia12, Becerra Mauricio12, Teodoro Liberty12, Dagerman Karen12, Spann Bryan M.12, Brewer James12, Vanderswag Helen12, Ziolkowski Jaimie12, Heidebrink Judith L.12, Zbizek-Nulph Lisa12, Lord Joanne L.12, Mason Sara S.12, Albers Colleen S.12, Knopman David12, Johnson Kris12, Villaneuva-
Meyer Javier12, Pavlik Valory12, Pacini Nathaniel12, Lamb Ashley12, Kass Joseph S.12, Doody Rachelle S.12, Shibley Victoria12, Chowdhury Munir12, Rountree Susan12, Dang Mimi12, Stern Yaakov12, Honig Lawrence S.12, Mintz Akiva12, Ances Beau12, Winkfield David12, Carroll Maria12, Stobbs-Cucchi Georgia12, Oliver Angela12, Creech Mary L.12, Mintun Mark A.12, Schneider Stacy12, Geldmacher David12, Love Marissa Natelson12, Griffith Randall12, Clark David12, Brockington John12, Marson Daniel12, Grossman Hillel12, Goldstein Martin A.12, Greenberg Jonathan12, Mitsis Effie12, Shah Raj C.12, Lamar Melissa12, Samuels Patricia12, Duara Ranjan12, Greig-Custo Maria T.12, Rodriguez Rosemarie12, Albert Marilyn12, Onyike Chiadi12, Farrington Leonie12, Rudow Scott12, Brichko Rottislav12, Kielb Stephanie12, Smith Amanda12, Raj Balebail Ashok12, Fargher Kristin12, Sadowski Martin12, Wisniewski Thomas12, Shulman Melanie12, Faustin Arline12, Rao Julia12, Castro Karen M.12, Ulysse Anaztasia12, Chen Shannon12, Sheikh Mohammed O.12, Singleton-
Garvin Jamika12, Doraiswamy P. Murali12, Petrella Jeffrey R.12, James Olga12, Wong Terence Z.12, Borges-Neto Salvador12, Karlawish Jason H.12, Wolk David A.12, Vaishnavi Sanjeev12, Clark Christopher M.12, Arnold Steven E.12, Smith Charles D.12, Jicha Gregory A.12, El Khouli Riham12, Raslau Flavius D.12, Lopez Oscar L.12, Oakley MaryAnn12, Simpson Donna M.12, Porsteinsson Anton P.12, Martin Kim12, Kowalski Nancy12, Keltz Melanie12, Goldstein Bonnie S.12, Makino Kelly M.12, Ismail M. Saleem12, Brand Connie12, Thai Gaby12, Pierce Aimee12, Yanez Beatriz12, Sosa Elizabeth12, Witbracht Megan12, Kelley Brendan12, Nguyen Trung12, Womack Kyle12, Mathews Dana12, Quiceno Mary12, Levey Allan I.12, Lah James J.12, Hajjar Ihab12, Cellar Janet S.12, Burns Jeffrey M.12, Swerdlow Russell H.12, Brooks William M.12, Silverman Daniel H.S.12, Kremen Sarah12, Tingus Kathleen12, Lu Po H.12, Bartzokis George12, Woo Ellen12, Teng Edmond12, Graff-Radford Neill R.12, Parfitt Francine12, Poki-Walker Kim12, Farlow Martin R.12, Hake Ann Marie12, Matthews Brandy R.12, Brosch Jared R.12, Herring Scott12, van Dyck Christopher H.12, Mecca Adam P.12, Good Susan P.12, MacAvoy Martha G.12, Carson Richard E.12, Varma Pradeep12, Chertkow Howard12, Vaitekunis Susan12, Hosein Chris12, Black Sandra12, Stefanovic Bojana12, Heyn Chris (Chinthaka)12, Hsiung Ging-Yuek Robin12, Kim Ellen12, Mudge Benita12, Sossi Vesna12, Feldman Howard12, Assaly Michele12, Finger Elizabeth12, Pasternak Stephen12, Rachinsky Irina12, Kertesz Andrew12, Drost Dick12, Rogers John12, Grant Ian12, Muse Brittanie12, Rogalski Emily12, Robson Jordan12, Mesulam M.-Marsel12, Kerwin Diana12, Wu Chuang-Kuo12, Johnson Nancy12, Lipowski Kristine12, Weintraub Sandra12, Bonakdarpour Borna12, Pomara Nunzio12, Hernando Raymundo12, Sarrael Antero12, Rosen Howard J.12, Miller Bruce L.12, Perry David12, Turner Raymond Scott12, Johnson Kathleen12, Reynolds Brigid12, MCCann Kelly12, Poe Jessica12, Sperling Reisa A.12, Johnson Keith A.12, Marshall Gad A.12, Yesavage Jerome12, Taylor Joy L.12, Chao Steven12, Coleman Jaila12, White Jessica D.12, Lane Barton12, Rosen Allyson12, Tinklenberg Jared12, Belden Christine M.12, Atri Alireza12, Clark Kelly A.12, Zamrini Edward12, Sabbagh Marwan12, Killiany Ronald12, Stern Robert12, Mez Jesse12, Kowall Neil12, Budson Andrew E.12, Obisesan Thomas O.12, Ntekim Oyonumo E.12, Wolday Saba12, Khan Javed I.12, Nwulia Evaristus12, Nadarajah Sheeba12, Lerner Alan12, Ogrocki Paula12, Tatsuoka Curtis12, Fatica Parianne12, Maillard Pauline12, Olichney John12, Carmichael Owen12, Bates Vernice12, Capote Horacio12, Rainka Michelle12, Borrie Michael12, Lee T-Y12, Bartha Rob12, Johnson Sterling12, Asthana Sanjay12, Carlsson Cynthia M.12, Perrin Allison12, Burke Anna12, Scharre Douglas W.12, Kataki Maria12, Tarawneh Rawan12, Hart David12, Zimmerman Earl A.12, Celmins Dzintra12, Miller Delwyn D.12, Boles Ponto Laura L.12, Smith Karen Ekstam12, Koleva Hristina12, Shim Hyungsub12, Nam Ki Won12, Schtulz Susan K.12, Williamson Jeff D.12, Craft Suzanne12, Cleveland Jo12, Yang Mia12, Sink Kaycee M.12, Ott Brian R.12, Drake Jonathan12, Tremont Geoffrey12, Daiello Lori A.12, Ritter Aaron12, Bernick Charles12, Munic Donna12, O'Connell Abigail12, Mintzer Jacobo12, Wiliams Arthur12, Masdeu Joseph12, Shi Jiong12, Garcia Angelica12, Newhouse Paul12, Potkin Steven12, Salloway Steven12, Malloy Paul12, Correia Stephen12, Kittur Smita12, Pearlson Godfrey D.12, Blank Karen12, Anderson Karen12, Flashman Laura A.12, Seltzer Marc12, Hynes Mary L.12, Santulli Robert B.12, Relkin Norman12, Chiang Gloria12, Lee Athena12, Lin Michael12, Ravdin Lisa12, Sood Ajay12, Blanchard Kimberly S.12, Fleischman Debra12, Arfanakis Konstantinos12, Varon Daniel12, Greig Maria T.12, Goldstein Bonnie12, Martin Kimberly S.12, Reist Christopher12, Sadowsky Carl12, Martinez Walter12, Villena Teresa12, Rosen Howard12, Marshall Gad12, Peskind Elaine R.12, Petrie Eric C.12, Li Gail12,
Affiliation:
1. Department of Clinical Science Lund, Lund University, Lund, Sweden 2. Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden 3. IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy 4. Reina Sofia Alzheimer Center, CIEN Foundation, Instituto de Salud Carlos III, Madrid, Spain 5. Centro de Investigacion Biomédica en Red Sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain 6. Memory Clinic, Skåne University Hospital, Malmö, Sweden 7. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy 8. Department of Diagnostic Radiology, Clinical Sciences, Lund University, Lund, Sweden 9. Image and Function, Skåne University Hospital, Lund, Sweden 10. Department of Neurology, Skåne University Hospital, Lund, Sweden 11. Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden 12. for the Alzheimer’s Disease Neuroimaging Initiative
Abstract
ImportanceThe 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.ObjectiveTo 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 ParticipantsCross-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.ExposuresPresence of α-syn pathology, estimated by baseline CSF SAA α-syn.Main Outcomes and MeasuresThe 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.ResultsA 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 <.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 RelevanceIn 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.
Publisher
American Medical Association (AMA)
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