Study Population The study population for this protocol includes 64 male and female volunteers, with and without TBI between the ages of 18 and 55 recruited from Walter Reed National Military Medical Center (WRNMMC), National Intrepid Center of Excellence (NiCoE), NIH Clinical Center, CNRM Phenotyping Core, CNRM Recruitment Core, and the McGuire Veterans Administration Medical Center in Richmond, VA. The study design will consist of three study groups;the experimental group and two control groups. Design This is a randomized, blinded, placebo-controlled, pilot study in which we will study CVR in chronic TBI patients using MRI BOLD with hypercapnia challenge before and after administration of sildenafil. We will collect and assay blood samples from these patients to determine whether the PDE5 inhibitor sildenafil is effective in improving cerebrovascular reactivity, and will assess the safety and tolerability of sildenafil in a TBI population. In addition, we will assay circulating endothelial progenitor cells in TBI, in order to examine the relationship between this biomarker of vascular health and persistent chronic symptoms, as well as to assess long-term effect of sildenafil on vasculogenesis. The study design will consist of three study groups;the experimental group and two control groups. In the Experimental Group (Group 1) we will enroll twenty four (24) male and female adult participants with persistent TBI symptoms lasting more than six months after the injury. Participants in Group 1 (the experimental group) will be randomized into a blinded, placebo-controlled, double cross-over study. In Group 2 we will enroll twenty male and female adult participants to serve as age and gender-matched healthy controls. In Group 3 we will enroll twenty male and female adult participants who have experienced a TBI, have recovered, are asymptomatic six months or more post injury, and are matched for age and gender to groups 1 and 2. Participants in all three groups will have an MRI scan at baseline, which will include a hypercapnia challenge to measure the increase in BOLD signal during hypercapnia. Participants enrolled in Group 1 (experimental) will have three study visits over period of approximately eighteen (18) weeks. The Baseline Visit (Visit 1) procedures including consenting, MRI with and without hypercapnia, blood sampling, medical interview and physical and neurological exam and administration of sildenafil during the hypercapnia challenge, will take about 5 hours. Procedures at the subsequent two study visits for Group 1 which are similar to Visit 1 will take approximately 4 hours. Participants enrolled in Groups 2 and 3 participate only in the Baseline Visit. Outcome Measures The primary outcome measure will be global CVR to hypercapnia, 1 hour after the administration of sildenafil 50 mg orally. The secondary outcome measure will be an assessment of safety and tolerability of sildenafil, 25 mg orally twice daily for approximately 8 weeks, in a symptomatic, chronic TBI population. Tertiary outcome measures will explore the effect of sildenafil on post-concussive symptoms, neuropsychometric performance, number of circulating endothelial progenitor cells (EPCs), and whether the acute effect of sildenafil on CVR persists after 8 weeks of therapy. Blood will also be collected and sent to a biorepository for future analysis, including DNA. In addition, neuropsychological testing will be performed to assess functional and cognitive impairment.

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