Injury cascades in TBI-related neurodegeneration

Traumatic brain injury (TBI) is a widely recognized risk factor for neurodegenerative disease. The purpose of this review is to provide an update on the state of the science related to injury cascades in TBI-related neurodegeneration. Acute and chronic pathological outcomes of TBI are similar to those seen in several neurodegenerative conditions, suggesting common linking pathways. Initial research described severe TBI patients with post-mortem identification of abnormal proteins, such as amyloid deposits. History of mild TBI (mTBI) is less consistently associated with heightened risk of neurodegenerative outcomes, but specific populations with complicated medical histories and comorbidities may be more susceptible. Our understanding of a pathological signature associated with repetitive mTBI and/or subclinical brain trauma advanced significantly over the past decade, and is now commonly referred to as chronic traumatic encephalopathy. We discuss hypotheses linking TBI to neurodegenerative disease, and the importance of considering factors like injury severity, timing of injury (early life versus older age), injury frequency, and repetitive subclinical brain trauma when extrapolating results from current literature to certain populations. We describe the challenges to obtaining the data necessary for accurate epidemiological research and determination of true risk magnitude, and note the importance of developing treatment-based approaches to risk mitigation.