Grant: Team Grant: External Insults to the Nervous System

Survivors of traumatic brain injury (TBI), whether single moderate or severe injury (sTBI) or repetitive mild (mTBI), are at risk of later neurodegenerative complications such as dementia, and/or chronic traumatic encephalopathy; CTE. While the risk of developing late neurodegeneration is uncertain, we are beginning to understand this as a complex process emerging years after the injury. In addition to such delayed neurodegeneration, about a quarter of TBI survivors show delayed neurological decline late after TBI - described as negative neuroplasticity. Furthermore, up to 30% of patients sustaining mild TBI (mTBI) have symptoms that persist for weeks to years, an outcome often referred to as post-concussive syndrome (PCS) occurring in both adults and children. The cellular drivers, and molecular mechanisms of such progressive and persistent neurocognitive deterioration syndromes are, as yet, unclear. However, evidence is accumulating that neuroinflammation may be a key nexus for many late consequences of TBI. We hypothesize that neuroinflammation is a key contributor to outcome in TBI, and seek to: •understand links between acute and chronic neuroinflammation in a range of human TBI severities •explore the contribution of the adaptive immune response in driving persistent immune activation, •examine how persistent neuroinflammation links to imaging and neurological deterioration •use models of mild and severe TBI to understand the biology that underpins these processes, and •develop translational frameworks correlating pathophysiology & pathology in human & experimental TBI The outputs and insights that emerge from these studies will inform research in a large ongoing international collaboration: the International Traumatic Brain Injury Research (InTBIR) initiative (https://intbir.nih.gov/).