Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease
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Published:2023-12-01
Issue:12
Volume:80
Page:1353
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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:
Shirzadi Zahra1, Schultz Stephanie A.1, Yau Wai-Ying W.1, Joseph-Mathurin Nelly2, Fitzpatrick Colleen D.1, Levin Raina1, Kantarci Kejal3, Preboske Gregory M.3, Jack Clifford R.3, Farlow Martin R.4, Hassenstab Jason2, Jucker Mathias56, Morris John C.2, Xiong Chengjie2, Karch Celeste M.2, Levey Allan I.7, Gordon Brian A.2, Schofield Peter R.89, Salloway Stephen P.10, Perrin Richard J.2, McDade Eric2, Levin Johannes11, Cruchaga Carlos2, Allegri Ricardo F.12, Fox Nick C.13, Goate Alison2, Day Gregory S.14, Koeppe Robert15, Chui Helena C.16, Berman Sarah17, Mori Hiroshi18, Sanchez-Valle Raquel19, Lee Jae-Hong20, Rosa-Neto Pedro21, Ruthirakuhan Myuri22, Wu Che-Yuan22, Swardfager Walter22, Benzinger Tammie L. S.2, Sohrabi Hamid R.23, Martins Ralph N.24, Bateman Randall J.2, Johnson Keith A.1, Sperling Reisa A.1, Greenberg Steven M.1, Schultz Aaron P.1, Chhatwal Jasmeer P.1, Weiner Michael W.25, Aisen Paul25, Petersen Ronald25, Jack Clifford R.25, Jagust William25, Trojanowki John Q.25, Toga Arthur W.25, Beckett Laurel25, Green Robert C.25, Saykin Andrew J.25, Morris John C.25, Perrin Richard J.25, Shaw Leslie M.25, Khachaturian Zaven25, Carrillo Maria25, Potter William25, Barnes Lisa25, Bernard Marie25, González Hector25, Ho Carole25, Hsiao John K.25, Jackson Jonathan25, Masliah Eliezer25, Masterman Donna25, Okonkwo Ozioma25, Ryan Laurie25, Silverberg Nina25, Fleisher Adam25, Sacrey Diana Truran25, Fockler Juliet25, Conti Cat25, Veitch Dallas25, Neuhaus John25, Jin Chengshi25, Nosheny Rachel25, Ashford Miriam25, Flenniken Derek25, Kormos Adrienne25, Montine Tom25, Rafii Michael25, Raman Rema25, Jimenez Gustavo25, Donohue Michael25, Gessert Devon25, Salazar Jennifer25, Zimmerman Caileigh25, Cabrera Yuliana25, Walter Sarah25, Miller Garrett25, Coker Godfrey25, Clanton Taylor25, Hergesheimer Lindsey25, Smith Stephanie25, Adegoke Olusegun25, Mahboubi Payam25, Moore Shelley25, Pizzola Jeremy25, Shaffer Elizabeth25, Sloan Brittany25, Harvey Danielle25, Forghanian-Arani Arvin25, Borowski Bret25, Ward Chad25, Schwarz Christopher25, Jones David25, Gunter Jeff25, Kantarci Kejal25, Senjem Matthew25, Vemuri Prashanthi25, Reid Robert25, Fox Nick C.25, Malone Ian25, Thompson Paul25, Thomopoulos Sophia I.25, Nir Talia M.25, Jahanshad Neda25, DeCarli Charles25, Knaack Alexander25, Fletcher Evan25, Tosun-Turgut Duygu25, Chen Stephanie Rossi25, Choe Mark25, Crawford Karen25, Yushkevich Paul A.25, Das Sandhitsu25, Koeppe Robert A.25, Reiman Eric M.25, Chen Kewei25, Mathis Chet25, Landau Susan25, Cairns Nigel J.25, Householder Erin25, Franklin Erin25, Bernhardt Haley25, Taylor-Reinwald Lisa25, Korecka Magdalena25, Figurski Michael25, Neu Scott25, Nho Kwangsik25, Risacher Shannon L.25, Apostolova Liana G.25, Shen Li25, Foroud Tatiana M.25, Nudelman Kelly25, Faber Kelley25, Wilmes Kristi25, Thal Leon25, Silbert Lisa C.25, Lind Betty25, Crissey Rachel25, Kaye Jeffrey A.25, Carter Raina25, Dolen Sara25, Quinn Joseph25, Schneider Lon S.25, Pawluczyk Sonia25, Becerra Mauricio25, Teodoro Liberty25, Dagerman Karen25, Spann Bryan M.25, Brewer James25, Vanderswag Helen25, Ziolkowski Jaimie25, Heidebrink Judith L.25, Zbizek-Nulph Lisa25, Lord Joanne L.25, Mason Sara S.25, Albers Colleen S.25, Knopman David25, Johnson Kris25, Villaneuva-Meyer Javier25, Pavlik Valory25, Pacini Nathaniel25, Lamb Ashley25, Kass Joseph S.25, Doody Rachelle S.25, Shibley Victoria25, Chowdhury Munir25, Rountree Susan25, Dang Mimi25, Stern Yaakov25, Honig Lawrence S.25, Mintz Akiva25, Ances Beau25, Winkfield David25, Carroll Maria25, Stobbs-Cucchi Georgia25, Oliver Angela25, Creech Mary L.25, Mintun Mark A.25, Schneider Stacy25, Geldmacher David25, Love Marissa Natelson25, Griffith Randall25, Clark David25, Brockington John25, Marson Daniel25, Grossman Hillel25, Goldstein Martin A.25, Greenberg Jonathan25, Mitsis Effie25, Shah Raj C.25, Lamar Melissa25, Samuels Patricia25, Duara Ranjan25, Greig-Custo Maria T.25, Rodriguez Rosemarie25, Albert Marilyn25, Onyike Chiadi25, Farrington Leonie25, Rudow Scott25, Brichko Rottislav25, Kielb Stephanie25, Smith Amanda25, Raj Balebail Ashok25, Fargher Kristin25, Sadowski Martin25, Wisniewski Thomas25, Shulman Melanie25, Faustin Arline25, Rao Julia25, Castro Karen M.25, Ulysse Anaztasia25, Chen Shannon25, Sheikh Mohammed O.25, Singleton-Garvin Jamika25, Doraiswamy P. Murali25, Petrella Jeffrey R.25, James Olga25, Wong Terence Z.25, Borges-Neto Salvador25, Karlawish Jason H.25, Wolk David A.25, Vaishnavi Sanjeev25, Clark Christopher M.25, Arnold Steven E.25, Smith Charles D.25, Jicha Gregory A.25, El Khouli Riham25, Raslau Flavius D.25, Lopez Oscar L.25, Oakley MaryAnn25, Simpson Donna M.25, Porsteinsson Anton P.25, Martin Kim25, Kowalski Nancy25, Keltz Melanie25, Goldstein Bonnie S.25, Makino Kelly M.25, Ismail M. Saleem25, Brand Connie25, Thai Gaby25, Pierce Aimee25, Yanez Beatriz25, Sosa Elizabeth25, Witbracht Megan25, Kelley Brendan25, Nguyen Trung25, Womack Kyle25, Mathews Dana25, Quiceno Mary25, Levey Allan I.25, Lah James J.25, Hajjar Ihab25, Cellar Janet S.25, Burns Jeffrey M.25, Swerdlow Russell H.25, Brooks William M.25, Silverman Daniel H.S.25, Kremen Sarah25, Tingus Kathleen25, Lu Po H.25, Bartzokis George25, Woo Ellen25, Teng Edmond25, Graff-Radford Neill R.25, Parfitt Francine25, Poki-Walker Kim25, Farlow Martin R.25, Hake Ann Marie25, Matthews Brandy R.25, Brosch Jared R.25, Herring Scott25, van Dyck Christopher H.25, Mecca Adam P.25, Good Susan P.25, MacAvoy Martha G.25, Carson Richard E.25, Varma Pradeep25, Chertkow Howard25, Vaitekunis Susan25, Hosein Chris25, Black Sandra25, Stefanovic Bojana25, Heyn Chris (Chinthaka)25, Hsiung Ging-Yuek Robin25, Kim Ellen25, Mudge Benita25, Sossi Vesna25, Feldman Howard25, Assaly Michele25, Finger Elizabeth25, Pasternak Stephen25, Rachinsky Irina25, Kertesz Andrew25, Drost Dick25, Rogers John25, Grant Ian25, Muse Brittanie25, Rogalski Emily25, Robson Jordan25, Mesulam M.-Marsel25, Kerwin Diana25, Wu Chuang-Kuo25, Johnson Nancy25, Lipowski Kristine25, Weintraub Sandra25, Bonakdarpour Borna25, Pomara Nunzio25, Hernando Raymundo25, Sarrael Antero25, Rosen Howard J.25, Miller Bruce L.25, Perry David25, Turner Raymond Scott25, Johnson Kathleen25, Reynolds Brigid25, MCCann Kelly25, Poe Jessica25, Sperling Reisa A.25, Johnson Keith A.25, Marshall Gad A.25, Yesavage Jerome25, Taylor Joy L.25, Chao Steven25, Coleman Jaila25, White Jessica D.25, Lane Barton25, Rosen Allyson25, Tinklenberg Jared25, Belden Christine M.25, Atri Alireza25, Clark Kelly A.25, Zamrini Edward25, Sabbagh Marwan25, Killiany Ronald25, Stern Robert25, Mez Jesse25, Kowall Neil25, Budson Andrew E.25, Obisesan Thomas O.25, Ntekim Oyonumo E.25, Wolday Saba25, Khan Javed I.25, Nwulia Evaristus25, Nadarajah Sheeba25, Lerner Alan25, Ogrocki Paula25, Tatsuoka Curtis25, Fatica Parianne25, Maillard Pauline25, Olichney John25, Carmichael Owen25, Bates Vernice25, Capote Horacio25, Rainka Michelle25, Borrie Michael25, Lee T-Y25, Bartha Rob25, Johnson Sterling25, Asthana Sanjay25, Carlsson Cynthia M.25, Perrin Allison25, Burke Anna25, Scharre Douglas W.25, Kataki Maria25, Tarawneh Rawan25, Hart David25, Zimmerman Earl A.25, Celmins Dzintra25, Miller Delwyn D.25, Boles Ponto Laura L.25, Smith Karen Ekstam25, Koleva Hristina25, Shim Hyungsub25, Nam Ki Won25, Schtulz Susan K.25, Williamson Jeff D.25, Craft Suzanne25, Cleveland Jo25, Yang Mia25, Sink Kaycee M.25, Ott Brian R.25, Drake Jonathan25, Tremont Geoffrey25, Daiello Lori A.25, Ritter Aaron25, Bernick Charles25, Munic Donna25, O'Connell Abigail25, Mintzer Jacobo25, Wiliams Arthur25, Masdeu Joseph25, Shi Jiong25, Garcia Angelica25, Newhouse Paul25, Potkin Steven25, Salloway Steven25, Malloy Paul25, Correia Stephen25, Kittur Smita25, Pearlson Godfrey D.25, Blank Karen25, Anderson Karen25, Flashman Laura A.25, Seltzer Marc25, Hynes Mary L.25, Santulli Robert B.25, Relkin Norman25, Chiang Gloria25, Lee Athena25, Lin Michael25, Ravdin Lisa25, Sood Ajay25, Blanchard Kimberly S.25, Fleischman Debra25, Arfanakis Konstantinos25, Varon Daniel25, Greig Maria T.25, Goldstein Bonnie25, Martin Kimberly S.25, Reist Christopher25, Sadowsky Carl25, Martinez Walter25, Villena Teresa25, Rosen Howard25, Marshall Gad25, Peskind Elaine R.25, Petrie Eric C.25, Li Gail25, Noble James M.25, Voglein Jonathan25, Chrem Mendez Patricio25, Surace Ezequiel25, Ikonomovic Snezana25, Nadkarni Neelesh K.25, Lopera Francisco25, Ramirez Laura25, Aguillon David25, Leon Yudy25, Ramos Claudia25, Alzate Diana25, Baena Ana25, Londono Natalia25, Moreno Sonia25, Laske Christoph25, Kuder-Buletta Elke25, Graber-Sultan Susanne25, Preische Oliver25, Hofmann Anna25, Ikeuchi Takeshi25, Kasuga Kensaku25, Niimi Yoshiki25, Ishii Kenji25, Senda Michio25, Cash Dave25, Roh Jee Hoon25, Riddle Meghan C.25, Menard William25, Bodge Courtney25, Surti Mustafa25, Takada Leonel Tadao25, Farlow Martin25, Sanchez-Gonzalez VJ25, Orozco-Barajas Maribel25, Renton Alan E.25, Esposito Bianca T.25, Karch Celeste M.25, Marsh Jacob25, Fernanadez Victoria25, Jerome Gina25, Herries Elizabeth25, Llibre-Guerra Jorge25, Johnson Erik C.B.25, Seyfried Nicholas T.25, Brooks William S.25, Bechara Jacob A25, Franklin Erin E.25, Chen Allison25, Chen Charles25, Flores Shaney25, Hantler Nancy25, Hornbeck Russ25, Jarman Steve25, Keefe Sarah25, Koudelis Deborah25, Massoumzadeh Parinaz25, McCullough Austin25, McKay Nicole25, Nicklaus Joyce25, Pulizos Christine25, Wang Qing25, Mishall Sheetal25, Sabaredzovic Edita25, Deng Emily25, Candela Madison25, Smith Hunter25, Hobbs Diana25, Scott Jalen25, Xiong Chengjie25, Wang Peter25, Xu Xiong25, Li Yan25, Gremminger Emily25, Ma Yinjiao25, Bui Ryan25, Lu Ruijin25, Martins Ralph25, Sosa Ortiz Ana Luisa25, Daniels Alisha25, Courtney Laura25, Mori Hiroshi25, Supnet-Bell, PhD (CSB) Charlene25, Xu Jinbin25, Ringman John25, Barthelemy Nicolas25, Smith Jennifer25,
Affiliation:
1. Massachusetts General Hospital, Brigham and Women’s Hospital, Harvard Medical School, Boston 2. Washington University in St Louis School of Medicine, St Louis, Missouri 3. Department of Radiology, Mayo Clinic, Rochester, Minnesota 4. Indiana Alzheimer’s Disease Research Center, Indianapolis 5. Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany 6. German Center for Neurodegenerative Diseases (DZNE), Tübingen, Tübingen, Germany 7. Emory University School of Medicine, Atlanta, Georgia 8. Neuroscience Research Australia, Sydney, New South Wales, Australia 9. School of Biomedical Sciences, University of New South Wales, Sydney, New South Wales, Australia 10. Alpert Medical School of Brown University, Providence, Rhode Island 11. Department of Neurology, Ludwig-Maximilians-Universität München, German Center for Neurodegenerative Diseases, site Munich, Munich Cluster for Systems Neurology, Munich, Germany 12. Fleni Neurological Institute, Buenos Aires, Argentina 13. UK Dementia Research Institute, University College London, London, United Kingdom 14. Department of Neurology, Mayo Clinic, Jacksonville, Florida 15. Department of Radiology, University of Michigan, Ann Arbor 16. Keck School of Medicine, University of Southern California, Los Angeles 17. Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania 18. Osaka Metropolitan University Medical School, Osaka, Nagaoka Sutoku University, Osaka City, Niigata, Japan 19. Neurological Tissue Bank Hospital Clinic, IDIBAPS, Barcelona, Spain 20. Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea 21. Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada 22. Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada 23. Centre for Healthy Ageing, School of Psychology, Health Future Institute, Murdoch University, Perth, Western Australia, Australia 24. School of Medical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia 25. for the Dominantly Inherited Alzheimer Network and the Alzheimer’s Disease Neuroimaging Initiative
Abstract
ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.
Publisher
American Medical Association (AMA)
Subject
Neurology (clinical)
Cited by
3 articles.
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