The heterogeneity of disease and repair mechanisms in the white matter (WM) of the central nervous system demands greater specificity from noninvasive imaging markers. The fundamental hypothesis guiding this proposal is that the specificity of magnetic resonance (MR) imaging can be increased by using a multiparametric approach that exploits the complementary information between MR parameters. Despite advances in quantitative MR techniques, these do not provide suitable endpoints for clinical trials of novel treatments because they do not reliably measure the state of axons and myelin sheaths or discriminate confounding pathologies. This lack of specificity impedes clinical research on potentially treatable WM diseases, including multiple sclerosis (MS), by frustrating attempts to track the neuropathology before, during and after interventions directed at myelin repair, such as glial cell transplantation. Previous imaging studies have generally focused on 1 or 2 techniques to the exclusion of others and have typically done so in the setting of marked disease heterogeneity (e.g., as commonly seen in MS and its animal models), such that the variety of pathological changes exceeds the number of imaging parameters employed to characterize them. This study will reverse this largely unsuccessful trend by combining a more comprehensive imaging approach with a more reductionist disease model: the shaking pup, a canine mutant with a profound paucity of myelin but without the confounding effects of axonal loss, inflammation or edema. Relationships of multiple MR parameters, taken separately and in combination, with electron micrographic measures of axonal and myelin volume and density will be characterized in controls and shaking pups, before and after glial cell transplantation. The study will determine which MR parameters are most reproducible, which combinations of parameters characterize the tissue microenvironment with the greatest specificity, and which are best able to track post-transplant myelin repair in vivo. The study will advance the theoretical understanding of the pathologic substrates of measured MR phenomena in WM disease. It will have immediate relevance to clinical imaging of the human brain and serve as a baseline for future therapeutic trials of novel myelin repair strategies. Lay Summary: This study will examine the poorly understood relationships between microscopic changes in brain tissue in the """"""""white-matter"""""""" diseases (e.g. MS, the most common disabling disease of people aged 18-45) and changes observable on magnetic resonance imaging (MRI) scans. MRI is essential for evaluating novel treatments in living patients because early results may not be readily apparent from a patient's symptoms. The study will also examine the possibility of reversing the damage in brain tissue by transplanting cells with reparative potential. ? ? ?
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