Neocortical and hippocampal amyloid-β and tau measures associate with dementia in the oldest-old - PubMed (original) (raw)

Neocortical and hippocampal amyloid-β and tau measures associate with dementia in the oldest-old

John L Robinson et al. Brain. 2011 Dec.

Abstract

The emergence of longevity in the modern world has brought a sense of urgency to understanding age-related neurodegenerative diseases such as Alzheimer's disease. Unfortunately, there is a lack of consensus regarding the correlation between the pathological substrates of neurodegeneration and dementia status, particularly in the oldest-old. To better understand the pathological correlates of dementia in the oldest-old, we characterized the topographical spread and severity of amyloid-β, tau, TDP-43 and α-synuclein pathologies in the 90+ Study, a prospective longitudinal population-based study of ageing and dementia. Neuropathological analysis with immunohistochemically labelled sections was carried out blind to clinical diagnosis on the first 108 participants of the 90+ Study who came to autopsy including participants with dementia (n = 66) and without dementia (n = 42). We used quantitative and/or semi-quantitative measures to assess the burden of amyloid-β, tau, TDP-43 and α-synuclein pathologies as well as hippocampal sclerosis. Amyloid-β and tau were the predominant pathologies in the 90+ Study cohort and both amyloid-β area and tau area occupied measures were strongly associated with the presence of dementia, as was Braak staging but semi-quantitative plaque scores were not. Notably, TDP-43 pathology also correlated with dementia, while α-synuclein distribution did not. In addition, hippocampal sclerosis was specific to participants with dementia and correlated with the presence of limbic TDP-43. In contrast to previous reports, we found that tau and amyloid-β continue to be robust pathological correlates of dementia, even in the oldest-old. While individuals with no dementia had limited hippocampal tau and neocortical amyloid-β pathology, dementia associated with an expansion in pathology, including increased neocortical tau and hippocampal amyloid-β plaques, more abundant neocortical amyloid-β deposition and hippocampal sclerosis with its attendant TDP-43 pathology.

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Figure 1

Figure 1

Neuropathology means according to dementia status. Dementia associated with (A–C) neocortical and (D–F) hippocampal pathology. Neocortically, dementia associated with (A) a severe total amyloid-β plaque burden and (B) an outward spread of tau neurofibrillary tangles. (C) The CERAD plaque scores were not significant. Hippocampal proteinopathies included (D) an increase in amyloid-β plaques in the CA/subiculum and (E) an increase in neuritic tau levels in CA2/CA1. (F) Hippocampal sclerosis was present in a subset of participants with dementia (29%; n = 19) and tightly correlated with limbic TDP-43 pathology. Box plots display the lower (light grey) and upper (dark grey) interquartile range overlaid with a model depicting mean values (red) for each group. D = dementia; hs = hippocampal sclerosis; ND = not dementia.

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