Antemortem volume loss mirrors TDP-43 staging in older adults with non-frontotemporal lobar degeneration

Alexandre Bejanin, Melissa E. Murray, Peter Martin, Hugo Botha, Nirubol Tosakulwong, Christopher G. Schwarz, Matthew L. Senjem, Gael Chételat, Kejal Kantarci, Clifford R. Jack, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Caterina Giannini, Joseph E. Parisi, Dennis W. Dickson, Jennifer L. Whitwell, Keith A. Josephs

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Abstract

Over the past decade, the transactive response DNA-binding protein of 43 kDa (TDP-43) has been recognized as a major protein in normal and pathological ageing, increasing the risk of cognitive impairment and dementia. In conditions distinct from the frontotemporal lobar degenerations, TDP-43 appears to progress in a stereotypical pattern. In the present study, we aimed at providing a better understanding of the effects of TDP-43 and other age-related neuropathologies on cross-sectional grey matter volume in a cohort of non-FTLD subjects. We included 407 individuals with an antemortem MRI and post-mortem brain tissue from the Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic Alzheimer's Disease Patient Registry, or the Mayo Clinic Study of Aging. All individuals were assigned pathological stages for TDP-43, tau, amyloid-β, Lewy bodies, argyrophilic grain disease and vascular pathologies. Robust regressions were performed in regions of interest and voxel-wise to explore the relationships between TDP-43 stages and grey matter volume while controlling for other pathologies. Grey matter volumes adjusted for pathological and demographic variables were also computed for each TDP-43-positive case to further characterize the sequential involvement of brain structures associated with TDP-43, irrespective of the TDP-43 staging scheme. Robust regressions showed that the extent of TDP-43 pathology was associated with the extent of grey matter atrophy. Specifically, we found that the volume in medial temporal regions (i.e. amygdala, entorhinal cortex, hippocampus) decreased progressively with advancing TDP-43 stages. Importantly, these effects were of similar magnitude to those related to tau stages. Additional analyses using adjusted grey matter volume demonstrated a sequential pattern of volume loss associated with TDP-43, starting within the medial temporal lobe, followed by early involvement of the temporal pole, and eventually encompassing additional temporal and frontal regions. Altogether, this study demonstrates the major and independent contribution of TDP-43 pathology on neurodegeneration and provides further insight into the regional distribution of TDP-43 in non-FTLD subjects. Along with previous studies, these findings emphasized the importance of targeting TDP-43 in future clinical trials to prevent its detrimental effect on grey matter volume and, eventually, cognition.

Original languageEnglish (US)
Pages (from-to)3621-3635
Number of pages15
JournalBrain : a journal of neurology
Volume142
Issue number11
DOIs
StatePublished - Nov 1 2019

Fingerprint

Temporal Lobe
Pathology
Alzheimer Disease
Frontotemporal Lobar Degeneration
Lewy Bodies
Entorhinal Cortex
DNA-Binding Proteins
Brain
Amygdala
Vascular Diseases
Amyloid
Cognition
Atrophy
Dementia
Registries
Gray Matter
Hippocampus
Demography
Clinical Trials
Research

Keywords

  • neuropathology
  • radiological-pathological study
  • tau
  • TDP-43
  • β-amyloid

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

@article{d73cd1b1769e4cd283062af7a91313d1,
title = "Antemortem volume loss mirrors TDP-43 staging in older adults with non-frontotemporal lobar degeneration",
abstract = "Over the past decade, the transactive response DNA-binding protein of 43 kDa (TDP-43) has been recognized as a major protein in normal and pathological ageing, increasing the risk of cognitive impairment and dementia. In conditions distinct from the frontotemporal lobar degenerations, TDP-43 appears to progress in a stereotypical pattern. In the present study, we aimed at providing a better understanding of the effects of TDP-43 and other age-related neuropathologies on cross-sectional grey matter volume in a cohort of non-FTLD subjects. We included 407 individuals with an antemortem MRI and post-mortem brain tissue from the Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic Alzheimer's Disease Patient Registry, or the Mayo Clinic Study of Aging. All individuals were assigned pathological stages for TDP-43, tau, amyloid-β, Lewy bodies, argyrophilic grain disease and vascular pathologies. Robust regressions were performed in regions of interest and voxel-wise to explore the relationships between TDP-43 stages and grey matter volume while controlling for other pathologies. Grey matter volumes adjusted for pathological and demographic variables were also computed for each TDP-43-positive case to further characterize the sequential involvement of brain structures associated with TDP-43, irrespective of the TDP-43 staging scheme. Robust regressions showed that the extent of TDP-43 pathology was associated with the extent of grey matter atrophy. Specifically, we found that the volume in medial temporal regions (i.e. amygdala, entorhinal cortex, hippocampus) decreased progressively with advancing TDP-43 stages. Importantly, these effects were of similar magnitude to those related to tau stages. Additional analyses using adjusted grey matter volume demonstrated a sequential pattern of volume loss associated with TDP-43, starting within the medial temporal lobe, followed by early involvement of the temporal pole, and eventually encompassing additional temporal and frontal regions. Altogether, this study demonstrates the major and independent contribution of TDP-43 pathology on neurodegeneration and provides further insight into the regional distribution of TDP-43 in non-FTLD subjects. Along with previous studies, these findings emphasized the importance of targeting TDP-43 in future clinical trials to prevent its detrimental effect on grey matter volume and, eventually, cognition.",
keywords = "neuropathology, radiological-pathological study, tau, TDP-43, β-amyloid",
author = "Alexandre Bejanin and Murray, {Melissa E.} and Peter Martin and Hugo Botha and Nirubol Tosakulwong and Schwarz, {Christopher G.} and Senjem, {Matthew L.} and Gael Ch{\'e}telat and Kejal Kantarci and Jack, {Clifford R.} and Boeve, {Bradley F.} and Knopman, {David S.} and Petersen, {Ronald C.} and Caterina Giannini and Parisi, {Joseph E.} and Dickson, {Dennis W.} and Whitwell, {Jennifer L.} and Josephs, {Keith A.}",
year = "2019",
month = "11",
day = "1",
doi = "10.1093/brain/awz277",
language = "English (US)",
volume = "142",
pages = "3621--3635",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "11",

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TY - JOUR

T1 - Antemortem volume loss mirrors TDP-43 staging in older adults with non-frontotemporal lobar degeneration

AU - Bejanin, Alexandre

AU - Murray, Melissa E.

AU - Martin, Peter

AU - Botha, Hugo

AU - Tosakulwong, Nirubol

AU - Schwarz, Christopher G.

AU - Senjem, Matthew L.

AU - Chételat, Gael

AU - Kantarci, Kejal

AU - Jack, Clifford R.

AU - Boeve, Bradley F.

AU - Knopman, David S.

AU - Petersen, Ronald C.

AU - Giannini, Caterina

AU - Parisi, Joseph E.

AU - Dickson, Dennis W.

AU - Whitwell, Jennifer L.

AU - Josephs, Keith A.

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Over the past decade, the transactive response DNA-binding protein of 43 kDa (TDP-43) has been recognized as a major protein in normal and pathological ageing, increasing the risk of cognitive impairment and dementia. In conditions distinct from the frontotemporal lobar degenerations, TDP-43 appears to progress in a stereotypical pattern. In the present study, we aimed at providing a better understanding of the effects of TDP-43 and other age-related neuropathologies on cross-sectional grey matter volume in a cohort of non-FTLD subjects. We included 407 individuals with an antemortem MRI and post-mortem brain tissue from the Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic Alzheimer's Disease Patient Registry, or the Mayo Clinic Study of Aging. All individuals were assigned pathological stages for TDP-43, tau, amyloid-β, Lewy bodies, argyrophilic grain disease and vascular pathologies. Robust regressions were performed in regions of interest and voxel-wise to explore the relationships between TDP-43 stages and grey matter volume while controlling for other pathologies. Grey matter volumes adjusted for pathological and demographic variables were also computed for each TDP-43-positive case to further characterize the sequential involvement of brain structures associated with TDP-43, irrespective of the TDP-43 staging scheme. Robust regressions showed that the extent of TDP-43 pathology was associated with the extent of grey matter atrophy. Specifically, we found that the volume in medial temporal regions (i.e. amygdala, entorhinal cortex, hippocampus) decreased progressively with advancing TDP-43 stages. Importantly, these effects were of similar magnitude to those related to tau stages. Additional analyses using adjusted grey matter volume demonstrated a sequential pattern of volume loss associated with TDP-43, starting within the medial temporal lobe, followed by early involvement of the temporal pole, and eventually encompassing additional temporal and frontal regions. Altogether, this study demonstrates the major and independent contribution of TDP-43 pathology on neurodegeneration and provides further insight into the regional distribution of TDP-43 in non-FTLD subjects. Along with previous studies, these findings emphasized the importance of targeting TDP-43 in future clinical trials to prevent its detrimental effect on grey matter volume and, eventually, cognition.

AB - Over the past decade, the transactive response DNA-binding protein of 43 kDa (TDP-43) has been recognized as a major protein in normal and pathological ageing, increasing the risk of cognitive impairment and dementia. In conditions distinct from the frontotemporal lobar degenerations, TDP-43 appears to progress in a stereotypical pattern. In the present study, we aimed at providing a better understanding of the effects of TDP-43 and other age-related neuropathologies on cross-sectional grey matter volume in a cohort of non-FTLD subjects. We included 407 individuals with an antemortem MRI and post-mortem brain tissue from the Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic Alzheimer's Disease Patient Registry, or the Mayo Clinic Study of Aging. All individuals were assigned pathological stages for TDP-43, tau, amyloid-β, Lewy bodies, argyrophilic grain disease and vascular pathologies. Robust regressions were performed in regions of interest and voxel-wise to explore the relationships between TDP-43 stages and grey matter volume while controlling for other pathologies. Grey matter volumes adjusted for pathological and demographic variables were also computed for each TDP-43-positive case to further characterize the sequential involvement of brain structures associated with TDP-43, irrespective of the TDP-43 staging scheme. Robust regressions showed that the extent of TDP-43 pathology was associated with the extent of grey matter atrophy. Specifically, we found that the volume in medial temporal regions (i.e. amygdala, entorhinal cortex, hippocampus) decreased progressively with advancing TDP-43 stages. Importantly, these effects were of similar magnitude to those related to tau stages. Additional analyses using adjusted grey matter volume demonstrated a sequential pattern of volume loss associated with TDP-43, starting within the medial temporal lobe, followed by early involvement of the temporal pole, and eventually encompassing additional temporal and frontal regions. Altogether, this study demonstrates the major and independent contribution of TDP-43 pathology on neurodegeneration and provides further insight into the regional distribution of TDP-43 in non-FTLD subjects. Along with previous studies, these findings emphasized the importance of targeting TDP-43 in future clinical trials to prevent its detrimental effect on grey matter volume and, eventually, cognition.

KW - neuropathology

KW - radiological-pathological study

KW - tau

KW - TDP-43

KW - β-amyloid

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U2 - 10.1093/brain/awz277

DO - 10.1093/brain/awz277

M3 - Article

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JO - Brain

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SN - 0006-8950

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