It has been postulated that there could be a connection between traumatic brain injury (TBI) and motor neuron disease (MND), including amyotrophic lateral sclerosis (ALS). As chronic traumatic encephalopathy (CTE) is caused by repeated TBI and is a newly examined disease, there has been little evaluation of the potential relationship between CTE and ALS. It was proposed that CTE is a risk factor for not only MND, but also ALS. There is significant evidence that even a single TBI is a risk factor for Parkinson's disease (PD), thought to be invoked by the inflammatory process that the brain undergoes following a TBI. General rigorous physical activity with trauma to the trunk or extremities does not appear to be a risk factor for ALS. However, physical activity with associated head traumas, especially repeated head traumas, does seem to increase the likelihood of developing ALS. The biological mechanism for this is suspected to be increase in free radicals during exercise in individuals who are predisposed to decreased antioxidant function. Additionally, individuals who have suffered repeated head trauma, even amongst the general population in a non-athletic setting, has been shown to drastically increase the individual's chance of developing ALS. CTE, which is most common in athletes, is speculated to be caused by TAR DNA-binding protein 43 (TDP-43), tau neurofibrillary tangle (NFT), and beta-amyloid (A-Beta) protein inclusions in brain tissue following a multitude of TBI during high level sport activity. There are individuals who suffer initially CTE, followed by ALS, indicating CTE is clearly a risk factor for ALS. Anatomically, the TDP-43, NTF, and A-Beta; inclusions are present in the brain tissue of both individuals with CTE alone as well as the individuals with CTE and ALS. The anatomic difference between these two pathologies is the inclusion of these three proteins in the spinal cord of ALS patients as well. Unfortunately, there are indications that previous studies of professional athletes and their development of ALS have presented with significant issues including confounding factors of the subpopulation and sample sizing. Additionally, the anatomical cause of TBI leading to ALS is still unknown. Further evaluation on the relationship between head injury and ALS must be dedicated to investigating the mechanism involved in developed PD versus ALS following TBI. The biologic sequence following TBI that leads to ALS must be examined and compared to individuals whom develop ALS but did not suffer TBI. Moreover, an assessment must be made to determine what causes some individuals to develop protein inclusions solely in the brain tissue, leading to CTE, and some individuals to have an advancement of the protein inclusions into the spinal cord, leading additionally to CTE followed by ALS.

Chronic Traumatic Encephalopathy (CTE) has been linked to contact sports, most notably boxing and American football, due to their propensity for repetitive head impacts. Concerns in the community for the safety of athletes in all contact sports has driven a significant amount of research into concussions, their long term effects, and strategies for treatment and prevention. Knowledge of long term brain health in response to neurotrauma is limited, a gap especially noticeable in the literature on non-catastrophic brain injuries sustained as a child. Concussion is a common injury that is often self-resolving with no lasting neurologic or cognitive deficits. Although repetitive brain trauma is hypothesized to be necessary and sufficient to lead to CTE, no human or animal models have definitively demonstrated the pathophysiologic connection or confirmed the mechanism of symptoms. The research to date has been case based, lacking prospective cohorts, with data complicated by convenience sampling. These factors limit the generalizability of conclusions. CTE is neuropathologically defined with variable symptoms; however, it is only diagnosable at postmortem autopsy making the etiology and prevalence difficult to understand. As more research is published to understand if there is an association between a neurocognitive degenerative disease and contact sports, the concentration is on professional athletes. Yet professional athletes do not represent the overwhelming majority of all contact sport participants. The proposed study will compare adults who participated in youth football, but not beyond the high school level, to a control group of adults who did not play contact sports. Evaluating their cognitive function with an online assessment, the Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A), data will be analyzed for signs of clinical cognitive impairment. The objective is to measure adults who represent the high percentage of youth football players who do not continue to the advanced levels. Data obtained from this study will help communities make informed decisions, and create the foundation for future studies on long term benefits and risks of contact sports for children.

Contact and collision sports (CCS) expose athletes to countless repetitive head impacts (RHI) across a single season, potentially leading to increased risk of long-term difficulties in cognition and the development of neurodegenerative disease. There is mixed literature on whether RHI from CCS result in changes to white matter and long-term neurobehavioral outcomes, therefore this research project seeks to provide supporting evidence by comparing the total volume of fluid-attenuated inversion recovery (FLAIR) white matter lesions in individuals with a history of RHI from CCS to those without a history of RHI from the Boston University Alzheimer’s Disease Research Center (BU ADRC). The RHI participants were matched to a group of non-RHI participants based on age (+/- 5 years). Effects of RHI on white matter hyperintensities (WMHs) are evaluated, while considering hippocampal volume across RHI and non-RHI groups. When controlling for age, sex, education, and total hippocampal volume, those with a history of football were found to have a significantly greater WMH volume (p=.02) compared to those without a history of football play. Compared to the non-RHI group, the RHI group including all athletes (n=42) had a greater WMH volume, although it did not reach a level of significance (p=.91). This investigation provided preliminary evidence for a link between high RHI exposure and WMHs in football players, and a non-significant relationship between RHI and increased WMHs in those with a history of CCS compared to individuals in the non-RHI group. Future research should expand upon this investigation, by examining RHI exposure and WMH consequences in a diverse assortment of sports, follow athletes longitudinally for repeated in vivo MRIs and post-mortem neuropathological confirmation, and include more female athletes.

BACKGROUND: Sports-related head trauma has become a major public health concern with significant consequences including persistent post-concussion syndrome (pPCS) and chronic traumatic encephalopathy (CTE). pPCS is a condition where symptoms of single concussion persist years beyond the initial injury. CTE has been characterized as a condition with insidious onset following a latent period after substantial exposure to repetitive head impacts (RHI). Timing of symptom onset usually distinguishes these conditions, however in certain clinical situations a definitive diagnosis is not always clear. For these situations, a measurable distinguishing variable is necessary. LITERATURE REVIEW: Concussions are the most common form of traumatic brain injury (TBI) and are associated with a variety of neurological symptoms that usually resolve within weeks. Post-concussion syndrome (PCS) refers to cases where symptoms continue months beyond this window, and pPCS is defined as symptoms continuing over years. These conditions are temporally related single concussive events. CTE is the hallmark condition related to RHI and remains difficult to fully characterize as it currently can only be diagnosed post-mortem. Clinical features of CTE are similar to those of pPCS with notable behavioral/mood symptoms in its earliest stages, and progression to severe cognitive decline over time. Current research has shown executive dysfunction to be a common impairment among these conditions. The difference in level of dysfunction between them, if one exists, is yet to be measured. PROPOSED PROJECT: A cross-sectional analysis of executive function in four groups. A control without history of mTBI or football exposure (Non-Football – pPCS), a second control of asymptomatic subjects with football exposure (Football – pPCS), a group of pPCS patients with non-athletic mTBI history (Non-Football + pPCS), and a group of pPCS patients with football exposure (Football + pPCS). Executive functioning will be evaluated using the BRIEF-A assessment. Results will be compared to determine if significant differences in executive functioning exist between the groups. CONCLUSIONS: With previous studies showing a correlation between CTE pathological stage, worsening executive function, and increased RHI exposure, further investigation into using executive function as a distinguishing variable between early stage CTE and pPCS is warranted. SIGNIFICANCE: Results of this study, if significant, could be applied clinically to assess risk of early stage CTE in athletes with prolonged post-concussion symptoms. If results are not significant, they may still be utilized for a better understanding of the effects of isolated mTBIs and RHI on executive functioning, and provide valuable information for ongoing longitudinal studies.

Youth football players ages 8-12 may incur hundreds of repeated head impacts (RHI) each season. Evidence suggests concussive brain injury during childhood may disrupt normal developmental processes resulting in long-term impairments. However, little research has investigated the long-term effects of incurring RHI during critical periods of neurodevelopment. Rapid myelination and cerebral blood flow rates, peaks in regional cortical thickness and volumes of specific structures, refinement of regional connectivity, and other neurodevelopmental changes occurring in the brain from ages 10-12 could create a window of vulnerability to RHI. The objective of this research was to determine the relationship between exposure to RHI prior to age 12, during a critical period of neurodevelopment, and later-life brain structure and function. Former National Football League (NFL) players ages 40-65 were divided into two groups based on their age of first exposure (AFE) to RHI through tackle football: AFE <12 and AFE ≥12. In the first study, we observed significantly lower scores on objective tests of executive functioning, memory, and estimated verbal IQ in those who began playing football prior to age 12 compared to those who began playing at age 12 or older. Next, we used diffusion tensor imaging (DTI) to examine the structural integrity of the corpus callosum (CC) and observed that the AFE <12 group had significantly lower fractional anisotropy (FA) as well as a greater decline in FA with age in anterior CC regions than the AFE ≥12 group. Lastly, we used advanced DTI tractography techniques to examine seven CC regions. Significant differences between AFE groups in associations between CC diffusion measures and cognition, mood, and behavior were found. The results of this research suggest that incurring RHI through tackle football during a critical neurodevelopmental period prior to age 12 may result in later-life structural and functional consequences, including cognitive, mood, and behavioral impairments; alterations in white matter structure; and greater vulnerability of white matter to the normal aging process. If replicated with longitudinal designs, larger samples, and athletes whose highest level of play was youth, high school, or college, these findings may have implications for safety recommendations for youth sports.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by a pathognomonic distribution of hyperphosphorylated tau accumulations in neurons, astrocytes, and cell processes, situated around vessels at the depths of cortical sulci. Case reports of CTE pathology exhibit a common exposure to repetitive head impacts (RHI), suggesting that RHI are a necessary factor in the disease’s etiology. Currently, it is only possible to definitively diagnose CTE after death using histopathological techniques and consensus-based neuropathological diagnostic criteria recently established by the National Institute of Health and National Institute of Neurological Disorders and Stroke. Though considerable progress has been made in characterizing the neuropathology of CTE, less is known about the clinical aspects of the disease. Specifically, additional research is needed to identify disease-specific clinical manifestations, clinicopathological correlations, and a means of diagnosis during life, all of which are critical to developing future epidemiological studies, preventative measures, and treatment trials. Moreover, it is not yet known which specific aspects of RHI exposure (type, frequency, duration) are causally linked to developing clinically meaningful neurological impairments or CTE neuropathology, nor have studies identified risk-modifying factors, such as genotype (e.g. APOE). The objective of this dissertation’s published works was to systematically address these gaps in knowledge. First, to define a common clinical presentation of CTE, we conducted a retrospective analysis of medical records and semi-structured next-of-kin reports of 36 former athletes with autopsy-confirmed CTE without comorbid neurodegenerative disease. We then published clinical diagnostic criteria for CTE based on a systematic review of clinical features exhibited in 202 former athlete cases and a pooled analysis of 83 neuropathologically confirmed CTE cases. In subsequent analyses, we operationalized clinical criteria to investigate specific clinicopathological associations between tau, amyloid beta, age, APOE genotype, and clinical outcomes and utilized the clinical criteria to explore potential risk-factors related to RHI from boxing and football. Lastly, we developed a metric to quantify cumulative RHI exposure in retired, living, football players. Using this metric, our study was the first to indicate a causal relationship between cumulative RHI exposure and risk of later life cognitive, mood, and behavioral impairment. These studies are preliminary, and our results require replication and validation in larger, longitudinal prospective studies.

Clinical Researchers recently identified NFL players and US military veterans as high-risk populations for sustaining repetitive Traumatic Brain Injury (TBI) and developing the neurodegenerative disease Chronic Traumatic Encephalopathy (CTE). American culture celebrates military veterans as national heroes, and NFL players as popular athletes and social icons. Both subcultures are constructed around hyper-masculine ideals embedded in tenants of violence and aggression, suffer repeated TBIs due to this nature, and are ultimately at high-risk for developing CTE. The TBI/CTE phenomenon also affects family members who assume care-taking responsibilities for these first two populations as their loved one’s symptoms persist. The purpose of this research is to understand the TBI/CTE experiences of NFL players, military veterans, and their caretakers, and how all three populations intersect with mediatization and the social and medical legitimation of TBI/CTE in America. Using narratives from all three populations, I explore how power dynamics within the NFL and US military have intersected with modern media outlets and functioned to socio-medically legitimize a sick role for those who suffer from persistent symptoms of TBI and CTE.

CTE is a progressive neurodegenerative disease defined by p-tau lesions in characteristic locations of the brain, leading to cognitive impairment as well as mood and behavioral dysfunction. Exposure to repetitive head impacts is a major risk factor for developing CTE; however, additional risk factors and secondary modulating factors, which may expand available treatment and prevention options, are still being elucidated. Studies into the glymphatic system, a system of waste clearance in the brain thought to be activated during sleep, have implicated glymphatic dysfunction in the clearance of toxic proteins like amyloid-beta and hyperphosphorylated tau, as well as in cognitive decline in neurodegenerative disorders like Alzheimer’s Disease, bringing into question whether sleep, through impacting glymphatic clearance, may act as a modulating factor in the development of CTE. In the present study, we began to characterize the presence of sleep disorders and their co-morbid conditions in a cohort of former college football players to gain better insight into their prevalence and the health outcomes of those with sleep conditions. Our results found higher rates of sleep apnea in the study sample, as well as an association between diagnosis with sleep apnea and diagnosis with dementia, AD, MCI, CTE, and similar disorders. Sleep apnea was significantly associated with depression, anxiety, high cholesterol, and diabetes. Further research into whether sleep disorders exacerbate CTE pathology or clinical symptoms, and whether treatment of sleep symptoms leads to better outcomes for patients with CTE, is necessary to further elucidate a potential connection.

Military-related blast-exposure and sports-related closed-head impact-injury are associated with traumatic brain injury (TBI) and chronic traumatic encephalopathy (CTE), a tau protein neurodegenerative disease. Despite growing awareness of links between TBI and CTE, the mechanisms underpinning this association, and relationship to concussive and subconcussive head injury, are poorly understood. This dissertation addresses the hypothesis that blast-exposure and impact-injury induce traumatic acceleration of the head and injurious forces in the brain that led to structural brain damage (TBI) and chronic sequelae, including CTE. This hypothesis was addressed in five specific aims: 1) develop a blast shock tube instrument and impact instrument to deliver relevant blast-exposure and impact-injury to mice, 2) validate a mouse model of single blast-exposure that recapitulates brain pathology in blast-exposed military veterans diagnosed with CTE, 3) validate a mouse model of single-repeat closed-head impact-injury that recapitulates brain pathology in contact sport athletes diagnosed with CTE, 4) match kinematics of blast and impact models using high-speed videography, 5) deploy kinematically-matched mouse models of single blast-exposure and single-repeat closed-head impact-injury to investigate mechanisms that trigger experimental concussion and post-traumatic sequelae. Blast and impact injuries were shown to cause similar CTE-linked brain pathologies, including microvasculopathy, neuroinflammation, astrogliosis, and phosphorylated tauopathy. Despite similarities in chronic consequences, blast-exposure and impact-injury produced different acute neurological responses. Surprisingly, impact-injured mice demonstrated signs of experimental concussion, whereas blast-exposed mice with comparable head kinematics did not. Computational modeling indicated that point loading of forces during impact, as opposed to distributed loading in blast, caused ipsilateral spikes in cortical shear stress which we conclude to be responsible for experimental concussion. The blast-exposure and impact-injury models have been and will continue to be invaluable tools for elucidating the mechanisms of and relationships between concussion, TBI, and CTE. / 2019-07-09T00:00:00Z

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with exposure to repetitive head impacts (RHI) in contact sports. No treatments are currently available. Much of the focus in CTE has been on the microtubule-binding protein tau, which tends to accumulate within neurons and glia around blood vessels at the depths of cortical sulci. The mechanisms of tau accumulation and propagation in CTE are still unknown. The predilection for the perivascular region suggests inherent structural and/or cellular vulnerabilities in this area. Astrocytes are glial cells in this perivascular region that help form the blood brain barrier (BBB) and the neurovascular unit (NVU). Their endfeet envelop blood vessels and help transport nutrients from the blood into the brain, as well as clear harmful waste products out of the brain. Astrocytes are also vital players in many of the brain’s other normal physiological functions, including providing structural and metabolic support to neurons and maintenance of ion and water homeostasis. In response to injury or disease, astrocytes undergo a series of structural and functional changes in a process known as reactive astrogliosis. Astrogliosis is widely considered a hallmark of brain pathology, however, only recently have we begun to understand its functional implications. Astrocytes can respond heterogeneously to CNS insults, including either loss or increase of homeostatic functions, or gain of new, possibly toxic functions. These different astrocytic responses can either assist in recovery or further exacerbate injury. Our current understanding of how astrocytes are altered in RHI and CTE is limited. A degenerative phenotype has been identified in older donors with later stage CTE, but its presence in younger donors with earlier stage disease is unknown. The hypothesis of this study is that exposure to repetitive head trauma causes astrocytes to become reactive and adopt altered phenotypes, including loss of homeostatic functions, in brain areas known to be biomechanically susceptible to the shearing forces of head trauma, such as the perivascular region and interface of the grey and white matter at the depth of the cortical sulcus. These altered phenotypes are expected to be found in athletes with and without pathological tau deposition, highlighting astrocytes as potential therapeutic targets in the post-traumatic injury cascade. Specifically, I seek to characterize reactive astrocyte phenotypes and assess changes in their perivascular function in the brains of former American football players with and without a neuropathological diagnosis of CTE.