Beyond the game: understanding the neuropathology and enduring impacts of chronic traumatic encephalopathy

Abstract

Chronic Traumatic Encephalopathy (CTE) is a progressive neurodegenerative disease characterized by aggregation of phosphorylated tau as well as astrogliosis. Currently, CTE can only be diagnosed post-mortem and is most likely to be found in former professional athletes, especially in contact sports. However, military veterans and domestic violence victims may also suffer from this disease, increasing the prevalence. CTE is correlated to the number of traumatic brain injuries (TBI) or subconcussive impacts received, usually in childhood or adolescence. Mild TBI induces mechanisms to regain homeostasis which include a hypermetabolic state, increased intracellular calcium, and inflammatory signaling molecules in the acute phase. After the acute phase, all of these proteins and mechanisms are downregulated to create depressed neuronal signaling, neuronal death, and glial cell pathology. The immune response to mTBI causes a permeable blood-brain barrier (BBB) which leads to further neuroinflammation and further vascular injury. Post-mortem studies on brains with CTE show progressive aggregation of phosphorylated-tau neurofibrillary tangles (NFTs), diffuse axonal injury (DAI), and accumulations of thread-like astrocytes. Gross cerebral atrophy, widening of the ventricles, and wider sulcal depths are also indicative of CTE diagnosis. The McKee Staging Scheme allows for characterization and comparison of varying severities of CTE between individuals. These changes in brain chemistry can be seen through behavioral, motor, and memory symptoms in patients, similar to those in Alzheimer's Disease. A common symptom of CTE is abnormal mood changes which include apathy, depression, and aggression. The NFTs of p-tau have neurotoxic effects and destabilize microtubules. Astrocyte pathology also leads to decreased gliotransmitter release and therefore fewer neuronal depolarizations. Due to plasticity of the brain, this may lead to neuronal death and pruning. Though there are no conclusive results of the mechanisms which make TBI or repetitive head injury (RHI) transform into the neurodegenerative disease, research into connections between the two is ongoing. Chronic neuroinflammation, a permeable BBB, and an autoimmune response may contribute to the pathophysiology and progression of CTE. Currently, researchers are working to find a way to diagnose CTE before patient death. So far, blood-based biomarkers demonstrate the most promising possibilities. Drawbacks of blood-based biomarkers, such as lack of protein specificity, still exist. The studies reviewed in this paper highlight significant findings in current academic research, identify those most at risk for development of CTE, and suggest possible modes of CTE development after TBI or RHI. The findings demonstrate the importance of education and prevention in youth sports and demand major sports organizations to take responsibility for the health and safety of their athletes. The data also finds that future research will be critical for diagnosis, treatment, and prognosis for patients with CTE.