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  • Review Article
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Chronic neuropathologies of single and repetitive TBI: substrates of dementia?

Abstract

Traumatic brain injury (TBI) has long been recognized to be a risk factor for dementia. This association has, however, only recently gained widespread attention through the increased awareness of 'chronic traumatic encephalopathy' (CTE) in athletes exposed to repetitive head injury. Originally termed 'dementia pugilistica' and linked to a career in boxing, descriptions of the neuropathological features of CTE include brain atrophy, cavum septum pellucidum, and amyloid-β, tau and TDP-43 pathologies, many of which might contribute to clinical syndromes of cognitive impairment. Similar chronic pathologies are also commonly found years after just a single moderate to severe TBI. However, little consensus currently exists on specific features of these post-TBI syndromes that might permit their confident clinical and/or pathological diagnosis. Moreover, the mechanisms contributing to neurodegeneration following TBI largely remain unknown. Here, we review the current literature and controversies in the study of chronic neuropathological changes after TBI.

Key Points

  • Traumatic brain injury (TBI) represents the strongest environmental risk factor for dementia

  • Current evidence indicates a possible 'dose' and frequency-dependent association between TBI and risk of neurodegenerative disease

  • The human pathology of survival from TBI is best described as a 'polypathology', featuring amyloid-β, tau and TDP-43 pathologies, together with white matter degradation, neuronal loss and neuroinflammation

  • The chronic pathologies following single and repetitive injuries show similarities, although comparative studies are lacking at present

  • TBI may offer an opportunity for better understanding of the evolution of pathologies in a wider range of neurodegenerative diseases

  • There is an urgent need to extend existing tissue banks dedicated to TBI and establish further networked archives to provide broad international research access

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Figure 1: Cerebral atrophy following survival from a single moderate to severe TBI.
Figure 2: Tau and amyloid-β pathology after TBI.
Figure 3: Neuroinflammation and white matter degeneration after TBI.
Figure 4: Interaction between TBI and 'normal' ageing: a hypothesis.

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References

  1. Molgaard, C. A. et al. Epidemiology of head trauma and neurocognitive impairment in a multi-ethnic population. Neuroepidemiology 9, 233–242 (1990).

    CAS  PubMed  Google Scholar 

  2. Mortimer, J. A., French, L. R., Hutton, J. T. & Schuman, L. M. Head injury as a risk factor for Alzheimer's disease. Neurology 35, 264–267 (1985).

    CAS  PubMed  Google Scholar 

  3. Mortimer, J. A. et al. Head trauma as a risk factor for Alzheimer's disease: a collaborative re-analysis of case–control studies. EURODEM Risk Factors Research Group. Int. J. Epidemiol. 20 (Suppl. 2), S28–S35 (1991).

    PubMed  Google Scholar 

  4. Graves, A. B. et al. The association between head trauma and Alzheimer's disease. Am. J. Epidemiol. 131, 491–501 (1990).

    CAS  PubMed  Google Scholar 

  5. O'Meara, E. S. et al. Head injury and risk of Alzheimer's disease by apolipoprotein E genotype. Am. J. Epidemiol. 146, 373–384 (1997).

    CAS  PubMed  Google Scholar 

  6. Salib, E. & Hillier, V. Head injury and the risk of Alzheimer's disease: a case control study. Int. J. Geriatr. Psychiatry 12, 363–368 (1997).

    CAS  PubMed  Google Scholar 

  7. Guo, Z. et al. Head injury and the risk of AD in the MIRAGE study. Neurology 54, 1316–1323 (2000).

    CAS  PubMed  Google Scholar 

  8. Schofield, P. W. et al. Alzheimer's disease after remote head injury: an incidence study. J. Neurol. Neurosurg. Psychiatry 62, 119–124 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Plassman, B. L. et al. Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias. Neurology 55, 1158–1166 (2000).

    CAS  PubMed  Google Scholar 

  10. Fleminger, S., Oliver, D. L., Lovestone, S., Rabe-Hesketh, S. & Giora, A. Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication. J. Neurol. Neurosurg. Psychiatry 74, 857–862 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Lye, T. C. & Shores, E. A. Traumatic brain injury as a risk factor for Alzheimer's disease: a review. Neuropsychol. Rev. 10, 115–129 (2000).

    CAS  PubMed  Google Scholar 

  12. Faul, M., Xu, L., Wald, M. M. & Coronado, V. G. Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths, 2002–2006. Centers for Disease Control and Prevention [online], (2010).

    Google Scholar 

  13. Thurman, D. J. et al. Traumatic brain injury in the United States: a report to Congress. Centers for Disease Control and Prevention [online]. (1999).

    Google Scholar 

  14. Martland, H. Punch drunk. J. Am. Med. Assoc. 91, 1103–1107 (1928).

    Google Scholar 

  15. Millspaugh, J. Dementia pugilistica. U. S. Nav. Med. Bull. 35, 297–303 (1937).

    Google Scholar 

  16. Critchley, M. Medical aspects of boxing, particularly from a neurological standpoint. Br. Med. J. 1, 357–362 (1957).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Payne, E. E. Brains of boxers. Neurochirurgia (Stuttg.) 11, 173–188 (1968).

    CAS  Google Scholar 

  18. Corsellis, J. A., Bruton, C. J. & Freeman-Browne, D. The aftermath of boxing. Psychol. Med. 3, 270–303 (1973).

    CAS  PubMed  Google Scholar 

  19. Omalu, B. I. et al. Chronic traumatic encephalopathy in a national football league player: part II. Neurosurgery 59, 1086–1092 (2006).

    PubMed  Google Scholar 

  20. Omalu, B. I. et al. Chronic traumatic encephalopathy in a National Football League player. Neurosurgery 57, 128–134 (2005).

    PubMed  Google Scholar 

  21. McKee, A. C. et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J. Neuropathol. Exp. Neurol. 68, 709–735 (2009).

    PubMed  Google Scholar 

  22. McKee, A. C. et al. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J. Neuropathol. Exp. Neurol. 69, 918–929 (2010).

    CAS  PubMed  Google Scholar 

  23. Omalu, B. I., Fitzsimmons, R. P., Hammers, J. & Bailes, J. Chronic traumatic encephalopathy in a professional American wrestler. J. Forensic Nurs. 6, 130–136 (2010).

    PubMed  Google Scholar 

  24. Omalu, B. I., Hamilton, R. L., Kamboh, M. I., DeKosky, S. T. & Bailes, J. Chronic traumatic encephalopathy (CTE) in a National Football League Player: case report and emerging medicolegal practice questions. J. Forensic Nurs. 6, 40–46 (2010).

    PubMed  Google Scholar 

  25. Omalu, B. et al. Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes. Neurosurgery 69, 173–183 (2011).

    PubMed  Google Scholar 

  26. Goldstein, L. E. et al. Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Sci. Transl. Med. 4, 134ra60 (2012).

    PubMed  PubMed Central  Google Scholar 

  27. McKee, A. C. et al. The spectrum of disease in chronic traumatic encephalopathy. Brain 136, 43–64 (2013).

    PubMed  Google Scholar 

  28. Omalu, B. et al. Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide. Neurosurg. Focus 31, E3 (2011).

    PubMed  Google Scholar 

  29. Hof, P. R., Knabe, R., Bovier, P. & Bouras, C. Neuropathological observations in a case of autism presenting with self-injury behavior. Acta Neuropathol. 82, 321–326 (1991).

    CAS  PubMed  Google Scholar 

  30. Roberts, G. W., Whitwell, H. L., Acland, P. R. & Bruton, C. J. Dementia in a punch-drunk wife. Lancet 335, 918–919 (1990).

    CAS  PubMed  Google Scholar 

  31. Williams, D. J. & Tannenberg, A. E. Dementia pugilistica in an alcoholic achondroplastic dwarf. Pathology 28, 102–104 (1996).

    CAS  PubMed  Google Scholar 

  32. Mawdsley, C. & Ferguson, F. R. Neurological disease in boxers. Lancet 2, 799–801 (1963).

    Google Scholar 

  33. Spillane, J. D. Five boxers. Br. Med. J. 2, 1205–1210 (1962).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Roberts, G. Brain Damage in Boxers: A Study of the Prevalence of Traumatic Encephalopathy Among Ex-Professional Boxers (Pitman, London, 1969).

    Google Scholar 

  35. Jordan, B. D. et al. CT of 338 active professional boxers. Radiology 185, 509–512 (1992).

    CAS  PubMed  Google Scholar 

  36. Jordan, B. D., Matser, E. J., Zimmerman, R. D. & Zazula, T. Sparring and cognitive function in professional boxers. Phys. Sportsmed. 24, 87–98 (1996).

    CAS  PubMed  Google Scholar 

  37. Loosemore, M., Knowles, C. H. & Whyte, G. P. Amateur boxing and risk of chronic traumatic brain injury: systematic review of observational studies. BMJ 335, 809 (2007).

    PubMed  PubMed Central  Google Scholar 

  38. Guskiewicz, K. M. et al. Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery 57, 719–726 (2005).

    PubMed  Google Scholar 

  39. Lehman, E. J., Hein, M. J., Baron, S. L. & Gersic, C. M. Neurodegenerative causes of death among retired National Football League players. Neurology 79, 1970–1974 (2012).

    PubMed  PubMed Central  Google Scholar 

  40. Chandra, V., Philipose, V., Bell, P. A., Lazaroff, A. & Schoenberg, B. S. Case–control study of late onset “probable Alzheimer's disease”. Neurology 37, 1295–1300 (1987).

    CAS  PubMed  Google Scholar 

  41. Amaducci, L. A. et al. Risk factors for clinically diagnosed Alzheimer's disease: a case–control study of an Italian population. Neurology 36, 922–931 (1986).

    CAS  PubMed  Google Scholar 

  42. Broe, G. A. et al. A case–control study of Alzheimer's disease in Australia. Neurology 40, 1698–1707 (1990).

    CAS  PubMed  Google Scholar 

  43. Ferini-Strambi, L., Smirne, S., Garancini, P., Pinto, P. & Franceschi, M. Clinical and epidemiological aspects of Alzheimer's disease with presenile onset: a case control study. Neuroepidemiology 9, 39–49 (1990).

    CAS  PubMed  Google Scholar 

  44. van Duijn, C. M. et al. Head trauma and the risk of Alzheimer's disease. Am. J. Epidemiol. 135, 775–782 (1992).

    CAS  PubMed  Google Scholar 

  45. Katzman, R. et al. Development of dementing illnesses in an 80-year-old volunteer cohort. Ann. Neurol. 25, 317–324 (1989).

    CAS  PubMed  Google Scholar 

  46. Launer, L. J. et al. Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work Groups. European Studies of Dementia. Neurology 52, 78–84 (1999).

    CAS  PubMed  Google Scholar 

  47. Williams, D. B., Annegers, J. F., Kokmen, E., O'Brien, P. C. & Kurland, L. T. Brain injury and neurologic sequelae: a cohort study of dementia, parkinsonism, and amyotrophic lateral sclerosis. Neurology 41, 1554–1557 (1991).

    CAS  PubMed  Google Scholar 

  48. Mehta, K. M. et al. Head trauma and risk of dementia and Alzheimer's disease: The Rotterdam Study. Neurology 53, 1959–1962 (1999).

    CAS  PubMed  Google Scholar 

  49. Sullivan, P., Petitti, D. & Barbaccia, J. Head trauma and age of onset of dementia of the Alzheimer type. JAMA 257, 2289–2290 (1987).

    CAS  PubMed  Google Scholar 

  50. Gedye, A., Beattie, B. L., Tuokko, H., Horton, A. & Korsarek, E. Severe head injury hastens age of onset of Alzheimer's disease. J. Am. Geriatr. Soc. 37, 970–973 (1989).

    CAS  PubMed  Google Scholar 

  51. Nemetz, P. N. et al. Traumatic brain injury and time to onset of Alzheimer's disease: a population-based study. Am. J. Epidemiol. 149, 32–40 (1999).

    CAS  PubMed  Google Scholar 

  52. Brandenburg, W. & Hallervorden, J. Dementia pugilistica with anatomical findings [German]. Virchows Arch. 325, 680–709 (1954).

    CAS  PubMed  Google Scholar 

  53. Neubuerger, K. T., Sinton, D. W. & Denst, J. Cerebral atrophy associated with boxing. AMA Arch. Neurol. Psychiatry 81, 403–408 (1959).

    CAS  PubMed  Google Scholar 

  54. Constantinidis, J. & Tissot, R. Generalized Alzheimer's neurofibrillary lesions without senile plaques. (Presentation of one anatomo-clinical case) [French]. Schweiz. Arch. Neurol. Neurochir. Psychiatr. 100, 117–130 (1967).

    CAS  PubMed  Google Scholar 

  55. Ferguson, F. R. & Mawdsley, C. Chronic Encephalopathy in Boxers: 8th International Congress of Neurology, Vienna (Wiener Medizinischen Akademie, Vienna, 1965).

    Google Scholar 

  56. Grahmann, H. & Ule, G. Diagnosis of chronic cerebral symptoms in boxers (dementia pugilistica & traumatic encephalopathy of boxers) [German]. Psychiatr. Neurol. 134, 261–283 (1957).

    CAS  Google Scholar 

  57. Roberts, G. W., Allsop, D. & Bruton, C. The occult aftermath of boxing. J. Neurol. Neurosurg. Psychiatry 53, 373–378 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Jordan, B. D. et al. Apolipoprotein E ε4 and fatal cerebral amyloid angiopathy associated with dementia pugilistica. Ann. Neurol. 38, 698–699 (1995).

    CAS  PubMed  Google Scholar 

  59. Schmidt, M. L., Zhukareva, V., Newell, K. L., Lee, V. M. & Trojanowski, J. Q. Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer's disease. Acta Neuropathol. 101, 518–524 (2001).

    CAS  PubMed  Google Scholar 

  60. Saing, T. et al. Frontal cortex neuropathology in dementia pugilistica. J. Neurotrauma 29, 1054–1070 (2012).

    PubMed  PubMed Central  Google Scholar 

  61. Nowak, L. A., Smith, G. G. & Reyes, P. F. Dementia in a retired world boxing champion: case report and literature review. Clin. Neuropathol. 28, 275–280 (2009).

    CAS  PubMed  Google Scholar 

  62. Areza-Fegyveres, R. et al. Dementia pugilistica with clinical features of Alzheimer's disease. Arq. Neuropsiquiatr. 65, 830–833 (2007).

    PubMed  Google Scholar 

  63. Drachman, D. & Newall, K. Case 12–1999—a 67-year-old man with three years of dementia. N. Engl. J. Med. 340, 1269–1277 (1999).

    Google Scholar 

  64. Farbota, K. D. et al. Longitudinal volumetric changes following traumatic brain injury: a tensor-based morphometry study. J. Int. Neuropsychol. Soc. 18, 1006–1018 (2012).

    PubMed  PubMed Central  Google Scholar 

  65. Ross, D. E. et al. Progressive brain atrophy in patients with chronic neuropsychiatric symptoms after mild traumatic brain injury: a preliminary study. Brain Inj. 26, 1500–1509 (2012).

    PubMed  Google Scholar 

  66. Ross, D. E. Review of longitudinal studies of MRI brain volumetry in patients with traumatic brain injury. Brain Inj. 25, 1271–1278 (2011).

    PubMed  Google Scholar 

  67. Tomaiuolo, F. et al. Gross morphology and morphometric sequelae in the hippocampus, fornix, and corpus callosum of patients with severe non-missile traumatic brain injury without macroscopically detectable lesions: a T1 weighted MRI study. J. Neurol. Neurosurg. Psychiatry 75, 1314–1322 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Warner, M. A. et al. Assessing spatial relationships between axonal integrity, regional brain volumes, and neuropsychological outcomes after traumatic axonal injury. J. Neurotrauma 27, 2121–2130 (2010).

    PubMed  PubMed Central  Google Scholar 

  69. Allsop, D., Haga, S., Bruton, C., Ishii, T. & Roberts, G. W. Neurofibrillary tangles in some cases of dementia pugilistica share antigens with amyloid β-protein of Alzheimer's disease. Am. J. Pathol. 136, 255–260 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Geddes, J. F., Vowles, G. H., Nicoll, J. A. & Revesz, T. Neuronal cytoskeletal changes are an early consequence of repetitive head injury. Acta Neuropathol. 98, 171–178 (1999).

    CAS  PubMed  Google Scholar 

  71. Hof, P. R. et al. Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimer's disease cases. Acta Neuropathol. 85, 23–30 (1992).

    CAS  PubMed  Google Scholar 

  72. Casson, I. R. et al. Brain damage in modern boxers. JAMA 251, 2663–2667 (1984).

    CAS  PubMed  Google Scholar 

  73. Bogdanoff, B. & Natter, H. M. Incidence of cavum septum pellucidum in adults: a sign of boxer's encephalopathy. Neurology 39, 991–992 (1989).

    CAS  PubMed  Google Scholar 

  74. Bodensteiner, J. B. & Schaefer, G. B. Dementia pugilistica and cavum septi pellucidi: born to box? Sports Med. 24, 361–365 (1997).

    CAS  PubMed  Google Scholar 

  75. Macpherson, P. & Teasdale, E. CT demonstration of a 5th ventricle—a finding to KO boxers? Neuroradiology 30, 506–510 (1988).

    CAS  PubMed  Google Scholar 

  76. Schwidde, J. T. Incidence of cavum septi pellucidi and cavum Vergae in 1,032 human brains. AMA Arch. Neurol. Psychiatry 67, 625–632 (1952).

    CAS  PubMed  Google Scholar 

  77. Haglund, Y. & Bergstrand, G. Does Swedish amateur boxing lead to chronic brain damage? 2. A retrospective study with CT and MRI. Acta Neurol. Scand. 82, 297–302 (1990).

    CAS  PubMed  Google Scholar 

  78. Adams, J. H., Graham, D. I., Murray, L. S. & Scott, G. Diffuse axonal injury due to nonmissile head injury in humans: an analysis of 45 cases. Ann. Neurol. 12, 557–563 (1982).

    CAS  PubMed  Google Scholar 

  79. Adams, J. H. et al. Diffuse axonal injury in head injury: definition, diagnosis and grading. Histopathology 15, 49–59 (1989).

    CAS  PubMed  Google Scholar 

  80. Johnson, V. E., Stewart, W. & Smith, D. H. Axonal pathology in traumatic brain injury. Exp. Neurol. http://dx.doi.org/10.1016/j.expneurol.2012.01.013.

  81. Johnson, V. et al. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain (in press).

  82. Geddes, J. F., Vowles, G. H., Robinson, S. F. & Sutcliffe, J. C. Neurofibrillary tangles, but not Alzheimer-type pathology, in a young boxer. Neuropathol. Appl. Neurobiol. 22, 12–16 (1996).

    CAS  PubMed  Google Scholar 

  83. Baugh, C. M. et al. Chronic traumatic encephalopathy: neurodegeneration following repetitive concussive and subconcussive brain trauma. Brain Imaging Behav. 6, 244–254 (2012).

    PubMed  Google Scholar 

  84. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).

    CAS  PubMed  Google Scholar 

  85. Corsellis, J. A. & Brierley, J. B. Observations on the pathology of insidious dementia following head injury. J. Ment. Sci. 105, 714–720 (1959).

    CAS  PubMed  Google Scholar 

  86. Rudelli, R., Strom, J. O., Welch, P. T. & Ambler, M. W. Posttraumatic premature Alzheimer's disease. Neuropathologic findings and pathogenetic considerations. Arch. Neurol. 39, 570–575 (1982).

    CAS  PubMed  Google Scholar 

  87. Smith, C., Graham, D. I., Murray, L. S. & Nicoll, J. A. Tau immunohistochemistry in acute brain injury. Neuropathol. Appl. Neurobiol. 29, 496–502 (2003).

    CAS  PubMed  Google Scholar 

  88. Johnson, V. E., Stewart, W. & Smith, D. H. Widespread tau and amyloid-beta pathology many years after a single traumatic brain injury in humans. Brain Pathol. 22, 142–149 (2012).

    CAS  PubMed  Google Scholar 

  89. Dale, G. E., Leigh, P. N., Luthert, P., Anderton, B. H. & Roberts, G. W. Neurofibrillary tangles in dementia pugilistica are ubiquitinated. J. Neurol. Neurosurg. Psychiatry 54, 116–118 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Johnson, V. E., Stewart, W. & Smith, D. H. Traumatic brain injury and amyloid-β pathology: a link to Alzheimer's disease? Nat. Rev. Neurosci. 11, 361–370 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Roberts, G. W., Gentleman, S. M., Lynch, A. & Graham, D. I. βA4 amyloid protein deposition in brain after head trauma. Lancet 338, 1422–1423 (1991).

    CAS  PubMed  Google Scholar 

  92. Roberts, G. W. et al. β amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 57, 419–425 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Ikonomovic, M. D. et al. Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury. Exp. Neurol. 190, 192–203 (2004).

    CAS  PubMed  Google Scholar 

  94. Huber, A., Gabbert, K., Kelemen, J. & Cervos-Navarro, J. Density of amyloid plaques in brains after head trauma. J. Neurotrauma 10 (Suppl. 1), S180 (1993).

    Google Scholar 

  95. Adams, J. H. et al. Diffuse axonal injury in head injury: definition, diagnosis and grading. Histopathology 15, 49–59 (1989).

    CAS  PubMed  Google Scholar 

  96. Gentleman, S. M., Nash, M. J., Sweeting, C. J., Graham, D. I. & Roberts, G. W. β-amyloid precursor protein (βAPP) as a marker for axonal injury after head injury. Neurosci. Lett. 160, 139–144 (1993).

    CAS  PubMed  Google Scholar 

  97. Sherriff, F. E., Bridges, L. R. & Sivaloganathan, S. Early detection of axonal injury after human head trauma using immunocytochemistry for β-amyloid precursor protein. Acta Neuropathol. 87, 55–62 (1994).

    CAS  PubMed  Google Scholar 

  98. Smith, D. H. et al. Accumulation of amyloid beta and tau and the formation of neurofilament inclusions following diffuse brain injury in the pig. J. Neuropathol. Exp. Neurol. 58, 982–992 (1999).

    CAS  PubMed  Google Scholar 

  99. Smith, D. H., Chen, X. H., Iwata, A. & Graham, D. I. Amyloid β accumulation in axons after traumatic brain injury in humans. J. Neurosurg. 98, 1072–1077 (2003).

    CAS  PubMed  Google Scholar 

  100. Chen, X. H., Johnson, V. E., Uryu, K., Trojanowski, J. Q. & Smith, D. H. A lack of amyloid β plaques despite persistent accumulation of amyloid β in axons of long-term survivors of traumatic brain injury. Brain Pathol. 19, 214–223 (2009).

    PubMed  Google Scholar 

  101. Gultekin, S. H. & Smith, T. W. Diffuse axonal injury in craniocerebral trauma. A comparative histologic and immunohistochemical study. Arch. Pathol. Lab. Med. 118, 168–171 (1994).

    CAS  PubMed  Google Scholar 

  102. Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).

    CAS  PubMed  Google Scholar 

  103. Chen-Plotkin, A. S., Lee, V. M. & Trojanowski, J. Q. TAR DNA-binding protein 43 in neurodegenerative disease. Nat. Rev. Neurol. 6, 211–220 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Geser, F., Martinez-Lage, M., Kwong, L. K., Lee, V. M. & Trojanowski, J. Q. Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases. J. Neurol. 256, 1205–1214 (2009).

    PubMed  PubMed Central  Google Scholar 

  105. Neumann, M., Kwong, L. K., Sampathu, D. M., Trojanowski, J. Q. & Lee, V. M. TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: protein misfolding diseases without amyloidosis. Arch. Neurol. 64, 1388–1394 (2007).

    PubMed  Google Scholar 

  106. King, A. et al. 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 30, 408–419 (2010).

    PubMed  Google Scholar 

  107. Johnson, V. E., Stewart, W., Trojanowski, J. Q. & Smith, D. H. Acute and chronically increased immunoreactivity to phosphorylation-independent but not pathological TDP-43 after a single traumatic brain injury in humans. Acta Neuropathol. 122, 715–726 (2011).

    PubMed  PubMed Central  Google Scholar 

  108. Mann, D. M., Yates, P. O. & Hawkes, J. The pathology of the human locus ceruleus. Clin. Neuropathol. 2, 1–7 (1983).

    CAS  PubMed  Google Scholar 

  109. Shaw, K. et al. TUNEL-positive staining in white and grey matter after fatal head injury in man. Clin. Neuropathol. 20, 106–112 (2001).

    CAS  PubMed  Google Scholar 

  110. Maxwell, W. L. et al. There is differential loss of pyramidal cells from the human hippocampus with survival after blunt head injury. J. Neuropathol. Exp. Neurol. 62, 272–279 (2003).

    CAS  PubMed  Google Scholar 

  111. Maxwell, W. L., MacKinnon, M. A., Smith, D. H., McIntosh, T. K. & Graham, D. I. Thalamic nuclei after human blunt head injury. J. Neuropathol. Exp. Neurol. 65, 478–488 (2006).

    PubMed  Google Scholar 

  112. Williams, S. et al. In situ DNA fragmentation occurs in white matter up to 12 months after head injury in man. Acta Neuropathol. 102, 581–590 (2001).

    CAS  PubMed  Google Scholar 

  113. Royal College of Physicians of London. Committee on Boxing. Report on the Medical Aspects of Boxing (Royal College of Physicians of London, London, 1969).

  114. Reichard, R. R., Smith, C. & Graham, D. I. The significance of β-APP immunoreactivity in forensic practice. Neuropathol. Appl. Neurobiol. 31, 304–313 (2005).

    CAS  PubMed  Google Scholar 

  115. Strich, S. J. Diffuse degeneration of the cerebral white matter in severe dementia following head injury. J. Neurol. Neurosurg. Psychiatry 19, 163–185 (1956).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Perry, V. H., Nicoll, J. A. & Holmes, C. Microglia in neurodegenerative disease. Nat. Rev. Neurol. 6, 193–201 (2010).

    PubMed  Google Scholar 

  117. Brettschneider, J. et al. Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis. PLoS ONE 7, e39216 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Brettschneider, J. et al. Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral sclerosis. Acta Neuropathol. 123, 395–407 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Loane, D. J. & Byrnes, K. R. Role of microglia in neurotrauma. Neurotherapeutics 7, 366–377 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Gentleman, S. M. et al. Long-term intracerebral inflammatory response after traumatic brain injury. Forensic Sci. Int. 146, 97–104 (2004).

    CAS  PubMed  Google Scholar 

  121. Ramlackhansingh, A. F. et al. Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol. 70, 374–383 (2011).

    PubMed  Google Scholar 

  122. Adams, C. W. & Bruton, C. J. The cerebral vasculature in dementia pugilistica. J. Neurol. Neurosurg. Psychiatry 52, 600–604 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Blaylock, R. L. & Maroon, J. Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy-A unifying hypothesis. Surg. Neurol. Int. 2, 107 (2011).

    PubMed  PubMed Central  Google Scholar 

  124. Walker, A., Caveness, W. & Critchley, M. (Eds). The Late Effects of Head Injury (Charles C. Thomas, Springfield, IL, 1969).

    Google Scholar 

  125. Center for the Study of Traumatic Encephalopathy—Boston University [online], (2012).

  126. Braak, H. & Braak, E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18, 351–357 (1997).

    CAS  PubMed  Google Scholar 

  127. Braak, H., Thal, D. R., Ghebremedhin, E. & Del Tredici, K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70, 960–969 (2011).

    CAS  PubMed  Google Scholar 

  128. Tokuda, T., Ikeda, S., Yanagisawa, N., Ihara, Y. & Glenner, G. G. Re-examination of ex-boxers' brains using immunohistochemistry with antibodies to amyloid β-protein and tau protein. Acta Neuropathol. 82, 280–285 (1991).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by NIH grants NS038104 (D. H. Smith and W. Stewart), NS056202 and AG038911 (D. H. Smith). In addition, we would like to thank Dr Nadia Dahmane and Dr Amaya Wolf for assistance with translation of articles in French and German, respectively.

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V. E. Johnson and W. Stewart researched data for the article. All three authors made substantial contributions to discussions of the content, writing the article, and review and/or editing of the manuscript before submission.

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Correspondence to William Stewart.

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Smith, D., Johnson, V. & Stewart, W. Chronic neuropathologies of single and repetitive TBI: substrates of dementia?. Nat Rev Neurol 9, 211–221 (2013). https://doi.org/10.1038/nrneurol.2013.29

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