Chronic neuropathologies of single and repetitive TBI: substrates of dementia?

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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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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.

Correspondence to William Stewart.

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