ABSTRACT This K24 Midcareer Investigator Award in Patient-Oriented Research is a revision. The objectives of this proposal focus on developing mentees at Vanderbilt University Medical Center, and expanding the research expertise of the candidate. Specifically, this award will ensure that the candidate protected time to commit to ongoing and expanded mentoring efforts of mentees engaging in clinical research that focuses patient-oriented research, and acquire new imaging expertise that applies quantitative magnetic resonance imaging (MRI) methods to patients who suffer from age-related neurodegenerative dementing disorders. This proposal will allow the investigator to expand his research efforts into a new patient population, develop experience with working in a programmatic research consortium, and advance clinical research efforts to addressing neuroimaging biomarkers. The Career Development Plan focuses on training in high-field and ultra-high- field MRI methods, where hands on training with expert collaborators and consultants will be supplemented with coursework pertinent to the research objectives. Development in 3 tesla and 7 tesla methods will be applied to a rare disease patient population with pure autonomic failure, who may convert to dementia with Lewy Bodies, an Alzheimer Disease-related dementia. The Mentoring Plan is designed to focus on helping mentees succeed in developing their academic research career. Specifically, the mentoring plan will ensure that early stage neurologists who are applying for K-awards (i.e. K23, K01, and K76) will have appropriate mentorship as they develop research methodologies, and build research expertise. Additional support from consultants will allow the applicant to develop of a mentoring approach that is tailored to the physician- scientist. There are extensive institutional resources at VUMC which will ensure completion of this goal. Finally, the career development focus which develops new imaging techniques will be facilitated by the Research Plan. This project will assess neurodegenerative changes that occur in patient with alpha-synuclein disorders. These include the prodromal state of pure autonomic failure, as well as Parkinson’s disease, and Dementia with Lewy bodies. The aim is to understand how changes to iron, neuromelanin, and macromolecular content can be used as objective imaging biomarkers of age-related neurodegenerative diseases, advancing imaging candidates that can quantitate severity and extent of these biologic changes. By acquiring data on patients who are part of the Autonomic Rare Disease Consortium, the candidate can test the hypothesis that early reductions in brainstem neuromelanin, elevated iron deposition, and elevated macromolecular content will identify patients likely to convert from prodromal to central alpha-synuclein disorders. Integrating MRI data with clinical observations from the detailed clinical investigations will allow improvements to prediction models of dis...