Traumatic Brain Injury and Risk of Neurodegenerative Disorder

Biol Psychiatry. 2022 Mar 1;91(5):498-507. doi: 10.1016/j.biopsych.2021.05.025. Epub 2021 Jun 2.


Traumatic brain injury (TBI), particularly of greater severity (i.e., moderate to severe), has been identified as a risk factor for all-cause dementia and Parkinson's disease, with risk for specific dementia subtypes being more variable. Among the limited studies involving neuropathological (postmortem) confirmation, the association between TBI and risk for neurodegenerative disease increases in complexity, with polypathology often reported on examination. The heterogeneous clinical and neuropathological outcomes associated with TBI are likely reflective of the multifaceted postinjury acute and chronic processes that may contribute to neurodegeneration. Acutely in TBI, axonal injury and disrupted transport influences molecular mechanisms fundamental to the formation of pathological proteins, such as amyloid-β peptide and hyperphosphorylated tau. These protein deposits may develop into amyloid-β plaques, hyperphosphorylated tau-positive neurofibrillary tangles, and dystrophic neurites. These and other characteristic neurodegenerative disease pathologies may then spread across brain regions. The acute immune and neuroinflammatory response involves alteration of microglia, astrocytes, oligodendrocytes, and endothelial cells; release of downstream pro- and anti-inflammatory cytokines and chemokines; and recruitment of peripheral immune cells. Although thought to be neuroprotective and reparative initially, prolongation of these processes may promote neurodegeneration. We review the evidence for TBI as a risk factor for neurodegenerative disorders, including Alzheimer's dementia and Parkinson's disease, in clinical and neuropathological studies. Further, we describe the dynamic interactions between acute response to injury and chronic processes that may be involved in TBI-related pathogenesis and progression of neurodegeneration.

Keywords: Dementia; Neurodegeneration; Neuroinflammation; Neuropathology; Traumatic brain injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Alzheimer Disease* / metabolism
  • Brain / metabolism
  • Brain Injuries, Traumatic* / complications
  • Brain Injuries, Traumatic* / metabolism
  • Brain Injuries, Traumatic* / pathology
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Humans
  • Neurodegenerative Diseases* / metabolism
  • Parkinson Disease* / metabolism