ADVANCED DIFFUSION BIOMARKERS OF BRAIN INJURY IN SUBARACHNOID HEMORRHAGE

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 DESCRIPTION (provided by applicant): Candidate: Dr. Terrance T. Kummer is a basic neuroscientist and neurocritical care physician whose prior research in the field of neuromuscular synaptogenesis contributed significantly to our understanding of trans- synaptic communication in the development of the mammalian neuromuscular junction. Recently, Dr. Kummer completed a study of early brain injury mechanisms following subarachnoid hemorrhage (SAH) in an animal model and in patients. This work led to the identification of a novel hemorrhagic brain injury mechanism- axonal injury-that provided an unexpected connection between stroke and brain trauma. Dr. Kummer now seeks a career development award to facilitate his short-term goals of completing an innovative extension of his prior studies reaching independence as a researcher, and successfully competing for an NIH R01 grant. The protected time, and training in crucial research approaches provided by a career development award are essential to Dr. Kummer's success in this endeavor. They are also an essential step towards accomplishing his long-term goal of improving outcomes after hemorrhagic brain injury by becoming a leading scientific contributor to his field. Dr. Kummer's career development plan includes additional training in animal surgery, behavioral analysis, and quantitative histological analysis. Dr. Kummer will also undertake additional training in the principles and application of diffusion MRI relevant to his proposed project and career goals. He will further acquire advanced statistical knowledge, translational research training, and instruction in the responsible conduct of research. Environment: Washington University (WU) is exceptionally well-equipped and accomplished in advanced neuroimaging research, and has a reputation for collaboration and support of junior investigators. The Biomedical Magnetic Resonance Laboratory at WU is equipped with multiple high-field strength and high- gradient small animal MRI scanners, and is operated by a large community of acclaimed scientists. The neurological disease-oriented basic science community at WU is one of the largest in the world, and home to leading scientists such as David Holtzman, Randall Bateman, and David Brody, and is supported by numerous well-funded core laboratories through the Hope Center for Neurological Disorders. The Neurology and Neurosurgery Intensive Care Unit at WU, where Dr. Kummer is an attending, is particularly well-known for the application of innovative, acute neuroimaging to brain injured patients, especially after brain hemorrhage. Overall, WU is the ideal institution for Dr. Kummer's career development and the success of the proposed project. Research: SAH from the rupture of an intracranial aneurysm is the most devastating variant of vascular brain injury, carrying a 1-month mortality rate of nearly 50%. The primary disabilities reported by survivors are cognitive, social, and emotional deficits with likely diffuse or multifocal pathologial correlates that are unknown and invisible to standard imaging modalities. Although the great majority of SAH research focuses on delayed compilations, the most important determinant of outcome is the severity of the acute injury. We therefore propose to investigate the mechanisms of early brain injury (EBI) after SAH by linking histopathologically- defined EBI subtypes to long-term behavioral outcomes in a mouse model using translational diffusion MRI biomarkers. Our central hypothesis, supported by our preliminary data, is that advanced diffusion MRI parameters will identify functionally-relevant pathology after SAH and predict behavioral outcomes, implicating distinct EBI mechanisms. We will first determine the regional contribution and temporal evolution of EBI pathways after SAH (SA1) using gold-standard quantitative histological analysis at defined time points post- injury. Based on our preliminary studies and prior reports, we will target mechanical injury, microthrombosis, and acute ischemia. We will then identify and validate advanced diffusion biomarkers of distinct EBI pathways (SA2) using two MRI approaches, diffusion kurtosis imaging and generalized q-sampling imaging. Lastly, we will identify the mechanistic correlates of cognitive, social, and emotional outcomes after SAH (SA3) by using these MRI biomarkers to determine which EBI pathways best correlate with important behavioral outcomes in our model system. This study will have a sustained impact on the SAH field by supplying fundamental knowledge about the spatial and temporal evolution of EBI and its relationship to long-term outcomes. It will furthermore validate innovative translational biomarkers that predict behavioral impairments with the greatest relevance to patients, and are linked to potentially intervenable EBI pathways. The proposed studies will position Dr. Kummer to exploit a niche in advanced small animal and human diffusion MRI in line with his clinical expertise and conducive to his career goals.