A population-based study of head injury, cognitive function and pathological markers

Sarah Naomi James; Jennifer M. Nicholas; Christopher A. Lane; Thomas D. Parker; Kirsty Lu; Ashvini Keshavan; Sarah M. Buchanan; Sarah E. Keuss; Heidi Murray-Smith; Andrew Wong; David M. Cash; Ian B. Malone; Josephine Barnes; Carole H. Sudre; William Coath; Lloyd Prosser; Sebastien Ourselin; Marc Modat; David L. Thomas; Jorge Cardoso; Amanda Heslegrave; Henrik Zetterberg; Sebastian J. Crutch; Jonathan M. Schott; Marcus Richards; Nick C. Fox

doi:10.1002/acn3.51331

A population-based study of head injury, cognitive function and pathological markers

Sarah Naomi James^*, Jennifer M. Nicholas, Christopher A. Lane, Thomas D. Parker, Kirsty Lu, Ashvini Keshavan, Sarah M. Buchanan, Sarah E. Keuss, Heidi Murray-Smith, Andrew Wong, David M. Cash, Ian B. Malone, Josephine Barnes, Carole H. Sudre, William Coath, Lloyd Prosser, Sebastien Ourselin, Marc Modat, David L. Thomas, Jorge CardosoAmanda Heslegrave, Henrik Zetterberg, Sebastian J. Crutch, Jonathan M. Schott, Marcus Richards, Nick C. Fox

^*Corresponding author for this work

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

3 Citations (Scopus)

Abstract

Objective: To assess associations between head injury (HI) with loss of consciousness (LOC), ageing and markers of later-life cerebral pathology; and to explore whether those effects may help explain subtle cognitive deficits in dementia-free individuals. Methods: Participants (n = 502, age = 69–71) from the 1946 British Birth Cohort underwent cognitive testing (subtests of Preclinical Alzheimer Cognitive Composite), ¹⁸F-florbetapir Aβ-PET and MR imaging. Measures include Aβ-PET status, brain, hippocampal and white matter hyperintensity (WMH) volumes, normal appearing white matter (NAWM) microstructure, Alzheimer’s disease (AD)-related cortical thickness, and serum neurofilament light chain (NFL). LOC HI metrics include HI occurring: (i) >15 years prior to the scan (ii) anytime up to age 71. Results: Compared to those with no evidence of an LOC HI, only those reporting an LOC HI>15 years prior (16%, n = 80) performed worse on cognitive tests at age 69–71, taking into account premorbid cognition, particularly on the digit-symbol substitution test (DSST). Smaller brain volume (BV) and adverse NAWM microstructural integrity explained 30% and 16% of the relationship between HI and DSST, respectively. We found no evidence that LOC HI was associated with Aβ load, hippocampal volume, WMH volume, AD-related cortical thickness or NFL (all p > 0.01). Interpretation: Having a LOC HI aged 50’s and younger was linked with lower later-life cognitive function at age ~70 than expected. This may reflect a damaging but small impact of HI; explained in part by smaller BV and different microstructure pathways but not via pathology related to AD (amyloid, hippocampal volume, AD cortical thickness) or ongoing neurodegeneration (serum NFL).

Original language	English
Pages (from-to)	842-856
Number of pages	15
Journal	Annals of Clinical and Translational Neurology
Volume	8
Issue number	4
DOIs	https://doi.org/10.1002/acn3.51331
Publication status	Published - Apr 2021

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10.1002/acn3.51331

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James, S. N., Nicholas, J. M., Lane, C. A., Parker, T. D., Lu, K., Keshavan, A., Buchanan, S. M., Keuss, S. E., Murray-Smith, H., Wong, A., Cash, D. M., Malone, I. B., Barnes, J., Sudre, C. H., Coath, W., Prosser, L., Ourselin, S., Modat, M., Thomas, D. L., ... Fox, N. C. (2021). A population-based study of head injury, cognitive function and pathological markers. Annals of Clinical and Translational Neurology, 8(4), 842-856. https://doi.org/10.1002/acn3.51331

@article{61953be1e23d437382df309f74decd13,

title = "A population-based study of head injury, cognitive function and pathological markers",

abstract = "Objective: To assess associations between head injury (HI) with loss of consciousness (LOC), ageing and markers of later-life cerebral pathology; and to explore whether those effects may help explain subtle cognitive deficits in dementia-free individuals. Methods: Participants (n = 502, age = 69–71) from the 1946 British Birth Cohort underwent cognitive testing (subtests of Preclinical Alzheimer Cognitive Composite), 18F-florbetapir Aβ-PET and MR imaging. Measures include Aβ-PET status, brain, hippocampal and white matter hyperintensity (WMH) volumes, normal appearing white matter (NAWM) microstructure, Alzheimer{\textquoteright}s disease (AD)-related cortical thickness, and serum neurofilament light chain (NFL). LOC HI metrics include HI occurring: (i) >15 years prior to the scan (ii) anytime up to age 71. Results: Compared to those with no evidence of an LOC HI, only those reporting an LOC HI>15 years prior (16%, n = 80) performed worse on cognitive tests at age 69–71, taking into account premorbid cognition, particularly on the digit-symbol substitution test (DSST). Smaller brain volume (BV) and adverse NAWM microstructural integrity explained 30% and 16% of the relationship between HI and DSST, respectively. We found no evidence that LOC HI was associated with Aβ load, hippocampal volume, WMH volume, AD-related cortical thickness or NFL (all p > 0.01). Interpretation: Having a LOC HI aged 50{\textquoteright}s and younger was linked with lower later-life cognitive function at age ~70 than expected. This may reflect a damaging but small impact of HI; explained in part by smaller BV and different microstructure pathways but not via pathology related to AD (amyloid, hippocampal volume, AD cortical thickness) or ongoing neurodegeneration (serum NFL).",

author = "James, {Sarah Naomi} and Nicholas, {Jennifer M.} and Lane, {Christopher A.} and Parker, {Thomas D.} and Kirsty Lu and Ashvini Keshavan and Buchanan, {Sarah M.} and Keuss, {Sarah E.} and Heidi Murray-Smith and Andrew Wong and Cash, {David M.} and Malone, {Ian B.} and Josephine Barnes and Sudre, {Carole H.} and William Coath and Lloyd Prosser and Sebastien Ourselin and Marc Modat and Thomas, {David L.} and Jorge Cardoso and Amanda Heslegrave and Henrik Zetterberg and Crutch, {Sebastian J.} and Schott, {Jonathan M.} and Marcus Richards and Fox, {Nick C.}",

note = "Funding Information: This study is principally funded by grants from Alzheimer{\textquoteright}s Research UK (ARUK‐PG2014‐1946, ARUK‐PG2017‐1946), the Medical Research Council Dementias Platform UK (CSUB19166), the Wolfson Foundation (PR/ylr/18575) and The Drake Foundation. The biomarker analyses are funded by the Brain Research Trust (UCC14191) and Weston Brain Institute and Selfridges Group Foundation award (176724). Florbetapir amyloid tracer is kindly provided by AVID Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly) who had no part in the design of the study. The MRC National Survey of Health and Development is funded by the Medical Research Council (MC_UU_12019/1, MC_UU_12019/3). The NSHD, MR and AW are funded by the Medical Research Council (MC_UU_12019/1, MC_UU_12019/3). Some researchers are supported by the NIHR Queen Square Dementia BRU (JMS, NCF), UCL Hospitals Biomedical Research Centre (JMS), Leonard Wolfson Experimental Neurology Centre (JMS, NCF, MM, DT). JB is supported by an Alzheimer{\textquoteright}s Research UK Senior Fellowship. TP is supported by a Wellcome Trust Clinical Research Fellowship (200109/Z/15/Z). AK was supported by a Wolfson Foundation Clinical Research Fellowship. CS is supported by an Alzheimer{\textquoteright}s Society Junior Fellowship (AS‐JF‐17‐011). MM is supported by an Alzheimer{\textquoteright}s Society Project Grant (AS‐PG‐15‐025). SC is supported by an Alzheimer{\textquoteright}s Research UK Senior Research Fellowship (ARUK‐SRF2013‐8). SO receives funding from the EPSRC (EP/H046410/1, EP/J020990/1, EP/K005278), the MRC (MR/J01107X/1), the EU‐FP7 project VPH‐DARE@IT (FP7‐ICT‐2011‐9‐601055), and NIHR BRC UCLH/UCL High Impact Initiative. HZ acknowledges support from the UCL/UCLH NIHR Biomedical Research Centre, the UK Dementia Research Institute at UCL and a Wellcome Trust Multi‐User Equipment Grant. JMS acknowledges the EPSRC (EP/J020990/1) and European Union{\textquoteright}s Horizon 2020 research and innovation programme (Grant 666992) and a Weston Brain Institute and Selfridges Group Foundation award (176724). NCF acknowledges support from the UCL/UCLH NIHR Biomedical Research Centre, an NIHR Senior Investigator award and the UK Dementia Research Institute at UCL. Funding Information: HZ is a co‐founder of Brain Biomarker Solutions, a GU Ventures‐based platform company at the University of Gothenburg, has served on advisory boards of Roche Diagnostics, Wave, Samumed and CogRx and has given lectures in symposia sponsored by Biogen and Alzecure. NCF has received research funding from Eisai, Elan, Eli Lilly, GE, IXICO, Janssen, Lundbeck, Pfizer, Roche Sanofi‐Aventis and Wyeth. NCF has served on a Data Safety Monitoring Committee for Biogen. JS has received research funding from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly), has consulted for Roche Pharmaceuticals, Biogen, and Eli Lilly, given educational lectures sponsored by GE, Eli Lilly and Biogen, and serves on a Data Safety Monitoring Committee for Axon Neuroscience SE. All other authors have no conflicts of interest to declare. Publisher Copyright: {\textcopyright} 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = apr,

doi = "10.1002/acn3.51331",

language = "English",

volume = "8",

pages = "842--856",

journal = "Annals of Clinical and Translational Neurology",

issn = "2328-9503",

publisher = "John Wiley and Sons Ltd",

number = "4",

}

James, SN, Nicholas, JM, Lane, CA, Parker, TD, Lu, K, Keshavan, A, Buchanan, SM, Keuss, SE, Murray-Smith, H, Wong, A, Cash, DM, Malone, IB, Barnes, J, Sudre, CH, Coath, W, Prosser, L, Ourselin, S , Modat, M, Thomas, DL, Cardoso, J, Heslegrave, A, Zetterberg, H, Crutch, SJ, Schott, JM, Richards, M & Fox, NC 2021, 'A population-based study of head injury, cognitive function and pathological markers', Annals of Clinical and Translational Neurology, vol. 8, no. 4, pp. 842-856. https://doi.org/10.1002/acn3.51331

TY - JOUR

T1 - A population-based study of head injury, cognitive function and pathological markers

AU - James, Sarah Naomi

AU - Nicholas, Jennifer M.

AU - Lane, Christopher A.

AU - Parker, Thomas D.

AU - Lu, Kirsty

AU - Keshavan, Ashvini

AU - Buchanan, Sarah M.

AU - Keuss, Sarah E.

AU - Murray-Smith, Heidi

AU - Wong, Andrew

AU - Cash, David M.

AU - Malone, Ian B.

AU - Barnes, Josephine

AU - Sudre, Carole H.

AU - Coath, William

AU - Prosser, Lloyd

AU - Ourselin, Sebastien

AU - Modat, Marc

AU - Thomas, David L.

AU - Cardoso, Jorge

AU - Heslegrave, Amanda

AU - Zetterberg, Henrik

AU - Crutch, Sebastian J.

AU - Schott, Jonathan M.

AU - Richards, Marcus

AU - Fox, Nick C.

N1 - Funding Information: This study is principally funded by grants from Alzheimer’s Research UK (ARUK‐PG2014‐1946, ARUK‐PG2017‐1946), the Medical Research Council Dementias Platform UK (CSUB19166), the Wolfson Foundation (PR/ylr/18575) and The Drake Foundation. The biomarker analyses are funded by the Brain Research Trust (UCC14191) and Weston Brain Institute and Selfridges Group Foundation award (176724). Florbetapir amyloid tracer is kindly provided by AVID Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly) who had no part in the design of the study. The MRC National Survey of Health and Development is funded by the Medical Research Council (MC_UU_12019/1, MC_UU_12019/3). The NSHD, MR and AW are funded by the Medical Research Council (MC_UU_12019/1, MC_UU_12019/3). Some researchers are supported by the NIHR Queen Square Dementia BRU (JMS, NCF), UCL Hospitals Biomedical Research Centre (JMS), Leonard Wolfson Experimental Neurology Centre (JMS, NCF, MM, DT). JB is supported by an Alzheimer’s Research UK Senior Fellowship. TP is supported by a Wellcome Trust Clinical Research Fellowship (200109/Z/15/Z). AK was supported by a Wolfson Foundation Clinical Research Fellowship. CS is supported by an Alzheimer’s Society Junior Fellowship (AS‐JF‐17‐011). MM is supported by an Alzheimer’s Society Project Grant (AS‐PG‐15‐025). SC is supported by an Alzheimer’s Research UK Senior Research Fellowship (ARUK‐SRF2013‐8). SO receives funding from the EPSRC (EP/H046410/1, EP/J020990/1, EP/K005278), the MRC (MR/J01107X/1), the EU‐FP7 project VPH‐DARE@IT (FP7‐ICT‐2011‐9‐601055), and NIHR BRC UCLH/UCL High Impact Initiative. HZ acknowledges support from the UCL/UCLH NIHR Biomedical Research Centre, the UK Dementia Research Institute at UCL and a Wellcome Trust Multi‐User Equipment Grant. JMS acknowledges the EPSRC (EP/J020990/1) and European Union’s Horizon 2020 research and innovation programme (Grant 666992) and a Weston Brain Institute and Selfridges Group Foundation award (176724). NCF acknowledges support from the UCL/UCLH NIHR Biomedical Research Centre, an NIHR Senior Investigator award and the UK Dementia Research Institute at UCL. Funding Information: HZ is a co‐founder of Brain Biomarker Solutions, a GU Ventures‐based platform company at the University of Gothenburg, has served on advisory boards of Roche Diagnostics, Wave, Samumed and CogRx and has given lectures in symposia sponsored by Biogen and Alzecure. NCF has received research funding from Eisai, Elan, Eli Lilly, GE, IXICO, Janssen, Lundbeck, Pfizer, Roche Sanofi‐Aventis and Wyeth. NCF has served on a Data Safety Monitoring Committee for Biogen. JS has received research funding from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly), has consulted for Roche Pharmaceuticals, Biogen, and Eli Lilly, given educational lectures sponsored by GE, Eli Lilly and Biogen, and serves on a Data Safety Monitoring Committee for Axon Neuroscience SE. All other authors have no conflicts of interest to declare. Publisher Copyright: © 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/4

Y1 - 2021/4

N2 - Objective: To assess associations between head injury (HI) with loss of consciousness (LOC), ageing and markers of later-life cerebral pathology; and to explore whether those effects may help explain subtle cognitive deficits in dementia-free individuals. Methods: Participants (n = 502, age = 69–71) from the 1946 British Birth Cohort underwent cognitive testing (subtests of Preclinical Alzheimer Cognitive Composite), 18F-florbetapir Aβ-PET and MR imaging. Measures include Aβ-PET status, brain, hippocampal and white matter hyperintensity (WMH) volumes, normal appearing white matter (NAWM) microstructure, Alzheimer’s disease (AD)-related cortical thickness, and serum neurofilament light chain (NFL). LOC HI metrics include HI occurring: (i) >15 years prior to the scan (ii) anytime up to age 71. Results: Compared to those with no evidence of an LOC HI, only those reporting an LOC HI>15 years prior (16%, n = 80) performed worse on cognitive tests at age 69–71, taking into account premorbid cognition, particularly on the digit-symbol substitution test (DSST). Smaller brain volume (BV) and adverse NAWM microstructural integrity explained 30% and 16% of the relationship between HI and DSST, respectively. We found no evidence that LOC HI was associated with Aβ load, hippocampal volume, WMH volume, AD-related cortical thickness or NFL (all p > 0.01). Interpretation: Having a LOC HI aged 50’s and younger was linked with lower later-life cognitive function at age ~70 than expected. This may reflect a damaging but small impact of HI; explained in part by smaller BV and different microstructure pathways but not via pathology related to AD (amyloid, hippocampal volume, AD cortical thickness) or ongoing neurodegeneration (serum NFL).

AB - Objective: To assess associations between head injury (HI) with loss of consciousness (LOC), ageing and markers of later-life cerebral pathology; and to explore whether those effects may help explain subtle cognitive deficits in dementia-free individuals. Methods: Participants (n = 502, age = 69–71) from the 1946 British Birth Cohort underwent cognitive testing (subtests of Preclinical Alzheimer Cognitive Composite), 18F-florbetapir Aβ-PET and MR imaging. Measures include Aβ-PET status, brain, hippocampal and white matter hyperintensity (WMH) volumes, normal appearing white matter (NAWM) microstructure, Alzheimer’s disease (AD)-related cortical thickness, and serum neurofilament light chain (NFL). LOC HI metrics include HI occurring: (i) >15 years prior to the scan (ii) anytime up to age 71. Results: Compared to those with no evidence of an LOC HI, only those reporting an LOC HI>15 years prior (16%, n = 80) performed worse on cognitive tests at age 69–71, taking into account premorbid cognition, particularly on the digit-symbol substitution test (DSST). Smaller brain volume (BV) and adverse NAWM microstructural integrity explained 30% and 16% of the relationship between HI and DSST, respectively. We found no evidence that LOC HI was associated with Aβ load, hippocampal volume, WMH volume, AD-related cortical thickness or NFL (all p > 0.01). Interpretation: Having a LOC HI aged 50’s and younger was linked with lower later-life cognitive function at age ~70 than expected. This may reflect a damaging but small impact of HI; explained in part by smaller BV and different microstructure pathways but not via pathology related to AD (amyloid, hippocampal volume, AD cortical thickness) or ongoing neurodegeneration (serum NFL).

UR - http://www.scopus.com/inward/record.url?scp=85102271107&partnerID=8YFLogxK

U2 - 10.1002/acn3.51331

DO - 10.1002/acn3.51331

M3 - Article

AN - SCOPUS:85102271107

SN - 2328-9503

VL - 8

SP - 842

EP - 856

JO - Annals of Clinical and Translational Neurology

JF - Annals of Clinical and Translational Neurology

IS - 4

ER -

A population-based study of head injury, cognitive function and pathological markers

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