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Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease that has been brought to light in recent years regarding its long-term effects on subjects of repeated head trauma in the form of traumatic brain injuries (TBI). CTE has been made infamous due to recent publications regarding the effects it has had on the American football world, resulting in the extraordinarily diminished quality of life of current and former players. The disease has cause many long-term effects affecting patients physically and mentally. This review aims at exploring the significance of CTE in sports, understanding the biology behind the disease as we know it now, current approaches to better understanding the disease, and steps to take in the future to fully comprehend the effects of CTE in the lives of those affected and potentially prevent it from occurring.
The United States obsession with football is easy to see with the sheer number of athletes flocking to play on the gridiron. There are approximately 1.8 million football players spread amongst the high school, collegiate, and professional levels according to the NFL and the NCAA. With all these players comes the risk of injury associated with the violent contact sport that is football. Over the course of a single season, with practices and games included, it is estimated that a player will receive around 1400-1500 hits to the head. This risk is increased in certain positions, such as linebacker and linemen, and lowered for other skill positions such as kickers and punters. These hits can range from base level hits to concussive hits, increasing in frequency during games. Amongst the high school and collegiate levels, it is estimated that there are about 300,000 concussions diagnosed each year. This makes up 10% of all TBI diagnoses each year according to the CDC. One risk involved with the sheer amount of hits involved with the sport comes from the sub-concussive hits that are do not lead to directly diagnosable effects, leaving the condition unmonitored and untreated. The overall result of these brain injuries can lead to increased odds of impairment in overall cognition, with increased impairment associated with those that played starting at a younger age.
According to the CDC, mild versions of TBI, regularly named as concussions, are blows to the head that result in the jarring of the brain, causing the brain to bounce around within the skull, potentially causing damage to cells such as chemical and physical changes or death of cells. The immediate effects of a concussion are the swelling of impact area, hypoxic damage to surrounding cells and tissue, and direct damage to axons in the form of shearing (Kiraly 2007). Swelling itself is a result of the shearing of the blood vessels, causing microhemorrhage, and resulting in the loss of blood flow to regions of the brain. This immediately affects the cognition of victims of concussions as analyzed by Immediate Postconcussion Assessment and Cognitive Testing, resulting in impaired abilities to take the test. The swelling also affects the stability of the integrity of the surround cells by damaging the microtubule and axonal mechanisms, leading to immediate affects such as loss of consciousness or slowed reaction times (Johnson 2013). These injuries also affect the ability of the cell to repair properly over time, contributing to the development of diseases such as CTE. The tau protein, which is a protein associated with microtubules, particularly the stability of tubulin formation, has been identified as a prime target for understanding the structural irregularities that occur following TBI, leading up to CTE and other neurodegenerative disorders.
What are the exact mechanisms that the tau protein is in charge of that are contributing to the degenerative nature of CTE? Tau proteins are particularly found in larger numbers in neurons, making them more likely to be found in the CNS. They are however, not the only protein in their class, microtubule associated proteins (MAP) (Harada 1994). The tau protein is particularly important for maintaining the stability and flexibility of the distal portions of the axons of the nerves, as opposed to the dendrites and proximal axonal regions which are more actively stabilized by other MAPs. This distinction is important when relating back to one of the core direct effects from a concussion, namely the axonal shearing that occurs during the event. As a result, the tau proteins that are maintaining the stability of the microtubules in the axon are directly affected during the shearing of the axon. These proteins can be found phosphorylated in fiber bundles in the brain, which is used as a marker for CTE in many studies currently. The fibrous bundles found in large groups then can affect the signaling of the surrounding cells, specifically around immunoreactive astrocytes, especially axons, interfering with normally occurring processes and increasing the likelihood of neurodegenerative disorders like CTE (McKee 2009). The last of the three immediate effects of TBI, hypoxic damage, is particularly important in understanding why damage occurs immediately, and what makes the side effects of TBI last. With swelling occurring, blood flow to other parts of the brain are impaired, leaving the brain in a hypoxic state (Badjatia et. al 2009). As a result of this, many cells in the immediate area affected die over the course of the next few hours until swelling subsides. The main concern in regards to loss of cells is the axons that begin swelling upon initial injury, potentially leading to their disconnection. This affect, combined with the axonal shearing, lead to potentially life-threatening conditions that require immediate medical attention. Diagnosis of TBIs are difficult though due to the lack of clear physical signs, such as visible bruising or bleeding. Instead, tests of cognition are the only form of immediate testing on site of injury. Swelling can be diagnosed by MRI, allowing doctors to properly diagnose specific regions of the head that are affected.
Short term effects of TBI include headaches, sleeping troubles, motor function troubles, and memory loss. Motor function deficiencies can be linked to the damaged neurons, leading to delayed or lack of signaling between nerves, ultimately altering physical capabilities of subjects prior to repair. Headaches and sleep loss are due to immediate damage to the brain from swelling, causing pain for the former, and altered concentration for the latter. This neuronal damage can also be linked to effects of memory loss as nerves have trouble signaling that is associated with memory formation.
Initially following TBI, there are a few mechanisms that aim at immediate response, namely the introduction of pro-inflammatory molecules to damaged area in the form of nuclear factors and interleukins. These responses, while necessary for immediate stabilization and localization of the injury, also lead to some of the later affects associated with the swelling of the regions of the brain. This swelling also introduces microglia, the local macrophage cells, into the target area, allowing for adhesion and degradation of cells. Long-Lasting Effects of TBI and Development to CTE Long term effects of TBI vary depending on severity and frequency of past injuries. It is entirely possible to receive no long-term effects with minimal TBI and proper diagnosis and treatment. However, long term effects can range from chronic headaches (Suzuki 2017), seizures (Vella 2017), motor sensory problems (Padula 2017), and behavioral changes. Chronic headaches are seen in subjects of TBI long term between two to four times an hour during a sleeping period, which is significantly higher than the zero seen on average in control subjects. Seizures can be seen within up to five months following injury, and are more likely and more severe was severity of TBI increase. Motor function is impaired as seen in extreme cases like boxers and American football players, namely lowered responsiveness and memory loss. Behavioral changes are also notable exhibited in long term effects, especially in the form of depressive behavior. In some case studies involving American football players, depression, memory loss, paranoia, poor judgement, anger, aggression, irritability, confusions, and other symptoms were documented at significantly higher rates than that of normal subjects. These bizarre behaviors also may have played into the tragic deaths experienced by 80% of subjects in the forms of suicide, high-speed chase, or gun-shot wound.
There are very limited treatment options available for TBIs and CTE as a part of the delicate nature that is associated with the injury itself. There are a few different cognition tests that can be run as a way to relatively measure the ability of a person to respond properly to signals following a potential TBI instance. In addition to this, more definitive methods, namely magnetic resonance imaging (MRI), allow for more complete diagnoses as opposed to behavior tests. Treatment options have been made available using novel therapeutic methods. Human-placenta-derived mesenchymal stem cells have been used to minimize TBI injuries (Kim 2017). Stem cells are injected to target areas at specific time points, 4 and 24 hours post injury. This has been shown to reduce inflammatory response and minimized the damage to surrounding cells associated with swelling and hypoxia.
There are many directions being taken as a way to treat TBIs and their development into CTE. The main approaches being taken are understanding what molecules might be markers for a TBI to allow for proper diagnosis, behavioral studies that aim to understand the ability of subjects immediately following a TBI and the long-term effects that may be seen, and lastly the use of model organisms as a way better understand what mechanisms are involved in TBI and CTE. In an effort to find ways to more effectively diagnose a TBI of any nature, researchers have been looking for different marker molecules that can be used to determine whether a brain injury occurred and the severity of it. As such, a few markers have been looked into as potential candidates such as CCL11, glial fibrillary acidic protein (GFAP), microtubule associated protein tau (MAPτ), myelin basic protein (MBP), neurofilament heavy chain protein (NF-H), neuron-specific enolase (NSE), s100ß, and ubiquitin C-terminal hydrolase-L-1 (UCHL1). Each of the markers has been found in the blood in association with head trauma, and have been associated with different stages of the immediate injuries involved with TBI. All are more associated with the buildup of misfolded proteins in the extracellular space of within the brain, contributing to long term affects mentioned before. In order to study TBIs in mass, model organisms are being used as effective tools to allow researchers to observe effects of TBIs. Mouse models have been particular organism of choice due to their similar brain structure and the number of shared genes between mice and humans. Concussive studies are carried out on the mice allowing for observation of differences in behavior as well as gene expression, giving further leads into directions in which to continue research.
In an effort to better understand TBI and CTE, it is important to expand upon the directions that have been established currently. The three main areas to work on in the field would be development of biomarkers, model organisms, and treatment. The development of biomarkers will be entirely necessary in order to allow for physicians and scientists to properly diagnose and study the disease as it begins, develops, and ends. This will allow for more effective ways to diagnose and study the disease than the current model for CTE, namely observing brains post-mortem. With the ability to potentially diagnose and track CTE as it develops and spreads, it will give researchers better insight into how to approach the disease in the future. Model organisms can be an effective way to help identify these biomarkers while not putting human lives at risk. While some model organisms have been developed, others, namely Xenopus laevis, have the potential to allow for the study of TBIs and CTE in vivo. X. laevis, is a particularly good candidate for this research due to the transparency of the brain in the tadpole stages and the particularly long life-span of the organism. The transparency of the head will allow for simplified observation of what activity may be occurring in the brain since no skull or non-transparent skin will be in the way to hinder visibility. In addition to this, the long life-span of X. laevis introduces a better idea of long-term effects of repeated TBI and what may lead to CTE, allowing for behavioral studies as time progresses and the frogs enter older ages, more accurately depicting the effects of CTE as it is associated with age in comparison with humans to other model organisms. Treatment options to attack the three main symptoms of TBI, namely swelling, hypoxia, and axonal shearing, may also arise from these studies and allow for better repair mechanisms to be introduced as options for handling TBIs and CTE. It may be possible to attack the swelling problem by limiting inflammation in target sites and instead introducing microglia directly to necessary site. This could minimize damage associated with hypoxia from regions other than immediately affected site while also allowing necessary repair to damaged tissues and cells.
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