Brain atrophy in multiple sclerosis (MS) patients is a marker of severely damaging and irreversible pathological processes. It is detectable with magnetic resonance imaging (MRI) in the earliest stage of disease and it is correlated with disability. Yet few long-term studies have specifically investigated factors that lead to brain tissue loss in vivo. Previous work has shown that focal tissue damage, represented as visible lesions on MRI, is only weakly associated with atrophy progression. Furthermore, various techniques have demonstrated that normal-appearing tissue on MRI is frequently abnormal in MS brains, but the relationship between this diffuse pathology and atrophy has not been determined. The overall goal for this project is to gain insight on the pathologic mechanisms of irreversible tissue destruction in MS brains. The project is designed to utilize and extend an existing longitudinal dataset from a group of MS patients who have been followed with MRI and clinical exams for the past 4-13 years. Advanced methods for quantitative MRI analysis will be used in three specific aims to test the main hypothesis: that tissue loss in MS stems from focal damage in lesions as well as from diffuse pathologic processes in the normal-appearing brain tissue. The first aim is to measure changes in individual lesions and determine correlations with atrophy in order to clarify the role of focal tissue damage. The second aim will address the role of diffuse tissue damage. Serial diffusion tensor imaging and magnetization transfer imaging will be used to measure tissue damage in normal-appearing brain tissue, and correlations with atrophy and clinical disease progression will be determined. A second component of this aim is to correlate MRI measures of diffuse tissue damage to histopathology in post-mortem brain tissue. The third and final specific aim is to study MRI measurements of both focal and diffuse tissue damage in individual brain structures in order to determine factors that lead to variability in atrophy between structures. Completion of these aims will lead to a better understanding of the processes leading to irreversible tissue destruction due to MS. In addition, the new MRI analysis techniques developed for this project are likely to be beneficial for evaluating new drug therapies, monitoring patients, and predicting long-term disease severity.