Quantitative MRI-PET Imaging of Pulmonary Fibrosis

项目摘要/摘要 该项目的目标是开发和实施一种MR-PET肺成像工具，以准确地量化 与肺纤维化相关的分子异常。特发性肺纤维化(IPF)是一种进行性的 最终是致命的疾病，从确诊之日起中位生存期不到4年。治疗方法 由于高度可变的临床病程和对致病机制的了解很少，选择仍然有限。 目前诊断和监测IPF的策略包括肺活检、肺功能测试 肺功能，以及高分辨率计算机断层扫描等解剖成像工具。然而，这些方法 在早期发现疾病、确定疾病活动性、提供准确的预后或 监测治疗反应。分子成像可能是一种更敏感的替代方法 检测早期纤维化，并有可能区分新的、活跃的纤维化和稳定的疾病-紧急 以及未得到满足的临床需求。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。我们的中心假设是 有创的MR辅助的胶原堆积的PET成像将使我们能够捕捉到正在进行的肺的范围 因此，它可以作为一种可行的疾病活动性衡量标准。磁共振(MR)成像 可以提供形态、生理、代谢和分子过程的多种读数，而正电子 发射断层扫描(PET)为询问病理生物学提供了极高的灵敏度。高级磁共振和正电子发射计算机断层扫描 技术在肿瘤学、心血管疾病和神经疾病方面产生了重大影响。然而， 由于低质子密度和快速信号，它们在肺部成像中的应用历来受到限制 磁共振成像中空气-组织界面的易感性伪影引起的衰减，而正电子发射计算机断层扫描的定量仍然具有挑战性 由于呼吸运动、光子衰减以及组织、空气和血液成分的区域差异。最近， 我们研制了一种用于纤维化成像的镓(Ga)-68标记的胶原结合的PET探针。体外测量 显示博莱霉素损伤的纤维化肺的摄取率是对照组的5倍。然而，无论是在活体动物中 首次在人体内进行的研究表明，PET信号的差异为35%-40%。这一差异突出了 运动、衰减和部分体积校正在PET定量中的重要性。我们的初步模拟 结果表明，衰减和运动校正显著提高了成像对比度。最近的技术 并行成像、超短回波时间(UTE)和旋转相位编码等先进技术已成为可能 先进的肺部质子磁共振成像技术。因此，同步MR-PET有望提高PET的定量 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 衰减效果。利用成像技术的进步和灵敏的胶原蛋白靶向探针， 这项建议旨在建立一种MR-PET肺成像工具，以准确定量胶原沉积在 以精确评估IPF患者的肺部疾病活动性。

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.