PROJECT SUMMARY The overall objective of the parent grant is to determine whether the progression of multiple sclerosis is linked to iron-related oligodendroglia dysfunction in the deep gray matter. The candidate research addresses one of the most significant limitations of the parent grant methodology, i.e., the co-dependence of the involved surro- gate iron imaging metrics on myelin and the resulting uncertainty concerning the interpretation of specific study outcomes. The research will explore an advanced multi-parametric analysis approach developed by the candi- date to improve the specificity of outcome measures toward iron. The research will investigate three hypothe- ses: (i) demyelination adds substantial variation to the surrogate iron marker in the parent grant; (ii) separation of iron and myelin contributions will yield greater iron decline measurements in patients; and (iii) a link exists between iron loss and demyelination in the same region. The rationale for the first two hypotheses is that con- founding effects of demyelination on the iron metrics counteract the effects of iron loss, reducing the sensitivity toward iron loss. The rationale for the third hypothesis is that iron-containing oligodendrocytes are also respon- sible for myelination. The research training program has three milestones: (i) adjustment of the analysis method toward the specific imaging metrics used in the parent grant, (ii) application of the method and statisti- cal analysis analogously to the parent grant research, and (iii) publication of results and methods. The candi- date’s career goal is to become a faculty in biomedical sciences with both teaching and research responsibili- ties. The candidate is currently at the predoctoral career stage. The following career stage toward the candi- date’s goal will be a postdoctoral fellow. A 2.5-years career development plan aims to further the candidate’s ability to pursue a career in research and teaching. The plan includes objectives to expand the candidate’s skillset toward the clinical neurological application and interpretation of advanced imaging methods and pre- pare postgraduate fellowship award submissions based on the research results generated. The training plan specifically addresses both unique challenges faced by the candidate and typical barriers and impediments encountered by most trainees. The PI serves as the candidate’s primary mentor and is supported by a team of co-mentors with expertise in complementary topic areas relevant for the candidate’s future career.