Radiology - Theses

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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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    Longitudinal volumetric analysis of white matter hyperintensities on magnetic resonance imaging in aging and Alzheimer’s dementia
    Tran, Bob Anh ( 2014)
    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.