MRI of cerebral metabolic reactivity

 描述(申请人提供)：这些研究的长期目标是了解脑缺氧的生理后果，以及正常的体内平衡机制的失败如何导致脑部疾病。人们一直致力于了解脑血管储备如何影响脑部疾病，但这只是故事的一半；要了解对缺氧影响的耐受性，我们还需要知道限制大脑代谢活动的可能性。目前提案的中心前提是 在缺氧或缺血时，如果能增加脑血流量(CBF)或降低氧代谢(CMRO2)，就能维持脑组织的存活，这两者都能导致局部组织氧合(PtiO2)的保存。氧稳态的一个重要决定因素是局部二氧化碳；我们最近发现，在低氧过程中，二氧化碳对CMRO2的影响增加。因此，二氧化碳提供了一种机制，既增加了CBF(和O2输送)，又减少了CMRO2(和O2消耗)。我们假设，大脑对局部缺氧的耐受性取决于这些血流动力学和代谢反应在低氧状态下对二氧化碳的局部强度(增加CBF和降低CMRO2)，这两者都起到保护组织氧合的作用。该项目的目标是确定CBF和CMRO2(因此PtiO2)是否在已知缺氧敏感性差异的区域的缺氧期间表现出这种预期的二氧化碳敏感性差异。我们的方法允许测量局部CBF和CMRO2的反应，基于一种新的多间隔模型血氧水平依赖(BOLD)信号。在目标1中，我们将测试我们的新MRI测量区域CMRO2对二氧化碳/低氧的反应性的重复性和变异来源。在目标2中，我们测试了我们的假设，即对缺血损伤具有抵抗力的区域能够更好地最大化局部CBF和CMRO2对局部二氧化碳的敏感性。这一建议为解决脑缺血病理生理学中的基本机制问题提供了一种新的途径。这项研究的终点将是一种经过验证的方法来表征CMRO2在缺氧中的反应性，并检验我们关于人脑局部缺氧脆弱性的假设。这些研究还将为将这些新的MRI工具转化为评估脑部疾病的缺血脆弱性奠定基础和限制。

 DESCRIPTION (provided by applicant): The longterm goal of these studies is to understand the physiological consequences of cerebral hypoxia, and how failure of normal homeostatic mechanisms contributes to cerebral disease. Much attention has been devoted to understanding how cerebrovascular reserve impacts cerebral disease, however this tells only half the story; to understand tolerance to the effects of hypoxia, we also need to know the potential to limit cerebral metabolic activity. The central premise of the current proposal is that during hypoxia or ischemia cerebral tissue viability can maintained if the cerebral blood flow (CBF) can be increased or oxygen metabolism (CMRO2) can be reduced, both of which lead to preservation of local tissue oxygenation (PtiO2). An important determinant of oxygen homeostasis is local CO2; we recently discovered that during hypoxia the influence of CO2 on CMRO2 is increased. Thus CO2 provides a mechanism to both increase CBF (and O2 delivery) and decrease CMRO2 (and O2 consumption). We hypothesize that regional hypoxia tolerance in the brain is determined by the local strength of these hemodynamic and metabolic responses to CO2 in hypoxia (increasing CBF and decreasing CMRO2), which both act to preserve tissue oxygenation. The goals of this project are to determine if CBF and CMRO2 (and hence PtiO2) exhibit this expected difference in CO2 sensitivity during hypoxia in regions with know differences in hypoxia sensitivity. Our methodology allows measurement of regional CBF and CMRO2 responses, based on a novel multi-compartment model Blood Oxygenation Level-dependent (BOLD) signals. In Aim 1 we will test the reproducibility and sources of variance of our new MRI measurements of regional CMRO2 reactivity to CO2 / hypoxia. In Aim 2 we test our hypothesis that regions that are resistant to ischemic insults are better able to maximize local CBF and CMRO2 sensitivity to local CO2. This proposal presents a novel approach to address basic mechanistic questions in cerebral ischemic pathophysiology. The endpoint of this study will be a validated method to characterize CMRO2 reactivity in hypoxia, and a test of our hypothesis regarding regional hypoxia vulnerability in the human brain. These studies will also establish the basis and limitations for translating these novel MRI tools to evaluate ischemic vulnerability in cerebral disease.