This thesis presents methods for quantitative MRI analysis of brain injury, repair and degeneration in multiple sclerosis (MS) that provide new insights into disease pathogenesis and evolution. / Demyelinated and inflammatory white-matter lesions are hallmark features of MS. A methodology is described to detect regions of acute white-matter lesions that undergo myelin destruction and repair based on analysis of magnetization transfer ratio (MTR) images. Validation is performed based on histopathology and error is assessed based on same-day scans. To quantify the spatial extent and temporal evolution of myelin destruction and repair, data from a 3-year clinical trial is analyzed using this method. Approximately 20% of acute lesion voxels show some repair over the initial 7 months. In subsequent months, there is little further repair, but some increases in the lesion volume undergoing demyelination. / Although less conspicuous on conventional MRI, there is considerable MS pathology in the brain tissue outside of white-matter lesions. An image-processing methodology was developed to obtain accurate metrics that quantify change over time in whole-brain MTR (associated with changes in myelin-density) and in T2 relaxation time (associated with changes in inflammatory edema). These metrics, in addition to metrics of brain atrophy and axonal integrity, were used to quantify brain injury and degeneration following immunoablation and autologous hematopoietic stem cell transplantation therapy for MS. Pronounced brain volume loss was detected immediately following therapy, associated with decreased myelin density and not resolution of edema. / Post-mortem histopathology has revealed abnormalities in the cortical grey-matter of MS patients that appear to be independent of white-matter lesions. A methodology to quantify neocortical injury and degeneration that yields cross-sectional and longitudinal metrics of cortical thickness and grey-matter/white-matter interface integrity both globally and regionally is presented and validated. MS patients with progressive disability showed greater decreases in cortical metrics compared to MS patients with stable disability. / The quantitative MRI analysis methods presented in this thesis are applicable to MRI data obtained in clinical trials of therapies for MS, have the necessary sensitivity and specificity to assess therapeutic efficacy, and provide new insights into disease pathogenesis and evolution.

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