Thesis (M.Clin.Psych.) - University of Queensland, 2006. / Includes bibliography.

Thesis (Ph. D.)--West Virginia University, 2007. / Title from document title page. Document formatted into pages; contains x, 415 p. : col. ill. Includes abstract. Includes bibliographical references (p. 324-368).

Cognitive fatigue (CF) presents a considerable challenge for individuals with multiple sclerosis (MS) often negatively impacting quality of life. CF can be defined as a decrease in, or inability to sustain, optimal task performance throughout the duration of a continuous cognitive task. The following dissertation presents three original research reports which evaluate CF in MS in three distinct ways using a multidimensional approach. The objective of this dissertation was to comprehensively evaluate and quantify this frequently misunderstood symptom of the disease. The first report examines four theoretical models of CF in MS which evaluate the interrelatedness of disease severity, fatigue, depression, and sleep quality in order to determine their predictive roles with regard to CF. The second report assesses CF longitudinally by examining whether or not the ability to perform optimally on a continuous cognitive task changes as the disease progresses across a three-year time interval. The final report objectively quantifies CF in MS by evaluating changes in global and regional cerebral blood flow during a task of sustained attention using arterial spin labeling perfusion fMRI. Results of all three reports are further discussed in terms of clinical and research implications. CF is a symptom of MS not readily apparent to outside observers but presents a very real burden for people with the disease that negatively impacts their ability to lead active and productive lives. These individuals may be discriminated against because CF has thus far been a largely unverifiable subjective experience. The totality of these three studies allows for a multidimensional quantification of CF. By providing objective support to the self-reports of individuals with MS, not only can they achieve much needed validation, but this can also lead to interventions that may provide further direct benefit to their health-related quality of life.

Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases, in part by modulating adaptive and innate immune responses. Since metabolism governs the phenotype and function of immune cells, the aim of this thesis was to investigate whether NSCs have the ability to regulate the immunometabolic components underpinning neuroinflammation. Herein I have identified a new mechanism by which transplanted somatic and directly-induced NSCs counteract CNS-compartmentalised chronic inflammation in mice. NSC transplantation reduces the immunometabolite succinate in the cerebrospinal fluid, while decreasing the burden of mononuclear phagocyte (MP) infiltration and secondary CNS damage. Mechanistically, the anti-inflammatory activity of NSCs arises in response to succinate released by inflammatory MPs, which activates succinate receptor 1 (SUCNR1)/GPR91 on NSCs, thus initiating prostaglandin E2 secretion and extracellular succinate scavenging. This work uncovers a succinate-SUCNR1 axis in NSCs that clarifies how stem cells respond to inflammatory metabolic signals to inhibit the activation of pro-inflammatory MPs in the chronically inflamed brain.

Background: Malnutrition and gastrointestinal (GI) involvement are common in patients with systemic sclerosis (SSc). Despite malnutrition being common, little is known about its associations and predictors. Although patients are frequently screened and assessed for malnutrition, different clinically applicable assessment modalities in SSc have not been compared. An understanding of the relationship between dietary intake and energy expenditure is important for nutritional assessment and management. However, studies have not compared these. For many years, home parenteral nutrition (HPN) has been used in patients with intestinal failure, but little outcome data exists to support its role in SSc. GI involvement results in dysmotility, the underlying mechanism for the development of which is unknown. However, autonomic dysfunction has been proposed. Aims: To explore aspects of the nutritional assessment and management of patients with SSc. To seek associations and predictors of nutritional decline. To investigate for a link between GI dysmotility and autonomic dysfunction. Methods: Study 1: A retrospective review of the survival and outcome data of patients commenced on HPN over 22 years. Study 2: An assessment of 168 patients recruited over 12 months and restudied after approximately 1 year. Assessment included demographics, clinical data, GI and functional questionnaires, nutrition screening tool, oral aperture, mid-upper arm and 4-site anthropometry, bioelectrical impedance and biochemical testing. Re-study included weight change. Study 3: A 3 day assessment of dietary intake and energy expenditure using food record charts and SenseWear® Armband involving 36 patients recruited to Study 2. Study 4: Patients and matched controls completed GI and autonomic questionnaires, an autonomic battery, a gastric emptying study and postprandial cardiovascular measures and GI sensations and symptoms scores. Results: Study 1: The cumulative probabilities of surviving on HPN at 2, 5 and 10 years were 75%, 37% and 23%. HPN-associated complication rates were low. Study 2: Nutritional screening failed to identify all patients who lost weight. Mid-arm circumference correlated with body mass index (BMI) and weight change. Four-site anthropometry correlated with BMI more strongly (r=0.65 vs. r=0.49) than bioelectrical impedance analysis. Small intestinal, but not oesophageal, involvement correlated with baseline nutritional status. No clear predictors of nutritional decline were identified. Study 3: Predicted energy intakes correlated with measured expenditures, but absolute values differed. Energy intakes did not correlate with expenditures. Study 4: Autonomic measures did not correlate with gastric emptying. However, autonomic results were hindered by patient-related and technical limitations. Conclusion: Nutritional screening tools cannot be relied upon to detect all at risk patients. MAC and 4-site anthropometry may have a role in nutritional assessment. When an accurate appreciation of energy requirements is needed, kinematic monitors should be used rather than predictive equations. For those patients who progress to intestinal failure, HPN is safe and effective. Autonomic studies were inconclusive. However, the autonomic apparatus has been refined for utilisation in more definitive studies in younger patients.

Interstitial lung disease is one of the main causes of mortality in Systemic Sclerosis. The course of the disease is clinically variable where patients can suffer from a range of stable disease to rapid progressive clinical deterioration. Therefore, it is important to identify biomarkers that can predict the clinical course of patients in order to provide early treatment. We evaluated 1129 proteins utilizing novel high-throughput SOMAlogic proteomic technology from the serum of 13 LSSc, 13 progressive ILD and 11 stable ILD patients. Calpain-1 was significantly elevated in progressive ILD patients (median 15129 RFU, 11091-24561) compared to LSSc patients (12759, 9904-15498, p=0.0015) and stable ILD patients (11876, 10271-14249, p=0.0005). Coagulation Factor V was significantly lower in the progressive ILD patients (7161 RFU, 2140-8296) compared to LSSc patients (10311 RFU, 6396-12260, p=0.001) and stable ILD patients (9646 RFU, 6510-11941, p=0.0016). The combination of Coagulation Factor V and Calpain-1 produced an area under the curve of 0.97 (95% CI, 0.921-0.99), sensitivity of 99% and specificity of 91% for the identification of progressive ILD. We have identified a combination of proteins that show potential to be prognostic biomarkers for ILD in SSc. / 2016-12-31T00:00:00Z

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects between 14,000 to 15,000 Americans. The upper and lower motor neurons degenerate, which eventually causes muscle paralysis, atrophy, and ultimately death from respiratory failure. It has a high treatment cost as well as a high toll on the patient and their families and friends. Currently, there are only two drugs approved by the FDA for the treatment of ALS: riluzole and edaravone. Research is constantly being conducted to understand and develop further treatment modalities, however, many drugs have failed to demonstrate significant improvement in phase III trials. One of the pathophysiology that these drugs, including riluzole, target is excitotoxicity of the motor neurons. This review will briefly expand upon the different trials that were conducted targeting the excitotoxicity pathway. Although they may have not been successful in prolonging survival in ALS patients, we can learn from these studies and build upon them.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2009.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.

This qualitative study explored the psychosocial experiences of children and adolescents with early-onset multiple sclerosis. In particular, an emphasis was placed on examing peer relationships and social behaviours in relation to these experiences. MS is a chronic neurological disease primarily affecting young adults. However, a proportion of MS patients have onset during childhood and adolescence. Very little is know about the psychosocial impact of MS on these children and adolescents. In particular, youth with MS may be at risk for negative peer experiences due to their chronic illness. Previous research suggested that negative peer experiences increase the risk of poor psychosocial development. In addition, research suggested that the social behaviours of these youth also impact the nature of their experiences with peers. Ultimately, this research aimed to provide insight into the psychoscial experiences of youth with MS and the role of their peer relationships. Six linked parent-youth pairs, from the MS Clinic in Calgary, AB, participated in semi-structured interviews to identify the issues that are pertinent to the participants' own experiences. Constant comparison analysis was then used to summarize the rante of psychosocial experiences in the adolescent participants. Data analysis was derived from grounded theory, which provided a framework for examining and categorizing interview data into themes. The categories were then constructed logically and systematically into a theoretical model which represented the data. Through this innovative grounded theory, a theoretical paradigm for understanding the psychosocial experiences of adolescents with MS was developed. The theory was comprised of two core categories: "the grief experience" and "dynamic relationships', each with several sub-categories. There were two primary conclusions drawn from the theory. The first reflected the significance of grief in understanding psychosocial experiences in adolescents with MS. The second identified that peer relationships play a variety of roles in this grief process. The second identified that peer relationships play a variety of roles in this grief process. The results of this study have many implications for the role of counsellors in the treatments of adolescents with MS. This model can act as a foundation for guiding therapeutic treatment of adolescents with MS. This model can act as a foundation for guiding therapeutic treatment and promoting future research in the area of psychosocial development in children and adolescents with early-onset MS. / xiv, 181 leaves ; 28 cm.