1932

Abstract

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is most often identified in postmortem autopsies of individuals exposed to repetitive head impacts, such as boxers and football players. The neuropathology of CTE is characterized by the accumulation of hyperphosphorylated tau protein in a pattern that is unique from that of other neurodegenerative diseases, including Alzheimer's disease. The clinical features of CTE are often progressive, leading to dramatic changes in mood, behavior, and cognition, frequently resulting in debilitating dementia. In some cases, motor features, including parkinsonism, can also be present. In this review, the historical origins of CTE are revealed and an overview of the current state of knowledge of CTE is provided, including the neuropathology, clinical features, proposed clinical and pathological diagnostic criteria, potential in vivo biomarkers, known risk factors, and treatment options.

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2015-03-28
2024-06-20
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Literature Cited

  1. Abbas K, Shenk TE, Poole VN, Breedlove EL, Leverenz LJ. et al. 2014. Alteration of default mode network in high school football athletes due to repetitive subconcussive mild traumatic brain injury: a resting-state functional magnetic resonance imaging study. Brain Connect In press [Google Scholar]
  2. Bailes JE, Petraglia AL, Omalu BI, Nauman E, Talavage T. 2013. Role of subconcussion in repetitive mild traumatic brain injury. J. Neurosurg. 119:1235–45 [Google Scholar]
  3. Baugh CM, Stamm JM, Riley DO, Gavett BE, Shenton ME. et al. 2012. Chronic traumatic encephalopathy: neurodegeneration following repetitive concussive and subconcussive brain trauma. Brain Imaging Behav. 6:244–54 [Google Scholar]
  4. Bazarian JJ, Zhu T, Zhong J, Janigro D, Rozen E. et al. 2014. Persistent, long-term cerebral white matter changes after sports-related repetitive head impacts. PLOS ONE 9:e94734 [Google Scholar]
  5. Beach TG, Monsell SE, Phillips LE, Kukull W. 2012. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010. J. Neuropathol. Exp. Neurol. 71:266–73 [Google Scholar]
  6. Bernick C, Banks S. 2013. What boxing tells us about repetitive head trauma and the brain. Alzheimers Res. Ther. 5:23 [Google Scholar]
  7. Bowman KM, Blau A. 1940. Psychotic states following head and brain injury in adults and children. See Brock 1940 309–59
  8. Braak H, Thal DR, Ghebremedhin E, Del Tredici K. 2011. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70:960–69 [Google Scholar]
  9. Breedlove EL, Robinson M, Talavage TM, Morigaki KE, Yoruk U. et al. 2012. Biomechanical correlates of symptomatic and asymptomatic neurophysiological impairment in high school football. J. Biomech. 45:1265–72 [Google Scholar]
  10. Brock S. 1940. Injuries of the Skull, Brain and Spinal Cord. Neuropsychiatric, Surgical, and Medico-Legal Aspects Baltimore, MD: Williams & Wilkins [Google Scholar]
  11. Carroll EJ Jr. 1936. Punch-drunk. Am. J. Med. Sci. 191:706–12 [Google Scholar]
  12. Chien DT, Bahri S, Szardenings AK, Walsh JC, Mu F. et al. 2013. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J. Alzheimers Dis. 34:457–68 [Google Scholar]
  13. Corsellis JAN, Bruton CJ, Freeman-Browne D. 1973. The aftermath of boxing. Psychol. Med. 3:270–303 [Google Scholar]
  14. Crawford F, Wood M, Ferguson S, Mathura V, Gupta P. et al. 2009. Apolipoprotein E–genotype dependent hippocampal and cortical responses to traumatic brain injury. Neuroscience 159:1349–62 [Google Scholar]
  15. Daneshvar DH, Nowinski CJ, McKee AC, Cantu RC. 2011a. The epidemiology of sport-related concussion. Clin. Sports Med. 30:1–17 [Google Scholar]
  16. Daneshvar DH, Riley DO, Nowinski CJ, McKee AC, Stern RA, Cantu RC. 2011b. Long-term consequences: effects on normal development profile after concussion. Phys. Med. Rehabil. Clin. N. Am. 22:683–700 [Google Scholar]
  17. Davenport EM, Whitlow CT, Urban JE, Espeland MA, Jung Y. et al. 2014. Abnormal white matter integrity related to head impact exposure in a season of high school varsity football. J. Neurotrauma 31:1617–24 [Google Scholar]
  18. Delaney JS, Lacroix VJ, Leclerc S, Johnston KM. 2002. Concussions among university football and soccer players. Clin. J. Sport Med. 12:331–38 [Google Scholar]
  19. Fainaru-Wada M, Fainaru S. 2013. League of Denial: The NFL, Concussions and the Battle for Truth New York: Crown Archetype [Google Scholar]
  20. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA. et al. 1997. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA 278:1349–56 [Google Scholar]
  21. Finnoff JT, Jelsing EJ, Smith J. 2011. Biomarkers, genetics, and risk factors for concussion. PM&R 3:S452–59 [Google Scholar]
  22. Fleminger S, Oliver D, Lovestone S, Rabe-Hesketh S, Giora A. 2003. Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication. J. Neurol. Neurosurg. Psychiatry 74:857–62 [Google Scholar]
  23. Ford JH, Giovanello KS, Guskiewicz KM. 2013. Episodic memory in former professional football players with a history of concussion: an event-related functional neuroimaging study. J. Neurotrauma 30:1683–701 [Google Scholar]
  24. Friedman G, Froom P, Sazbon L, Grinblatt I, Shochina M. et al. 1999. Apolipoprotein E-ε4 genotype predicts a poor outcome in survivors of traumatic brain injury. Neurology 52:244–48 [Google Scholar]
  25. Gandy S, DeKosky ST. 2012. APOE ε4 status and traumatic brain injury on the gridiron or the battlefield. Sci. Transl. Med. 4:134ed34 [Google Scholar]
  26. Gardner A, Iverson GL, McCrory P. 2014. Chronic traumatic encephalopathy in sport: a systematic review. Br. J. Sports Med. 48:84–90 [Google Scholar]
  27. Gavett BE, Stern RA, Cantu RC, Nowinski CJ, McKee AC. 2010. Mild traumatic brain injury: a risk factor for neurodegeneration. Alzheimers Res. Ther. 2:18 [Google Scholar]
  28. Geddes J, Vowles G, Robinson S, Sutcliffe J. 1996. Neurofibrillary tangles, but not Alzheimer-type pathology, in a young boxer. Neuropathol. Appl. Neurobiol. 22:12–16 [Google Scholar]
  29. Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Cantu RC. et al. 2005. Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery 57:719–26 [Google Scholar]
  30. Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Harding HP. et al. 2007. Recurrent concussion and risk of depression in retired professional football players. Med. Sci. Sports Exerc. 39:903–9 [Google Scholar]
  31. Hart J Jr, Kraut MA, Womack KB, Strain J, Didehbani N. et al. 2013. Neuroimaging of cognitive dysfunction and depression in aging retired national football league players: a cross-sectional study. JAMA Neurol. 70:326–35 [Google Scholar]
  32. Health Dig 1936. Punch-drunk boxers and football players. N. Y. State J. Med. 36:1654 [Google Scholar]
  33. Hessen E, Nestvold K, Sundet K. 2006. Neuropsychological function in a group of patients 25 years after sustaining minor head injuries as children and adolescents. Scand. J. Psychol. 47:245–51 [Google Scholar]
  34. Hof P, Bouras C, Buee L, Delacourte A, Perl D, Morrison J. 1992. Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimer's disease cases. Acta Neuropathol. 85:23–30 [Google Scholar]
  35. Homeopath. Med. Soc. State PA 1933. Psychoneurosis. Hahnemannian Mon. 68:305–6 [Google Scholar]
  36. Johnson J. 1969. Organic psychosyndromes due to boxing. Br. J. Psychiatry 115:45–53 [Google Scholar]
  37. Jordan BD. 1992. Neurologic injuries in boxing. Medical Aspects of Boxing BD Jordan 150–52 Boca Raton, FL: CRC Press [Google Scholar]
  38. Jordan BD. 1998. Dementia pugilistica. Neurobiology of Primary Dementia MF Folstein 191–204 Washington, DC: Am. Psychiatr. Publ. [Google Scholar]
  39. Jordan BD. 2000. Chronic traumatic brain injury associated with boxing. Semin. Neurol. 20:179–85 [Google Scholar]
  40. Jordan BD. 2013. The clinical spectrum of sport-related traumatic brain injury. Nat. Rev. Neurol. 9:222–30 [Google Scholar]
  41. Jordan BD, Relkin NR, Ravdin LD, Jacobs AR, Bennett A, Gandy S. 1997. Apolipoprotein E ε4 associated with chronic traumatic brain injury in boxing. JAMA 278:136–40 [Google Scholar]
  42. Kapogiannis D, Boxer A, Schwartz JB, Abner EL, Biragyn A. et al. 2015. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease. FASEB J 29589–96 [Google Scholar]
  43. Kerr ZY, Marshall SW, Guskiewicz KM. 2012. Reliability of concussion history in former professional football players. Med. Sci. Sports Exerc. 44:377–82 [Google Scholar]
  44. Koerte IK, Ertl-Wagner B, Reiser M, Zafonte R, Shenton ME. 2012. White matter integrity in the brains of professional soccer players without a symptomatic concussion. JAMA 308:1859–61 [Google Scholar]
  45. Koerte IK, Lin A, Muehlmann M, Rauchmann B, Cooper K. et al. 2015. Post-traumatic cognitive disorders. Imaging of Neurodegenerative Disorders S Kanekar New York: Thieme Publ. In press [Google Scholar]
  46. Kutner KC, Erlanger DM, Tsai J, Jordan B, Relkin NR. 2000. Lower cognitive performance of older football players possessing apolipoprotein E ε4. Neurosurgery 47:651–58 [Google Scholar]
  47. Landau SM, Breault C, Joshi AD, Pontecorvo M, Mathis CA. et al. 2013. Amyloid-β imaging with Pittsburgh compound B and florbetapir: comparing radiotracers and quantification methods. J. Nucl. Med. 54:70–77 [Google Scholar]
  48. Langlois JA, Rutland-Brown W, Wald MM. 2006. The epidemiology and impact of traumatic brain injury: a brief overview. J. Head Trauma Rehabil. 21:375–78 [Google Scholar]
  49. Lehman EJ, Hein MJ, Baron SL, Gersic CM. 2012. Neurodegenerative causes of death among retired National Football League players. Neurology 79:1970–74 [Google Scholar]
  50. Levin B, Bhardwaj A. 2014. Chronic traumatic encephalopathy: a critical appraisal. Neurocrit. Care 20:334–44 [Google Scholar]
  51. Lipton ML, Kim N, Zimmerman ME, Kim M, Stewart WF. et al. 2013. Soccer heading is associated with white matter microstructural and cognitive abnormalities. Radiology 268:850–57 [Google Scholar]
  52. Marchi N, Bazarian JJ, Puvenna V, Janigro M, Ghosh C. et al. 2013. Consequences of repeated blood-brain barrier disruption in football players. PLOS ONE 8:e56805 [Google Scholar]
  53. Martland H. 1928a. Exhibit: types of traumatic cerebral hemorrhages. Hemorrhages due to concussion and their relationship to post-traumatic psychoses, and the condition known as “punch-drunk.”. N. Y. Pathol. Soc. Trans. Arch. Pathol. 6:542–44 [Google Scholar]
  54. Martland HS. 1928b. Punch drunk. JAMA 91:1103–7 [Google Scholar]
  55. Martland HS. 1943. Intracranial injuries and their sequelae and punch drunk. Ther. Intern. Dis. 3:291–301 [Google Scholar]
  56. McAllister TW, Ford JC, Flashman LA, Maerlender A, Greenwald RM. et al. 2014. Effect of head impacts on diffusivity measures in a cohort of collegiate contact sport athletes. Neurology 82:63–69 [Google Scholar]
  57. McCrory P, Meeuwisse WH, Kutcher JS, Jordan BD, Gardner A. 2013. What is the evidence for chronic concussion-related changes in retired athletes: behavioural, pathological and clinical outcomes?. Br. J. Sports Med. 47:327–30 [Google Scholar]
  58. McCrory P, Zazryn T, Cameron P. 2007. The evidence for chronic traumatic encephalopathy in boxing. Sports Med. 37:467–76 [Google Scholar]
  59. McKee AC, Cantu RC, Nowinski CJ, Hedley-Whyte ET, Gavett BE. et al. 2009. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J. Neuropathol. Exp. Neurol. 68:709–35 [Google Scholar]
  60. McKee AC, Robinson ME. 2014. Military-related traumatic brain injury and neurodegeneration. Alzheimers Dement. 10:S242–53 [Google Scholar]
  61. McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE. et al. 2013. The spectrum of disease in chronic traumatic encephalopathy. Brain 136:43–64 [Google Scholar]
  62. McKinlay A, Dalrymple-Alford J, Horwood L, Fergusson D. 2002. Long term psychosocial outcomes after mild head injury in early childhood. J. Neurol. Neurosurg. Psychiatry 73:281–88 [Google Scholar]
  63. Mez J, Stern RA, McKee AC. 2013. Chronic traumatic encephalopathy: Where are we and where are we going?. Curr. Neurol. Neurosci. Rep. 13:1–12 [Google Scholar]
  64. Mitsis E, Riggio S, Kostakoglu L, Dickstein D, Machac J. et al. 2014. Tauopathy PET and amyloid PET in the diagnosis of chronic traumatic encephalopathies: studies of a retired NFL player and of a man with FTD and a severe head injury. Transl. Psychiatry 4:e441 [Google Scholar]
  65. Montenigro P, Baugh C, Daneshvar D, Mez J, Budson A. et al. 2014. Clinical subtypes of chronic traumatic encephalopathy: literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome. Alzheimers Res. Ther. 6:68 [Google Scholar]
  66. Mueller FO. 2001. Catastrophic head injuries in high school and collegiate sports. J. Athl. Train. 36:312–15 [Google Scholar]
  67. Neselius S, Brisby H, Theodorsson A, Blennow K, Zetterberg H, Marcusson J. 2012. CSF-biomarkers in Olympic boxing: diagnosis and effects of repetitive head trauma. PLOS ONE 7:e33606 [Google Scholar]
  68. Ng TS, Lin AP, Koerte IK, Pasternak O, Liao H. et al. 2014. Neuroimaging in repetitive brain trauma. Alzheimers Res. Ther. 6:10 [Google Scholar]
  69. Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH. 2005. Chronic traumatic encephalopathy in a National Football League player. Neurosurgery 57:128–34 [Google Scholar]
  70. Osnato M. 1929. The role of trauma in various neuropsychiatric conditions. Am. J. Psychiatry 86:643–60 [Google Scholar]
  71. Osnato M, Giliberti V. 1927. Postconcussion neurosis-traumatic encephalitis: a conception of postconcussion phenomena. Arch. Neurol. Psychiatry 18:181–214 [Google Scholar]
  72. Otto M, Holthusen S, Bahn E, Söhnchen N, Wiltfang J. et al. 2000. Boxing and running lead to a rise in serum levels of S-100B protein. Int. J. Sports Med. 21:551–55 [Google Scholar]
  73. Peskind ER, Petrie EC, Cross DJ, Pagulayan K, McCraw K. et al. 2011. Cerebrocerebellar hypometabolism associated with repetitive blast exposure mild traumatic brain injury in 12 Iraq war veterans with persistent post-concussive symptoms. NeuroImage 54:S76–82 [Google Scholar]
  74. Plassman BL, Havlik R, Steffens D, Helms M, Newman T. et al. 2000. Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias. Neurology 55:1158–66 [Google Scholar]
  75. Powell JW, Barber-Foss KD. 1999. Traumatic brain injury in high school athletes. JAMA 282:958–63 [Google Scholar]
  76. Prins ML, Hovda DA. 2003. Developing experimental models to address traumatic brain injury in children. J. Neurotrauma 20:123–37 [Google Scholar]
  77. Provenzano FA, Jordan B, Tikofsky RS, Saxena C, Van Heertum RL, Ichise M. 2010. F-18 FDG PET imaging of chronic traumatic brain injury in boxers: a statistical parametric analysis. Nucl. Med. Commun. 31:952–57 [Google Scholar]
  78. Roberts A. 1969. Brain Damage in Boxers: A Study of the Prevalence of Traumatic Encephalopathy Among Ex-Professional Boxers London: Pitman Med. Sci. Publ. [Google Scholar]
  79. Sayed N, Culver C, Dams-O'Connor K, Hammond F, Diaz-Arrastia R. 2013. Clinical phenotype of dementia after traumatic brain injury. J. Neurotrauma 30:1117–22 [Google Scholar]
  80. Scully F. 1937a. Punch-drunk football stars. ! Milwaukee Journal Sept. 29 3 [Google Scholar]
  81. Scully F. 1937b. Stumble-backs—Does football make players stupid?. Liberty 14:4135–37 [Google Scholar]
  82. Shah SA, Prough DS, Garcia JM, DeWitt DS, Hellmich HL. 2006. Molecular correlates of age-specific responses to traumatic brain injury in mice. Exp. Gerontol. 41:1201–5 [Google Scholar]
  83. Shahim P, Tegner Y, Wilson DH, Randall J, Skillbäck T. et al. 2014. Blood biomarkers for brain injury in concussed professional ice hockey players. JAMA Neurol. 71:684–92 [Google Scholar]
  84. Shin W, Mahmoud S, Sakaie K, Banks S, Lowe M. et al. 2014. Diffusion measures indicate fight exposure-related damage to cerebral white matter in boxers and mixed martial arts fighters. Am. J. Neuroradiol. 35:285–90 [Google Scholar]
  85. Singh R, Meier TB, Kuplicki R, Savitz J, Mukai I. et al. 2014. Relationship of collegiate football experience and concussion with hippocampal volume and cognitive outcomes. JAMA 311:1883–88 [Google Scholar]
  86. Slobounov S, Gay M, Johnson B, Zhang K. 2012. Concussion in athletics: ongoing clinical and brain imaging research controversies. Brain Imaging Behav. 6:224–43 [Google Scholar]
  87. Small GW, Kepe V, Siddarth P, Ercoli LM, Merrill DA. et al. 2013. PET scanning of brain tau in retired National Football League players: preliminary findings. Am. J. Geriatr. Psychiatry 21:138–44 [Google Scholar]
  88. Stamm JM, Bourlas AP, Baugh CM, Fritts NG, Daneshvar DH. et al. 2015. Age of first exposure to football and later-life cognitive impairment in former NFL players. Neurology In press [Google Scholar]
  89. Stein TD, Alvarez VE, McKee AC. 2014. Chronic traumatic encephalopathy: a spectrum of neuropathological changes following repetitive brain trauma in athletes and military personnel. Alzheimers Res. Ther. 6:4 [Google Scholar]
  90. Stern RA, Daneshvar DH, Baugh CM, Seichepine DR, Montenigro PH. et al. 2013. Clinical presentation of chronic traumatic encephalopathy. Neurology 81:1122–29 [Google Scholar]
  91. Stern RA, Riley DO, Daneshvar DH, Nowinski CJ, Cantu RC, McKee AC. 2011. Long-term consequences of repetitive brain trauma: chronic traumatic encephalopathy. PM&R 3:S460–67 [Google Scholar]
  92. Strain J, Didehbani N, Cullum CM, Mansinghani S, Conover H. et al. 2013. Depressive symptoms and white matter dysfunction in retired NFL players with concussion history. Neurology 81:25–32 [Google Scholar]
  93. Sundström A, Nilsson L-G, Cruts M, Adolfsson R, Van Broeckhoven C, Nyberg L. 2007. Increased risk of dementia following mild head injury for carriers but not for non-carriers of the APOE ε4 allele. Int. Psychogeriatr. 19:159–65 [Google Scholar]
  94. Talavage TM, Nauman EA, Breedlove EL, Yoruk U, Dye AE. et al. 2010. Functionally-detected cognitive impairment in high school football players without clinically-diagnosed concussion. J. Neurotrauma 31:327–38 [Google Scholar]
  95. Teasdale GM, Murray GD, Nicoll JAR. 2005. The association between APOE ε4, age and outcome after head injury: a prospective cohort study. Brain 128:2556–61 [Google Scholar]
  96. Teasdale GM, Nicoll JAR, Murray G, Fiddes M. 1997. Association of apolipoprotein E polymorphism with outcome after head injury. Lancet 350:1069–71 [Google Scholar]
  97. Thorndike A. 1952. Serious recurrent injuries of athletes: contraindications to further competitive participation. New Engl. J. Med. 247:554–56 [Google Scholar]
  98. Turner RC, Lucke-Wold BP, Robson MJ, Omalu BI, Petraglia AL, Bailes JE. 2012. Repetitive traumatic brain injury and development of chronic traumatic encephalopathy: a potential role for biomarkers in diagnosis, prognosis, and treatment?. Front. Neurol. 3:186 [Google Scholar]
  99. Victoroff J. 2013. Traumatic encephalopathy: review and provisional research diagnostic criteria. NeuroRehabilitation 32:211–24 [Google Scholar]
  100. Zhou W, Xu D, Peng X, Zhang Q, Jia J, Crutcher KA. 2008. Meta-analysis of APOE 4 allele and outcome after traumatic brain injury. J. Neurotrauma 25:279–90 [Google Scholar]
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