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Preliminary consensus criteria define the pathognomonic lesion of CTE as patchy tau pathology within neurons and astrocytes at the depths of cortical sulci. However, the specific tau isoform composition and post-translational modifications in CTE remain largely unexplored. Using immunohistochemistry, we performed tau phenotyping of CTE neuropathologies and compared this to a range of tau pathologies, including Alzheimer\u2019s disease, primary age-related tauopathy, ageing-related tau astrogliopathy and multiple subtypes of frontotemporal lobar degeneration with tau inclusions. Cases satisfying preliminary consensus diagnostic criteria for CTE neuropathological change (CTE-NC) were identified (athletes, n\u2009=\u200910; long-term survivors of moderate or severe TBI, n\u2009=\u20094) from the Glasgow TBI Archive and Penn Neurodegenerative Disease Brain Bank. In addition, material from a range of autopsy-proven ageing-associated and primary tauopathies in which there was no known history of exposure to TBI was selected as non-injured controls (n\u2009=\u200932). Each case was then stained with a panel of tau antibodies specific for phospho-epitopes (PHF1, CP13, AT100, pS262), microtubule-binding repeat domains (3R, 4R), truncation (Tau-C3) or conformation (GT-7, GT-38) and the extent and distribution of staining assessed. Cell types were confirmed with double immunofluorescent labelling. Results demonstrate that astroglial tau pathology in CTE is composed of 4R-immunoreactive thorn-shaped astrocytes, echoing the morphology and immunophenotype of astrocytes encountered in ageing-related tau astrogliopathy. In contrast, neurofibrillary tangles of CTE contain both 3R and 4R tau, with post-translational modifications and conformations consistent with Alzheimer\u2019s disease and primary age-related tauopathy. Our observations establish that the astroglial and neurofibrillary tau pathologies of CTE are phenotypically distinct from each other and recapitulate the tau immunophenotypes encountered in ageing and Alzheimer\u2019s disease. As such, the immunohistochemical distinction of CTE neuropathology from other mixed 3R\/4R tauopathies of Alzheimer\u2019s disease and ageing may rest solely on the pattern and distribution of pathology.<\/jats:p>","DOI":"10.1093\/brain\/awaa071","type":"journal-article","created":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T20:15:44Z","timestamp":1582834544000},"page":"1572-1587","source":"Crossref","is-referenced-by-count":70,"title":["Tau immunophenotypes in chronic traumatic encephalopathy recapitulate those of ageing and Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"143","author":[{"given":"John D","family":"Arena","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Penn Center for Brain Injury and Repair, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas H","family":"Smith","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Penn Center for Brain Injury and Repair, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward B","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA"},{"name":"Translational Neuropathology Research Laboratory, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garrett S","family":"Gibbons","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J","family":"Irwin","sequence":"first","affiliation":[{"name":"Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John L","family":"Robinson","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia M -Y","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Q","family":"Trojanowski","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Stewart","sequence":"first","affiliation":[{"name":"Department of Neuropathology, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK"},{"name":"Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, G12 8QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria E","family":"Johnson","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Penn Center for Brain Injury and Repair, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,5,11]]},"reference":[{"key":"2020052115183746300_awaa071-B1","doi-asserted-by":"crossref","first-page":"3737","DOI":"10.1242\/jcs.113.21.3737","article-title":"C-terminal inhibition of tau assembly in vitro and in Alzheimer\u2019s disease","volume":"113 (Pt 21","author":"Abraha","year":"2000","journal-title":"J Cell Sci"},{"key":"2020052115183746300_awaa071-B2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s004010000283","article-title":"Distinct isoforms of tau aggregated in neurons and glial cells in brains of patients with Pick\u2019s disease, corticobasal degeneration and progressive supranuclear palsy","volume":"101","author":"Arai","year":"2001","journal-title":"Acta Neuropathol"},{"key":"2020052115183746300_awaa071-B3","doi-asserted-by":"crossref","first-page":"8325","DOI":"10.1021\/bi027348m","article-title":"Inhibition of tau polymerization by 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