Understanding neurodegeneration after traumatic brain injury: from mechanisms to clinical trials in dementia

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.

Persistent Neurovascular Unit Dysfunction: Pathophysiological Substrate and Trigger for Late-Onset Neurodegeneration After Traumatic Brain Injury

“…Consistent with our relational inference, increasing supporting evidence obtained by animal models and human postmortem studies has suggested NVU dysfunction an important causative factor for post-TBI neurodegeneration (Figure 2; Graham and Sharp, 2019;LoBue et al, 2019). These evidences also explain the induction of chronic neuroinflammation, persistent oxidative stress, and neurodegenerative protein aggregation after the initial injury.…”

“…Additionally, age at trauma has been suggested to be a determinant of the TBI victims' susceptibility to ALS (Seals et al, 2016;Pupillo et al, 2018). Notably, although vulnerability to neurodegenerative diseases has been indicated in patients with TBI of any severity, this increased susceptibility is more common in survivors sustaining moderateto-severe TBI (Hayes et al, 2017;Graham and Sharp, 2019;LoBue et al, 2019), and these patients have a 1.8-fold increase in neurodegenerative disease risk compared with those with mild TBI (Raj et al, 2017).…”

“…Early after the initial injury, TBI can induce the production of pathological proteins, whose neurotoxicity contributes directly to persistent abnormalities of brain structure and function, with these proteinopathies lasting for months or years (Goldstein et al, 2012;Johnson et al, 2012Johnson et al, , 2013aHay et al, 2015;Williams et al, 2018). Intriguingly, post-TBI proteinopathies have similarities to multiple neurodegenerative diseases (Smith et al, 2013;Graham and Sharp, 2019). For instance, pathological accumulation of Aβ and neurofibrillary tangles comprising hyperphosphorylated neuronal tau brings about the development of AD (Zenaro et al, 2017), similarly, α-synuclein is linked to PD (Kalia and Lang, 2016).…”

“…Furthermore, TDP-43 is considered the primary disease-related protein in ALS, and TDP-43 proteinopathy also features in other neurodegenerative disorders such as AD, PD, and Huntington's disease (HD;Johnson et al, 2011). However, TDP-43 proteinopathy after TBI is more obscure and several controversial areas remain (Graham and Sharp, 2019). The study by Wiesner et al (2018) addressed that brain trauma could boost ALS-related TDP-43 pathology, whereas the extent was modulated by ALS-related gene mutations, and the process was indicated to reversible and incapable of triggering ALS progression and neuronal vulnerability.…”

Omega-3 Polyunsaturated Fatty Acids Alleviate Traumatic Brain Injury by Regulating the Glymphatic Pathway in Mice

“…TBI, or sudden damage of the brain resulted from violent jolt or blow to the head, is a significant risk factor for neurodegenerative diseases including Parkinson's disease and Alzheimer's disease (8,9). TBI is associated with various neurological dysfunctions, including impaired cognitive function and motor coordination such as poor performances in the Morris water maze test and wire hang test (10).…”