The long-term goal of this multidisciplinary project is to understand the relationship between axonal injury, blood brain barrier (BBB) damage and the human serum proteome as a prerequisite to the identification of an accurate mild traumatic brain injury (mild TBI) serum marker. Such a marker is vital to the development of strategies to reduce the disabilities from this injury. The key underlying assumption of the current proposal is that axonal injury is the structural substrate behind post-mild TBI neurologic dysfunction. The recent development of diffusion tensor imaging (DTI), a dynamic form of MRI, now makes possible the detection of axonal injury in the human brain. A cohort of 37 mild TBI subjects and 37 age and gender-matched orthopedic controls will be assembled to validate DTI as a measure of clinically significant axonal injury, determine the relationship between axonal injury and BBB damage, and identify proteins unique to axonal injury after mild TBI using proteomic analysis of serum. Clinical outcomes will be assessed by neurobehavioral functioning, post-concussive symptoms and quality of life. Specific Aims: 1. Compare DTI to conventional MRI and serum S-100B at 12 hours, 1 week and 4 weeks post-injury, and determine the clinical significance of the axonal injury detected. 2. Identify BBB damage after mild TBI and relate to axonal injury and clinical outcome. 3. Identify serum proteins unique to axonal injury after mild TBI using SELDI protein chip analysis of exchange-fractionated serum. At the conclusion of the award period, we will be poised to validate putative mild TBI serum markers in a separate cohort, prior to the development of hardened assays for clinical use. Mild TBI is an important public health problem in the US for which there is currently no objective diagnostic aid and no treatment. Not only does this injury affect 1.2 million Americans annually, it also frequently affects US soldiers involved in combat operations abroad and public safety personnel who survive terrorist attacks. Disturbances in simple reaction time and other cognitive functions can interfere with the important duties these individuals must perform, putting themselves and others at risk. The development of a rapid means of diagnosing axonal injury is not only a necessary prerequisite to the development of future therapies, it is essential to determining the ability of these key individuals to perform their critical duties.