PROJECT SUMMARY/ABSTRACT The prevalence of primary hypertension (HTN) in children has increased significantly, a public health phenomenon that parallels the current childhood obesity epidemic. This increase in childhood primary HTN foreshadows an impending epidemic of premature cerebrovascular and cardiovascular disease. Already there is evidence that HTN in adolescence and young adulthood is associated with cognitive decline and stroke in midlife and beyond. However, there are significant evidence gaps regarding the current approach to treatment of pediatric HTN, largely because HTN-associated events, such as stroke, occur in later decades, making outcomes based treatment guidelines elusive. One strategy is to use early biomarkers of hypertensive target organ damage (TOD) to predict clinical outcomes. However, reliable biomarkers of hypertensive TOD to the brain in youth are lacking. Our goal is to identify and evaluate early biomarkers of TOD to the brain to help focus studies on HTN treatment, and eventually modify the trajectory of HTN-induced morbidity. Our previous results showing decreased neurocognitive test performance in HTN youth suggest that treating HTN beginning in adolescence represents an opportunity to reduce subsequent cognitive decline and dementia later in life, heretofore an elusive goal. However, the degree of structural brain injury in HTN youth and its reversibility are not known. We now propose to study white matter microstructural integrity using diffusion magnetic resonance imaging (dMRI) as an anatomic correlate of hypertensive TOD to the brain in adolescents. The presence of altered white matter integrity could serve as a novel biomarker of hypertensive TOD to the brain in youth and could provide a pathomechanistic link between adolescent HTN and subsequent cognitive outcomes. In combination with neurocognitive testing, dMRI findings would serve as study outcomes to allow practical longitudinal research on the effect of early HTN treatment on the brain in adolescence and beyond. We propose to compare dMRI metrics of untreated, newly diagnosed hypertensive adolescents to that of matched normotensive controls. As secondary measures, we will also assess the impact of HTN on vascular reactivity and functional connectivity via resting state functional MRI. We will evaluate the association between altered dMRI metrics and HTN severity, and we will evaluate the correlation between neuroimaging parameters and neurocognitive test performance. In an observational exploratory aim, we will determine if there are longitudinal changes in neuroimaging parameters after 18 months of usual care antihypertensive therapy in newly diagnosed HTN subjects. This proposal represents a logical and innovative extension of our work and will lay critical groundwork for the development of evidence-based treatment guidelines to improve downstream cognitive outcomes.