Quantitative MRI-PET Imaging of Pulmonary Fibrosis

项目概要/摘要 本项目的目标是开发和实施一种MR-PET肺部成像工具， 与肺纤维化相关的分子异常。特发性肺纤维化（IPF）是一种进行性 最终是致命的疾病，从诊断开始的中位生存期不到4年。治疗 由于高度可变的临床过程和对致病机制知之甚少，选择仍然有限。 目前诊断和监测IPF的策略包括肺活检、肺功能检查， 肺功能和解剖成像工具，如高分辨率计算机断层扫描。然而，这些方法 在早期检测疾病、确定疾病活动性、提供准确预后或 监测治疗反应。分子成像可能是一种替代方法， 检测早期纤维化，并有可能区分新的、活动性纤维化和稳定性疾病-紧急 未满足的临床需求。提高定量成像工具确定IPF疾病活动性的能力 将改善患者护理并促进急需的药物开发。我们的核心假设是，非- 胶原蛋白积聚的侵入性MR辅助PET成像将使我们能够捕获正在进行的肺 因此可作为一种可行的疾病活动性指标。磁共振成像 可以提供形态学、生理学、代谢和分子过程的多种读数，而正电子 发射断层扫描（PET）提供了精细的灵敏度来询问病理生物学。高级MR和PET 这些技术在肿瘤学、心血管疾病和神经系统疾病方面产生了重大影响。然而，在这方面， 由于低质子密度和快速信号 由于MRI的空气-组织界面处的敏感性伪影而引起的衰减，而PET量化仍然具有挑战性 这是由于呼吸运动、光子衰减以及组织、空气和血液成分的区域变化。最近， 我们开发了镓（Ga）-68标记的胶原结合PET探针用于纤维化成像。离体测定 显示博来霉素损伤的纤维化肺中的摄取比对照高5倍。然而，无论是在体内动物， 首次人体研究显示PET信号差异为35- 40%。这种差异突出了 PET定量中运动、衰减和部分容积校正的重要性。我们的初步模拟 结果表明，衰减和运动校正实质上增加了成像对比度。最近的技术 诸如并行成像、超短回波时间（UTE）和旋转相位编码之类的进步已经使得 先进的肺部质子磁共振成像因此，同步MR-PET有望改善PET定量 通过使用空间和时间相关的MR信息来校正运动、部分体积和光子 衰减效应利用成像技术的进步和敏感的胶原靶向探针， 该提案旨在建立一种MR-PET肺成像工具，以准确量化肺组织中的胶原沉积， IPF患者的肺部，以精确评估疾病活动性。

Project Summary/Abstract The goal of this project is to develop and implement a MR-PET lung imaging tool to accurately quantify molecular abnormalities associated with pulmonary fibrosis. 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. Yet these methods are limited in their ability to detect disease early, determine disease activity, provide accurate prognosis 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. Advancing the capacity of quantitative imaging tools to determine IPF disease activity would improve patient care and facilitate much-needed drug development. Our central hypothesis is that non- invasive MR-aided PET imaging of collagen accumulation will allow us to capture the extent of ongoing lung injury in IPF patients and thus service as a viable disease activity measure. Magnetic resonance (MR) imaging can provide multiple readouts of morphology, physiology, metabolism, and molecular processes, while positron emission tomography (PET) offers exquisite sensitivity to interrogate pathobiology. Advanced MR and PET techniques have had major impacts in oncology, cardiovascular diseases, and neurological disorders. However, their application to lung imaging 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. Recently, we developed a gallium(Ga)-68 labeled collagen binding PET probe for fibrosis imaging. Ex vivo measurement showed a 5-fold higher uptake in bleomycin injured fibrotic lungs than controls. However, both in vivo animal and first-in-human studies showed a PET signal difference of 35-40%. This discrepancy highlights the importance of motion, attenuation and partial volume correction in PET quantification. Our preliminary simulation results show that attenuation and motion correction substantially increase the imaging contrast. Recent technical advances such as parallel imaging, ultra-short time to echo (UTE) and rotating phase encoding have enabled advanced proton MR imaging of the lung. Thus simultaneous MR-PET promises to improve PET quantification by using the spatially and temporally correlated MR information to correct for motion, partial volume and photon attenuation effects. Capitalizing on the technical advances in imaging and the sensitive collagen-targeted probe, this proposal aims to establish an MR-PET lung imaging tool to accurately quantify collagen deposition in the lung of IPF patients for precise assessment of disease activity.