DEFINING THE ISCHEMIC PENUMBRA WITH MAGNETIC RESONANCE OXYGEN METABOLISM

描述（由申请人提供）：候选人是来自华盛顿大学的MD培训卒中神经学家和来自杜克大学的本科培训生物医学工程师，长期致力于开发和发展一项独立研究项目，研究新型成像模式，以描绘急性缺血性卒中患者的存活脑组织。有了这个5年的职业发展奖，她计划收集必要的工具和技能，成为急性缺血性中风患者病理生理学的专家，以找到可以定义缺血半暗带的成像特征。她的研究和职业计划概述了她将如何实现她的短期目标，以完成拟议的目标，学习特定的神经成像技能。此外，她还确定了在向独立过渡过程中将采取的步骤。职业发展计划将由临床科学家、中风专家和脑血管科主任Jin-Moo Lee，MD，PhD和经验丰富的MR物理学家Weili Lin，PhD共同指导，他的实验室专注于MRI的创新临床应用-这是一个独特的合并，使候选人成为急性中风成像领域成功的独立研究者。候选人在华盛顿大学召集了几位在脑血流和代谢、神经放射学和生物统计学方面具有专业知识的顾问。此外，神经病学主席大卫霍尔茨曼博士表示完全支持她的项目和职业目标。总而言之，她有一个导师和合作者团队，他们深深致力于并投入到她向独立的过渡中。这位候选人选择领导一个理想的项目，因为她有生物医学工程的背景，而且她对一流学术机构以患者为导向的中风研究充满热情。 华盛顿大学医学院每年都成功地培养了许多K奖获得者。在过去的十年中，神经病学系培养了20多名成功的K获奖者。华盛顿大学以其以患者为导向的生物脑成像研究而闻名，将为她感兴趣的研究领域提供一个出色的环境，并提供大量资源支持成像基础设施。 华盛顿大学获得了NIH资助的SPOTRIAS（急性卒中转化研究专业项目）资助，该资助将为候选人拟议研究的几个方面提供必要的资源。这位候选人正处于职业生涯早期的关键时期，最近从中风研究员过渡到初级教师。她在未来5年的成功将取决于受保护的时间，以获得一对一的指导，正式课程，非正式研讨会，前往会议的好处，重要的是，时间来执行本赠款提案内的研究。目前，由于短tPA窗口关闭后延迟住院，一小部分卒中患者接受急性干预（目前tPA在卒中发作后4.5小时内给药）。因此，中风仍然是美国和世界范围内残疾的主要原因。虽然基于人群的研究表明IV tPA的治疗时间窗是固定的，但实际治疗时间窗可能因个体而异，这取决于各种生理变量，如侧支血流或既存合并症。一种能够描绘理论缺血半暗带的成像方式对于个体化治疗窗口将是非常宝贵的。损伤的两个阈值与此直接相关：一个定义不可逆损伤的组织，另一个描述可逆损伤的组织（后者是治疗的目标）。虽然很多注意力都集中在MR弥散（DWI）和灌注（PWI）加权成像用于此目的的效用，一个局限性是，组织损伤的阈值取决于中风发作和成像之间的时间间隔。来自正电子发射断层扫描（PET）研究的几条证据表明，脑氧代谢率（CMRO 2）的测量可以以时不变的方式识别有梗死风险的存活组织。虽然PET目前可用，但几个操作障碍限制了其在急性卒中中的应用，例如需要现场回旋加速器。我们最近开发了一种能够测量氧代谢指数（MR-OMI）的MR成像方法，该参数与CMRO 2密切相关。在本申请中，我们建议利用MR-OMI来确定两个阈值，以识别急性缺血性卒中患者人群中可逆性和不可逆性损伤的脑组织。我们将确定这些阈值的预测值，与其他研究充分的MR衍生指数相比。此外，我们将检查可能改变这些损伤阈值的变量，包括成像时间、组织类型（灰色与白色物质）和基线临床特征。

DESCRIPTION (provided by applicant): 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.