Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis

Emily L. Dennis; Samantha Vervoordt; Maheen M. Adamson; Amiri Houshang; Erin D. Bigler; Karen Caeyenberghs; James H. Cole; Kristen Dams-O'Connor; Evelyn M. Deutscher; Ekaterina Dobryakova; Helen M. Genova; Jordan H. Grafman; Asta K. Håberg; Torgeir Hellstrøm; Andrei Irimia; Vassilis E. Koliatsos; Hannah M. Lindsey; Abigail Livny; David K. Menon; Tricia L. Merkley; Abdalla Z. Mohamed; Stefania Mondello; Martin M. Monti; Virginia F.J. Newcombe; Mary R. Newsome; Jennie Ponsford; Amanda Rabinowitz; Hanne Smevik; Gershon Spitz; Umesh M. Venkatesan; Lars T. Westlye; Ross Zafonte; Paul M. Thompson; Elisabeth A. Wilde; Alexander Olsen; Frank G. Hillary

doi:10.1002/ana.26952

Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis

Emily L. Dennis, Samantha Vervoordt, Maheen M. Adamson, Amiri Houshang, Erin D. Bigler, Karen Caeyenberghs, James H. Cole, Kristen Dams-O'Connor, Evelyn M. Deutscher, Ekaterina Dobryakova, Helen M. Genova, Jordan H. Grafman, Asta K. Håberg, Torgeir Hellstrøm, Andrei Irimia, Vassilis E. Koliatsos, Hannah M. Lindsey, Abigail Livny, David K. Menon, Tricia L. MerkleyAbdalla Z. Mohamed, Stefania Mondello, Martin M. Monti, Virginia F.J. Newcombe, Mary R. Newsome, Jennie Ponsford, Amanda Rabinowitz, Hanne Smevik, Gershon Spitz, Umesh M. Venkatesan, Lars T. Westlye, Ross Zafonte, Paul M. Thompson, Elisabeth A. Wilde, Alexander Olsen^*, Frank G. Hillary^*

^*Corresponding author for this work

Physical Medicine and Rehabilitation

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

3 Scopus citations

Abstract

Objective: The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. Given evidence that a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using structural magnetic resonance imaging (MRI) data. Complicated mild, moderate, and severe TBI (cmsTBI) is associated with a higher predicted age difference (PAD), but the progression of PAD over time remains unclear. We sought to examine whether PAD increases as a function of time since injury (TSI) and if injury severity and sex interacted to influence this progression. Methods: Through the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n = 343), along with controls, for a total sample size of n = 540, to replicate and extend prior findings in the study of TBI brain age. Cross-sectional T1w-MRI data were aggregated across 7 cohorts, and brain age was established using a similar brain age algorithm to prior work in TBI. Results: Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find strong evidence supporting a link between PAD and cognitive performance. Interpretation: This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability in brain morphometry, eventually leading to further changes in the decades after a single cmsTBI. ANN NEUROL 2024;96:365–377.

Original language	English (US)
Pages (from-to)	365-377
Number of pages	13
Journal	Annals of neurology
Volume	96
Issue number	2
DOIs	https://doi.org/10.1002/ana.26952
State	Published - Aug 2024

Funding

NIH/NINDS R61NS120249 to Dr. Dennis. Dr. Menon is an Emeritus Senior Investigator of the National Institute for Health Research, UK, and is supported by the CENTER\u2010TBI grant from the European Union and the TBI\u2010REPORTER grant from UKRI, NIHR, AR UK and UK Ministry of Defense. Israel Innovation Authority, \u201CMagneton\u201D Grant to Dr Livny. Maryland Technology Development Corporation1 R01 EY028039 Congressionally Directed Medical Research, JH Discovery Award to Dr. Koliatsos. National Institute for Health and Care Research (NIHR) Advanced Fellowship to Dr. Newcombe. NHMRC Early Career Fellowship to Dr. Spitz. NIH grants R01NS100973, R01AG079957 and RF1AG082201, DoD contract W81XWH\u201018\u20101\u20100413, an anonymous donor family, and the Hanson\u2010Thorell Research Scholarship Fund at the University of Southern California to Dr. Irimia. NIH/NIA R01AG061028, NIH/NINDS RF1NS115268, NIH/NINDS RF1NS128961 and NIH/NINDS/NICHD1U01NS086625\u201001 to Dr. Dams\u2010O'Connor. NIH/NINDS R01\u2010NS121107 to Dr. Dobryakova. PA Health Research Grant SAP #4100077082 to Dr. Hillary. The European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (ERC Starting Grant, Grant agreement No. 802998) and the Research Council of Norway (249795) to Dr. Westlye. To Dr. Caeyenberghs: The Victorian Near\u2010miss Award Pilot is administered by veski for the Victorian Health and Medical Research Workforce Project on behalf of the Victorian Government and the Association of Australian Medical Research Institutes. Funding for the Pilot has been provided by the Victorian Department of Jobs, Precincts and Regions. The Liaison Committee between the Central Norway Regional Health Authority (RHA) and the Norwegian University of Science and Technology (NTNU) (2020/39645) to Dr. Olsen. Tiny Blue Dot Foundation to Dr. Monti. Transport Accident Commission to Dr. Ponsford. NIH U54EB020403, R01MH116147, R56AG058854, P41EB015922, R01MH111671 to Dr. Thompson. VA R&D SPIRE AWARD. Dr. Olsen is a co\u2010founder and owner of Nordic Brain Tech AS. Dr. Zafonte received royalties from: (1) Oakstone for an educational CD\u2010 Physical Medicine and Rehabilitation a Comprehensive Review; (2) Demos publishing for serving as co\u2010 editor of the text Brain Injury Medicine. Dr Zafonte serves on the Scientific Advisory Board of Myomo, Oxeia Biopharma, Biodirection and ElMINDA. He also evaluates patients in the MGH Brain and Body\u2010TRUST Program which is funded by the NFL Players Association. Dr. Adamson is the CEO & Founder of Soof Solutions Inc. Dr. Cole is a scientific advisor and shareholder of Claritas HealthTech PTE and of BrainKey. Dr. Thompson received partial research support from Biogen, Inc., for research unrelated to this manuscript.

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1002/ana.26952

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Dennis, E. L., Vervoordt, S., Adamson, M. M., Houshang, A., Bigler, E. D., Caeyenberghs, K., Cole, J. H., Dams-O'Connor, K., Deutscher, E. M., Dobryakova, E., Genova, H. M., Grafman, J. H., Håberg, A. K., Hellstrøm, T., Irimia, A., Koliatsos, V. E., Lindsey, H. M., Livny, A., Menon, D. K., ... Hillary, F. G. (2024). Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis. Annals of neurology, 96(2), 365-377. https://doi.org/10.1002/ana.26952

@article{366359905eee4c959c6cfe656ffec4a4,

title = "Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis",

abstract = "Objective: The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. Given evidence that a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using structural magnetic resonance imaging (MRI) data. Complicated mild, moderate, and severe TBI (cmsTBI) is associated with a higher predicted age difference (PAD), but the progression of PAD over time remains unclear. We sought to examine whether PAD increases as a function of time since injury (TSI) and if injury severity and sex interacted to influence this progression. Methods: Through the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n = 343), along with controls, for a total sample size of n = 540, to replicate and extend prior findings in the study of TBI brain age. Cross-sectional T1w-MRI data were aggregated across 7 cohorts, and brain age was established using a similar brain age algorithm to prior work in TBI. Results: Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find strong evidence supporting a link between PAD and cognitive performance. Interpretation: This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability in brain morphometry, eventually leading to further changes in the decades after a single cmsTBI. ANN NEUROL 2024;96:365–377.",

author = "Dennis, {Emily L.} and Samantha Vervoordt and Adamson, {Maheen M.} and Amiri Houshang and Bigler, {Erin D.} and Karen Caeyenberghs and Cole, {James H.} and Kristen Dams-O'Connor and Deutscher, {Evelyn M.} and Ekaterina Dobryakova and Genova, {Helen M.} and Grafman, {Jordan H.} and H{\aa}berg, {Asta K.} and Torgeir Hellstr{\o}m and Andrei Irimia and Koliatsos, {Vassilis E.} and Lindsey, {Hannah M.} and Abigail Livny and Menon, {David K.} and Merkley, {Tricia L.} and Mohamed, {Abdalla Z.} and Stefania Mondello and Monti, {Martin M.} and Newcombe, {Virginia F.J.} and Newsome, {Mary R.} and Jennie Ponsford and Amanda Rabinowitz and Hanne Smevik and Gershon Spitz and Venkatesan, {Umesh M.} and Westlye, {Lars T.} and Ross Zafonte and Thompson, {Paul M.} and Wilde, {Elisabeth A.} and Alexander Olsen and Hillary, {Frank G.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.",

year = "2024",

month = aug,

doi = "10.1002/ana.26952",

language = "English (US)",

volume = "96",

pages = "365--377",

journal = "Annals of neurology",

issn = "0364-5134",

publisher = "John Wiley & Sons Inc.",

number = "2",

}

Dennis, EL, Vervoordt, S, Adamson, MM, Houshang, A, Bigler, ED, Caeyenberghs, K, Cole, JH, Dams-O'Connor, K, Deutscher, EM, Dobryakova, E, Genova, HM, Grafman, JH, Håberg, AK, Hellstrøm, T, Irimia, A, Koliatsos, VE, Lindsey, HM, Livny, A, Menon, DK, Merkley, TL, Mohamed, AZ, Mondello, S, Monti, MM, Newcombe, VFJ, Newsome, MR, Ponsford, J, Rabinowitz, A, Smevik, H, Spitz, G, Venkatesan, UM, Westlye, LT, Zafonte, R, Thompson, PM, Wilde, EA, Olsen, A & Hillary, FG 2024, 'Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis', Annals of neurology, vol. 96, no. 2, pp. 365-377. https://doi.org/10.1002/ana.26952

TY - JOUR

T1 - Accelerated Aging after Traumatic Brain Injury

T2 - An ENIGMA Multi-Cohort Mega-Analysis

AU - Dennis, Emily L.

AU - Vervoordt, Samantha

AU - Adamson, Maheen M.

AU - Houshang, Amiri

AU - Bigler, Erin D.

AU - Caeyenberghs, Karen

AU - Cole, James H.

AU - Dams-O'Connor, Kristen

AU - Deutscher, Evelyn M.

AU - Dobryakova, Ekaterina

AU - Genova, Helen M.

AU - Grafman, Jordan H.

AU - Håberg, Asta K.

AU - Hellstrøm, Torgeir

AU - Irimia, Andrei

AU - Koliatsos, Vassilis E.

AU - Lindsey, Hannah M.

AU - Livny, Abigail

AU - Menon, David K.

AU - Merkley, Tricia L.

AU - Mohamed, Abdalla Z.

AU - Mondello, Stefania

AU - Monti, Martin M.

AU - Newcombe, Virginia F.J.

AU - Newsome, Mary R.

AU - Ponsford, Jennie

AU - Rabinowitz, Amanda

AU - Smevik, Hanne

AU - Spitz, Gershon

AU - Venkatesan, Umesh M.

AU - Westlye, Lars T.

AU - Zafonte, Ross

AU - Thompson, Paul M.

AU - Wilde, Elisabeth A.

AU - Olsen, Alexander

AU - Hillary, Frank G.

PY - 2024/8

Y1 - 2024/8

N2 - Objective: The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. Given evidence that a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using structural magnetic resonance imaging (MRI) data. Complicated mild, moderate, and severe TBI (cmsTBI) is associated with a higher predicted age difference (PAD), but the progression of PAD over time remains unclear. We sought to examine whether PAD increases as a function of time since injury (TSI) and if injury severity and sex interacted to influence this progression. Methods: Through the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n = 343), along with controls, for a total sample size of n = 540, to replicate and extend prior findings in the study of TBI brain age. Cross-sectional T1w-MRI data were aggregated across 7 cohorts, and brain age was established using a similar brain age algorithm to prior work in TBI. Results: Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find strong evidence supporting a link between PAD and cognitive performance. Interpretation: This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability in brain morphometry, eventually leading to further changes in the decades after a single cmsTBI. ANN NEUROL 2024;96:365–377.

AB - Objective: The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. Given evidence that a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using structural magnetic resonance imaging (MRI) data. Complicated mild, moderate, and severe TBI (cmsTBI) is associated with a higher predicted age difference (PAD), but the progression of PAD over time remains unclear. We sought to examine whether PAD increases as a function of time since injury (TSI) and if injury severity and sex interacted to influence this progression. Methods: Through the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n = 343), along with controls, for a total sample size of n = 540, to replicate and extend prior findings in the study of TBI brain age. Cross-sectional T1w-MRI data were aggregated across 7 cohorts, and brain age was established using a similar brain age algorithm to prior work in TBI. Results: Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find strong evidence supporting a link between PAD and cognitive performance. Interpretation: This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability in brain morphometry, eventually leading to further changes in the decades after a single cmsTBI. ANN NEUROL 2024;96:365–377.

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DO - 10.1002/ana.26952

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JO - Annals of neurology

JF - Annals of neurology

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ER -

Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis

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