Traumatic Brain Injury and Risk of Neurodegenerative Disorder

Abstract

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.

Figure 1.

Conceptual representation of the post–traumatic brain injury evolution of acute to chronic response, potentially including neurodegenerative disease pathways. 1) Initial protective activation of astrocytes persists toward chronic morphology, contributing to deleterious effects of advanced aging and neurodegeneration, including prolonged proinflammatory cytokine release, disruption of BBB integrity, and glymphatic system disturbance. 2) Resident microglia react, potentially exacerbating neurotoxicity through prolonged activation or primed morphology, resulting in local and diffuse proinflammatory cytokine release (represented by blue dots), contributing to longer-term secondary injury. 3) Insult because of injury results in structural and myelin damage to the axon. Progressive Wallerian degeneration occurs through axonal transport disruption and secondary disconnection. 4) Sheering forces result in microtubule-dissociated tau and aberrant phosphorylation, possibly through coaccumulation of multiple protein kinases and phosphatases that regulate tau hyperphosphorylation, such as delta-secretase, glycogen synthase kinase-3β, and c-Jun N-terminal kinase. Progressive accumulation of phosphorylated tau exacerbates mitochondrial transport disruption and cell apoptosis. 5) APP is acutely increased, potentially leading to coaccumulation of Aβ peptide, BACE1, and PS1 in axons of white and gray matter over time after injury. Aβ, amyloid-β; APP, amyloid precursor protein; BACE1, β-secretase 1; BBB, blood-brain barrier; NFT, neurofibrillary tangle; PS1, presenilin-1. Created with BioRender.com.