Thesis (M. Sc.)--University of Alberta, 2009. / Title from pdf file main screen (viewed on Dec. 22, 2009). "A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Master of Science in Animal Science, Department of Agricultural, Food and Nutritional Science, University of Alberta." Includes bibliographical references.

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.

The bovine spongiform encephalopathy (BSE) crisis was a significant shock to the Canadian agricultural sector. On May 20, 2003, it was announced that an animal infected with BSE had been identified. The economic aftermath of this discovery was described as horrendous (AGO, 2004). Economic crises, such as the Canadian BSE agricultural crisis, are rare events. The rarity of these episodes supplies a unique opportunity for analysis. According to a policy review by the Alberta Auditor General (AGO, 2004), the agricultural economics discipline appeared to be of little assistance in the crisis policy design process. This research addresses this problem by exploring economic theory and policy via detailed empirical investigation. Specifically, this study evaluates agricultural support policies and producer risk preferences in the aftermath of the Canadian BSE crisis. Three research chapters address questions related to cow-calf producer behaviour and government policy. Chapter 2 focuses on designing emergency aid programs and calculating short-run quantitative benchmarks for crisis relief at the farm-level. Chapter 3 estimates observed risk preferences for a sample of Albertan cow-calf producers. Differential risk preferences help to explain diverse production responses following agricultural crises. The final research chapter, chapter 4, examines Canadas primary risk management program when there is potential for catastrophic price risk. In particular, vertical and horizontal equity criteria are used to scrutinize the distribution of net AgriStability benefits across a heterogeneous sample of cow-calf producers.

名古屋大学博士学位論文 学位の種類 : 博士(医学)(論文) 学位授与年月日:平成5年4月6日 氏平伸子氏の博士論文として提出された

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Thesis (M.A. in agribusiness)--Washington State University. / Includes bibliographical references.

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.