Abstract
Chronic traumatic encephalopathy (CTE) formerly known as dementia pugilistica is a long-term neurodegenerative disorder associated with repeated subconcussive head injuries in high-contact sports. We reviewed the existing literature on CTE and examined epidemiological trends, risk factors, and its temporal progression, and proposed the underlying pathophysiological mechanisms that may provide unique insights to clinicians with an in-depth understanding of the disease to aid in the diagnosis and prevention, and provide future perspectives for research via search of Medline and Cochrane databases as well as manual review of bibliographies from selected articles and monographs. The prevalence of CTE in recent years is on the rise and almost exclusively affects men, with pathologic signs characterized by progressive memory loss, behavioral changes, and violent tendencies with some patients demonstrating Parkinsonian-like symptoms and signs. Many patients with CTE die following suicide, accident, or complications of drug or alcohol use. Postmortem pathologic analysis is characterized by neurofibrillary tangles and Aβ plaques in 50 % of cases. Currently, there are no ante-mortem diagnostic criteria, but modern imaging techniques such as functional magnetic resonance (MR) imaging, MR spectroscopy, and diffusion tension imaging hold promise for delineating the future diagnostic criteria. Further long-term longitudinal studies are warranted to investigate risk factors that will enhance understanding of the disease progression and its pathogenesis.
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Martland HS. Punch drunk. JAMA. 1928;91:1103–7.
Omalu B, Bailes J, Hamilton RL, Kamboh MI, Hammers J, Case M, Fitzsimmons R. Emerging histomorphologic phenotypes of chronic traumatic encephalopathy [CTE] in American athletes. Neurosurgery. 2011;69(1):173–83.
Gavett BE, Stern RA, Cantu RC, Nowinski CJ, McKee AC. Mild traumatic brain injury: a risk factor for neurodegeneration. Alzheimers Res Ther. 2010;2:18.
Heilbronner RL, Bush SS, Ravdin LD, Barth JT, Iverson GL, Ruff RM, Lovell MR, Barr WB, Echemendia RJ, Broshek DK. Neuropsychological consequences of boxing and recommendations to improve safety: a National Academy of Neuropsychology education paper. Arch Clin Neuropsychol. 2009;24:11–9.
Kaste M, Kuurne T, Vilkki J, Katevuo K, Sainio K, Meurala H. Is chronic brain damage in boxing a hazard of the past? Lancet. 1982;2:1186–8.
Casson IR, Sham R, Campbell EA, Tarlau M, Didomenico A. Neurological and CT evaluation of knocked-out boxers. J Neurol Neurosurg Psychiatr. 1982;45:170–4.
Gavett BE, Stern RA, McKee AC. Chronic traumatic encephalopathy: a potential late effect of sport-related concussive and subconcussive head trauma. Clin Sports Med. 2011;30:179–88.
McKee AC, Cantu RC, Nowinski CJ, Hedley-Whyte ET, Gavett BE, Budson AE, Santini VE, Lee HS, Kubilus CA, Stern RA. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 2009;68:709–35.
Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH. Chronic traumatic encephalopathy in a National Football League player. Neurosurgery. 2005;57(128):34 discussion 128–34.
Erlanger DM, Kutner KC, Barth JT, Barnes R. Neuropsychology of sports-related head injury: Dementia Pugilistica to Post Concussion Syndrome. Clin Neuropsychol. 1999;13:193–209.
Jordan BD, Matser EJ, Zimmerman RD, Zazula T. Sparring and cognitive function in professional boxers. Phys Sportsmed. 1996;24:87–98.
DeKosky ST, Ikonomovic MD, Gandy S. Traumatic brain injury–football, warfare, and long-term effects. N Engl J Med. 2010;363:1293–6.
Roberts GW, Allsop D, Bruton C. The occult aftermath of boxing. J Neurol Neurosurg Psychiatr. 1990;53:373–8.
Jordan BD, Relkin NR, Ravdin LD, Jacobs AR, Bennett A, Gandy S. Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA. 1997;278:136–40.
Hazrati LN, Tartaglia MC, Diamandis P, Davis KD, Green RE, Wennberg R, Wong JC, Ezerins L, Tator CH. Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology. Front Hum Neurosci. 2013;7:222.
Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Cantu RC, Randolph C, Jordan BD. Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery. 2005;57(4):719–26.
Corsellis JA, Bruton CJ, Freeman-Browne D. The aftermath of boxing. Psychol Med. 1973;3:270–303.
Costanza A, Weber K, Gandy S, Bouras C, Hof PR, Giannakopoulos P, Canuto A. Review: contact sport-related chronic traumatic encephalopathy in the elderly: clinical expression and structural substrates. Neuropathol Appl Neurobiol. 2011;37:570–84.
Porter MD. A 9-year controlled prospective neuropsychologic assessment of amateur boxing. Clin J Sport Med. 2003;13:339–52.
Yoshiyama Y, Uryu K, Higuchi M, Longhi L, Hoover R, Fujimoto S, McIntosh T, Lee VM, Trojanowski JQ. Enhanced neurofibrillary tangle formation, cerebral atrophy, and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model. J Neurotrauma. 2005;22:1134–41.
Uryu K, Laurer H, McIntosh T, Praticò D, Martinez D, Leight S, Lee VM, Trojanowski JQ. Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J Neurosci. 2002;22:446–54.
Mannix R, Meehan WP, Mandeville J, Grant PE, Gray T, Berglass J, Zhang J, Bryant J, Rezaie S, Chung JY, Peters NV, Lee C, Tien LW, Kaplan DL, Feany M, Whalen M. Clinical correlates in an experimental model of repetitive mild brain injury. Ann Neurol. 2013;. doi:10.1002/ana.23858.
Zetterberg H, Hietala MA, Jonsson M, Andreasen N, Styrud E, Karlsson I, Edman A, Popa C, Rasulzada A, Wahlund LO, Mehta PD, Rosengren L, Blennow K, Wallin A. Neurochemical aftermath of amateur boxing. Arch Neurol. 2006;63:1277–80.
Ikonomovic MD, Uryu K, Abrahamson EE, Ciallella JR, Trojanowski JQ, Lee VM, Clark RS, Marion DW, Wisniewski SR, DeKosky ST. Alzheimer’s pathology in human temporal cortex surgically excised after severe brain injury. Exp Neurol. 2004;190:192–203.
Bazarian JJ, Cernak I, Noble-Haeusslein L, Potolicchio S, Temkin N. Long-term neurologic outcomes after traumatic brain injury. J Head Trauma Rehabil. 2009;24:439–51.
Yuen TJ, Browne KD, Iwata A, Smith DH. Sodium channelopathy induced by mild axonal trauma worsens outcome after a repeat injury. J Neurosci Res. 2009;87:3620–5.
Blaylock RL, Maroon J. Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy-A unifying hypothesis. Surg Neurol Int. 2011;2:107.
Liang Z, Liu F, Iqbal K, Grundke-Iqbal I, Gong CX. Dysregulation of tau phosphorylation in mouse brain during excitotoxic damage. J Alzheimers Dis. 2009;17:531–9.
Liu MC, Kobeissy F, Zheng W, Zhang Z, Hayes RL, Wang KK. Dual vulnerability of tau to calpains and caspase-3 proteolysis under neurotoxic and neurodegenerative conditions. ASN Neuro. 2011;3:e00051.
Molinuevo JL, Llado A, Rami L. Memantine: targeting glutamate excitotoxicity in Alzheimer’s disease and other dementias. Am J Alzheimers Dis Other Demen. 2005;20:77–85.
Rahman A, Ting K, Cullen KM, Braidy N, Brew BJ, Guillemin GJ. The excitotoxin quinolinic acid induces tau phosphorylation in human neurons. PLoS One. 2009;4:e6344.
Hu NW, Klyubin I, Anwyl R, Rowan MJ. GluN2B subunit-containing NMDA receptor antagonists prevent Abeta-mediated synaptic plasticity disruption in vivo. Proc Natl Acad Sci USA. 2009;106:20504–9.
Adams JH, Doyle D, Ford I, Gennarelli TA, Graham DI, McLellan DR. Diffuse axonal injury in head injury: definition, diagnosis and grading. Histopathology. 1989;15:49–59.
Yang XF, Wang H, Wen L. From myelin debris to inflammatory responses: a vicious circle in diffuse axonal injury. Med Hypotheses. 2011;77:60–2.
Saing T, Dick MC, Nelson PT, Kim RC, Cribbs DH, Head E. Frontal cortex neuropathology in dementia pugilistica. J Neurotrauma. 2012;29(6):1054–70.
Tokuda T, Ikeda S, Yanagisawa N, Ihara Y, Glenner GG. Re-examination of ex-boxers’ brains using immunohistochemistry with antibodies to amyloid beta-protein and tau protein. Acta Neuropathol. 1991;82:280–5.
Geddes JF, Vowles GH, Nicoll JA, Revesz T. Neuronal cytoskeletal changes are an early consequence of repetitive head injury. Acta Neuropathol. 1999;98:171–8.
McKee AC, Gavett BE, Stern RA, Nowinski CJ, Cantu RC, Kowall NW, Perl DP, Hedley-Whyte ET, Price B, Sullivan C, Morin P, Lee HS, Kubilus CA, Daneshvar DH, Wulff M, Budson AE. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. 2010;69:918–29.
King A, Sweeney F, Bodi I, Troakes C, Maekawa S, Al-Sarraj S. Abnormal TDP-43 expression is identified in the neocortex in cases of dementia pugilistica, but is mainly confined to the limbic system when identified in high and moderate stages of Alzheimer’s disease. Neuropathology. 2010;30:408–19.
Johnson VE, Stewart W, Trojanowski JQ, Smith DH. Acute and chronically increased immunoreactivity to phosphorylation-independent but not pathological TDP-43 after a single traumatic brain injury in humans. Acta Neuropathol. 2011;122:715–26.
Casson IR, Siegel O, Sham R, Campbell EA, Tarlau M, DiDomenico A. Brain damage in modern boxers. JAMA. 1984;251:2663–7.
McLatchie G, Brooks N, Galbraith S, Hutchison JS, Wilson L, Melville I, Teasdale E. Clinical neurological examination, neuropsychology, electroencephalography and computed tomographic head scanning in active amateur boxers. J Neurol Neurosurg Psychiatr. 1987;50:96–9.
Haglund Y, Eriksson E. Does amateur boxing lead to chronic brain damage? A review of some recent investigations. Am J Sports Med. 1993;21:97–109.
Haglund Y, Persson HE. Does Swedish amateur boxing lead to chronic brain damage? 3. A retrospective clinical neurophysiological study. Acta Neurol Scand. 1990;82:353–60.
Inglese M, Makani S, Johnson G, Cohen BA, Silver JA, Gonen O, Grossman RI. Diffuse axonal injury in mild traumatic brain injury: a diffusion tensor imaging study. J Neurosurg. 2005;103:298–303.
Chen J, Jin H, Zhang Y, Liang Q, Liao H, Guo Z, Han X. MRS and diffusion tensor image in mild traumatic brain injuries. Asian Pac J Trop Med. 2012;5:67–70.
Carlock KS, Williams JP, Graves GC. MRI findings in headbangers. Clin Imaging. 1997;21:411–3.
Kim J, Whyte J, Patel S, et al. A Perfusion fMRI study of the neural correlates of sustained-attention and working-memory deficits in chronic traumatic brain injury. Neurorehabil Neural Repair. 2012;26(7):870–80.
Lin A, Ramadan S, Box H, Stanwell P, Stern R. Neurochemical Changes in Athletes with Chronic Traumatic Encephalopathy; 2010. http://rsna2010.rsna.org/program/event_display.cfm?em_id=9012638. Accessed 28 June 2012.
Fodero-Tavoletti MT, Okamura N, Furumoto S, et al. 18F-THK523: a novel in vivo tau imaging ligand for Alzheimer’s disease. Brain. 2011;134:1089–100.
Gavett BE, Cantu RC, Shenton M, Lin AP, Nowinski CJ, McKee AC, Stern RA. Clinical appraisal of chronic traumatic encephalopathy: current perspectives and future directions. Curr Opin Neurol. 2011;24:525–31.
Omalu B. Emerging histomorphologic phenotypes of chronic traumatic encephalopathy [CTE] in American athletes—case 15. Neurosurgery. 2011;69(1):173–83.
Friedman G, Froom P, Sazbon L, Grinblatt I, Shochina M, Tsenter J, Babaey S, Yehuda B. Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury. Neurology. 1999;52:244–8.
Mayeux R, Schupf N. Blood-based biomarkers for Alzheimer’s disease: plasma Abeta40 and Abeta42, and genetic variants. Neurobiol Aging. 2011;32(Suppl 1):S10–9.
Giacino JT, Whyte J, Bagiella E, Kalmar K, Childs N, Khademi A, Eifert B, Long D, Katz DI, Cho S, Yablon SA, Luther M, Hammond FM, Nordenbo A, Novak P, Mercer W, Maurer-Karattup P, Sherer M. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med. 2012;366:819–26.
Willmott C, Ponsford J. Efficacy of methylphenidate in the rehabilitation of attention following traumatic brain injury: a randomised, crossover, double blind, placebo controlled inpatient trial. J Neurol Neurosurg Psychiatr. 2009;80:552–7.
Kim YW, Shin JC, An YS. Effects of methylphenidate on cerebral glucose metabolism in patients with impaired consciousness after acquired brain injury. Clin Neuropharmacol. 2009;32:335–9.
Khuman J, Zhang J, Park J, Carroll JD, Donahue C, Whalen MJ. Low-level laser light therapy improves cognitive deficits and inhibits microglial activation after controlled cortical impact in mice. J Neurotrauma. 2012;29:408–17.
Amen DG, Wu JC, Taylor D, Willeumier K. Reversing brain damage in former NFL players: implications for traumatic brain injury and substance abuse rehabilitation. J Psychoact Drugs. 2011;43:1–5.
Arundine A, Bradbury CL, Dupuis K, Dawson DR, Ruttan LA, Green RE. Cognitive behavior therapy after acquired brain injury: maintenance of therapeutic benefits at 6 months posttreatment. J Head Trauma Rehabil. 2012;27:104–12.
Haglund Y, Bergstrand G. Does Swedish amateur boxing lead to chronic brain damage? 2. A retrospective study with CT and MRI. Acta Neurol Scand. 1990;82(5):297–302.
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Levin, B., Bhardwaj, A. Chronic Traumatic Encephalopathy: A Critical Appraisal. Neurocrit Care 20, 334–344 (2014). https://doi.org/10.1007/s12028-013-9931-1
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DOI: https://doi.org/10.1007/s12028-013-9931-1