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

本研究的目的是开发一种无创、无挑战、广泛可用的脑氧摄取分数（OEF）定量绘图方法。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中的缺血缺氧。局部OEF是组织活力和功能的一种重要的直接生物标志物，非常适合用于评估和分层这些神经系统疾病的治疗。广泛分布的MRI提供了克服15 O PET的潜力，15 O PET是当前的参考标准，但由于其有限的可用性而未在临床上使用。在MRI中，OEF的定量映射需要从MRI信号估计脱氧血红素浓度[dH]。已经提出了三种主要方法来从MRI幅度信号估计[dH]。然而，它们通常遭受差的灵敏度和繁重的数据采集方案，因为它们利用的MRI幅度信号对[dH]具有复杂的依赖性。因此，在临床环境中没有常规使用基于MRI的OEF标测。此外，这些方法均未根据现行参比标准品15 O PET进行验证。 最近，我们开发了一种有前途的、新型的、基于MRI的非侵入性OEF方法，该方法不需要血管挑战，并利用单一常规MR序列。通过将常被忽略的MRI相位信号的定量磁化率映射（QSM）建模和MRI幅度信号的定量血氧水平依赖（qBOLD）建模相结合，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扩散性其他磁化率源。在我们的初步数据中，QQ已在健康成人中验证了15 O-PET，并显示缺血性卒中、多发性硬化和脑肿瘤的OEF异常。然而，对于临床使用，应改进QQ的数据采集和处理方案，以确保OEF的准确性，因为在短回波时间内缺乏数据，并且在当前设置中使用基于梯度的求解器的非最佳信号建模阻碍了准确的OEF估计。 在本K99/R 00项目中，我们将通过改进QQ，建立一个临床上适用的定量OEF标测MRI工具集，该工具集经过验证，可用于每台MRI扫描仪。我们将通过四个具体目标来实现这一目标。目标1.开发用于MRI-OEF标测的最佳数据采集。目标2.开发数据处理算法，用于稳健的OEF估计。目标3。根据15 O PET进行MRI-OEF的技术确认。目标4。在颅内狭窄患者中进行MRI-OEF的临床确认。我们的经验和初步数据给了我们信心，我们将很有可能成功这个拟议的项目。该项目将及时产生一种新型、经验证、无创、无挑战、常规可用和定量的MRI OEF标测，有可能取代有创、复杂的当前标准15 O PET OEF。该工具将有助于更好地理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.