Early Detection of Changes in Pulmonary Gas Exchange by Hyperpolarized Xe MRI

描述(申请人提供)：可以说，阻碍慢性肺部疾病治疗进展的最大差距是缺乏足够敏感、全面和非侵入性的手段来评估肺功能。在填补这一空白之前，患者将接受对他们不起作用的药物，新疗法的开发将仍然昂贵、缓慢，而且基本上不会成功。因此，我们研究的长期目标是开发和实施一种非侵入性和纵向成像心肺功能和结构的所有相关方面的方法。我们的方法使用超极化(HP)129Xe磁共振成像来成像通风、微结构和气体交换。这项应用的目的是优化我们最近展示的通过129Xe磁共振成像人体局部气体交换的能力，使用优化的方法来测量和了解静息灌注的异质性，并展示该成像方法的敏感性，以比目前可能的更早地检测局部肺功能的变化。中心假设是，与可用的手段相比，区域气体交换是肺功能早期变化最敏感的标志。这项拟议研究的基本原理是，开发一种可以非侵入性地评估区域气体交换的方法，通过提供一种可以重复使用的更敏感和更具体的测量方法，将极大地加速肺部医学的研究。因此，拟议的研究与NIH任务中有关通过开发和加快生物医学技术的应用来改善健康的部分相关。在强大的初步数据的指导下，中心假设将通过追求三个具体目标来检验：1)优化3D血液选择性129Xe气体交换MRI；2)建立作为时间、体位和心输出量的函数的图像重复性；以及3)成像放射治疗期间局部气体交换的时间演变。完成这些目标将确立这种新方法与黄金标准相比的实用性、敏感性和局限性，同时将其定位为肺部医学研究的敏感生物标志物。第一个目标是将目前气体交换图像的分辨率提高8倍，增加纤维化的特异性，并建立管理收购的关键磁共振物理学。第二个目标将揭示已经在初步研究中观察到的129Xe气体交换静止不均匀的关键决定因素，并建立它们的重复性。最终目的是将这些技术和发展洞察力结合在一起，以检验129Xe MRI将比目前可用的手段更早检测到气体交换变化的假设。建议的方法是创新的，因为它利用了HP 129Xe MRI的独特特性和一种创新的获取来成像肺部最基本的功能-气体交换。这项拟议的研究意义重大，因为正在开发的成像方法有望为气体进入肺微循环提供一个长期寻求的窗口，作为疾病状态变化的先兆。

DESCRIPTION (provided by applicant): Arguably the biggest gap preventing progress in treating chronic pulmonary diseases is the lack of a sufficiently sensitive, comprehensive, and non-invasive means to evaluate lung function. Until this gap is filled, patients will receive medications that don't work for them, and development of new therapies will remain expensive, slow, and largely unsuccessful. The long-term goal of our research, therefore, is to develop and implement a means to image all relevant aspects of cardiopulmonary function and structure, non-invasively and longitudinally. Our approach uses hyperpolarized (HP) 129Xe MRI to image ventilation, microstructure, and gas exchange. The objective of this application is to optimize our recently demonstrated capability to image regional gas exchange by 129Xe MRI in human subjects, to use the optimized method to measure and understand resting perfusion heterogeneity, and to demonstrate the sensitivity of this imaging approach to detect changes regional lung function much earlier than currently possible. The central hypothesis is that regional gas exchange is the most sensitive marker of early changes in pulmonary function compared to available means. The rationale for the proposed research is that developing a method that can non-invasively evaluate regional gas exchange will dramatically accelerate research in pulmonary medicine by providing a more sensitive and specific measurement that can be used repeatedly. Thus, the proposed research is relevant to that part of the NIH Mission that pertains to improving health by developing and accelerating the application of biomedical technologies. Guided by strong preliminary data, the central hypothesis will be tested by pursuing three Specific Aims: 1) Optimize 3D blood-selective 129Xe gas exchange MRI 2) Establish image reproducibility as a function of time, posture, and cardiac output, and 3) Image the temporal evolution of regional gas exchange during radiation therapy. Completion of these aims will establish the utility, sensitivity and limitations of this new method compared to gold standards, while positioning it as a sensitive biomarker for research in pulmonary medicine. The first aim is expected to improve the current gas exchange image resolution 8-fold, add specificity for fibrosis, and establish the key MR physics governing the acquisition. The second aim will uncover the key determinants of the resting heterogeneity of 129Xe gas exchange already observed in preliminary studies and establish their reproducibility. The final aim brings these technical and developmental insights together to test the hypothesis that 129Xe MRI will detect alterations in gas exchange earlier than currently available means. The proposed approach is innovative because it exploits the unique properties of HP 129Xe MRI and an innovative acquisition to image lungs' most fundamental function - gas exchange. The proposed research is significant because the imaging method being developed is expected to provide a long-sought window on gas transfer into the pulmonary microcirculation as a harbinger of changing disease status.