Multiple sclerosis (MS) is the most common cause of neurological disability in young adults in the developed world. Given the clinical heterogeneity in MS, it is difficult to predict the rate at which an individual will accumulate disability. Natural history studies in MS have provided insight but many questions remain unanswered. MS registries fulfil an important role in providing longitudinal data from multi-centric MS cohorts. The analyses described in this thesis were performed using an international MS database, the MSBase Registry, which currently contains records of over 21,000 people with MS from clinics in 64 countries. Expanded Disability Status Scale (EDSS) scores recorded in the MSBase Registry were used to examine disability progression, by ranking scores at specific disease durations, as used to devise the MS Severity Score (MSSS). I demonstrated strong correlation in EDSS rank over five-year periods, from four years after MS onset, suggesting that the concept of EDSS ranking could be useful in predicting later disease severity. I then sought to determine which clinical features influenced EDSS rank change, observing that factors such as gender, relapse rate, treatment exposure and brain imaging findings predicted this outcome, using quantile regression models. These results may prove useful for clinicians in the design of treatment algorithms and clinical trial endpoints in MS. Using the MSBase Registry, the relationship between pregnancy and MS was examined. I confirmed that pregnancy has a favourable effect on relapses but that relapse rate increases in the. postpartum period, as shown in previous studies. A novel association between pre-conception treatment exposure and postpartum relapses was observed. This could allow neurologists to employ a strategy to minimise risk of postpartum relapses in women with MS who are planning conception. Identifying those people with MS who are at high risk of developing disability is becoming increasingly important given the advent of new MS therapies. It is also vital to improve our understanding of the effect of pregnancy on MS, given that onset is common during childbearing years. With these issues in mind, I performed analyses of longitudinal data from the MSBase Registry, producing findings of clinical interest to neurologists worldwide.

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A study was performed to examine association between polymorphisms of the apolipoprotein E gene, and of the cannabinoid receptor 1 gene and neuropsychological impairment in multiple sclerosis. A relationship was seen between an exonic polymorphism of the cannabinoid receptor and neuropsychological impairment which withstood correction for multiple ssting. The strongest factor determining neuropsychological impairment was assessment of premorbid intellectual function.

Background Fatigue is one of the most complex and severely disabling symptoms in multiple sclerosis (MS). There is an absence of a clear definition of fatigue and Uttle consensus exists on its relationship to the other features of MS. The underlying pathophysiology of MS fatigue is unknown and there are no effective treatments. Fatigue has been thought of as difficult to define and usually considered to be multidimensional. These two points, however, immediately present a paradox for the measurement of fatigue, since the fundamental principles of measurement require both strict definition and unidimensionality. The central hypothesis was that the phenomenon of fatigue, as a symptom in multiple sclerosis, could be defined in a detailed and coherent way and could then be measured, in order to facilitate understanding of its pathophysiology. The hypothesis was proven and in doing so many questions regarding the fundamental nature of atigue in MS were answered. It also provided the basis from which to pose questions, in a logical manner, regarding the underlying pathophysiology of the symptom.

Multiple Sclerosis is the most commonly found neurological condition among young adults and in early adulthood. Symptoms exhibit ‘disease heterogeneity’ and vary from sufferer to sufferer. Cognitive impairments in the domains of processing speed, memory, attention, visuospatial perception and executive function are commonly found. Literature Review: A systematic review of the literature on screening for cognitive impairments is presented. The paper considers the key measures of validity and reliability for the screening tests reviewed and uses a standard appraisal tool to assess the methodology of each study. The review concludes that, of the wide variety of tools, which will be best to use is dependent upon the needs of the client and the resources of the service assessing them. Research Report: The study examined the combined validity of two short screening tests – the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) and Symbol Digit Modalities Test (SDMT). Logistic regression was used to generate a combined score for the two tests which was compared to the Minimal Assessment of Cognitive Function In Multiple Sclerosis (MACFIMS) psychometric battery as a ‘gold standard’ measure and Receiver Operating Characteristic (ROC) analysis carried out. While the sample was underpowered, the logistic regression method produced superior area under the curve for the combined scores. Clinical implications of the results, recommendations based on the findings and potential future research projects were discussed. Critical Appraisal: A reflective account of the process of carrying out the research and what was learned from it is provided.

Multiple sclerosis (MS) is the predominant cause of persistent, non-traumatic neurological disability in young adults of the western world. The disease is defined by inflammation and neurodegeneration, however, the precise mechanisms underlying immunopathogenesis and neurodegeneration remain to be fully comprehended. Pathological mechanisms implicated in MS include, for example: (i) hypoxia-like tissue injury, (ii) impaired neuronal transport, and (iii) cytokine-mediated immunopathogenesis and these were therefore investigated in this thesis. Hypoxia-like tissue injury has been associated with MS, and the action of hypoxia inducible factor (HIF)-1 has been suggested to protect against such injury. To investigate a potential beneficial effect of the HIF-1 pathway in MS, HIF-1 was pharmacologically stabilised in a murine model of MS. However, no effect on disease development or progression was observed, suggesting that a general induction of H1F 1-dependent pathways may not be a viable therapeutic avenue for MS A molecular motor protein termed kinesin family member 21 B (K1F21 B) that has a suggested function in neuronal transport has recently been implicated in MS as a potential disease-associated candidate gene. A histopathological analysis demonstrated the expression of KIF21B in the neuronal compartment of human post mortem brain tissue. Intriguingly, however, differential expression of KIF21B was only detected in the immunological compartment and was associated with increasing demyelinating lesion activity. This observation is striking as it implies an immunological rather than neuronal role of K1F21 B in MS. Whilst interleukin (I L)-9 and its receptor (IL-9R) have been implicated in a murine model of MS, this cytokine pathway has not been previously characterised in the human disease. Histopathological examination demonstrated a low frequency of lL-9/1L -9 1~ expressing immune cells in MS lesions, suggesting a minor role of the immunological arm of this pathway in the central nervous system. However, in the neuronal compartment there was a notable inverse correlation between IL-9R levels and white matter lesion activity that implicates IL-9R signalling in the modulation of neurona1 responses in MS pathology. Collectively this work provides new insight into several different aspects of MS pathogenesis.