title: Epidemiological pathology of Tau in the ageing brain: application of staging for neuropil threads (BrainNet Europe protocol) to the MRC cognitive function and ageing brain study.
abstract: BACKGROUND
  Deposition of abnormally phosphorylated tau (phospho-tau) occurs in Alzheimer's disease but also with brain ageing. The Braak staging scheme focused on neurofibrillary tangles, but abundant p-tau is also present in neuropil threads, and a recent scheme has been proposed by the BrainNet Europe consortium for staging tau pathology based on neuropil threads. We determined the relationship of threads to tangles, and the value of staging for threads in an unselected population-representative ageing brain cohort. We also determined the prevalence of astroglial tau pathologies, and their relationship to neuronal tau. Phospho-tau pathology was determined by immunohistochemistry (AT8 antibody) in the MRC-CFAS neuropathology cohort. Neuropil threads were staged using the BrainNet Europe protocol for tau pathology, and compared with Braak tangle stages. Astroglial tau pathology was assessed in neo-cortical, mesial temporal and subcortical areas.
  
  
  RESULTS
  Cases conformed well to the hierarchical neuropil threads staging of the BrainNet Europe protocol and correlated strongly with Braak staging (r=0.84, p < 0.001). Based on the areas under the receiver operator curves (AUC), incorporating either threads or tangle staging significantly improved dementia case identification to a similar degree over age alone (Braak stage X (2)(1)=10.1, p=0.002; BNE stage X (2)(1)=9.7, p=0.002). Thorn-shaped astrocytes, present in 40 % of cases, were most common in mesial temporal lobe, then brainstem, and were associated with subpial tau-positive neurites (mesial temporal: X (2)(1)=61.3, p < 0.001; brainstem: X (2)(1)=47.9, p < 0.001). Adding thorn astrocytes did not improve dementia prediction (AUC: X (2)(1)=0.77, p=0.381), but there was a weak relationship between numbers of areas involved and staging for threads or tangles (r=0.17, p=0.023). Neuropil threads develop hierarchically in parallel with neurofibrillary tangles.
  
  
  CONCLUSIONS
  The BrainNet Europe staging protocol is straightforward to apply, and offers similar predictive value for dementia to Braak tangle staging. Astroglial tauopathy, particularly thorn shaped astrocyte formation, does not relate to dementia status, but the association with phospho-tau neurites may suggest a pathogenic relationship to neuronal tau pathology.
authors: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, S10 2HQ, UK.
authors: Stephen B
authors: SB
authors: Wharton
authors: Department of Radiology, University of Cambridge, Cambridge, UK.|Institute of Public Health, University of Cambridge, Cambridge, UK.
authors: Thais
authors: T
authors: Minett
authors: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, S10 2HQ, UK.
authors: David
authors: D
authors: Drew
authors: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, S10 2HQ, UK.
authors: Gillian
authors: G
authors: Forster
authors: MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
authors: Fiona
authors: F
authors: Matthews
authors: Institute of Public Health, University of Cambridge, Cambridge, UK.
authors: Carol
authors: C
authors: Brayne
authors: Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, S10 2HQ, UK. p.g.ince@sheffield.ac.uk.
authors: Paul G
authors: PG
authors: Ince
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D015331:Cohort Studies; D018450:Disease Progression; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D008297:Male; D016874:Neurofibrillary Tangles / Q000473:pathology; D019600:Neuropil Threads / Q000473:pathology*; D010766:Phosphorylation; D011569:Psychiatric Status Rating Scales; D024801:Tauopathies / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins