Increased Risk of Aging-Related Neurodegenerative Disease after Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) survivors frequently suffer from chronically progressive complications, including significantly increased risk of developing aging-related neurodegenerative disease. As advances in neurocritical care increase the number of TBI survivors, the impact and awareness of this problem are growing. The mechanisms by which TBI increases the risk of developing aging-related neurodegenerative disease, however, are not completely understood. As a result, there are no protective treatments for patients. Here, we review the current literature surrounding the epidemiology and potential mechanistic relationships between brain injury and aging-related neurodegenerative disease. In addition to increasing the risk for developing all forms of dementia, the most prominent aging-related neurodegenerative conditions that are accelerated by TBI are amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson’s disease (PD), and Alzheimer’s disease (AD), with ALS and FTD being the least well-established. Mechanistic links between TBI and all forms of dementia that are reviewed include oxidative stress, dysregulated proteostasis, and neuroinflammation. Disease-specific mechanistic links with TBI that are reviewed include TAR DNA binding protein 43 and motor cortex lesions in ALS and FTD; alpha-synuclein, dopaminergic cell death, and synergistic toxin exposure in PD; and brain insulin resistance, amyloid beta pathology, and tau pathology in AD. While compelling mechanistic links have been identified, significantly expanded investigation in the field is needed to develop therapies to protect TBI survivors from the increased risk of aging-related neurodegenerative disease.

Protective Roles of Hydrogen Sulfide in Alzheimer’s Disease and Traumatic Brain Injury

“…This pathologic process is poorly understood, and, to date, there are no protective treatments for patients. It is well-established that there is considerable overlap in pathology between TBI and AD [25], and H 2 S is involved in various biological functions after TBI, including the response to oxidative stress in the brain. Due to the brain's voracious need for the constant generation of ATP, which generates free radicals as a by-product, and the brain's abundance of metal ions and phospholipids that generate additional oxidative products, the brain, even under normal circumstances, is constantly exposed to high levels of oxidative stress.…”

“…For instance, the triplicated gene for cystathionine β-synthase (CBS) on chromosome 21 in Down syndrome increases H 2 S levels throughout the body, which suppresses complex IV of the mitochondrial electron transport chain [22][23][24]. This article focuses on the neuroprotective roles of H 2 S in vivo in the brain and its protective efficacy in both AD and traumatic brain injury (TBI), one of the leading risks factors for AD [25].…”

Predicting shock-induced cavitation using machine learning: implications for blast-injury models

“…Symptoms of bTBI include visual dysfunction, headaches, balance, and impulse control impairment ( Capó-Aponte et al, 2012 ; Bryden et al, 2019 ). Blast injury is also associated with an increased probability and severity of post-traumatic stress disorder (PTSD) and increased chances of developing neurodegenerative disorders ( Barker et al, 2023 ; Borinuoluwa and Ahmed, 2023 ). Diagnostics, treatment, and prevention of bTBI are dependent on an understanding of the mechanisms through which blast exposure damages the brain ( Marsh and Bentil, 2021 ).…”

Longitudinal in vivo monitoring of axonal degeneration after brain injury

“… 2 An early and chronic consequence of TBI is axonal degeneration, which impairs brain circuitry and leads to neuronal death. 3 , 4 TBI also increases the risk of aging-related neurodegenerative diseases, 5 including Alzheimer’s disease (AD) 6 and Parkinson’s disease (PD). 7 Although the mechanism for this link is unknown, axonal degeneration is thought to play a fundamental role in the process.…”