Abstract

Alzheimer’s disease (AD) is defined by amyloid (A) and tau (T) pathologies, with T better correlated to neurodegeneration (N). However, T and N have complex regional relationships in part related to non-AD factors that influence N. With machine learning, we assessed heterogeneity in 18F-flortaucipir vs. 18F-fluorodeoxyglucose positron emission tomography as markers of T and neuronal hypometabolism (NM) in 289 symptomatic patients from the Alzheimer’s Disease Neuroimaging Initiative. We identified six T/NM clusters with differing limbic and cortical patterns. The canonical group was defined as the T/NM pattern with lowest regression residuals. Groups resilient to T had less hypometabolism than expected relative to T and displayed better cognition than the canonical group. Groups susceptible to T had more hypometabolism than expected given T and exhibited worse cognitive decline, with imaging and clinical measures concordant with non-AD copathologies. Together, T/NM mismatch reveals distinct imaging signatures with pathobiological and prognostic implications for AD.

In Alzheimer’s disease (AD) tau and neurodegeneration have complex regional relationships. Here, the authors show neuronal hypometabolism discordant with tau burden defines functional resilience or susceptibility to Alzheimer’s pathology via limbic/cortical axes. Susceptible groups have faster cognitive decline and evidence of non-Alzheimer’s pathologies.

Details

Title
Dissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease
Author
Duong Michael Tran 1   VIAFID ORCID Logo  ; Das, Sandhitsu R 2 ; Lyu Xueying 3 ; Xie, Long 4 ; Richardson, Hayley 5 ; Xie, Sharon X 6 ; Yushkevich, Paul A 7 ; Weiner, Michael 8 ; Aisen, Paul 9 ; Petersen, Ronald 10 ; Jack, Clifford R, Jr 10 ; Jagust, William 11 ; Trojanowki, John Q 12 ; Toga, Arthur W 13 ; Beckett, Laurel 14 ; Green, Robert C 15 ; Saykin, Andrew J 16 ; Morris, John C 17 ; Shaw, Leslie M 12 ; Liu Enchi 18 ; Montine, Tom 19 ; Thomas, Ronald G 9 ; Donohue, Michael 9 ; Walter, Sarah 9 ; Gessert Devon 9 ; Sather Tamie 9 ; Jimenez-Maggiora, Gustavo 9 ; Harvey, Danielle 14 ; Bernstein, Matthew 10 ; Fox, Nick 20 ; Thompson, Paul 13 ; Schuff Norbert 8 ; DeCarli, Charles 14 ; Borowski Bret 10 ; Gunter, Jeff 10 ; Senjem Matt 10 ; Vemuri Prashanthi 10 ; Jones, David 10 ; Kantarci Kejal 10 ; Ward, Chad 10 ; Koeppe, Robert A 21 ; Foster, Norm 22 ; Reiman, Eric M 23 ; Chen, Kewei 23 ; Mathis, Chet 24 ; Landau, Susan 11 ; Cairns, Nigel J 17 ; Householder, Erin 25 ; Taylor-Reinwald, Lisa 17 ; Lee, Virginia M-Y 12 ; Korecka Magdalena 12 ; Figurski Michal 26 ; Crawford, Karen 13 ; Neu, Scott 13 ; Foroud, Tatiana M 16 ; Shen, Li 27 ; Faber, Kelley 16 ; Kim, Sungeun 16 ; Nho Kwangsik 16 ; Khachaturian Zaven 28 ; Frank, Richard 29 ; Snyder, Peter J 30 ; Molchan, Susan 31 ; Kaye, Jeffrey 32 ; Quinn, Joseph 32 ; Lind, Betty 32 ; Carter, Raina 32 ; Dolen, Sara 32 ; Schneider, Lon S 13 ; Pawluczyk Sonia 13 ; Beccera Mauricio 13 ; Liberty, Teodoro 13 ; Spann, Bryan M 13 ; Brewer, James 30 ; Vanderswag Helen 30 ; Fleisher, Adam 33 ; Heidebrink, Judith L 21 ; Lord, Joanne L 21 ; Mason, Sara S 10 ; Albers, Colleen S 10 ; Knopman, David 10 ; Johnson, Kris 10 ; Doody, Rachelle S 34 ; Villanueva-Meyer, Javier 34 ; Chowdhury Munir 34 ; Rountree, Susan 34 ; Dang, Mimi 34 ; Stern, Yaakov 35 ; Honig, Lawrence S 35 ; Bell, Karen L 35 ; Ances Beau 17 ; Carroll, Maria 17 ; Leon, Sue 17 ; Mintun Mark A 17 ; Schneider, Stacy 17 ; Oliver, Angela 36 ; Griffith, Randall 36 ; Clark, David 36 ; Geldmacher, David 36 ; Brockington, John 36 ; Roberson, Erik 36 ; Grossman, Hillel 37 ; Mitsis Effie 37 ; deToledo-Morrell Leyla 38 ; Shah, Raj C 38 ; Duara Ranjan 39 ; Varon, Daniel 39 ; Greig, Maria T 39 ; Roberts, Peggy 39 ; Albert, Marilyn 40 ; Onyike Chiadi 40 ; D’Agostino Daniel II 40 ; Kielb, Stephanie 40 ; Galvin, James E 41 ; Pogorelec, Dana M 41 ; Cerbone Brittany 41 ; Michel, Christina A 41 ; Rusinek, Henry 41 ; de Leon Mony J 41 ; Glodzik Lidia 41 ; De, Santi Susan 41 ; Murali, Doraiswamy P 42 ; Petrella, Jeffrey R 42 ; Wong, Terence Z 42 ; Clark, Christopher M 12 ; Arnold, Steven E 43 ; Karlawish, Jason H 12 ; Wolk, David A 44 ; Smith, Charles D 45 ; Jicha, Gregory 45 ; Hardy, Peter 45 ; Sinha Partha 45 ; Oates, Elizabeth 45 ; Conrad, Gary 45 ; Lopez, Oscar L 24 ; Oakley, MaryAnn 24 ; Simpson, Donna M 24 ; Porsteinsson, Anton P 46 ; Goldstein, Bonnie S 46 ; Kim, Martin 46 ; Makino, Kelly M 46 ; Saleem, Ismail M 46 ; Brand, Connie 46 ; Mulnard, Ruth A 47 ; Thai Gaby 47 ; McAdams-Ortiz, Catherine 47 ; Womack, Kyle 48 ; Mathews, Dana 48 ; Quiceno, Mary 48 ; Diaz-Arrastia, Ramon 49 ; King, Richard 48 ; Weiner, Myron 48 ; Cook, Kristen Martin 48 ; Devous, Michael 48 ; Levey, Allan I 50 ; Lah, James J 50 ; Cellar, Janet S 50 ; Burns, Jeffrey M 51 ; Anderson, Heather S 51 ; Swerdlow, Russell H 51 ; Apostolova Liana 26 ; Tingus Kathleen 26 ; Woo, Ellen 26 ; Silverman, Daniel H, S 26 ; Lu, Po H 26 ; Bartzokis, George 26 ; Graff-Radford, Neill R 52 ; Parfitt, Francine 52 ; Kendall, Tracy 52 ; Johnson, Heather 52 ; Farlow, Martin R 16 ; Hake, Ann Marie 16 ; Matthews, Brandy R 16 ; Herring, Scott 16 ; Hunt, Cynthia 16 ; van Dyck Christopher H 53 ; Carson, Richard E 53 ; MacAvoy, Martha G 53 ; Chertkow Howard 54 ; Bergman, Howard 54 ; Hosein, Chris 54 ; Black, Sandra 55 ; Stefanovic Bojana 55 ; Caldwell, Curtis 55 ; Hsiung, Ging-Yuek Robin 56 ; Feldman, Howard 56 ; Mudge Benita 56 ; Assaly Michele 56 ; Kertesz, Andrew 57 ; Rogers, John 58 ; Bernick, Charles 59 ; Munic Donna 59 ; Kerwin, Diana 60 ; Mesulam Marek Marsel 60 ; Lipowski Kristine 60 ; Chuang-Kuo, Wu 60 ; Johnson, Nancy 60 ; Sadowsky, Carl 61 ; Martinez, Walter 61 ; Villena, Teresa 61 ; Turner, Raymond Scott 62 ; Johnson, Kathleen 62 ; Reynolds, Brigid 62 ; Sperling, Reisa A 15 ; Johnson, Keith A 15 ; Marshall, Gad 15 ; Frey, Meghan 15 ; Yesavage Jerome 63 ; Taylor, Joy L 63 ; Lane, Barton 63 ; Rosen, Allyson 63 ; Tinklenberg Jared 63 ; Sabbagh, Marwan N 64 ; Belden, Christine M 64 ; Jacobson, Sandra A 64 ; Sirrel, Sherye A 64 ; Kowall, Neil 65 ; Killiany, Ronald 65 ; Budson, Andrew E 65 ; Norbash, Alexander 65 ; Johnson, Patricia Lynn 65 ; Obisesan, Thomas O 66 ; Wolday Saba 66 ; Allard, Joanne 66 ; Lerner, Alan 67 ; Ogrocki Paula 67 ; Hudson, Leon 67 ; Fletcher, Evan 68 ; Carmichael, Owen 68 ; Olichney, John 68 ; Kittur Smita 69 ; Borrie, Michael 70 ; T-Y, Lee 70 ; Bartha, Rob 70 ; Johnson, Sterling 71 ; Asthana Sanjay 71 ; Carlsson, Cynthia M 71 ; Potkin, Steven G 72 ; Preda, Adrian 72 ; Nguyen, Dana 72 ; Tariot Pierre 23 ; Reeder, Stephanie 23 ; Bates Vernice 73 ; Capote Horacio 73 ; Rainka Michelle 73 ; Scharre, Douglas W 74 ; Kataki, Maria 74 ; Adeli Anahita 74 ; Zimmerman, Earl A 75 ; Celmins Dzintra 75 ; Brown, Alice D 75 ; Pearlson, Godfrey D 76 ; Blank, Karen 76 ; Anderson, Karen 76 ; Santulli, Robert B 77 ; Kitzmiller, Tamar J 77 ; Schwartz, Eben S 77 ; Sink, Kaycee M 78 ; Williamson, Jeff D 78 ; Garg Pradeep 78 ; Watkins, Franklin 78 ; Ott, Brian R 79 ; Querfurth, Henry 79 ; Tremont, Geoffrey 79 ; Salloway, Stephen 80 ; Malloy, Paul 81 ; Correia, Stephen 81 ; Rosen, Howard J 8 ; Miller, Bruce L 8 ; Mintzer Jacobo 82 ; Spicer, Kenneth 82 ; Bachman, David 82 ; Finger Elizabether 83 ; Pasternak, Stephen 83 ; Rachinsky Irina 83 ; Drost, Dick 83 ; Pomara Nunzio 84 ; Hernando Raymundo 84 ; Sarrael Antero 84 ; Schultz, Susan K 85 ; Boles Ponto Laura L 85 ; Shim Hyungsub 85 ; Smith, Karen Ekstam 85 ; Relkin, Norman 86 ; Chiang, Gloria 86 ; Ravdin, Lisa 86 ; Smith, Amanda 87 ; Fargher, Kristin 87 ; Ashok, Raj Balebail 87 ; Nasrallah, Ilya M 7   VIAFID ORCID Logo 

1  University of Pennsylvania, Department of Radiology, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Department of Bioengineering, School of Engineering and Applied Sciences, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
2  University of Pennsylvania, Department of Neurology, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Alzheimer’s Disease Research Center, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
3  University of Pennsylvania, Department of Bioengineering, School of Engineering and Applied Sciences, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
4  University of Pennsylvania, Department of Radiology, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
5  University of Pennsylvania, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
6  University of Pennsylvania, Alzheimer’s Disease Research Center, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
7  University of Pennsylvania, Department of Radiology, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Department of Bioengineering, School of Engineering and Applied Sciences, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Alzheimer’s Disease Research Center, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
8  University of California San Francisco, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
9  University of California San Diego, San Diego, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
10  Mayo Clinic, Rochester, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X) 
11  University of California Berkeley, Berkeley, USA (GRID:grid.47840.3f) (ISNI:0000 0001 2181 7878) 
12  University of Pennsylvania, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
13  University of Southern California, Los Angeles, USA (GRID:grid.42505.36) (ISNI:0000 0001 2156 6853) 
14  University of California Davis, Davis, USA (GRID:grid.27860.3b) (ISNI:0000 0004 1936 9684) 
15  Brigham and Women’s Hospital, Harvard Medical School, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
16  Indiana University, Bloomington, USA (GRID:grid.411377.7) (ISNI:0000 0001 0790 959X) 
17  Washington University St. Louis, St. Louis, USA (GRID:grid.4367.6) (ISNI:0000 0001 2355 7002) 
18  Janssen Alzheimer Immunotherapy, South San Francisco, USA (GRID:grid.25879.31) 
19  University of Washington, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657) 
20  University of London, London, UK (GRID:grid.4464.2) (ISNI:0000 0001 2161 2573) 
21  University of Michigan, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
22  University of Utah, Salt Lake City, USA (GRID:grid.223827.e) (ISNI:0000 0001 2193 0096) 
23  Banner Alzheimer’s Institute, Phoenix, USA (GRID:grid.418204.b) (ISNI:0000 0004 0406 4925) 
24  University of Pittsburgh, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
25  University of Southern California, Los Angeles, USA (GRID:grid.42505.36) (ISNI:0000 0001 2156 6853); Washington University St. Louis, St. Louis, USA (GRID:grid.4367.6) (ISNI:0000 0001 2355 7002) 
26  University of California, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
27  University of Pennsylvania, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); Indiana University, Bloomington, USA (GRID:grid.411377.7) (ISNI:0000 0001 0790 959X) 
28  Khachaturian, Radebaugh & Associates, Inc and Alzheimer’s Association’s Ronald and Nancy Reagan’s Research Institute, Chicago, USA (GRID:grid.411377.7) 
29  General Electric, Boston, USA (GRID:grid.418143.b) (ISNI:0000 0001 0943 0267) 
30  Brown University, Providence, USA (GRID:grid.40263.33) (ISNI:0000 0004 1936 9094) 
31  National Institute on Aging/National Institutes of Health, Bethesda, USA (GRID:grid.419475.a) (ISNI:0000 0000 9372 4913) 
32  Oregon Health and Science University, Portland, USA (GRID:grid.5288.7) (ISNI:0000 0000 9758 5690) 
33  Banner Alzheimer’s Institute, Phoenix, USA (GRID:grid.418204.b) (ISNI:0000 0004 0406 4925); Brown University, Providence, USA (GRID:grid.40263.33) (ISNI:0000 0004 1936 9094) 
34  Baylor College of Medicine, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X) 
35  Columbia University Medical Center, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675) 
36  University of Alabama Birmingham, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000000106344187) 
37  Mount Sinai School of Medicine, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
38  Rush University Medical Center, Chicago, USA (GRID:grid.240684.c) (ISNI:0000 0001 0705 3621) 
39  Wien Center, Vienna, Austria (GRID:grid.240684.c) 
40  Johns Hopkins University, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
41  New York University, New York, USA (GRID:grid.137628.9) (ISNI:0000 0004 1936 8753) 
42  Duke University Medical Center, Durham, USA (GRID:grid.189509.c) (ISNI:0000000100241216) 
43  University of Pennsylvania, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); Massachusetts General Hospital, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
44  University of Pennsylvania, Department of Bioengineering, School of Engineering and Applied Sciences, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Alzheimer’s Disease Research Center, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
45  University of Kentucky, Lexington, USA (GRID:grid.266539.d) (ISNI:0000 0004 1936 8438) 
46  University of Rochester Medical Center, Rochester, USA (GRID:grid.412750.5) (ISNI:0000 0004 1936 9166) 
47  University of California, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243) 
48  University of Texas Southwestern Medical School, Dallas, USA (GRID:grid.267313.2) (ISNI:0000 0000 9482 7121) 
49  University of Pennsylvania, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Texas Southwestern Medical School, Dallas, USA (GRID:grid.267313.2) (ISNI:0000 0000 9482 7121) 
50  Emory University, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502) 
51  University of Kansas, Medical Center, Lawrence, USA (GRID:grid.412016.0) (ISNI:0000 0001 2177 6375) 
52  Mayo Clinic, Jacksonville, USA (GRID:grid.417467.7) (ISNI:0000 0004 0443 9942) 
53  Yale University School of Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
54  McGill University, Montreal Jewish General Hospital, Montreal, USA (GRID:grid.47100.32) 
55  Sunnybrook Health Sciences, Toronto, Canada (GRID:grid.413104.3) (ISNI:0000 0000 9743 1587) 
56  University of British Columbia Clinic for AD and Related Disorders, British Columbia, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830) 
57  Cognitive Neurology St. Joseph’s, Toronto, Canada (GRID:grid.17091.3e); St. Joseph’s Health Care, Toronto, Canada (GRID:grid.416448.b) (ISNI:0000 0000 9674 4717) 
58  Cognitive Neurology St. Joseph’s, Toronto, Canada (GRID:grid.416448.b); St. Joseph’s Health Care, Toronto, Canada (GRID:grid.416448.b) (ISNI:0000 0000 9674 4717) 
59  Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, USA (GRID:grid.239578.2) (ISNI:0000 0001 0675 4725) 
60  Northwestern University, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507) 
61  Premiere Research Institute Palm Beach Neurology, West Palm Beach, USA (GRID:grid.477769.c) 
62  Georgetown University Medical Center, Washington, USA (GRID:grid.411667.3) (ISNI:0000 0001 2186 0438) 
63  Stanford University, Santa Clara County, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
64  Banner Sun Health Research Institute, Sun City, USA (GRID:grid.414208.b) (ISNI:0000 0004 0619 8759) 
65  Boston University, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558) 
66  Howard University, Washington, USA (GRID:grid.257127.4) (ISNI:0000 0001 0547 4545) 
67  Case Western Reserve University, Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847) 
68  University of California, Davis, Sacramento, USA (GRID:grid.27860.3b) (ISNI:0000 0004 1936 9684) 
69  Neurological Care of CNY, New York, USA (GRID:grid.27860.3b) 
70  Parkwood Hospital, Parkwood, USA (GRID:grid.27860.3b) 
71  University of Wisconsin, Madison, USA (GRID:grid.28803.31) (ISNI:0000 0001 0701 8607) 
72  University of California, Irvine BIC, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243) 
73  Dent Neurologic Institute, Amherst, USA (GRID:grid.417854.b) 
74  Ohio State University, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943) 
75  Albany Medical College, Albany, USA (GRID:grid.413558.e) (ISNI:0000 0001 0427 8745) 
76  Hartford Hospital, Olin Neuropsychiatry Research Center, Hartford, USA (GRID:grid.277313.3) (ISNI:0000 0001 0626 2712) 
77  Dartmouth Hitchcock Medical Center, Albany, USA (GRID:grid.413480.a) (ISNI:0000 0004 0440 749X) 
78  Wake Forest University Health Sciences, Winston-Salem, USA (GRID:grid.412860.9) (ISNI:0000 0004 0459 1231) 
79  Rhode Island Hospital, Providence, USA (GRID:grid.240588.3) (ISNI:0000 0001 0557 9478) 
80  Brown University, Providence, USA (GRID:grid.40263.33) (ISNI:0000 0004 1936 9094); Butler Hospital, Providence, USA (GRID:grid.273271.2) (ISNI:0000 0000 8593 9332) 
81  Butler Hospital, Providence, USA (GRID:grid.273271.2) (ISNI:0000 0000 8593 9332) 
82  Medical University South Carolina, Charleston, USA (GRID:grid.259828.c) (ISNI:0000 0001 2189 3475) 
83  St. Joseph’s Health Care, Toronto, Canada (GRID:grid.416448.b) (ISNI:0000 0000 9674 4717) 
84  Nathan Kline Institute, Orangeburg, USA (GRID:grid.250263.0) (ISNI:0000 0001 2189 4777) 
85  University of Iowa College of Medicine, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) 
86  Cornell University, Ithaca, USA (GRID:grid.5386.8) (ISNI:000000041936877X) 
87  University of South Florida: USF Health Byrd Alzheimer’s Institute, Tampa, USA (GRID:grid.170693.a) (ISNI:0000 0001 2353 285X) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-022-28941-1
ProQuest document ID
2641595892
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.