In a case series of 202 former football players whose brains were donated for research, 87% of the participants had neuropathologic evidence of chronic traumatic encephalopathy (CTE), according to a study published in the July 25 issue of JAMA. Among 111 players who played in the National Football League (NFL), 99% had CTE. A progressive clinical course was common in players with mild and severe CTE pathology. The results suggest that CTE may be related to prior participation in football, the researchers said.

The report by Jesse Mez, MD, MS, Assistant Professor of Neurology at Boston University, and colleagues describes the largest CTE case series to date. A limitation of the study, however, is that brain donation programs are associated with ascertainment bias. Awareness of a possible link between repetitive head trauma and CTE may have motivated players with signs of brain injury and their families to participate in the study. “Therefore, caution must be used in interpreting the high frequency of CTE in this sample, and estimates of prevalence cannot be concluded or implied from this sample,” Dr. Mez and colleagues said.

Findings From a Brain Bank

CTE is a progressive neurodegenerative disease associated with repetitive head trauma. To study the neuropathology and clinical presentation of brain donors with exposure to repetitive head trauma, investigators in 2008 established the Veterans Affairs–Boston University–Concussion Legacy Foundation Brain Bank.

The present study assessed donors who participated in American football at any level of play. Outcomes included neuropathologic diagnoses of neurodegenerative diseases, including CTE; CTE neuropathologic severity; and informant-reported athletic history and clinical presentation.

Investigators conducted retrospective telephone clinical assessments with informants to determine participants’ clinical presentations, including timelines of behavior, mood, and cognitive symptoms. Neither the researchers nor the informants knew the participants’ neuropathology during the interview. Online questionnaires ascertained participants’ athletic and military histories. Pathologists were blinded to exposure data and clinical information.

Level of Play

Among the 202 former football players (median age at death, 66), CTE was neuropathologically diagnosed in 177 players. Participants with CTE had played football for a mean of 15.1 years.

Investigators diagnosed CTE in three of 14 players (21%) whose highest level of play was at the high school level, 48 of 53 players (91%) who played at the college level, nine of 14 players (64%) who played at the semiprofessional level, seven of eight players (88%) who played in the Canadian Football League, and 110 of 111 players (99%) who played in the NFL. Pathologists did not diagnose CTE in two participants whose highest level of play was before high school.

The three players with CTE whose highest level of play was in high school had mild CTE pathology (ie, stage I or II), whereas the majority of former college, semiprofessional, and professional players had severe pathology (ie, stage III or IV).

Among the 111 CTE cases with standardized informant reports on clinical symptoms, a progressive clinical course was reported in 85% of participants with mild CTE pathology and in 100% of participants with severe CTE pathology.

Among the 27 players with mild CTE pathology, 96% had behavioral or mood symptoms or both, 85% had cognitive symptoms, and 33% had signs of dementia. Among the 84 players with severe CTE pathology, 89% had behavioral or mood symptoms or both, 95% had cognitive symptoms, and 85% had signs of dementia.

“Nearly all of the former NFL players in this study had CTE pathology, and this pathology was frequently severe,” Dr. Mez and colleagues said. “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.”

Future studies should assess how factors such as age at first exposure to football, duration of play, player position, cumulative hits, and linear and rotational acceleration of hits may influence outcomes, the researchers said.

Opportunities for Symptomatic Treatment

The rate of symptomatic CTE may be lower in an unselected population of former football players, said Gil D. Rabinovici, MD, Professor of Neurology at the University of California, San Francisco, in an accompanying editorial.

“The prevalence of cognitive and behavioral symptoms in the autopsy cohort was 88% and 95%, respectively,” he said. “In contrast, questionnaire-based ascertainment of neuropsychiatric symptoms among retired NFL players found that the prevalence of memory symptoms and depression was 5% to 20%. Acknowledging that questionnaires are an insensitive method for detecting neurodegenerative disease, the large discrepancy suggests that the rates of symptomatic CTE may be lower in an unselected cohort of former players.”

In addition, this study and prior studies suggest that there may be opportunities to improve care of patients with CTE. “Potentially treatable contributing factors are found in many patients, including high rates of substance abuse, affective disorders, headaches, and sleep disturbances,” Dr. Rabinovici said. “Thus, at-risk patients may benefit from a multidisciplinary medical team to optimize symptomatic treatment and maximize patient function and quality of life.”

—Jake Remaly

Suggested Reading

Mez J, Daneshvar DH, Kiernan PT, et al. Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA. 2017;318(4):360-370.

Rabinovici GD. Advances and gaps in understanding chronic traumatic encephalopathy: From pugilists to American football players. JAMA. 2017;318(4):338-340.

Study Details CTE in Football Players

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