Using MRI and Atlas-based Volumetrics to Investigate Grey Matter Atrophy in Animal Models of Multiple Sclerosis
Date
2023-06
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Abstract
Loss of brain volume known as atrophy, occurs at an accelerated rate in Multiple Sclerosis (MS) compared to healthy adults and is closely associated with clinical disability and disease progression. To better understand and treat atrophy, mouse models that feature atrophy along with other aspects of MS pathology are needed. The objective of this thesis was to utilize magnetic resonance imaging (MRI) and atlas-based volumetrics to investigate animal models of MS for atrophy and determine if they are suitable for studying atrophy in MS. First, we investigated the experimental autoimmune encephalomyelitis (EAE) model commonly used to study neuroinflammation in MS. EAE mice had lower brain volumes at chronic long-term disease duration with atrophy identified in both white (WM) and grey matter (GM) regions including the cerebral cortex, cerebellum, hippocampus, corpus callosum, basal forebrain, midbrain, optic tract, and colliculus. Like MS, atrophy was associated with neurodegeneration and long-term physical disability. Next, to validate these results, we measured atrophy in EAE along with cerebral blood flow (CBF), another aspect of MS pathology possibly associated with atrophy. Using continuous arterial spin labelling MRI, we observed a reduction in cortical CBF at peak clinical disease and long-term disease in EAE. Reduced CBF at peak clinical disease appears to be related to systemic inflammation and blood brain barrier breakdown as reduced CBF was also seen in the systemic inflammation controls. Reduced CBF at long-term was instead correlated with atrophy. Finally, we investigated the cuprizone model, commonly used to study demyelination. Following chronic demyelination, atrophy was seen in WM and subcortical GM regions including the corpus callosum, internal capsule, stria terminalis, striatum, thalamus, and globus pallidus. Atrophy coincided with demyelination, and WM axonal injury, but not neuronal or axonal loss. This lack of neuroaxonal loss suggests demyelination alone is not sufficient to cause neurodegeneration and the inflammatory infiltration seen in EAE and MS may be necessary. Overall, this thesis provides a foundation for future studies into atrophy in animal models of MS and demonstrates the utility of our methods for assessing neuroprotective therapies or investigating the pathophysiology behind atrophy in MS.
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Keywords
Multiple Sclerosis (MS), Magnetic Resonance Imaging (MRI), Experimental Autoimmune Encephalomyelitis (EAE), Cuprizone, Atrophy, Atlas-based Volumetrics, Cerebral Blood Flow
Citation
Hamilton, A. M. (2023). Using MRI and atlas-based volumetrics to investigate grey matter atrophy in animal models of Multiple Sclerosis (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.