Quantitative MRI-PET Imaging of Pulmonary Fibrosis

摘要 行政补充将帮助PI在履行职责的同时保持生产力 责任，并实现母K25项目的目标，以开发和实施MR-PET肺 成像工具，以准确量化与肺纤维化相关的分子异常。特发 肺纤维化（IPF）是一种进行性和最终致命的疾病，中位生存期不到4年 从诊断的时候起。由于高度可变的临床过程和不良的治疗选择仍然有限， 了解致病机制。目前诊断和监测IPF的策略包括肺活检， 测量整体肺功能的肺功能测试，以及解剖成像工具，如高分辨率 计算机断层扫描。然而，这些方法在早期发现疾病、确定疾病 活性，提供准确的预后或监测治疗反应。分子成像可能是一种 另一种方法对检测早期纤维化更敏感， 稳定性疾病引起的活动性纤维化-迫切且未满足的临床需求。提高量化能力 用于确定IPF疾病活动性的成像工具将改善患者护理并促进急需的药物治疗。 发展磁共振（MR）成像可以提供形态学、生理学 代谢和分子过程，而正电子发射断层扫描（PET）提供了精致的灵敏度， 询问病理生物学先进的MR和PET技术对肿瘤学产生了重大影响， 心血管疾病和神经系统疾病。然而，它们在肺成像中的应用已经被 由于低质子密度和由于空气中的磁化率伪影导致的快速信号衰减， 组织界面进行MRI，而PET定量由于呼吸运动、光子 衰减和组织、空气和血液组分的区域变化。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。离体测量显示， 博莱霉素损伤的纤维化肺中。然而，无论是在体内动物和首次在人体内的研究表明， PET信号差异为35- 40%。这种差异突出了运动、衰减和局部运动的重要性。 PET定量中的体积校正。我们的初步模拟结果表明，衰减和运动 校正基本上增加了成像对比度。最近的技术进步，如并行成像，超 短回波时间（UTE）和旋转相位编码使得能够对肺进行先进的质子MR成像。 因此，同步MR-PET有望通过使用空间和时间上的同步来改善PET量化。 相关的MR信息，以校正运动、部分体积和光子衰减效应。充分利用 成像技术的进步和敏感的胶原靶向探针，本建议旨在建立一个 MR-PET肺成像工具可准确量化IPF患者肺中的胶原沉积， 评估疾病活动。

Abstract The administrative supplement will help the PI to maintain productivity while fulfilling her caregiving responsibilities and achieve the goal of the parent K25 project to develop and implement an 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 courses 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. 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 on 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 artifacts 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.