Radiology - Theses

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    An investigation of motor disabilities in people with multiple sclerosis using advanced magnetic resonance imaging
    Strik, Myrte ( 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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    Advanced imaging techniques in cerebrovascular disease
    Amukotuwa, Shalini Ambika ( 2020)
    This dissertation aims to investigate how advanced imaging techniques can improve diagnosis, prognostication and treatment delivery in patients with cerebrovascular disease. Six original publications are presented in which perfusion imaging and new software algorithms are used to address clinical need in two specific cerebrovascular disease entities: acute ischemic stroke (AIS) and dural arteriovenous fistulas (DAVFs). AIS patients with anterior circulation large vessel occlusions (LVO) can be successfully treated with mechanical thrombectomy. Patient triage to thrombectomy requires identification of an LVO, the target of therapy, as well as the likelihood of benefit from reperfusion and the potential risk of complication. This assessment must be accurate, fast and efficient since stroke is a time-critical emergency. This poses a challenge for stroke centres because an increasing number of patients are being screened since extension of the thrombectomy window to 24 hours. Additionally, non-tertiary level hospitals are now required to perform acute stroke imaging despite lacking around-the-clock neuroradiology expertise. The first four publications explore how perfusion imaging and automated software algorithms can be used to expedite triage while maintaining high diagnostic accuracy for identifying patients who are likely to benefit from treatment. The first study introduces and describes a new fully-automated deterministic software algorithm for detecting LVOs on computed tomography (CT) angiography, then validates it in a large cohort of 926 AIS patients that was enriched for LVOs. The algorithm had high sensitivity (97%) and moderate specificity (74%) for detecting LVOs. The second study then applied this algorithm to a consecutive cohort of 477 “code stroke” patients presenting to a large regional hospital, with the aim of field testing it in the real world clinical setting where automated LVO detection tools are most likely to be used. The high sensitivity (94%) and negative predictive value (98%), combined with fast processing times, suggest that it can be used as a screening tool to assist radiologists and expedite diagnosis of LVOs. Patients with LVOs who have large infarct cores are unlikely to benefit from thrombectomy and have an increased risk of complication. CT perfusion (CTP) with fully automated post-processing is widely used to exclude patients with large infarct cores from treatment. Previous studies that validated CTP for this purpose had some key limitations. These were addressed in the third study, which sought to determine whether automated estimation of the infarct core on perfusion, based on reduced relative cerebral blood flow (rCBF), is sufficiently accurate for patient triage to thrombectomy. A novel approach was adopted, allowing almost perfectly temporally and volumetrically matched diffusion and perfusion data to be compared in a cohort of 119 prospectively enrolled patients. 94% of patients were correctly triaged using reduced rCBF, suggesting that fully automated perfusion-based measurement of the infarct core can be used for individual patient triage. Despite widespread use of CT, magnetic resonance imaging (MRI) remains the first-line modality for stroke patients in Europe and Asia. One of the most time-consuming sequences is T2*-weighted gradient recalled echo (T2*GRE), which is used to detect haemorrhage that contraindicates reperfusion therapies. Dynamic susceptibility contrast perfusion weighted imaging (DSC-PWI), which is used primarily to delineate the ischemic penumbra, is also sensitive to haemorrhage. The agreement between DSC-PWI and T2*GRE for detection of haemorrhage was assessed in the fourth study on 393 MRI scans from a cohort of 221 AIS patients. Almost perfect agreement (k > 0.90) was shown for detection of acute haemorrhage. This suggests that DSC-PWI is sufficient for haemorrhage screening when it is included in the AIS MRI protocol. Arterial spin label (ASL) is an entirely non-invasive MR perfusion technique that is an alternative to DSC-PWI. While its use in AIS is limited, it has been serendipitously discovered that ASL signal in venous structures indicates the presence of shunting. Intracranial DAVFs are a type of shunting lesion that can be difficult to detect on structural imaging. The diagnostic performance and added value of ASL for detection of DAVFs was assessed in the fifth study, in a cohort of 156 patients. Venous ASL signal had a high sensitivity (94%), negative predictive value (98%) and specificity (88%) for the presence a DAVF. Including ASL in the MRI protocol improved diagnostic confidence and performance. The sixth study assessed the accuracy of ASL for identifying cortical vein drainage, the main risk factor for haemorrhage in DAVF patients. In a cohort of 34 patients, ASL was found to have a sensitivity of 91% and specificity of 96% for the presence of cortical vein drainage. These findings suggest that an MRI protocol augmented with ASL can be used to non-invasively screen for DAVFs and differentiate between high-risk fistulas requiring treatment and low-risk lesions that can be managed with observation. To conclude, a summary of the findings is presented along with the impact of the work, its limitations and future directions for research.
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    Multiple sclerosis: investigating early neural changes with advanced MRI
    Gajamange, Sanuji Imasha ( 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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    Tremor in multiple sclerosis: neuroimaging perspective
    Boonstra, Frederique Maria Christina ( 2019)
    Multiple sclerosis (MS) is a common autoimmune disorder of the central nervous system (CNS), characterised by inflammation, demyelination and neurodegeneration. The clinical presentation and disease course of MS is heterogeneous, which reflects the multifocal nature of damage within the CNS. Almost half of the MS population experiences a tremor in the later stages of the disease. Tremor significantly increases disease severity and worsens patients’ quality of life. Current understanding of tremor pathophysiology in MS is incomplete and mostly based on treatment studies, clinical observation studies, or neuroimaging studies of parkinsonian tremor and essential tremor. Focused imaging assessments of defined neural pathways associated with tremor can help improve our understanding of complex pathophysiology of MS tremor. This could benefit the current lack of effective, noninvasive and long-term treatment options for tremor. This thesis provides a comprehensive examination of the pathophysiology of tremor in MS. The first experimental chapter confirms the hypothesis that the cerebello-thalamo-cortical tract is involved in tremor pathophysiology. Specifically, the pilots study finds a positive correlation between thalamic and superior cerebellar peduncle atrophy and tremor severity. In the second experimental chapter, we aimed to develop a functional imaging task that will allow in vivo imaging of tremor pathology. We introduced a novel joystick task, which showed to elicit the MS-related tremor while playing the game. Furthermore, we showed good reproducibility, which is great for the longitudinal part of this thesis. In the third experimental chapter, we applied the joystick imaging task in a large sample of tremor and non-tremor MS patients. We supported that pathology along the cerebello-thalamo-cortical tract is instrumental in tremor pathology. Interestingly, we also found increased functional activation within sensorimotor integration and motor planning areas in MS tremor, which negatively correlated to tremor severity. In the final experimental chapter, we examined the central effects of onabotulinumtoxinA (BoNT-A) for the treatment of tremor in a randomized controlled trial. We found that patients that received BoNT-A had improved tremor and reduced activation within the sensorimotor integration regions. The change in tremor severity correlated with the change in activation, indicated that BoNT-A has a central effect as well as a local effect. Collectively, these findings suggest that the clinical presentation of tremor in MS is influenced by a tremor network consisting of both structural and functional aspects. Specifically, atrophy and inflammation along the cerebello-thalamo-cortical tract is thought to be more causal to tremor. Contrarily, functional activation is thought to be compensatory to alleviate tremor severity. Intramuscular injection of BoNT-A reduced tremor severity and the activation within the sensorimotor integration area. The central effect of BoNT-A is thought to be due to the lower need for the compensatory functional activation. Together, both structural and functional aspects of the tremor network in MS need to be consider when trying to monitor tremor over time and to find effective treatments options.
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    The associations between physical activity and magnetic resonance imaging in people at risk of Alzheimer's disease
    Merkel, Bernd ( 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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    Acute stroke imaging: predicting response to therapy
    Campbell, Bruce C. V. ( 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.