期刊
BRAIN
卷 142, 期 -, 页码 3621-3635出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awz277
关键词
TDP-43; tau; beta-amyloid; radiological-pathological study; neuropathology
资金
- National Institutes of Health [R01 AG011378, R01 AG015866, R01 AG034676, R01 AG037491, R01 AG041851, R01 NS097495, P50 AG016574, U01 AG006786, U01 NS100620]
- Gerald and Henrietta Rauenhorst Foundation
- Elsie and Marvin Dekelboum Family Foundation
- Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic
- Mayo Foundation for Medical Education and Research
- Fondation Therese et Rene Planiol
- Conseil Regional de Normandie
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-beta, 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.
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