Award Number: W81XWH-08-2-0018 TITLE: "Brain Vulnerability to Repeated Blast Overpressure and Polytrauma” PRINCIPAL INVESTIGATOR: Joseph B. Long, PhD CONTRACTING ORGANIZATION: The Geneva Foundation

Age-dependent variations in the pathophysiology of blast-induced traumatic brain injury (bTBI) may influence efficacy of therapies for mitigation of damage. Since War fighters who sustain bTBI are typically exposed to a combination of blast overpressure (BOP) and a biomechanical perturbation related to acceleration and/or impact, BOP and weight drop injury were combined into a dual insult model to compare bTBI in different age rats. Anesthetized 10-wks and 24-wks old rats were exposed to BOP in a shock tube (19 psi total) followed immediately by weight-drop (500 g, 150 cm). Brain and plasma were collected through 14 d post-injury. Axonal degeneration and inflammation were revealed in both groups by silver stained or anti-Iba1 immunostained sections, respectively. GFAP increased at 6 h and 14 d in older rats but decreased at 6 h in younger rats. Contactin-associated protein-2 (Caspr2) increased in older rats at 14 d post-injury, but was unchanged in younger rats. In both age groups, MCP-1 increased in the CSF and plasma at 6 h post-injury. Cdc25A and p21 increased in younger rats at 6 h post-injury, whereas only p21 increased in older injured rats. These biomarkers revealed time-dependent brain injury and neuroinflammatory processes which varied by age. They further indicate that the molecular responses directing DNA repair and regulation of cell proliferation after bTBI may also differ in an age-dependent manner.