Multiple sclerosis (MS) is an immune-mediated disorder characterized by neuroinflammation, demyelination, and neurodegeneration that results in the degradation of neurological structures within the central nervous system (CNS). This degradation of neurological structures often has a substantial impact on the ambulatory abilities of people living with MS, with an estimated 30% of the MS population requiring a wheelchair for mobility (i.e., nonambulatory). Unfortunately, current pharmacological interventions have limited efficacy for those with progressed disability and alternative strategies for disease management must be considered, such as exercise training. To date, most of the MS exercise training literature has not focused on nonambulatory people with MS, limiting evidence-based exercise recommendations for this population. As such, the central purpose of this dissertation was to inform exercise prescription and delivery for nonambulatory people with MS. In order to achieve this goal, three studies were conducted. The first study in this dissertation (presented across two manuscripts) evaluated the safety and physiological response of nonambulatory people with MS to three adapted exercise modalities (arm cycle ergometer, recumbent stepper, functional electrical stimulation cycle). This study determined that acute adapted exercise was well-tolerated by nonambulatory people with MS, with few adverse events reported across all exercise sessions. Notably, participants favoured recumbent stepper and functional electrical stimulation cycling exercise over arm cycle ergometer exercise. Further, participants were capable of exercising at an intensity that satisfied the American College of Sport Medicine’s criteria for moderate-to-vigorous physical activity on all adapted modalities. This suggests all tested modalities are capable of promoting improvements in health-related fitness outcomes. The second study, a systematic review and meta-analysis, explored outcome measures that capture ‘participation’ in MS exercise trials, and the influence of exercise training on ‘participation’. Described within the International Classification of Functioning, Disability and Health (ICF) as the “involvement in life situations”, ‘participation’ outcomes provide insight into the impact of MS on everyday life. Findings from this study demonstrated variability in how ‘participation’ has been captured, with an emphasis on items describing ‘mobility’. Further, the meta-analysis revealed that exercise training had a moderate, positive effect on outcomes that capture participation, a novel finding regarding the benefits of exercise training in MS. The final study of this dissertation, an online-based survey, identified perceived exercise benefits, barriers, and needs among nonambulatory people with MS. This study demonstrated that nonambulatory people with MS perceive health improvements and personal accomplishments as the greatest benefits associated with exercise engagement. The sample also cited environmental challenges and MS symptoms as prominent barriers to exercise engagement. The current sample identified that exercise facilities, specifically exercise equipment, were failing to accommodate their exercise needs. Collectively, the findings from this dissertation will help address prominent gaps in the exercise training literature involving nonambulatory people with MS. Addressing such gaps will contribute to advancing evidence-informed exercise interventions, promoting measurable health improvements, and ultimately increasing engagement in exercise for nonambulatory people with MS,

Multiple Sclerosis (MS) is an autoimmune disease characterized by demyelination and axon degeneration of the central nervous system that is accompanied by a wide range of symptoms. It is well established that physical activity is associated with a wide variety of health benefits, including improving fitness, MS-related symptoms and function in the MS population. However, despite the potential benefits associated with physical activity participation, most people living with MS remain physically inactive. In 2012, new evidence-based physical activity guidelines (PAGs) for adults with MS were released. The PAGs suggest that for health benefits, adults aged 18-64 years with mild to moderate disability need at least 30 minutes of moderate intensity aerobic physical activity two days per week and strength training for major muscle groups two times per week. The purpose of this dissertation was to determine the association between physical activity and health and to explore physical activity as a potential disease-modifying therapy in the MS population. This was completed through a series of three projects focusing on the PAGs for adults with MS. The focus of the first study of this dissertation was on the implementation of the PAGs. The results from this study revealed that direct referral to physical activity from a physician is twice as effective as simply providing information about physical activity with respect to adhering to the PAG recommendations in people with MS (65.2 % vs. 32.8 % for direct referral and control groups, respectively). Further, the results revealed that a high self-efficacy for exercise at baseline may be an additional predictor to PAG adherence. The purpose of the second study of this dissertation was to validate the PAGs for people with MS within a community-based intervention, and to affirm that following the PAGs for 16 weeks would result in improvements in fitness, mobility, fatigue symptoms and quality of life. The results from the second study confirm the effectiveness of the PAGs for people with MS for improving health, as significant improvements were observed in VO2 peak (+32 %), strength (+8-20 %), mobility (+14 %), fatigue symptoms (-40 %) and quality of life (+10-24 %). The purpose of the third and final study was to determine the effect of exercise on brain function and cognition in a sample of adults living with MS. Following the PAGs for 16 weeks led to significant improvements in processing speed and memory in adults living with MS. Overall, the results from this dissertation are extremely promising and highlight the importance of physical activity with respect to improving aspects of health and the effect it can have on MS-related symptoms and cognition in the MS population. Novel findings in this dissertation present convincing evidence that physicians should refer patients with MS to participate in exercise to improve MS-related symptoms and overall well-being. / Thesis / Doctor of Philosophy (PhD)

The study explored the nature of the involvement of certain demographic (gender, age and education), cognitive (specifically executive functions) and psychological factors (personality changes and other psychosocial issues) in the disease process in a group of MS patients. A sample of 20 adults (8 male and 12 female) with a mean age of 47,65 years was employed. The assessments procedure entailed a set of neuropsychological measures, a 16 PF questionnaire and a semi-structured interview (with a significant other) from which certain qualitative themes were extracted. The MS sufferers showed deficiencies on measures of executive function, a 16 PF profile in accordance with that of individuals with physical illness and the qualitative themes revolved around issues such as mood, independence, work-status, self-confidence and cognitive difficulties. The data resulting from these assessments supported one another and served to enrich our knowledge regarding the life world of the person with MS. / Psychology / MSc. (Psychology)

Thesis (PhD)--Stellenbosch University, 2003. / ENGLISH ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Current knowledge suggests that MS is associated with autoimmunity and that infectious agents and hereditary factors may be involved. The demonstration of a higher recurrence risk of MS in families (4-5%) compared with the general population (0.1%) provides strong evidence for a genetic basis. Extensive analyses of the entire human genome to identify new genes that may underlie MS have indicated that several genes may contribute to disease susceptibility, but these remain largely unidentified. In this study candidate genes involved in iron metabolism and immunology have been analysed for the first time within the context of both autoimmune and infectious disease susceptibility, in order to investigate the role of genetic and viral factors implicated in the pathogenesis of MS. The Z-DNA forming repeat polymorphism in the promoter region of the solute carrier family 11 (proton-coupled divalent ion transporters) member 1 (SLC11A1) gene was found to be significantly associated with MS (P<0.01) in the genetically homogeneous Afrikaner population of South Africa, but not in the German and French populations using a case-control study and transmission linkage disequilibrium approach, respectively. However, significant differences were observed in genotype distribution between German MS patients with a primary- and secondary progressive disease course (P<0.05), and between the German patients with relapsing remitting and primary progressive MS (P<0.05). These findings provide further evidence that the SLC11A1 gene is associated with MS, most likely due to its role in iron homeostasis. In order to investigate the influence of viruses in the apparent multi-step aetiology of MS, serum and peripheral blood mononuclear cells (PBMCs) of MS patients, close relatives and unrelated controls were screened for the presence of MS-associated retrovirus (MSRV) and two herpes virus (HHV-6 and EBV) sequences. Detection of the pol gene expression of MSRV in the serum RNA of 69% of South African MS patients and in 70% of their unaffected close relatives, whilst absent in the serum of 39 unrelated healthy control individuals (P<0.001), indicated that virus infections affect the population risk but not the familial risk in MS. HHV-6 sequences were also present at a significantly lower frequency (P<0.04) in the PBMCs of unrelated controls (5%) compared to MS patients (22.5%). A point mutation (77C^G) in the gene encoding protein-tyrosine phosphatase, receptortype C (PTPRC), which is essential for activation of T and B cells, was found to be associated with MS in the German population. Analysis of the Afrikaner and German study populations included in our study did not indicate a causative role for the PTPRC gene in MS. However, it seems likely that this mutation may contribute to disease expression, since in one of the South African families with two MS affected sibs, the most severely affected sister was heterozygous for the 77C-»G mutation. The PTPRC mutation may therefore be of significance in disease prognosis. The multidisciplinary study approach has led to a stepwise accumulation of scientific information, which forever changed our understanding of the disease process underlying MS. / AFRIKAANSE OPSOMMING: Veelvoudige sklerose (VS) is ‘n kroniese inflammatoriese siekte van die sentrale senuweestelsel. Oor die algemeen word aanvaar dat VS geassosieerd is met outoimmuniteit en dat infektiewe agente en oorerflike faktore ’n rol speel. Die hoër herhalingsrisiko van VS in families (4-5%) in vergelyking met die voorkoms in die algemene populasie (0.1%) dui op 'n genetiese basis. Alhoewel volledige analise van die mensgenoom om gene onderliggend aan VS te identifiseer aangedui het dat verskeie gene waarskynlik bydra tot vatbaarheid vir die siekte, is die aard van die gene wat betrokke is grootliks onbekend. In hierdie studie is kandidaatgene betrokke by ystermetabolisme en immunulogie vir die eerste keer geanaliseer binne die konteks van beide outoimmuun en infektiewe siekte vatbaarheid, ten einde die rol van genetiese en virale faktore in die patogenese van VS te ondersoek. Die Z-DNS herhalingsvolgorde polimorfisme in die promotor area van die SLC11A1 geen was betekenisvol geassosieerd met VS (P<0.01) in die geneties homogene Afrikaner populasie van Suid-Afrika. ’n Soortgelyke assosiasie kon egter nie aangetoon word in die Duitse en Franse populasies deur gebruik te maak van onderskeidelik ‘n gevalle-kontrole studie en transmissie-koppelings-disekwilibrium benadering nie. Betekenisvolle verskille in die genotipe verspreiding is egter tussen Duitse VS pasiente met ‘n sekonder- en primer progressiewe verloop van die siekte (P<0.05), en tussen die Duitse pasiente met terugvallende en primere progressiewe VS aangetoon (P<0.05). Hierdie bevinding verskaf verdere bewyse dat die SLC11A1 geen geassosieerd is met VS, heel waarskynlik weens die rol van die geen in yster-homeostase. Ten einde die invloed van virusse in die etiologie van VS te ondersoek is serum en witbloedselle van VS pasiente, naby-verwante familielede en nie-verwante kontroles getoets vir die teenwoordigheid van die VS-geassosieerde retrovirus (MSRV) en twee herpesvirus (HHV-6 en EBV) geenvolgordes. Die pol geen uitdrukking van MSRV was teenwoordig in die serum RNA van 69% van die Suid-Afrikaanse VS pasiente en in 70% van hul ongeaffekteerde naby-verwante familielede, terwyl dit afwesig was in 39 nieverwante kontrole individue (P<0.001). Dit dui daarop dat virusse waarskynlik die risiko vir VS meer in die populasie verhoog as in families. HHV-6 was ook teenwoordig teen ‘n beduidende laer frekwensie (P<0.04) in nie-verwante kontroles (5%) in vergeleke met VS pasiente. ‘n Puntmutasie (77C-G) in die geen wat kodeer vir die proteien tirosien fosfatase reseptor tipe C (PTPRC), wat belangrik is vir aktivering van T- en B-helperselle, is vroeer gevind om geassosieerd te wees met VS in die Duitse populasie. Analise van die Afrikaner en Duitse populasies in ons studie het egter geen bewyse gelewer dat die PTPRC geen ‘n rol speel in VS nie. Dit egter is moontlik dat hierdie mutasie bydra tot die uitdrukking van VS, aangesien die mees geaffekteerde VS pasient in een van die Suid- Afrikaanse families met twee geaffekteerde susters positief getoets het vir die mutasie. Die mutasie mag dus van belang wees in die prognose van VS. Die multidissiplinere studie-benadering en stapsgewyse insameling van wetenskaplike inligting het gelei tot ’n nuwe perspektief ten opsigte van die siekteproses onderliggend aan VS.

Thesis (M.S.)--Ball State University, 2009. / Title from PDF t.p. (viewed on Apr. 16, 2010). Includes bibliographical references (p. 36-37).

Thesis (M.S.)--University of Wisconsin-Madison, 1992. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 55-63).

Thesis (Ph. D.)--West Virginia University, 2006. / Title from document title page. Document formatted into pages; contains xi, 214 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 155-173).

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The study explored the nature of the involvement of certain demographic (gender, age and education), cognitive (specifically executive functions) and psychological factors (personality changes and other psychosocial issues) in the disease process in a group of MS patients. A sample of 20 adults (8 male and 12 female) with a mean age of 47,65 years was employed. The assessments procedure entailed a set of neuropsychological measures, a 16 PF questionnaire and a semi-structured interview (with a significant other) from which certain qualitative themes were extracted. The MS sufferers showed deficiencies on measures of executive function, a 16 PF profile in accordance with that of individuals with physical illness and the qualitative themes revolved around issues such as mood, independence, work-status, self-confidence and cognitive difficulties. The data resulting from these assessments supported one another and served to enrich our knowledge regarding the life world of the person with MS. / Psychology / MSc. (Psychology)

Mitogen driven differentiation of mononuclear cells is a useful model of antibody synthesis and secretion in humans. We have studied Pokeweed mitogen (PWM) induced immunoglobulin secretion in vitro in both healthy individuals and multiple sclerosis patients. Within the healthy population we have identified individuals who consistently secrete low levels of IgG in response to PWM and others who secrete very high levels. The underlying mechanisms involved in low response are not well understood. We have observed that the peripheral blood mononuclear cells (PBMC) obtained from low responders differ from those obtained from high responders in each of the following: Their T-helper cell subset contains a higher ratio of T suppressor-inducer cells over T helper-inducer cells; their PBMC contain a higher level of in vivo radiation-sensitive suppression; their PBMC generate a lower autologous mixed lymphocyte response; and their B lymphocytes secrete lower amounts of IgG when mixed with heterologous high responder T helper cells. These results suggest the response involves the interactions between T helper cell subsets, T suppressor cells and B lymphocytes and that the level of response is the sum of the contribution of each subset. PWM induced immunoglobulin secretion was measured in multiple sclerosis patients during different phases of clinical disease activity. Relapsing-remitting multiple sclerosis patients in early relapse secreted less immunoglobulin than patients with prolonged relapse, suggesting that immune function varies with clinical disease activity. Testing the level of PWM induced immunoglobulin secretion in relapsing-remitting multiple sclerosis patients during the clinically stable phase suggested that those patients who secreted high levels of IgG in response to PWM were more likely to suffer a clinical relapse within 6 months than those patients who secreted a low amount. Chronic progressive multiple sclerosis patients secreted higher amounts of immunoglobulin in this assay than healthy control individuals. This group of multiple sclerosis patients also had; (i) reduced Concanavalin A (Con A) suppressor cell activity measured both by the ability to suppress a/ Con A induced proliferation and b/ PWM induced IgG secretion in heterologous cell cultures and; (ii) reduced percentages of T cells expressing T suppressor and T suppressor-inducer markers. The treatment of chronic progressive multiple sclerosis patients in vivo with lymphoblastoid interferon resulted in a dramatic reduction in level of PWM induced immunoglobulin secretion without alteration in Concanavalin A induced suppression or in the percentages of T cells expressing subset specific markers. The PWM induced IgG secretion assay is a valuable technique for investigating the regulation of humoral immunity in both health and disease. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate