The Neuropathology of Chronic Traumatic Encephalopathy: The Status of the Literature

Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head trauma, including concussion and asymptomatic subconcussive impacts. CTE was first recognized in boxers almost a century ago and has been identified more recently in contact sports athletes, military veterans exposed to blast, and victims of domestic violence. Like most neurodegenerative diseases, CTE is diagnosed conclusively by a neuropathological examination of brain tissue. CTE is characterized by the buildup of hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs), neurites, and, sometimes, astrocytes, surrounding small blood vessels in a patchy distribution at the sulcal depths of the cerebral cortex. In 2015, using the McKee proposed criteria for the neuropathological diagnosis of CTE, a consensus panel of expert neuropathologists confirmed CTE as a unique neurodegenerative disease with a pathognomonic lesion and published the preliminary NINDS (National Institute of Neurological Disorders and Stroke) criteria for CTE. Since that time, the NINDS criteria for CTE have been implemented and validated in multiple international publications. Using the NINDS criteria, the largest clinicopathological series of CTE to date was reported that included 177 former American football players, including 110 (99%) of 111 former National Football League players, 48 (91%) of 53 former college football players, and 3 (21%) of 14 former high school players. Studies have also shown a significant association between cumulative exposure to repetitive head trauma, as judged by the length of American football playing career, and risk for and severity of CTE. There is also a significant relationship of the length of football playing career with p-tau pathology, inflammation, white matter rarefaction, and age at death in CTE. While p-tau pathology, inflammation, white matter rarefaction, and arteriolosclerosis contribute to dementia in CTE, whether they also influence the behavioral and mood symptoms in CTE has yet to be determined. There have been several instances of aging-related tau astrogliopathy (ARTAG), a common astrocytic pathology in the elderly, misdiagnosed as CTE in the recent literature, provoking claims that CTE pathology is present in people not known to have experienced repetitive head trauma. Although ARTAG is often found in CTE, the pathognomonic lesion of CTE is a neuronal lesion consisting of NFTs and neurites, with or without p-tau immunoreactive astrocytes. Some authors consider beta -amyloid (A beta) to be a primary feature of CTE, yet the data indicate that CTE is a primary tauopathy, with A beta deposition a function of age and inheritance of the ApoEe4 allele. Some authors also question the progressive nature of CTE pathology, although there is clear evidence in most individuals that p-tau pathology increases in density and affects more brain regions with survival. This review is intended to outline the status of the evidence-based literature regarding CTE neuropathology and to address the misrepresentations and confusions that have arisen in recent reviews and a letter of correspondence.