Authors: John Arena; Victoria Johnson; Edward Lee; Josephine Fullerton; John Trojanowski; William Stewart; Douglas Smith (Philadelphia, PA)
Introduction: Traumatic brain injury (TBI) is recognized as a risk factor for neurodegenerative disease, including chronic traumatic encephalopathy (CTE), where accumulation of pathologic tau protein within neurons and astrocytes at the depths of cortical sulci has been described as a potentially distinguishing neuropathologic feature. However, it is unknown whether the tau species in CTE are distinct from other neurodegenerative diseases. Here we performed tau phenotyping and mapping in post-mortem cases of CTE for comparison with well-characterized pathologies, including Alzheimer’s disease (AD), primary tauopathies and aging-related tau astrogliopathy (ARTAG). Methods: From the Glasgow TBI Archive and the Penn Neurodegenerative Disease Brain Bank, cases were selected as: athletes with history of repetitive mild TBI and long-term survivors of single severe TBI with CTE pathology (n=8); uninjured controls with ARTAG (n=6); AD (n=2); and primary tauopathies (n=3). Immunohistochemistry was performed to determine tau phenotypes using antibodies to phosphoepitopes (PHF1, CP13, AT100, pS262), microtubule-binding repeat domains (3R, 4R), truncation (Tau-C3) and AD-conformation selective tau (GT-7, GT-38). Additionally, maps of neuronal and astroglial tau pathologies were generated to evaluate cortical distributions. Results: TBI-associated astroglial pathology was comprised of 4R tau-positive thorn-shaped astrocytes concentrated at the depths of cortical sulci, identical in both morphology and immunoreactivity profile to those of ARTAG. In contrast, neurofibrillary tangles (NFTs) were comprised of both 3R and 4R tau, with post-translational modifications and conformations consistent with AD and aging controls. Interestingly, in contrast with current descriptions of CTE, our data show astrocytes but not NTFs preferentially concentrate towards the depths of sulci. Conclusion: Here we demonstrate that neuronal and astroglial tau phenotypes in CTE are indistinguishable from AD and aging-associated pathologies. Additionally, the distinctive distribution of sulcal depth pathology in CTE appears primarily astroglial. These findings underscore the need for further characterization to determine whether CTE is a distinct neuropathological entity.