Transactive response DNA-binding protein of 43 kDa (TDP-43) is the major protein found within pathological inclusions in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) (Neumann et al., 2006). TDP-43 is a ubiquitously expressed protein mainly involved in RNA metabolism. It is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family and in its normal state is predominantly found in the nucleus. In its pathological state TDP-43 is cleaved, phosphorylated, ubiquitinated, and located in cytoplasmic or nuclear inclusions. Along with ALS and FTLD, TDP-43 is also observed in many other neurodegenerative diseases. Pathological TDP-43 inclusions have been previously reported in cases of Chronic Traumatic Encephalopathy (CTE) (King et al., 2010)(McKee et al., 2010)(Saing et al., 2012)(Hazrati et al., 2013), however no previous study has reported on the incidence and extent of TDP-43 cellular inclusions in a large cohort of autopsy cases diagnosed with CTE. This study finds that TDP-43 inclusions are a frequent feature of CTE, as TDP-43 inclusions are identified in 43% (20/47) of subjects in a CTE+, FTLD-, low-likelihood-of-AD cohort. Furthermore, this study finds that in CTE there is no consistent initial focus of TDP-43 pathology which spreads to neighboring regions as the disease progresses. Despite the lack of a clear progression of TDP-43 pathology, a TDP Staging Scheme for CTE which accurately reflects the extent and severity of TDP-43 pathology in not only the study cohort, but likely in all subjects without FTLD, was established. Four stages were identified: TDP Stage 0 showed no TDP-43 inclusions in the substantia nigra, dorsolateral frontal cortex, or dentate gyrus; TDP Stage 1 showed inclusions in either the substantia nigra or the dorsolateral frontal cortex; TDP Stage 2 showed inclusions either in the dentate gyrus or in both the substantia nigra and the dorsolateral frontal cortex; and TDP Stage 3 showed inclusions in the substantia nigra, dorsolateral frontal cortex, and dentate gyrus. Finally, a correlation was found between the presence of TDP-43 inclusions and the levels of activated microglia in the dorsolateral frontal cortex of CTE+ subjects. This finding aligns with the theory that the pathological changes of TDP-43 found in CTE are driven by the pro-inflammatory cytokines released by chronically activated microglia.

In the past decade, numerous studies have examined the correlation between repetitive head trauma in athletes who participated in contact sports and the development of various personality, behavioral, and cognitive changes. Autopsy data from these athletes have uncovered unique patterns of neuropathology that are believed to be associated with the observed clinical symptoms, and together characterize a condition known as chronic traumatic encephalopathy (CTE). Historically, the condition was known as “dementia pugilistica” commonly found in boxers; however, recent studies have identified cases of CTE in retired football players, hockey players, soccer players, war veterans, and other non-athletes. CTE is a progressive disease and clinical signs often appear many years after the trauma. These symptoms frequently include depression, aggression, suicidality, short-term memory loss, and executive functioning impairments. Postmortem examinations of individuals with CTE reveal distinct gross and microscopic pathology, including atrophy of the frontal and temporal cortices, sulcal accumulation of hyperphosphorylated tau, -amyloid deposition, and TAR DNA-binding protein 43 abnormalities. Although current hypotheses suggest that repetitive head trauma causes the development of CTE, the lack of prospective studies hinders our ability to definitively determine its etiology. Likewise, the inability to diagnose CTE in vivo has constrained our attempts to systematically examine the disease’s progressive nature. The goal of this paper is to review the past and current literature on CTE in boxers and football players. We also discuss current hypotheses concerning CTE’s clinical presentation and neuropathology, and situate CTE within the context of other neurodegenerative diseases. Finally, we address the current limitations of CTE research and propose key objectives for future studies.

BACKGROUND: The accumulation of misfolded proteins is a hallmark of many neurodegenerative disorders, including Chronic Traumatic Encephalopathy (CTE). Intracellular protein degradation pathways appear to be insufficient in preventing or halting disease progression. A brain-wide waste clearance pathway mediated by astroglial aquaporin-4 (AQP4) water channels in the perivascular space called the “glymphatic system” has recently been identified. Disruption of this system due to mislocalization of AQP4 away from perivascular astrocytic endfeet (“depolarization”) is linked to reductions in solute clearance and the build up of toxic metabolites in different neurologic conditions associated with aging and traumatic brain injury. Accumulation of aggregated tau protein around blood vessels at the depths of cortical sulci is considered the pathognomonic lesion of CTE, and may reflect impairment of glymphatic pathway function in these perivascular spaces. OBJECTIVES: To investigate whether changes in AQP4 expression or perivascular AQP4 polarization are present in CTE and to assess their relationship with CTE lesions. Additionally, AQP4 expression in CTE will be compared to subjects with a pathological diagnosis of Alzheimer’s disease (AD) and non-pathological controls without a history of head trauma. METHODS: Postmortem frontal cortex samples from neuropatholigcally confirmed cases of CTE, AD, and non-pathological controls were provided by the VA-BU-CLF Brain Bank. Fixed tissue samples were cut at 20 microns from each case and immunofluorescently stained for AQP4, glial fibrillary acidic protein (GFAP), and phosphorylated tau (AT-8). Slides were imaged using a Zeiss 880 Airyscan confocal microscope and analyzed using the HALO image software analysis platform. RESULTS: Increased perivascular AQP4 polarization was significantly associated with lesional vessels compared to non-lesional vessels in CTE (p=0.0187). When assessed between groups, CTE showed less AQP4 polarization surrounding non-lesional vessels compared to controls, and seemingly higher polarization around lesional vessels compared to AD, however these differences were not statistically significant. CONCLUSIONS: Blood brain barrier (BBB) breakdown is a common occurrence following traumatic brain injury (TBI) and has previously been confirmed in postmortem cases of CTE. The findings reported in the current study showing increased, rather than decreased, perivascular AQP4 polarization around lesional vessels compared to non-lesional vessels in CTE may therefore reflect a compensatory mechanism of astrocytes in response to secondary vasogenic edema in the face of chronic inflammation and disrupted BBB integrity, rather than acute cytotoxic edema which is likely the main driver of AQP4 depolarization reported in previous studies.

Chronic Traumatic Encephalopathy (CTE) is a neuropathological disease that has been associated with contact sports involving repetitive brain injury. This disease is becoming more well-known due to an increase in media coverage, most notably for its possible association with professional football players. This has led to growing concern for the risks of participating in contact sports and the need for further research. There still remains much to be learned about this neurodegenerative disease. The current understanding of the epidemiology and risk factors for this disease are limited by biases in methodology, generalizability, and the use of retrospective data. The only method to diagnose CTE is via autopsy, which has contributed to some of these limitations. The pathogenesis of the disease involves hyper-phosphorylated (p-tau) tau accumulation in distinct areas in the cerebral cortex, leading to neuronal disfunction. The most accepted risk factor for this disease is recurrent brain trauma. Clinically, it can present with varying cognitive, mood, and behavior symptoms and different ages of onset, which often leads to a misdiagnosis of other neurodegenerative diseases. There are a few proposed treatments for CTE but more clinical trials must be performed before any are accepted in clinical practice. One potential modifying factor for CTE symptomology is cognitive reserve (CR). CR is an individual brain’s ability to cope with insults such as neuropathological disease, trauma, and the normal ageing process. Higher CR has shown to have a positive effect on other neuropathologies such as Alzheimer’s Disease (AD). This led to a preliminary study of CR which showed that one measure of CR, occupational attainment, was associated with delayed onset of symptoms of CTE. Our study builds upon this preliminary study by also examining the effect of CR on clinical symptoms of CTE. We expand on this study by using a previously validated tool to measure CR, including aspects such as education, occupational attainment, and social/leisure activities. Our study also includes subjects from other contact sports at varying levels of participation. The results of our study will provide a better understanding of the relationship between CR and clinical symptoms of CTE. This will allow future research to build upon these results and continue to advance our knowledge of this disease. These advances allow changes to be made in clinical practice and athletic organizations in order to improve an individual’s quality of life.

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease that is associated with repetitive traumatic brain injury like those sustained in sport, military combat, and other activities with repetitive head impact exposure. Repetitive head impacts typically cause mild traumatic brain injury (mTBI) resulting in both concussive and subconcussive injury. Repeated mTBIs injuries appear to cause an abnormal accumulation of proteins, including hyperphosphorylated tau (p-tau) and TDP-43, progressive axonal failure with gradual structural degradation, microvascular disruption, breach of blood-brain barrier, neuroinflammation and microglial activation; each of these manifestations lead to axonal degeneration and neuronal death, which impairs neuronal pathways and are likely to give rise to CTE symptoms. CTE can be microscopically characterized mainly by p-tau accumulation in perivascular spaces and at the depths of the cortical sulci. Clinical presentation of CTE may include behavioral, mood, cognitive, or motor symptoms. Some of the common symptoms include impulsivity, aggression, anxiety, depression, memory impairment, dementia, and suicidality. The Locus Coeruleus (LC), a nucleus in the pons of the brainstem, is suspected to be involved in CTE. The LC provides the main source of norepinephrine to the entire brain and is critical for its control over arousal, behaviors, attention, and memory. Dysfunction of the locus coeruleus has shown to cause a wide array of symptoms, many of which are similar to those seen in CTE. Furthermore, the LC is affected in many other neurodegenerative diseases and is believed to be responsible for the progressive and widespread nature of the various diseases and their clinical symptoms. Although the LC has been implicated in CTE there have been no studies examining LC pathology in relation to the disease progression or its symptoms. We hypothesize LC CTE pathology should increase with the severity of CTE. Furthermore, increased CTE pathology in the LC should create disturbances to the LC and the LC-NE system and manifest clinically. Specifically, LC CTE pathology may be associated with age of onset of general behavioral and cognitive symptoms as well as individual symptoms and outcomes including impulsivity, depression, depressed mood and death by suicide. To determine this, a postmortem study was performed on 184 individuals with a history of RHI and no comorbid diseases examining the relationship between AT8-immunopositive tau density in the LC and various clinical variables. The study found that LC AT8 density showed a significant positive correlation with duration of repetitive head impact (RHI) exposure when controlled for age. There also was a significant increase in LC AT8-immunoreactive tau in cases with stage III and IV CTE compared to those with no CTE and stage I and II CTE, and AT8 density was predictive of CTE stage when controlled for age. There were no significant relationships found between density of LC AT8-immunoreactive tau and age of any CTE symptom onset or individual symptom (impulsivity, depressed mood, MDD, death by suicide) presence. Future studies should continue to evaluate CTE pathology in the LC and its effects on both the pathological and clinical characteristics of the disease.

Thesis advisor: Stephanie Greene / This paper addresses the recent concerns about concussions in the sport of football and elaborates on the medical findings, litigation, and ethical questions that have surrounded the issue. The goal is to present a compelling case for change in how concussions are viewed and handled in the sport. By using concrete examples to explain the lasting effects concussions have had on players after their careers have ended, I hope to show the need for change. I will explore the most recent developments of chronic traumatic encephalopathy in order to show its harmful reach and will touch upon litigation that has been filed by players who experienced post career problems. In addition, through the insight of current college players as well as referencing my own experience as a Division I College Football player, I wish to establish an emotional connection in the paper and unveil the roots of the problem – the toxic nature of the football culture. I am optimistic that this inquiry will help cultivate a culture change through a variety of approaches. First, I indicate the need for a transformation of the football culture. Second, I suggest a formal, mandatory education to inform players at all levels about concussions, subconcussive hits, and the potential diseases that can stem from. Third, I propose new penalties for players, coaches, support staff, and all involved in player safety in an attempt to further prevent head injuries. This thesis attacks the issue of concussions in football from all angles. It calls for the football community to accept the severity of concussions, educate on concussions, and prevent repeated concussions in order to prompt action. / Thesis (BS) — Boston College, 2016. / Submitted to: Boston College. Carroll School of Management. / Discipline: Departmental Honors. / Discipline: Other.

Every year an estimated 42 million people worldwide suffer a mild traumatic brain injury (MTBI) or concussion, with approximately 3.6 million sports related concussions occurring yearly in the United States alone (Bailes, 2015, Azad et al., 2015). An MTBI is an acute brain injury resulting from mechanical energy to the head from external forces (Bailes 2015). Symptoms of an MTBI include visual disturbances, dizziness, nausea and vomiting, light sensitivity, loss of balance, and a general feeling of fatigue (Bailes 2015). MTBI’s are first diagnosed through changes in ImPACT baseline scores as well as Vestibular Ocular Motor Screening (Mucha et al., 2014). Repetitive MTBI and/or repetitive sub-concussive head trauma have been tentatively linked to increased risk for a variety of neurodegenerative diseases including chronic traumatic encephalopathy (CTE) (Gardner et al., 2015). The major limitation of the link between MTBI and CTE is that CTE can only be diagnosed post-mortem (Azad et al., 2015). Due to that limitation, the prevalence of CTE is unknown and the amount of MTBI or sub-concussive trauma exposure necessary to produce CTE is unclear (Gardner et al., 2015). Newer methods of research including SNTF immunostaining and L-COSY are being further developed and studied to better diagnose MTBI and its link to CTE by exploring changes in brain protein formation and brain neurochemistry (Johnson et al., 2015, Lin et al., 2015). Through research development and case studies on professional American football players and boxers, a link between MTBI, particularly repetitive MTBI and CTE has been formed (Maroon et al., 2014).

Traumatic brain injury (TBI) is a serious public health concern. Although moderate and severe forms of TBI receive considerable attention, mild TBI accounts for the majority of all injuries. The first two aims of this work used a rodent model of mild blast to simulate primary injury (damage from the blast wave only). The first aim evaluated potential changes in interneurons containing the calcium-binding proteins calretinin or parvalbumin. In addition, morphological changes in astrocytes and microglia were assessed. Brains were analyzed 48 hours and one month following exposure to single or repeated blasts, with a focus on the hippocampus due to its integral role in learning and memory. Results showed significant region-specific alterations in microglia morphology 48 hours following blast. The absence of structural alterations in microglia one month following blast indicated that the regional hippocampal vulnerability may be transient. The second aim compared glial morphologies in the retina and brain (the lateral geniculate nucleus, superior colliculus, and visual cortex) 48 hours or one month following multiple blasts. Fiber degeneration has received considerable attention, however, less is known about the status of glia throughout the visual pathway following mild blasts. Although no structural alterations were detected, it is possible that alterations in glia occurred at a more acute time scale as changes in glia can be rapid and reversible. The final aim of this work focused on the immunocytochemical characterization of tau pathology in the visual cortices of human postmortem brains with advanced chronic traumatic encephalopathy (CTE). CTE is a devastating tauopathy associated with mild, repetitive TBIs. Although visual deficits are reported in CTE, the primary visual cortex is often spared. The main hypothesis under investigation was whether visual association areas would have tau pathology, despite sparing of primary visual cortex. In addition, a sub-class of interneurons containing parvalbumin was used to evaluate a potential cell-specific vulnerability. Results showed increased tau pathology in visual association areas in advanced CTE, that was largely absent from the primary visual cortex. There was no effect on parvalbumin positive interneurons. The results of this work provides valuable insight regarding potential cell-specific resistance to CTE pathology. / 2018-11-03T00:00:00Z

Postmortem brains from young athletes with a history of repetitive concussive head injury and military service personnel with history of blast neurotrauma revealed evidence of parenchymal contusion, myelinated axonopathy, microvasculopathy, neuroinflammation, neurodegeneration, and phosphorylated tauopathy consistent with chronic traumatic encephalopathy (CTE) (L. E. Goldstein et al., 2012). The mechanisms by which head trauma induces acute concussion and chronic sequelae are unknown. To elucidate the mechanistic connection between traumatic brain injury (TBI), acute concussion and chronic sequelae, including CTE, require the use of animal models. This doctoral dissertation investigated the hypothesis that closed-head impact injury in mice triggers acute neurological signs associated with sport-related concussion as well as brain pathologies and functional sequelae associated with CTE. To test this hypothesis, we developed a mouse model of impact neurotrauma that utilizes a momentum transfer device to induce non-skull deforming head acceleration, triggering transient neurological signs consistent with acute concussion and traumatic brain injury (TBI) in unanesthetized C57BL/6 mice. The Boston University Concussion Scale (BUCS) was developed to assess neurological signs that are consistent with acute concussion in humans. Mice exhibited contralateral circling and limb weakness, locomotor abnormalities, and impaired gait and balance that recapitulate acute concussion in humans. Concussed mice recovered neurological function within three hours, but demonstrated persistent myelinated axonopathy, microvasculopathy, neuroinflammation, and phosphorylated tauopathy consistent with early CTE. Concussive impact injury also induced blood-brain barrier disruption, neuroinflammation (including infiltration peripheral monocytes and activation microglia), impaired hippocampal axonal conduction, and defective long-term potentiation (LTP) of synaptic transmission in medial prefrontal cortex. Kinematic analysis during impact injury revealed head acceleration of sufficient intensity to induce acute concussion, traumatic brain injury (TBI), early CTE-linked pathology, and related chronic sequelae. Surprisingly, the presence or degree of concussion measured by BUCS did not correlate with brain injury. Moreover, concussion was observed following impact injury but not blast exposure under conditions that induce comparable head kinematics. Empirical pressure measurements and dynamic modeling revealed greater pressure on the head and compression wave loading in the brain during impact compared to blast neurotrauma. These findings suggest acute concussion is triggered by focal loading of energy that transit the brain before onset of macroscopic head motion. By contrast, the forces associated with rapid head motion is sufficient to induce CTE-linked pathology. Our results indicate that while acute concussion and chronic sequelae may be triggered by the same insult, the pathophysiological responses underpinning these effects are engaged through distinct mechanisms and time domains. Our results indicate that concussion is neither necessary nor sufficient to induce acute brain injury or chronic sequelae, including CTE. / 2018-02-17T00:00:00Z

Thesis (M.A.)--Boston University / Sports-related concussions are a very large public health concern and have only recently been brought into the national spotlight, thanks largely to the increased media coverage following the deaths of several current and former players of the National Football League (NFL). This problem extends not only to professional athletes, but reaches down through college, high school and to our youth athletes as well. The symptoms resulting from concussion are diverse and include both acute and long-term effects, and could have particularly debilitating effects on the developing brains of young athletes. Various neurocognitive deficits, as well as neurodegenerative diseases such as chronic traumatic encephalopathy (CTE) have been associated with concussions. Research about both the short and long-term effects of concussions has been growing in recent years, and will continue to grow as advanced neuroimaging tools and biomarkers become better developed. This will improve diagnostic capabilities, result in better prognoses, as well as treatments and prevention. This review analyzes current literature in order to evaluate the lasting impacts of sports-related concussions. By showing the effects of sports-related concussions, especially on the developing brain, policy changes aimed at the prevention of concussion in sports will be suggested, specifically in terms of mitigating the adverse effects of concussions on brain development.