title: Re-examining tau-immunoreactive pathology in the population: granulovacuolar degeneration and neurofibrillary tangles.
abstract: BACKGROUND
  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. Aggregated tau is also associated with granulovacuolar degeneration (GVD). The relationships between tau, GVD, NFT and dementia are unclear.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Hippocampal 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.
  
  
  CONCLUSIONS
  Current 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.
authors: Department of Public Health and Primary Care, Institute of Public Health, Forvie Site, University of Cambridge School of Clinical Medicine, Box 113 Cambridge Biomedical Campus, Cambridge, CB2 0SP, UK. seh66@medschl.cam.ac.uk.
authors: Sally
authors: S
authors: Hunter
authors: Department of Public Health and Primary Care, Institute of Public Health, Forvie Site, University of Cambridge School of Clinical Medicine, Box 113 Cambridge Biomedical Campus, Cambridge, CB2 0SP, UK. tsm34@medschl.cam.ac.uk.|Department of Radiology, University of Cambridge School of Clinical Medicine, Box 218, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. tsm34@medschl.cam.ac.uk.
authors: Thais
authors: T
authors: Minett
authors: Institute of Neuroscience, Henry Wellcome Building for Neuroecology, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. tuomo.polvikoski@newcastle.ac.uk.
authors: Tuomo
authors: T
authors: Polvikoski
authors: Institute of Neuroscience, Henry Wellcome Building for Neuroecology, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. elizabeta.mukaetova-ladinska@newcastle.ac.uk.
authors: Elizabeta
authors: E
authors: Mukaetova-Ladinska
authors: Department of Public Health and Primary Care, Institute of Public Health, Forvie Site, University of Cambridge School of Clinical Medicine, Box 113 Cambridge Biomedical Campus, Cambridge, CB2 0SP, UK. cb105@medschl.cam.ac.uk.
authors: Carol
authors: C
authors: Brayne
mesh_terms: D000369:Aged, 80 and over; D003704:Dementia / Q000378:metabolism / Q000473:pathology; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D008137:Longitudinal Studies; D008297:Male; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D012720:Severity of Illness Index; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins