Abstract
IntroductionAlzheimer’s disease (AD) is associated with neurofibrillary pathology, including neurofibrillary tangles (NFT), neuritic plaques (NP) and neuropil threads containing aggregated microtubule associated protein tau. Aggregated tau is also associated with granulovacuolar degeneration (GVD). The relationships between tau, GVD, NFT and dementia are unclear.MethodsWe assessed hippocampal (CA1) tau-immunoreactive GVD and NFT pathology in brain donations from the population-representative Cambridge City over 75s Cohort (CC75C) using the CERAD protocol and a modified protocol that included a morphological characterisation of tau-immunoreactive deposits within neurons as NFTs or as GVD. Associations between GVD, NFT and dementia were investigated.ResultsHippocampal pyramidal neurons affected with either NFT or GVD are common in the older population. Some tau-immunoreactive deposits resemble ghost GVD neurons. Tau immunoreactivity identified GVD in 95 % cases rated as none with haematoxylin and eosin staining. Both severe NFT (odds ratio (OR) 7.33, 95 % confidence interval (CI) 2.01; 26.80, p = 0.003) and severe GVD (OR 7.48, 95 %(CI) 1.54; 36.24, p = 0.012) were associated with dementia status. Increasing NFT (OR 2.47 95 %(CI) 1.45; 4.22, p = 0.001) and GVD (OR 2.12 95 %(CI) 1.23; 3.64, p = 0.007) severities are associated with increasing dementia severity. However, when the analyses were controlled for other neuropathologies (NFT, NP, Tar-DNA binding Protein-43 and amyloid deposits), the associations between GVD and dementia lost significance.ConclusionsCurrent neuropathological assessments do not adequately evaluate the presence and severity of the GVD pathology and its contribution to dementia remains unclear. We recommend that protocols to assess GVD should be developed for routine use and that tau, in a non-PHF associated conformation, is reliably associated with GVD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-015-0141-2) contains supplementary material, which is available to authorized users.
Highlights
Alzheimer’s disease (AD) is associated with neurofibrillary pathology, including neurofibrillary tangles (NFT), neuritic plaques (NP) and neuropil threads containing aggregated microtubule associated protein tau
We examined the pathology of tau-IR granulovacuolar degeneration (GVD) and NFT in detail in the cornus ammonis (CA) fields of the hippocampus in the population-based Cambridge City over-75s Cohort (CC75C) with an antibody against the C-terminal portion of tau that is not dependent on phosphorylation or Paired helical filament (PHF)-specific epitopes
We found more GVD pathology using tau-IR than was detected by H & E, suggesting that GVD is missed with current protocols
Summary
Alzheimer’s disease (AD) is associated with neurofibrillary pathology, including neurofibrillary tangles (NFT), neuritic plaques (NP) and neuropil threads containing aggregated microtubule associated protein tau. Alzheimer’s disease (AD) is characterised clinically by memory loss, cognitive impairment and behavioural problems [1], and neuropathologically by neuronal and synaptic loss and by various deposits containing the amyloid-beta protein (Aβ) and aggregated microtubuleassociated protein tau in the form of neurofibrillary pathologies including neurofibrillary tangles (NFT), The tau-associated pathologies, visualised by various methods and assessed using both the CERAD protocol [2, 3] and Braak staging [5, 8], include NFT, NP and NT. The presence of extracellular ghost NFT, the remains of NFT after the neuron has died, are noted in both CERAD and Braak staging These are assessed on haematoxylin and eosin (H & E) or silver stained slides because many tau-IR epitopes associated with NFT are lost [10]
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