Brain Advance Access published online on March 24, 2009
Brain, doi:10.1093/brain/awp059
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Hippocampal tau pathology is related to neuroanatomical connections: an ageing population-based study
1 Academic Unit of Pathology, University of Sheffield, London, UK 2 Department of Public Health and Primary Care, University of Cambridge, London, UK 3 Reta Lila Weston Institute of Neurological Studies, UCL, Institute of Neurology, London, UK 4 MRC Biostatistics Unit, Cambridge, UK
Correspondence to:
Dr S.B. Wharton, Academic Unit of Pathology, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK E-mail: s.wharton{at}sheffield.ac.uk
Deposits of abnormally phosphorylated tau protein are found in numerous neurodegenerative disorders; the ‘tauopathies’, which include Alzheimer's and Pick's diseases, but tau pathology is also found in the ageing brain. Variation in tau pathology in brain ageing and its relationship to development of tauopathies and cognitive impairment remains unclear. We aimed to determine the extent and pattern of spread of tau pathology in the hippocampus, a susceptible region important in dementia and milder states of memory impairment, using hippocampal samples from the elderly population-based Medical Research Council Cognitive Function and Ageing Study neuropathology cohort. Tau deposition was assessed in hippocampal anatomical sub-regions using the AT8 antibody to phosphorylated tau and isoform-specific antibodies to 3 and 4-repeat tau (RD3 and RD4). Aβ pathology was also assessed. In this population sample, which includes the full ageing spectrum from individuals with no cognitive impairment to those with dementia satisfying clinico-pathology criteria for Alzheimer's disease, we have demonstrated a high prevalence at death of tau pathology. AT8, Aβ, RD3 and RD4 showed similar regional distribution and increased RD3 was noted in late-stage ghost tangles. Aβ was shown to be a poor explanatory variable for tau pathology. Tau deposition progressed in a hierarchical manner. Hippocampal input regions and projection zones (such as lateral entorhinal cortex, CA1/subiculum border and outer molecular layer of dentate) were initially affected, with anterograde progression though the hippocampal circuitry. Six hippocampal tau anatomical stages were defined, each linking projectionally to their adjacent stages, suggesting spread of tau malfunction through neuroanatomical pathways in hippocampal ageing. These stages were significantly associated with dementia, and may provide a clinically useful tool in the clinico-pathological assessment of dementia and mild cognitive impairment.
Key Words: tau; neurodegeneration; dementia; ageing; Alzheimer's disease
Abbreviations: Aβ, Amyloid-beta; DG, dentate gyrus; EC, entorhinal cortex; GT, ghost tangles; IML, inner molecular layer of the dentate; LEC, lateral entorhinal cortex; MEC, medial entorhinal cortex; NFT, neurofibrillary tangle; NTh, Neuropil threads; NT, tau+ve neurones; NP, Neuritic plaques; OML, outer molecular layer of the dentate; SLM, stratum lacunosum-moleculare; SO, stratum oriens; SP, stratum pyramidale; SR, stratum radiatum; TEC, transentorhinal cortex.
Received September 25, 2008. Revised February 1, 2009. Accepted February 13, 2009.