Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease thought to be caused, at least in part, by repetitive brain trauma, including concussive and subconcussive injuries. It is thought to result in executive dysfunction, memory impairment, depression and suicidality, apathy, poor impulse control, and eventually dementia. Beyond repetitive brain trauma, the risk factors for CTE remain unknown. CTE is neuropathologically characterized by aggregation and accumulation of hyperphosphorylated tau and TDP-43. Recent postmortem findings indicate that CTE may affect a broader population than was initially conceptualized, particularly contact sport athletes and those with a history of military combat. Given the large population that could potentially be affected, CTE may represent an important issue in public health. Although there has been greater public awareness brought to the condition in recent years, there are still many research questions that remain. Thus far, CTE can only be diagnosed post-mortem. Current research efforts are focused on the creation of clinical diagnostic criteria, finding objective biomarkers for CTE, and understanding the additional risk factors and underlying mechanism that causes the disease. This review examines research to date and suggests future directions worthy of exploration.
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Amyotrophic lateral sclerosis
Amyloid precursor protein
Blood oxygen level dependent
Chronic traumatic encephalopathy
Chronic traumatic enceohalomyelopathy
Diffusion tensor imaging
Functional magnetic resonance imaging
Microtubule-associated protein tau
Magnetic resonance imaging
Magnetic Resonance Spectroscopy
Positron emission tomography
Single photon emission computed tomography
Susceptibility weighted imaging
TAR DNA-binding protein 43
Traumatic brain injury
Amen, D. G., Newberg, A., Thatcher, R., Jin, Y., Wu, J., Keator, D., et al. (2011). Impact of playing American professional football on long-term brain function. Journal of Neuropsychiatry and Clinical Neuroscience, 23(1), 98–106.
Ashwal, S., Holshouser, B. A., Shu, S. K., Simmons, P. L., Perkin, R. M., Tomasi, L. G., et al. (2000). Predictive value of proton magnetic resonance spectroscopy in pediatric closed head injury. Pediatric Neurology, 23(2), 114–125.
Ashwal, S., Babikian, T., Gardner-Nichols, J., Freier, M., Tong, K. A., & Holshouser, B. A. (2006). Susceptibility-weighted imaging and proton magnetic resonance spectroscopy in assessment of outcome after pediatric traumatic brain injury. Archives of Physical Medicine and Rehabilitation, 87(12, Supplement), 50–58.
Blaylock, R. L., & Maroon, J. (2011). Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy-A unifying hypothesis. Surgical Neurology International, 2, 107.
Brooks, W. M., Friedman, S. D., & Gasparovic, C. (2001). Magnetic resonance spectroscopy in traumatic brain injury. Journal of Head Trauma Rehabilitation, 16(2), 149–164.
Chastain, C. A., Oyoyo, U. E., Zipperman, M., Joo, E., Ashwal, S., Shutter, L. A., et al. (2009). Predicting outcomes of traumatic brain injury by imaging modality and injury distribution. Journal of Neurotrauma, 26(8), 1183–1196.
Cimatti, M. (2006). Assessment of metabolic cerebral damage using proton magnetic resonance spectroscopy in mild traumatic brain injury. Journal of Neurosurgical Sciences, 50(4), 83–88.
Colbert, C. A., Holshouser, B. A., Aaen, G. S., Sheridan, C., Oyoyo, U., Kido, D., et al. (2010). Value of cerebral microhemorrhages detected with susceptibility-weighted MR Imaging for prediction of long-term outcome in children with nonaccidental trauma. Radiology, 256(3), 898–905.
Corsellis, J. A., Bruton, C. J., & Freeman-Browne, D. (1973). The aftermath of boxing. Psychological Medicine, 3(3), 270–303.
Covassin, T., & Elbin, R. J. (2011). The female athlete: the role of gender in the assessment and management of sport-related concussion. Clinics in Sports Medicine, 30, 125–131, x.
Crawford, F., Wood, M., Ferguson, S., Mathura, V., Gupta, P., Humphrey, J., et al. (2009). Apolipoprotein E-genotype dependent hippocampal and cortical responses to traumatic brain injury. Neuroscience, 159(4), 1349–1362.
Crisco, J. J., Fiore, R., Beckwith, J. G., Chu, J. J., Bronlinson, P. G., Duma, S., et al. (2010). Frequency and location of head impact exposures in individual collegiate football players. Journal of Athletic Training, 45, 549–559.
De Meyer, G., Shapiro, F., Vanderstichele, H., et al. (2010). Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Archives of Neurology, 67(8), 949–956.
Dick, R. W. (2009). Is there a gender difference in concussion incidence and outcomes? British Journal of Sports Medicine, 43(Suppl 1), i46–i50.
Dubois, B., Feldman, H. H., Jacova, C., Cummings, J. L., Dekosky, S. T., Barberger-Gateau, P., et al. (2007). Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurology, 6(8), 734–746.
Field, M., Collins, M. W., Lovell, M. R., & Maroon, J. (2003). Does age play a role in recovery from sports related concussion? A comparison of high school and collegiate athletes. Journal of Pediatrics, 142, 546–553.
Friedman, G., Froom, P., Sazbon, L., Grinblatt, I., Shochina, M., Tsenter, J., et al. (1999). Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury. Neurology, 52(2), 244–248.
Galvin, J. E., Price, J. L., Yan, Z., Morris, J. C., & Sheline, Y. I. (2011). Resting bold fMRI differentiates dementia with Lewy bodies vs Alzheimer disease. Neurology, 76(21), 1797–1803.
Gavett, B. E., Stern, R. A., Cantu, R. C., Nowinski, C. J., & McKee, A. C. (2010). Mild traumatic brain injury: a risk factor for neurodegeneration. Alzheimer’s Research and Therapy, 2, 18.
Gavett, B. E., Stern, R. A., & McKee, A. C. (2011a). Chronic traumatic encephalopathy: a potential late effect of sport-related concussive and subconcussive head trauma. Clinic in Sports Medicine, 30(1), 179–188.
Gavett, B. E., Cantu, R. C., Shenton, M., Lin, A. P., Nowinski, C. J., McKee, A. C., Stern, R. A. (2011b). Clinical appraisal of chronic traumatic encephalopathy: current perspectives and future directions. Current Opinion in Neurology, 24(6), 525–531.
Geddes, J. F., Vowles, G. H., Nicoll, J. A., & Revesz, T. (1999). Neuronal cytoskeletal changes are an early consequence of repetitive head injury. Acta Neuropathologica, 98, 171–178.
Greenwald, R. M., Gwin, J. T., Chu, J. J., & Crisco, J. J. (2008). Head impact severity measures for evaluating mild traumatic brain injury risk exposure. Neurosurgery, 62, 789–798. discussion, 798.
Henry, L. C., Tremblay, S., & Boulanger, Y. (2010). Neurometabolic changes in the acute phase following sports concussions correlate with symptom severity. Journal of Neurotrauma, 27(1), 65–76.
Hill, J. M., Bhattacharjee, P. S., & Neumann, D. M. (2007). Apolipoprotein E alleles can contribute to the pathogenesis of numerous clinical conditions including HSV-1 corneal disease. Experimental Eye Research, 84(5), 801–811.
Hof, P. R., Knabe, R., Bovier, P., & Bouras, C. (1991). Neuropathological observations in a case of autism presenting with self-injury behavior. Acta Neuropathologica, 82, 321–326.
Holshouser, B. A., Tong, K. A., Ashwal, S., & Proton, M. R. (2005). Spectroscopic imaging depicts diffuse axonal injury in children with traumatic brain injury. AJNR American Journal of Neuroradiology, 26(5), 1276–1285.
Immonen, R. J., Kharatishvili, I., Gröhn, H., Pitkänen, A., & Gröhn, O. H. (2009). Quantitative MRI predicts long-term structural and functional outcome after experimental traumatic brain injury. Neuroimage, 45(1), 1–9.
Jack, C. R., Jr., Albert, M. S., Knopman, D. S., McKhann, G. M., Sperling, R. A., Carrillo, M. C., et al. (2011). Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s and Dementia, 7(3), 257–262.
Jordan, B. D., Relkin, N. R., Ravdin, L. D., Jacobs, A. R., Bennett, A., & Gandy, S. (1997). Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA, 278, 136–140.
Katzman, R., Galasko, D. R., Saitoh, T., Chen, X., Pay, M. M., Booth, A., et al. (1996). Apolipoprotein-epsilon4 and head trauma: synergistic or additive risks? Neurology, 46(3), 889–891.
Kutner, K. C., Erlanger, D. M., Tsai, J., Jordan, B., & Relkin, N. R. (2000). Lower cognitive performance of older football players possessing apolipoprotein E epsilon4. Neurosurgery, 47, 651–657. discussion 657–658.
Lin, A., Ramadan, S., Box, H., et al. (2010). Neurochemical changes in athletes with chronic traumatic encephalopathy. Chicago: Radiological Society of North America.
Lipton, M. L., Gulko, E., Zimmerman, M. E., Friedman, B. W., Kim, W., Kim, M., Gellella, E., et al. (2009). Diffusion-tensor imaging implicates prefrontal axonal injury in executive function impairment following very mild traumatic brain injury. Radiology, 252(3), 816–824.
Liu, A. Y., Maldjian, J. A., Bagley, L. J., Sinson, G. P., & Grossman, R. I. (1999). Traumatic brain injury: diffusion-weighted MR imaging findings. American Journal of Neuroradiology, 20, 1636–1641.
Mann, D. M., Brown, A. M., Prinja, D., Jones, D., & Davies, C. A. (1990). A morphological analysis of senile plaques in the brains of non-demented persons of different ages using sliver, immunocytochemical and lectin histochemical staining techniques. Neuropathology and Applied Neurobiology, 16, 17–25.
Martland, H. S. (1928). Punch drunk. JAMA, 91, 1103–1107.
Masterman, D. L., Mendez, M. F., Fairbanks, L. A., & Cummings, J. L. (1997). Sensitivity, specificity, and positive predictive value of technetium 99-HMPAO SPECT in discriminating Alzheimer’s disease from other dementias. Journal of Geriatric Psychiatry and Neurology, 10(1), 15–21.
McKee, A. C., Cantu, R. C., Nowinski, C. J., Hedley-Whyte, E. T., Gavett, B. E., Budson, A. E., et al. (2009). Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. Journal of Neuropathology and Experimental Neurology, 68(7), 709–735.
McKee, A. C., Gavett, B. E., Stern, R. A., Nowinski, C. J., Cantu, R. C., Kowall, N. W., et al. (2010). TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. Journal of Neuropathology and Experimental Neurology, 69, 918–929.
McKhann, G. M., Knopman, D. S., Chertkow, H., Hyman, B. T., Jack, C. R., Jr., Kawas, C. H., et al. (2011). The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s and Dementia, 7(3), 263–269.
Millspaugh, J. A. (1937). Dementia pugilistica. US Naval Medical Bulletin, 35, 297–303.
Omalu, B. I., DeKosky, S. T., Minster, R. L., Kamboh, M. I., Hamilton, R. L., & Wecht, C. H. (2005). Chronic traumatic encephalopathy in a National Football League player. Neurosurgery, 57, 128–134. discussion, 128–134.
Omalu, B. I., DeKosky, S. T., Hamilton, R. L., Minster, R. L., Kamboh, M. I., Shakir, A. M., et al. (2006). Chronic traumatic encephalopathy in a national football league player: part II. Neurosurgery, 59, 1086–1092. discussion, 1092–1093.
Omalu, B. I., Fitzsimmons, R. P., Hammers, J., & Bailes, J. (2010). Chronic traumatic encephalopathy in a professional American wrestler. Journal of Forensic Nursing, 6, 130–136.
Omalu, B., Bailes, J., Hamilton, R. L., Kamboh, M. I., Hammers, J., Case, M., et al. (2011). Emerging histomorphologic phenotypes of chronic traumatic encephalopathy [CTE] in American athletes. Neurosurgery, 69(1), 173–183. discussion 183.
Prabhu, S. P. (2011). The role of neuroimaging in sport-related concussion. Clinics in Sports Medicine, 1, 103–114.
Pullela, R., Raber, J., Pfankuch, T., Ferriero, D. M., Claus, C. P., Koh, S. E., et al. (2006). Traumatic injury to the immature brain results in progressive neuronal loss, hyperactivity and delayed cognitive impairments. Developmental Neuroscience, 28, 396–409.
Roberson, E. D., Scearce-Levie, K., Palop, J. J., Yan, F., Cheng, I. H., Wu, T., et al. (2007). Reducing endogenous tau ameliorates amyloid beta induced deficits in an Alzheimer’s disease mouse model. Science, 316, 750–754.
Roberts, G. W., Whitwell, H. L., Acland, P. R., & Bruton, C. J. (1990). Dementia in a punch-drunk wife. Lancet, 335, 918–919.
Ross, B. D., Ernst, T., Kreis, R., Haseler, L. J., Bayer, S., Danielsen, E., et al. (1998). 1 H MRS in acute traumatic brain injury. Journal Magnetic Resonance Imaging, 8(4), 829–840.
Schmidt, M. L., Zhukareva, V., Newell, K. L., Lee, V. M.-Y., & Trojanowski, J. Q. (2001). Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer’s disease. Acta Neuropathologica, 101, 518–524.
Schneider, G. E. (1979). Is it really better to have your brain lesion early? A revision of the “Kennard principle”. Neuropsychologia, 17, 557–583.
Seeley, W. W., Crawford, R. K., Zhou, J., Miller, B. L., & Greicius, M. D. (2009). Neurodegenerative diseases target large-scale human brain networks. Neuron, 62(1), 42–52.
Shutter, L., Tong, K. A., & Holshouser, B. A. (2004). Proton MRS in acute traumatic brain injury: role for glutamate/glutamine and choline for outcome prediction. Journal of Neurotrauma, 21(12), 1693–1705.
Sperling, R. A., Dickerson, B. C., Pihlajamaki, M., Vannini, P., LaViolette, P. S., Vitolo, O. V., et al. (2010). Functional alterations in memory networks in early Alzheimer’s disease. Neuromolecular Medicine, 12(1), 27–43.
Sperling, R. A., Aisen, P. S., Beckett, L. A., Bennett, D. A., Craft, S., Fagan, A. M., et al. (2011). Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s and Dementia, 7(3), 280–292.
Spiotta, A. M., Shin, J. H., Bartsch, A. J., & Benzel, E. C. (2011). Subconcussive impact in sports: a new era of awareness. World Neurosurgery, 75(2), 175–178.
Stern, Y. (2007). Cognitive reserve: Theory and applications. Philadelphia: Taylor & Francis.
Stern, R. A., Riley, D. O., Daneshvar, D. H., Nowinski, C. J., Cantu, R. C., McKee, A. C. (2011a). Long-term consequences of repetitive brain trauma: chronic traumatic encephalopathy. PM&R, 10 Suppl 2, S460–467.
Stern, R. A., Anderson, S., & Gavett, B. (2011b). Executive functioning. In A. E. Budson & N. W. Kowell (Eds.), The handbook of Alzheimer’s disease and other dementias (pp. 369–415). New York: Wiley-Blackwell.
Talavage, T. M., Nauman, E. A., Breedlove, E. L., Yoruk, U., Dye, A. E., Morigaki, K., Feuer, H., Leverenz, L. J. (2010). Functionally-detected cognitive impairment in high school football players without clinically-diagnosed concussion. Journal of Neurotrauma, [Epub ahead of print.].
Teasdale, G. M., Nicoll, J. A., Murray, G., & Fiddes, M. (1997). Association of Apolipoprotein E polymorphism with outcome after head injury. Lancet, 350, 1069–1071.
Tubbs, R. S., Krishnamurthy, S., Verma, K., Shoja, M. M., Loukas, M., Mortazavi, M. M., et al. (2011). Cavum velum, interpositum, cavum septum pellucidum, and cavum vergae: a review. Childs Nervous System, 27, 1927–1930.
Vagnozzi, R., Signoretti, S., & Tavazzi, B. (2008). Temporal window of metabolic brain vulnerability to concussion: a pilot 1H-magnetic resonance spectroscopic study in concussed athletes-part III. Neurosurgery, 62(6), 1286–1296.
Zhou, J., Greicius, M. D., Gennatas, E. D., Growdon, M. E., Jang, E., Jang, J. Y., Rabinovici, G. D., et al. (2010). Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer’s disease. Brain, 133(5), 1352–1367.
This work was supported by grants from the National Institutes of Health (P30 AG13846; R01 NS078337), as well as a grant from the National Operating Committee on Standards for Athletic Equipment, and an unrestricted gift from the National Football League.
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Baugh, C.M., Stamm, J.M., Riley, D.O. et al. Chronic traumatic encephalopathy: neurodegeneration following repetitive concussive and subconcussive brain trauma. Brain Imaging and Behavior 6, 244–254 (2012). https://doi.org/10.1007/s11682-012-9164-5
- Chronic traumatic encephalopathy
- Traumatic brain injury
- Dementia pugilistica