A deep learning framework identifies dimensional representations of Alzheimer’s Disease from brain structure
Authors: Yang Zhijian , Nasrallah Ilya M. , Shou Haochang , Wen Junhao , Doshi Jimit , Habes Mohamad , Erus Guray , Abdulkadir Ahmed , Resnick Susan M. , Albert Marilyn S. , Maruff Paul , Fripp Jurgen , Morris John C. , Wolk David A. , Davatzikos Christos ,   iSTAGING Consortium, Fan Yong , Bashyam Vishnu , Mamouiran Elizabeth , Melhem Randa , Pomponio Raymond , Sahoo Dushyant , Ashish Singh , Skampardoni Ioanna , Sreepada Lasya , Srinivasan Dhivya , Yu Fanyang , Tirumalai Sindhuja Govindarajan , Cui Yuhan , Zhou Zhen , Wittfeld Katharina , Grabe Hans J. , Tosun Duygun , Bilgel Murat , An Yang , Marcus Daniel S. , LaMontagne Pamela , Heckbert Susan R. , Austin Thomas R. , Launer Lenore J. , Sotiras Aristeidis , Espeland Mark , Masters Colin L. , Völzk Henry , Johnson Sterling C. , Ferrucci Luigi , Bryan R. Nick ,   Baltimore Longitudinal Study of Aging (BLSA),   Alzheimer’s Disease Neuroimaging Initiative (ADNI), Weiner Michael , Aisen Paul , Petersen Ronald , Jack Clifford R. , Jagust William , Trojanowki John Q. , Toga Arthur W. , Beckett Laurel , Green Robert C. , Saykin Andrew J. , Shaw Leslie M. , Liu Enchi , Montine Tom , Thomas Ronald G. , Donohue Michael , Walter Sarah , Gessert Devon , Sather Tamie , Jiminez Gus , Harvey Danielle , Bernstein Matthew , Fox Nick , Thompson Paul , Schuff Norbert , DeCArli Charles , Borowski Bret , Gunter Jeff , Senjem Matt , Vemuri Prashanthi , Jones David , Kantarci Kejal , Ward Chad , Koeppe Robert A. , Foster Norm , Reiman Eric M. , Chen Kewei , Mathis Chet , Landau Susan , Cairns Nigel J. , Householder Erin , Reinwald Lisa Taylor , Lee Virginia , Korecka Magdalena , Figurski Michal , Crawford Karen , Neu Scott , Foroud Tatiana M. , Potkin Steven , Shen Li , Kelley Faber , Kim Sungeun , Nho Kwangsik , Kachaturian Zaven , Frank Richard , Snyder Peter J. , Molchan Susan , Kaye Jeffrey , Quinn Joseph , Lind Betty , Carter Raina , Dolen Sara , Schneider Lon S. , Pawluczyk Sonia , Beccera Mauricio , Teodoro Liberty , Spann Bryan M. , Brewer James , Vanderswag Helen , Fleisher Adam , Heidebrink Judith L. , Lord Joanne L. , Mason Sara S. , Albers Colleen S. , Knopman David , Johnson Kris , Doody Rachelle S. , Meyer Javier Villanueva , Chowdhury Munir , Rountree Susan , Dang Mimi , Stern Yaakov , Honig Lawrence S. , Bell Karen L. , Ances Beau , Carroll Maria , Leon Sue , Householder Erin , Mintun Mark A. , Schneider Stacy , OliverNG Angela , Griffith Randall , Clark David , Geldmacher David , Brockington John , Roberson Erik , Grossman Hillel , Mitsis Effie , deToledo-Morrell Leyla , Shah Raj C. , Duara Ranjan , Varon Daniel , Greig Maria T. , Roberts Peggy , Albert Marilyn , Onyike Chiadi , D’Agostino Daniel , Kielb Stephanie , Galvin James E. , Pogorelec Dana M. , Cerbone Brittany , Michel Christina A. , Rusinek Henry , de Leon Mony J. , Glodzik Lidia , De Santi Susan , Doraiswamy P. Murali , Petrella Jeffrey R. , Wong Terence Z. , Arnold Steven E. , Karlawish Jason H. , Smith Charles D. , Jicha Greg , Hardy Peter , Sinha Partha , Oates Elizabeth , Conrad Gary , Lopez Oscar L. , Oakley MaryAnn , Simpson Donna M. , Porsteinsson Anton P. , Goldstein Bonnie S. , Martin Kim , Makino Kelly M. , Ismail M. Saleem , Brand Connie , Mulnard Ruth A. , Thai Gaby , Mc Adams Ortiz Catherine , Womack Kyle , Mathews Dana , Quiceno Mary , Arrastia Ramon Diaz , King Richard , Weiner Myron , Cook Kristen Martin , DeVous Michael , Levey Allan I. , Lah James J. , Cellar Janet S. , Burns Jeffrey M. , Anderson Heather S. , Swerdlow Russell H. , Apostolova Liana , Tingus Kathleen , Woo Ellen , Silverman Daniel H. S. , Lu Po H. , Bartzokis George , Radford Neill R. Graff , ParfittH Francine , Kendall Tracy , Johnson Heather , Farlow Martin R. , Hake Ann Marie , Matthews Brandy R. , Herring Scott , Hunt Cynthia , van Dyck Christopher H. , Carson Richard E. , MacAvoy Martha G. , Chertkow Howard , Bergman Howard , Hosein Chris , Black Sandra , Stefanovic Bojana , Caldwell Curtis , Hsiung Ging Yuek Robin , Feldman Howard , Mudge Benita , Past Michele Assaly , Kertesz Andrew , Rogers John , Trost Dick , Bernick Charles , Munic Donna , Kerwin Diana , Mesulam Marek Marsel , Lipowski Kristine , Wu Chuang Kuo , Johnson Nancy , Sadowsky Carl , Martinez Walter , Villena Teresa , Turner Raymond Scott , Johnson Kathleen , Reynolds Brigid , Sperling Reisa A. , Johnson Keith A. , Marshall Gad , Frey Meghan , Yesavage Jerome , Taylor Joy L. , Lane Barton , Rosen Allyson , Tinklenberg Jared , Sabbagh Marwan N. , Belden Christine M. , Jacobson Sandra A. , Sirrel Sherye A. , Kowall Neil , Killiany Ronald , Budson Andrew E. , Norbash Alexander , Johnson Patricia Lynn , Obisesan Thomas O. , Wolday Saba , Allard Joanne , Lerner Alan , Ogrocki Paula , Hudson Leon , Fletcher Evan , Carmichael Owen , Olichney John , DeCarli Charles , Kittur Smita , Borrie Michael , Lee T. Y. , Bartha Rob , Johnson Sterling , Asthana Sanjay , Carlsson Cynthia M. , Potkin Steven G. , Preda Adrian , Nguyen Dana , Tariot Pierre , Fleisher Adam , Reeder Stephanie , Bates Vernice , Capote Horacio , Rainka Michelle , Scharre Douglas W. , Kataki Maria , Adeli Anahita , Zimmerman Earl A. , Celmins Dzintra , Brown Alice D. , Pearlson Godfrey D. , Blank Karen , Anderson Karen , Santulli Robert B. , Kitzmiller Tamar J. , Schwartz Eben S. , SinkS Kaycee M. , Williamson Jeff D. , Garg Pradeep , Watkins Franklin , Ott Brian R. , Querfurth Henry , Tremont Geoffrey , Salloway Stephen , Malloy Paul , Correia Stephen , Rosen Howard J. , Miller Bruce L. , Mintzer Jacobo , Spicer Kenneth , Bachman David , Finger Elizabether , Pasternak Stephen , Rachinsky Irina , Rogers John , Kertesz Andrew , Drost Dick , Pomara Nunzio , Hernando Raymundo , Sarrael Antero , Schultz Susan K. , Ponto Laura L. Boles , Shim Hyungsub , Smith Karen Elizabeth , Relkin Norman , Chaing Gloria , Raudin Lisa , Smith Amanda , Fargher Kristin , Raj Balebail Ashok 
Published: December 2021

Heterogeneity of brain diseases is a challenge for precision diagnosis/prognosis. We describe and validate Smile-GAN (SeMI-supervised cLustEring-Generative Adversarial Network), a semi-supervised deep-clustering method, which examines neuroanatomical heterogeneity contrasted against normal brain structure, to identify disease subtypes through neuroimaging signatures. When applied to regional volumes derived from T1-weighted MRI (two studies; 2,832 participants; 8,146 scans) including cognitively normal individuals and those with cognitive impairment and dementia, Smile-GAN identified four patterns or axes of neurodegeneration. Applying this framework to longitudinal data revealed two distinct progression pathways. Measures of expression of these patterns predicted the pathway and rate of future neurodegeneration. Pattern expression offered complementary performance to amyloid/tau in predicting clinical progression. These deep-learning derived biomarkers offer potential for precision diagnostics and targeted clinical trial recruitment.