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.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality around the world. It has multiple causative factors including sports injuries, vehicular accidents, war, and other forms of trauma. Though patients can recover, it has the potential to cause mild to severe persistent cognitive deficits. Medical treatment involves treating individual problems as they arise; this treatment is based upon clinical signs. Developing a standard of care for TBI is complex due to the difficulty in finding common cell and molecular changes in TBI variants that can be prevented or ameliorated. Tumor necrosis factor (TNF) is a prominent inflammatory cytokine present in all forms of traumatic brain injury. It is the target of multiple therapies in other disease processes. As TNF inhibitors lead to billions of dollars in worldwide sales, their use in neuropathologies is an active research area. XPro1595, a preclinical drug developed by Xencor, uniquely inhibits more than 99% of soluble TNF. However, there is only one published study to date on the effects of XPro1595 in any model of traumatic brain injury. The purpose of this study was to characterize the presence of TNF and the proinflammatory TNFR1 pathway in a controlled cortical impact (CCI) mouse model of TBI and to determine if XPro1595 could improve behavioral and neuropathological outcomes. TNF and the TNFR1 pathway have shown to be chronically present in a CCI mouse model for at least two weeks. Injured animals treated with one course of the drug did not show any improvements in spatial learning or memory. However, decreased activity in the TNFR1 pathway and changes in glial markers indicated that XPro1595 lessened neuroinflammation via this mechanism. This study suggests potential benefits of XPro1595 in TBI that could lead to a common standard of care.

Children and adolescents with concussion display aberrant functional connectivity in some of the major neurocognitive networks. This includes the Default Mode Network, Central Executive Network and Salience Network. Using resting state fMRI, the purpose of this thesis was to explore the functional connectivity of cognition-related networks in youth experiencing concussion. With a prospective cohort study, the functional connectivity (defined as the temporal coherence between spatially separated brain regions) of children and adolescents ages 10-18 years old was evaluated in relation to a number of demographic and injury-specific factors including recovery length, age at the time of injury, symptom severity, and neurocognitive performance. The results showed two general trends: (1) a reduction in connectivity (i.e., hypoconnectivity) between the regions of the Default Mode Network, and (2) an increase in connectivity (i.e., hyperconnectivity) between additional sensory-related regions like the cerebellum and hippocampus. The Default Mode Network, which processes self-referential information, has a long-protracted development across childhood through adulthood. Given that the participants in this cohort exhibited reduced functional connectivity within the Default Mode Network and between the Default Mode Network and other neurocognitive networks suggests that this is an area of vulnerability in youth in the event of concussion. Increased connectivity between the Central Executive Network and Salience Network, and between cognitive- and sensory-related regions such as the hippocampus and cerebellum might be interpreted as a compensatory mechanism to supplement deficits of the Default Mode Network. This thesis sheds light on important concussion-related regions for future research to investigate further and delves into the possible neural mechanisms contributing to the cognitive, sensory, mood, and sleep disturbances in children and adolescents with concussion. / Dissertation / Doctor of Philosophy (PhD) / Your brain at rest is not resting. In fact, your many brain regions are continuously communicating even during rest to maintain important communication between them. This communication between brain regions is termed functional connectivity. When you receive a blow to the head, face, neck, or another part of your body that senses a biomechanical force to your brain, the functional connectivity (i.e., communication lines) between your brain regions may be altered. A blow of this nature is considered a concussion, also known as a mild traumatic brain injury. With disruptions to the typical functional connectivity between your brain regions following a concussion, you may experience difficulty in managing cognitive tasks, emotions, and body coordination. Among those most vulnerable to the effects of concussion are children and adolescents whose brains have yet to develop fully. The goal of this thesis was to evaluate the functional connectivity between brain regions of children and adolescents to determine how brain communication might be disrupted following concussion. These evaluations were done using functional magnetic resonance imaging (fMRI) of the brains of children and adolescents ages 10-18 years old. It was discovered that the functional connectivity of the frontal lobe is related severity of post-concussion symptoms such that individuals with worse symptoms had reduced functional connectivity in the frontal lobe compared to individuals who reported less severe symptoms. Further, children and adolescents with longer recovery periods have a different level of functional connectivity in the temporal lobe compared to youth with relatively shorter recovery periods. This might suggest that both of these regions could provide prognostic value in determining who might have worse symptoms or a longer recovery time following injury. In comparison to children and adolescents who have not had a concussion, children and adolescents experiencing a concussion are more likely to have abnormal functional connectivity between the hippocampus and cerebellum, which are particularly involved in processing sensory information and navigation. This was interpreted to mean that the brain responded to the concussion by increasing the communication between regions that might help a child with a concussion coordinate their bodies so that they can move from place to place. This was additionally supported by a further investigation which showed that children and adolescents have reduced communication between areas of the brain that might allow them to process information about the self (e.g., memories, sensations, relationships with others, etc.). Overall, the results demonstrated that following a concussion, children and adolescents may have a deficit in the functioning of the frontal lobe in a specific region that allows them to process cognitive and sensory information. This might explain why concussion leads to poor memory, body coordination, sensitivity to light and sounds, and even difficulty sleeping. Their brains might then compensate for the disruption by increasing alternate pathways of communication. Together these findings open gateways for future researchers to look more deeply at the specific regions affected by concussion in youth. It draws attention to the many neurocognitive, emotional, and somatic symptoms a child with a concussion exhibits and their symptoms’ underlying neurological processes.

Subconcussive impacts have become a growing concern particularly with respect to contact sports. It is believed that minimal head impacts can cause cerebral perturbations that initiate an immune response creating a window of vulnerability. Evidence suggests that additional head insults sustained during this window of vulnerability elicit an exaggerated inflammatory response and exacerbate cognitive deficits. Therefore, determining the lower limits of systematic perturbation resulting from low-level impacts is of critical importance in expanding our understanding of cerebral vulnerability and recovery. However, the vast majority of experimental investigations of subconcussion fail to model single impact events and instead focus on cumulative insults. Additionally, these animal models employ impact magnitudes used to model mild Traumatic Brain Injury. The present investigation aimed to address this gap in knowledge through the utilization of a pneumatically controlled, closed-head, blunt impact device capable of producing repeatable, defined, subconcussive head impacts within a rat model. Thermography was used as a noninvasive measure of inflammation and system perturbations with respect to local (head) and global (thorax and abdomen) temperature changes. Cognitive function was assessed using an Open Field Test and Novel Object Recognition test. Neuroinflammation was measured by assessment of GFAP and iba-1 within the hippocampus and corpus callosum. To investigate the tolerance and the persistence of cerebral vulnerability, measurement outcomes were assessed at six timepoints of recovery, 0, 0.5, 1, 4, 7, and 14 days. Thermal disturbances were detected directly after impact, followed by an apparent recovery, 0.5- and 1-day post-impact. A latent temperature increase was observed after 4- and 7-days of recovery coinciding with decreased risk-avoidance behaviors, a modest upregulation of iba-1, and a marked downregulation of GFAP. Short-term memory deficits became apparent after 7-days of recovery. A decrease in locomotor activity and an upregulation of GFAP was observed concomitant to a persistent decrease in risk-avoidance despite thermal, short-term memory, and iba-1 measurements recovery 14-days post-impact. Overall, these results indicate that low magnitude subconcussive impacts can produce latent thermal, behavioral, and histological disturbances uncharacteristic for a head injury model suggestive of a biomechanical threshold of altered pathodynamics that fail to fully recover after 14 days.

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