Abstract
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that occurs in association with repetitive traumatic brain injury experienced in sport and military service. In most instances, the clinical symptoms of the disease begin after a long period of latency ranging from several years to several decades. The initial symptoms are typically insidious, consisting of irritability, impulsivity, aggression, depression, short-term memory loss and heightened suicidality. The symptoms progress slowly over decades to include cognitive deficits and dementia. The pathology of CTE is characterized by the accumulation of phosphorylated tau protein in neurons and astrocytes in a pattern that is unique from other tauopathies, including Alzheimer’s disease. The hyperphosphorylated tau abnormalities begin focally, as perivascular neurofibrillary tangles and neurites at the depths of the cerebral sulci, and then spread to involve superficial layers of adjacent cortex before becoming a widespread degeneration affecting medial temporal lobe structures, diencephalon and brainstem. Most instances of CTE (>85% of cases) show abnormal accumulations of phosphorylated 43 kDa TAR DNA binding protein that are partially colocalized with phosphorylated tau protein. As CTE is characterized pathologically by frontal and temporal lobe atrophy, by abnormal deposits of phosphorylated tau and by 43 kDa TAR DNA binding protein and is associated clinically with behavioral and personality changes, as well as cognitive impairments, CTE is increasingly categorized as an acquired frontotemporal lobar degeneration. Currently, some of the greatest challenges are that CTE cannot be diagnosed during life and the incidence and prevalence of the disorder remain uncertain. Furthermore, the contribution of age, gender, genetics, stress, alcohol and substance abuse to the development of CTE remains to be determined.
Highlights
The concept that chronic neurodegeneration might occur after minor brain trauma was first introduced in 1927 by Osnato and Gilberti, who studied 100 clinical cases of concussion of the brain, defined as a blow to the head with loss of consciousness with or without post-traumatic amnesia or skull fracture, and found several instances in which the clinical symptoms persisted and secondary degenerative changes developed, a condition they termed traumatic encephalitis [1]
Staging system Based on our recent analysis of postmortem brains from 68 subjects with Chronic traumatic encephalopathy (CTE) (all men ranging in age from 17 to 98 years, including 64 athletes, 21 military veterans (86% of whom were athletes) and one individual who engaged in self-injurious headbanging behavior), CTE can be classified into four pathological stages based on a stereotyped pattern of structural change and tau pathology [29]
43 kDa TAR DNA binding protein (TDP-43) abnormalities are found in most CTE cases; in advanced CTE, TDP-43 pathology is severe and widespread
Summary
The concept that chronic neurodegeneration might occur after minor brain trauma was first introduced in 1927 by Osnato and Gilberti, who studied 100 clinical cases of concussion of the brain, defined as a blow to the head with loss of consciousness with or without post-traumatic amnesia or skull fracture, and found several instances in which the clinical symptoms persisted and secondary degenerative changes developed, a condition they termed traumatic encephalitis [1]. A postmortem study of a collegeeducated woman involved in a serious motor vehicle accident at age 39, who developed progressive dementia and parkinsonism 11 years later, showed evidence of multiple neurodegenerations including atypical AD, severe LBD (with exceptionally large Lewy bodies), axonopathy and TDP-43 proteinopathy [53]. In the Goldstein model of blast neurotrauma, wild-type mice exposed to a single controlled sublethal blast developed p-tau immunoreactivity, axonopathy, microvascular pathology, and widespread astrocytosis and microgliosis similar to early CTE changes found after blast-related or sportsrelated concussion [28] These mice showed slowed axonal conduction and impaired spatial learning and memory that persisted for 1 month after blast exposure. A similar study using 18-month-old human tau transgenic mice that express wild-type human tau isoforms on a null murine tau background found significant increases in p-tau immunoreactivity, reactive astrocytosis and microgliosis in mice exposed to repetitive mTBI, but not in mice exposed to single mTBI [84]
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