McKee cautions that the study has some limitations and doesn't attempt to pinpoint a CTE rate. The brains studied were mostly donated by concerned families, which means they weren't random and not necessarily representative of all men who have played football.
"A family is much more likely to donate if they're concerned about their loved one - if they're exhibiting symptoms or signs that are concerning them, or if they died accidentally or especially if they committed suicide," she said. "It skews for accidental deaths, suicide and individuals with disabling or discomforting symptoms."
While the study isn't focused on causality, McKee says it provides "overwhelming circumstantial evidence that CTE is linked to football."
The NFL pledged $100 million for concussion-related research last September - $60 million on technological development, with an emphasis on improving helmets, and $40 million earmarked for medical research - and in a statement a league spokesman expressed appreciation for the latest study.
"The medical and scientific communities will benefit from this publication and the NFL will continue to work with a wide range of experts to improve the health of current and former NFL athletes," said NFL spokesman Brian McCarthy. "As noted by the authors, there are still many unanswered questions relating to the cause, incidence and prevalence of long-term effects of head trauma such as CTE. The NFL is committed to supporting scientific research into CTE and advancing progress in the prevention and treatment of head injuries."
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The study marks the largest CTE case series ever published. The research was drawn from a brain bank established and maintained by the VA Boston Healthcare System, Boston University School of Medicine and the Concussion Legacy Foundation.
The 177 brains found to have CTE belonged to former players who had an average of 15 years of football experience. In addition to the NFL diagnoses, the group included three of 14 who played at the high school level, 48 of 53 who played in college, nine of 14 who competed semiprofessionally and seven of eight who played in the Canadian Football League.
"To me, it's very concerning that we have college-level players who have severe CTE who did not go on to play professionally," McKee said. "That means they most likely retired before the age of 25 and we still are seeing in some of those individuals very severe repercussions."
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The researchers distinguished between mild and severe cases of CTE, finding the majority of former college (56 percent), semipro (56 percent) and professional (86 percent) players to have exhibited severe pathology.
The impact of concussions and head trauma meted out on the football field has been an active area of study in recent years. And while much of the research has highlighted the potential long-term dangers posed by football, JAMA Neurology published a study this month that showed not all former players suffer from cognitive impairment.
Researchers at the University of Pennsylvania looked at Wisconsin men who graduated high school in 1957, comparing those who played football in school and those who didn't. The men were assessed for depression and cognitive impairment later in life - in their 60s and 70s - and the research found similar outcomes for those who played high school football and those who didn't.
That study also had its limitations, and the authors noted that the game 60 years ago is different in many ways from the present-day high school football experience, from playing style to equipment to the rule book.
The Boston University study doesn't necessarily reflect the same era of football. According to the researchers, the vast majority of the brains studied belonged to players who played in the 1960s or later. In addition to examining the brains, researchers interviewed family members and loved ones of the deceased former players and found that behavioral and mood symptoms were common with those who suffered from CTE, including impulsivity, signs of depression, anxiety, hopelessness and violent tendencies.
While the disease can currently only be diagnosed post-mortem, the researchers urge for a wide-ranging longitudinal study to better understand the impact head trauma has on football players across all levels.
In the meantime, the brain bank has about 425 donated brains at its disposal, including those from men and women who played a variety of sports, as well as military veterans, with many more pledged.
"It's not an inert study," McKee said. "This is a very large resource that will advance research in many directions. . . . The whole point is to advance and accelerate our knowledge of CTE in order to aid the living people who are at risk for it or who have it."
