This K24 Midcareer Investigator Award in Patient-Oriented Research will provide five years of support to enhance a program of research and mentoring for the applicant in Neuroimaging in Depression Treatment Studies. The treatment of major depression in late life is an important health problem with a large and growing number of affected individuals. Many investigators have found that patients with late-onset depression, particularly those with cerebrovascular disease risk factors (VRF), are likely to have a slower and less complete response to antidepressant treatment. It has been proposed VRF may predispose to occult cerebrovascular disease in the form of frontal cortex deep white matter hyperintensities (FDWMH) and subcortical gray matter hyperintensities (SCGMH), collectively referred to as T2H. This may contribute to the development of late life depression by interrupting pathways involved in mood regulation. The overall goals of the applicant's research are 1) to continue the transition from cross-sectional studies to treatment outcome studies investigating brain pathophysiological factors that predict treatment outcome and 2) to train junior investigators from a range of clinical backgrounds in the design and conduct of neuroimaging studies in assessing treatment outcome of depression. The proposal describes the applicant's current research program and the career development and mentoring activities planned for the 5-year duration of the K24. Two NIH grants are ongoing: one will determine if severity of T2H and frontal executive dysfunction predict less antidepressant treatment response; the other will determine if late life depression is associated with abnormalities in 5-HT2A receptor regulation by antidepressants. Career development activities for the PI in MRI diffusion tensor imaging are described to further delineate the prognostic value of T2H and their ischemic nature and a third project is described to use these measures in longitudinal studies of white matter ischemic changes. Trainees will engage in these projects, take coursework in neuroimaging and clinical investigation and complete a research proposal over the 2-year training period. K24 support will provide the applicant with protected time to carry out depression treatment outcome studies in late life depression and to increase the mentoring of beginning clinical investigators in neuroimaging studies in depression.