Our current understanding of the mechanisms involved in long-term effects of repeated head injuries, particularly related to sports, only recently have gained significant public awareness and general interest. Much of the media attention has focused on chronic traumatic encephalopathy (CTE), which may result from multiple concussions and/or subconcussive blows resulting in a neurodegenerative process that appears in some ways to clinically and histopathologically resemble features seen in tau-related dementias and amyotrophic lateral sclerosis (ALS) along with features of parkinsonism and is associated almost invariably with depression (13,16,17,27). According to some surveys, although underreporting may be sevenfold or more, the incidence of sport-related concussions is estimated to affect between five and eight events per 1000 player hours, which translates into about 1.6 to 3.8 million concussions per year in the United States or about 10% of all head and spinal cord injuries (3,10,27,44). This trend is observed also in other contact sports including rugby, soccer, boxing, wrestling, basketball, field hockey, volleyball, and lacrosse at similarly high rates (10,43). Female high school athletes have been found to have at least double the risk of concussion compared with their male counterparts (27). National Football League players aged 30 to 49 years have developed some degree of cognitive impairment, dementia, emotional lability, and depression reported at about 1.9%, which is about a 20-time higher prevalence than the age-matched population in the general public (1). These symptoms were recognized clinically as early as the 1920s and were termed “punch drunk syndrome” to describe these findings that were seen in professional boxers (17,44). The disorder has had many names over the years and now is termed CTE. The exact mechanism of developing this condition is not well understood still, although repetitive head trauma is a constant.
Research into this area has been sparked significantly by the rising public awareness of the serious long-term effects of sports-related concussions and subconcussive brain trauma. Currently, the definitive diagnosis of CTE relies on a postmortem examination, and a great deal of research efforts are being directed at in vivo confirmatory diagnostic testing that can help to determine who is at greatest risk of developing CTE and identifying CTE early (47). Being able to identify individuals with a high risk of developing CTE will hopefully allow for effective prevention or treatment strategies to be implemented and reduce the burden of this process.
The clinical manifestations of CTE have been described numerous times in the literature since the early 20th century (9). In 1928, Martland (29) coined the term “punch drunk” to describe the signs and symptoms observed in boxers, especially those who experienced considerable head trauma. Millspaugh (35) used the term “dementia pugilistica” in 1937 for the syndrome consisting of motor deficits and mental confusion also seen in boxers. By the 1960s, “chronic traumatic encephalopathy” had come to encompass both these terms in describing the neurologic deterioration that ensued after repetitive traumatic brain injury (34).
Now it is understood that the clinical manifestations of CTE are similar to neurodegenerative diseases and are thought to be progressive. Patients usually present in midlife and several years after end of exposure to repetitive head trauma (9,40,46). Onset is earlier than sporadic Alzheimer’s dementia (AD) and frontotemporal dementia (FTD). Initial symptoms include impaired cognition, mood, and behavior. These encompass short-term memory problems, difficulty with executive function, depression and/or apathy, impulsivity, emotional instability, substance abuse, and even suicidal ideations and behavior (39,46). Later manifestations are more severe and progressive, including worsening memory, worsening executive function, speech difficulties, motor impairment as observed in gait difficulties and parkinsonism, and aggressive and irritable behavior. Ultimately, such severe impairments result in dementia (9,32,46).
A soon-to-be-published study of 68 cases (in press) suggests that the clinical presentation of CTE is a distinct entity from concussions and postconcussive syndrome (PCS). As stated earlier, CTE is not a result of the accumulation of prior injuries but rather progressive neuronal dysfunction and death. Thus, it may arise in patients who had no prior symptomatology (46). This would explain the manifestation of symptoms years after removal from exposure to repetitive traumatic injury (40). It also may arise in individuals who had complete resolution of PCS symptoms. Lastly, some cases involve overlap, more specifically subsiding PCS symptoms with progressively worsening CTE symptoms (46).
Since 2010, there has been mention of a motor neuron disease that may be associated with CTE. Referred to as chronic traumatic encephalomyelopathy, it includes many manifestations: weakness, fasciculations, atrophy, dysarthria, dysphagia, gait difficulties, and hyperactive deep tendon reflexes. These clinical findings correlated with the presence of a transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) in the spinal cord in patients with history of repeated traumatic brain injury (TBI) and confirmed histopatholic CTE (32).
Pathophysiology and Histopathology
Gross pathological findings in CTE include atrophy, enlargement of the lateral and third ventricles, a fenestrated cavum septum pellucidum, and scarring with neuronal loss of the cerebellar tonsils. Atrophy is usually greatest in the frontal and temporal lobes, followed by the parietal lobe; the occipital lobe largely has been unaffected. Within the temporal lobes, the entorhinal cortex, hippocampus, and amygdala experience the most atrophy, which are similar findings to that of AD. Lastly, some cases demonstrate pallor of the substantia nigra, similar to Parkinson’s disease, and pallor of the locus ceruleus, as in AD (32).
In 2002, Omalu et al. (38,41) first described histopathological findings of CTE in an American football player. These closely resembled some of the characteristic changes observed in AD — widespread tau deposits with few neurofibrillary tangles (NFTs) and without the presence of amyloid deposits. Further studies demonstrated that these hyperphosphorylated tau bodies were identical to those found in AD. Also, the pattern of pathology in patients with CTE typically was split into two categories — those with diffuse amyloid plaques and hyperphosphorylated tau and those with only widespread, abundant tau (33). The presence of specific apolipoprotein E (APOE) genotypes has been associated with either one of these pathologies, but our work at the Boston Universities Center for the Study of Traumatic Encephalopathy in nearly 70 cases has not confirmed the genetic APOE link thus far (25,33,40). Lastly, TAR DNA-binding protein 43 (TDP-43) recently has been established as the major pathological protein in FTD with or without motor neuron disease/ALS as well as in other neurodegenerative diseases, such as ALS, AD, and boxing-related CTE (18,28,32). As stated earlier, TDP-43 may be found in the spinal cord of some CTE patients, leading to an ALS-type clinical presentation (32). Its importance lies in its ability to mediate the response of the neuronal cytoskeleton to axonal injury (36).
A recent study demonstrated that even a single TBI could lead to both clinical and histopathological findings consistent with CTE. In this retrospective cohort postmortem study, patients had been classified into two groups. The first included individuals who had experienced only a single episode of TBI between 1 and 47 years prior to death, and the second included individuals without any history of TBI. Postmortem brain tissue from the hippocampus, corpus callosum, cingulated gyrus, and insula then was prepared and labeled with immunohistochemical staining for NFT and amyloid beta plaques. Results showed that NFTs were rare in young, uninjured patients but were abundant and diffuse in about one third of TBI patients. Furthermore, there was a higher density of amyloid beta plaques in TBI individuals. These findings were indicative of the neurodegenerative nature of CTE (24).
Despite these histopathological findings, the exact pathophysiological mechanism behind them has yet to be elucidated. The process of immunoexcitotoxicity, which had been attributed before for the pathological and neurodevelopmental changes in autism and Gulf War Syndrome, has been postulated to be also a possible etiology of CTE (4). Olney and Sharpe (37) had described initially the phenomenon of excitotoxicity as the consequence of neuronal exposure to excessive extracellular glutamate. He had observed that glutamate caused a delayed reaction and resultant death of neurons. Further studies demonstrated that this mechanism involved glutamate binding to receptors that caused massive intracellular influx of calcium and resultant triggering of cell death signaling pathways (11,15,19). Within the central nervous system, the primary sources of glutamate are microglia and astrocytes (48,49). The cascade leading to cell death involves production of reactive oxygen species, reactive nitrogen species, lipid peroxidation products (LPPs), prostaglandins (PGs), and nitric oxide in addition to activation of microglia (8). Activated microglia can then go on to secrete cytokines, chemokines, and PGs as well as free radicals, LPPs, and excitotoxins, thus perpetuating the cascade in a cyclic and synergistic fashion (2,5,42). Improved knowledge of these mechanisms will help us to develop imaging techniques that will be more sensitive to detection of CTE.
Various magnetic resonance imaging (MRI) sequences have proven to be of value in the diagnosis of CTE. Functional MRIs have proven to help differentiate among various neurodegenerative disease, including Alzheimer’s disease, Lewy body dementia, and FTD (33). Thus, they also may be effective in distinguishing CTE from these other types of neurodegenerative states. Meanwhile, susceptibility-weighted MRI can identify microhemorrhages and also may have predictive value for long-term outcomes in pediatric TBIs (12). Lastly, diffusion tensor imaging magnetic resonance (DTI) is sensitive for diffuse axonal injury.
Magnetic resonance spectroscopy (MRS) has recently become more relevant due to its ability to noninvasively measure in vivo brain chemistry. Prior studies have shown that TBI causes decreased N-acetyl aspartate, increased choline (Cho) and lipid, and increased glutamate and glutamine. These findings are indicative of neuronal damage, cell membrane damage, and excitotoxic activity, respectively (16). A recent study analyzed MRS findings in both the acute and chronic postinjury phases of concussed athletes versus nonconcussed athletes of similar demographics. Concussed athletes experienced acute neurometabolic impairment in prefrontal and motor cortices, and while there was some recovery in the chronic phase, a level of impairment remained in the motor cortices (20).
Ultimately, the best way to prevent developing CTE is to prevent the inciting factor of concussion and or a high volume of subconcussive brain trauma in the first place. Protective equipment and more strict rules of play have been mandated in sports such as boxing after 1983, and these probably significantly reduced the rate of fatal head injuries. Additionally, a professional boxing career is typically much shorter, down from 19 to 5 years, and the number of matches has been reduced from an average of 336 to 13, likely resulting in significantly reduced rates of repeat severe concussion events and reducing the risk of developing long-term effects such as CTE (22). Helmets have been mandated in many contact sports such as American football; however, to date, there is no evidence that helmets actually reduce the incidence of concussion. In fact, the use of protective gear may actually lead to more aggressive play and may result in an increased incidence of concussion, although severe traumatic brain injury and fatal head impact-related injuries may be reduced with the protective gear (10,21,43). Using a Head Impact Telemetry System on concussed high school football players, Broglio et al. (7) found no significant correlation between impact and postconcussive outcome.
Monitoring an athlete’s injuries at the sideline and making return-to-play decisions for sports-related injuries have been made using various protocols over the years. The Standardized Concussion Assessment Tool (SCAT) was published in 2005 from the Second International Consensus meeting on Concussion in Sport held in Prague in 2004 (31) and was based on other existing models including the Standardized Assessment tool for Concussion, the sideline concussion check, and the American Academy of Neurology assessment tool. In 2009, the second version of this assessment tool was published from the Third International Consensus meeting on Concussion in Sport held in Zurich in 2009, called SCAT2, (6). This is the assessment tool that is currently in wide use and is a validated assessment tool (21,23,30,45).
Some research into preventing the severity of concussion-related neurodegenerative processes focus on amyloid lowering medications, which have shown some effectiveness in rat studies (14). Further research into preventing the damaging effects of concussion and in protecting athletes from concussion in the first place is ongoing.
One of the largest sources of data for understanding the anatomy and pathophysiology of CTE comes from Boston University’s Center for the Study of CTE, which has more than 500 affected former athletes registered in their brain and spinal cord donation registry (44). From here, postmortem anatomical and histopathological analyses have helped to shed light on the presence and distribution of tau protein and NFTs as well as beta-amyloid (Aβ) deposits in neural tissue, and additional studies on surviving athletes may lead to finding biochemical markers and other physiological testing that can be used to detect CTE early in its course. Genetic testing for apolipoprotein (ApoE ε4) has been studied and at this time does not have a clear role in determining risk of developing CTE; furthermore, it is unclear how this would impact whether a player would be allowed to compete (26).
Blaylock and Maroon (4) suggest that the process of activated microglial cells in immunoexcitotoxicity may cause many of the findings seen in CTE and other related brain dysfunction syndromes after injury and may provide a unifying explanation for the accumulation of hyperphosphorylated tau and the development of the spectrum of findings seen in CTE. Returning activated microglial cells to a more normal function may be a target for therapy after injury occurs, which may limit or reverse the effects of CTE, but more research in this area is still needed.
Identification of biomarkers for CTE in which a “signature” profile would be indicative of a disease process, such as low cerebrospinal fluid (CSF) Aβ and elevated CSF tau for AD, would be extremely useful in early detection and is being investigated currently (46).
Additionally, imaging studies including high-resolution MRI with various sequences including DTI, vertebro-basilar insufficiency (VBI), and single-photon emission computed tomography (SPECT) have been used to identify injured brain tissue with some promising initial results. EEG has been used to show physiological slowing and appeared to correlate with the number of concussions and the development of CTE.
Sports-related head injuries are a major public health problem that needs further investigation in the pathophysiological mechanisms that lead to CTE. Although the use of protective equipment such as helmets for certain sports has been mandated by the National Collegiate Athletic Association (NCAA), this may not reduce the development of CTE, and we need to increase our understanding and awareness of these mechanisms in order to develop a preventive strategy. There are some similarities and overlap between CTE and neurodegenerative diseases such as Alzheimer’s disease, ALS, and parkinsonism; however, clearly distinct neuropathological findings between these disease entities show that they are in fact not identical.
Currently, there is no readily available imaging modality or biochemical marker that can accurately and reproducibly detect the presence of early concussion or the development of CTE; however, the use of DTI may show some correlation between the imaging findings and the severity of concussion and may prove to be useful in the diagnosis and long-term management of athletes and patients with concussion. Other studies including electrophysiological testing such as event-related potential (ERP) in association with neuropsychological testing can help to detect the onset of this condition as well but is not able to predict those who will eventually develop CTE before it occurs.
The clinical exam still remains the standard method of concussion detection, and return-to-play decisions are made based on these findings with tools such as the SCAT2 described earlier, in addition to formal neuropsychological testing. Currently, while the symptoms of CTE may be treated, there is no treatment available to arrest or retard the progression of the disease. With further research, hopefully, these treatments can be developed.
The authors declare no conflict of interest and do not have any financial disclosures.
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