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.

Keywords: Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; dementia; frontotemporal dementia; neurodegeneration; neuroinflammation; oxidative stress; proteostasis; traumatic brain injury.

Figure 1

TBI leads to an increase in ROS, which chemically modify proteins, lipids, and nucleic acids, deplete endogenous antioxidants, and activate cellular responses via Nrf2. Oxidative stress causes mitochondrial dysfunction, inflammation, ferroptosis, and ultimately neurodegeneration.

Figure 2

Potential mechanisms by which TBI increases the risk of aging-related neurodegenerative disease, both generally (dotted arrow in top panel) as well as specifically (dotted arrows in bottom panels) in ALS, FTD, PD, and AD. The red arrows indicate an increased risk of the specified condition.