Affiliations: [a] Cognitive Neuroscience Laboratory, School of Psychology, Social Work and Social Policy, University of South Australia, Australia | [b] Institute of Public Health, University of Cambridge, UK | [c] MRC Biostatistics Unit, Cambridge, UK | [d] Department of Neuroscience, Sheffield Institute of Translational Neuroscience, University of Sheffield, UK | [e] Neuroscience Research Australia(NeuRA), University of New South Wales, Australia | [f] Institute of Mental Health, Nottingham, UK
Correspondence:
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Correspondence to: Dr. Hannah A.D. Keage, Cognitive Neuroscience Laboratory, School of Psychology, Social Work and Social Policy, University of South Australia, GPO BOX 2741, Adelaide 5001, Australia. Tel.: +618 8302 4340; Fax: +618 8302 4377; E-mail: [email protected].
Abstract: Background:The significance of TDP-43 pathology in relation to aging and dementia in the population is unclear. Objective:We aimed to determine the prevalence of transactive response DNA-binding protein of 43 kDA (TDP-43) neuronal inclusions in a population-based sample, and associations with age group at death (≤90 and >90 years) and clinical dementia status prior to death. Further, we investigate associations between TDP-43 inclusions and other key dementia-related neuropathologies (plaques, tangles, and neuronal loss) within the hippocampus and entorhinal and temporal cortices. Methods:All brain donors within the Cambridge City over-75 s Cohort (CC75C), which is population-based and longitudinally tracked (n = 228), were included. Age at death ranged from 78 to 106 years. TDP-43 neuronal inclusions were assessed in the hippocampus, entorhinal cortex, and temporal cortex. These data were combined with existing clinical and neuropathological data. Results:TDP-43 neuronal inclusions were present in 27% of the sample, 36% of those with clinical dementia and 18% without dementia. Individuals who died later (>90 years) or with clinical dementia were more likely to show TDP-43 inclusions. Hippocampal and entorhinal TDP-43 inclusions were significantly associated with dementia severity and increasing age, taking into account other neuropathologies. TDP-43 neuronal inclusions appeared to be co-localize with severe neuronal loss. Conclusion:Findings indicate that hippocampal and entorhinal TDP-43 inclusions are important substrates of late onset dementia which appear to co-localize with severe neuronal loss, but not with Alzheimer’s disease markers of amyloid and tau. This broadens the accepted view of TDP-43 pathology in dementias.
