This article presents a brief history and literature review of chronic traumatic encephalopathy (CTE) in professional athletes that played contact sports. The hypothesis that CTE results from concussion or sub-concussive blows is based largely on several case series investigations with considerable bias. Evidence of CTE in its clinical presentation has not been generally noted in studies of living retired athletes. However, these studies also demonstrated limitation in research methodology. This paper aims to present a balanced perspective amidst a politically charged subject matter.
Key points
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Case series studies that describe the neuropathology of chronic traumatic encephalopathy have generated a hypothesis that some former athletes may develop neurodegeneration later in life.
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Studies of aging retired contact sport athletes, generally including age-matched control groups, suggest early onset dementia is rare.
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Imaging studies of former contact sport athletes have yielded mixed results but PET studies seem close to being able to identify CTE in living persons.
Introduction
There has been a dramatic increase in understanding the long-term neurocognitive and mental health consequences of playing contact sports. This article begins by discussing the possible link between repetitive head injuries and neuropathologic and neurocognitive disorders. Then we discuss mental health problems commonly found in this population and their radiologic findings. Lastly, we review other causes of neurocognitive and mental health disorders in this population that are independent of repetitive head injuries.
Chronic traumatic encephalopathy
History
The links between head injuries during sports and impairments in neurocognitive and mental health have been studied since 1928 when forensic pathologist Harrison Martland wrote about the typical tremors, slowed movement, confusion, and speech problems found in boxers with dementia pugilistic. The term chronic traumatic encephalopathy (CTE) was first used in 1949 to describe the “punch-drunk” syndrome in boxers, and was initially believed to only affect boxers who took considerable blows to the head and not athletes who played other contact sports. In 1973 Corsellis and colleagues described 15 cases where there was pronounced neuropathologic changes including ventricular dilatation, cavum septum pellucidum enlargement, and neurofibrillary tangles. The National Institutes of Health held a consensus meeting in 2015 to define the neuropathologic criteria for CTE diagnosis, and concluded, with acceptable agreement (61%), that pathognomonic lesions for CTE were abnormal perivascular accumulation of tau in neurons, astrocytes, and cell processes in an irregular pattern at the depths of the sulci of the frontal, temporal, or parietal cortices. Goldfinger and colleagues re-examined the specimens of the brains studied by Corsellis and only found half of the 14 specimens qualified as CTE using the more recent National Institutes of Health–approved criteria. CTE is considered a neurodegenerative disorder but clearly there is not solid agreement on what pathologists should use as the gold standard for diagnosis.
Forensic pathologist Bennet Omalu in 2005 is credited for bringing attention to the disease in the nonboxer population when he published a case-report of a 50-year-old former National Football League (NFL) athlete with suspected CTE who presented with gross neurobehavioral impairments before dying by suicide. There has been an exponential increase in research describing the long-term effects of repetitive head injuries since the first case-reports were published. In 2009, McKee and colleagues, from the Boston University brain bank, described CTE in three more cases of former athletes, two of whom were boxers. In 2013, McKee and colleagues described postmortem analysis of 85 former NFL and National Hockey League (NHL) athletes, most with a history of repetitive mild traumatic brain injury ranging in age from 17 to 98, and found 65 (76.5%) had CTE. The more recent research publication by Mez and colleagues on the association of CTE and football, also from the Boston University group, reported that of 111 NFL players, 110 (99.1%) showed evidence of CTE on postmortem examination using the new 2015 criteria. In the total sample of 202 high school, college, and professional football players, various degrees of CTE were diagnosed in 177 of these players (87.6%). In a follow-up study Mez and colleagues reported on 266 former American football players, where 233 (87.6%) met diagnostic criteria for CTE. They found a correlation between years played and severity of CTE. All of the athletes represented in the study had their brains donated to the brain bank managed by Boston University. All of the pathologic studies were conducted by the same pathologist, thus no evaluation of interrater reliability. There was no comparison group. The authors provided a discussion of ascertainment bias; simply stated, families of individuals with cognitive deficits were far more likely to donate the brain of their deceased family member for study. The collaborative effort led by Boston University to create a brain bank has been instrumental to the expansion of research on CTE. Their research suggests CTE is prevalent among athletes that play contact sports, especially at the professional level. However, the sample studied may not be representative of the entire population of former contact sport athletes.
Pathophysiology
The pathophysiology of CTE is complex, and we must begin with the classical finding of CTE. The pathognomonic findings of CTE include abnormal perivascular accumulation of tau in an irregular pattern at the depths of the sulci of the frontal, temporal, or parietal cortices. But where does this tau come from? Tau is a microtubule-associated protein present in the neuron. It promotes the assembly and maintenance of microtubules, which are responsible for intracellular transport, axonal morphology, and cell physiology. Tau is a fundamental component in the brain, because it is responsible for maintaining neuronal integrity and axoplasmic transport. , Recent animal research has shown that traumatic brain injuries can cause shearing of microtubules, , releasing tau into the extracellular space that subsequently undergoes hyperphosphorylation and deposits in the cortex. The hyperphosphorylated tau is unable to perform its normal function and the brain does not have a system of removing excess tau. Tau begins to accumulate and can even form widespread plaques in severe cases. This can cause direct and indirect effects on the surrounding tissues, which can lead to further neurodegeneration. , Higher concentrations of tau correlate with greater neurocognitive dysfunction in severe cases of CTE ; however, the presence of tau on histochemical assessment is not specific to a history of repetitive head trauma or playing sports. , Rather, it is more suggestive of neurodegeneration than healthy aging.
Traumatic encephalopathy syndrome
Definition
As a result of the research on former NFL athletes and the retrospective diagnoses of impaired cognitive and psychosocial function in athletes with autopsy-confirmed CTE, there has been a movement toward developing a clinical diagnostic criterion for individuals who experienced chronic exposure to repetitive head impacts presenting with cognitive and psychological complaints. That is, CTE is the neuropathologic determination of disease confirmed at autopsy, whereas traumatic encephalopathy syndrome (TES) represents the clinical symptoms, including behavioral, cognitive, and psychological complaints, in individuals who have experienced repetitive head trauma. , More work is needed to define the clinical diagnostic criteria for TES because recent work indicated that approximately 50% of a sample of men with clinical depression met the research criteria for TES.
Is there a direct relationship between the diagnosis of CTE and behavioral decline and/or cognitive deficits? Gavett and colleagues conducted interviews with friends and family members of people who had documented CTE. They described a consistent pattern of impairment in cognition, executive function, mood, behavior (impulsivity), and signs of motor neuron disease. Stern and colleagues conducted a similar retrospective analysis of 36 deceased athletes (average age of death 56.8 years) with confirmed CTE (mostly former NFL athletes and a few former NHL athletes). Three of these athletes were asymptomatic, 11 had cognitive dysfunction, 13 had behavior alterations that gradually became mood changes, and 10 were diagnosed with dementia. Using next-of-kin interviews, Alosco and colleagues studied 25 professional football players (mean age at death, 65 years) with autopsy-confirmed stage III or IV CTE. They found that 25 of 25 had cognitive symptoms and their age of cognitive decline was inversely related to their cognitive reserve.
In vivo studies in living, retired contact sport athletes have found conflicting results regarding the prevalence of TES. Hart and colleagues compared 34 former NFL athletes (average age, 62) with 28 age and education matched control subjects. Control subjects were drawn from a larger sample of subjects from another study and were excluded if they had any cognitive impairments. Among the 34 retired NFL athletes they found eight to qualify as mild cognitive impairment and two had dementia. Of the two with dementia, one had vascular dementia associated with diabetes and stroke, whereas the other was of unknown cause. Casson and colleagues examined 45 retired NFL players (average age, 45; average career of almost 7 years) and found no evidence of cognitive decline. Esopenko and colleagues studied 33 former professional ice hockey players (average age, 54) and compared them with 18 age-matched control subjects. They found few differences on a full range of cognitive measures and no differences on critical cognitive factors, such as memory. They found that the athletes performed much better on all of the measures of cognition than the athletes expected they would perform. McMillan and colleagues examined a sample of 52 former international rugby athletes (average age, 53) and 29 age-matched control subjects. They also found minimal differences; the only exception, athletes did poorly on one test of verbal learning. Importantly, the mean scores for both groups on almost every measure of cognition were in the average range for age and there were no differences in mental health or daily functioning between the retired athletes and the control group. Tarazi and colleagues compared 45 retired Canadian Football League players (average age, 53) with 25 age-matched control subjects. They found no evidence of motor decline and found no differences on objective measures of memory, attention, or processing speed. However, they reported that the athletes perceived themselves as having cognitive problems. Despite the lack of any objective evidence of decline, the authors chose to emphasize the self-reported cognitive problems as evidence of modern CTE, as opposed to classic CTE, which would have also included motor decline. Willer and colleagues published three papers from the same sample population in 2018. The authors compared 21 retired NFL and NHL players (average age, 54) with 21 age-matched, noncontact sport athletes. They did not find significant differences in executive functioning or mood disorders, or the incidence of mild cognitive impairment. The authors commented that the control subjects were recruited from an athletic population who were competitive in their youth and continued to remain active and competitive through their 50s, 60s, and 70s. The Willer and colleagues studies also reported that retired contact sport athletes self-described many more problems with cognition and executive function than was apparent on objective testing. They also found the former NHL/NFL athletes were anxious with most of that anxiety because of the belief that they might develop CTE and have a rapid decline in function.
The studies of cognitive and behavioral impairment in former contact sport athletes are summarized in Table 1 . The number of subjects represented in these studies is 235, average age 54, yet only two were identified as having dementia, and only one of these as possible TES. There was no evidence across studies of cognitive impairment outside normal aging and mixed results with respect to behavioral functioning, with one study finding superior executive functioning and one finding inferior executive functioning. It is possible that, despite the best efforts to encourage participation, studies of retired athletes are only able to recruit the healthiest, thereby underrepresenting those with dementia. It is also possible that the prevalence of early onset dementia or TES is simply not as high as once believed.
| Author, Year | Athlete Sample | Mean Age | Control Sample | Cognitive Impairment | Behavioural Impairment |
|---|---|---|---|---|---|
| Hart et al, 2013 | NFL, N = 34 | 62 | N = 28 | 8 MCI 2 Dementia | 8 depressed |
| Casson et al, 2014 | NFL, N = 45 | 46 | 0 | 0 Dementia | 9 depressed |
| Tarazi et al, 2018 | CFL, N = 45 | 53 | N = 25 | 0 Dementia | Superior EF in athletes |
| Esopenko et al, 2017 | NHL, N = 38 | 54 | N = 20 | 0 Dementia | Reduced EF in athletes |
| McMillan et al, 2017 | Rugby, N = 52 | 54 | N = 29 | 0 Dementia | No differences |
| Willer et al, 2018 | NHL/NFL, N = 21 | 56 | N = 21 | 8 MCI, 0 dementia | 5 depressed, 7 anxious |
Large epidemiologic studies have also failed to find an association between contact sport exposure and neurocognitive impairments. In one such long-term study, they compared 834 men 65 years of age who had participated in American high school football with a sample of 1858 men from the same high schools who did not play football and there were no differences in rates of cognitive impairment or depression. In a similar study, Janssen and colleagues compared 296 high school football athletes (aged 60–80) with 190 athletes from the same high school and era who played noncontact sports. There were no differences in the rates of various neurologic diseases that would lead to dementia. Recent work from the CARE Consortium, including data from 3422 current male American collegiate football players and 914 noncontact sport athletes, found that exposure to head contact before age 12 was not associated with neurocognitive deficits while in college. The pattern of self-reported issues with cognition versus objective measures of cognitive decline turns out to be a common finding. A recent meta-analysis of studies published to-date suggests that a history of sports-related concussion impacts cognitive domains, such as psychomotor function, executive function, and memory. However, the authors conclude that the cause and effect relationship between sports-related concussion and long-term health outcomes is limited by the lack of high-quality and adequately powered prospective studies in the field. This confirms that although there is now a stronger understanding of the potential mechanisms involved in the processes underlying concussion, the epidemiologic evidence, and the strength of this evidence, to support the long-term effects on cognition remains unclear. Understanding whether concussion in sport is significantly associated with worsening of cognitive function in later life is of paramount importance. Uncovering this possible association would have immediate repercussion on current play policy and regulations, and possibly on the listing of cognitive decline as an occupational disease for former players.
Other neurocognitive and mental health consequences
Epidemiologic studies have reported some evidence of neurodegenerative disease in contact sport athletes aside from CTE. In a cohort study of nearly 3500 NFL alumni, overall mortality rates were lower than the general US population; however, rates of Alzheimer disease and amyotrophic lateral sclerosis were three and four times higher, respectively, than the general population. Similar results were found in a recent study examining cause of death in a large sample of former professional Scottish soccer players (N = 1180) compared with age-matched community-dwelling adults (N = 3807). The former professional soccer players showed a lower prevalence of all-cause mortality and ischemic heart disease, but showed a higher prevalence of death attributed to neurodegenerative disease (1.7% vs 0.5%). These studies compared general and neurologic health outcomes in professional contact sport athletes with the general population. One recent study examined causes of death in former Major League Baseball players, who have little exposure to repetitive head trauma, to former NFL players. The authors found that former NFL players had elevated all-cause mortality rates, and in particular, higher rates of death that included cardiovascular and neurodegenerative disease compared with former Major League Baseball players. Yet, it should be noted that other studies have failed to find an association between participating in American football at the high school level and neurodegenerative diseases, including Alzheimer disease, amyotrophic lateral sclerosis, or Parkinson disease. ,
Mood disorders seem to be present in many members of the retired athlete population. In one of the earliest studies of psychosocial function in former NFL players, Guskiewicz and colleagues found that a history of concussion was associated with lifetime diagnosis of depression, and moreover, that the prevalence of depression diagnoses increased in those with recurrent concussions. Furthermore, the risk of developing depression in former NFL players who have experienced concussions increases over time, ranging from 3% having a clinical diagnosis of depression in the no concussion group to 26.8% being diagnosed in the 10+ concussion group. Similar results have been shown between self-reported depression, impulsivity, and aggression with concussion history in former collegiate Division I athletes. In this sample, former athletes with three or more concussions were 2.4 times more likely to have moderate to severe depression and those with two or more concussions had higher mean impulsivity and aggression scores, compared with former athletes with no concussion history. Didehbani and colleagues found increased symptoms of depression in retired NFL players when compared with healthy age- and education-matched participants, but also that the number of lifetime concussions was significantly related to depression total scores. Results from the United States based National Longitudinal Study of Adolescent to Adult Health, which followed athletes starting at 16 years of age for approximately 13 years, found playing American high school football did not impact cognitive abilities, depressive symptoms, or suicidal ideation. However, there was a trend toward increased suicidal ideation in athletes with a history of contact sports, whereas the noncontact sport group showed a trend toward an increase in depressive symptoms. Most of the studies that suggest there is a significantly higher rate of depression in former contact sport athletes are postmortem studies. , , Well-designed, longitudinal studies, however, have not found an increased rate, and some have even found a lower rate of suicide among retired contact sport athletes.
Radiologic investigations of long-term consequences
Several imaging studies have been conducted to identify the possible long-term consequences of playing contact sports. Most of these studies have been performed with retired American football players and may not be generalizable to all contact sports. Koerte and colleagues used MRI to compare structural differences in the brains of 72 retired professional football players and 12 noncontact athlete control subjects. They found that retired football players had a greater incidence of having an enlarged cavum septum pellucidum associated with brain atrophy. The finding was also found by Gardner and colleagues in 17 retired professional football players and 17 matched control subjects. MRI studies have found other structural differences, with retired football players having greater cortical thinning and significantly smaller bilateral hippocampal volume. This cortical thinning is also seen in retired professional soccer players who have had a long history of heading.
Some studies have not found a correlation between a lifetime history of concussion and structural differences. Terry and Miller found no differences in cognitive function or brain volumes in those who had experienced two or more concussions compared with those with no concussion history, although better overall cognitive function was correlated with adjusted gray matter volumes. Importantly, their sample was matched for age, education, estimated premorbid IQ, and current concussion symptomatology. Additionally, in contrast to research suggesting that exposure to American football before the age of 12 was associated with greater cognitive impairment, Solomon and colleagues found that years pre–high school football was not related to cognitive impairment or neurologic neuroradiologic abnormalities. Zivadinov and colleagues performed multimodal radiologic assessment in 21 retired contact sport athletes (mean age, 56) and compared them with 21 age-matched noncontact sport athletes. The authors found no significant structural differences between the two groups. The noncontact sport group had a higher incidence of microbleeds that was not clinically significant.
Stern and colleagues used flortaucipir PET to compare 26 former NFL athletes (mean age, 57) with 31 control subjects (mean age, 60). The athletes were carefully selected as high risk for CTE, based on years played and position played. The athletes also had objective signs of cognitive and neuropsychiatric impairment. The control subjects had no signs of impairment and no history of concussion. The athletes had higher p-tau levels measured by PET than control subjects. Importantly, the p-tau levels were highest in the regions of the brain that are potentially affected by CTE. The authors note that the results represent group differences and we are not at the point where elevated CTE-associated tau can be detected on an individual basis.
Other health conditions leading to neurocognitive decline
A lot of attention has been given to the neurocognitive and mental health consequences of head injuries in retired contact sport athletes, but little consideration has been given to other causes of neurocognitive decline, such as lifestyle issues or a history of musculoskeletal pain, that is not directly related to a history of head injuries. Athletes just starting out in their professional careers may lack proper dietary and lifestyle education for post-professional sport life and may develop improper habits during retirement. Haider and colleagues compared the estimated energy expenditure and nutritional intake of 21 retired contact sport athletes with 21 age-matched athletic control subjects. They found retired contact sport athletes were significantly overweight and less physically active, important risk factors of cognitive decline. Lack of physical activity has been associated with brain atrophy, neuroinflammation, and vulnerability to trauma and disease, whereas regular exercise has been linked to several neurocognitive benefits. Willeumier and colleagues studied 38 overweight and 38 healthy-weight retired NFL players (average age, 57 years) and showed that players with higher body mass index had significantly more cognitive decline, which suggests it is an independent risk factor in retired contact sport athletes. This higher body mass index was also associated with decreased activation of the prefrontal cortex.
Lastly, professional contact sport athletes train vigorously and often sustain orthopedic injuries, resulting in several sources of chronic pain and/or disability throughout their lives. The sensory and emotional experience of pain, and its deleterious impact on mental health and cognitive functioning, could contribute to early neurocognitive decline. Increased pain intensity has been linked to impaired attention, reduced psychomotor speed, executive dysfunction, and impaired working memory, all of which are risk factors for early neurocognitive decline. Chronic pain may also lead to maladaptive coping mechanisms or substance abuse, further affecting neurocognitive functioning. High levels of pain in athletes have been linked to prior or recurrent injuries and/or multiple surgeries. , A systematic review identified chronic pain to be significantly associated with abnormalities in neurobehavioral functioning (ie, deficits in memory, processing speed, and attention). It has also been shown that higher levels of chronic pain are strongly correlated with psychiatric manifestations, such as anxiety and depression.
Summary
Bennet Omalu published his first study of an American football player showing CTE in 2005. Since then there has been significant interest in CTE and the risks of playing contact sport at the professional level and the amateur level. This interest has been generated by the politics of sport as much as the scientific pursuit of knowledge. The reactions of the professional sports world to the possibility of long-term damage from concussions was initially one of denial, thus polarizing the general public and to some extent the scientific community into CTE believers and those who were perceived to have affiliations with sports or sport teams (whether they have such an affiliation or not). A recent article in the Washington Post (Will Hobson, January 22, 2020) describes how Dr Omalu went from pathologist (as portrayed by Will Smith in the movie Concussion) to CTE activist.
The most supportive evidence of CTE has been generated by the studies conducted by Boston University, an organization that some have seen as having a bias. The brain bank at Boston University was cofounded by the Concussion Legacy Foundation, which has a primary purpose of creating safer sports through education and to end CTE through prevention and research. CTE, therefore becomes a foregone conclusion for the Brain Bank cofounded by this organization. Most of the understanding, and resulting public discourse on CTE has come from their research, which has largely been a case series design with no control subjects. This is considered to be the lowest level of evidence, that is, research that has a complete absence of any control groups and has no published evaluation of the reliability or validity of the diagnosis. In general, this research is seen as hypothesis-generating rather hypothesis-testing.
The scientific studies of aging athletes in vivo, intended to evaluate TES, have fared only slightly better. They at least had comparison groups, although there are some important questions regarding the ideal control population to compare with professional athletes who played contact sports. These studies face similar difficulties to the pathology case series with identifying the extent to which the populations studied are representative of the population of contact sport athletes as a whole. The hypothesis of each of these studies is that some of the contact sport athletes will demonstrate characteristics of early onset dementia. When we combine the results of all of these studies we see little evidence of dementia; however, because each study relied on volunteer participation it is possible that athletes who were worried about their mental status or had been diagnosed with dementia did not wish to participate or did not have the means. When studies do not find a difference between the contact sport athletes and the comparison groups that does not necessarily mean that the two groups are the same. Rather, it could easily mean that the studies did not examine the variables that would be different between the groups. Still, the end result is that the in vivo studies of aging contact sport athletes produced results that are diametrically opposed to the case series results of the Boston University group.
The studies of former athletes using advanced imaging probably yield the best chance of providing meaningful answers to the questions about the long-term effects of concussion in those that played contact sports. The results thus far have been mixed, although the recent study by Stern and colleagues using PET technology offers perhaps the best study to date to track TES in retired athletes who are still alive. There are unanswered questions with this study, such as whether the control group is a true comparison group, but a positive finding of hyperphosphorylated tau on PET scans being similar to the hypothesized locations based on the CTE case studies is encouraging. The representativeness of the former NFL athletes in this study is also in question but this type of research is certainly what is needed in the future.
The highly controversial nature of the topic of CTE has led to an unfortunate polarization of the public as a whole and many researchers and clinicians. It is safe to say that some former contact sport athletes will face some level of neurodegeneration because of their sport-related concussions. It is also likely, given the available research on living athletes, that the rates of neurodegeneration are low. Concerns about children and sports-related concussion and the likelihood of experiencing neurodegeneration are legitimate but there is insufficient evidence to countermand the known benefits of sport participation. Future research must somehow avoid the polarizing trap that allowed much of the current research to be misrepresented or misinterpreted. Otherwise future studies will suffer and the important questions that remain about the long-term effects of concussion on athletes will not be answered. In the meantime, the specter of CTE has at least played a significant role in establishing much better sport safety protocols and validated consensus of concussion management for amateur and professional athletes; albeit there is still room for improvement for recreational athletes. The proper and timely management of concussion is essential if one is to influence the long-term effects of concussion and that is the focus of most of the articles in this special compilation. With or without the fear of CTE, validated and independent research, in conjunction with the proper management of concussion, must be the foremost priority if future generations of children who want to be involved in sport are to be protected.
Clinic care points
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Concussion may have long term consequences or may not.
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The benefits of organized sports may be greater than the potential long term effects.
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The removal of bias in research will lead to more useful conclusions regarding the long term consequences of contact sports.
Disclosure
The authors have nothing to disclose.
References
Related posts:
Epidemiology of Sport-Related Concussion
Biomechanics of Sport-Related Neurological Injury
Rehabilitation of Sport-Related Concussion
Neuroimaging in Sports-Related Concussion
Considerations for Athlete Retirement After Sport-Related Concussion
Future Directions in Sports-Related Concussion Management
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