- Email: [email protected]
Junior Seau: An Illustrative Case of Chronic Traumatic Encephalopathy and Update on Chronic Sports-Related Head Injury
Accepted Manuscript Junior Seau - An Illustrative Case of Chronic Traumatic Encephalopathy and Update on Chronic Sports-Related Head Injury Tej D. Azad, BA, Amy Li, BA, Arjun V. Pendharkar, MD, Anand Veeravagu, MD, Gerald A. Grant, MD PII:
S1878-8750(15)01375-3
DOI:
10.1016/j.wneu.2015.10.032
Reference:
WNEU 3327
To appear in:
World Neurosurgery
Received Date: 14 June 2015 Revised Date:
12 October 2015
Accepted Date: 13 October 2015
Please cite this article as: 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 Neurosurgery (2015), doi: 10.1016/j.wneu.2015.10.032. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Junior Seau - An Illustrative Case of Chronic Traumatic Encephalopathy and Update on Chronic Sports-Related Head Injury
*contributed equally
Corresponding Author:
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Key words: American football Chronic traumatic injury Sports-related injury Traumatic brain injury
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Gerald A. Grant Stanford University School of Medicine 300 Pasteur Drive Stanford, CA 94305 Phone - 650-497-8775 Fax – 650-725-5086 Email – [email protected]
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Department of Neurosurgery, Stanford University School of Medicine
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Tej D. Azad BA*, Amy Li BA*, Arjun V. Pendharkar MD, Anand Veeravagu MD, Gerald A. Grant MD
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Abstract
Background
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Few neurologic diseases have captured the nation’s attention more completely than chronic traumatic encephalopathy (CTE) discovered in the postmortem autopsies of professional athletes, most notably professional football players. The tragic case of Junior Seau, a Hall of Fame linebacker, has been the most
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high profile confirmed case of CTE. Here we describe Seau’s case, which concluded in an autopsy
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conducted at the National Institutes of Health, confirming the diagnosis.
Case Description
Since 1990, Junior Seau had a highly distinguished 20-year career playing for the National Football League as a linebacker from which he sustained multiple concussions. He committed suicide on May 2, 2012 at age 43, after which an autopsy confirmed a diagnosis of CTE. His clinical history was significant
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for a series of behavioral disturbances. Seau’s history and neuropathological findings were used to better understand the pathophysiology, diagnosis, and possible risk factors for CTE.
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Conclusions
This high-profile case reflects an increasing awareness for CTE as a long-term consequence of multiple
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traumatic brain injuries. The previously unforeseen neurological risks of American football has begun to cast doubt into the safety of the sport.
Key words: Chronic traumatic injury, traumatic brain injury, sports-related injury, American football
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Introduction
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The likelihood of suffering mild traumatic brain injuries (TBI) from sports participation is quite high, with estimates of 1.6 to 3.8 million occurring each year in the United States (20). Mild TBI results from a traumatic disruption of brain function that with cognitive sequelae that ranges in severity, from transient focal neurological deficits to a loss of consciousness (16,18). Concussion is related to mild TBI, though
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its definition is more elusive. The 4th International Conference on Concussion in Sport held in Zurich in
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2012 agreed to define concussion as “a complex pathophysiological process affecting the brain, induced by biomechanical force” (22). Features of a concussion include a rapid onset of neurological impairment that can resolve spontaneously within minutes to hours and a functional (rather than structural) disturbance of the brain (22). Concussion is a subset of mild TBI, though mild TBI can include subconcussive impacts as well. Sports-related mild TBI occurs most commonly in collision heavy contact
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sports such as boxing, American football, rugby, ice hockey, soccer, and martial arts (16,38). In American football, for example, players can sustain hundreds of repetitive mild TBI in practices and games which may be concussive (symptomatic) or subconcussive (asymptomatic but still may lead to increased risk
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over time) (1,7,13).
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Repetitive mild TBI is thought to contribute to the development of chronic traumatic encephalopathy (CTE), a neurodegenerative disease pathologically confirmed by the presence of a unique pattern of hyperphosphorylated tau neurofibrillary and astrocytic tangles in the brain (11,23,34). This disease has received national media attention because of several famous former National Football League (NFL) players who committed suicide and were afterwards diagnosed with CTE. Postmortem analyses of early clinical symptoms associated with CTE have identified headaches and behavioral changes that include aggression, mood swings, and suicidality; CTE is also associated with a range of cognitive impairment and motor deficits that can manifest after a period of latency following mild TBI (16,25,35).
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Currently, CTE diagnosis can only be confirmed posthumously with an autopsy (14). Given this diagnostic limitation, the incidence of CTE is unknown along with the number and severity of mild TBI
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required for CTE development. True causation of CTE following mild TBI is also still lacking but the association has been postulated in several players. We describe the case of Junior Seau, one of the
greatest linebackers in NFL history and the recipient of national media attention after his suicide by a
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self-inflicted gunshot wound to the chest in May 2012; Seau was diagnosed with CTE after his death. We
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further examine the historical origins, clinical characteristics, and pathophysiology of CTE.
Case Report
Patient History
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Born January 19, 1969, Junior Seau played American football competitively for his high school and college before being drafted to play for the NFL professionally in 1990 (Figure 1). After a highly distinguished 20-year career playing for the NFL as a linebacker, he was posthumously inducted into the
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Class of 2015 Pro Football Hall of Fame. Seau had never self-reported any head injuries, but both his family friend and ex-wife later revealed to the press that Seau had experienced multiple concussions
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throughout his long football career as a linebacker (9).
Clinical Presentation
Seau had complained of headaches, episodes of dizziness, and insomnia since as early as the 1990s. Seau’s ex-wife recalled to the media, “When he would come home from games, he would go straight to the room… [He’d] lower the blinds, the blackout blinds, and just say, ‘Quiet, my head is, is burning’” (5). After Seau’s retirement from the NFL in 2010, his family and friends reported surprising behavioral changes that included withdrawal, heavy alcohol consumption, reckless business and financial decisions,
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and gambling. Seau also became more aggressive and sometimes violent with his close friends and family, which was reported as uncharacteristic. He was arrested on October 18, 2010 for a domestic
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violence incident with his girlfriend (4).
On May 2, 2012, Seau was found dead from apparent suicide at age 43. According to his publicly
released autopsy report from the Office of the Medical Examiner, County of San Diego, California (Case
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Number 12-00960), Seau had no history of smoking or illicit drug use, and his alcohol history was that he “drank socially.” His prescription medications found at the time of his death included 10 mg Zolpidem,
Postmortem Diagnosis of CTE
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500-125 mg Amoxicillin, 500 mg naproxen, and 50 mg propylthiouracil (45).
Seau’s brain, which was donated by his family, was examined at the National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke in July 2012. The NIH reported that
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neuropathological analyses of Seau’s brain revealed “multi-focal tauopathy consistent with a diagnosis of chronic traumatic encephalopathy” (30). The regional distribution of tau neurofibrillary tangles observed in his brain was consistent with CTE and made other possible neurologic disease unlikely. Tau
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neurofibrillary tangles, neuropil threads, and scattered glial tangles in the neocortex were found in the sulcal depths of the frontal and superior temporal cortex, though some neocortical sections showed a
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preferential presence of neurofibrillary tangles in the superficial cortical layers. Neurofibrillary tangles were more intermittently identified in the CA4 sector of the hippocampus, pyriform and insular cortex, nucleus accumbens, basal forebrain, hypothalamus, midbrain, and pons. No neuritic plaques, amyloid deposits, or classical and cortical Lewy bodies were detected. In addition, localized scarring was found in the left frontal lobe that reflected an old traumatic brain injury (29).
Discussion
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History of CTE The conceptualization of CTE is attributed to Dr. Harrison Martland who described a constellation of
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symptoms that appeared to be the result of repeated blows to the head, using the term ‘punch drunk,’ in 1928. Such symptoms included acute gait unsteadiness, mental deterioration, and parkinsonian-like
symptoms (21). Since Martland’s report, a variety of terms have been used to refer to this syndrome.
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Since initial reports had described the symptoms in professional boxers, Parker characterized the disease as a "traumatic encephalopathy of pugilists" and Millspaugh coined the term “dementia pugilistica”
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(27,36). CTE’s modern terminology can be traced to 1949, designated by Critchley (8), although the first case of neuropathologically confirmed CTE in an NFL athlete was made in 2005 (34).
Pathophysiology
CTE is a neurodegenerative disease characterized by neuronal and astrocytic accumulation of
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hyperphosphorylated tau (Figure 2). The accumulation pattern is distinct from that of other tauopathies, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration. CTE differs notably from AD - CTE histology demonstrates presence of tau-reactive astrocytes, which are not observed in AD, and
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lacks the beta amyloid (Aβ) neuritic plaques characteristic of AD (25,46). Moreover, tau deposition in CTE predominantly localizes to superficial cortical layers, sulcal depths, perivascular, periventricular, and
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subpial distribution. Abnormal accumulations of malformed TAR DNA binding protein 43 (TDP-43) are observed in CTE and are associated with CTE symptoms (24,25,39).
Diagnosis
Currently, diagnosis of CTE can only be definitely established histologically via autopsy (Table 1) (23,25). In vivo diagnosis of CTE is sorely needed to conduct research on risk factors and epidemiology and to perform clinical trials for prevention and treatment. Sensitive and specific biomarkers for CTE are being developed and include structural and neurochemical imaging techniques and positron emission
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tomography (PET) with new ligands that selectively bind to p-tau (3,31). These approaches hold promise to detect underlying neuropathological changes of CTE during the life of the athlete prospectively. It will still be critical to keep a detailed prospective diary of an athlete’s concussion history in addition to on the
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field sensors either in the helmet or mouthguard (15). However, as in Seau’s case, the clinical features directly associated with these changes have only recently been described and have been based on
retrospective reports of family members of deceased individuals who received a neuropathological
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diagnosis of CTE (42).
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McKee et al. have proposed a four stage system of CTE categorization, based on severity (Table 2). The authors describe specific histopathology to identify each stage and found anatomic and clinical correlates of the system. The more advanced the stage, the greater the decrease in brain weight and more pronounced the cognitive dysfunctions (p<0.05) (25).
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Risk Factors
Seau’s case, taken with a plethora of other studies, implicates the role of repetitive brain impacts as a potential risk factor for CTE (3,23). While no proof of causation exists between repetitive mild TBIs and
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CTE development, an association between the two is consistent throughout the scientific literature. Professional athletes have received a large share of media attention with regard to CTE risk, but any
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individual exposed to repeated head injuries has also been associated with a higher risk of developing CTE. This vulnerability for repetitive TBI has been demonstrated in military veterans with blast exposure (12). The relationship between repetitive head injury and CTE is likely nuanced - series of individuals with history of mild traumatic injury have reported post-mortem diagnosis of CTE ranging from 63-71% (25,32).
While the age at which CTE can develop is not established, histopathological evidence of CTE has been reported in football players as young as 17 years of age (19). However, repetitive head impact exposures
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of younger football players between ages 9 and 12 are well documented (6). A recent study of retired NFL players found that those who had started playing tackle football before age 12 had significantly greater cognitive deficits than those who began playing after age 12 (41). This suggests that repeated mild
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TBIs at a critical age of crucial brain development can have lasting cognitive impacts and neuropsychological sequelae and may contribute to the development of CTE.
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McKee et al. reported that of 53 subjects who had played football as their primary sport, 42 demonstrated evidence of CTE upon autopsy. Within this CTE-positive cohort, number of years played (p < 0.0001),
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years since retirement (p< 0.0001) and age at death (p < 0.0001) were significantly correlated with pathological stage of CTE. Family reported number of concussions (p= 0.184); years of education (p = 0.134), lifetime steroid use (p = 0.731) and position played (p = 0.407) were not significantly related to CTE stage (25).
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Though McKee et al. did not find position played to be associated with CTE, other studies have revealed associations between position played and risk for head injury (2,7). A study of 314 collegiate athletes (286,636 head impacts) revealed a median of 420 head impacts per season, and that defensive linemen,
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linebackers, and offensive linemen sustained the highest number of impacts per season, but also the lowest magnitude collisions (7). After his death, Junior Seau’s closest friends and family revealed that the
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linebacker received a large number of head injuries during his football career (9). Because these injuries were never officially reported, it is unclear how much of an effect his position—known to sustain some of the highest number of impacts per season—had on his individual vulnerability to mild traumatic brain injuries and subsequent development of CTE. Nevertheless, position-associated differences in head impact had been reported previously (26).
There has also been evidence reported of association between the apolipoprotein E ε4 (ApoE4) gene and severity of head injury (17,47). ApoE4 has also been associated with poor outcome after head injury
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(10,42). McKee et al. found that of 68 CTE-positive individuals, no significant association between CTE diagnosis and ApoE ε4 allele genotype could be established (25). However, more study is needed to
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confirm or reject a genetic component of risk for CTE.
TBI has long been understood as a risk factor for dementia (40). Even with the heightened attention and awareness around this association, important questions about TBI and CTE remain unanswered. While
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histopathology has revealed postmortem evidence of substrates of cognitive impairment, the mechanisms contributing to neurodegeneration following TBI are largely unknown. The use of high profile cases such
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as that of Junior Seau catalyzes more research critically needed in the field of mild TBI and the causes of CTE.
Conclusions
The increasing public awareness of CTE, especially among high-profile NFL players such as Junior Seau,
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has substantially impacted the sports community. In 2014, the NFL Players Association received lawsuits from former NFL players alleging that the NFL did not adequately inform them about the high risk of recurrent mild TBI on their long-term health and that the organization should have done more to protect
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its players (37). The NFL has published a protocol detailing the protective measures a player must follow after a concussion (28). Nevertheless, it is uncertain whether head injuries are being consistently reported
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and this protocol followed for every player given the profession’s high pressure to return to play.
Tables and Figures
Table 1. Diagnostic histopathologic criteria for CTE Table 2. Proposed CTE staging Figure 1. Junior Seau with the New England Patriots, December 14, 2008. Photograph by JJ Hall, distributed under a CC-BY-2.0 license (http://creativecommons.org/licenses/by/2.0). Cropped. Figure 2. CTE histopathology from Stern et al. 2011 (43). [Top Panel] Comparison between normal brain (left) and CTE-confirmed brain (right). The brain with CTE identified neurofibrillary degeneration
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most severe at sulci depths in the frontal cortex, nucleus basalis of Meynert (nbM), insular cortex (ins), amygdala (a), entorhinal cortex (ec), and temporal cortex. [Lower Panels] Tau-immunostained neurofibrillary tangles are predominantly present at the sulci depths (A, 60x magnification), observed in both neurons and astrocytes (B, 350x magnification), densely found in medial temporal lobe structures with absence of neuritic plaques (C, 150x magnification), preferentially centered around small blood vessels and in subpial patches (D, 150x magnification), and present in cortical layers II and III (E, 150x magnification). Neurofibrillary tangles can be observed in a Betz cell of the primary motor cortex (F, 350x magnification). Perivascular tau neurofibrillary tangles are typically present (G, 150x magnification). Permission obtained from Elsevier Ltd © Stern RA et al.: PM&R 3(10 Suppl 2):S460467, 2011. License Number: 3603171380030, April 6, 2015.
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Table 1. Diagnostic histopathologic criteria for CTE Perivascular foci of p-tau immunoreactive astrocytic tangles and neurofibrillary tangles
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Irregular cortical distribution of p-tau immunoreactive neurofibrillary tangles and astrocytic tangles with a predilection for the depth of cerebral sulci Clusters of subpial and periventricular astrocytic tangles in the cerebral cortex, diencephalon, basal ganglia and brainstem Neurofibrillary tangles in the cerebral cortex located preferentially in the superficial layers
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Table 2. Proposed CTE staging •
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Perivascular hyperphosphorylated tau neurofibrillary tangles in focal epicenters at sulci depths in cerebral cortexes Some axonal loss
Stage 2
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Spread of tau pathology to superficial cortical layers adjacent to the focal epicenters Some axonal loss
Stage 3
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Tau pathology widespread and dense in frontal, insular, temporal, parietal, and septal cortices, diencephalon, brainstem, and spinal cord; also in medial temporal lobe including hippocampus, entorhinal cortex, and amygdala Evidence of mild cerebral atrophy and depigmentation of substantia nigra Severe and diffuse axonal loss
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Widespread tau pathology in most regions of the cerebral cortex and medial temporal lobe Further atrophy and gross abnormalities that are more severe than previous stages Abundant neuronal loss and gliosis of cerebral cortex and areas such as the amygdala and hippocampus Marked astrocytic triangles presence and neuronal loss and gliosis of the cerebral cortex, amygdala, and hippocampus Severe and diffuse axonal loss
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Stage 4
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Stage 1
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Highlights
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CTE diagnosis can only be confirmed posthumously with an autopsy, and the incidence and true
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causation of CTE is therefore unknown.
We discuss the clinical case of Junior Seau, one of the greatest linebackers in NFL history, who
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was diagnosed with CTE after his violent suicide. He had suffered repetitive mild traumatic brain
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injuries to the head during his career and had severe behavioral changes upon retirement.
The neuropathological analyses of Seau’s brain revealed the regional distribution of tau neurofibrillary tangles consistent with CTE.
Seau’s case, along with other studies, implicates the role of repetitive brain impacts as a potential
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risk factor for CTE.
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ABBREVIATIONS: AD: Alzheimer’s disease ApoE4: Apolipoprotein E ε4
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CTE: Chronic traumatic encephalopathy NFL: National Football League NIH: National Institutes of Health
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TBI: Traumatic brain injury
S1878-8750(15)01375-3
DOI:
10.1016/j.wneu.2015.10.032
Reference:
WNEU 3327
To appear in:
World Neurosurgery
Received Date: 14 June 2015 Revised Date:
12 October 2015
Accepted Date: 13 October 2015
Please cite this article as: 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 Neurosurgery (2015), doi: 10.1016/j.wneu.2015.10.032. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Junior Seau - An Illustrative Case of Chronic Traumatic Encephalopathy and Update on Chronic Sports-Related Head Injury
*contributed equally
Corresponding Author:
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Key words: American football Chronic traumatic injury Sports-related injury Traumatic brain injury
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Gerald A. Grant Stanford University School of Medicine 300 Pasteur Drive Stanford, CA 94305 Phone - 650-497-8775 Fax – 650-725-5086 Email – [email protected]
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Department of Neurosurgery, Stanford University School of Medicine
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Tej D. Azad BA*, Amy Li BA*, Arjun V. Pendharkar MD, Anand Veeravagu MD, Gerald A. Grant MD
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Abstract
Background
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Few neurologic diseases have captured the nation’s attention more completely than chronic traumatic encephalopathy (CTE) discovered in the postmortem autopsies of professional athletes, most notably professional football players. The tragic case of Junior Seau, a Hall of Fame linebacker, has been the most
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high profile confirmed case of CTE. Here we describe Seau’s case, which concluded in an autopsy
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conducted at the National Institutes of Health, confirming the diagnosis.
Case Description
Since 1990, Junior Seau had a highly distinguished 20-year career playing for the National Football League as a linebacker from which he sustained multiple concussions. He committed suicide on May 2, 2012 at age 43, after which an autopsy confirmed a diagnosis of CTE. His clinical history was significant
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for a series of behavioral disturbances. Seau’s history and neuropathological findings were used to better understand the pathophysiology, diagnosis, and possible risk factors for CTE.
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Conclusions
This high-profile case reflects an increasing awareness for CTE as a long-term consequence of multiple
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traumatic brain injuries. The previously unforeseen neurological risks of American football has begun to cast doubt into the safety of the sport.
Key words: Chronic traumatic injury, traumatic brain injury, sports-related injury, American football
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Introduction
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The likelihood of suffering mild traumatic brain injuries (TBI) from sports participation is quite high, with estimates of 1.6 to 3.8 million occurring each year in the United States (20). Mild TBI results from a traumatic disruption of brain function that with cognitive sequelae that ranges in severity, from transient focal neurological deficits to a loss of consciousness (16,18). Concussion is related to mild TBI, though
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its definition is more elusive. The 4th International Conference on Concussion in Sport held in Zurich in
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2012 agreed to define concussion as “a complex pathophysiological process affecting the brain, induced by biomechanical force” (22). Features of a concussion include a rapid onset of neurological impairment that can resolve spontaneously within minutes to hours and a functional (rather than structural) disturbance of the brain (22). Concussion is a subset of mild TBI, though mild TBI can include subconcussive impacts as well. Sports-related mild TBI occurs most commonly in collision heavy contact
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sports such as boxing, American football, rugby, ice hockey, soccer, and martial arts (16,38). In American football, for example, players can sustain hundreds of repetitive mild TBI in practices and games which may be concussive (symptomatic) or subconcussive (asymptomatic but still may lead to increased risk
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over time) (1,7,13).
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Repetitive mild TBI is thought to contribute to the development of chronic traumatic encephalopathy (CTE), a neurodegenerative disease pathologically confirmed by the presence of a unique pattern of hyperphosphorylated tau neurofibrillary and astrocytic tangles in the brain (11,23,34). This disease has received national media attention because of several famous former National Football League (NFL) players who committed suicide and were afterwards diagnosed with CTE. Postmortem analyses of early clinical symptoms associated with CTE have identified headaches and behavioral changes that include aggression, mood swings, and suicidality; CTE is also associated with a range of cognitive impairment and motor deficits that can manifest after a period of latency following mild TBI (16,25,35).
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Currently, CTE diagnosis can only be confirmed posthumously with an autopsy (14). Given this diagnostic limitation, the incidence of CTE is unknown along with the number and severity of mild TBI
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required for CTE development. True causation of CTE following mild TBI is also still lacking but the association has been postulated in several players. We describe the case of Junior Seau, one of the
greatest linebackers in NFL history and the recipient of national media attention after his suicide by a
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self-inflicted gunshot wound to the chest in May 2012; Seau was diagnosed with CTE after his death. We
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further examine the historical origins, clinical characteristics, and pathophysiology of CTE.
Case Report
Patient History
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Born January 19, 1969, Junior Seau played American football competitively for his high school and college before being drafted to play for the NFL professionally in 1990 (Figure 1). After a highly distinguished 20-year career playing for the NFL as a linebacker, he was posthumously inducted into the
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Class of 2015 Pro Football Hall of Fame. Seau had never self-reported any head injuries, but both his family friend and ex-wife later revealed to the press that Seau had experienced multiple concussions
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throughout his long football career as a linebacker (9).
Clinical Presentation
Seau had complained of headaches, episodes of dizziness, and insomnia since as early as the 1990s. Seau’s ex-wife recalled to the media, “When he would come home from games, he would go straight to the room… [He’d] lower the blinds, the blackout blinds, and just say, ‘Quiet, my head is, is burning’” (5). After Seau’s retirement from the NFL in 2010, his family and friends reported surprising behavioral changes that included withdrawal, heavy alcohol consumption, reckless business and financial decisions,
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and gambling. Seau also became more aggressive and sometimes violent with his close friends and family, which was reported as uncharacteristic. He was arrested on October 18, 2010 for a domestic
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violence incident with his girlfriend (4).
On May 2, 2012, Seau was found dead from apparent suicide at age 43. According to his publicly
released autopsy report from the Office of the Medical Examiner, County of San Diego, California (Case
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Number 12-00960), Seau had no history of smoking or illicit drug use, and his alcohol history was that he “drank socially.” His prescription medications found at the time of his death included 10 mg Zolpidem,
Postmortem Diagnosis of CTE
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500-125 mg Amoxicillin, 500 mg naproxen, and 50 mg propylthiouracil (45).
Seau’s brain, which was donated by his family, was examined at the National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke in July 2012. The NIH reported that
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neuropathological analyses of Seau’s brain revealed “multi-focal tauopathy consistent with a diagnosis of chronic traumatic encephalopathy” (30). The regional distribution of tau neurofibrillary tangles observed in his brain was consistent with CTE and made other possible neurologic disease unlikely. Tau
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neurofibrillary tangles, neuropil threads, and scattered glial tangles in the neocortex were found in the sulcal depths of the frontal and superior temporal cortex, though some neocortical sections showed a
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preferential presence of neurofibrillary tangles in the superficial cortical layers. Neurofibrillary tangles were more intermittently identified in the CA4 sector of the hippocampus, pyriform and insular cortex, nucleus accumbens, basal forebrain, hypothalamus, midbrain, and pons. No neuritic plaques, amyloid deposits, or classical and cortical Lewy bodies were detected. In addition, localized scarring was found in the left frontal lobe that reflected an old traumatic brain injury (29).
Discussion
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History of CTE The conceptualization of CTE is attributed to Dr. Harrison Martland who described a constellation of
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symptoms that appeared to be the result of repeated blows to the head, using the term ‘punch drunk,’ in 1928. Such symptoms included acute gait unsteadiness, mental deterioration, and parkinsonian-like
symptoms (21). Since Martland’s report, a variety of terms have been used to refer to this syndrome.
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Since initial reports had described the symptoms in professional boxers, Parker characterized the disease as a "traumatic encephalopathy of pugilists" and Millspaugh coined the term “dementia pugilistica”
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(27,36). CTE’s modern terminology can be traced to 1949, designated by Critchley (8), although the first case of neuropathologically confirmed CTE in an NFL athlete was made in 2005 (34).
Pathophysiology
CTE is a neurodegenerative disease characterized by neuronal and astrocytic accumulation of
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hyperphosphorylated tau (Figure 2). The accumulation pattern is distinct from that of other tauopathies, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration. CTE differs notably from AD - CTE histology demonstrates presence of tau-reactive astrocytes, which are not observed in AD, and
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lacks the beta amyloid (Aβ) neuritic plaques characteristic of AD (25,46). Moreover, tau deposition in CTE predominantly localizes to superficial cortical layers, sulcal depths, perivascular, periventricular, and
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subpial distribution. Abnormal accumulations of malformed TAR DNA binding protein 43 (TDP-43) are observed in CTE and are associated with CTE symptoms (24,25,39).
Diagnosis
Currently, diagnosis of CTE can only be definitely established histologically via autopsy (Table 1) (23,25). In vivo diagnosis of CTE is sorely needed to conduct research on risk factors and epidemiology and to perform clinical trials for prevention and treatment. Sensitive and specific biomarkers for CTE are being developed and include structural and neurochemical imaging techniques and positron emission
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tomography (PET) with new ligands that selectively bind to p-tau (3,31). These approaches hold promise to detect underlying neuropathological changes of CTE during the life of the athlete prospectively. It will still be critical to keep a detailed prospective diary of an athlete’s concussion history in addition to on the
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field sensors either in the helmet or mouthguard (15). However, as in Seau’s case, the clinical features directly associated with these changes have only recently been described and have been based on
retrospective reports of family members of deceased individuals who received a neuropathological
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diagnosis of CTE (42).
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McKee et al. have proposed a four stage system of CTE categorization, based on severity (Table 2). The authors describe specific histopathology to identify each stage and found anatomic and clinical correlates of the system. The more advanced the stage, the greater the decrease in brain weight and more pronounced the cognitive dysfunctions (p<0.05) (25).
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Risk Factors
Seau’s case, taken with a plethora of other studies, implicates the role of repetitive brain impacts as a potential risk factor for CTE (3,23). While no proof of causation exists between repetitive mild TBIs and
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CTE development, an association between the two is consistent throughout the scientific literature. Professional athletes have received a large share of media attention with regard to CTE risk, but any
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individual exposed to repeated head injuries has also been associated with a higher risk of developing CTE. This vulnerability for repetitive TBI has been demonstrated in military veterans with blast exposure (12). The relationship between repetitive head injury and CTE is likely nuanced - series of individuals with history of mild traumatic injury have reported post-mortem diagnosis of CTE ranging from 63-71% (25,32).
While the age at which CTE can develop is not established, histopathological evidence of CTE has been reported in football players as young as 17 years of age (19). However, repetitive head impact exposures
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of younger football players between ages 9 and 12 are well documented (6). A recent study of retired NFL players found that those who had started playing tackle football before age 12 had significantly greater cognitive deficits than those who began playing after age 12 (41). This suggests that repeated mild
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TBIs at a critical age of crucial brain development can have lasting cognitive impacts and neuropsychological sequelae and may contribute to the development of CTE.
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McKee et al. reported that of 53 subjects who had played football as their primary sport, 42 demonstrated evidence of CTE upon autopsy. Within this CTE-positive cohort, number of years played (p < 0.0001),
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years since retirement (p< 0.0001) and age at death (p < 0.0001) were significantly correlated with pathological stage of CTE. Family reported number of concussions (p= 0.184); years of education (p = 0.134), lifetime steroid use (p = 0.731) and position played (p = 0.407) were not significantly related to CTE stage (25).
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Though McKee et al. did not find position played to be associated with CTE, other studies have revealed associations between position played and risk for head injury (2,7). A study of 314 collegiate athletes (286,636 head impacts) revealed a median of 420 head impacts per season, and that defensive linemen,
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linebackers, and offensive linemen sustained the highest number of impacts per season, but also the lowest magnitude collisions (7). After his death, Junior Seau’s closest friends and family revealed that the
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linebacker received a large number of head injuries during his football career (9). Because these injuries were never officially reported, it is unclear how much of an effect his position—known to sustain some of the highest number of impacts per season—had on his individual vulnerability to mild traumatic brain injuries and subsequent development of CTE. Nevertheless, position-associated differences in head impact had been reported previously (26).
There has also been evidence reported of association between the apolipoprotein E ε4 (ApoE4) gene and severity of head injury (17,47). ApoE4 has also been associated with poor outcome after head injury
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(10,42). McKee et al. found that of 68 CTE-positive individuals, no significant association between CTE diagnosis and ApoE ε4 allele genotype could be established (25). However, more study is needed to
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confirm or reject a genetic component of risk for CTE.
TBI has long been understood as a risk factor for dementia (40). Even with the heightened attention and awareness around this association, important questions about TBI and CTE remain unanswered. While
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histopathology has revealed postmortem evidence of substrates of cognitive impairment, the mechanisms contributing to neurodegeneration following TBI are largely unknown. The use of high profile cases such
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as that of Junior Seau catalyzes more research critically needed in the field of mild TBI and the causes of CTE.
Conclusions
The increasing public awareness of CTE, especially among high-profile NFL players such as Junior Seau,
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has substantially impacted the sports community. In 2014, the NFL Players Association received lawsuits from former NFL players alleging that the NFL did not adequately inform them about the high risk of recurrent mild TBI on their long-term health and that the organization should have done more to protect
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its players (37). The NFL has published a protocol detailing the protective measures a player must follow after a concussion (28). Nevertheless, it is uncertain whether head injuries are being consistently reported
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and this protocol followed for every player given the profession’s high pressure to return to play.
Tables and Figures
Table 1. Diagnostic histopathologic criteria for CTE Table 2. Proposed CTE staging Figure 1. Junior Seau with the New England Patriots, December 14, 2008. Photograph by JJ Hall, distributed under a CC-BY-2.0 license (http://creativecommons.org/licenses/by/2.0). Cropped. Figure 2. CTE histopathology from Stern et al. 2011 (43). [Top Panel] Comparison between normal brain (left) and CTE-confirmed brain (right). The brain with CTE identified neurofibrillary degeneration
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most severe at sulci depths in the frontal cortex, nucleus basalis of Meynert (nbM), insular cortex (ins), amygdala (a), entorhinal cortex (ec), and temporal cortex. [Lower Panels] Tau-immunostained neurofibrillary tangles are predominantly present at the sulci depths (A, 60x magnification), observed in both neurons and astrocytes (B, 350x magnification), densely found in medial temporal lobe structures with absence of neuritic plaques (C, 150x magnification), preferentially centered around small blood vessels and in subpial patches (D, 150x magnification), and present in cortical layers II and III (E, 150x magnification). Neurofibrillary tangles can be observed in a Betz cell of the primary motor cortex (F, 350x magnification). Perivascular tau neurofibrillary tangles are typically present (G, 150x magnification). Permission obtained from Elsevier Ltd © Stern RA et al.: PM&R 3(10 Suppl 2):S460467, 2011. License Number: 3603171380030, April 6, 2015.
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Table 1. Diagnostic histopathologic criteria for CTE Perivascular foci of p-tau immunoreactive astrocytic tangles and neurofibrillary tangles
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Irregular cortical distribution of p-tau immunoreactive neurofibrillary tangles and astrocytic tangles with a predilection for the depth of cerebral sulci Clusters of subpial and periventricular astrocytic tangles in the cerebral cortex, diencephalon, basal ganglia and brainstem Neurofibrillary tangles in the cerebral cortex located preferentially in the superficial layers
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Table 2. Proposed CTE staging •
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Perivascular hyperphosphorylated tau neurofibrillary tangles in focal epicenters at sulci depths in cerebral cortexes Some axonal loss
Stage 2
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Spread of tau pathology to superficial cortical layers adjacent to the focal epicenters Some axonal loss
Stage 3
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Tau pathology widespread and dense in frontal, insular, temporal, parietal, and septal cortices, diencephalon, brainstem, and spinal cord; also in medial temporal lobe including hippocampus, entorhinal cortex, and amygdala Evidence of mild cerebral atrophy and depigmentation of substantia nigra Severe and diffuse axonal loss
• • • •
TE D
•
Widespread tau pathology in most regions of the cerebral cortex and medial temporal lobe Further atrophy and gross abnormalities that are more severe than previous stages Abundant neuronal loss and gliosis of cerebral cortex and areas such as the amygdala and hippocampus Marked astrocytic triangles presence and neuronal loss and gliosis of the cerebral cortex, amygdala, and hippocampus Severe and diffuse axonal loss
AC C
Stage 4
EP
• •
M AN U
Stage 1
AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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Highlights
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CTE diagnosis can only be confirmed posthumously with an autopsy, and the incidence and true
•
RI PT
causation of CTE is therefore unknown.
We discuss the clinical case of Junior Seau, one of the greatest linebackers in NFL history, who
SC
was diagnosed with CTE after his violent suicide. He had suffered repetitive mild traumatic brain
•
M AN U
injuries to the head during his career and had severe behavioral changes upon retirement.
The neuropathological analyses of Seau’s brain revealed the regional distribution of tau neurofibrillary tangles consistent with CTE.
Seau’s case, along with other studies, implicates the role of repetitive brain impacts as a potential
EP
TE D
risk factor for CTE.
AC C
•
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ABBREVIATIONS: AD: Alzheimer’s disease ApoE4: Apolipoprotein E ε4
RI PT
CTE: Chronic traumatic encephalopathy NFL: National Football League NIH: National Institutes of Health
AC C
EP
TE D
M AN U
SC
TBI: Traumatic brain injury