Postmortem evidence shows the prevalence of chronic traumatic encephalopathy (CTE) in football players is extremely high, in findings that suggest these athletes may be at increased risk for long-term neurologic sequelae.
A team of investigators from multiple institutions in Boston, Massachusetts, and Stanford, California, analyzed the brains of 202 football players and found that CTE was neuropathologically diagnosed in 87% of the entire cohort, including 110 (99%) of the 111 National Football League (NFL) players.
The neuropathologic severity of CTE increased with the level of play. All 3 former high school players had mild pathology, and most former college, semi-professional, and professional players had severe pathology.
“Because this was not a population-based study, we cannot use it to determine how common CTE is in the general population, but the fact that we could amass 177 instances of CTE over an 8-year period, while only screening brain donors for exposure, lets us know that this disease is not a rarity among individuals with high levels of exposure to head injuries,” said Daniel Daneshvar, MD, PhD, co-first author on the study and a resident at Stanford University.
“Although at this point we cannot make any firm sweeping public health statements about what types of hits cause CTE or about other risk factors, such as genetic risk, we can say that the fact that so many athletes develop CTE is very concerning, considering that we have children as young as 8 years old playing football and potentially subjecting themselves to this disease,” he told Medscape Medical News.
The study was published online in the July 25 issue of JAMA.
Suicide, Dementia
A progressive neurodegenerative condition associated with repetitive head trauma, criteria for neuropathologic diagnosis of CTE, and a staging scheme of pathologic severity were proposed in 2013. In 2014, comprehensive interviews of informants were developed and incorporated to assess clinicopathologic correlation in CTE.
In 2015, neuropathologic 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).
The purpose of the current study was to incorporate the NINDS-NIBIB criteria for diagnosis of CTE and the improved methods for clinicopathologic correlation into an approach that determined the neuropathologic and clinical features of a case series of deceased football players with CTE whose brains had been donated for research.
The researchers conducted retrospective clinical evaluations using online surveys and structured and semi-structured postmortem telephone interviews.
Informants provided a detailed history that included a timeline of cognitive, behavioral, mood, and motor symptoms. The researchers also assessed other neuropsychiatric symptoms and causes of death and obtained information regarding demographics, educational attainment, athletic history (including type of sports played, level, position, age at first exposure, and duration), military history, and traumatic brain injury history, including the number of concussions.
The neuropathologic evaluation was conducted in accordance with the 2015 NINDS-NIBIB consensus conference as well as well-established criteria for other neuropathologic diseases.
In particular, neuropathologic criteria for CTE require at least one perivascular p-tau lesion, consisting of p-tau aggregates in neurons, astrocytes, and cell processes around a small blood vessel. There are several other supporting features, such as p-tau pretangles and neurofibrillary tangles (NFTs) or extracellular tangles in various regions of the brain.
CTE p-tau pathology was classified into four stages based on the number and location of the perivascular epicenters of p-tau NFTs and neurites (ie, CTE lesions). Stages II and I are considered to be mild, while stages III and IV are considered to be severe.
CTE was neuropathologically diagnosed in 87% (n = 177) of the total sample of 202 deceased former football players (median age at death, 66 years [interquartile range [IQR], 47 – 76 years]).
Among players diagnosed, the median age at death was 67 years (IQR, 52 – 77 years); the mean duration of football participation was 15.1 years (standard deviation [SD], 5.2), including 0 of 2 pre–high school, 21% of high school, 91% of college, 64% of semiprofessional, 88% of Canadian Football League, and 99% (110 of 111) of NFL players.
Neuropathologic severity of CTE was “distributed across the highest level of play,” the researchers report, with all 3 former high school players having mild pathology and most former college (27 [56%]), semiprofessional (5 [56%]), and professional (101 [86%]) players having severe pathology.
Twenty-six of the 27 participants (96%) with mild CTE pathology (stages I and II) 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 (stages III and IV), 75 (89%) had behavioral or mood symptoms or both, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia.
The median age at death for participants with mild and severe CTE pathology was 44 years (IQR, 29 – 64 years) and 71 years (IQR, 64 – 79 years), respectively.
Participants with longer duration of play had more severe pathology (mean duration, 13 years [SD, 4.2] for those with mild CTE pathology and 15.8 years [SD, 5.3] for those with severe CTE pathology).
Suicide was the most common cause of death for participants with mild CTE pathology (12 [27%]). In severe CTE pathology, neurodegenerative conditions (62 [47%]) were the most common causes of death.
“Astounding” Findings
Informant reports on clinical symptoms revealed that a progressive clinical course was common in participants with both mild and severe CTE pathology, occurring in 23 (85%) mild cases and 84 (100%) severe cases. In all cases, mood and behavioral symptoms, as well as impulsivity, depressive symptoms, apathy, and anxiety, were common.
Hopelessness, explosiveness, verbal violence, physical violence, and suicidality occurred in 18 (69%), 18 (67%), 17 (63%), 14 (52%), and 15 (56%) mild cases, respectively. Cognitive symptoms were common in participants with both mild and severe CTE pathology, with symptoms occurring in 23 (85%) mild cases and 80 (95%) severe cases.
Among the 111 patients with CTE for whom standardized informant reports on clinical symptoms were available, 47 (42.3%) initially presented with cognitive symptoms, 48 (43.2%) presented with behavior or mood symptoms, and 16 (14.4%) presented with both cognitive and behavior or mood symptoms.
Perivascular clusters of p-tau immunoreactive NFTs diagnostic for CTE (ie, CTE lesions) were found in the cerebral cortex in all cases. In cases with severe CTE pathology, accumulations of amyloid-β, α-synuclein, and TDP-43 were also common.
In severe cases of CTE pathology, diagnoses of comorbid neurodegenerative diseases were also common.
The authors note several important limitations, primarily that the cohort was a “convenience sample” of brains gleaned from a brain donation program.
Dr Daneshvar explained the implications of using a convenience sample.
“We had a skewed sample because individuals who choose to donate their loved ones’ or their own brains to a research center focusing on CTE have some concerns that there is an increased possibility of a neurodegenerative disease process.”
Nevertheless, “we created the most methodologically rigorous brain bank to study long-term effects of brain trauma. And with this cohort, we are not only characterizing individuals who passed away but also learning as much as we can from these donors and apply it to individuals who are still alive.”
The way to do this is to “better understand the mechanism of this disease,” he said.
“Something about the brain being hit repetitively causes tau to form abnormal structures associated with CTE. We do not know what that is, and we are hoping the brain bank will allow us to begin to address that question. The fact that such a high proportion of our cohort had CTE was astounding,” he said.
Link Difficult to Deny
Commenting on the study for Medscape Medical News, Gil Rabinovici, MD, professor of neurology, University of California, San Francisco, said that the study “confirms in a much larger sample earlier observations from case studies and smaller series that CTE is commonly found in the brains of former players whose brains are donated to autopsy, particularly those who played professionally.”
Dr Rabinovici, who is the author of an accompanying editorial, noted other contributions, including “the detailed assessment for postmortem changes associated with other brain disease like Alzheimer’s, Parkinson’s, and ALS [amyotrophic lateral sclerosis].” Additionally, “through retrospective interviews, the researchers were able to describe the neurologic and psychiatric symptoms associated with different stages of CTE pathology.”
He raised some concerns regarding the “inherent limitations of the study.”
“I think it is increasingly difficult to deny a link between CTE and repeated traumatic brain injury, be it through contact sports or other mechanisms,” but “I think it is fair to challenge how generalizable the findings are to an unbiased sample of football players, or those that participated in other contact sports.”
Translating the findings into clinical practice can be “difficult, since we do not have a way of detecting CTE in living people, but certainly CTE should be considered in the differential diagnosis of exposed individuals who experience neurological and psychiatric decline.”
Because the symptoms are not specific to CTE, “every effort should be made to assess for and treat any potentially treatable factors.”
He noted that study findings have important public health implications.
“The authors found CTE changes not only in professional players but also in some individuals who played at the collegiate and even high school level, suggesting that lower levels of exposure may be sufficient to lead to brain injury. The latter point is more significant than findings in pro players, from a public health point of view.”
“We need to be much more aware of the symptoms of concussion and be strict about return to play rules. While there is more awareness than there was a few years ago, there is still room for improvement, particularly in youth sports,” he added.
He warned that this might not be enough. “It may be not only the concussions but also the subconcussive blows — head impacts that do not lead to a full-blown concussion but make athletes feel as if ‘they got their bell rung’ — that add to the risk of CTE, therefore changes that prevent or minimize the risk of head impacts should be on the agenda of all sports.”
Dr Daneshvar agreed. “The fact that so many of these individuals with CTE were diagnosed with other disease processes in their life may indicate that often, CTE is not on the clinician’s differential.”
He noted that research into CTE is “still in its infancy,” and there are currently no disease-modifying agents. Nevertheless, “at least being able to provide some understanding of what is going on might be helpful for individuals, caregivers, or other loved ones as they navigate the disease process.”
The study was supported by a grant from the National Institute of Mental Health. Dr Daneshvar has disclosed no relevant financial relationships. Other study authors reported multiple sources of research funding. Dr Rabinovici receives research support from Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, and Piramal. He has received consulting or speaking honoraria from Eisai, Genentech, Lundbeck, Merck, Putnam, and Roche and receives an honorarium for his duties as an associate editor for JAMA Neurology.
JAMA. Published online July 25, 2017. Abstract, Editorial
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