Radiology - Theses
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Multiple sclerosis: investigating early neural changes with advanced MRI
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.
Tremor in multiple sclerosis: neuroimaging perspective
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.
The preoperative MRI assessment of adult intracranial diffuse gliomas
MRI (Magnetic Resonance Imaging), is an integral part of the management of intracranial diffuse gliomas, consisting of both astrocytomas and oligodendrogliomas, and ongoing improvements in MRI technology continually enhance its value. While advanced MRI techniques are adding to the functional information available, standard sequences remain the mainstay of the assessment, and are also being improved. Initially, MRI provides critical diagnostic information and aids neurosurgical planning, but its role is expanding beyond these primary functions, as outlined in this thesis. Improved identification and delineation of the tumour allows optimal management by surgical resection and adjuvant radiotherapy. MRI is also important for prognostication, by identifying features that may convey a better or worse prognosis. The addition of MRI information to clinical data and the histopathological assessment thus provides the most comprehensive assessment of the individual patient. The recent 2016 update to the WHO classification of central nervous system tumours has led to significant changes in the histological characterisation of gliomas, now providing an integrated genotypic and phenotypic classification1. The two steps in the genotypic classification of gliomas is testing for an isocitrate dehydrogenase (IDH) mutation, and if present, determination of 1p/19q status1. There are logistic and cost issues, however, and MRI can aid decision-making. The value of MRI in this context is greatest when access to definitive testing methods is limited, and the focus on the molecular phenotype in the new WHO classification increases the potential for a combined histologic-MRI assessment method at such centres. Due to its ability to assess the entire tumour and provide non-invasive characterisation over time, MRI also has the potential to overcome some of the limitations of both the phenotypic and genotypic assessment, including sampling error, intra-tumoural heterogeneity and monoallelic gene expression. Information obtained by MRI is also increasing our understanding of the disease, well demonstrated by the growing interest in the non-enhancing component of tumour. Gliomas are essentially incurable, with recurrence almost inevitable despite optimal therapy. There is thus growing interest in advanced surgical techniques aimed at more aggressive management, and accurate delineation of the tumour by MRI provides a critical guide to the surgeon.
Effect of physical activity on progression of cerebrovascular disease in older adults at risk or alzheimer's disease
Objective: Alzheimer's disease (AD) is a form of dementia without cure. Dementias are the only condition out of the top 10 causes of mortality worldwide without cure and represent a significant health burden. White matter hyperintensities (WMH) are a biomarker of brain white matter disease, and are associated with a number of neuropsychiatric disorders including dementia. WMH progression has been shown to be reduced by vascular risk factor (VRF) control. Physical activity (PA) has also been shown to slow the progression of WMH, control VRF related disease and has also been shown to reduce cognitive decline. It is therefore postulated that PA can slow WMH progression and could perhaps be a lifestyle related treatment that slows cognitive decline, which would have great public health implications. Conventional manual segmentation (CMS) is the current gold standard in WMH volumetry. Side-by-side (SBS) segmentation has shown promise in WMH visual rating scales and other areas in radiology but has not yet been applied to manual segmentation of WMH lesions. We hypothesise that PA slows WMH progression, and this progression is slower in ApoE ε4 and PET Amyloid beta status negative patients. We also hypothesise that there is a concomitant positive association between baseline cognition measures and WMH progression. Finally, we hypothesise that side by side segmentation will give WMH volumes with more significant clinical associations than the traditional segmentation methods. Method: Data was obtained as part of the AIBL Active trial. Participants are older adults at risk of AD with at least one VRF. Imaging data was obtained on a Siemens 3T Tim Trio scanner. Images were processed according to accepted standards, with FLAIR images used for WMH volumetry, and MPRAGE images used to obtain estimated total intracranial volume (ETIV). WMH were manually segmented under expert neuroradiologist guidance (A/Prof P. Phal), firstly obtaining CMS volumes and then SBS volumes. These volumes were corrected for ETIV and log transformed, then compared against age, gender, VRF, baseline functional fitness, Years of education, cognitive group (SMC/MCI) and baseline neurocognitive assessments using correlations, and subsequently general linear models. Results: In older adults at risk of AD with at least one VRF, exercise over a 24 month period was not associated with a slowing of WMH progression. There was also no association between baseline functional fitness assessment and WMH progression. ApoE ε4 and PET Amyloid beta status were also not associated with a slowing of WMH progression. We did find correlations between WMH volume and age with both methods, with baseline WMH significantly predicting progression. Systolic blood pressure was also associated with WMH progression in correlations in the CMS general linear model. Anxiety was inversely associated with WMH progression while other cognitive measures were not. Side-by-side manual segmentation did not result in significant clinical differences compared to conventional manual segmentation. Conclusion: Based on our results we were unable to show effectiveness of physical activity in older adults at risk of AD in slowing WMH progression. We also cannot conclude that SBS WMH segmentation is more effective than accepted methods.
The associations between physical activity and magnetic resonance imaging in people at risk of Alzheimer's disease
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.
Longitudinal volumetric analysis of white matter hyperintensities on magnetic resonance imaging in aging and Alzheimer’s dementia
The experience of neurocognitive aging can be highly variable between individuals, with some passing into their twilight years with intact and healthy cognition while others find their mental faculties perceptibly dimmed or even impaired to the point of debilitation, with dementias such as Alzheimer’s dementia (AD) seated at this extremity of the spectrum. The burgeoning proportion of the population that is aged makes the identification of biological factors that influence cognitive trajectory with advancing age a high priority. White matter changes, evident as T2 signal hyperintensities on magnetic resonance imaging (MRI) and reflective of small vessel damage and disease, occur with increasing frequency with age and are common in the elderly, including those with dementia. Shown to be associated with cognitive impairment and AD, their relationship to vascular risk factors (VRF), association to other structural brain changes and influence on cognition remains to be clarified. A combination of manual and automated segmentation methods were applied to brain MRI from elderly patients being followed longitudinally in the Australian Imaging, Biomarkers and Lifestyles (AIBL) flagship study, yielding quantitative values for WMH, cerebral cortex and cortical structures selectively susceptible in AD. Age is a well-established risk factor for WMH, while the vascular changes underpinning white matter lesions has lead to a number of VRFs evaluated and suggested as risk factors. In this study, of the participant demographics only age was significantly associated with WMH measured both at baseline and longitudinally, while hypertension and smoking were the only VRFs found to have a significant effect in models of WMH volume. Cognitive decline and impairment is strongly related to hippocampal volume, particularly in AD patients. Amyloid is also a hallmark of AD pathology and is believed to mediate disease by its direct neurotoxic effects. In the presence of the neuropathological changes of AD the contribution of white matter lesions on cognition is not clear. This study did not find a direct relationship between WMH and cognitive decline or impairment, which were instead associated with amyloid burden and ApoE allele status. However, there was a higher burden of WMH in subjects with a significant amyloid burden and in particular in AD patients. WMH burden and rate of increase was also related to the lower cortical, hippocampal and amygdala volumes. WMH are a surrogate of microvascular damage, which can lead to impairment of vascular drainage and consequently reduced clearance of amyloid. Overall this study found that while the strength of the relationship between VRFs and WMH were not as strong in this study population, there was a significant association with cortical change and amyloid pathology, which in turn are factors in cognitive decline and impairment. This provides further evidence to support a role for cerebrovascular pathology in the pathogenesis of AD.
Magnetic resonance imaging in spinal trauma
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)
Acute stroke imaging: predicting response to therapy
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.