Radiology - Theses
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ItemAn investigation of motor disabilities in people with multiple sclerosis using advanced magnetic resonance imaging( 2020)Multiple sclerosis (MS) is an autoimmune disorder of the brain and spinal cord, and the most common cause of neurological disability in young adults. The presentation of MS is highly heterogeneous with an unknown aetiology and no known cure, presenting as inflammation, demyelination and axonal injury/loss. MS pathology is disseminated throughout the central nervous system leading to a broad range of symptoms including cognitive dysfunctions, bowel and bladder problems, fatigue, sensory disturbances and difficulties with walking and balance. Up to 90% of people with MS experience motor impairments that significantly worsen with increasing disease severity, and which can affect both the upper and lower limbs. Motor impairments are often highly debilitating, ranging from muscle weakness, coordination loss, tremors to spasticity. However, while the pathophysiological mechanisms underpinning motor impairments in MS have been widely studied, they are not currently well understood. This is particularly true for early disease, a time when personalised treatment strategies can be formulated and will have maximal effect, preventing future deterioration and accumulation of disability. Consequently, there is an urgent need to understand the pathophysiology underlying motor impairments in MS and elucidate the microstructural and functional changes that occur at their earliest manifestation. To this end, we investigated the pathophysiology of motor impairments associated with dexterity and mobility in people with MS using advanced magnetic resonance imaging (MRI). Our investigations included functional resting-state (Chapters 2.1 and 2.2) and task (Chapter 3.1) MRI, diffusion weighted imaging (Chapter 3.2) and ultra-high field MRI (Chapters 3.1 and 3.2). Our findings consistently demonstrated a clear link between the development of motor impairments and alterations in the structure/function of the sensorimotor system, a system responsible for the integration of sensory information with motor processing in order to facilitate and maintain movement. Specifically, studying the sensorimotor system in its entirety using network analyses in a large cohort of people with MS, we identified functional disturbances within the sensorimotor system of patients with serious disabilities (Chapter 2.1), with disturbances particularly predictive of future progression of upper and lower limb impairments (Chapter 2.2). Further, using high resolution ultra-high field MRI and measures of motor behaviour in a cohort of patients with minimal motor impairments (Chapters 3.1 and 3.2), we similarly found a link between changes in the function and microstructure of the sensorimotor system and the presence of subtle impairments in hand function and walking. These findings provide evidence for the role of the sensorimotor network in the development of motor impairments. Potentially, the sensorimotor network might be central to the development of motor impairments in MS and represent a useful target for the development of imaging biomarkers for use in treatment development as well as understanding and monitoring the evolution of motor impairments. From this and subsequent work, it is hoped that this knowledge will lead to more effective treatments and management of patients, alleviating the burden of these impairments.
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ItemMultiple sclerosis: investigating early neural changes with advanced MRI( 2018)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.