title: TDP-43 pathology in the population: prevalence and associations with dementia and age.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cognitive Neuroscience Laboratory, School of Psychology, Social Work and Social Policy, University of South Australia, Australia.
authors.forename: Hannah A D
authors.initials: HA
authors.lastname: Keage
authors.affiliation: Institute of Public Health, University of Cambridge, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Hunter
authors.affiliation: MRC Biostatistics Unit, Cambridge, UK.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Matthews
authors.affiliation: Department of Neuroscience, Sheffield Institute of Translational Neuroscience, University of Sheffield, UK.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ince
authors.affiliation: Neuroscience Research Australia(NeuRA), University of New South Wales, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Hodges
authors.affiliation: Institute of Public Health, University of Cambridge, UK.
authors.forename: Suvi R K
authors.initials: SR
authors.lastname: Hokkanen
authors.affiliation: Department of Neuroscience, Sheffield Institute of Translational Neuroscience, University of Sheffield, UK.
authors.forename: J Robin
authors.initials: JR
authors.lastname: Highley
authors.affiliation: Institute of Mental Health, Nottingham, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Dening
authors.affiliation: Institute of Public Health, University of Cambridge, UK.
authors.forename: Carol
authors.initials: C
authors.lastname: Brayne
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D001921:Brain / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D018672:Community Health Planning; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003704:Dementia / Q000453:epidemiology* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D015995:Prevalence; D011569:Psychiatric Status Rating Scales
chemical_list: D004268:DNA-Binding Proteins
keywords: Aging; Alzheimer's disease; TDP-43; aging; dementia; population