Abstract
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 β-amyloid (Aβ) to be a primary feature of CTE, yet the data
indicate that CTE is a primary tauopathy, with Aβ 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.
Keywords
neuropathology - chronic traumatic encephalopathy - neurodegenerative disease - tauopathies
