Simultaneous Xe129 MRI of Regional Lung Ventilation and Gas Uptake in COPD

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是美国第四大死因，也是近年来年龄调整死亡率上升的唯一主要原因。随着对 COPD 涉及的遗传和分子途径的了解取得进展，越来越需要改进的工具来表征肺功能，以用于将遗传亚型与表型表达耦合、监测对新治疗的功能反应或帮助快速开发新型呼吸药物等应用。尽管如此，尽管医学成像技术取得了无数的进步，但以适合人类常规应用的方式获得肺最基本生理功能（气体输送到空气空间以及肺实质和血液吸收气体）的体内区域描述和量化仍然具有挑战性。为了解决这一未满足的需求，该项目利用了我们小组最近开发的一种方法，该方法基于超极化氙 129 (hypXe129) 的磁共振成像 (MRI)，该方法允许同时观察通气（气体输送）和气体摄取的 3D 分布，以及基于相关通气的区域气体摄取的量化，来自适合呼吸功能受损受试者的单次短暂屏气采集。 该项目的首要目标是实施并在人类受试者中验证该技术的关键改进，包括能够在图像中分别描绘溶解在红细胞中的 hypXe129 部分和溶解在肺实质/血浆中的部分。第二个目标是通过测量健康受试者中作为测量参数和肺充气函数的信号行为来表征健康肺部的气体摄取，如溶解的 hypXe129 信号所反映的那样，然后根据信号行为数据导出优化方案，用于测量气体摄取的相关 3D 分布。这些优化的方案将在患有轻度和重度慢性阻塞性肺病的受试者中得到验证。第三个也是最后一个目标是对 20 名健康对照受试者、10 名肺量测定正常的吸烟者和 30 名 COPD 受试者（从 GOLD 1 到 3 期）进行探索性研究，以根据疾病严重程度来表征溶解的 hypXe129 以及溶解在红细胞和肺实质/血浆中的 hypXe129 分数的标准化气体摄取分布。这些气体摄取结果将与标准胸部计算机断层扫描 (CT) 和肺功能测试的结果进行比较。拟议项目的成功完成将产生通气和气体摄取同步 MR 成像方法的改进、优化版本，该方法提供标准化的区域气体摄取值，可以在受试者之间进行定量比较。该技术提供了有关肺部的重要功能信息，这是任何现有临床成像方式都无法提供的，并且具有提供有关 COPD 的独特、生理相关和临床重要信息的巨大潜力。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and is the only major cause of death for which the age-adjusted death rate has increased in recent years. As progress is made in understanding the genetic and molecular pathways involved in COPD, there is a growing need for improved tools to characterize lung function for applications such as coupling genetic subtypes to phenotype expression, monitoring functional response to new treatments, or aiding in the rapid development of novel respiratory drugs. Nonetheless, despite a myriad of technical advances in medical imaging, it remains challenging to obtain in-vivo regional depiction and quantification of the most basic physiological functions of the lung - gas delivery to the airspaces and gas uptake by the lung parenchyma and blood - in a manner suitable for routine application in humans. To address this unmet need, this project takes advantage of a method recently developed by our group, based on magnetic resonance imaging (MRI) of hyperpolarized xenon-129 (hypXe129), that permits simultaneous observation of the 3D distributions of ventilation (gas delivery) and gas uptake, as well as quantification of regional gas uptake based on the associated ventilation, from a single short breath-hold acquisition suitable for subjects with compromised respiratory function. The first aim of this project is to implement, and validate in human subjects, key improvements to this technique, including the ability to separately depict in the images the fraction of hypXe129 dissolved in red blood cells and that dissolved in lung parenchyma/plasma. The second aim is to characterize gas uptake in the healthy lung, as reflected by dissolved-hypXe129 signals, by measuring signal behaviors as a function of measurement parameters and lung inflation in healthy subjects, and then derive optimized protocols, based on the signal-behavior data, for measuring the associated 3D distributions of gas uptake. These optimized protocols will be validated in subjects with mild and severe COPD. The third and final aim is to perform an exploratory study in 20 healthy control subjects, 10 smokers with normal spirometry and 30 subjects with COPD, ranging from GOLD stage 1 to 3, to characterize, as a function of disease severity, the normalized gas- uptake distributions for dissolved hypXe129 and for the fractions of hypXe129 dissolved in red blood cells and lung parenchyma/plasma. These gas-uptake results will be compared to results from standard computed tomography (CT) of the chest and pulmonary function testing. Successful completion of the proposed project will result in an improved, optimized version of the method for simultaneous MR imaging of ventilation and gas uptake that provides normalized regional gas-uptake values, which can be quantitatively compared among subjects. This technique offers important functional information about the lung, which is not available from any existing clinical imaging modality, and has substantial potential to provide unique, physiologically relevant, and clinically important information about COPD.