QUANTIFICATION OF LUNG VENTILATION AND STRUCTURE BY 3HE MRI

描述(由申请者提供)：肺气肿是美国和世界范围内的一个主要医学问题。在这项拨款申请中，我们建议开发非侵入性肺形态计量学，作为这种衰弱疾病的改进诊断方法。我们的技术基于超极化3He气体的扩散磁共振成像，并允许在体内对肺泡表面积、肺泡密度和腺泡气道半径进行3D断层成像-这些参数几十年来一直被肺生理学家用作量化肺气肿的金标准，但以前只能通过侵入性肺活检进行测量。作为之前资助期间的一部分，我们获得了30名在肺气肿早期有已知吸烟史的受试者的活体肺形态测量数据。这一数据揭示了肺形态计量学中非常特殊的变化，这是常规临床测试没有意识到的，表明我们的技术是检测肺微结构早期变化的非常敏感的工具。此更新应用程序的主要目标是将活体肺形态测量技术的诊断潜力扩展到肺气肿的所有阶段，以确定肺实质的结构变化。为了实现这一目标，我们将：(I)通过计入进行性肺组织破坏对3He气体扩散的影响，扩展我们目前的肺内气体扩散数学模型；(Ii)以非侵入性方式建立不同年龄段无吸烟史健康受试者肺微结构的基线参数；(Iii)无创表征受试者在肺气肿初期至晚期的肺微结构变化；(Iv)针对直接形态计量学测量对我们的技术进行验证。总体而言，我们建议进一步开发和验证我们先进的用于对人类肺部进行成像的MRI技术，将其作为肺气肿变化的卓越的、特定的特征，并应用这些技术来促进我们对肺气肿发生的微观结构变化的理解，这些变化发生在广泛的年龄和疾病阶段。随着肺气肿的进展，从最初的肺泡变形开始到以肺功能急剧丧失为特征的晚期，肺泡水平的微结构变化的全面图像将被阐明。我们的新方法具有足够的敏感性，可以及早发现和诊断肺气肿，为改善患者的治疗结果提供机会，并有可能为临床试验中监测药物疗效提供安全和非侵入性的体内生物标志物。 公共卫生相关性：这项研究的主要目标是进一步发展我们先进的用于人类肺部成像的MRI技术-活体肺形态测量-作为对肺气肿变化的更好、更灵敏的表征，并应用该技术来促进我们对肺气肿发生在不同年龄和疾病阶段的肺泡和呼吸道变化的理解。这项技术是基于超极化3He气体扩散磁共振成像技术。这一结果将为肺气肿的进展提供新的临床见解，从最初的肺泡变形到以肺功能急剧丧失为特征的最后阶段。

DESCRIPTION (provided by applicant): Emphysema is a major medical problem in the US and worldwide. In this grant application we propose to develop non-invasive lung morphometry as an improved diagnostic of this debilitating disease. Our technique is based on diffusion MRI with hyperpolarized 3He gas and allows in vivo 3D tomographic estimation of the lung alveolar surface area, alveolar density, and acinar airway radii - parameters that have been used by lung physiologists for decades as the gold standard for quantifying emphysema but were previously only measurable through invasive lung biopsy. As part of the previous grant period, we obtained in vivo lung morphometry data on 30 subjects with known smoking histories in the early stages of emphysema. This data revealed very specific changes in lung morphometry which were not appreciated with conventional clinical tests, suggesting that our technique is a very sensitive tool for detecting early changes in the lung microstructure. The main goal of this Renewal Application is to extend the diagnostic potential of the in vivo lung morphometry technique for identifying structural changes in lung parenchyma to all stages of emphysema. To achieve this goal we will: (i) extend our current mathematical model of gas diffusion in lungs by incorporating the effects of progressive lung tissue destruction on 3He gas diffusion; (ii) non-invasively establish the baseline parameters of lung microstructure in healthy human subjects without smoking histories over a range of age categories; (iii) non-invasively characterize the changes in lung microstructure for subjects in the initial through advanced stages of emphysema; (iv) validate our technique against direct morphometric measurements. Overall, we propose to further develop and validate our advanced MRI techniques for imaging of the human lung as superior, specific characterization of emphysematous changes in lung, and apply these techniques to advance our understanding of the microstructural changes that occur in emphysema, across a wide range of age and disease stages. A comprehensive picture of the changes in lung microstructure at the alveolar level with emphysema progression will be elucidated, from the initial onset of alveolar deformation to the advanced stages, characterized by a dramatic loss of lung function. Our novel methods are sufficiently sensitive to allow early detection and diagnosis of emphysema, providing an opportunity to improve patient treatment outcomes, and have the potential to provide safe and non-invasive in vivo biomarkers for monitoring drug efficacy in clinical trials. PUBLIC HEALTH RELEVANCE: The main goal of this study is to further develop our advanced MRI technique for imaging of the human lung - in vivo lung morphometry - as a superior, more sensitive characterization of emphysematous changes, and apply this technique to advance our understanding of the changes in lung alveoli and airways that occur in emphysema, across a wide range of ages and disease stages. This technique is based on diffusion MRI with hyperpolarized 3He gas. The results will provide new clinical insights into emphysema progression, from the initial onset of the alveolar deformation to the final stages, characterized by dramatic loss of lung function.