“Chronic traumatic encephalopathy (CTE) is a progressive neurodegeneration associated with repetitive head trauma.1- 8 See JAMA for the complete report.

“In 2013, based on a report of the clinical and pathological features of 68 men with CTE (including 36 football players from the current study), criteria for neuropathological diagnosis of CTE and a staging scheme of pathological severity were proposed.6 Two clinical presentations of CTE were described; in one, the initial features developed at a younger age and involved behavioral disturbance, mood disturbance, or both; in the other, the initial presentation developed at an older age and involved cognitive impairment. 9

“In 2014, a methodologically rigorous approach to assessing clinicopathological correlation in CTE was developed using comprehensive structured and semistructured informant interviews and online surveys conducted by a team of behavioral neurologists and neuropsychologists. 10

“In 2015, the neuropathological criteria for diagnosis of CTE were refined by a panel of expert neuropathologists organized by the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering (NINDS-NIBIB). 8

“Using the NINDS-NIBIB criteria to diagnose CTE and the improved methods for clinicopathological correlation, the purpose of this study was to determine the neuropathological and clinical features of a case series of deceased football players neuropathologically diagnosed as having CTE whose brains were donated for research.

“Study Recruitment: In 2008, as a collaboration among the VA Boston Healthcare System, Bedford VA, Boston University (BU) School of Medicine, and Sports Legacy Institute (now the Concussion Legacy Foundation [CLF]), a brain bank was created to better understand the long-term effects of repetitive head trauma experienced through contact sport participation and military-related exposure. The purpose of the brain bank was to comprehensively examine the neuropathology and clinical presentation of brain donors considered at risk of development of CTE.

“Clinical data were collected into a Federal Interagency Traumatic Brain Injury Research–compliant database. Since tracking began in 2014, for 98 (81%) brain donations to the VA-BU-CLF Brain Bank, the next of kin approached the brain bank near the time of death. The remaining brain donors were referred by medical examiners (11 [9%]), recruited by a CLF representative (7 [6%]), or participated in the Brain Donation Registry during life (5 [4%]) (eFigure in the Supplement).

“Discussion: In a convenience sample of 202 deceased former players of American football who were part of a brain donation program, a high proportion were diagnosed neuropathologically with CTE. The severity of CTE pathology was distributed across the highest level of play, with all former high school players having mild pathology and the majority of former college, semiprofessional, and professional players having severe pathology. Behavior, mood, and cognitive symptoms were common among those with mild and severe CTE pathology and signs of dementia were common among those with severe CTE pathology.

“Nearly all of the former NFL players in this study had CTE pathology, and this pathology was frequently severe. These findings suggest that CTE may be related to prior participation in football and that a high level of play may be related to substantial disease burden. Several other football-related factors may influence CTE risk and disease severity, including but not limited to age at first exposure to football, duration of play, player position, cumulative hits, and linear and rotational acceleration of hits. Recent work in living former football players has shown that age at first exposure may be related to impaired cognitive performance29 and altered corpus callosum white matter30 and that cumulative hits may be related to impairment on self-report and objective measures of cognition, mood, and behavior,31 although it is unclear if any of these outcomes are related to CTE pathology.

“Furthermore, it is unclear if symptomatic hits (concussions) are more important than asymptomatic hits resulting in subconcussive injury. As with other neurodegenerative diseases, age may be related to risk and pathological severity in CTE. It will be important for future studies to resolve how different measures of exposure to football and age influence the outcome.

“In cases with severe CTE pathology, accumulations of amyloid-β, α-synuclein, and TDP-43 were common. These findings are consistent with previous studies that show deposition of multiple neurodegenerative proteins after exposure to TBI32 and with work showing that neuritic amyloid-β plaques are associated with increased CTE neuropathological stage.33 Diagnoses of comorbid neurodegenerative diseases, including AD, Lewy body disease, motor neuron disease, and frontotemporal lobar degeneration, were also common in cases with severe CTE pathology.Overall, 19% of participants with CTE had comorbid Lewy body disease, which aligns with a recent observation by Crane et al34 regarding the increased prevalence of Lewy body pathology after single TBI. Chronic traumatic encephalopathy was not assessed in the analysis by Crane et al; to investigate the possibility of CTE after single TBI would require more extensive sampling of the depths of the cortical sulci with ptau immunostaining, as silver stains typically do not detect CTE pathology.

“Behavioral, mood, and cognitive symptoms were common among participants with either mild or severe CTE pathology. In participants with severe CTE pathology, there was marked ptau pathology in brain regions that have been associated with symptoms frequently reported: impulsivity, depressive symptoms, apathy, anxiety, and explosivity (prefrontal cortex, amygdala, locus coeruleus); episodic memory symptoms (hippocampus and entorhinal and perirhinal cortices); and attention and executive function symptoms (prefrontal cortex). Participants with mild CTE pathology often had these symptoms despite having relatively circumscribed cortical pathology and absence of ptau pathology in the hippocampus, entorhinal cortex, or amygdala.This may suggest that other pathologies not captured by the pathological data set, such as neuroinflammation, axonal injury, or astrocytosis, or pathologies in neuroanatomical regions not evaluated contribute to these clinical symptoms. Microglial neuroinflammation appears to precede tau accumulation in CTE,35 suggesting it may play a role in early symptoms.

“Informants reported that 43% of participants had behavior or mood symptoms as their initial presentation. Many of these participants had a substance use disorder, demonstrated suicidality, or had a family history of psychiatric illness. Behavior or mood symptoms may be the initial presentation for a subset of individuals with CTE, or alternatively, CTE ptau pathology may lower the threshold for psychiatric manifestations in susceptible individuals. These clinical observations confirm and expand on previous reports of 2 primary clinical presentations of CTE.9

“There is substantial evidence that CTE is a progressive, neurodegenerative disease. In this study, 107 participants (96%) had a progressive clinical course based on informant report. In addition, pathological severity of CTE was correlated with age at death (Table 3). However, a postmortem study evaluates brain pathology at only 1 time point and is by definition cross-sectional. In addition, the participants were not observed longitudinally during life. Although associations with age in cross-sectional samples can result from age-related progression within individuals, they can also arise from birth cohort effects, differential survival, or age-related differences in how individuals were selected into the study. Population-based prospective studies are needed to address the issue of progression of CTE pathology and age at symptom onset.

“The strengths of this study are that this is the largest CTE case series ever described to our knowledge, more than doubling the size of the 2013 report,6 and that all participants were exposed to a relatively similar type of repetitive head trauma while playing the same sport. In addition, the comprehensive neuropathological evaluation and retrospective clinical data collection were independently performed while blinded to the findings of the other investigators.

“Conclusions: In a convenience sample of deceased football players who donated their brains for research, a high proportion had neuropathological evidence of CTE, suggesting that CTE may be related to prior participation in football.

See the complete report in the following reference: [Mez J, Daneshvar DH, Kiernan PT, Abdolmohammadi B, Alvarez VE, Huber BR, Alosco ML, Solomon TM, Nowinski CJ, McHale L, Cormier KA, Kubilus CA, Martin BM, Murphy L, Baugh CM, Montenigro PH, Chaisson CE, Tripodis Y, Kowall NW, Weuve J, McClean MD, Cantu RC, Goldstein LE, Katz DI, Stern RA, Stein TD, McKee AC. Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football. JAMA. 2017;318(4):360-370. doi:10.1001/jama.2017.8334]

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