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.

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The human prion protein (PrP) gene (PRNP) codon 129 (M/V) polymorphism is a susceptibility factor for variant Creutzfeldt-Jakob Disease (vCJD) and a major determinant of clinico-pathological phenotype in sporadic CJD. The role of codon 129 in defining susceptibility and strain transmission properties has been investigated in three lines of transgenic mice that express human PrP. The human PRNP gene has directly replaced the murine version, by gene targeting, and variation at codon 129 has given the three genotype lines (HuMM, HuMV, and HuVV). The genetics of these three mouse lines are otherwise identical, and therefore differences in transmission properties can be directly attributable to the codon 129 genotype. vCJD inoculation has shown that all three codon 129 genotype mice are susceptible with a ranking of transmission efficiency of HuMM>HuMV>HuVV. HuMM mice develop the most widespread neuropathology with features similar to human vCJD. Subclinical infection was noted in each mouse line. These data suggest that the vCJD strain is transmissible to humans of each of the three codon 129 genotypes, implying that non-MM cases of human infection with bovine spongiform encephalopathy (BSE) may exist but with long subclinical incubation periods. Inoculation of material from blood transfusion associated vCJD showed no change in transmission properties suggesting that the threat of a future epidemic of human-to-human vCJD infection has not been increased by adaptation of the vCJD strain. However the route of infection, for example via blood transfusion or surgery, may be more efficient that the original oral route of BSE infection. sCJD is classified into six subgroups according to clinico-pathological features, and defined by codon 129 genotype and electrophoretic mobility type (1 or 2) of disease associated PrPSc (MM1, MM2, MV1, MV2, VV1, VV2). Typical cases from each subgroup have shown specific transmission properties suggesting that the subgrouping is defining separate disease strains. The commonest subgroup (MM1) was the most transmissible and the HuVV mouse line the most susceptible host. These data outline the transmission risk from all sCJD types to recipients of each codon 129 genotype should an infection event occur, and show the significant role of recipient codon 129 genotype in defining the clinical or subclinical state and the success or failure of transmission. This is important for determining individual risk following known exposure, and for modelling the potential of iatrogenic infection from sCJD patients.

L’encéphalopathie hépatique (EH) se développe chez les patients atteints d’une maladie du foie et se caractérise par de nombreuses anomalies neuropsychiatriques. L’insuffisance hépatique aiguë (IHA) se caractérise par une perte progressive de l’état de conscience, par une augmentation rapide de l’œdème cérébral et une augmentation de la pression intracrânienne entraînant une herniation cérébrale et la mort. Plusieurs facteurs sont responsables du développement de l’EH mais depuis une centaine d’années, l’hyperammonémie qui peut atteindre des concentrations de l’ordre de plusieurs millimolaires chez les patients atteints d’IHA aux stades de coma est considérée comme un facteur crucial dans la pathogenèse de l’EH. La présente thèse comprend 4 articles suggérant l’implication de nouveaux mécanismes pathogéniques dans le développement de l’EH et de l’œdème cérébral associés à l’IHA et tente d’expliquer l’effet thérapeutique de l’hypothermie et de la minocycline dans la prévention de l’EH et de l’œdème cérébral: 1. L’IHA induite par dévascularisation hépatique chez le rat se caractérise par une augmentation de la production de cytokines pro-inflammatoires cérébrales (IL-6, IL-1, TNF-). Cette observation constitue la première évidence directe que des mécanismes neuro-inflammatoires jouent une rôle dans la pathogenèse de l’EH et de l’œdème cérébral associés à l’IHA (Chapitre 2.1, articles 1 et 2). 2. L’activation de la microglie telle que mesurée par l’expression de marqueurs spécifiques (OX42, OX-6) coïncide avec le développement de l’encéphalopathie (stade coma) et de l’œdème cérébral et s’accompagne d’une production accrue de cytokines pro-inflammatoires cérébrales (Chapitre 2.1, article 1 et 2). 3. Un stress oxydatif/nitrosatif causé par une augmentation de l’expression de l’oxyde nitrique synthétase et une augmentation de la synthèse d’oxyde nitrique cérébral participe à la pathogénèse des complications neurologiques de l’IHA (Chapitre 2.3, articles 3 et 4). 4. Des traitements anti-inflammatoires tels que l’hypothermie et la minocycline peuvent constituer de nouvelles approches thérapeutiques chez les patients atteints d’IHA (Chapitre 2.1, article 1; Chapitre 2.2, article 2). 5. Les effets bénéfiques de l’hypothermie et de la minocycline sur les complications neurologiques de l’IHA expérimentale s’expliquent, en partie, par une diminution du stress oxydatif/nitrosatif (Chapitre 2.3, article 3; Chapitre 2.4, article 4). / Hepatic encephalopathy (HE) contains a spectrum of neuropsychiatric abnormalities observed in patients with liver disease. A quick worsening of consciousness and increasingly growing cerebral edema, high intracranial pressure, which leads to cerebral herniation and death, are characteristics of acute liver failure (ALF). Multiple factors are found responsible for the development of HE, whereas, over 100 years, hyperammonia is considered the most crucial factor in defining the pathogenesis of HE in ALF, which can increase to millimolar concentrations in the brain at the coma stages of HE. The present thesis comprises 4 articles, which demonstrates new pathogenic mechanisms involved in the development of HE and cerebral edema in ALF, and elucidates part of the therapeutic mechanism of hypothermia and minocycline in the prevention of HE and cerebral edema during ALF. The major findings are listed below: (1) Experimental ALF leads to the increase in brain production of proinflammatory cytokines (IL-6, IL-1, TNF-α), and provides the first direct evidence that central inflammatory mechanisms play a role in the pathogenesis of the encephalopathy and brain edema in ALF (chapter 2.1 - article 1; chapter 2.1 - article 2). (2) Activation of cerebral microglia, measured by OX-42, OX-6, predicts the presence of severe encephalopathy (coma) and brain edema in rats with ischemic ALF, which accompanies the increased production of brain proinflammatory cytokines (chapter 2.1 - article 1; chapter 2.2 - article 2). (3) Oxidative/nitrosative stress participates in the pathogenesis of brain edema and its complications in experimental ALF animals with ischemic liver failure. The increases in cerebral NOS isoform expression caused by ALF were sufficient to cause increased NO production in the brain (chapter 2.3 - article 3; chapter 2.4 - article 4). (4) Anti-inflammatory treatment, such as hypothermia or antibiotics, may be beneficial in patients with ALF (chapter 2.1 - article 1; chapter 2.2 - article 2). (5) The beneficial effect of both hypothermia and minocycline on the neurological complications of experimental ALF is mediated, at least in part, by reduction of brain-derived oxidative/nitrosative stress (chapter 2.3 - article 3; chapter 2.4 - article 4).

We studied Heart Rate Variability (HRV) evolution during therapeutic hypothermia in newborns with hypoxic ischemic encephalopathy (HIE) using spectral analysis. We hypothesized that HRV measures are predictive of neurological outcome in babies with HIE. Non-stationarity in the data causes inaccurate quantification of the spectral power. A modification was proposed to power spectral analysis approach to mitigate the effect of non-stationarity. The modified and the standard approaches were applied to cardiac beat-to-beat intervals of newborns receiving hypothermia treatment. The performance of the approaches in distinguishing the RRi dynamics of two groups of newborns was assessed using area under the receiver operating characteristic (ROC) curve. Our results showed that the modified spectral analysis distinguished the two groups of neonates better than the standard approach. These results may be useful in identifying the deteriorating physiology of the infants receiving hypothermia treatment early in time and strategize alternate interventions for them.