BME PhD Prospectus Defense - Chad Tagge

Starts:
2:00 pm on Wednesday, March 6, 2013
Ends:
4:00 pm on Wednesday, March 6, 2013
Location:
Room 408, 670 Albany St. Floor 4 (Medical Campus)
Committee:
Prof. Lee Goldstein (Advisor, Chair)
Prof. Mark Grinstaff (BME)
Prof. Steven Colburn (BME)
Prof. Ann Mckee (Neurology, BUSM) Prof. Robert Cantu (Neurosurgery, BUSM)

Title: "Elucidating the Pathology of Impact-Induced Traumatic Brain Injury"

Abstract:
Traumatic brain injury (TBI) ranks among the leading causes of traumatic death and is a leading cause of serious long-term disability.(Thurman 1999) Each year over 1.5 million Americans sustain traumatic brain injuries (Rutland-Brown 2006). Recent case series point to impact-induced TBI and repetitive concussion as predisposing factors that increase the risk of developing two newly-recognized neurodegenerative disorders, chronic traumatic encephalophay (CTE) (Mckee 2009, McKee 2010, Baugh 2012) . The neuropathology of these related disorders includes tau-associated neurofibrillary tangles with perivascular and deep sulcal distribution, widespread myelinated fiber loss, chronic neuroinflammation, and progressive neurodegeneration.
Our collaborative research team at Boston Universty School of Medicine and Boston VA Healthcare System recently reported the first case series of postmortem human brains from U.S. military veterans with blast exposure and/or concussive TBI and found evidence of CTE that was indistinguishable from a comparison group of young athletes with histories of repetitive TBI and neuropathologically-confirmed CTE (Goldstein 2012) In the same study, we developed a blast neurotrauma model that recapitulated CTE-linked neuropathology in wildtype C57BL/6 mice two weeks after single blast exposure. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Blast-exposed mice developed CTE neuropathology, phosphorylated tauopathy, microvascular disruption, chronic neuroinflammation, myelinated axonopathy, and neurodegeneration in the absence of focal tissue damage (Goldstein 2012).
As with blast neurotrauma, we hypothesize that trauma-induced head acceleration is the primary mechanism of injury leading to CTE in repetitive impact TBI. We hypothesize that the biomechanical forces transmitted to structures in the brain during closed-head impact-induced TBI generate shearing forces that disrupt microvascular integrity, activate neuroinflammatory responses, and initiate pathogenic cascades that lead to persistent TBI and late-emerging CTE. We propose two aims to investigate these hypotheses. In Aim 1, we will develop and systematically characterize a murine closed-head impact TBI model system that induces controlled traumatic head acceleration in all three Cartesian planes of motion. Using high-speed videography, we will analyze the kinematics of head motion during closed-head impact. In Aim 2, we will characterize and correlate temporal and regional patterns of CTE-linked neuropathology, microvascular disruption, neuroinflammation, and neurobehavioral deficits in the murine impact TBI model system developed in Aim 1. The proposed interdisciplinary translational project will investigate the pathobiology and mechanisms underpinning impact TBI and late-emerging neuropathological consequences using a custom closed-head impact delivery system which is capable of delivering single or repeat impacts across a range of scaled velocities corresponding to human injury. Comprehensive neuropathological analysis, immunophenotyping, and neurobehavioral analyses will be used to characterize focal tauopathy, neuroinflammation, and corresponding functional deficits. The results of these studies will advance understanding and mechanismof impact-induced TBI and CTE. Insight gained from this work will facilitate development of urgentlyneeded diagnostics and therapeutics for these devastating neurological disorders.