IMPORTANCE Players of American football may be at increased risk of long-term neurological conditions, particularly chronic traumatic encephalopathy (CTE). OBJECTIVE To determine the neuropathological and clinical features of deceased football players with CTE. DESIGN, SETTING, AND PARTICIPANTS Case series of 202 football players whose brains were donated for research. Neuropathological evaluations and retrospective telephone clinical assessments (including head trauma history) with informants were performed blinded. Online questionnaires ascertained athletic and military history. EXPOSURES Participation in American football at any level of play. MAIN OUTCOMES AND MEASURES Neuropathological diagnoses of neurodegenerative diseases, including CTE, based on defined diagnostic criteria; CTE neuropathological severity (stages I to IV or dichotomized into mild [stages I and II] and severe [stages III and IV]); informant-reported athletic history and, for players who died in 2014 or later, clinical presentation, including behavior, mood, and cognitive symptoms and dementia. RESULTS Among 202 deceased former football players (median age at death, 66 years [interquartile range, 47–76 years]), CTE was neuropathologically diagnosed in 177 players (87%; median age at death, 67 years [interquartile range, 52–77 years]; mean years of football participation, 15.1 [SD, 5.2]), including 0 of 2 pre–high school, 3 of 14 high school (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8 Canadian Football League (88%), and 110 of 111 National Football League (99%) players. Neuropathological severity of CTE was distributed across the highest level of play, with all 3 former high school players having mild pathology and the majority of former college (27 [56%]), semiprofessional (5 [56%]), and professional (101 [86%]) players having severe pathology. Among 27 participants with mild CTE pathology, 26 (96%) had behavioral or mood symptoms or both, 23 (85%) had cognitive symptoms, and 9 (33%) had signs of dementia. Among 84 participants with severe CTE pathology, 75 (89%) had behavioral or mood symptoms or both, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia. CONCLUSIONS AND RELEVANCE 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.

The chronic effects of repetitive head impacts (RHI) on the development of neuroinflammation and its relationship to chronic traumatic encephalopathy (CTE) are unknown. Here we set out to determine the relationship between RHI exposure, neuroinflammation, and the development of hyperphosphorylated tau (ptau) pathology and dementia risk in CTE. We studied a cohort of 66 deceased American football athletes from the Boston University-Veteran’s Affairs-Concussion Legacy Foundation Brain Bank as well as 16 non-athlete controls. Subjects with a neurodegenerative disease other than CTE were excluded. Counts of total and activated microglia, astrocytes, and ptau pathology were performed in the dorsolateral frontal cortex (DLF). Binary logistic and simultaneous equation regression models were used to test associations between RHI exposure, microglia, ptau pathology, and dementia. Duration of RHI exposure and the development and severity of CTE were associated with reactive microglial morphology and increased numbers of CD68 immunoreactive microglia in the DLF. A simultaneous equation regression model demonstrated that RHI exposure had a significant direct effect on CD68 cell density (p < 0.0001) and ptau pathology (p < 0.0001) independent of age at death. The effect of RHI on ptau pathology was partially mediated through increased CD68 positive cell density. A binary logistic regression demonstrated that a diagnosis of dementia was significantly predicted by CD68 cell density (OR = 1.010, p = 0.011) independent of age (OR = 1.055, p = 0.007), but this effect disappeared when ptau pathology was included in the model. In conclusion, RHI is associated with chronic activation of microglia, which may partially mediate the effect of RHI on the development of ptau pathology and dementia in CTE. Inflammatory molecules may be important diagnostic or predictive biomarkers as well as promising therapeutic targets in CTE.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild traumatic brain injury. It is defined pathologically by the abnormal accumulation of tau in a unique pattern that is distinct from other tauopathies, including Alzheimer’s disease (AD). Although trauma has been suggested to increase amyloid β peptide (Aβ) levels, the extent of Aβ deposition in CTE has not been thoroughly characterized. We studied a heterogeneous cohort of deceased athletes and military veterans with neuropathologically diagnosed CTE (n = 114, mean age at death = 60) to test the hypothesis that Aβ deposition is altered in CTE and associated with more severe pathology and worse clinical outcomes. We found that Aβ deposition, either as diffuse or neuritic plaques, was present in 52 % of CTE subjects. Moreover, Aβ deposition in CTE occurred at an accelerated rate and with altered dynamics in CTE compared to a normal aging population (OR = 3.8, p < 0.001). We also found a clear pathological and clinical dichotomy between those CTE cases with Aβ plaques and those without. Aβ deposition was significantly associated with the presence of the APOE ε4 allele (p = 0.035), older age at symptom onset (p < 0.001), and older age at death (p < 0.001). In addition, when controlling for age, neuritic plaques were significantly associated with increased CTE tauopathy stage (β = 2.43, p = 0.018), co-morbid Lewy body disease (OR = 5.01, p = 0.009), and dementia (OR = 4.45, p = 0.012). A subset of subjects met the diagnostic criteria for both CTE and AD, and in these subjects both Aβ plaques and total levels of Aβ1–40 were increased at the depths of the cortical sulcus compared to the gyral crests. Overall, these findings suggest that Aβ deposition is altered and accelerated in a cohort of CTE subjects compared to normal aging and that Aβ is associated with both pathological and clinical progression of CTE independent of age.

The highly addictive drug methamphetamine has been associated with impairments in social cognitions as evidenced by changes in users' behaviors. Physiological changes in brain structure and functioning, particularly in the frontal lobe, have also been identified. The authors propose a biopsychosocial approach to understanding the effects of methamphetamine addiction by relating the physiological effects of the drug to the behaviors and social cognitions of its users, through the application of the theory of mind paradigm. Although onset of methamphetamine use has been linked to the desire for socialization, chronic use has been associated with an increase in depression, aggressiveness, and social isolation, behaviors that also implicate involvement of the frontal lobe. The reviewed literature provides strong circumstantial evidence that social-cognitive functioning is significantly impacted by methamphetamine use and that the social isolation, depression, and aggressiveness associated with chronic use is due to more than just the social withdrawal associated with addiction. Treatment considerations for methamphetamine must therefore consider the role of social cognition, and pharmacological responses must address the documented impact of the drug on frontal lobe functioning.

In this sample of deceased tackle football players, younger age of exposure to tackle football was not associated with CTE pathological severity, but predicted earlier neurobehavioral symptom onset. Youth exposure to tackle football may reduce resiliency to late-life neuropathology. These findings may not generalize to the broader tackle football population, and informant-report may have affected the accuracy of the estimated effects. Ann Neurol 2018;83:886-901.