DEFINING THE ISCHEMIC PENUMBRA WITH MAGNETIC RESONANCE OXYGEN METABOLISM

应聘者描述(申请人提供)：应聘者是华盛顿大学医学博士毕业的中风神经学家，杜克大学本科毕业的生物医学工程师，长期致力于开发和发展一项独立的研究计划，研究新的成像方式，以描绘急性缺血性中风患者的存活脑组织。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的病理生理学专家，找到可以定义缺血性半影区的成像特征。她的研究和职业规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，她还明确了她在向独立过渡过程中将采取的步骤。职业发展计划将由在中风研究方面拥有丰富经验的临床科学家、中风专家和脑血管科主任李振武医学博士和林伟立博士共同指导，前者是一位经验丰富的磁共振物理学家，其实验室专注于MRI的创新临床应用-这是一次独特的合并，使候选人能够成为急性中风成像领域的一名成功的独立研究员。这位候选人已经在华盛顿大学召集了几名额外的顾问和顾问，他们拥有脑血流和新陈代谢、神经放射学和生物统计学方面的专业知识。此外，神经病学主席大卫·霍尔茨曼博士表示，他完全支持她的项目和职业目标。总而言之，她有一个由导师和合作者组成的团队，他们对她向独立的过渡做出了坚定的承诺和投资。考虑到她在生物医学工程方面的背景，以及她在一流学术机构对以患者为导向的中风研究的热情，这位候选人选择了领导一个理想的项目。华盛顿大学医学院每年成功地培训了大量的K奖获得者。在过去的十年里，神经内科培养了20多名成功的K奖获得者。华盛顿大学以其面向患者的生物脑成像研究而闻名世界，它将为其感兴趣的研究领域提供一个出色的环境，并为成像基础设施提供巨大的资源支持。华盛顿大学被授予NIH资助的SPOTRIAS(急性中风转化性研究专门计划)赠款，该赠款将提供必要的资源，以支持候选人提议的研究的几个方面。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员。她在未来5年的成功将取决于有保障的时间，以获得一对一指导、正式课程作业、非正式研讨会、参加会议的好处，以及更重要的是，有时间在这项拨款计划内进行研究。目前，一小部分中风患者在短暂的tPA窗口关闭后，由于延迟入院而接受急性干预(目前tPA在中风发病后4.5小时内给予)。因此，中风仍然是美国和世界范围内导致残疾的主要原因。虽然基于人群的研究表明，静脉注射tPA的治疗时间窗是固定的，但实际的治疗时间窗很可能因个体而异，这取决于各种生理变量，如侧支循环或先前存在的并存疾病。一种能够描绘理论上的缺血半暗带的成像方式对于个体化治疗窗将是非常宝贵的。有两个损伤阈值与此目的直接相关：一个定义不可逆转的损伤组织，另一个定义可逆损伤的组织(后者是治疗的目标)。虽然磁共振弥散(DWI)和灌注(PWI)加权成像在这方面的应用已经引起了很大的关注，但有一个局限性是，组织损伤的阈值取决于卒中发病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，测量大脑氧利用代谢率(CMRO2)可以以不变的方式识别存在梗死风险的活组织。虽然目前可以使用正电子发射计算机断层扫描，但有几个操作障碍限制了它在急性中风中的应用，例如需要现场回旋加速器。我们最近开发了一种磁共振成像方法，能够测量氧代谢指数(MR-OMI)，这是一个与CMRO2密切相关的参数。在这一应用中，我们建议利用MR-OMI来确定在急性缺血性中风患者群体中识别可逆和不可逆损伤的脑组织的两个阈值。我们将确定这些阈值的预测值，并与其他经过充分研究的MR衍生指数进行比较。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(灰质与白质)和基线临床特征。 公共卫生相关性：在美国，中风是导致残疾的主要原因；然而，由于延迟到达医院超过当前批准的治疗窗口，只有3%的中风患者接受了早期医疗干预(静脉注射tPA)。在超急性卒中期间，一种能够区分活脑组织和死亡组织的成像方式将指导未来的中风治疗，允许个性化的治疗时间窗。这种技术将允许在不需要时机的情况下对选定的患者进行治疗，并有望提高疗效并减少潜在的副作用。

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. PUBLIC HEALTH RELEVANCE: 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.