Liver Parametric PET

项目摘要 非酒精性脂肪性肝病（NAFLD）影响美国大约三分之一的普通人群。 States.非酒精性脂肪性肝炎（NASH）-一种更严重的NAFLD形式-在5-10%的NAFLD中发展 患者（即，5-10在美国有100万人），在肝脏疾病的背景下具有肝脏炎症的标志。 脂肪变性NASH与单纯性肝脂肪变性的鉴别对于NAFLD患者的管理至关重要， NASH与加速进展为终末期肝病（肝衰竭和肝癌）相关 并且与肝脏相关的死亡率比单纯脂肪肝高得多。虽然非侵入性成像方法 虽然已经开发了量化肝脏脂肪和肝纤维化的方法，但对新的成像方法的需求尚未得到满足， 和分级肝脏炎症。本计画的目标是发展一种正电子发射断层摄影术（PET）方法 以实现肝脏炎症的非侵入性评估和NASH诊断。使用广泛使用的 放射性示踪剂18F-氟脱氧葡萄糖（FDG），我们提出了一种肝脏参数PET方法，使用动态扫描 和示踪动力学建模。我们假设通过肝脏参数PET测量的葡萄糖转运可以 准确表征NASH基础的肝脏炎症。实现这一点的一个主要挑战是 技术是肝脏是具有来自肝动脉和门静脉的双重血液供应的独特器官， 动力学建模需要双血输入函数（DBIF）的知识，这在 人体PET研究。我们的初步工作通过开发一种新的 优化衍生的DBIF建模方法。通过改进的动力学模型，我们在飞行员中发现 临床研究表明，血液-组织葡萄糖转运率K1与肝脏组织学密切相关， 炎症分级。该提案的重点是进一步发展和优化肝脏的方法学 参数PET，并验证其评估肝脏炎症和诊断NASH患者的有效性 关于NAFLD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是肝脏炎症的有效且独特的PET生物标志物;（3）联合收割机 参数化PET结合CT或MR方法用于NASH的多参数诊断;（4）缩短肝脏扫描时间 参数PET从一小时到十五分钟。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及 NASH分级所提出的方法将填补非侵入性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深刻影响临床 NAFLD患者的管理和新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.