Sports Concussion and Chronic Traumatic Encephalopathy: Finding a Path Forward

Abstract

Sports concussion has recently assumed special importance because of the widely publicized entity of chronic traumatic encephalopathy (CTE). Identified primarily in former contact sports athletes with repeated mild traumatic brain injury (mTBI), CTE is a distinct tauopathy that can only be diagnosed postmortem and for which no specific treatment is available. Although the hazards of repeated mTBI are generally acknowledged, a spirited controversy has developed because a firm link between sports concussion and CTE has been questioned. We briefly review the history of CTE, discuss areas of uncertainty, and offer suggestions to assist neurologists confronting these issues and advance understanding of this vexing problem. ANN NEUROL 2023;93:222–225

Concussion in sports has attracted increasing attention in recent years, stimulated in large part by the highly visible emergence of chronic traumatic encephalopathy (CTE), a dementia syndrome proposed to result from repetitive head trauma, including concussion and subconcussive forces. Identified mainly in former contact sports athletes but also in those who experienced other circumstances of repetitive impact mild traumatic brain injury (mTBI), CTE is a purely neuropathological diagnosis that is currently defined by a unique pattern of phosphorylated tau (pTau) aggregation. As yet, there are no criteria for a diagnosis of CTE in life, and there is currently no effective treatment. Among many questions raised by this work is the relationship of CTE to repeated concussions or subconcussive blows to the head. This controversy recently came into sharp focus at an International Consensus Conference on Concussion in Sport, ¹ where opinions ranged from acceptance of a clear link to skepticism about any established connection. Given the frequency with which concussion occurs in sports and other settings, and the potential for gaining more insight into preventable and potentially reversible causes of dementia, careful consideration of the possible relationship between mTBI and the later development of cognitive decline is warranted.

A Brief History

The neuropathology of CTE was first described in a postmortem series of brains from amateur and professional boxers in 1973, and this report was preceded by decades of clinical observations of boxers who developed various combinations of cognitive, mood, and motor symptoms in the years following their careers. ² However, most of our modern understanding of CTE began with a 2005 autopsy report of a former professional football player who developed neurobehavioral dysfunction years after his career ended and whose brain disclosed CTE neuropathology. ³ Since then, a series of reports, many from a group at Boston University, ⁴ , ⁵ , ⁶ have contributed further neuropathological data to this field, and CTE has been characterized as a progressive tauopathy resulting from repeated concussions or subconcussive blows. The growing number of cases detected in former athletes whose brains were referred to the Boston group and others has prompted the assertion that CTE is common and vastly underrecognized. Whereas most of the reported cases have been found on postmortem examinations of professional or older athletes with long careers involving contact or collision sports, a few cases have been detected in the brains of young athletes with relatively short exposures to such forces, leading some to conclude that even relatively short spans of such exposures might lead to the characteristic neuropathological lesions of CTE.

Clinical study of sports concussion has also proceeded in earnest. Beginning in 2001, for example, a consensus process was developed as the side product of a convening of concussion specialists invited by the International Ice Hockey Federation, the International Olympic Committee, and the International Federation of Football Associations to provide an educational conference for medical professionals engaged in the care of hockey players, Olympic athletes, and soccer players around the globe. ⁷ The conference organizers saw the opportunity for this highly specialized group of medical experts known as the Concussion in Sport Group (CISG) to reach consensus as to definitions, assessments, and management approaches that have become more detailed and influential over the years. Addressing the issue of CTE in 2017, the 5th CISG gathering in Berlin drew the conclusion that a cause‐and‐effect relationship between exposure to contact sports and CTE had not yet been demonstrated. ⁸ In contrast, another international group recently applied the Bradford Hill criteria and found “convincing evidence” of a causal relationship between repetitive head impacts and the development of CTE. ⁹ Strong opinions continue to animate both sides of this controversy. ¹

As might be expected from the enormous popularity of American football, the literature on CTE has generated much concern in the general public, and also not unexpectedly, the sports community has been reluctant to acknowledge its existence. Although a great deal has been written about the unintentional head injuries of football, and to a lesser extent hockey, far less attention has been focused on sports in which such blows are intentional, such as boxing and mixed martial arts. One is left to wonder why “sports” in which the objective is to produce brain injury receive less scrutiny, especially given the historical evidence of links between boxing and neurodegenerative disease and death. ¹⁰ As an example, although many professional medical organizations had called for an outright ban on boxing in the 1980s, the American Academy of Neurology has since then adopted a more neutral posture, and currently has no official position on the matter.

A lingering problem is the inability to diagnose CTE during life. Consensus diagnostic criteria were published in 2021 by an expert panel convened by the National Institute of Neurological Diseases and Stroke that proposed criteria for the clinical diagnosis of “traumatic encephalopathy syndrome” (TES) in patients whose neurobehavioral deterioration following exposure to repetitive head impacts could not be explained by any other health condition. ¹¹ This consensus statement attempted to establish a useful approach to the evaluation and care of those whose clinical condition could represent CTE, but the fact remains that the diagnosis can only be made postmortem.

Neuropathology

Exposures to TBI correlate with increased risk of dementia and higher rates of disability, potentially affecting a large proportion of the population, although these associations have not yet been specifically explored with large‐scale studies for underlying neuropathology. ¹² , ¹³ Although some may consider CTE a possible explanation, several challenges arise in answering how CTE impacts the general public. For instance, autopsy rates in the United States have fallen steadily in recent years, now to <10% even including forensic autopsies. ¹⁴ Moreover, brains are not usually examined for CTE at autopsy. In the forensic setting, the majority of brains are only examined grossly and in the fresh state. Routine, nonforensic autopsy brains, particularly in academic centers, are often examined both grossly and microscopically, but the testing necessary to diagnose CTE—immunohistochemistry for pTau—is only performed as indicated. The only environments where the requisite testing routinely occurs are research brain repositories, mostly those concerned with aging and neurodegeneration, where substantial collection biases exist.

A few studies have nevertheless provided a glimpse into the prevalence of CTE in the community at large. A 2021 study reported on 532 brains of elderly individuals from the general public donated to a neurodegenerative brain bank, including 107 cases with remote mTBI and loss of consciousness. ¹⁵ There were only 3 cases of CTE (0.6%), none of which, interestingly, was among the 107 mTBI cases. ¹⁴ In an earlier study from a similar brain bank, CTE was reported in 21 of 66 elderly former contact sport athletes (32%), and in none of 198 controls. ¹⁶ Finally, a study of 225 military brains found a CTE rate of 4.4%, despite high rates of both military and civilian mTBI in the decedents. ¹⁷ These studies suggest that in community populations (as opposed to cohorts selected for repetitive mTBI such as contact sports athletes), mTBI‐related disability, including dementia, is not widely attributable to CTE, at least by its present definition.

CTE is currently diagnosed by using pTau immunohistochemistry to identify a pathognomonic lesion characterized by pTau accumulation within neurons in a perivascular distribution at the depths of cortical sulci (Fig 1). ¹⁸ An important point is that sulcal depth‐ and perivascular‐predominant pTau pathology is not a pattern observed in other tauopathies. Also noteworthy is that identification of one lesion is presently sufficient to diagnose CTE. This practice could be criticized, as a single microscopic lesion may not reflect any symptomatology, but a similar diagnostic approach is used in many neurodegenerative diseases that also have minimal neuropathological criteria regardless of clinical symptoms. However, for well‐established neurodegenerative diseases, principally Alzheimer disease, clinically validated neuropathological staging criteria allow for the correspondence of pathological severity with likelihood of dementia. ¹⁹ The development and validation of these criteria required decades of prospective research. By comparison, the state of knowledge of CTE is evolving, and the clinical validation of proposed neuropathological staging criteria will take many years. Therefore, a diagnosis of CTE does not imply clinical manifestations, and we do not know the extent of neuropathology needed to correlate with the likelihood of symptoms.

FIGURE 1.

Pathognomonic chronic traumatic encephalopathy‐related lesion in the depth of a cerebral cortical sulcus in a 54‐year‐old subject with a history of having played American football. Phospho‐tau immunochemistry was applied to temporal cortex (AT8 antibody). [Color figure can be viewed at www.annalsofneurology.org]

Regarding a dose–response relationship with mTBI and CTE risk, it is established that repeated impact mTBI is associated with CTE development, and duration and level of play in contact sports may also be influential. ⁹ However, the precise “dose” of mTBI necessary to trigger CTE neuropathology remains unknown. Although most cases are documented in those with longstanding mTBI exposure, such as elite athletes, CTE has been found in amateur athletes with less exposure, and even in association with a single documented mTBI. Individual factors, such as genetic predispositions, may play a role, but discovery of these has been elusive. Questions regarding alcohol, drug use, and heart disease in CTE pathogenesis have emerged, but no evidence supports an etiologic connection between these factors and the pathognomonic lesion of CTE.

Clinical Implications

To neurologists, CTE presents a conundrum in many respects. As mentioned above, the diagnosis presents a major challenge, as the consensus criteria for a corresponding clinical disorder of TES ¹¹ do not necessarily identify CTE, and conventional neuroimaging cannot be relied on to disclose any specific findings. The imaging of tau in the living brain with positron emission tomography has much promise for improving clinical diagnosis, but tau binding has thus far been nonspecific and not diagnostically useful. ²⁰ Also potentially helpful may be blood and cerebrospinal fluid biomarkers such as tau and neurofilament light, but these are still investigational; plasma total tau, for example, is elevated after subconcussive head impacts in college football players, but it is uncertain whether it correlates with the severity or number of impacts. ²¹ Another gap in knowledge is what types of head injury may be associated with CTE, an issue highlighted by the proposal of subconcussion, an event presumably caused by a head blow less forceful than that which causes concussion, but lacking a precise definition. The prevalence of CTE is also unknown; whereas published cases now number in the hundreds, it is not clear how many people with repeated concussions would not have the disease if examined at autopsy. An acquisition bias thus exists such that we have a numerator of identified cases, but not a denominator based on the population at risk. In this regard, it is of considerable interest that CTE appears to be uncommon in military personnel who have also had repeated mTBI. ¹⁶ Perhaps the most difficult clinical problem is that the wide range of reported clinical features (such as cognitive impairment, depression, and motor dysfunction) can suggest to previously concussed people that they have CTE when many other explanations may be more plausible. ²² Thus the propensity to engage in self‐diagnosis may seriously hinder the seeking and obtaining of care that can be helpful even if CTE is not the cause of symptoms. ²²

Conclusions

A wealth of evidence supports the notion that physical trauma to the brain can have deleterious effects on cognition, mood, and motor function, and it is highly probable that multiple blows to the head are more harmful than one alone. Although the currently available, albeit limited, population data may suggest that CTE is uncommon relative to the number of individuals who sustain repeated mTBI, we tentatively conclude that repeated impact mTBI may lead to the neuropathology of CTE in some individuals. Many questions, however, remain unanswered. Although some data support a dose–response relationship between repeated mTBI and CTE, we do not yet know the extent of mTBI that is necessary to predict a high likelihood of CTE development. The neuropathology of CTE, especially when minimal, can also exist in the absence of symptoms, and thus we also do not know the extent of CTE neuropathology necessary to predict clinical manifestations. In the future, we look forward to detailed longitudinal investigation of people with repeated impact mTBI, using clinical evaluation combined with neuroimaging and fluid biomarkers, to enable accurate in vivo diagnosis and follow‐up of CTE based on solid neuroscientific evidence. We can then hope that the information so disclosed may lead to prevention of, and effective treatments for, this emerging neurobehavioral problem.

Author Contributions

All authors contributed to the conceptualization and writing of this article.

Disclaimer

The information/content, conclusions, and/or opinions expressed herein do notnecessarily represent the official position or policy of, nor should anyofficial endorsement be inferred on the part of, Uniformed Services University, the Department of Defense, the US Veterans Administration, the U.S. Government orthe Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.

Potential Conflicts of Interest

Nothing to report.