Background: Chronic traumatic encephalopathy (CTE) is an enigma that has become synonymous with combat sports over the past few decades. Mixed martial arts (MMA) is a combat sport that is growing in popularity world-wide. The objective of this study is to determine the factors associated with head trauma among MMA athletes. Methods: Logistic regression analyses using SPSS 20 was employed to model putative covariates against the dichotomous outcomes of unconsciousness (for the full dataset) and diagnosed concussion (for the enriched subset of fighters who were rendered unconscious). Results: Increasing age, black or African-American ethnicity, shorter rest periods between fights, increasing numbers of significant clinch strikes landed, significant distance body strikes landed and power strikes landed to the body at distance are all factors associated with being diagnosed with a concussion among the fighters rendered unconscious. Conclusion: If bolstered by confirming laboratory and clinical evidence, policies should be developed for implementation by MMA governing bodies to help reduce incidences of head trauma and concussion, built around fighters’ demographic and behavioural characteristics. In particular, enforcing a mandatory rest period between fights and placing an upper limit on fighters’ age are ideas worth exploring.

In the study of diseases such as chronic traumatic encephalopathy (CTE), the ability to gather retrospective estimates of an individual’s total repetitive head impacts (RHI) is paramount. Although the exact mechanism responsible for the development of CTE is still unknown, it is well accepted that RHI play a critical role. Until recently, however, the methodology used to collect retrospective estimates of RHI have been very limited. In the beginning of 2016, Montenigro et al. from the Boston University’s Alzheimer’s Disease and CTE Center published a new method of RHI estimation called the Cumulative Head Impact Index (CHII). The CHII was developed by collecting self-reported football histories (years of play, positions of play and levels of play), and using that data to extrapolate the findings of short-term helmet-accelerometer studies into career-long estimates of cumulative head impacts. In addition to publishing this new method, Montenigro et al. (2016) also determined that the CHII was very successful at predicting later-life neurobehavioral and cognitive impairment, an essential ability of any RHI estimate intended to be used in CTE research. Participants in the Montenigro et al. (2016) analysis were part of an ongoing longitudinal study where individuals take yearly surveys of their neurobehavioral and cognitive well-being in addition to answering surveys about sports participation, head injuries and overall wellbeing. Participants had played football at the high school or college level, but had not played any other contact sports. This thesis serves as an initial validation of that publication, and also tests the ability of the CHII to predict later-life impairment in a more diverse population of athletes. Participants in this thesis were selected from the same ongoing longitudinal study according to two distinct sets of inclusion and exclusion criteria. For the purposes of conducting a validation study, the first set of criteria were identical to those used by Montenigro et al. (2016). The second experimental set allowed for participants who had participated in a secondary contact sport if it was at the high school level or below. These two sets of criteria resulted in 70 “validation” participants, and 82 “experimental” participants. Using the same methods as Montenigro et al. 2016, we calculated the CHII for all participants, and examined the ability of the CHII to predict later-life impairment. Our findings validated that the CHII was indeed successful at predicting later-life impairment from cumulative head impacts among the validation group of 70 participants. In particular, the CHII successfully predicted a threshold dose-response relationship between CHI and apathy (p >0.001), depression (p >0.001), executive function dysregulation (p >0.001), and self-reported cognitive impairment (p >0.001). We then found that the CHII was much less successful at predicting impairment in the experimental group of 82, only finding significance in measures of apathy (p=0.0502) and executive function dysregulation (p=0.0277). Overall, our findings indicate that the CHII is an excellent improvement in methods of estimating RHI in people whose only contact sport is football.

The diagnostic lesions of neurodegenerative tauopathies, such as chronic traumatic encephalopathy (CTE) and Alzheimer’s disease (AD), are located in the cortex, however, white matter pathology is a contributing factor to neurodegeneration. At all stages of disease, white matter axonal and glial morphological abnormalities are present in CTE. Similarly, white matter changes may emerge before cortical pathology in AD. White matter irregularities bear functional consequences, as they are associated to some of the most common and onerous symptoms of these diseases, like cognitive deficits and depression. Individuals with AD present with both reduced white matter integrity and cognitive symptoms starting early in disease progression. In CTE, which is triggered by repetitive head impacts (RHI), individuals are particularly vulnerable to white matter damage as RHI exposure alone is sufficient to injure white matter tracts and induce depression symptoms. In this dissertation, I investigated the cellular and molecular presentation of white matter glial cells, including astrocytes, oligodendrocytes (OLs), and microglia in CTE and AD as compared to controls. To investigate white matter pathology, I examined glial cells on a cellular level. Neuropathologically-verified CTE samples were compared to RHI-experienced controls, with both groups containing samples with and without depressed mood. CTE with depressed mood had reduced myelin and increased neuroinflammatory peripheral cells compared to non-depressed CTE and contained increased numbers of microglia compared to non-depressed CTE and control samples. Using single-nucleus transcriptomics in neuropathologically-verified CTE samples compared to matched RHI-naïve controls, OL loss, iron aggregates, OL iron trafficking dysregulation, and two distinct astrocyte subpopulations were detected in CTE white matter. AD white matter, compared to the same control samples in the same brain region, was also depleted of OLs by single-nucleus transcriptomics. However, OLs did not demonstrate iron-related transcriptional profile like those in CTE and, in further contrast, displayed increased numbers of microglia and astrocytes. Together, these findings implicate previously uncharacterized white matter glia in the neurodegenerative process of CTE and AD and further elucidate the etiology of neurodegeneration-related symptoms in CTE. These findings may aid in the development of therapeutics targeting glial contributions to the pathologic processes of both CTE and AD.

With the advancement of protective gear and medical aid, soldiers are now surviving traumatic experiences that were once fatal. As a result, the prevalence of brain injury and posttraumatic stress disorder in military service members has grown. Those who have obtained brain injury are at risk of developing chronic traumatic encephalopathy, a neurodegenerative syndrome. To date, there is no cure, treatment, or diagnostic method (besides autopsy) for chronic traumatic encephalopathy. Because chronic traumatic encephalopathy and posttraumatic stress disorder present many of the same symptoms and have the possibility of deriving from the same traumatic experience, an investigation of a potential link is necessary. This study explores the possibility of chronic traumatic encephalopathy being misdiagnosed as posttraumatic stress disorder. This is done by analyzing the frequency of brain injury along with the comorbidity of posttraumatic stress disorder and brain injury. This thesis also proclaims the need for research that attempts to develop diagnostic criterion and treatment methods for chronic traumatic encephalopathy.

Background: According to the Center for Disease Control and Prevention, approximately 1.6 to 3.8 million Americans suffer a sports related concussion each year. Concussion is defined as a transient alteration of the brain structure caused by a direct or indirect force. During the last decade, a vast amount of clinical research on the long term effects of repetitive head trauma has occurred, especially on the subject of chronic traumatic encephalopathy (CTE), depression and dementia. Objective: The purpose of this literature review is to examine the literature pertaining to multiple concussion and the long-term effects of multiple concussion such as neurodegenerative diseases and psychological. Methods: A literature review was conducted using an electronic search of the following databases: MEDLINE, Cochrane Database of Systematic Reviews, and SportDiscus. The key search terms included were concussion, "sport concussion" and "sports concussion". One of the above three terms needed to be in conjunction with one of the following key search terms: depression, dementia, "mild cognitive impairment", "chronic traumatic encephalopathy" (CTE), or "psychological disorder". Additional inclusion criteria also included studies that targeted the adult athlete population who had sustained more than one concussion. Studies only were included if they were peer-reviewed, in the English language, and were published after 1990. To be included in the review, the study must have examined the long term effects of repetitive concussion. Results: The research completed to date suggests there is a strong correlation between the number of concussions an athlete suffers and the long-term ramifications of neurodegenerative and psychological disorders. However, more research is needed.

Over 15 million contact sports players and military veterans are at risk for the development of chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with exposure to repetitive head impacts (RHI) that sometimes presents with parkinsonian motor symptoms, although very little is understood about how these individuals develop parkinsonism. CTE is characterized by accumulation of hyperphosphorylated tau protein (p-tau), and diagnosis requires the presence of neuronal tau in the form of neurofibrillary tangles at the depth of cortical sulci. We performed quantitative immunoassays for markers of neurovascular inflammation within the postmortem dorsolateral frontal cortex of participants with and without a history of RHI and CTE (n = 156), and tested for associations with RHI, microgliosis, and tau pathology measures. Levels of vascular injury-associated markers were increased in CTE compared to RHI-exposed and -naïve controls. Markers increased with RHI exposure duration and were associated with increased microglial density and tau pathology. Histologically, there was significantly increased ICAM1 staining of the microvasculature, extracellular space, and astrocytes at the sulcal depths in high stage CTE compared to both low stage CTE and controls. Multifocal perivascular immunoreactivity for serum albumin was present in all RHI-exposed individuals. These findings demonstrate that vascular injury markers are associated with RHI exposure, duration, and microgliosis, are elevated in CTE, and increase with disease severity. We next performed a cross-sectional analysis of all brain donors with CTE and without comorbid neurodegenerative disease (n=495) in the UNITE Brain Bank. Participants with parkinsonism (CTE-p, n=119) had a higher mean age at death (71.5 years (y)) than participants without parkinsonism (CTE-np, n=362, 54.1 y) and exhibited a higher rate of dementia than CTE-np participants. CTE-p participants had a more severe CTE stage and nigral pathology (NFTs, neuronal loss, and more frequent Lewy bodies), though the majority of cases were negative for nigral Lewy bodies. In American football players, simultaneous regression analysis demonstrated that nigral NFTs and neuronal loss mediate a connection between years of play and parkinsonism in CTE. In this cross-sectional study of contact sports athletes with CTE, years of contact sports participation was associated with SN proteinopathy and neuronal loss, and these pathologies were associated with parkinsonism. Finally, in a postmortem cohort (n=392) of brain donors with CTE without comorbid neurodegenerative disease, we used linear regression modelling to analyze the associations between isodendritic core nuclei pathology (semiquantitative neurofibrillary tangles (NFTs), neurites, and neuronal loss scores) and CTE disease severity, RHI exposure duration (years of contact sport play), and informant-reported cognitive and daily function as assessed by the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ), respectively. Overall, isodendritic core (IC) NFT scores increase with disease stage, Initially in the locus coeruleus and finally in the median raphe nuclei. Neuronal loss occurred at later disease stages than NFT accumulation. RHI exposure was associated with p-tau pathology for all IC regions. NFTs and neuronal loss in the substantial nigra were associated with increased CDS scores (i.e., worse cognitive function), and neuronal loss in the substantia nigra and locus coeruleus were associated with increased FAQ scores (i.e., worse daily function). We are able to show CTE is similar in distribution of p-tau pathology to progressive supranuclear palsy (PSP), a disease that is thought to primarily affect subcortical regions, especially by end stage disease. These results demonstrate the vulnerability of the isodendritic core nuclei to p-tau pathology and neuronal loss in CTE, and suggest that their involvement contributes to cognitive and functional symptoms during life. This work highlights the possible linkage between neuroinflammation leading to nigral p-tau accumulation and neuron loss which likely underlies the development and progression of parkinsonian motor symptoms in CTE.

Football safety has increased over time, in part due to improvements in equipment and body mechanics, but there are still inherent risks involved, including exposure to repetitive head impacts (RHI). Significant head impacts can result in a constellation of symptoms including nausea, vomiting, headache, dizziness, and amnesia, which typically assist in the diagnosis of concussion. However, it has been shown that subconcussive impacts may result in microstructural changes and physiological alterations in the brain. This is particularly concerning because athletes may be undergoing changes in the brain in the absence of outwardly visible symptoms. Poorer neurologic outcomes later in life have been associated with cumulative exposure rather than number of diagnosed concussions. Accelerometers installed in helmets have shown that college football players may receive up to 1,850 head impacts throughout the course of one season. The concussion rate is obviously much lower, indicating there are a high number of head impacts per diagnosed concussion. Axons are especially susceptible to damage from RHI because of their extension throughout the nervous system. The subtle changes thought to result from RHI are not easy to measure, but several modalities have been proposed. These include diffusion tensor imaging (DTI), plasma tau protein, and King-Devick testing. The proposed study will look to quantify cumulative head impact exposure in college football players prior to the start of a season and see if this has any impact on the variables. They will then participate in one season of football wearing helmet accelerometers to measure the number of head impacts sustained. Changes in the variables will be compared to non-contact sport college athletes. Data will be analyzed to determine if number of head impacts correlates with changes in variables and if prior head impact exposure has any effect on these changes. Data obtained from this study will have significant implications in the field of head injury. It may strengthen the use of several markers of brain injury that could be utilized in the future. Additionally, the effects of cumulative head impact exposure and one season of head impacts will be thoroughly examined. This information can be provided to trainers, coaches, and athletes to further improve football safety.

BACKGROUND: Although concussion and sport-related traumatic brain injury is being acknowledged as a major public issue, especially in professional football players, current study is mostly limited to retrospective studies and post-mortem autopsies. The purpose of this study is to identify a potential association between concussion and neurodegenerative disease in athletes, and propose a prospective approach of studying concussion and its effect. METHODS: A total of 26 studies related to concussion in athletes and published after January 2000 were collected from PubMed and Google Scholar. More recent papers with higher citation counts were given the priority. RESULTS: Retired professional football players showed five times greater risk for mild cognitive impairment, three times greater risk for memory loss, and four times greater risk for amyotrophic lateral sclerosis and Alzheimer disease. Autopsy results from football players also revealed findings consistent with chronic traumatic encephalopathy. Population with the Apolipoprotein E (APOE) promoter G-219T TT (Thymine-Thymine) genotype showed increased susceptibility for concussion. CONCLUSION: This study revealed that a history of concussion has statistically significant associations with high incidence of neurodegenerative diseases in professional athletes. In addition, the results suggest the 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitril(FDDNP)-positron emission tomography tau binding patterns and the APOE promoter G-219T TT genotype provide a new approach to study and monitor the progression of neurodegenerative conditions in athletes.

Tauopathies are a group of neurodegenerative diseases characterized by the abnormal deposition of the protein tau, a microtubule stabilizing protein. Under normal physiological conditions tau is a highly soluble protein that is not prone to aggregation. In disease states alterations to tau lead to enhanced fibril formation and aggregation, eventually forming neurofibrillary tangles (NFTs). The exact cause for NFT deposition is unknown, but increased post-translational modifications and mutations to the tau gene can increase tangle formation. Tauopathic brains are stuck in a detrimental cycle, with cellular dysfunction contributing to the development of tau pathology and the development of tau pathology contributing to cellular dysfunction. The exact mechanisms by which each part of the cycle contributes to the other are still being explored. To investigate the unique contributions of each part of this cycle we utilized two separate models of tauopathy: one chronic and one acute. Overall this project provides novel insight into the role of pathological tau as both a cause, and a consequence, of cellular dysfunction. To understand how development of tau pathology contributes to cellular dysfunction we studied chronic disease models. Using human brain tissue we found that under normal conditions tau associates with ribosomes but that this interaction is enhanced in Alzheimer’s disease brains. We then used in vitro and in vivo models of tauopathy to show that this association causes a decrease in protein synthesis. Finally, we show that wild type tau and mutant tau reduce protein translation to similar levels. To understand how general cellular dysfunction contributes to development of pathology we used an acute model of tauopathy through traumatic brain injury (TBI). We injured rTg4510 tau transgenic mice at different ages to investigate the effect of TBI on tau fibrillization (2 month old) and the effect of TBI on tau already in NFTs (4.5 month old). In 2 month old mice, we found that tau hyperphosphorylation was decreased at 24 hours and increased at 7 days post injury, and that tau oligomerization was decreased at 24 hours post injury. We also found that tau fibrillization was not increased after 24 hours or 7 days post injury. In 4.5 month old mice, we found that TBI did not increase or decrease tangle counts in the brain, but we did qualitatively observe decreased variability within groups. Overall these studies contribute novel understanding of tau’s role in different disease states. We identified a functional consequence of the interaction between tau and ribosomes, and demonstrated that a single head impact did not increase tau fibril formation within 7 days of injury. While human diseases associated with TBI show neurofibrillary tangle deposition, we have yet to recreate that aspect of the disease in research models of TBI. Our findings support the need for further investigation into the nuances of tau in disease, especially following TBI.

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head trauma and mild traumatic brain injuries (mTBIs) and has been associated with contact sports such as football, boxing, and ice hockey. CTE is a slowly progressing neurological disease that is often clinically associated with symptoms of memory loss, decline in cognitive function, behavioral changes such as increased impulsivity and aggression, and/or suicidal thoughts. Advanced stages of the disease present with more severe neurological changes such as dementia, speech and gait abnormalities, and parkinsonism. Amyotrophic Lateral Sclerosis (ALS, also known as Lou Gehrig Disease) is a progressive and fatal neurodegenerative disease characterized by motor neuron loss and corticospinal tract degeneration. While 90-95% of ALS cases are sporadic in nature, many genetic mutations have been identified that contribute to familial forms of the disease. The etiology of sporadic ALS is unknown but it is likely caused by a complex interaction of various genetic and environmental risk factors. Epidemiological evidence suggests that one such risk factor is brain trauma, the main risk factor associated with the development of CTE. In this study the spinal cord tissue of twelve athletes diagnosed with CTE who also developed a progressive motor neuron disease and showed symptoms of profound muscle weakness, atrophy, spasticity, and fasciculations several years before death was examined. The spinal cord tissue from these 12 CTE cases with motor neuron disease (CTE+MND) was compared to the spinal cord tissue of 10 sporadic ALS control cases. Results showed a difference in frequency of tau pathology between the two disease cohorts, as one-third of CTE+MND cases and none of the ALS cases showed tau immunoreactivity. In addition, TDP-43 immunoreactivity was present in every CTE+MND case but one and was present in all ALS cases. Motor neuron inclusions were positive for both FUS and p62 in both cohorts, and no distinct differences were observed cystatin C pathology. Overall, this suggests that the spinal cord inclusions in CTE+MND have a similar composition to sporadic ALS. However, there is an increased frequency of tau pathology in CTE+MND though this result did not reach statistical significance in this study.