Development and Validation of MRI Mapping of Brain Oxygen Metabolism for Clinical Use

这项研究的目的是开发一种无创、无挑战和广泛可用的方法来定量绘制脑氧提取分数(OEF)。由于大脑持续消耗总供氧量的20%，缺氧容易导致严重的脑组织损伤，如中风和阿尔茨海默病的缺血缺氧。区域性OEF是组织活性和功能的基本的、直接的生物标志物，是评估和分层治疗这些神经疾病的理想选择。广泛分布的MRI提供了克服150度PET的潜力，150度PET是目前的参考标准，但由于其可获得性有限，在临床上没有使用。在MRI中，OEF的定量标测需要从MRI信号中估计脱氧血红素浓度[dh]。已经提出了三种主要的方法来从MRI幅度信号估计[dh]。然而，由于他们利用的核磁共振幅度信号对[dh]有复杂的依赖关系，他们通常遭受着低灵敏度和繁琐的数据采集方案的困扰。因此，还没有基于MRI的OEF标测被常规应用于临床。此外，这些方法都没有对照当前的参考标准15O PET进行验证。最近，我们开发了一种有前景的、新颖的、基于MRI的非侵入性OEF方法，该方法不需要血管挑战，并且使用单一的常规MR序列。通过将常被忽视的MRI时相信号的定量磁化率图(QSM)模型和MRI幅度信号的定量血氧水平相关(QBOLD)模型相结合，我们的模型(QSM+qBOLD=QQ)可以区分静脉血管中的脱氧血红素铁和弥漫性的其他敏感源。在我们的初步数据中，QQ已经在健康成年人中与15O-PET进行了验证，并在缺血性中风、多发性硬化症和脑肿瘤中显示了OEF异常。然而，在临床应用中，QQ的数据采集和处理方案需要改进，以确保OEF的准确性，因为在目前的环境下，回波时间较短的数据缺乏和基于梯度求解器的非最佳信号建模阻碍了OEF的准确估计。在这个K99/R00项目中，我们将建立一个临床上易于应用的MRI工具集，用于定量OEF映射，通过改进QQ，该工具集已得到验证，并可用于每台MRI扫描仪。我们将通过4个具体目标来实现这一目标。目的：1.开发用于MRI-OEF标测的最佳数据采集。目的2.开发稳健OEF估计的数据处理算法。目的3.对照15OPET进行MRI-OEF的技术验证。目的4.对颅内狭窄患者进行MRI-OEF的临床验证。我们的经验和初步数据给了我们信心，我们很有可能成功这个拟议的项目。该项目将及时产生一种新的、有效的、非侵入性的、无挑战的、常规可用的定量MRI OEF成像，为取代有创的、复杂的当前标准150 PET OEF提供了可能性。这一工具将有助于更好地了解和管理神经血管疾病，例如中风。

The objective of this proposed research is to develop a noninvasive, challenge-free, and widely available method for quantitative mapping of cerebral oxygen extraction fraction (OEF). As the brain continuously consumes 20% of the total oxygen supply, oxygen deficiency easily causes severe brain tissue damages as in hypoxia in ischemia in stroke and Alzheimer's disease. Regional OEF is an essential, direct biomarker for tissue viability and function and highly desired for evaluating and stratifying treatments in these neurologic disorders. Widely distributed MRI provides the potential to overcome the 15O PET, the current reference standard but clinically not used due to its limited availability. In MRI, quantitative mapping of OEF requires estimating deoxyheme concentration [dH] from the MRI signal. Three major approaches have been proposed to estimate [dH] from MRI magnitude signal. However, they commonly suffer from poor sensitives and burdensome data acquisition schemes as the MRI magnitude signal which they utilize has a complex dependence on [dH]. Consequently, no MRI-based OEF mapping has been routinely used in clinical setting. Furthermore, none of these methods have been validated against the current reference standard, 15O PET. Recently, we developed a promising, novel, non-invasive MRI-based OEF method that requires no vascular challenge and utilizes a single routine MR sequence. By integrating quantitative susceptibility mapping (QSM) modeling of often neglected MRI phase signal and quantitative blood oxygenation level dependent (qBOLD) modeling of MRI magnitude signal, our model (QSM+qBOLD=QQ) can distinguish deoxyheme iron in venous vasculature from diffusive other susceptibility sources. In our preliminary data, QQ has been validated against 15O-PET in healthy adults and showed OEF abnormalities in ischemic stroke, multiple sclerosis, and brain tumor. However, for clinical use, data acquisition and processing scheme of QQ should be improved to ensure the accuracy of OEF as a lack of data at short echo time and a non-optimal signal modeling with gradient-based solvers in current setting hinders the accurate OEF estimation. In this K99/R00 project, we will establish a clinically readily applicable MRI toolset for quantitative OEF mapping, which is validated and available to every MRI scanner, by improving QQ. We will achieve this through 4 specific aims. Aim1. Develop optimal data acquisition for MRI-OEF mapping. Aim 2. Develop data processing algorithms for robust OEF estimation. Aim 3. Perform technical validation of MRI-OEF against 15O PET. Aim 4. Perform clinical validation of MRI-OEF in patients with intracranial stenosis. Our experience and preliminary data give us confidence that we will very likely succeed this this proposed project. In a timely fashion, the project will lead to a novel, validated, non-invasive, challenge-free, routinely usable and quantitative MRI OEF mapping, offering the potential to replace invasive, complicated current standard 15O PET OEF. This tool will lead to better understanding and management of neurovascular disorders, e.g. stroke.