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Review
Understanding neurodegeneration after traumatic brain injury: from mechanisms to clinical trials in dementia
  1. Neil SN Graham1,2,
  2. David J Sharp1,2,3
  1. 1 Brain Sciences, Imperial College London, London, UK
  2. 2 UK DRI Care Research & Technology Centre, Imperial College London, London, United Kingdom
  3. 3 The Royal British Legion Centre for Blast Injury Studies, Department of Bioengineering, Imperial College London, London, United Kingdom
  1. Correspondence to Professor David J Sharp, Brain Sciences, Imperial College London, London, UK; david.sharp{at}imperial.ac.uk

Abstract

Traumatic brain injury (TBI) leads to increased rates of dementia, including Alzheimer’s disease. The mechanisms by which trauma can trigger neurodegeneration are increasingly understood. For example, diffuse axonal injury is implicated in disrupting microtubule function, providing the potential context for pathologies of tau and amyloid to develop. The neuropathology of post-traumatic dementias is increasingly well characterised, with recent work focusing on chronic traumatic encephalopathy (CTE). However, clinical diagnosis of post-traumatic dementia is problematic. It is often difficult to disentangle the direct effects of TBI from those produced by progressive neurodegeneration or other post-traumatic sequelae such as psychiatric impairment. CTE can only be confidently identified at postmortem and patients are often confused and anxious about the most likely cause of their post-traumatic problems. A new approach to the assessment of the long-term effects of TBI is needed. Accurate methods are available for the investigation of other neurodegenerative conditions. These should be systematically employed in TBI. MRI and positron emission tomography neuroimaging provide biomarkers of neurodegeneration which may be of particular use in the postinjury setting. Brain atrophy is a key measure of disease progression and can be used to accurately quantify neuronal loss. Fluid biomarkers such as neurofilament light can complement neuroimaging, representing sensitive potential methods to track neurodegenerative processes that develop after TBI. These biomarkers could characterise endophenotypes associated with distinct types of post-traumatic neurodegeneration. In addition, they might profitably be used in clinical trials of neuroprotective and disease-modifying treatments, improving trial design by providing precise and sensitive measures of neuronal loss.

  • traumatic brain injury
  • dementia
  • cognition
  • acquired brain injury
  • image analysis

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Footnotes

  • Correction notice This article has been corrected since it was published Online First. Affiliation has been added for both authors "UK DRI Care Research & Technology Centre, Imperial College London". Funding statement has been amended to include this also.

  • Contributors NG and DS jointly formulated the plan and wrote the paper.

  • Funding NG was supported by an Alzheimer’s Research UK Clinical Research Fellowship (ARUKCRF2017A-1) and Imperial Health Charity Pre-Doctoral Fellowship (RF16/100016). DS was supported by a National Institutes of Health Research Professorship (NIHR-RP-011- 048), the NIHR Imperial College Biomedical Research Centre and the UK DRI Care Research & Technology Centre, Imperial College London.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; externally peer reviewed.

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