Team Physician’s Corner
Talking With Parents of High School Football Players About Chronic Traumatic Encephalopathy
M
A Concise Summary Shawn Love,*y BS, and Gary S. Solomon,*yz PhD Investigation performed at Vanderbilt University Medical Center, Nashville, Tennessee, USA Over the past decade, athletic-related chronic traumatic encephalopathy (CTE) has garnered a great deal of attention in the popular press and, more recently, in the scientific press. With increasing frequency, sports medicine practitioners and providers are faced with questions from the parents of high school football players about CTE and the risk posed to children who participate in this or other contact or collision sports. The purpose of this review was to summarize the research on CTE in an attempt to provide some evidence-based answers to frequently asked questions in clinics from parents. Addressed are (1) the definitions of CTE and its symptoms, (2) the evidence for CTE in football, (3) abnormal tau protein, (4) the use of neuroimaging in CTE diagnosis, (5) risk for CTE, (6) CTE diagnosis in youth, (7) CTE and its relationship to suicide, and (8) contact and collision sports as a risk factor for permanent brain injury or death. Keywords: chronic traumatic encephalopathy; concussion; traumatic brain injury; sports; football
demonstrated. This increased awareness of concussions in general and CTE in particular may be a factor in decreasing football participation. Indeed, involvement in youth football has declined; according to the National Sporting Goods Association, the organization used by the US Census Bureau for the country’s sports participation data, tackle football participation rates dropped by almost 13% between 2011 and 2012, most notably among players aged 7 to 11 years.11 Meanwhile, widespread media attention has undoubtedly led to changes in the public’s perception of football, as well as contact and collision sports in general. In fact, concussion is the only injury in sports medicine that is regulated by law in 49 of the 50 states in the United States (a bill is pending in the 50th state). As parents, coaches, and educators have become increasingly concerned about the potential long-term effects of concussive injury in football, primary health care providers have been faced more frequently with the clinical question, ‘‘Will my child develop CTE?’’ The goal of this paper is to provide health care providers with a concise overview of the current evidence related to CTE so that they may address, with a state-of-the-science evidence base, questions from the parents of high school football players who are concerned that their children may develop this syndrome.
In recent years, an overwhelming amount of media attention has been directed toward sports concussions, particularly in American football. Concussion, or mild traumatic brain injury (TBI), is defined by the International Concussion in Sport Group18 as ‘‘a complex pathophysiological process affecting the brain, induced by biomechanical forces.’’ This media emphasis on sports concussions has coincided with the burgeoning concussion research that has surfaced over the past decade focused on the neurodegenerative syndrome chronic traumatic encephalopathy (CTE). Although it has been understood for more than 85 years that repetitive brain injury is associated with an increased risk for developing neurodegenerative changes in adults,16 a definitive causal link between concussions and CTE in American high school football has yet to be z Address correspondence to Gary S. Solomon, PhD, Vanderbilt University School of Medicine, Department of Neurological Surgery, 1500 21st Avenue South, Neurosurgery Clinic, Suite 1506, Nashville, TN 37232, USA (e-mail: [email protected]). *Vanderbilt University School of Medicine, Nashville, Tennessee, USA. y Vanderbilt Sports Concussion Center, Nashville, Tennessee, USA. One or more of the authors has declared the following potential conflict of interest or source of funding: G.S.S. receives consulting fees for clinical services from the Nashville Predators and the Tennessee Titans, receives royalties from book sales, and is a member of the Professional Advisory Board of ImPACT, for which he receives expense reimbursement for meeting attendance.
WHAT IS CTE?
The American Journal of Sports Medicine, Vol. 43, No. 5 DOI: 10.1177/0363546514535187 Ó 2014 The Author(s)
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dementia pugilistica, as it was originally known1—to one linked to athletes in contact sports, especially American football.19,22 Within the past 10 years, research groups led by Drs Ann McKee and Bennet Omalu have offered new definitions of CTE,19,22 which prompted Gardner et al8 to suggest that that there are ‘‘classic’’ and ‘‘modern’’ definitions of CTE, given their clinicopathologic differences. Suggesting that CTE has a clear environmental origin, these groups have proposed that head injury, both concussive and subconcussive, leads to neuropathologic changes and the subsequent development of a series of neuropsychiatric symptoms, behavioral changes, and cognitive deficits. They have noted that the diagnosis of CTE is made postmortem; the brains of these athletes contain widespread neurofibrillary tangles (NFTs) composed of abnormal aggregates of hyperphosphorylated tau protein within distinct brain regions.19,23 Importantly, both groups have relied heavily on the presence of NFTs and hyperphosphorylated tau protein as the primary neuropathologic basis for CTE diagnosis. A key difference in the two definitions lies in the number of brain insults required to develop CTE; whereas Omalu et al22 stated that CTE can result from a single insult, McKee et al20 asserted that repetitive insults are critical to CTE development. Conversely, it should be noted that the existence of the CTE syndrome itself has been questioned.25 In his critique of the CTE syndrome, Randolph25 concluded that there are (1) no established consensus or empirical clinical or neuropathologic criteria diagnosing CTE, (2) no controlled epidemiologic data related to CTE, and (3) no clinical syndrome unique to CTE on the basis of recent cross-sectional, clinical studies of cognitively impaired retired professional football players.
WHAT ARE THE SYMPTOMS OF CTE, AND WHEN DOES IT START? In general, CTE is described across definitions as comprising a broad set of clinical signs and symptoms, including neuropsychiatric and behavioral changes (eg, depression, mood lability, agitation, impulsivity, and aggression), parkinsonism, dysarthria, gait abnormalities, and cognitive deficits, including impairments of memory, attention, executive functioning, and language.8,9,19 In contrast to more classic neurodegenerative diseases, CTE has been described as a syndrome that manifests within 1 to 2 decades after retirement from contact or collision sports. McKee et al20 and Omalu et al22 stated that CTE begins 8 to 10 years after retirement, while McCrory,17 in his review of the literature, reported that symptoms may manifest as late as 10 to 20 years after retirement.
WHAT SCIENTIFIC LITERATURE IS THERE TO SUPPORT THE DIAGNOSIS OF CTE IN FOOTBALL PLAYERS? Retrospective cohort studies conducted by McKee et al19,20 and Omalu et al22 have revealed neuropathologic evidence
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of CTE in autopsies of former athletes. In all 3 studies,19,20,22 the diagnosis of CTE was based on the criteria posited by each group at that point in time. The initial cohort study by McKee et al19 reported CTE findings in the brains of 51 individuals postmortem (no control subjects were reported). Forty-six of the 51 were athletes, 5 of these 46 were professional football players, and nearly all others (n = 39) were boxers. Three years later, McKee et al20 followed up with a report of 85 individuals with histories significant for repetitive mild TBI. Fifty of the 68 who were found to be positive for CTE were professional (n = 34), semiprofessional (n = 1), collegiate (n = 9), and high school (n = 6) football players (the 5 professional football players from the 2009 paper are assumed to be included in the 2012 professional patient cohort). The remaining individuals who demonstrated neuropathologic signs of CTE included boxers, a wrestler, war veterans, and a person who exhibited head-banging behavior. Eighteen control ‘‘cognitively intact’’ subjects with negative histories of mild TBI were included in this study, with 1 female subject, 3 athletes, and a mean age of 62.0 6 17.4 years. Although 11 of the 18 control subjects were positive for hyperphosphorylated tau protein, none of these was reported to have the deposition pattern of abnormal tau protein said to be specific for CTE by McKee et al. In 2011, Omalu et al22 reported similar findings of CTE when they conducted postmortem assessments of the brains of 17 athletes (14 professional and 3 high school athletes; no control patients were reported). Seven of the 8 professional football players were CTE positive, while 1 of the 3 high school athletes (a soccer player) was said to have undefined ‘‘incipient’’ CTE. The most comprehensive review to date was by Gardner et al,8 who summarized data from 158 published case studies of CTE, including 85 cases with autopsy data. In their summary of the 85 cases with neuropathologic findings, they reported that 44 (51.8%) had CTE plus other neuropathology, 17 (20%) had pure CTE neuropathology, 20 (23.5%) had no neuropathology, and 4 (4.7%) had other neuropathology but no CTE. Neuropathologic data specific to high school football players are unavailable.
ARE CONCUSSIONS THE ONLY CAUSE OF ABNORMAL TAU PROTEIN FORMATION IN THE BRAIN? The answer is no. Karantzoulis and Randolph13 listed 20 different neuropathologic conditions associated with abnormal tau protein aggregation in the brain, including Alzheimer disease, frontotemporal dementia, Lewy body disease, and other neuropathologic conditions. Tau protein is an intracellular protein present in the human brain that serves to fortify microtubules structurally.4 Mutations in this protein, whether genetic and/or environmental, may lead to unregulated hyperphosphorylation of tau protein, which leads to cell breakdown, neuronal death, and aggregation into larger NFTs. The focus of CTE research published by McKee et al19,20 and Omalu et al22 has been on the presence of abnormal tau protein as a neuropathologic signature of CTE.
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However, research by Braak et al3 into the stages of Alzheimer disease yielded insight into the presence of abnormal tau protein in both pathologic states and as a component of normal aging. One of the hallmark features of the condition is the presence of widespread intracellular NFTs. It is not until Braak stages V and VI (of 10 stages), in which there is extensive neocortical NFT deposition, that a clinical diagnosis of Alzheimer disease is made. It should be noted that the tau protein pathology depicted by CTE researchers most closely resembles Braak stages I and II, in which tau protein is restricted primarily to the entorhinal cortex, hippocampus, and nearby cortical areas. In an assessment of 2332 consecutive and unselected autopsy cases, Braak et al3 found that NFT stages I and II were present in roughly 10% of patients in their teens, in .20% of patients in their 20s, in nearly 40% of those in their 30s, in .40% in their 40s, and in .70% in their 50s and 60s. The authors also noted that NFT stages III to VI could be found in individuals as young as 30 years of age. Finally, Braak et al3 reported that 100% of the patients aged . 29 years had some sort of abnormal tau protein development. Thus, the findings of tau protein deposition in the recent autopsy analyses of athletes as young as their 20s may not be surprising. Although CTE is considered to be a distinct neuropathologic process, tau protein may be found in individuals undergoing the normal aging process independent of head trauma. It should be noted, however, that both McKee et al19,20 and Omalu et al22 reported that the distribution of abnormal tau protein is qualitatively different in CTE versus other neurodegenerative diseases. However, this has not been crossvalidated by other groups of neuropathologists. Ramage et al24 reported a greater incidence of abnormal tau protein deposition in the brains of drug abusers (opiate abusers \40 years of age) compared with controls (44% vs 19%). In a parallel finding, Cottler et al6 found that more than half (52%) of the 644 surveyed players from the National Football League (NFL) reported opioid use during their NFL playing careers, and most of these (71%) reported abuse. The prevalence of current opiate use (7%) among the NFL retirees was 3 times higher than that of the general population.
CAN NEUROIMAGING BE USED TO DIAGNOSE CTE? Given the specific neuropathologic changes of CTE, one might assume that neuroimaging might be useful diagnostically. On the basis of recent studies, this hypothesis remains equivocal. Small et al30 at the University of California, Los Angeles, reported that CTE may be diagnosable in vivo. Using 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl) amino]-2-naphthyl}-ethylidene)malononitrile (FDDNP)– tau marked positron emission tomographic scans, they found increased FDDNP binding in the amygdala and subcortical regions of 5 retired NFL players (aged 45-73 years) compared with controls. However, elevated FDDNP signals also can be associated with depressive14 and cognitive31 symptoms in normal aging. Alternatively, in 2013, Hart et al10 performed neuroimaging studies and
The American Journal of Sports Medicine
measured neuropsychological functioning in 34 retired NFL players with an average of 9.7 years of experience. Diffusion tensor imaging and fluid-attenuated inversion recovery sequences revealed white matter tract abnormalities, but the authors interpreted these results as being inconsistent with CTE. The neuropsychological testing revealed no relationship between the number of years played and the level of cognitive impairment. Although neuroimaging may be a useful modality in the in vivo detection of CTE in the future, the diagnosis at present remains limited to autopsy and the detection of specific amounts and patterns of abnormal tau protein deposition.20,21
WHAT ARE THE CHANCES AN ATHLETE WILL DEVELOP CTE? Although the incidence rate for dementia pugilistica in professional boxers has been estimated to be about 17%,26 scientific studies have yet to elucidate the epidemiology of CTE in nonboxing athletes. Given the current requirement of specific tau protein abnormalities in postmortem diagnosis and the overlap with other neuropathologies, the current incidence of CTE remains unknown. Gavett et al9 estimated that at least 3.7% of NFL players will develop CTE in their lifetimes, on the basis of neuropathologic evidence of the disease in 12 of 321 American football players whose deaths occurred between February 2008 and June 2010. The number of concussive and/or subconcussive events, as well as the amount of athletic exposure required to trigger neurodegenerative change and the subsequent development of CTE in football players, is unknown at present. In contrast to CTE, the prevalence of other forms of dementia (eg, Alzheimer disease, amyotrophic lateral sclerosis, or Parkinson disease) in retired NFL players has been the subject of several studies. First, Weir et al32 reported in a 2009 survey study that 6.1% of NFL retirees reported dementia or dementia-related disease in comparison with 1.9% of the general population. Three years later, Lehman et al15 reported that the mortality rate for neurodegenerative disease (Alzheimer dementia, Parkinson disease, and amyotrophic lateral sclerosis) in former NFL players is 3 times higher than that of the general population. That study, however, has been criticized for its lack of statistical power due to its small sample size.9 Contrary to Lehman et al’s study, Savica et al28 found that the risk for neurodegenerative disease in a cohort of 438 former Minnesota high school football players was no different than in a control cohort of 140 non-football-playing male classmates.
HOW MANY ADOLESCENTS AND YOUNG ADULTS HAVE BEEN DIAGNOSED WITH CTE? According to data provided by the National Federation of State High School Associations,21 approximately 1.09 million male and female high school athletes participated in
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11-player football in the 2011-2012 school year. Of the 158 total reported cases of CTE in the scientific literature,8 fewer than 7 were in high school–aged individuals. McKee et al20 reported CTE-positive findings in 6 high school football players, while Omalu et al22 identified ‘‘incipient’’ CTE in 1 high school soccer player (although the definition of ‘‘incipient’’ was unclear). To date, there has been a total of fewer than 7 potential cases of CTE in high school athletes.
DOES CTE CAUSE SUICIDE? Between 2011 and 2013, suicide was a cause of death in 6 football players diagnosed with CTE.12 These deaths have undoubtedly escalated the media attention and may have contributed to the public perception of a CTE-suicide link. Despite implications that CTE may be a risk factor for suicide, there are currently no published studies corroborating CTE in the causation of suicide.12 In the United States, the suicide rate is almost twice that of the homicide rate, and persons are more likely to die from suicide than by motor vehicle accidents.27 Baron et al1 conducted an epidemiologic study that analyzed the death rates associated with cardiovascular disease in retired NFL players. Although the focus of the study was cardiovascular disease as a cause of death, it was found that NFL retirees were actually less likely to die from suicide than those in the general population. Depression and substance abuse29 are considered to be the highest risk factors for suicide. That said, the causes of suicide are often multifaceted and may be too intertwined to be distilled to a single specific cause. This is especially true for concussions and tau proteinopathy, whose causal relationship to suicide has yet to be scientifically substantiated.12 A recent 41-year study of the Swedish population7 found an increased risk for suicide and premature fatality in patients with histories of TBI, but the patients in that study were limited to those with moderate to severe TBI, and cases of concussion, or mild TBI, were excluded.
ARE CONTACT AND COLLISION SPORTS A MAJOR RISK FACTOR FOR SEVERE BRAIN INJURY OR DEATH? Parents are increasingly concerned that football-related concussions will lead to CTE. It may be helpful to consider the risk for serious TBI in adolescents in an appropriate overall context. In 2013, Boden et al2 reviewed the 243 football-related fatalities among high school and collegiate football players reported to the National Center for Catastrophic Sports Injury Research from 1990 to 2010. Football fatalities averaged 12.2 per year, with 3.1 being related to brain injuries, with a slightly higher risk in collegiate versus high school athletes (odds ratio, 1.3; 95% CI, 0.5-3.2). Comparatively speaking, cardiac-related deaths averaged 5 per year, while heat-related deaths averaged 1.9 annually. There is evidence to indicate that in the adolescent population,
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there are greater risks for disabling brain injury or death from riding a bicycle, walking on the street, being in an automobile, or even swimming. According to the Centers for Disease Control and Prevention,5 in 2009, the number of fatalities among children younger than 19 years of age was 180 for pedal cyclists, 767 for pedestrians, 7497 for motor vehicle crashes, and 1413 for drowning. By no means are we suggesting that the death rate in football is acceptable. The point is to place the risk for death or permanent brain injury from football in a prevalence context. Although there is no risk-free activity or sport, it may be prudent to consider the risk-reward benefits of any behavior in the context of life in general.
SUMMARY AND CONCLUSIONS Chronic traumatic encephalopathy is described as a progressive neurodegenerative process associated with 1 or multiple blows to the head characterized by changes in mood, cognition, and behavioral functioning.3,4,7 The current (‘‘modern’’) definition of CTE has yet to crystallize but differs from the ‘‘classic’’ definition.8 The existence of CTE as a distinct neuropathologic syndrome has been questioned.8 We have reviewed the CTE data related to football players in particular. To date, no definitive epidemiologic studies of CTE have been published. CTE symptoms are said to develop anywhere from 8 to 20 years after retirement from collision sports. There have been fewer than 7 documented cases of CTE in American high school football players.19,20,22 The current evidence indicates that there is no definite relationship between CTE and suicide.12 Whether the presence of postmortem hyperphosphorylated tau protein alone signifies CTE is debatable. Abnormal tau protein formation may be sensitive to but not specific for CTE.25 Hyperphosphorylated tau protein may be also be present in as many as 20 neurodegenerative diseases, in substance abuse, and as a consequence of normal aging. There may be higher rates of dementia in American professional football players than in the general population.32 The single epidemiologic study of high school football players found no risk increase for degenerative disease due to football.28 Finally, the risk for catastrophic brain injury in football is actually lower than for many common, everyday activities. It is worth reiterating the conclusion of the 4th International Concussion in Sport Group consensus statement: ‘‘It was further agreed that a cause-and-effect relationship has not yet been demonstrated between CTE and concussions or exposure to contact sports. At present, the interpretation of causation in the modern CTE case studies should proceed cautiously.’’1 At present, there is little empirical scientific literature to answer a parent’s question with any degree of certainty about the actual probability of a child’s playing contact or collision sports and later developing CTE. When faced with these questions in our clinic, and assuming that all current clinical criteria for a return to play have been met by an athlete, we advise parents that on the basis of (1) current practice and consensus
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guidelines, (2) clinical examination, (3) all testing completed, and (4) the existing evidence base, we find no compelling reason to withhold an athlete from a return to competition. We explain that medical clearance at this point in time is no guarantee against future adverse outcomes or eventual complications. We encourage parents to become cognizant of best safety practices for their children’s sports and to ensure that adults supervising the activities are educated about concussion signs and symptoms. Parents are encouraged to consider carefully the potential risks and benefits of athletic participation for their children. We anticipate that future well-controlled, longitudinal studies will provide empirical answers to these questions. In the interim, and being cognizant of the current gaps in scientific knowledge, we present the current review with the intention of providing a concise, evidence-based summary of many of the questions about CTE encountered by primary care health providers. An online CME course associated with this article is available for 1 AMA PRA Category 1 CreditTM at http://ajsm-cme.sagepub.com. In accordance with the standards of the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of The American Orthopaedic Society for Sports Medicine that authors, editors, and planners disclose to the learners all financial relationships during the past 12 months with any commercial interest (A ‘commercial interest’ is any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients). Any and all disclosures are provided in the online journal CME area which is provided to all participants before they actually take the CME activity. In accordance with AOSSM policy, authors, editors, and planners’ participation in this educational activity will be predicated upon timely submission and review of AOSSM disclosure. Noncompliance will result in an author/editor or planner to be stricken from participating in this CME activity.
REFERENCES 1. Baron SL, Hein MJ, Lehman E, et al. Body mass index, playing position, race, and the cardiovascular mortality of retired professional football players. Am J Cardiol. 2012;109(6):889-896. 2. Boden B, Breit I, Beachler J, et al. Fatalities in high school and collegiate football players. Am J Sports Med. 2013;41(5):1108-1116. 3. Braak E, Griffing K, Arai K, et al. Neuropathology of Alzheimer’s disease: what is new since A. Alzheimer? Eur Arch Psychiatry Clin Neurosci. 1999;(Suppl 3):III14-III22. 4. Braak H, Del Tredici K. Alzheimer’s disease: pathogenesis and prevention. Alzheimers Dement. 2012;8(3):227-233. 5. Centers for Disease Control and Prevention. Vital signs: unintentional injury deaths among persons aged 0-19 years, United States, 20002009. Morbid Mortal Wkly Rep. 2012;61(15):270-276. 6. Cottler L, Abdallah B, Cummings S, et al. Injury, pain, and prescription opioid use among former National Football League (NFL) players. J Alcohol Drug Depend. 2011:116(1-3):188-194.
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7. Fazel S, Wolf A, Pillas D, Lichtenstein P, La˚ngstro¨m N. Suicide, fatal injuries, and other causes of premature mortality in patients with traumatic brain injury. JAMA Psychiatry. 2014;71(3):326-333. 8. Gardner A, Iverson GL, McCrory P. Chronic traumatic encephalopathy in sport: a systematic review. Br J Sports Med. 2014;48(2):84-90. 9. Gavett B, Stern R, McKee A. Chronic traumatic encephalopathy: a potential late effect of sport-related concussive and subconcussive head trauma. Clin Sports Med. 2011;30(1):179-188 10. Hart J, Kraut MA, Womack KB, et al. Neuroimaging of cognitive dysfunction and depression in aging retired National Football League players: a cross-sectional study. JAMA Neurol. 2013;70(3):326-335. 11. Irwin Broh Research. Sports Participation in the United States. 2013 ed. Prospect, IL: National Sporting Goods Association; 2013. 12. Iverson GL. Chronic traumatic encephalopathy and risk of suicide in former athletes. Br J Sports Med. 2014;48(2):162-164. 13. Karantzoulis S, Randolph C. Modern chronic traumatic encephalopathy in retired athletes: what is the evidence? Neuropsychol Rev. 2013;23(4):350-360. 14. Lavretsky H, Siddarth P, Kepe V, et al. Depression and anxiety symptoms are associated with cerebral FDDNP-PET binding in middleaged and older adults. Am J Geriatr Psychiatry. 2009;17(6):493-502. 15. Lehman E, Hein M, Baron S, Gersic C. Neurodegenerative causes of death among retired National Football League players. Neurology. 2012;79(19):1970-1974. 16. Martland H. Punch drunk syndrome. JAMA. 1928;91:1103-1107. 17. McCrory P. Sports concussion and the risk of chronic neurological impairment. Clin J Sport Med. 2011;21(1):6-12. 18. McCrory P, Meeuwisse W, Aubry M, et al. Consensus statement on concussion in sport: the 4th International Conference on Concussion in Sport held in Zurich, November 2012. Br J Sports Med. 2013;47(5):250-258. 19. McKee A, Cantu R, Nowinski C, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 2009;68(7):709-735. 20. McKee A, Stein T, Nowinski C, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain. 2012;135(1):1-22. 21. National Federation of State High School Associations. Participation statistics. http://www.nfhs.org/participation/SportSearch.aspx. Accessed January 15, 2014. 22. Omalu B, Bailes J, Hamilton R, et al. Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes. Neurosurgery. 2011;69(1):173-183. 23. Omalu B, DeKosky S, Hamilton R, et al. Chronic traumatic encephalopathy in a National Football League player: part II. Neurosurgery. 2006;59(5):1086-1092. 24. Ramage S, Anthony I, Carnie F, et al. Hyperphosphorylated tau and amyloid precursor protein deposition is increased in the brains of young drug abusers. Neuropathol Appl Neurobiol. 2005;31(4):439-448. 25. Randolph C. Is chronic traumatic encephalopathy a real disease? Curr Sports Med Rep. 2014;13(1):33-37. 26. Roberts GW, Allsop D, Bruton C. The occult aftermath of boxing. J Neurol Neurosurg Psychiatry. 1990;53(5):373-378. 27. Rockett IR, Regier MD, Kapusta ND, et al. Leading causes of unintentional and intentional injury mortality: United States, 2000-2009. Am J Public Health. 2012;102(1):84-92. 28. Savica R, Parisi J, Wold L, et al. High school football and risk of neurodegeneration: a community-based study. Mayo Clin Proc. 2012;87(4):335-340. 29. Schwenk TL, Gorenflo DW, Dopp RR, et al. Depression and pain in retired professional football players. Med Sci Sports Exerc. 2007;39(4):599-605. 30. Small GW, Kepe V, Siddarth P, et al. PET scanning of brain tau in retired National Football League players: preliminary findings. Am J Geriatr Psychiatry. 2013;21(2):138-144. 31. Small GW, Siddarth P, Kepe V, et al. PET of brain amyloid and tau predicts and tracks cognitive decline in people without dementia. Arch Neurol. 2012;69(2):215-222. 32. Weir D, Jackson J, Sonega A. Study of retired NFL players. Ann Arbor: University of Michigan Institute for Social Research; 2009.
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Talking With Parents of High School Football Players About Chronic Traumatic Encephalopathy
M
A Concise Summary Shawn Love,*y BS, and Gary S. Solomon,*yz PhD Investigation performed at Vanderbilt University Medical Center, Nashville, Tennessee, USA Over the past decade, athletic-related chronic traumatic encephalopathy (CTE) has garnered a great deal of attention in the popular press and, more recently, in the scientific press. With increasing frequency, sports medicine practitioners and providers are faced with questions from the parents of high school football players about CTE and the risk posed to children who participate in this or other contact or collision sports. The purpose of this review was to summarize the research on CTE in an attempt to provide some evidence-based answers to frequently asked questions in clinics from parents. Addressed are (1) the definitions of CTE and its symptoms, (2) the evidence for CTE in football, (3) abnormal tau protein, (4) the use of neuroimaging in CTE diagnosis, (5) risk for CTE, (6) CTE diagnosis in youth, (7) CTE and its relationship to suicide, and (8) contact and collision sports as a risk factor for permanent brain injury or death. Keywords: chronic traumatic encephalopathy; concussion; traumatic brain injury; sports; football
demonstrated. This increased awareness of concussions in general and CTE in particular may be a factor in decreasing football participation. Indeed, involvement in youth football has declined; according to the National Sporting Goods Association, the organization used by the US Census Bureau for the country’s sports participation data, tackle football participation rates dropped by almost 13% between 2011 and 2012, most notably among players aged 7 to 11 years.11 Meanwhile, widespread media attention has undoubtedly led to changes in the public’s perception of football, as well as contact and collision sports in general. In fact, concussion is the only injury in sports medicine that is regulated by law in 49 of the 50 states in the United States (a bill is pending in the 50th state). As parents, coaches, and educators have become increasingly concerned about the potential long-term effects of concussive injury in football, primary health care providers have been faced more frequently with the clinical question, ‘‘Will my child develop CTE?’’ The goal of this paper is to provide health care providers with a concise overview of the current evidence related to CTE so that they may address, with a state-of-the-science evidence base, questions from the parents of high school football players who are concerned that their children may develop this syndrome.
In recent years, an overwhelming amount of media attention has been directed toward sports concussions, particularly in American football. Concussion, or mild traumatic brain injury (TBI), is defined by the International Concussion in Sport Group18 as ‘‘a complex pathophysiological process affecting the brain, induced by biomechanical forces.’’ This media emphasis on sports concussions has coincided with the burgeoning concussion research that has surfaced over the past decade focused on the neurodegenerative syndrome chronic traumatic encephalopathy (CTE). Although it has been understood for more than 85 years that repetitive brain injury is associated with an increased risk for developing neurodegenerative changes in adults,16 a definitive causal link between concussions and CTE in American high school football has yet to be z Address correspondence to Gary S. Solomon, PhD, Vanderbilt University School of Medicine, Department of Neurological Surgery, 1500 21st Avenue South, Neurosurgery Clinic, Suite 1506, Nashville, TN 37232, USA (e-mail: [email protected]). *Vanderbilt University School of Medicine, Nashville, Tennessee, USA. y Vanderbilt Sports Concussion Center, Nashville, Tennessee, USA. One or more of the authors has declared the following potential conflict of interest or source of funding: G.S.S. receives consulting fees for clinical services from the Nashville Predators and the Tennessee Titans, receives royalties from book sales, and is a member of the Professional Advisory Board of ImPACT, for which he receives expense reimbursement for meeting attendance.
WHAT IS CTE?
The American Journal of Sports Medicine, Vol. 43, No. 5 DOI: 10.1177/0363546514535187 Ó 2014 The Author(s)
Chronic traumatic encephalopathy has shifted from a syndrome exclusive to boxers— ‘‘punch drunk’’ syndrome or 1260
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dementia pugilistica, as it was originally known1—to one linked to athletes in contact sports, especially American football.19,22 Within the past 10 years, research groups led by Drs Ann McKee and Bennet Omalu have offered new definitions of CTE,19,22 which prompted Gardner et al8 to suggest that that there are ‘‘classic’’ and ‘‘modern’’ definitions of CTE, given their clinicopathologic differences. Suggesting that CTE has a clear environmental origin, these groups have proposed that head injury, both concussive and subconcussive, leads to neuropathologic changes and the subsequent development of a series of neuropsychiatric symptoms, behavioral changes, and cognitive deficits. They have noted that the diagnosis of CTE is made postmortem; the brains of these athletes contain widespread neurofibrillary tangles (NFTs) composed of abnormal aggregates of hyperphosphorylated tau protein within distinct brain regions.19,23 Importantly, both groups have relied heavily on the presence of NFTs and hyperphosphorylated tau protein as the primary neuropathologic basis for CTE diagnosis. A key difference in the two definitions lies in the number of brain insults required to develop CTE; whereas Omalu et al22 stated that CTE can result from a single insult, McKee et al20 asserted that repetitive insults are critical to CTE development. Conversely, it should be noted that the existence of the CTE syndrome itself has been questioned.25 In his critique of the CTE syndrome, Randolph25 concluded that there are (1) no established consensus or empirical clinical or neuropathologic criteria diagnosing CTE, (2) no controlled epidemiologic data related to CTE, and (3) no clinical syndrome unique to CTE on the basis of recent cross-sectional, clinical studies of cognitively impaired retired professional football players.
WHAT ARE THE SYMPTOMS OF CTE, AND WHEN DOES IT START? In general, CTE is described across definitions as comprising a broad set of clinical signs and symptoms, including neuropsychiatric and behavioral changes (eg, depression, mood lability, agitation, impulsivity, and aggression), parkinsonism, dysarthria, gait abnormalities, and cognitive deficits, including impairments of memory, attention, executive functioning, and language.8,9,19 In contrast to more classic neurodegenerative diseases, CTE has been described as a syndrome that manifests within 1 to 2 decades after retirement from contact or collision sports. McKee et al20 and Omalu et al22 stated that CTE begins 8 to 10 years after retirement, while McCrory,17 in his review of the literature, reported that symptoms may manifest as late as 10 to 20 years after retirement.
WHAT SCIENTIFIC LITERATURE IS THERE TO SUPPORT THE DIAGNOSIS OF CTE IN FOOTBALL PLAYERS? Retrospective cohort studies conducted by McKee et al19,20 and Omalu et al22 have revealed neuropathologic evidence
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of CTE in autopsies of former athletes. In all 3 studies,19,20,22 the diagnosis of CTE was based on the criteria posited by each group at that point in time. The initial cohort study by McKee et al19 reported CTE findings in the brains of 51 individuals postmortem (no control subjects were reported). Forty-six of the 51 were athletes, 5 of these 46 were professional football players, and nearly all others (n = 39) were boxers. Three years later, McKee et al20 followed up with a report of 85 individuals with histories significant for repetitive mild TBI. Fifty of the 68 who were found to be positive for CTE were professional (n = 34), semiprofessional (n = 1), collegiate (n = 9), and high school (n = 6) football players (the 5 professional football players from the 2009 paper are assumed to be included in the 2012 professional patient cohort). The remaining individuals who demonstrated neuropathologic signs of CTE included boxers, a wrestler, war veterans, and a person who exhibited head-banging behavior. Eighteen control ‘‘cognitively intact’’ subjects with negative histories of mild TBI were included in this study, with 1 female subject, 3 athletes, and a mean age of 62.0 6 17.4 years. Although 11 of the 18 control subjects were positive for hyperphosphorylated tau protein, none of these was reported to have the deposition pattern of abnormal tau protein said to be specific for CTE by McKee et al. In 2011, Omalu et al22 reported similar findings of CTE when they conducted postmortem assessments of the brains of 17 athletes (14 professional and 3 high school athletes; no control patients were reported). Seven of the 8 professional football players were CTE positive, while 1 of the 3 high school athletes (a soccer player) was said to have undefined ‘‘incipient’’ CTE. The most comprehensive review to date was by Gardner et al,8 who summarized data from 158 published case studies of CTE, including 85 cases with autopsy data. In their summary of the 85 cases with neuropathologic findings, they reported that 44 (51.8%) had CTE plus other neuropathology, 17 (20%) had pure CTE neuropathology, 20 (23.5%) had no neuropathology, and 4 (4.7%) had other neuropathology but no CTE. Neuropathologic data specific to high school football players are unavailable.
ARE CONCUSSIONS THE ONLY CAUSE OF ABNORMAL TAU PROTEIN FORMATION IN THE BRAIN? The answer is no. Karantzoulis and Randolph13 listed 20 different neuropathologic conditions associated with abnormal tau protein aggregation in the brain, including Alzheimer disease, frontotemporal dementia, Lewy body disease, and other neuropathologic conditions. Tau protein is an intracellular protein present in the human brain that serves to fortify microtubules structurally.4 Mutations in this protein, whether genetic and/or environmental, may lead to unregulated hyperphosphorylation of tau protein, which leads to cell breakdown, neuronal death, and aggregation into larger NFTs. The focus of CTE research published by McKee et al19,20 and Omalu et al22 has been on the presence of abnormal tau protein as a neuropathologic signature of CTE.
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However, research by Braak et al3 into the stages of Alzheimer disease yielded insight into the presence of abnormal tau protein in both pathologic states and as a component of normal aging. One of the hallmark features of the condition is the presence of widespread intracellular NFTs. It is not until Braak stages V and VI (of 10 stages), in which there is extensive neocortical NFT deposition, that a clinical diagnosis of Alzheimer disease is made. It should be noted that the tau protein pathology depicted by CTE researchers most closely resembles Braak stages I and II, in which tau protein is restricted primarily to the entorhinal cortex, hippocampus, and nearby cortical areas. In an assessment of 2332 consecutive and unselected autopsy cases, Braak et al3 found that NFT stages I and II were present in roughly 10% of patients in their teens, in .20% of patients in their 20s, in nearly 40% of those in their 30s, in .40% in their 40s, and in .70% in their 50s and 60s. The authors also noted that NFT stages III to VI could be found in individuals as young as 30 years of age. Finally, Braak et al3 reported that 100% of the patients aged . 29 years had some sort of abnormal tau protein development. Thus, the findings of tau protein deposition in the recent autopsy analyses of athletes as young as their 20s may not be surprising. Although CTE is considered to be a distinct neuropathologic process, tau protein may be found in individuals undergoing the normal aging process independent of head trauma. It should be noted, however, that both McKee et al19,20 and Omalu et al22 reported that the distribution of abnormal tau protein is qualitatively different in CTE versus other neurodegenerative diseases. However, this has not been crossvalidated by other groups of neuropathologists. Ramage et al24 reported a greater incidence of abnormal tau protein deposition in the brains of drug abusers (opiate abusers \40 years of age) compared with controls (44% vs 19%). In a parallel finding, Cottler et al6 found that more than half (52%) of the 644 surveyed players from the National Football League (NFL) reported opioid use during their NFL playing careers, and most of these (71%) reported abuse. The prevalence of current opiate use (7%) among the NFL retirees was 3 times higher than that of the general population.
CAN NEUROIMAGING BE USED TO DIAGNOSE CTE? Given the specific neuropathologic changes of CTE, one might assume that neuroimaging might be useful diagnostically. On the basis of recent studies, this hypothesis remains equivocal. Small et al30 at the University of California, Los Angeles, reported that CTE may be diagnosable in vivo. Using 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl) amino]-2-naphthyl}-ethylidene)malononitrile (FDDNP)– tau marked positron emission tomographic scans, they found increased FDDNP binding in the amygdala and subcortical regions of 5 retired NFL players (aged 45-73 years) compared with controls. However, elevated FDDNP signals also can be associated with depressive14 and cognitive31 symptoms in normal aging. Alternatively, in 2013, Hart et al10 performed neuroimaging studies and
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measured neuropsychological functioning in 34 retired NFL players with an average of 9.7 years of experience. Diffusion tensor imaging and fluid-attenuated inversion recovery sequences revealed white matter tract abnormalities, but the authors interpreted these results as being inconsistent with CTE. The neuropsychological testing revealed no relationship between the number of years played and the level of cognitive impairment. Although neuroimaging may be a useful modality in the in vivo detection of CTE in the future, the diagnosis at present remains limited to autopsy and the detection of specific amounts and patterns of abnormal tau protein deposition.20,21
WHAT ARE THE CHANCES AN ATHLETE WILL DEVELOP CTE? Although the incidence rate for dementia pugilistica in professional boxers has been estimated to be about 17%,26 scientific studies have yet to elucidate the epidemiology of CTE in nonboxing athletes. Given the current requirement of specific tau protein abnormalities in postmortem diagnosis and the overlap with other neuropathologies, the current incidence of CTE remains unknown. Gavett et al9 estimated that at least 3.7% of NFL players will develop CTE in their lifetimes, on the basis of neuropathologic evidence of the disease in 12 of 321 American football players whose deaths occurred between February 2008 and June 2010. The number of concussive and/or subconcussive events, as well as the amount of athletic exposure required to trigger neurodegenerative change and the subsequent development of CTE in football players, is unknown at present. In contrast to CTE, the prevalence of other forms of dementia (eg, Alzheimer disease, amyotrophic lateral sclerosis, or Parkinson disease) in retired NFL players has been the subject of several studies. First, Weir et al32 reported in a 2009 survey study that 6.1% of NFL retirees reported dementia or dementia-related disease in comparison with 1.9% of the general population. Three years later, Lehman et al15 reported that the mortality rate for neurodegenerative disease (Alzheimer dementia, Parkinson disease, and amyotrophic lateral sclerosis) in former NFL players is 3 times higher than that of the general population. That study, however, has been criticized for its lack of statistical power due to its small sample size.9 Contrary to Lehman et al’s study, Savica et al28 found that the risk for neurodegenerative disease in a cohort of 438 former Minnesota high school football players was no different than in a control cohort of 140 non-football-playing male classmates.
HOW MANY ADOLESCENTS AND YOUNG ADULTS HAVE BEEN DIAGNOSED WITH CTE? According to data provided by the National Federation of State High School Associations,21 approximately 1.09 million male and female high school athletes participated in
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11-player football in the 2011-2012 school year. Of the 158 total reported cases of CTE in the scientific literature,8 fewer than 7 were in high school–aged individuals. McKee et al20 reported CTE-positive findings in 6 high school football players, while Omalu et al22 identified ‘‘incipient’’ CTE in 1 high school soccer player (although the definition of ‘‘incipient’’ was unclear). To date, there has been a total of fewer than 7 potential cases of CTE in high school athletes.
DOES CTE CAUSE SUICIDE? Between 2011 and 2013, suicide was a cause of death in 6 football players diagnosed with CTE.12 These deaths have undoubtedly escalated the media attention and may have contributed to the public perception of a CTE-suicide link. Despite implications that CTE may be a risk factor for suicide, there are currently no published studies corroborating CTE in the causation of suicide.12 In the United States, the suicide rate is almost twice that of the homicide rate, and persons are more likely to die from suicide than by motor vehicle accidents.27 Baron et al1 conducted an epidemiologic study that analyzed the death rates associated with cardiovascular disease in retired NFL players. Although the focus of the study was cardiovascular disease as a cause of death, it was found that NFL retirees were actually less likely to die from suicide than those in the general population. Depression and substance abuse29 are considered to be the highest risk factors for suicide. That said, the causes of suicide are often multifaceted and may be too intertwined to be distilled to a single specific cause. This is especially true for concussions and tau proteinopathy, whose causal relationship to suicide has yet to be scientifically substantiated.12 A recent 41-year study of the Swedish population7 found an increased risk for suicide and premature fatality in patients with histories of TBI, but the patients in that study were limited to those with moderate to severe TBI, and cases of concussion, or mild TBI, were excluded.
ARE CONTACT AND COLLISION SPORTS A MAJOR RISK FACTOR FOR SEVERE BRAIN INJURY OR DEATH? Parents are increasingly concerned that football-related concussions will lead to CTE. It may be helpful to consider the risk for serious TBI in adolescents in an appropriate overall context. In 2013, Boden et al2 reviewed the 243 football-related fatalities among high school and collegiate football players reported to the National Center for Catastrophic Sports Injury Research from 1990 to 2010. Football fatalities averaged 12.2 per year, with 3.1 being related to brain injuries, with a slightly higher risk in collegiate versus high school athletes (odds ratio, 1.3; 95% CI, 0.5-3.2). Comparatively speaking, cardiac-related deaths averaged 5 per year, while heat-related deaths averaged 1.9 annually. There is evidence to indicate that in the adolescent population,
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there are greater risks for disabling brain injury or death from riding a bicycle, walking on the street, being in an automobile, or even swimming. According to the Centers for Disease Control and Prevention,5 in 2009, the number of fatalities among children younger than 19 years of age was 180 for pedal cyclists, 767 for pedestrians, 7497 for motor vehicle crashes, and 1413 for drowning. By no means are we suggesting that the death rate in football is acceptable. The point is to place the risk for death or permanent brain injury from football in a prevalence context. Although there is no risk-free activity or sport, it may be prudent to consider the risk-reward benefits of any behavior in the context of life in general.
SUMMARY AND CONCLUSIONS Chronic traumatic encephalopathy is described as a progressive neurodegenerative process associated with 1 or multiple blows to the head characterized by changes in mood, cognition, and behavioral functioning.3,4,7 The current (‘‘modern’’) definition of CTE has yet to crystallize but differs from the ‘‘classic’’ definition.8 The existence of CTE as a distinct neuropathologic syndrome has been questioned.8 We have reviewed the CTE data related to football players in particular. To date, no definitive epidemiologic studies of CTE have been published. CTE symptoms are said to develop anywhere from 8 to 20 years after retirement from collision sports. There have been fewer than 7 documented cases of CTE in American high school football players.19,20,22 The current evidence indicates that there is no definite relationship between CTE and suicide.12 Whether the presence of postmortem hyperphosphorylated tau protein alone signifies CTE is debatable. Abnormal tau protein formation may be sensitive to but not specific for CTE.25 Hyperphosphorylated tau protein may be also be present in as many as 20 neurodegenerative diseases, in substance abuse, and as a consequence of normal aging. There may be higher rates of dementia in American professional football players than in the general population.32 The single epidemiologic study of high school football players found no risk increase for degenerative disease due to football.28 Finally, the risk for catastrophic brain injury in football is actually lower than for many common, everyday activities. It is worth reiterating the conclusion of the 4th International Concussion in Sport Group consensus statement: ‘‘It was further agreed that a cause-and-effect relationship has not yet been demonstrated between CTE and concussions or exposure to contact sports. At present, the interpretation of causation in the modern CTE case studies should proceed cautiously.’’1 At present, there is little empirical scientific literature to answer a parent’s question with any degree of certainty about the actual probability of a child’s playing contact or collision sports and later developing CTE. When faced with these questions in our clinic, and assuming that all current clinical criteria for a return to play have been met by an athlete, we advise parents that on the basis of (1) current practice and consensus
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guidelines, (2) clinical examination, (3) all testing completed, and (4) the existing evidence base, we find no compelling reason to withhold an athlete from a return to competition. We explain that medical clearance at this point in time is no guarantee against future adverse outcomes or eventual complications. We encourage parents to become cognizant of best safety practices for their children’s sports and to ensure that adults supervising the activities are educated about concussion signs and symptoms. Parents are encouraged to consider carefully the potential risks and benefits of athletic participation for their children. We anticipate that future well-controlled, longitudinal studies will provide empirical answers to these questions. In the interim, and being cognizant of the current gaps in scientific knowledge, we present the current review with the intention of providing a concise, evidence-based summary of many of the questions about CTE encountered by primary care health providers. An online CME course associated with this article is available for 1 AMA PRA Category 1 CreditTM at http://ajsm-cme.sagepub.com. In accordance with the standards of the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of The American Orthopaedic Society for Sports Medicine that authors, editors, and planners disclose to the learners all financial relationships during the past 12 months with any commercial interest (A ‘commercial interest’ is any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients). Any and all disclosures are provided in the online journal CME area which is provided to all participants before they actually take the CME activity. In accordance with AOSSM policy, authors, editors, and planners’ participation in this educational activity will be predicated upon timely submission and review of AOSSM disclosure. Noncompliance will result in an author/editor or planner to be stricken from participating in this CME activity.
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7. Fazel S, Wolf A, Pillas D, Lichtenstein P, La˚ngstro¨m N. Suicide, fatal injuries, and other causes of premature mortality in patients with traumatic brain injury. JAMA Psychiatry. 2014;71(3):326-333. 8. Gardner A, Iverson GL, McCrory P. Chronic traumatic encephalopathy in sport: a systematic review. Br J Sports Med. 2014;48(2):84-90. 9. Gavett B, Stern R, McKee A. Chronic traumatic encephalopathy: a potential late effect of sport-related concussive and subconcussive head trauma. Clin Sports Med. 2011;30(1):179-188 10. Hart J, Kraut MA, Womack KB, et al. Neuroimaging of cognitive dysfunction and depression in aging retired National Football League players: a cross-sectional study. JAMA Neurol. 2013;70(3):326-335. 11. Irwin Broh Research. Sports Participation in the United States. 2013 ed. Prospect, IL: National Sporting Goods Association; 2013. 12. Iverson GL. Chronic traumatic encephalopathy and risk of suicide in former athletes. Br J Sports Med. 2014;48(2):162-164. 13. Karantzoulis S, Randolph C. Modern chronic traumatic encephalopathy in retired athletes: what is the evidence? Neuropsychol Rev. 2013;23(4):350-360. 14. Lavretsky H, Siddarth P, Kepe V, et al. Depression and anxiety symptoms are associated with cerebral FDDNP-PET binding in middleaged and older adults. Am J Geriatr Psychiatry. 2009;17(6):493-502. 15. Lehman E, Hein M, Baron S, Gersic C. Neurodegenerative causes of death among retired National Football League players. Neurology. 2012;79(19):1970-1974. 16. Martland H. Punch drunk syndrome. JAMA. 1928;91:1103-1107. 17. McCrory P. Sports concussion and the risk of chronic neurological impairment. Clin J Sport Med. 2011;21(1):6-12. 18. McCrory P, Meeuwisse W, Aubry M, et al. Consensus statement on concussion in sport: the 4th International Conference on Concussion in Sport held in Zurich, November 2012. Br J Sports Med. 2013;47(5):250-258. 19. McKee A, Cantu R, Nowinski C, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 2009;68(7):709-735. 20. McKee A, Stein T, Nowinski C, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain. 2012;135(1):1-22. 21. National Federation of State High School Associations. Participation statistics. http://www.nfhs.org/participation/SportSearch.aspx. Accessed January 15, 2014. 22. Omalu B, Bailes J, Hamilton R, et al. Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes. Neurosurgery. 2011;69(1):173-183. 23. Omalu B, DeKosky S, Hamilton R, et al. Chronic traumatic encephalopathy in a National Football League player: part II. Neurosurgery. 2006;59(5):1086-1092. 24. Ramage S, Anthony I, Carnie F, et al. Hyperphosphorylated tau and amyloid precursor protein deposition is increased in the brains of young drug abusers. Neuropathol Appl Neurobiol. 2005;31(4):439-448. 25. Randolph C. Is chronic traumatic encephalopathy a real disease? Curr Sports Med Rep. 2014;13(1):33-37. 26. Roberts GW, Allsop D, Bruton C. The occult aftermath of boxing. J Neurol Neurosurg Psychiatry. 1990;53(5):373-378. 27. Rockett IR, Regier MD, Kapusta ND, et al. Leading causes of unintentional and intentional injury mortality: United States, 2000-2009. Am J Public Health. 2012;102(1):84-92. 28. Savica R, Parisi J, Wold L, et al. High school football and risk of neurodegeneration: a community-based study. Mayo Clin Proc. 2012;87(4):335-340. 29. Schwenk TL, Gorenflo DW, Dopp RR, et al. Depression and pain in retired professional football players. Med Sci Sports Exerc. 2007;39(4):599-605. 30. Small GW, Kepe V, Siddarth P, et al. PET scanning of brain tau in retired National Football League players: preliminary findings. Am J Geriatr Psychiatry. 2013;21(2):138-144. 31. Small GW, Siddarth P, Kepe V, et al. PET of brain amyloid and tau predicts and tracks cognitive decline in people without dementia. Arch Neurol. 2012;69(2):215-222. 32. Weir D, Jackson J, Sonega A. Study of retired NFL players. Ann Arbor: University of Michigan Institute for Social Research; 2009.
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