Wile it seems tragic enough that traumatic brain injury is one of the leading causes of death and disability, mounting evidence suggests that brain trauma may also initiate insidious neurodegenerative processes. Not only has brain trauma been shown to be a risk factor for developing Alzheimer's disease, we have found a primary brain pathology of Alzheimer's disease, plaques composed of beta-amyloid (Abeta), in brain trauma victims shortly following injury. In animal models of brain trauma we have observed remarkably prolonged atrophy, neuron death and axon degeneration following injury. We have also made a novel finding of Abeta accumulation following trauma in two distinct animal models of brain injury. Therefore we believe that we are uniquely poised to evaluate mechanisms underlying the relationship between brain trauma and neurodegeneration. We propose to evaluate brain trauma in both humans and relevant animal models to explore this relationship. Specifically, we propose to 1) examine progressive atrophy and degeneration in the brain trauma patients to establish the initiation of persistent neurodegenerative processes in humans, 2) evaluate mechanisms and temporal evolution of Abeta accumulation in brain injured humans and in relevant animal models, and 3) determine injury-specific pathologies including the accumulation of Abeta, in animal models of brain trauma that represent a range of injury biomechanics found in human brain trauma conditions. Identification of persistent neurodegeneration in brain injured humans may suggest a prolonged window of therapeutic opportunity while the characterization of post-traumatic Abeta accumulation in humans and animals may provide a new therapeutic target. In addition, an enhanced understanding of brain injury biomechanics that lead to neurodegenerative changes may aid in injury prevention strategies and patient management.
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