Evidence of a correlation between chronic traumatic encephalopathy (CTE) and playing American football was strengthened in the largest retrospective study cohort to date.

The progressive neurodegenerative disease associated with recurrent head trauma has been linked to football over the past decade. However, this new study took steps to solidify the connection by studying 202 deceased brains, more than double the size of a previous 2013 report.

First author Jesse Mez, MD, of Boston University, and his colleagues examined the brains donated to a brain bank jointly run by the VA Boston Healthcare System, Boston University, and the Concussion Legacy Foundation. They correlated their findings with interviews and questionnaires filled out in 2014 by those close to the donors (JAMA. 2017 Jul 25. doi: 10.1001/jama.2017.8334).

The donors were male, and a majority (79%) were white. The average age at death was 67 years. In the mild cases, there was an average of 13 years of play; in severe cases, the average was 15.8 years.

The researchers found evidence of CTE in 177 (88%) of the 202 brains of football players, with cases found in 3 (21%) who played only in high school, 48 (91%) who played in college, 9 (64%) semiprofessional players, 7 (88%) Canadian Football League players, and 110 (99%) NFL players, according to investigators.

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

Severity of CTE positively correlated with longer playing history and more competitive levels of play. According to the investigators, severe cases of CTE were found in none of the high school players, 27 college players (56%), 5 semiprofessional players (56%), 6 Canadian professional players (86%), and 95 NFL players (86%).

All participants with CTE commonly displayed certain symptoms regardless of severity level.

Impulsiveness occurred in 23 mild cases (89%) and 65 severe cases (80%). Depression was seen in 18 mild cases (67%) and 46 severe cases (56%). A total of 13 players (50%) with mild symptoms showed apathy, compared with 43 with severe symptoms (52%). Anxiety was reported for 14 mild cases (52%) and 41 severe cases (50%). Cognitive symptoms such as problems with memory and attention were also common at both levels of severity, with 19 cases (73%) and 18 cases (69%), respectively, among donors with mild CTE, and 76 (92%) and 67 (81%) among donors with severe CTE.

Those interviewed who were close to the donors also reported other behavior or mood symptoms that the investigators inferred to be related to CTE.

“Many of these participants had a substance use disorder, demonstrated suicidality, or had a family history of psychiatric illness,” the investigators wrote. “Behavior or mood symptoms may be the initial presentation for a subset of individuals with CTE, or alternatively, CTE [phosphorylated tau] pathology may lower the threshold for psychiatric manifestations in susceptible individuals.”

The investigators asserted that the correlation of CTE diagnosis and severity may be more nuanced than just how many times a player is hit.

“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,” Dr. Mez and his associates wrote. “Recent work in living former football players has shown that age at first exposure may be related to impaired cognitive performance and altered corpus callosum white matter and that cumulative hits may be related to impairment on self-report and objective measures of cognition, mood, and behavior, although it is unclear if any of these outcomes are related to CTE pathology.”

This study was limited by the potential bias of donors who participated in the program. Researchers acknowledge that public awareness of the issue of CTE and head trauma may have influenced players with symptoms to donate their brains, thereby increasing the CTE frequency in the sample.

In addition, the brain bank where the sample was taken is not representative of the entire population of American football players, as most donors played at the college, semi-professional, and professional level, as opposed to only high school or youth leagues.

The senior author of the study, Ann C. McKee, MD, discussed the study further in a related video interview.

The National Institute of Neurological Disorders and Stroke, the National Institute of Aging, the U.S. Department of Defense, the U.S. Department of Veterans Affairs, the National Operating Committee on Standards for Athletic Equipment, the Alzheimer’s Association, the Concussion Legacy Foundation, the Andlinger Family Foundation, the WWE, and the NFL supported the study. Five authors reported receiving support from relevant sources, including the NFL.

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VIDEO: Further CTE correlation found in deceased American football players