Dissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease

Alzheimer’s Disease Neuroimaging Initiative (ADNI)

doi:10.1038/s41467-022-28941-1

Dissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease

Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Research output: Contribution to journal › Article › peer-review

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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 (N_M) in 289 symptomatic patients from the Alzheimer’s Disease Neuroimaging Initiative. We identified six T/N_M clusters with differing limbic and cortical patterns. The canonical group was defined as the T/N_M 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/N_M mismatch reveals distinct imaging signatures with pathobiological and prognostic implications for AD.

Original language	English
Article number	1495
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-28941-1
State	Published - Dec 2022

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10.1038/s41467-022-28941-1

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@article{177a6664a112423a8f50758549a29282,

title = "Dissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer{\textquoteright}s disease",

abstract = "Alzheimer{\textquoteright}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{\textquoteright}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.",

author = "{Alzheimer{\textquoteright}s Disease Neuroimaging Initiative (ADNI)} and Duong, {Michael Tran} and Das, {Sandhitsu R.} and Xueying Lyu and Long Xie and Hayley Richardson and Xie, {Sharon X.} and Yushkevich, {Paul A.} and Michael Weiner and Paul Aisen and Ronald Petersen and Jack, {Clifford R.} and William Jagust and Trojanowki, {John Q.} and Toga, {Arthur W.} and Laurel Beckett and Green, {Robert C.} and Saykin, {Andrew J.} and Morris, {John C.} and Shaw, {Leslie M.} and Enchi Liu and Tom Montine and Thomas, {Ronald G.} and Michael Donohue and Sarah Walter and Devon Gessert and Tamie Sather and Gustavo Jimenez-Maggiora and Danielle Harvey and Matthew Bernstein and Nick Fox and Paul Thompson and Norbert Schuff and Charles DeCarli and Bret Borowski and Jeff Gunter and Matt Senjem and Prashanthi Vemuri and David Jones and Kejal Kantarci and Chad Ward and Koeppe, {Robert A.} and Norm Foster and Reiman, {Eric M.} and Kewei Chen and Chet Mathis and Susan Landau and Cairns, {Nigel J.} and Erin Householder and Lisa Taylor-Reinwald and Lee, {Virginia M.Y.} and Magdalena Korecka and Michal Figurski and Karen Crawford and Scott Neu and Foroud, {Tatiana M.} and Li Shen and Kelley Faber and Sungeun Kim and Kwangsik Nho and Zaven Khachaturian and Richard Frank and Snyder, {Peter J.} and Susan Molchan and Jeffrey Kaye and Joseph Quinn and Betty Lind and Raina Carter and Sara Dolen and Schneider, {Lon S.} and Sonia Pawluczyk and Mauricio Beccera and Liberty Teodoro and Spann, {Bryan M.} and James Brewer and Helen Vanderswag and Adam Fleisher and Heidebrink, {Judith L.} and Lord, {Joanne L.} and Mason, {Sara S.} and Albers, {Colleen S.} and David Knopman and Kris Johnson and Doody, {Rachelle S.} and Javier Villanueva-Meyer and Munir Chowdhury and Susan Rountree and Mimi Dang and Yaakov Stern and Honig, {Lawrence S.} and Bell, {Karen L.} and Beau Ances and Maria Carroll and Sue Leon and Mintun, {Mark A.} and Stacy Schneider and Angela Oliver and Randall Griffith and David Clark and David Geldmacher and John Brockington and Erik Roberson and Hillel Grossman and Effie Mitsis and Leyla deToledo-Morrell and Shah, {Raj C.} and Ranjan Duara and Daniel Varon and Greig, {Maria T.} and Peggy Roberts and Marilyn Albert and Chiadi Onyike and Daniel D{\textquoteright}Agostino and Stephanie Kielb and Galvin, {James E.} and Pogorelec, {Dana M.} and Brittany Cerbone and Michel, {Christina A.} and Henry Rusinek and {de Leon}, {Mony J.} and Lidia Glodzik and {De Santi}, Susan and Doraiswamy, {P. Murali} and Petrella, {Jeffrey R.} and Wong, {Terence Z.} and Clark, {Christopher M.} and Arnold, {Steven E.} and Karlawish, {Jason H.} and Wolk, {David A.} and Smith, {Charles D.} and Gregory Jicha and Peter Hardy and Partha Sinha and Elizabeth Oates and Gary Conrad and Lopez, {Oscar L.} and Oakley, {Mary Ann} and Simpson, {Donna M.} and Porsteinsson, {Anton P.} and Goldstein, {Bonnie S.} and Kim Martin and Makino, {Kelly M.} and Ismail, {M. Saleem} and Connie Brand and Mulnard, {Ruth A.} and Gaby Thai and Catherine McAdams-Ortiz and Kyle Womack and Kyle Womack and Mary Quiceno and Ramon Diaz-Arrastia and Richard King and Myron Weiner and Cook, {Kristen Martin} and Michael Devous and Levey, {Allan I.} and Lah, {James J.} and Cellar, {Janet S.} and Burns, {Jeffrey M.} and Anderson, {Heather S.} and Swerdlow, {Russell H.} and Liana Apostolova and Kathleen Tingus and Ellen Woo and Silverman, {Daniel H.S.} and Lu, {Po H.} and George Bartzokis and Graff-Radford, {Neill R.} and Francine Parfitt and Tracy Kendall and Heather Johnson and Farlow, {Martin R.} and Hake, {Ann Marie} and Matthews, {Brandy R.} and Scott Herring and Cynthia Hunt and {van Dyck}, {Christopher H.} and Carson, {Richard E.} and MacAvoy, {Martha G.} and Howard Chertkow and Howard Bergman and Chris Hosein and Sandra Black and Bojana Stefanovic and Curtis Caldwell and Hsiung, {Ging Yuek Robin} and Howard Feldman and Benita Mudge and Michele Assaly and Andrew Kertesz and John Rogers and Charles Bernick and Donna Munic and Diana Kerwin and Mesulam, {Marek Marsel} and Kristine Lipowski and Wu, {Chuang Kuo} and Nancy Johnson and Carl Sadowsky and Walter Martinez and Teresa Villena",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-28941-1",

language = "English",

volume = "13",

journal = "Nature communications",

issn = "2041-1723",

number = "1",

}

TY - JOUR

T1 - Dissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease

AU - Alzheimer’s Disease Neuroimaging Initiative (ADNI)

AU - Duong, Michael Tran

AU - Das, Sandhitsu R.

AU - Lyu, Xueying

AU - Xie, Long

AU - Richardson, Hayley

AU - Xie, Sharon X.

AU - Yushkevich, Paul A.

AU - Weiner, Michael

AU - Aisen, Paul

AU - Petersen, Ronald

AU - Jack, Clifford R.

AU - Jagust, William

AU - Trojanowki, John Q.

AU - Toga, Arthur W.

AU - Beckett, Laurel

AU - Green, Robert C.

AU - Saykin, Andrew J.

AU - Morris, John C.

AU - Shaw, Leslie M.

AU - Liu, Enchi

AU - Montine, Tom

AU - Thomas, Ronald G.

AU - Donohue, Michael

AU - Walter, Sarah

AU - Gessert, Devon

AU - Sather, Tamie

AU - Jimenez-Maggiora, Gustavo

AU - Harvey, Danielle

AU - Bernstein, Matthew

AU - Fox, Nick

AU - Thompson, Paul

AU - Schuff, Norbert

AU - DeCarli, Charles

AU - Borowski, Bret

AU - Gunter, Jeff

AU - Senjem, Matt

AU - Vemuri, Prashanthi

AU - Jones, David

AU - Kantarci, Kejal

AU - Ward, Chad

AU - Koeppe, Robert A.

AU - Foster, Norm

AU - Reiman, Eric M.

AU - Chen, Kewei

AU - Mathis, Chet

AU - Landau, Susan

AU - Cairns, Nigel J.

AU - Householder, Erin

AU - Taylor-Reinwald, Lisa

AU - Lee, Virginia M.Y.

AU - Korecka, Magdalena

AU - Figurski, Michal

AU - Crawford, Karen

AU - Neu, Scott

AU - Foroud, Tatiana M.

AU - Shen, Li

AU - Faber, Kelley

AU - Kim, Sungeun

AU - Nho, Kwangsik

AU - Khachaturian, Zaven

AU - Frank, Richard

AU - Snyder, Peter J.

AU - Molchan, Susan

AU - Kaye, Jeffrey

AU - Quinn, Joseph

AU - Lind, Betty

AU - Carter, Raina

AU - Dolen, Sara

AU - Schneider, Lon S.

AU - Pawluczyk, Sonia

AU - Beccera, Mauricio

AU - Teodoro, Liberty

AU - Spann, Bryan M.

AU - Brewer, James

AU - Vanderswag, Helen

AU - Fleisher, Adam

AU - Heidebrink, Judith L.

AU - Lord, Joanne L.

AU - Mason, Sara S.

AU - Albers, Colleen S.

AU - Knopman, David

AU - Johnson, Kris

AU - Doody, Rachelle S.

AU - Villanueva-Meyer, Javier

AU - Chowdhury, Munir

AU - Rountree, Susan

AU - Dang, Mimi

AU - Stern, Yaakov

AU - Honig, Lawrence S.

AU - Bell, Karen L.

AU - Ances, Beau

AU - Carroll, Maria

AU - Leon, Sue

AU - Mintun, Mark A.

AU - Schneider, Stacy

AU - Oliver, Angela

AU - Griffith, Randall

AU - Clark, David

AU - Geldmacher, David

AU - Brockington, John

AU - Roberson, Erik

AU - Grossman, Hillel

AU - Mitsis, Effie

AU - deToledo-Morrell, Leyla

AU - Shah, Raj C.

AU - Duara, Ranjan

AU - Varon, Daniel

AU - Greig, Maria T.

AU - Roberts, Peggy

AU - Albert, Marilyn

AU - Onyike, Chiadi

AU - D’Agostino, Daniel

AU - Kielb, Stephanie

AU - Galvin, James E.

AU - Pogorelec, Dana M.

AU - Cerbone, Brittany

AU - Michel, Christina A.

AU - Rusinek, Henry

AU - de Leon, Mony J.

AU - Glodzik, Lidia

AU - De Santi, Susan

AU - Doraiswamy, P. Murali

AU - Petrella, Jeffrey R.

AU - Wong, Terence Z.

AU - Clark, Christopher M.

AU - Arnold, Steven E.

AU - Karlawish, Jason H.

AU - Wolk, David A.

AU - Smith, Charles D.

AU - Jicha, Gregory

AU - Hardy, Peter

AU - Sinha, Partha

AU - Oates, Elizabeth

AU - Conrad, Gary

AU - Lopez, Oscar L.

AU - Oakley, Mary Ann

AU - Simpson, Donna M.

AU - Porsteinsson, Anton P.

AU - Goldstein, Bonnie S.

AU - Martin, Kim

AU - Makino, Kelly M.

AU - Ismail, M. Saleem

AU - Brand, Connie

AU - Mulnard, Ruth A.

AU - Thai, Gaby

AU - McAdams-Ortiz, Catherine

AU - Womack, Kyle

AU - Quiceno, Mary

AU - Diaz-Arrastia, Ramon

AU - King, Richard

AU - Weiner, Myron

AU - Cook, Kristen Martin

AU - Devous, Michael

AU - Levey, Allan I.

AU - Lah, James J.

AU - Cellar, Janet S.

AU - Burns, Jeffrey M.

AU - Anderson, Heather S.

AU - Swerdlow, Russell H.

AU - Apostolova, Liana

AU - Tingus, Kathleen

AU - Woo, Ellen

AU - Silverman, Daniel H.S.

AU - Lu, Po H.

AU - Bartzokis, George

AU - Graff-Radford, Neill R.

AU - Parfitt, Francine

AU - Kendall, Tracy

AU - Johnson, Heather

AU - Farlow, Martin R.

AU - Hake, Ann Marie

AU - Matthews, Brandy R.

AU - Herring, Scott

AU - Hunt, Cynthia

AU - van Dyck, Christopher H.

AU - Carson, Richard E.

AU - MacAvoy, Martha G.

AU - Chertkow, Howard

AU - Bergman, Howard

AU - Hosein, Chris

AU - Black, Sandra

AU - Stefanovic, Bojana

AU - Caldwell, Curtis

AU - Hsiung, Ging Yuek Robin

AU - Feldman, Howard

AU - Mudge, Benita

AU - Assaly, Michele

AU - Kertesz, Andrew

AU - Rogers, John

AU - Bernick, Charles

AU - Munic, Donna

AU - Kerwin, Diana

AU - Mesulam, Marek Marsel

AU - Lipowski, Kristine

AU - Wu, Chuang Kuo

AU - Johnson, Nancy

AU - Sadowsky, Carl

AU - Martinez, Walter

AU - Villena, Teresa

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85126850679&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-28941-1

DO - 10.1038/s41467-022-28941-1

M3 - Article

C2 - 35314672

AN - SCOPUS:85126850679

SN - 2041-1723

VL - 13

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 1495

ER -

Dissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease

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