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The quest for a myelin specific magnetic resonance marker of multiple sclerosis pathology : myelin water imaging Laule, Cornelia

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that is characterized by edema, inflammation, demyelination and axonal loss. However, the mechanisms underlying the clinical evolution and ultimate progression of MS and their relationship to these pathological features are still poorly understood. Magnetic resonance imaging (MRI) has been an invaluable tool for the visualization of MS abnormalities in brain. In this thesis, patients with multiple sclerosis were compared to healthy controls using two non-conventional MR techniques believed to be related to myelin content. First, a model for the evolution of magnetization transfer (MT) abnormalities in patients with MS was proposed based on data collected from a relatively small sample size. The MT ratio (MTR) of normal appearing white matter (NAWM) in brain is normal at clinical onset and then slowly decreases over time, correlating strongly with disease duration. This suggests that the gradual progression in disease seen in patients with MS may be due not only to new lesion formation, but also due to global changes in NAWM. In the immediate months before lesion appearance on conventional MRI there is an abrupt decrease in MTR. Lesion recovery is variable, with some lesions showing good recovery of MTR and others showing no recovery or worsening. The early behaviour of lesions may be predictive of future recovery. Chronic stable lesions have a constant and low MTR. In a larger cross-sectional study, MS normal appearing white matter in brain was found to have a higher water content and lower myelin water fraction than controls. Lesions have increased water content, and a heterogeneous reduction in myelin water fraction. The cause of the water content increase in lesions could be due to either edema or inflammation. As our understanding of T₂ improves, we may be able to distinguish between these two pathologies from the shape of the T₂ distribution. A simple model suggests that the observed 2.2% increase in water content and 16% decrease in myelin water fraction in MS NAWM are the result of diffuse myelin loss. Next, MT and myelin water imaging were compared in lesions and white matter for both an MS patient group, as well as a control group. The myelin water fraction of some white matter structures were found to correlate with MTR, while in others they did not. This regional dependence of the correlation between MTR and myelin water fraction is unexpected and has not been observed elsewhere. Myelin water imaging and MT imaging do however indeed probe different properties of brain tissue: myelin water imaging specifically measures the amount of water trapped between the myelin bilayer based on a given T₂ relaxation time range (typically 0-50ms), while MT probes the interaction between all of the semisolid protons with all of the aqueous protons. The previously observed dissociation between MTR and myelin water fraction is reasonable as while myelin water imaging is a specific marker for myelin content, MT is influenced by many factors which are unrelated to myelin content including exchange rates between the semi-solid and aqueous proton pools, pH and distribution of galactocerebrosides. A change in the size of either the semi-solid or aqueous pool would also effect the measured MT ratio, for example: accumulation of cells such as astrocytes and macrophages which would serve to increase the size of the semi-solid pool, thereby increasing MTR without any increase in myelin content. Likewise, an increase in the aqueous proton pool due to oedema would decrease MTR without any reduction in myelin content. Finally, pathological correlations with myelin water imaging in MS were investigated to validate this technique as an in-vivo measure of myelin content. Twenty-five brain samples were examined and a very strong correlation was found between myelin water imaging and myelin staining as measured by luxol fast blue optical density. The close relationship between myelin and axons is reflected in the strong correlation between the luxol fast blue and Bielschowsky stains which also explains the good correlation between myelin water fraction and the Bielschowsky optical density. This study supports the use of myelin water imaging to study myelin pathology and the role of demyelination and remyelination in MS.

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