Multiple sclerosis: investigating early neural changes with advanced MRI
AuthorGajamange, Sanuji Imasha
Document TypePhD thesis
Access StatusThis item is embargoed and will be available on 2021-10-21.
© 2018 Sanuji Imasha Gajamange
Multiple sclerosis (MS) is a common neurological disorder, pathologically characterised by the presence of inflammatory demyelinating lesions, and axonal degeneration. Approximately 85% of clinically definite MS patients initially present with a clinically isolated syndrome (CIS), defined as a neurological episode that is typically accompanied by one or more lesions within the central nervous system. Common symptoms included motor, sensory and cognitive dysfunction, all of which worsen with disease progression. Given that early treatment therapies are associated with better long-term clinical outcome, it is important to identify sensitive markers that are able to recognise patients who are more likely to develop severe MS at the earliest stages of the disease. Conventional magnetic resonance imaging (MRI) measures, such as lesion burden, correlate poorly with clinical outcome. Therefore, the principle aim of this thesis was to use advanced MRI techniques to investigate early disease processes of brain structure and function. Understanding these neural changes in CIS patients can provide an insight to the underlying mechanisms of MS, potentially identify early markers to monitor and predict clinical disability, and direct patients to appropriate treatment, especially to those who are at a greater risk of poor prognosis. In this thesis, three experimental chapters provide a comprehensive assessment of the underlying changes of the brain in patients presenting with CIS. In experiment 1, lesion load and measures of neurodegeneration were examined as prognostic markers for predicting long term disease severity. Results of experiment 1 revealed that number of newly appearing lesions was the strongest predictor of the rate of second clinical relapse after initial presentation. In experiment 2, an advanced diffusion MRI technique known as fixel-based analysis was used to examine early axonal degeneration. Results demonstrated that fixel-based approach is sensitive and specific to white matter axonal degeneration in early MS. In experiment 3, a multimodal approach was used to examine the neural correlates of cognitive dysfunction in CIS patients, and the underlying mechanisms of the disease. Due to the subtlety of cognitive dysfunction in CIS patients, a saccadic eye movement task was used to probe the cognitive function. Although saccade performance did not differ between groups, CIS patients exhibited increased functional MRI activation during the cognitive saccade task compared to healthy controls. Furthermore, poor saccade performance correlated with reduced functional MRI connectivity within cognitive brain networks. Neither brain volume nor microscopic measures of axonal degeneration were related to cognitive function. Collectively, these findings suggest that advanced MRI techniques were able to detect subtle structural and functional brain changes at the earliest stage of MS. The number of newly appearing lesions is a strong predictor of disease progression. However, axonal degeneration and functional reorganisation is potentially more sensitive to disease processes. A fixel-based approach provides improved sensitivity and specificity to early white matter axonal degeneration compared to conventional approaches. Furthermore, an early change to functional organisation is potentially an adaptive mechanism to preserve function; however, its efficiency is affected with increasing tissue damage. Once early measures degeneration and functional organisation are validated in larger longitudinal studies, they can potentially be used as markers in clinical trials to monitor and predict clinical progression.
Keywordsmultiple sclerosis; neuroimaging; magnetic resonance imaging; biomarkers
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