Liver Parametric PET

项目总结 非酒精性脂肪性肝病(NAFLD)影响着美国大约三分之一的总人口 各州。非酒精性脂肪性肝炎(NASH)是NAFLD的一种更严重的形式，发生在NAFLD的5%-10% 在美国有500-1000万人的患者，在肝脏环境中具有肝脏炎症的特征 脂肪变性。NASH与单纯性肝脂肪变性的鉴别对NAFLD AS患者的治疗至关重要 NASH与加速进展为终末期肝病(肝功能衰竭和肝癌)有关 与单纯脂肪肝相比，与肝脏相关的死亡率要高得多。虽然非侵入性成像方法有 已被开发用于量化肝脏脂肪和肝纤维化，但对新的成像方法的需求仍未得到满足 并对肝脏炎症分级。该项目的目标是开发一种正电子发射断层扫描(PET)方法 以实现对肝脏炎症和NASH诊断的非侵入性评估。使用广泛可访问的 放射性示踪剂18F-氟代脱氧葡萄糖(FDG)，我们提出了一种动态扫描的肝脏参数PET方法 和示踪剂动力学模型。我们假设通过肝脏参数PET测量的葡萄糖转运可以 准确描述NASH下的肝脏炎症。实现这一目标的一个主要挑战 技术是肝脏是一个独特的器官，有来自肝动脉和门静脉的双重血液供应， 需要双血输入函数(DBIF)的知识才能进行动力学建模，这在 人体正电子发射断层扫描研究。我们的初步工作通过开发一种小说来解决这一技术挑战 优化派生的DBIF建模方法。通过改进的动力学模型，我们在一个飞行员身上发现 血到组织葡萄糖转运率K1与肝脏组织学密切相关的临床研究 炎症分级。这项建议的重点是进一步发展和优化肝脏的方法学 参数PET及其在评估肝脏炎症和诊断NASH中的有效性 与非酒精性脂肪肝。更具体地说，我们将(1)开发肝脏参数PET的技术方法；(2)评估 葡萄糖转运率K1作为肝脏炎症的有效和独特的PET生物标志物；(3)结合肝脏 多参数NASH的CT或MR参数PET诊断(4)缩短肝脏扫描时间 参数PET从1小时到15分钟。这些具体目标的综合成果将是一个新的 18F-FDG PET用于肝脏炎症评估和检测的技术能力和有效性 给纳什评分。所提出的方法将填补无创评估肝脏炎症的关键空白。 脂肪肝。该项目的成功完成有可能对临床产生深远的影响 非酒精性脂肪肝患者的管理和新的NASH治疗的临床试验。

PROJECT SUMMARY Nonalcoholic fatty liver disease (NAFLD) affects approximately one-third of the general population in the United States. Nonalcoholic steatohepatitis (NASH) - a more severe form of NAFLD - develops in 5-10% of NAFLD patients (i.e., 5-10 million people in the US) with the hallmark of hepatic inflammation in the setting of hepatic steatosis. Differentiation of NASH from simple hepatic steatosis is vital for patient management in NAFLD as NASH is associated with accelerated progression into end-stage liver diseases (liver failure and liver cancer) and with much higher liver-related mortality than the simple fatty liver. While noninvasive imaging methods have been developed to quantify liver fat and liver fibrosis, there is an unmet need for new imaging methods to detect and grade liver inflammation. The goal of this project is to develop a positron emission tomography (PET) method to enable noninvasive assessment of liver inflammation and NASH diagnosis. Using the widely accessible radiotracer 18F-fluorodeoxyglucose (FDG), we propose a liver parametric PET method using dynamic scanning and tracer kinetic modeling. We hypothesize that glucose transport measured by liver parametric PET can accurately characterize the liver inflammation underlying NASH. One major challenge with enabling this technique is that the liver is a unique organ with dual blood supplies from the hepatic artery and portal vein, requiring the knowledge of dual-blood input function (DBIF) for kinetic modeling, which is difficult to obtain in human PET studies. Our preliminary work has addressed this technical challenge by developing a novel optimization-derived DBIF modeling approach. With improved kinetic modeling, we have discovered in a pilot clinical study that the blood-to-tissue glucose transport rate K1 was strongly associated with histological liver inflammation grades. The focus of this proposal is to further develop and optimize the methodology of liver parametric PET and validate its effectiveness for assessing liver inflammation and diagnosing NASH in patients with NAFLD. More specifically, we will (1) develop the technical method of liver parametric PET; (2) Evaluate glucose transport rate K1 as an effective and unique PET biomarker of liver inflammation; (3) Combine liver parametric PET with CT or MR methods for multiparametric NASH diagnosis; (4) Shorten the scan time of liver parametric PET from one hour to fifteen minutes. The integrated outcome of these specific aims will be a new technical capability and validation of 18F-FDG PET for liver inflammation assessment and for detecting and grading NASH. The proposed method will fill the critical gap for noninvasive assessment of liver inflammation in fatty liver disease. Successful completion of this project has the potential to profoundly impact the clinical management of NAFLD patients and clinical trials of new NASH treatments.