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MINI REVIEW article

Front. Neurol., 19 June 2018
Sec. Neurodegeneration

Chronic Traumatic Encephalopathy in Professional American Football Players: Where Are We Now?

\r\nTharmegan Tharmaratnam,*Tharmegan Tharmaratnam1,2*Mina A. IskandarMina A. Iskandar1Tyler C. TabobondungTyler C. Tabobondung3Iqdam TobbiaIqdam Tobbia4Prasaanthan Gopee-RamananPrasaanthan Gopee-Ramanan5Taylor A. TabobondungTaylor A. Tabobondung6
  • 1School of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
  • 2School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Al Muharraq, Bahrain
  • 3Department of Family Medicine, Michael G. DeGroote School of Medicine, McMaster University, Brantford General Hospital, Hamilton, ON, Canada
  • 4Department of Pathology and Clinical Microbiology, School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Adliya, Bahrain
  • 5Hamilton Health Sciences Centre, Department of Radiology, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
  • 6Department of Physical and Environmental Sciences, University of Toronto, Toronto, ON, Canada

Repetitive head trauma provides a favorable milieu for the onset of inflammatory and neurodegenerative processes. The result of long-lasting head trauma is chronic traumatic encephalopathy (CTE), a disease process well-recognized in boxers, military personnel, and more recently, in American football players. CTE is a chronic neurodegenerative disease with hallmarks of hyperphosphorylated tau (p-tau) aggregates and intercellular lesions of neurofibrillary tangles. The criteria for CTE diagnosis requires at least 1–2 focal perivascular lesions of p-tau in the cerebral cortex, at the depth of the sulci. These pathognomonic lesions aggregate within neurons and glial cells such as astrocytes, and cell processes within the vicinity of small blood vessels. CTE presents in a distinct topographical distribution pattern compared to other tauopathies such as AD and other age-related astrogliopathies. CTE also has an insidious onset, years after repetitive head trauma. The disease course of CTE is characterized by cognitive dysfunction, behavioral changes, and can progress to altered motor function with parkinsonian-like manifestations in later stages. This short review aims to summarize CTE in professional football, epidemiology, diagnosis based on neuroanatomical abnormalities, cognitive degeneration, and adverse mental health effects, as well as gaps in the literature and future directions in diagnostics, therapeutics, and preventive measures.

Introduction

Insight into repetitive brain trauma was first demonstrated by Martland in 1928, who characterized boxers to display “punch-drunk syndrome” from repeated blows to the head (1). Later on, this phenomenon was coined as dementia pugilistica: a term used to describe a physical-psychic syndrome that accumulated over a lengthy boxing career, which was less begrudged amongst boxers than “punch drunk” (2). Today this is referred to as chronic traumatic encephalopathy (CTE). CTE is defined as brain trauma that is either repetitive, episodic, or a single precipitating event, leading to progressive brain neurodegeneration (3). The exact pathophysiology between concussion and CTE is yet to be definitively explained, but is believed to be due to axonal perturbations as a consequence of brain trauma. This causes metabolic abnormalities and cytoskeletal disturbances in the neuronal milieu such as microtubule destabilization, leading to disease propagation via hyperphosphorylated p-tau accumulation (4). This finding has been well documented in athletes involved in contact sports such as American football and boxing, but also in non-civilian populations such as the military (5, 6). Recent studies have highlighted the prevalence of neurotrauma and CTE in American football (NFL) players. Omalu and colleagues were the first to demonstrate this phenomenon in 2005, through a series of case-reports based on autopsy findings of deceased players brains (710). Others have shown the impacts of repeated neurotrauma to manifest in cognitive impairment, neuroimaging anomalies (1113), and disruption in the cytological architecture of the brain (1416). Considering the large number of athletes engaged in contact sports such as football, this is a noteworthy public health concern that merits public attention and interests clinicians and scientists alike. For the purposes of this mini review, our discussion will be restricted to American football. Herein, we provide a primer on risk factors for CTE in NFL players, the distinguishing characteristics of this neurodegenerative condition, pathophysiology, and its association with suicide.

Mechanisms of Injury in the Development of CTE

American Football involves repetitive head trauma causing the brain to experience acceleration and deceleration forces (14, 17, 18), leading to coup/countercoup injuries. This can manifest in varying severity from concussions, or concussions of lesser magnitude (sub-concussion) to loss of consciousness (19). Over time, improperly managed brain trauma with inadequate recovery periods allow chronic inflammatory processes to lay the framework for CTE (14). Indeed, brain trauma without concussion can also lead to CTE (20, 21). It is believed that repetitive brain trauma leads to CTE through tau oligomerization following axonal deformation and microtubular destabilization (22). Over time, tau oligomers develop into paired helical, and straight filamentous neurofibrillary tangles (NFTs) (10, 13), which interfere with white matter tracts in the brain and cause signaling and communication abnormalities through denervation injury (2325). This aggregation of NFTs leads to tau propagation in a prion-like manner (26). Overall, there is an inflammatory state through cytokine and chemokine activation which can lead to an increased blood-brain barrier permeability (27). Omalu suggests that brain trauma results in kinase accumulation from neuroinflammatory processes (3) such as free radical generation from oxidative stress, microglia upregulation, mitochondrial dysfunction, and calcium imbalance, which result in hyperphosphorylated tau (3, 26, 28, 29) Recent work has also highlighted the role of tau acetylation (ac-tau) in the progression of CTE, and increased major histocompatibility receptor expression on neurons (27, 30). In lieu of these findings, the exact mechanism by which tau hyperphosphorylation leads to CTE from brain trauma remains yet to be definitively explained (3, 21).

Risk Factors for CTE

Current literature suggests that the primary risk factor for the development of CTE is repetitive head trauma (5, 18, 3134). Previous work by Guskiewicz et al. (35) has shown 61% of NFL players to have experienced at least 1 concussion within their careers (35). On the other hand, multiple concussions have been shown to be a risk factor for cognitive neurodegeneration and adverse effects on mental health in some individuals (35, 36), which may predispose them to develop CTE later in life. Generally, recovery can be expected from a single head impact with no CTE (19), however, experiencing 3 or more concussions is correlated to an increased risk of prolonged symptoms (37, 38). However, although documented cases of CTE are characterized by repetitive brain trauma, not all athletes exposed to brain trauma will necessarily develop CTE (39). Additionally, the frequency, duration, and magnitude of brain injury necessary to elicit the manifestations of CTE are not well understood in the literature (17, 19).

Genetic susceptibility has also been shown to be a predisposing factor in CTE development. Apolipoprotein (Apoε) is a 34-kDa glycosylated protein implicated as the primary source of cholesterol transport in the brain for neuronal repair (40). Individuals possessing the Apoε4 allele have been shown to have an increased risk of poor functional outcome (19). Compared to other isoforms, the Apoε4 variant has been associated with longer recovery times from neurotrauma, increased injury severity, and greater cognitive deficits in football players (4143). Kutner et al. (43) also suggest that football players with the Apoε4 allele experience worse clinical outcomes, compared to carriers of other isoforms (43). In a study by McKee et al. (14), 50% of CTE cases were shown to carry one ε4 allele, with one case demonstrating homozygosity (14). The Apoε4 allele has also been associated with β-amyloid deposition in CTE. However, more recent work has emerged to show that Apoε variation in CTE cases is no greater than that of the general population (15, 33).

In ex-NFL players, age of first exposure (AFE) to contact football has also been associated with neurological and psychiatric dysfunction in later life (23, 34, 44). Childhood and adolescence is a crucial period of immense neurological development and maturation (45). More specifically, ages 9–12 have been identified as key periods corresponding to peak gray and white matter volumes and neurological maturation of the hippocampus and amygdala (45, 46). The vulnerability of the brain during this critical period may be exploited through brain trauma via tackle football, although others argue that the neuroplasticity of the brain may compensate for the behavioral dysfunction from repeated trauma (28, 47). Alosco et al. (23) demonstrated that AFE<12 was associated with more than double the risk of cognitive impairment in later life. This was characterized by impairment in correlates of apathy (OR, 95% CI: 0.86, 0.76–0.97) and depression (OR, 95% CI: 0.85, 0.74–0.97), but not cognition (23). Schultz et al. (16) has shown similar findings, suggesting AFE to lead to detrimental changes in brain architecture in later life. In 86 symptomatic former NFL players, decreased thalamic volume was correlated with number of years played [p = 0.03 (left hemisphere), p = 0.03 (right hemisphere)]. Additionally, younger AFE has also been related to reduced left thalamic volume (p = 0.014) (16), and alterations in corpus callosum architecture (44), further highlighting the detrimental effects of repetitive head impacts.

Epidemiology of CTE

Quantifying the epidemiology of CTE requires further elucidation, as studies have largely involved cohorts with a history of repetitive brain trauma such as athletes (boxers, football players, wrestlers). This has led to an overestimation of prevalence (5) due to the incorporation of biased sampling methods such as lack of a control group. This is further exacerbated by the incapability to definitively diagnose CTE during life (31, 48). However, the studies that aim to identify the prevalence of CTE in football players have shown unequivocal findings. In the largest ever case series of CTE, involving 202 deceased former football players, Mez et al. (49) demonstrated the existence of CTE in 87%, including 99% ex-NFL Players (49). Additionally, the magnitude of disease burden was correlated to level of play, with high school athletes having mild CTE, and NFL players showcasing the most severe form of CTE. In a retrospective cohort study of 3,493 NFL players, Lehman et al. (50) concluded the risk of mortality due to neurodegenerative causes to be 3x higher than the general US population, and 4x higher for ALS and AD (50). Additionally, ex-NFL players over the age of 50 have also been shown to be 5x more likely to be diagnosed with dementia than national population averages (51).

A history of brain trauma also appears to be an antecedent for the onset of CTE. In a sample of 1721 cases of contact sport athletes, (52) reported CTE in 32% of cases, whereas no cases of CTE were found in patients with no prior brain trauma in the control group (52). This suggests that contact sport is a predisposing risk factor in the development of CTE. While the exact incidence of CTE is unknown, it may be attributed to duration of play, position, sport, age of first exposure, and genetics (32). To better quantify the prevalence of CTE, prospective studies are required to compare individuals with a history of repetitive brain trauma to healthy controls.

Diagnosis of CTE

Although emerging evidence has highlighted the use of 2-(1-{6-[(2-[F-18] fluoroethyl) (methyl)amino]-2-naphthyl}ethylidene) malononitrile-positron emission tomography ([F-18] FDDNP PET) and other neuroimaging techniques for a preliminary pre-mortem diagnosis (53, 54), a definitive CTE diagnosis is confirmed with post-mortem autopsy and immunohistochemistry for p-tau (15, 19, 26, 55). Generally, an autopsy of CTE will show distinct features that distinguish it from other taupathies such as Alzheimer's Disease (AD). This has offered some clarity in regard to the pathophysiological differences between the two diseases. The National Institute of Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Engineering (NINDS/NIBIB) consensus panel recently identified key preliminary findings of CTE (34, 56) and concluded that certain distinguishing features were sufficient to confirm a CTE diagnosis based on macroscopic and microscopic abnormalities. McKee et al. (34) also proposed a 4-stage classification system for CTE based on the extent of lesions and disease severity (See Table 1) (34). Prior to this, Omalu and colleagues proposed 4 distinct phenotypes of CTE (57).

TABLE 1
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Table 1. Grading system of CTE, based on a provisional four-stage classification scheme centered around the extent and severity of tau pathology.

Macroscopic and Microscopic Findings in CTE

The classical signs of CTE induced macroscopic changes are more commonly found in advanced forms of CTE, and rarely manifest in early stages (26). They include cerebral atrophy, reduced brain mass, enlarged lateral and third ventricles, cavum septum pellucidum, pale locus coeruleus, and diencephalon atrophy (19, 26, 34, 56). The required criteria for a diagnosis of CTE encompasses aggregates of hyperphosphorylated tau (p-tau) in glial cells such as astrocytes, neurons, and cell processes, within the vicinity of small vasculature and in the cortical sulci, which typically presents in an irregular pattern (34, 45). CTE and AD share have many similarities, as well as distinct differences (58). The primary criteria for the diagnosis of AD involves the post-mortem finding of Aβ amyloid and neuritic amyloid plaques in a laminar distribution, in the middle frontal gyrus, the superior and middle temporal gyri, and the inferior parietal lobule (59). Secondary amyloid depositions may also be found in areas such as the cerebellum and basal ganglia. These findings contrast with those in CTE cases, where Aβ plaques may be found in a diffuse pattern in sporadic loci, or none at all. In the case of AD, the location p-tau NFTs should largely overlap with those of Aβ amyloid (59), as well as their presence in the hippocampus (60). This contrasts with CTE, where definitively, p-tau aggregates are classically found in a spot-like fashion in the perivascular spaces around blood vessels, deep in the cortical sulci (34, 56). Supportive findings also include NFTs in the superficial layer (II-II) of the cerebral cortex, in cortical area 2 and 4 of the hippocampus. Additionally, the dimensions of NFTs in CTE are usually larger in size than those seen in AD (34, 61). Transactive response DNA-binding protein 43 (TDP-43) aggregates are also a common finding in the vast majority CTE cases, co-localized with p-tau NFTs (56, 58, 62). Although TDP-43 aggregates are found in AD cases, they are not co-localized with NFTs (63), which is another point of distinction between AD and CTE. Neuropathological sampling of TDP-43 should first be taken from the amygdala and hippocampus, and if positive, should also be investigated for in the temporal pole and frontal cortex (34, 56). Owing to the irregularities in lesion distribution however, additional sampling may also be required based on Alzheimer Disease Centers (National Institute on Aging-Alzheimer's Association (NIA-AA) criteria (64).

Symptoms and Cognitive Function

Typically, symptoms of CTE do not present immediately and typically occur in midlife, usually decades after the initial insult. In 51 confirmed cases of CTE, the mean onset of symptom presentation was 42.8 years of age (SD = 12.7) after initial exposure, but ranges from 25 to 76 years of age (14). Stein et al. (19) compiled confirmed cases of CTE from two studies and concluded an average of 15 years before symptom presentation, while the mean age of death was shown to be 59.3 years of age (14, 19). On average, symptom onset usually occurs around 8 years after retirement (14, 32), with a small proportion (33%) of athletes symptomatic at the time of retirement, and 50% becoming symptomatic within 4 years post-retirement (14). It is unclear why this latency period exists, but is believed to be a result of tau propagation from focal to widespread areas, as a consequence of progressive axonal disruption (4, 15). The symptoms of CTE typically present in sequelae of irritability, aggression, episodic memory impairment, cognitive dysfunction, suicidal ideation, rampant mood fluctuations, and depression (10, 14, 32, 49). This early symptomatic period is also associated with substance abuse, and high frequency of suicide (14, 57). As the disease progresses, more severe symptoms begin to manifest such as altered motor function and parkinsonian symptoms (3, 65). In its most advanced form, CTE may be difficult to distinguish from high-grade AD (3, 15, 57). However, owing to individual variability, not all patients will present with a latency period between brain trauma and symptomology (57). Indeed, Stern et al. (67) report CTE to present in two distinct patterns:

1) a young-age onset with initial behavior/mood perturbations that manifests at around age 35. These include impulsivity, aggressiveness, violent tendencies, and progression to deficits in cognition.

2) Late-age onset with cognitive deterioration, which presents around age 60. This subset is characterized by deficits in executive function and attention memory. This phenotype typically displays features of advanced CTE (66, 67). Individuals may also manifest symptoms via alterations in behavior and mood.

Previous work has also shown CTE to synergistically exist with other neurological disorders, such as Lewy Body Dementia (LBD), motor neuron disease such as Amyotrophic Lateral Sclerosis (26, 68) and AD (15, 26, 39, 52, 69). Dickstein et al. (70) has shown that 37% of ex NFL players with CTE meet diagnostic criteria for other neurodegenerative disorders such as LBD (70). This highlights the fact that the disease may not exist independently in its pure form (71) and may be attributed to widespread axonal disruption and progressively increased p-tau hyperphosphorylation, which serves as a stimulus for the deposition of other proteins such as β-amyloid, αβ-synuclein, and TDP-43 (3, 15). However, due to a lack of high-quality longitudinal studies, questions remain in regard to precise symptomology, warranting more research.

CTE as a Risk Factor for Suicide and Mortality

Despite prevailing media reports of several ex-NFL players taking their own lives, and post-mortem showing hallmark traits of CTE, no causal link exists between CTE and suicide (5). Previous work has shown that retired NFL players have a statistically lower risk of suicide compared to the general American population (72, 73). Despite the increased neurodegenerative mortality of this population (50), Lehman et al. (73) concluded that professional football players do not have an increased risk of suicide, but rather have a lower standard mortality rate (SMR) than the general USA population (SMR = 0.47;95% CI:0.24–0.82) (50, 73). Others have shown similar findings in NFL players, compared to race/ethnicity matched general population (72, 74), likely related to the healthy worker effect (74). A recent study has shown that playing in the NFL was not associated with an increased risk of long-term all-cause mortality (75). A leading cause of death of NFL players has been shown to be cardiometabolic disease (75), which may be attributable to increased body-mass index in specific positions, such as defensive linemen (74). Others have shown neurodegenerative causes to be the main cause of death, due to evidence of other co-morbidities such as LBD and Parkinsonian-related causes (49). The belief that CTE predisposes American football players to suicide is rooted in several high-profile cases (76) since 2009, which has led to an overestimation of suicide prevalence based on selection-bias (33). A retrospective cohort study examined mortality from suicide between 1920 and 2015 in a sample of 26,702 professional American football players and reported 26 suicides during this time period. 43% of these cases happened after 2009 and involved high profile players (77) such as Junior Seau, a hall-of-fame linebacker who ended his life, and was later diagnosed with CTE post-mortem (76, 78).

Future Directions in Potential In-vivo Diagnostics

Although studies of CTE have involved post-mortem analyses, [F-18] FDDNP PET is a promising tau imaging ligand that could be used 1 day to detect brain trauma in-vivo. In professional football players, [F-18] FDDNP PET has been shown to be an archetypal tau ligand, as the imaging pattern seen presents in a characteristic topographical distribution consistent with that of CTE (79), such as increased signal intensity in the medial temporal and frontal lobes (53). Additionally, [F-18] FDDNP PET binds preferentially to NFTs, p-tau, and β-amyloid (80). However, the few studies that exist on this imaging modality are limited by sample size. As such, larger trials are necessary to determine the true sensitivity and specificity of [F-18] FDDNP PET. PET imaging has been purported to be in its nascent stage in CTE diagnosis (80), however, significant strides are being made.

Another emerging imaging modality for consideration in this context is magnetic resonance imaging (MRI). The safety profile and consideration of magnetic resonance spectroscopy (MRS) as a “virtual biopsy” are conducive to inclusion in the emerging search for tools to diagnose CTE (81). Neurometabolites such as N-acetyl aspartate, choline, and glutamine/glutamate (NAA, Cho and Glx) are shown to have similar changes on MRS imaging to CTE pathological changes, although not specific (81). More recently, Ruprecht et al. (82) included 25 studies for qualitative synthesis in their systematic review on the characterization of CTE by MRI and MRS, finding that there is only partial comparability amongst published studies given presentation of diffusion MRI, structural MRI, functional MRI, and MRS (82). These authors found gender bias and inconsistently applied age-matched controls limit direct comparison. In general, current limitations of CTE assessment with MRI are studies with small sample sizes, lack of disease comparison groups, and inability to confirm CTE diagnosis in-vivo, rendering elucidation of a direct relationship between MRS and CTE currently lacking. Further ante- and postmortem research in the use of MRS is acknowledged to be necessary (81, 82).

Recently, the field has also advanced in identifying potential biomarkers of traumatic brain injury. There are a range of biomarkers approaching clinical validation (glial fibrillary acidic protein, S100B) and more emerging, such as microtubule associated protein-2 (MAP-2) and brain-derived neurotrophic factor (BDNF) (83, 84). In the future, the use of biomarkers in conjunction with diagnostic imaging, such as PET and MRI, offers a promising avenue for early diagnosis, monitoring of progression, and timely therapeutic interventions.

Future Directions in Potential Therapeutics

Recent work has shed light into the molecular etiopathogenesis of CTE, specifically the inflammatory cascade that results in hyperphosphorylated p-tau accumulation. A seminal paper by Lucke-Wold et al. (30), has shown that post-translational modification involves ac-tau at the lysine 280/281 (K280/K281) position in the paired helical filament-6 (PHF-6) motif, prior to hyperphosphorylation of the tau protein (30). Acetylation has been purported to be the initiating event that results in the vicious cycle of repetitive damage and imperfect repair, which may be from increased acetyltransferase enzyme p-300 levels, shifting the enzyme milieu to favor kinases over phosphatases (85). This “two-hit” mechanism of acetylation and phosphorylation leading to p-tau aggregation via microtubule destabilization provides the framework for future studies to inhibit this pathway. However, efforts aimed at inhibiting tau phosphorylation have elicited minimal advances in treatment. A new strategy could perhaps be pharmacological therapies aimed at inhibiting ac-tau in PHF-6. Studies in murine models have shown that salsalate, a non-steroidal anti-inflammatory drug (NSAID) reduces p-300 mediated acetylation of tau (30), resulting in improved cognition and reduced atrophy of brain regions such as the hippocampus. Lagraoui et al. (86) reported similar findings in a murine model of traumatic brain injury (TBI) (86). Salsalate was shown to inhibit inflammatory pathways after TBI proximal to the injury site via reduction in microglia/macrophage activation. Additionally, salsalate was also shown to induce genes implicated in neurogenesis (such as Tbr2) and neuroprotection (oxytocin and thyrotropin releasing hormone), while also improving functional recovery post-injury (30, 86). The earliest reported proof of principle study demonstrating that p-300 inhibition could be used to treat tauopathies was demonstrated in a seminal paper by Min et al. (87). Others have recently identified that methylene blue (MB), an inhibitor of tau aggregation, also modulates acetylation activity at K280/K281 (86), and may thus be promising if findings are consistent in large-scale human clinical trials. This may be explored in the future, in conjunction with therapies that enhance deacetylase activity such as HDAC-6 and sirtuin-1 (88) for synergism and potentiation. It is also crucial to prevent other steps involved in tau propagation such as tau oligomerization and dissemination from focal to widespread areas. Considering that hyperphosphorylated tau spreads in a prion-like manner, preventing this spread through p-tau monoclonal antibodies and competitive inhibitors of prion protein receptors that facilitate tau oligomer toxicity is also an area of consideration for future work (89). These new studies highlight the potential role of pharmacological therapy. In order for the field to move forward in terms of therapeutics, the development of drug targets should be multipronged as to target different stages of the inflammatory cascade after brain injury.

TABLE 2
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Table 2. Typical microscopic and macroscopic features found in each stage of CTE.

Current State and Future Directions

What is most concerning about NFL-associated CTE cases is their preventable nature. There is a preponderance of ex-NFL players that allege the NFL failed to provide information regarding the neuropsychiatric risks associated with playing professional football (78, 90). Recently, the NFL implemented numerous safeguards following increased awareness of CTE. These include limiting contact practices involving tackles to 1x/week and penalization of direct head impacts with substantial fines and disciplinary action. Additionally, an NFL associated website (https://www.playsmartplaysafe.com/) highlights the leagues updated concussion protocols and return-to-play guidelines; the NFL works to ensure concussed players adhere strictly to these return-to-play guidelines after brain trauma. This is in an effort to prevent exacerbation of injury, or occurrence of a second episode (91). Non-compliance with established concussion protocol is a current issue. This process can be long and there is an incentive to recover as quickly as possible (92). The result is an under-reporting of symptoms by athletes, to ensure a quicker return to play (93). Athletes and others involved in professional sports do not always consider the long-term implications that contact sports and repetitive head injury can have on their neuropsychiatric functioning in the future, and that is why we believe changes must be made.

Conclusions

Our understanding of CTE in American football players has improved immensely since the first case reports of Omalu and colleagues. It has now emerged that CTE has afflicted football players from bouts of head trauma. Despite these advances, more work is necessary to elucidate the underlying pathophysiological mechanisms, and the incidence and prevalence of disease burden in the general populace. There is a need to move beyond case reports and focus on more systematic studies examining CTE in sport and non-sport populations. At present, there is also no widely accepted clinical criteria for a diagnosis of CTE despite the preliminary work of McKee et al. (56) and others (94, 95). The field is moving forward with biomarkers nearing appropriate validation and in-vivo diagnostic techniques such as MRI and [F-18] FDDNP PET being explored, and therapeutic modalities showing promise in murine models. However more clinical human studies are warranted for timely diagnosis and appropriate management of CTE.

Author Contributions

TT was responsible for conception of the mini-review, manuscript drafting, submission, and was involved in all aspects of this paper. MI assisted in manuscript preparation and wrote pathological findings section. IT provided advice and guidance during the completion of the manuscript and assisted in submission process. PG-R wrote the future directions in in vivo potential diagnostics section. TCT assisted in manuscript drafting and wrote the future directions section. TAT critically edited the manuscript for intellectual content, and provided guidance. All authors edited and approved the final version of the manuscript, and agree to be accountable for all aspects of this work. The authors have no conflicts of interests to declare.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We would like to express our gratitude to Dr. Ann C. McKee from Boston University School of Medicine, for her insight and assistance in the completion of Tables 1, 2. This work has been supported by the Royal College of Surgeons in Ireland-MUB Postgraduate Research Fund.

References

1. Martland HS. Punch drunk. JAMA (1928) 91:1103–07. doi: 10.1001/jama.1928.02700150029009

CrossRef Full Text | Google Scholar

2. Millspaugh JA. Dementia pugilistica. US Naval Med Bull. (1937) 35:297–61.

3. Omalu BI. Chronic traumatic encephalopathy. Prog Neurol Surg. (2014) 28:38–49. doi: 10.1159/000358761

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Kriegel J, Papadopolos Z, Mckee AC. Chronic traumatic encephalopathy: is latency in symptom onset explained by tau propagation. Cold Spring Harb Perspect Med. (2018) 8:a024059. doi: 10.1101/cshperspect.a024059

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Asken BM, Sullan MJ, Dekosky ST, Jaffee MS, Bauer RM. Research gaps and controversies in chronic traumatic encephalopathy. JAMA Neurol. (2017) 74:1255. doi: 10.1001/jamaneurol.2017.2396

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Mufson EJ, He B, Ginsberg SD, Carper BA, Bieler GS, Crawford FC, et al. Gene profiling of nucleus basalis tau containing neurons in chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study. J Neurotrauma (2018) 35:1260–71. doi: 10.1089/neu.2017.5368

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Omalu BI, Dekosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH. Chronic Traumatic encephalopathy in a National Football League Player. Neurosurgery (2005) 57:128–134. doi: 10.1227/01.neu.0000163407.92769.ed

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Omalu BI, Dekosky ST, Hamilton RL, Minster RL, Kamboh MI, Shakir AM, et al. Chronic traumatic encephalopathy in a National Football League Player. Neurosurgery (2006) 59:1086–93. doi: 10.1227/01.neu.0000245601.69451.27

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Omalu BI, Bailes J, Hammers JL, Fitzsimmons RP. Chronic traumatic encephalopathy, suicides and parasuicides in professional American Athletes. Am J For Med Pathol. (2010a) 31:130–2. doi: 10.1097/paf.0b013e3181ca7f35

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Omalu BI, Hamilton RL, Kamboh IM, Dekosky ST, Bailes J. Chronic traumatic encephalopathy (CTE) in a National Football League Player. J For Nurs. (2010b) 6:40–6. doi: 10.1111/j.1939-3938.2009.01064.x

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Amen DG, Willeumier K, Omalu B, Newberg A, Raghavendra C, Raji CA. Perfusion Neuroimaging abnormalities alone distinguish National Football League Players from a healthy population. J Alzheimers Dis. (2016) 53:237–41. doi: 10.3233/jad-160207

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Hart J, Kraut MA, Womack KB, Strain J, Didehbani N, Bartz E, et al. Neuroimaging of cognitive dysfunction and depression in aging retired National Football League Players. JAMA Neurol. (2013) 70:326. doi: 10.1001/2013.jamaneurol.340

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Strain J, Didehbani N, Cullum CM, Mansinghani S, Conover H, Kraut MA, et al. Depressive symptoms and white matter dysfunction in retired NFL players with concussion history. Neurology (2013) 81:25–32. doi: 10.1212/wnl.0b013e318299ccf8

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Mckee AC, Cantu RC, Nowinski CJ, Hedley-Whyte ET, Gavett BE, Budson AE, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. (2009) 68:709–35. doi: 10.1097/nen.0b013e3181a9d503

PubMed Abstract | CrossRef Full Text | Google Scholar

15. McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain (2013) 136:43–64. doi: 10.1093/brain/aws307

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Schultz V, Stern RA, Tripodis Y, Stamm J, Wrobel P, Lepage C, et al. Age at first exposure to repetitive head impacts is associated with smaller thalamic volumes in former professional American Football Players. J Neurotrauma (2018) 35:278–85. doi: 10.1089/neu.2017.5145

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Aldag M, Armstrong RC, Bandis F, Bellgowan PSF, Bentley T, Biggerstaff S. The biological basis of chronic traumatic encephalopathy following blast injury: a literature review. J Neurotrauma (2017) 34:S-26–43. doi: 10.1089/neu.2017.5218

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Daneshvar DH, Baugh CM, Nowinski CJ, Mckee AC, Stern RA, Cantu RC. Helmets and mouth guards: the role of personal equipment in preventing sport-related concussions. Clin Sports Med. (2011) 30:145–63. doi: 10.1016/j.csm.2010.09.006

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Stein TD, Alvarez VE, McKee AC. Concussion in chronic traumatic encephalopathy. Curr Pain Head Rep. (2015a) 19:47. doi: 10.1007/s11916-015-0522-z

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Kawata K, Rubin LH, Wesley L, Lee JH, Sim T, Takahagi M, et al. Acute changes in plasma total tau levels are independent of subconcussive head impacts in college football players. J Neurotrauma (2018) 35:260–6. doi: 10.1089/neu.2017.5376

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Tagge CA, Fisher AM, Minaeva OV, Gaudreau-Balderrama A, Moncaster JA, Zhang XL, et al. Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model. Brain (2018) 141:422–58. doi: 10.1093/brain/awx350

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Hawkins BE, Krishnamurthy S, Castillo-Carranza DL, Sengupta U, Prough DS, Jackson GR, et al. rapid accumulation of endogenous tau oligomers in a rat model of traumatic brain injury. J Biol Chem. (2013) 288:17042–50. doi: 10.1074/jbc.m113.472746

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Alosco ML, Koerte IK, Tripodis Y, Mariani M, Chua AS, Jarnagin J, et al. White matter signal abnormalities in former National Football League players. Alzheimer Dement. (2018) 10:56–65. doi: 10.1016/j.dadm.2017.10.003

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart W. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain (2013) 136:28–42. doi: 10.1093/brain/aws322

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Multani N, Goswami R, Khodadadi M, Ebraheem A, Davis KD, Tator CH, et al. Erratum to: the association between white-matter tract abnormalities, and neuropsychiatric and cognitive symptoms in retired professional football players with multiple concussions. J Neurol. (2016) 263:1342. doi: 10.1007/s00415-016-8172-6

PubMed Abstract | CrossRef Full Text | Google Scholar

26. McKee AC, Stein TD, Kiernan PT, Alvarez VE. The neuropathology of chronic traumatic encephalopathy. Brain Pathol. (2015) 25:350–64. doi: 10.1111/bpa.12248

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Kornguth S, Rutledge N, Perlaza G, Bray J, Hardin A. A proposed mechanism for development of CTE following concussive events: head impact, water hammer injury, neurofilament release, and autoimmune processes. Brain Sci. (2017) 7:164. doi: 10.3390/brainsci7120164

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Blaylock RL, Maroon MJ. C. Chapter 3. Immunoexcitotoxicity as a Central mechanism of chronic traumatic encephalopathy – a unifying hypothesis. Biomark Traum Brain Injury RSC Drug Discov. (2011) 2:45–65. doi: 10.1039/9781849734745-00045

CrossRef Full Text | Google Scholar

29. Saulle M, Greenwald BD. Chronic traumatic encephalopathy: a review. Rehabil Res Pract. (2012) 2012:816069. doi: 10.1155/2012/816069

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Lucke-Wold B, Seidel K, Udo R, Omalu B, Ornstein M, Nolan R, et al. Role of tau acetylation in Alzheimer's disease and chronic traumatic encephalopathy: the way forward for successful treatment. J Neurol Neurosurg (2017) 4:140.

PubMed Abstract | Google Scholar

31. Gardner RC, Yaffe K. Epidemiology of mild traumatic brain injury and neurodegenerative disease. Mol Cell Neurosci. (2015) 66:75–80. doi: 10.1016/j.mcn.2015.03.001.

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Gavett BE, Stern RA, Mckee AC. Chronic traumatic encephalopathy: a potential late effect of sport-related concussive and subconcussive head trauma. Clin Sports Med. (2011) 30:179–88. doi: 10.1016/j.csm.2010.09.007

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Maroon JC, Winkelman R, Bost J, Amos A, Mathyssek C, Miele V. Correction: chronic traumatic encephalopathy in contact sports: a systematic review of all reported pathological cases. PLoS ONE (2015) 10:e.0130507. doi: 10.1371/journal.pone.0130507

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Mckee AC, Alosco ML, Huber BR. Repetitive head impacts and chronic traumatic encephalopathy. Neurosurg Clin North Am (2016) 27:529–35. doi: 10.1016/j.nec.2016.05.009

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Guskiewicz KM, Marshall SW, Bailes J, Mccrea M, Cantu RC, Randolph C, et al. Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery (2005) 57:719–726. doi: 10.1227/01.neu.0000175725.75780.dd

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Manley G, Gardner AJ, Schneider KJ, Guskiewicz KM, Bailes J, Cantu RC, et al. A systematic review of potential long-term effects of sport-related concussion. Br J Sports Med. (2017) 51:969–77. doi: 10.1136/bjsports-2017-097791

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Brody DL. Chief Concern: “Im worried i have chronic traumatic encephalopathy.” Ann Int Med. (2018) 168:285. doi: 10.7326/m17-2707

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Eisenberg MA, Andrea J, Meehan W, Mannix R. Time interval between concussions and symptom duration. Pediatrics (2013) 132:8–17. doi: 10.1542/peds.2013-0432d

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Hazrati LN, Tartaglia MC, Diamandis P, Davis KD, Green RE, Wennberg R, et al. Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology. Front Hum Neurosci. (2013) 7:222. doi: 10.3389/fnhum.2013.00222

PubMed Abstract | CrossRef Full Text | Google Scholar

40. Bales K. Apolipoprotein E, Amyloid, Alzheimer Disease. Mol Intervent. (2002) 2:363–75. doi: 10.1124/mi.2.6.363

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Ariza M. Influence of APOE polymorphism on cognitive and behavioural outcome in moderate and severe traumatic brain injury. J Neurol Neurosurg Psychiatry (2006) 77:1191–3. doi: 10.1136/jnnp.2005.085167

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Friedman G, Froom P, Sazbon L, Grinblatt I, Shochina M, Tsenter J, et al. Apolipoprotein E- 4 genotype predicts a poor outcome in survivors of traumatic brain injury. Neurology (1999) 52:244. doi: 10.1212/wnl.52.2.244

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Kutner KC, Erlanger DM, Tsai J, Jordan B, Relkin NR. Lower cognitive performance of older football players possessing apolipoprotein E ε4. Neurosurgery (2000) 47:651–58. doi: 10.1227/00006123-200009000-00026

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Stamm JM, Koerte IK, Muehlmann M, Pasternak O, Bourlas AP, Baugh CM, et al. Age at first exposure to football is associated with altered corpus callosum white matter microstructure in former professional football players. J Neurotrauma (2015) 32:1768–76. doi: 10.1089/neu.2014.3822

PubMed Abstract | CrossRef Full Text | Google Scholar

45. Lebel C, Walker L, Leemans A, Phillips L, Beaulieu C. Microstructural maturation of the human brain from childhood to adulthood. NeuroImage (2008) 40:1044–55. doi: 10.1016/j.neuroimage.2007.12.053

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Uematsu A, Matsui M, Tanaka C, Takahashi T, Noguchi K, Suzuki M, et al. Developmental trajectories of amygdala and hippocampus from infancy to early adulthood in healthy individuals. PLoS ONE (2012) 7:e46970. doi: 10.1371/journal.pone.0046970

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Anderson V, Spencer-Smith M, Leventer R, Coleman L, Anderson P, Williams J, et al. Childhood brain insult: can age at insult help us predict outcome? Brain (2009) 132:45–56. doi: 10.1093/brain/awn293

PubMed Abstract | CrossRef Full Text | Google Scholar

48. Tator CH. Chronic traumatic encephalopathy: how serious a sports problem is it? Br J Sports Med. (2013) 48:81–3. doi: 10.1136/bjsports-2013-093040

PubMed Abstract | CrossRef Full Text | Google Scholar

49. Mez J, Daneshvar DH, Kiernan PT, Abdolmohammadi B, Alvarez VE, Huber BR, et al. Clinicopathological evaluation of chronic traumatic encephalopathy in players of American Football. JAMA (2017) 318:360–70. doi: 10.1001/jama.2017.8334

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Lehman EJ, Hein MJ, Baron SL, Gersic CM. Neurodegenerative causes of death among retired National Football League players. Neurology (2012) 79:1970–4. doi: 10.1212/WNL.0b013e31826daf50

PubMed Abstract | CrossRef Full Text | Google Scholar

51. Weir DR, Jackson J. National Football League Player Care Foundation: Study of Retired NFL Players. Institute for Social Research 56. (2009)

Google Scholar

52. Bieniek KF, Ross OA, Cormier KA, Walton RL, Soto-Ortolaza A, Johnston AE, et al. Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank. Acta neuropathol (2015) 130:877–89. doi: 10.1007/s00401-015-1502-4

PubMed Abstract | CrossRef Full Text | Google Scholar

53. Omalu B, Small GW, Bailes J, Ercoli LM, Merrill DA, Wong KP, et al. Postmortem Autopsy-confirmation of antemortem [F-18]FDDNP-PET scans in a football player with chronic traumatic encephalopathy. Neurosurgery (2017) 82:237–46. doi: 10.1093/neuros/nyx536

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Small GW, Kepe V, Siddarth P, Ercoli LM, Merrill DA, Donoghue N, et al. PET scanning of brain tau in retired national football league players: preliminary findings. Am J Geriatr Psychiatry (2013) 21:138–44. doi: 10.1016/j.jagp.2012.11.019

PubMed Abstract | CrossRef Full Text | Google Scholar

55. Baugh CM, Robbins CA, Stern RA, McKee AC. Current understanding of chronic traumatic encephalopathy. Curr Treat Opt Neurol. (2014) 16:306. doi: 10.1007/s11940-014-0306-5

PubMed Abstract | CrossRef Full Text | Google Scholar

56. McKee AC, Cairns NJ, Dickson DW, Folkerth RD, Keene CD, Litvan I, et al. The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol. (2016) 131:75–86. doi: 10.1007/s00401-015-1515-z.

PubMed Abstract | CrossRef Full Text | Google Scholar

57. Omalu B, Bailes J, Hamilton RL, Kamboh MI, Hammers J, Case M, et al. Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes. Neurosurgery (2011) 69:173–83. doi: 10.1227/neu.0b013e318212bc7b

PubMed Abstract | CrossRef Full Text | Google Scholar

58. Stein TD, Alvarez VE, Mckee AC. Chronic traumatic encephalopathy: a spectrum of neuropathological changes following repetitive brain trauma in athletes and military personnel. Alzheimers Res Ther. (2014) 6:4. doi: 10.1186/alzrt234

PubMed Abstract | CrossRef Full Text | Google Scholar

59. Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, et al. National Institute on Aging–Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimer Dement. (2012) 8:1–13. doi: 10.1016/j.jalz.2011.10.007

PubMed Abstract | CrossRef Full Text | Google Scholar

60. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Tredici KD. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. (2006) 112:389–404. doi: 10.1007/s00401-006-0127-z

PubMed Abstract | CrossRef Full Text | Google Scholar

61. Hof PR, Bouras C, Buée L, Delacourte A, Perl DP, Morrison JH. Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimers disease cases. Acta Neuropathol. (1992) 85:23–30. doi: 10.1007/bf00304630

PubMed Abstract | CrossRef Full Text | Google Scholar

62. Mckee AC, Gavett BE, Stern RA, Nowinski CJ, Cantu RC, Kowall NW, et al. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. (2010) 69:918–29. doi: 10.1097/nen.0b013e3181ee7d85

PubMed Abstract | CrossRef Full Text | Google Scholar

63. Lippa CF, Rosso AL, Stutzbach LD, Neumann M, Lee VMY, Trojanowski JQ. Transactive response DNA-binding protein 43 burden in familial Alzheimer disease and down syndrome. Arch Neurol. (2009) 66:1483–8. doi: 10.1001/archneurol.2009.277

PubMed Abstract | CrossRef Full Text | Google Scholar

64. Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, et al. National institute on aging–Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathol. (2012) 123:1–11. doi: 10.1007/s00401-011-0910-3

PubMed Abstract | CrossRef Full Text | Google Scholar

65. Lenihan MW, Jordan BD. The clinical presentation of chronic traumatic encephalopathy. Curr Neurol Neurosci Rep. (2015) 15:23. doi: 10.1007/s11910-015-0541-5

PubMed Abstract | CrossRef Full Text | Google Scholar

66. McKee AC, Mez J, Abdolmohammadi B. Chronic traumatic encephalopathy in football players—reply. JAMA (2017) 318:2353. doi: 10.1001/jama.2017.16687

PubMed Abstract | CrossRef Full Text | Google Scholar

67. Stern RA, Daneshvar DH, Baugh CM, Seichepine DR, Montenigro PH, Riley DO, et al. Clinical presentation of chronic traumatic encephalopathy. Neurology (2013) 81:1122–9. doi: 10.1212/WNL.0b013e3182a55f7f

PubMed Abstract | CrossRef Full Text | Google Scholar

68. Moszczynski AJ, Strong W, Xu K, Mckee A, Brown A, Strong MJ. Pathologic Thr175tau phosphorylation in CTE and CTE with ALS. Neurology (2018) 90:e380–e387. doi: 10.1212/wnl.0000000000004899

PubMed Abstract | CrossRef Full Text | Google Scholar

69. Ling H, Morris HR, Neal JW, Lees AJ, Hardy J, Holton JL, et al. Mixed pathologies including chronic traumatic encephalopathy account for dementia in retired association football (soccer) players. Acta Neuropathol. (2017) 133:337–52. doi: 10.1007/s00401-017-1680-3

PubMed Abstract | CrossRef Full Text | Google Scholar

70. Dickstein D, Pullman M, Fernandez C, Short J, Kostakoglu L, Knesaurek K, et al. Structural MRI and molecular PET imaging (AV45 and AV1451) in the diagnosis of chronic traumatic encephalopathy in vivo: study of a retired NFL player (P4. 046). Neurology (2018) 86(16Supplement):P4.046

Google Scholar

71. Iverson GL, Keene CD, Perry G, Castellani RJ. The need to separate chronic traumatic encephalopathy neuropathology from clinical features. J Alzheimers Dis. (2017) 61:17–28. doi: 10.3233/jad-170654

PubMed Abstract | CrossRef Full Text | Google Scholar

72. Baron SL, Hein MJ, Lehman E, Gersic CM. Body mass index, playing position, race, and the cardiovascular mortality of retired professional football players. Am J Cardiol. (2012) 109:889–96. doi: 10.1016/j.amjcard.2011.10.050

PubMed Abstract | CrossRef Full Text | Google Scholar

73. Lehman EJ, Hein MJ, Gersic CM. Suicide mortality among retired national football league players who played 5 or more seasons. Am J Sports Med. (2016) 44:2486–91. doi: 10.1177/0363546516645093

PubMed Abstract | CrossRef Full Text | Google Scholar

74. Lincoln AE, Vogel RA, Allen TW, Dunn RE, Alexander K, Kaufman ND, et al Risk and causes of death among former national football league players (1986–2012). Med Sci Sports Exerc. (2018) 50:486–93. doi: 10.1249/mss.0000000000001466

PubMed Abstract | CrossRef Full Text | Google Scholar

75. Venkataramani A.S., Gandhavadi M, Jena AB. Association between playing american football in the national football league and long-term mortality. JAMA (2018) 319:800–6. doi: 10.1001/jama.2018.0140

PubMed Abstract | CrossRef Full Text | Google Scholar

76. Azad TD, Li A, Pendharkar AV, Veeravagu A, Grant GA. Junior Seau: an illustrative case of chronic traumatic encephalopathy and update on chronic sports-related head injury. World Neurosurg. (2016) 86:515.e11–6. doi: 10.1016/j.wneu.2015.10.032

PubMed Abstract | CrossRef Full Text | Google Scholar

77. Webner D, Iverson GL. Suicide in professional American football players in the past 95 years. Brain Injury (2016) 30:1718–21. doi: 10.1080/02699052.2016.1202451

PubMed Abstract | CrossRef Full Text | Google Scholar

78. Nowinski C. (2013). Hit Parade: the future of the sports concussion crisis. Cerebrum 2013:2.

PubMed Abstract | Google Scholar

79. Barrio JR, Small GW, Wong KP, Huang SC, Liu J, Merrill DA, et al. In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging. Proc Natl Acad Sci USA. (2015) 112:E2039–47. doi: 10.1073/pnas.1409952112

PubMed Abstract | CrossRef Full Text | Google Scholar

80. Lee B, Leavitt M, Bernick C, Leger G, Rabinovici G, Banks S. A systematic review of positron emission tomography of tau, amyloid beta, and neuroinflammation in chronic traumatic encephalopathy: the evidence to-date. J Neurotrauma (2018). doi: 10.1089/neu.2017.5558. [Epub ahead of print].

PubMed Abstract | CrossRef Full Text | Google Scholar

81. Alosco M, Jarnagin J, Rowland B, Liao H, Stern R, Lin A. Magnetic resonance spectroscopy as a biomarker for chronic traumatic encephalopathy. Semin Neurol. (2017) 37:503–9. doi: 10.1055/s-0037-1608764

PubMed Abstract | CrossRef Full Text | Google Scholar

82. Ruprecht R, Scheurer E, Lenz C. Systematic review on the characterization of chronic traumatic encephalopathy by MRI and MRS. J Magn Reson Imaging (2018) doi: 10.1002/jmri.26162. [Epub ahead of print].

PubMed Abstract | CrossRef Full Text | Google Scholar

83. Korley FK, Diaz-Arrastia R, Wu AHB, Yue JK, Manley GT, Sair HI, et al. Circulating brain-derived neurotrophic factor has diagnostic and prognostic value in traumatic brain injury. J Neurotrauma (2016) 33:215–25. doi: 10.1089/neu.2015.3949

PubMed Abstract | CrossRef Full Text | Google Scholar

84. Wang KK, Yang Z, Zhu T, Shi Y, Rubenstein R, Tyndall JA, et al An update on diagnostic and prognostic biomarkers for traumatic brain injury, Exp Rev Mol Diagn. (2018) 18:165–80. doi: 10.1080/14737159.2018.1428089

CrossRef Full Text

85. Lucke-Wold BP, Turner RC, Logsdon AF, Bailes JE, Huber JD, Rosen CL. Linking traumatic brain injury to chronic traumatic encephalopathy: identification of potential mechanisms leading to neurofibrillary tangle development. J Neurotrauma (2014) 31:1129–38. doi: 10.1089/neu.2013.3303

PubMed Abstract | CrossRef Full Text | Google Scholar

86. Lagraoui M, Sukumar G, Latoche JR, Maynard SK, Dalgard CL, Schaefer BC. Salsalate treatment following traumatic brain injury reduces inflammation and promotes a neuroprotective and neurogenic transcriptional response with concomitant functional recovery. Brain Behav Immun. (2017) 61:96–109. doi: 10.1016/j.bbi.2016.12.005

PubMed Abstract | CrossRef Full Text | Google Scholar

87. Min S-W, Chen X, Tracy TE, Li Y, Zhou Y, Wang C, et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med. (2015) 21:1154–1162. doi: 10.1038/nm.3951

PubMed Abstract | CrossRef Full Text | Google Scholar

88. Trzeciakiewicz H, Tseng J-H, Wander CM, Madden V, Tripathy A, Yuan C-X, et al. A dual pathogenic mechanism links tau acetylation to sporadic tauopathy. Sci Rep. (2017) 7:44102. doi: 10.1038/srep44102

PubMed Abstract | CrossRef Full Text | Google Scholar

89. Drummond E, Goni F, Liu S, Prelli F, Scholtzova H, Wisniewski T. (2018). Potential novel approaches to understand the pathogenesis and treat Alzheimer's disease. J Alzheimers Dis. doi: 10.3233/JAD-179909. [Epub ahead of print].

PubMed Abstract | CrossRef Full Text | Google Scholar

90. Korngold C, Farrell H.M., Fozdar M. The National Football League and chronic traumatic encephalopathy: legal implications. J Am Acad Psychiatry Law (2013) 41:430–6.

PubMed Abstract | Google Scholar

91. McLeod TCV, Lewis JH, Whelihan K, Bacon CEW. Rest and return to activity after sport-related concussion: a systematic review of the literature. J Athl Train. (2017) 52:262–87. doi: 10.4085/1052-6050-51.6.06

PubMed Abstract | CrossRef Full Text | Google Scholar

92. Navarro SM, Sokunbi OF, Haeberle HS, Schickendantz MS, Mont MA, Figler RA, et al. Short-term outcomes following concussion in the NFL: a study of player longevity, performance, and financial loss. Ortho J Sports Med. (2017) 5:2325967117740847. doi: 10.1177/2325967117740847.

PubMed Abstract | CrossRef Full Text | Google Scholar

93. Tjong VK, Baker PH, Cogan CJ, Montoya M, Lindley TR, Terry MA. Concussions in NCAA varsity football athletes: a qualitative investigation of player perception and return to sport. JAAOS Glob Res Rev. (2017) 1:e070. doi: 10.5435/JAAOSGlobal-D-17-00070

CrossRef Full Text | Google Scholar

94. Victoroff J. Traumatic encephalopathy: review and provisional research diagnostic criteria. NeuroRehabilitation (2013) 32:211–24. doi: 10.3233/NRE-130839

PubMed Abstract | CrossRef Full Text | Google Scholar

95. Montenigro PH, Baugh CM, Daneshvar DH, Mez J, Budson AE, Au R, et al. Clinical subtypes of chronic traumatic encephalopathy: literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome. Alzheimers Res Ther. (2014) 6:68. doi: 10.1186/s13195-014-0068-z

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: chronic traumatic encephalopathy, American football, traumatic brain injury, tau, neurodegeneration, tau protein, neurofibrillary tangles

Citation: Tharmaratnam T, Iskandar MA, Tabobondung TC, Tobbia I, Gopee-Ramanan P and Tabobondung TA (2018) Chronic Traumatic Encephalopathy in Professional American Football Players: Where Are We Now? Front. Neurol. 9:445. doi: 10.3389/fneur.2018.00445

Received: 18 March 2018; Accepted: 28 May 2018;
Published: 19 June 2018.

Edited by:

Xin-fu Zhou, University of South Australia, Australia

Reviewed by:

Susanna Amadio, Fondazione Santa Lucia (IRCCS), Italy
Michal Novak, Slovak Academy of Sciences (SAS), Slovakia

Copyright © 2018 Tharmaratnam, Iskandar, Tabobondung, Tobbia, Gopee-Ramanan and Tabobondung. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Tharmegan Tharmaratnam, tharmegan.tharmaratnam@gmail.com

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