Shannon Kolind

Conventional magnetic resonance imaging (MRI) is a useful qualitative clinical tool for diagnosing and monitoring neurodegenerative diseases. However, it is not capable of measuring diffuse and microstructural changes in normal-appearing white matter (NAWM). Advanced MRI can quantitatively describe the microenvironment in NAWM. Myelin water imaging (MWI) is a technique that uses multi-component T2 relaxation to quantify the amount of myelin present within a region of interest. The resulting measurement is termed the myelin water fraction (MWF) and has been shown to correlate with histological myelin measurements. The standard deviation of the MWF is thought to represent the heterogeneity of myelin within a region of interest. By dividing the standard deviation of the MWF by the mean MWF, the coefficient of variation is calculated. Known as the myelin heterogeneity index (MHI), this is thought to be the most sensitive measure derived from MWI since it captures both myelin damage and variability. Diffusion basis spectrum imaging (DBSI) is another quantitative MRI technique that detects the diffusion of water. DBSI separates the isotropic and anisotropic diffusion components within each voxel and uses the degree and direction of water molecule movements to describe the microstructure. Importantly to this study, the measure radial diffusivity is thought to negatively correlate with myelin content. I apply MWI and DBSI to Susac syndrome (SuS), a rare demyelinating disease often mistaken for the more common demyelinating disease multiple sclerosis (MS), and find that both advanced MRI techniques describe diffuse myelin damage seen in SuS, but not in MS or healthy controls. This suggests a newly identified pathology of SuS. I next focused on characterizing the 3 aforementioned MWI metrics (mean, standard deviation or MHI) in MS. The measures differentiated MS from healthy controls and correlated with disability due to MS. Different stages of the disease were better characterized by different metrics, depending on the amount, uniformity, and extent of myelin damage. Lastly, MWI discerned longitudinal changes in MS over 2 years. This thesis shows that advanced MRI techniques are able to measure microstructural damage not detectable by clinical MRI and furthers the understanding of pathologies of two demyelinating diseases.

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While conventional magnetic resonance imaging (MRI) is qualitatively useful for the diagnosis and clinical management of multiple sclerosis (MS), it has limitations in terms of detecting specific myelin loss and diffuse damage in the normal-appearing white matter. A non-conventional MRI technique, called myelin water imaging (MWI) can be achieved using multicomponent T₂ relaxation to provide a quantitative in vivo measurement of myelin, termed myelin water fraction (MWF). MWF has been proposed as a candidate MR marker of myelin content in the central nervous system. In this study, I present the application of MWI to gain a deeper insight into the diffuse white matter damage in MS. First, we found lower myelin content and higher myelin heterogeneity in brain and cervical spinal cord, as well as correlations between myelin heterogeneity and clinical disability in cervical spinal cord in progressive MS compared to healthy controls. We also found myelin abnormalities in the regional and global white matter in progressive solitary sclerosis, which has recently been proposed as a potential variant of MS. Finally, we demonstrated good global white matter MWF reproducibility (coefficient of variation = 2.77 %; Pearson’s r = 0.91, p
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