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.
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ItemThe associations between physical activity and magnetic resonance imaging in people at risk of Alzheimer's disease( 2016)The world’s ageing population is growing rapidly, and although longevity is a positive development, this involves an increasing prevalence of neurodegenerative diseases including dementias such as Alzheimer’s Disease (AD). This disease cannot be cured and the burgeoning proportion of the population that is aged leads to an urgent need to identify people who are at risk of developing AD in the future. Cerebrovascular disease (CVD) is a known risk factor for AD and modifiable CVD risk factors, which may delay the onset of AD, include diabetes, obesity, smoking or hypertension and the level of physical activity (PA). Magnetic resonance imaging (MRI) measures CVD by assessing white matter lesions that can be detected as T2-signal white matter hyperintensities. Additionally, hippocampal volumes, also assessed by MRI, are an important biomarker in the context of cognitive decline and AD. This thesis examines cross-sectional baseline data from older participants from the AIBL Active (AA) study in Melbourne, Australia. This randomised clinical trial is a longitudinal sub-study of the Australian Imaging Biomarkers and Lifestyle (AIBL) flagship study. The AA study aims to assess the effect of PA on the possible delay of CVD progression. All the participants have either subjective memory complaints or mild cognitive impairment and at least one vascular risk factor including diabetes, hypertension, obesity, dyslipidaemia or smoking.
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ItemMagnetic resonance imaging in spinal trauma( 1992)The Austin Hospital in Melbourne, houses the largest spinal trauma unit in Australia, and one of the largest in the world. It has long been recognised as a centre of excellence in the care of patients with spinal injuries, but, by the start of the last decade of the twentieth century, this unit lagged behind the rest of the world in a critically important diagnostic area: imaging of acute and chronic spinal trauma patients. Whilst encouraging preliminary work had come out of the United States suggesting that magnetic resonance imaging (MRI) could have a major role in management of spinal trauma patients, the economic climate in this country was such that there was little hope of an MRI unit being installed at the Austin, unless a significant on-site need could be demonstrated for this expensive technology. (From Preface)
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ItemAcute stroke imaging: predicting response to therapy( 2012)Acute ischemic stroke is caused by a blocked blood vessel in the cerebral circulation. It is the most common form of stroke worldwide and a major cause of disability and death. Treatments to re-open the blocked blood vessel and reperfuse the brain are available but their effectiveness, when applied to all patients, rapidly decreases over the first few hours after stroke onset. However, there is significant pathophysiological heterogeneity within acute stroke patients which can be revealed using advanced MRI and CT techniques. The principle of “ischemic penumbra” – hypoperfused and often non-functioning brain that will, nonetheless, potentially recover if reperfused – underlies all therapies aiming to restore blood flow in acute ischemic stroke. Perfusion-diffusion mismatch using MRI is a surrogate marker of ischemic penumbra that has been refined over the last decade. This thesis examines the validity of the mismatch paradigm and confirms the use of diffusion imaging as a reliable indicator of irreversibly damaged brain. Diffusion imaging at 24 hours (a commonly used timepoint to assess reperfusion and hemorrhage) is also established as an accurate measure of final infarct volume. This allows calculation of infarct growth as a surrogate outcome whilst minimising loss to follow-up and is a strong predictor of clinical recovery. A less predictable outcome is the proportion of hypoperfused brain that will proceed to infarction in the absence of reperfusion. Collateral blood flow is shown to be a dynamic phenomenon with alterations correlating with infarct growth. The relationship between collateral flow and perfusion-diffusion mismatch is explored. The mismatch paradigm is then translated to CT perfusion which is more widely accessible in most centres but has, until recently, lacked thorough validation. Perfusion thresholds such as Tmax>6sec translate directly to CT. The best correlate of diffusion imaging for infarct core is shown to be relative cerebral blood flow (relCBF), with the exact threshold highly dependent on the software used in the analysis. This is a shift from previous work which had suggested cerebral blood volume (CBV) was the optimal parameter. Applying mismatch-based treatment decisions in clinical practice is also examined with a comparison of simple visual assessment of mismatch with fully automated volumetric software and manual volumetric calculation. The risk of bleeding after reperfusion (hemorrhagic transformation) is the chief concern when considering reperfusion therapies. This thesis examines predictors of hemorrhage and how they may be applied in clinical practice. The ultimate aim is to move beyond simple time-based windows for treatment to an individualized treatment decision based on the particular pathophysiology revealed by imaging. The amount of potentially salvageable brain tissue can be weighed against the risk of hemorrhage to make an informed treatment decision.