Anatomically interpretable deep learning of brain age captures domain-specific cognitive impairment

Authors: Chenzhong Yin, Phoebe Imms, Mingxi Cheng, Anar Amgalan, Nahian F. Chowdhury, Roy J Massett, Nikhil N. Chaudhari, Xinghe Chen, Paul M. Thompson, Paul Bogdan, Andrei Irimia, the Alzheimer’s Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Ronald Petersen, 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 S. Khachaturian, María C. Carrillo, William Z. Potter, Lisa L. Barnes, Marie Bernard, Héctor Alfredo Baptista González, Carole Ho, John K. Hsiao, Jonathan Jackson, Eliezer Masliah, Donna Masterman, Ozioma C. Okonkwo, Richard J. Perrin, Laurie Ryan, Nina Silverberg, Adam Fleisher, Eli Lilly, Michael W. Weiner, Diana Truran Sacrey, Juliet Fockler, Cat Conti, Dallas P. Veitch, John Neuhaus, Chengshi Jin, Rachel L. Nosheny, Miriam T. Ashford, Derek Flenniken, Adrienne Kormos, Robert C. Green, Tom Montine, Cat Conti, Ronald Petersen, Paul Aisen, Michael S. Rafii, Rema Raman, Gustavo Jiménez, 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, Laurel Beckett, Danielle Harvey, Michael Donohue, Clifford R. Jack, Arvin Forghanian-Arani, Bret Borowski, Chad Ward, Christopher G. Schwarz, David Jones, Jeff Gunter, Kejal Kantarci, Matthew L. Senjem, Prashanthi Vemuri, Robert I. Reid, Nick C. Fox, Ian B. Malone, Paul M. Thompson, Sophia I. Thomopoulos, Talia M. Nir, Neda Jahanshad, Charles DeCarli, Alexander Knaack, Evan Fletcher, Danielle Harvey, Duygu Tosun, Stephanie Rossi Chen, Mark Choe, Karen Crawford, Paul A. Yushkevich, Sandhitsu R. Das, William Jagust, Robert A. Koeppe, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C. Morris, Richard J. Perrin, Nigel J. Cairns, Erin Householder, Erin Franklin, Haley Bernhardt, Lisa Taylor‐Reinwald, Leslie M. Shaw, John Q. Trojanowki, Magdalena Korecka, Michal Figurski, Arthur W. Toga, Karen Crawford, Scott Neu, Andrew J. Saykin, Kwangsik Nho, Shannon L. Risacher, Liana G. Apostolova, Li Shen, Tatiana M. Foroud, Kelly Nudelman, Kelley Faber, Kristi Wilmes, Michael W. Weiner, Leon J. Thal, Zaven S. Khachaturian, John K. Hsiao, Lisa C. Silbert, Betty Lind, Rachel Crissey, Jeffrey Kaye, Raina Carter, Sara Dolen, Joseph F. Quinn, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Karen Dagerman, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Jaimie Ziolkowski, Judith L. Heidebrink, Lisa Zbizek-Nulph, Joanne Lord, Lisa Zbizek-Nulph, Ronald Petersen, Sara S. Mason, Colleen S. Albers, David S. Knopman, Kris Johnson, Javier Villanueva-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 M. Ances, John C. Morris, 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 Goldstein, Jonathan Greenberg, Effie Mitsis, Raj C. Shah, Melissa Lamar, Patricia Samuels, Ranjan Duara, Maria T. Greig‐Custo, Rosemarie Rodriguez, Marilyn Albert, Chiadi U. Onyike, Leonie Farrington, Scott Rudow, Rottislav Brichko, Stephanie Kielb, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Martin Sadowski, Thomas Wısnıewskı, 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 Karlawish, S. J. Wolk, Sanjeev Vaishnavi, Christopher M. Clark, Steven E. Arnold, Charles D. Smith, Gregory A. Jicha, Riham El Khouli, Flavius D. Raslau, Oscar L. López, 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 Yáñez‐Rivera, Elizabeth Sosa, Megan Witbracht, Brendan Kelley, Trung Dung 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 Silverman, Sarah Kremen, Liana G. Apostolova, 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, Martha G. MacAvoy, Richard E. Carson, Pradeep Varma, Howard Chertkow, Susan Vaitekunis, Chris Hosein, Sandra E. Black, Bojana Stefanovic, Chris 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 Rogalskı, Jordan Robson, M.‐Marsel Mesulam, Diana Kerwin, Chuang‐Kuo Wu, Nancy Johnson, Kristine Lipowski, Sandra Weıntraub, Borna Bonakdarpour, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Howard J. Rosen, Bruce L. Miller, David C. 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, Bryan M. Spann, Kelly A. Clark, Edward Zamrini, Marwan Sabbagh, Ronald Killiany, Robert A. Stern, Jesse Mez, Neil W. Kowall, Andrew E. Budson, Thomas O. Obisesan, Oyonumo Ntekim, Saba Wolday, Javed Khan, Evaristus Nwulia, Sheeba Nadarajah, Alan J. Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Vernice Bates, Horacio Capote, Michelle Rainka, Michael Borrie, T‐Y Lee, Dr Rob Bartha, Sterling C. Johnson, Sanjay Asthana, Cynthia M. Carlsson, Allison Perrin, Anna Burke, Douglas W. Scharre, Maria Kataki, Rawan Tarawneh, Brendan Kelley, David Hart, Earl A. Zimmerman, Dzintra Celmins, Del D. Miller, Laura L. Boles Ponto, Karen Ekstam Smith, Hristina Koleva, Hyungsub Shim, Ki Won Nam, Susan K. Schultz, Jeff D. Williamson, Suzanne Craft, Jo Cleveland, Mia Yang, Kaycee M. Sink, Brian R. Ott, Jonathan Drake, Geoffrey Tremont, Lori A. Daiello, Jonathan Drake, Marwan Sabbagh, Aaron Ritter, Charles Bernick, Donna Munic, Akiva Mintz, Abigail O’Connelll, Jacobo Mintzer, Arthur Wiliams, Joseph C. Masdeu, Jiong Shi, Angelica Garcia, Marwan Sabbagh, Paul Newhouse, Steven G. Potkin, Stephen 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 Z. Lin, Lisa Ravdin, Michael W. Weiner, Paul Aisen, Ron Petersen, Michael W. Weiner, Paul Aisen, Ronald Petersen, Robert C. Green, Danielle Harvey, Clifford R. Jack, William Jagust, John C. Morris, Andrew J. Saykin, Leslie M. Shaw, Arthur W. Toga, John Q. Trojanowki, Thomas Neylan, Jordan Grafman, Robert C. Green, Tom Montine, Paul Aisen, Gustavo Jiménez, Michael Donohue, Devon Gessert, Jennifer Salazar, Caileigh Zimmerman, Sarah Walter, Olusegun Adegoke, Payam Mahboubi, Sarah Danowski, Godfrey Coker, Taylor Clanton, Jeremy Pizzola, Elizabeth Shaffer, Catherine Nguyen-Barrera, Thomas Neylan, Jacqueline Hayes, Shannon Finley, Danielle Harvey, Michael Donohue, Clifford R. Jack, Matthew Bernstein, Bret Borowski, Jeff Gunter, Matthew L. Senjem, Kejal Kantarci, Chad Ward, Duygu Tosun, Stephanie Rossi Chen, Susan Landau, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, John C. Morris, Richard J. Perrin, Erin Franklin, Leslie M. Shaw, John Q. Trojanowki, Magdalena Korecka, Michal Figurski, Arthur W. Toga, Karen Crawford, Scott Neu, Andrew J. Saykin, Tatiana M. Foroud, Steven G. Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Kristi Wilmes, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Karen Dagerman, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Yaakov Stern, Lawrence S. Honig, Akiva Mintz, Raj C. Shah, Ajay Sood, Kimberly S. Blanchard, Debra Fleischman, Konstantinos Arfanakis, Ranjan Duara, Daniel Varón, Maria T. Greig, P. Murali Doraiswamy, Jeffrey R. Petrella, Olga James, Salvador Borges‐Neto, Terence Z. Wong, Anton P. Porsteinsson, Kimberly S. Martin, Gaby Thai, Aimee Pierce, Christopher Reist, Beatriz Yáñez‐Rivera, Elizabeth Sosa, Megan Witbracht, Carl Sadowsky, Walter Martínez, Teresa Villena, Howard Rosen, David C. Perry, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Kelly McCann, Jessica Poe, Reisa A. Sperling, Keith A. Johnson, Gad A. Marshall, Christine M. Belden, Bryan M. Spann, Kelly A. Clark, Edward Zamrini, Marwan Sabbagh, Thomas O. Obisesan, Oyonumo Ntekim, Evaristus Nwulia, Sheeba Nadarajah, Sanjay Asthana, Cynthia M. Carlsson, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome Yesavage, Joy L. Taylor, Steven Chao, Jaila Coleman, Jessica D. White, Barton Lane, Allyson Rosen, Jared Tinklenberg, Michael Z. Lin, Gloria Chiang, Lisa Ravdin, Norman Relkin, Abigail O’Connelll, Jacobo Mintzer, Arthur Wiliams, Scott Mackin, Paul Aisen, Rema Raman, Gustavo Jimenez‐Maggiora, Michael Donohue, Devon Gessert, Jennifer Salazar, Caileigh Zimmerman, Sarah Walter, Olusegun Adegoke, Payam Mahboubi, Scott Mackin, Michael W. Weiner, Paul Aisen, Rema Raman, Clifford R. Jack, Susan Landau, Andrew J. Saykin, Arthur W. Toga, Charles DeCarli, Robert A. Koeppe, Robert C. Green, Erin Drake, Michael W. Weiner, Paul Aisen, Rema Raman, Mike Donohue, Scott Mackin, Craig Nelson, David Bickford, Meryl A. Butters, Michelle Zmuda, Clifford R. Jack, Matthew Bernstein, Bret Borowski, Jeff Gunter, Matthew L. Senjem, Kejal Kantarci, Chad Ward, Denise Reyes, Robert A. Koeppe, Susan Landau, Arthur W. Toga, Karen Crawford, Scott Neu, Andrew J. Saykin, Tatiana Foroud, Kelley Faber, Kwangsik Nho, Kelly Nudelman, Scott Mackin, Howard Rosen, Craig Nelson, David Bickford, Yiu Ho Au, Kelly Scherer, Daniel Catalinotto, Samuel Stark, Elise Ong, Dariella Fernandez, Meryl A. Butters, Michelle Zmuda, Oscar L. López, MaryAnn Oakley, Donna M. Simpson - Proceedings of the National Academy of Sciences, PNAS 2023 cited by 120

The gap between chronological age (CA) and biological brain age, as estimated from magnetic resonance images (MRIs), reflects how individual patterns of neuroanatomic aging deviate from their typical trajectories. MRI-derived brain age (BA) estimates are often obtained using deep learning models that may perform relatively poorly on new data or that lack neuroanatomic interpretability. This study introduces a convolutional neural network (CNN) to estimate BA after training on the MRIs of 4,681 cognitively normal (CN) participants and testing on 1,170 CN participants from an independent sample. BA estimation errors are notably lower than those of previous studies. At both individual and cohort levels, the CNN provides detailed anatomic maps of brain aging patterns that reveal sex dimorphisms and neurocognitive trajectories in adults with mild cognitive impairment (MCI, N = 351) and Alzheimer’s disease (AD, N = 359). In individuals with MCI (54% of whom were diagnosed with dementia within 10.9 y from MRI acquisition), BA is significantly better than CA in capturing dementia symptom severity, functional disability, and executive function. Profiles of sex dimorphism and lateralization in brain aging also map onto patterns of neuroanatomic change that reflect cognitive decline. Significant associations between BA and neurocognitive measures suggest that the proposed framework can map, systematically, the relationship between aging-related neuroanatomy changes in CN individuals and in participants with MCI or AD. Early identification of such neuroanatomy changes can help to screen individuals according to their AD risk.