The candidate is an MD-trained stroke neurologist from Washington University and an undergraduate- trained biomedical engineer from Duke University with long-term aspirations to develop and grow an independent research program investigating novel imaging modalities to delineate viable brain tissue in acute ischemic stroke patients. With this 5 year career development award, she plans to gather the tools and skill- set necessary to become an expert in the pathophysiology of acute ischemic stroke patients to find an imaging signature that can define the ischemic penumbra. Her research and career plans outline how she will accomplish her short term goals to complete the proposed aims, learning specific neuro-imaging skill-sets. In addition, she defines steps that she will take in the transition to independence. The career development plan will be co-mentored by Jin-Moo Lee, MD, PhD, a clinician-scientist, stroke expert, and Director of Cerebrovascular Division who has extensive experience in stroke research and Weili Lin, PhD, a seasoned MR physicist whose lab focuses on innovative clinical applications of MRI - a unique merger allowing the candidate to become a successful independent investigator in the field of acute stroke imaging. The candidate has assembled several additional consultants and advisors at Washington University with expertise in cerebral blood flow and metabolism, neuroradiology, and biostatistics. In addition, Dr. David Holtzman, the Chairman of Neurology, expresses his full support for her project and career goals. All together, she has a team of mentors and collaborators who are deeply committed and invested in her transition towards independence. The candidate has chosen to lead an ideal project given her background in biomedical engineering and her passion for patient-oriented stroke research at a premier academic institution. Washington University School of Medicine successfully trains numerous K awardees every year. Over the past decade, the Department of Neurology fostered over 20 successful K awardees. World-renowned for its patient-oriented biological brain imaging research, Washington University will provide an outstanding environment for her research field of interest with tremendous resources supporting the imaging infrastructure. Washington University was awarded the NIH-funded SPOTRIAS (Specialized Program of Translational Research in Acute Stroke) grant which will provide resources necessary to support several aspects of the candidate's proposed studies. The candidate is at a crucial period in her early career, recently transitioning from stroke fellow to junior faculty. Her success over the next 5 years will depend on protected time to gain the benefits of one-on-one mentoring, formal coursework, informal seminars, travel to conferences, and importantly, time to perform the studies within this grant proposal. Currently, a small percentage of stroke patients receive acute intervention due to delayed hospital presentation after the short tPA window has closed (currently tPA is administered up to 4.5 hours after stroke onset). Thus, stroke continues to be the leading cause of disability in the United States and worldwide. While population-based studies indicate that the therapeutic time-window for IV tPA is fixed, it is likely that the actual therapeutic time-window varies among individuals, depending on a variety of physiological variables, such as collateral flow or pre-existing co-morbidities. An imaging modality capable of delineating the theoretical ischemic penumbra would be invaluable for individualizing therapeutic windows. Two thresholds of injury are directly relevant for this purpose: one which defines irreversibly injured tissue, and another which delineates reversibly injured tissue (the latter is the target for therapy). While much attention has focused on the utility of MR diffusion (DWI) and perfusion (PWI) weighted imaging for this purpose, one limitation has been that thresholds for tissue injury are dependent on the time interval between stroke onset and imaging. Several lines of evidence derived from positron emission tomography (PET) studies suggest that measures of cerebral metabolic rate of oxygen utilization (CMRO2) may identify viable tissue at risk for infarction in a time-invariant manner. Although PET is currently available, several operational hurdles have limited its utility in acute stroke, such as the need for an onsite cyclotron. We have recently developed an MR imaging approach capable of measuring oxygen metabolic index (MR-OMI), a parameter closely related to CMRO2. In this application, we propose to utilize MR-OMI to determine the two threshold values that identify reversibly and irreversibly injured brain tissue in a population of acute ischemic stroke patients. We will determine the predictive values of these thresholds, compared to other well-studied MR-derived indices. Additionally, we will examine variables that may modify these thresholds of injury, including time-to-imaging, tissue type (gray vs. white matter), and baseline clinical characteristics.
Stroke is the leading cause of disability in the United States;however, only 3% of stroke patients receive early medical intervention (intravenous tPA) due to delayed arrival to the hospital beyond the currently approved therapeutic window. An imaging modality, such as proposed here, capable of distinguishing live brain tissue from dying tissue in the hyper-acute stroke period would guide future stroke therapies, permitting the individualization of therapeutic time-windows. Such a technique would permit treatment in select patients without need for timing, and promises to improve efficacy and reduce potential adverse side effects.
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