Work Accomplished/Background: Parkinson's disease (PD) is a common disease of aging that causes motor symptoms such as slow movement and tremor, as well as non-motor symptoms, such as cognitive difficulties and constipation. Non-motor symptoms can precede the development of motor symptoms by years?this observation has led to the hypothesis that PD has a long ?preclinical? period during which cells in the brain and peripheral nervous system are damaged, but the damage has not exceeded a threshold for motor symptom expression. We do not have validated methods to detect this ?preclinical? disease stage. Due to the long timecourse of PD, such biomarkers will be critical to evaluate the effects of new therapies as they become available. Using sophisticated magnetic resonance imaging (MRI) techniques that are sensitive to changes in the brain microstructure, we have shown differences between the brains of PD subjects and age-matched healthy controls. One such technique, diffusion tensor imaging (DTI), estimates the direction and magnitude of water movement inside and around nerve cells in the brain. Another technique, multicomponent relaxometry, is able to quantify the amount of water trapped inside the layers of the onion-like myelin sheaths that insulate nerve cells. In the past four years of our VA-funded research program, we have shown both diffusion and myelin measures to differ in PD patients in comparison to healthy controls. We hypothesize that these microstructural differences may be detectable in preclinical disease, and may predict ?conversion? from preclinical to clinical PD. For this proposal we plan to study two populations at higher than background risk for PD: Veterans who have been exposed to Agent Orange (AO) during service in Vietnam and have reduced sense of smell (hyposmia), and persons with rapid eye movement sleep behavior disorder (RBD), a condition that causes sleepers to act out their dreams. Objectives: (1) To evaluate the regional distribution and degree of microstructural difference in the brains of Veterans with high, medium, and low risk for the development of PD; (2) compare the rate of change in MRI microstructural measures between these groups; (3) determine to what degree microstructural measures predict the emergence of additional symptoms of PD (such as subtle motor impairment), or conversion to PD. Methods: This 4-year project will prospectively recruit a cohort of 135 Veterans with RBD, AO exposure with hyposmia, and AO exposure with normal olfactory function. Veterans will be recruited through the busy local VA sleep laboratory, while Veterans with AO exposure will be contacted through the National AO Examination Registry. AO-exposed Veterans will be mailed a standardized test of smell acuity as well as a sleep questionnaire, which will be used to select persons to join the study. Study procedures will include a brain MRI as well as detailed analyses of cognition and learning, movement speed, and walking ability (gait analysis). We will use these specific measures to divide our participant group into persons with low, medium, and high risk for the development of PD. Brain MRI microstructural measures and longitudinal changes within these measures will then be compared between groups. Significance for Veterans: PD currently affects 80,000 VA patients, and this number is expected to grow as Veterans who served in the Vietnam era enter peak ages for onset of the disease. This project will be the next step in understanding how PD progresses through the brain in vivo and in developing new MRI biomarkers to be used in clinical trials.