PET-MR Imaging of pulmonary fibrosis

项目摘要/摘要 这个项目的目标是使用肺的定量PET-MR成像来准确地量化分子 与肺纤维化相关的异常，以预测疾病进展，并提供早期 抗纤维化治疗是否可能有效的适应症。特发性肺纤维化(IPF)是一种 进展性和最终致命性疾病，中位生存期从确诊之日起不到4年。 由于高度多变的临床病程和对致病机理的了解，治疗选择仍然有限。 机械装置。目前诊断和监测IPF的策略包括肺活检、肺功能测试 测量全球肺功能，以及高分辨率计算机断层扫描等解剖成像工具 (HRCT)。然而，这些方法在及早发现疾病、确定疾病活动性方面的能力有限。 一项措施，或监测治疗反应。分子成像可能是另一种方法，即 更敏感地检测早期纤维化，并有可能区分新的活动纤维化和稳定的纤维化 疾病--紧急和未得到满足的临床需求。我们团队最近开发了一种I型胶原特异性正电子 发射断层扫描(PET)探针68Ga-CBP8，在动物模型中显示用于检测肺纤维化 在早期阶段，并能够监测治疗反应。该探头在健康人群中的初步数据 志愿者和IPF患者显示IPF肺对68Ga-CBP8的摄取显著高于IPF患者 肺功能正常。这一数据还表明，除了肺纤维化区域的探针摄取外， 经HRCT证实，放射学上“正常”的肺部有额外的探头摄取区域。 该探头可能对较低水平的纤维化比HRCT敏感和/或对疾病活动敏感，即 新形成的胶原蛋白。另一方面，磁共振成像(MRI)可以提供多种读数 形态、生理和功能。我们实验室使用动态增强磁共振成像的初步数据 (DCE-MRI)显示正常对照和IPF患者的DCE参数可区分异常和异常 正常肺，这些测量可以预测疾病的进展。肺部的定量MRI-PET已被证实 由于低质子密度和空气中磁化率伪影导致的快速信号衰减，历史上受到限制- MRI的组织界面，虽然由于呼吸运动、光子、PET量化仍然具有挑战性 组织、空气和血液成分的衰减和区域差异。然而，将这两种模式结合起来 拥有巨大的潜力来克服其中的一些限制。我们的中心假设是非侵入性分子 胶原堆积的成像将使我们能够捕捉到IPF患者持续肺损伤的程度和 使用DCE-MRI增强的胶原靶向PET的双模式成像方法将实现更多 准确检测疾病活动和治疗反应。

Project Summary/Abstract The goal of this project is to use quantitative PET-MR imaging of the lung to accurately quantify molecular abnormalities associated with pulmonary fibrosis, to predict disease progression, and to provide an early indication of whether anti-fibrotic therapy is likely to be effective. Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease with a median survival of less than 4 years from the time of diagnosis. The treatment options remain limited due to highly variable clinical course and poorly understood pathogenic mechanisms. Current strategies to diagnose and monitor IPF include lung biopsy, pulmonary function tests that measure global lung function, and anatomic imaging tools such as high-resolution computed tomography (HRCT). Yet these methods are limited in their ability to detect disease early, determine disease activity at any one measure, or monitor the therapeutic response. Molecular imaging may be an alternative approach that is more sensitive to detect early fibrosis and potentially capable of distinguishing new, active fibrosis from stable disease – urgent and unmet clinical needs. Our group recently developed a type I collagen-specific positron emission tomography (PET) probe, 68Ga-CBP8, which was shown in animal models to detect pulmonary fibrosis at an early stage and was capable of monitoring treatment response. Preliminary data with this probe in healthy volunteers and IPF patients demonstrated that 68Ga-CBP8 had significantly higher uptake in IPF lungs than in normal lungs. This data also showed that in addition to probe uptake in regions of lung with fibrosis as established by HRCT, there were additional areas of probe uptake in radiographically “normal” lung suggesting that the probe may be sensitive to lower levels of fibrosis than HRCT and/or sensitive to disease activity, i.e. newly formed collagen. Magnetic resonance imaging (MRI) on the other hand can provide multiple readouts of morphology, physiology, and function. Preliminary data from our lab using dynamic contrast enhanced-MRI (DCE-MRI) in healthy controls and IPF subjects indicated that DCE parameters can distinguish abnormal from normal lung, and that these measures may predict disease progression. Quantitative MRI-PET in lung has been historically limited because of low proton density and the fast signal decay due to susceptibility artefacts at air- tissue interfaces for MRI, while PET quantification remains challenging due to respiratory motion, photon attenuation and regional variations in tissue, air and blood fractions. However, combining the two modalities holds great potential to overcome some of these limitations. Our central hypothesis is that non-invasive molecular imaging of collagen accumulation will allow us to capture the extent of ongoing lung injury in IPF patients and that a bi-modal imaging approach using collagen-targeted PET augmented by DCE-MRI will enable more accurate detection of disease activity and treatment response.