Using MRI and Atlas-based Volumetrics to Investigate Grey Matter Atrophy in Animal Models of Multiple Sclerosis

Hamilton, Andrew Max

Using MRI and Atlas-based Volumetrics to Investigate Grey Matter Atrophy in Animal Models of Multiple Sclerosis

dc.contributor.advisor	Dunn, Jeff F.
dc.contributor.author	Hamilton, Andrew Max
dc.contributor.committeemember	Yong, V. Wee
dc.contributor.committeemember	Forkert, Nils D.
dc.date	2023-11
dc.date.accessioned	2023-06-23T17:39:39Z
dc.date.available	2023-06-23T17:39:39Z
dc.date.issued	2023-06
dc.description.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.
dc.identifier.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.
dc.identifier.uri	https://hdl.handle.net/1880/116648
dc.identifier.uri	https://dx.doi.org/10.11575/PRISM/41491
dc.language.iso	en
dc.publisher.faculty	Graduate Studies
dc.publisher.institution	University of Calgary
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subject	Multiple Sclerosis (MS)
dc.subject	Magnetic Resonance Imaging (MRI)
dc.subject	Experimental Autoimmune Encephalomyelitis (EAE)
dc.subject	Cuprizone
dc.subject	Atrophy
dc.subject	Atlas-based Volumetrics
dc.subject	Cerebral Blood Flow
dc.subject.classification	Neuroscience
dc.subject.classification	Radiology
dc.subject.classification	Biophysics--Medical
dc.title	Using MRI and Atlas-based Volumetrics to Investigate Grey Matter Atrophy in Animal Models of Multiple Sclerosis
dc.type	doctoral thesis
thesis.degree.discipline	Medicine – Neuroscience
thesis.degree.grantor	University of Calgary
thesis.degree.name	Doctor of Philosophy (PhD)
ucalgary.thesis.accesssetbystudent	I do not require a thesis withhold – my thesis will have open access and can be viewed and downloaded publicly as soon as possible.