Technical Validation of MR Biomarkers of Obesity-Associated NAFLD

好了！ 项目总结： 这项应用的广泛、长期目标是改善数百万肥胖或有肥胖风险的美国人的健康。 相关的非酒精性脂肪性肝病(NAFLD)，美国最常见的慢性肝病。之后 首次成功验证了肝脏脂肪变性的磁共振成像生物标记物，这是NAFLD最早的组织学特征 这项资助的周期，这项竞争性更新的重点是肝纤维化和炎症，非酒精性疾病的特征 脂肪性肝炎(NASH)，NAFLD的侵袭性亚型，可进展为肝硬变、肝癌和肝脏相关疾病 死亡。磁共振弹性成像(Mre)是一种非侵入性的量化组织硬度的方法，是基于成像的领先技术。 用于评估NAFLD的肝纤维化，但MRE在检测纤维化和NASH方面的真正诊断性能 从横向和纵向上监测它们的变化是不完全理解的。通过优化 并为这些目的严格评估MRE，我们将解决以下主要知识和技术差距 模糊了这项技术在临床护理和研究中的适当应用。目标1：优化MRE波场 严重肥胖的一代，既适用于常规2D-MRE，也适用于高级3D-MRE。目标2：描述 严重肥胖患者常规2D和先进3D-MRE的精确度(同日重复性、场强 再现性、读取器再现性、日间再现性)。目标3：确定常规2D- 和先进的3D-MRE在严重肥胖中a)横断面诊断纤维化和NASH，b)监测 纵向NASH的纤维化和消退。意义：通过确定的真实诊断性能 常规2D和先进的3D-MRE用于检测和监测肥胖患者的纤维化和NASH， 建议的研究将为适当利用MRE进行临床护理、临床试验和其他研究提供信息。 肥胖相关的非酒精性脂肪肝。此外，如果研究证实了先进的3D-MRE对早期检测的承诺 纳什，这将代表着一种改变游戏规则的新技术能力。创新：此应用程序在 三个主题领域：(1)研究设计：减肥患者的前瞻性横断面和纵向研究，a 具有技术挑战性的人群，疾病严重程度分布均衡，是实现科学目标的理想选择。(2) 波场生成：测试旨在生成高质量波场的新型灵活驱动器。(3)MRE分析： 在动物和人体初步研究中严格测试先进的3D-MRE重建和分析方法 对早期NASH的诊断有希望。研究设计和方法：这项两个现场研究的第一阶段将优化 通过识别最大限度提高MRE精度的驱动器类型和位置，在严重肥胖症患者中生成MRE波场。 使用最佳的驾驶员类型/位置，第二阶段将招募100名严重肥胖的成年人(50名/站点)进行减肥 在多个时间点进行2D和3D-MRE的前瞻性纵向研究中的手术。标准的参考标准 纤维化和NASH的存在及其变化将包括专家共识评分和定量图像分析 在手术时和6个月时进行成对的同期活检。互补性人体测量、实验室和 将获得磁共振成像方法，以确定影响MRE表现的因素，并为未来的研究开发假说。好了！

! PROJECT SUMMARY: This application's broad, long-term objective is to improve the health of millions of Americans with or at risk for obesity- associated non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the United States. After successfully validating MR imaging biomarkers for hepatic steatosis, the earliest histologic feature of NAFLD, in the first cycle of this grant, this competitive renewal focuses on hepatic fibrosis and inflammation, features of non-alcoholic steatohepatitis (NASH), the aggressive subtype of NAFLD that can progress to cirrhosis, liver cancer, and liver-related death. MR elastography (MRE), a noninvasive method to quantify tissue stiffness, is the leading imaging-based technique for assessing liver fibrosis in NAFLD, but the true diagnostic performance of MRE for detecting fibrosis and NASH cross-sectionally, and for monitoring their change longitudinally, is incompletely understood. By optimizing and rigorously evaluating MRE for these purposes, we will address major knowledge and technical gaps that have obscured the appropriate utilization of this technology in clinical care and research. Aim 1: Optimize MRE wavefield generation in severe obesity, applicable to both conventional 2D- and advanced 3D-MRE. Aim 2: Characterize the precision profile of conventional 2D- and advanced 3D-MRE in severe obesity (same-day repeatability, field-strength reproducibility, reader reproducibility, between-day reproducibility). Aim 3: Determine the accuracy of conventional 2D- and advanced 3D-MRE in severe obesity to a) diagnose fibrosis and NASH cross-sectionally and b) monitor change in fibrosis and resolution of NASH longitudinally. Significance: By determining the true diagnostic performance of conventional 2D- and advanced 3D-MRE for detecting and monitoring fibrosis and NASH in bariatric patients, the proposed research will inform the appropriate utilization of MRE for clinical care, clinical trials, and other research in obesity-associated NAFLD. Additionally, if the research confirms the promise of advanced 3D-MRE to detect early-stage NASH, this will represent a game-changing new technical capability. Innovation: This application brings innovation in three thematic areas: (1) Study design: prospective cross-sectional and longitudinal study in bariatric patients, a technically challenging population with balanced disease severity distribution ideal for addressing the scientific aims. (2) Wavefield generation: testing of new flexible drivers designed to generate high-quality wavefields. (3) MRE analysis: rigorous testing of advanced 3D-MRE reconstruction and analysis methods that in preliminary animal and human studies show promise for diagnosing early-stage NASH. Research design & methods: Phase 1 of this 2-site study will optimize MRE wavefield generation in severe obesity by identifying the driver type and position that maximize MRE precision. Using that optimal driver type/position, Phase 2 will enroll 100 severely obese adults (50/site) undergoing weight-loss surgery in a prospective longitudinal study with 2D- and 3D-MRE at multiple time points. Reference standards for the presence of fibrosis and NASH, and their change, will include expert consensus scoring and quantitative image analysis of paired contemporaneous biopsies obtained at surgery and at 6 months. Complementary anthropometric, laboratory, and MRI measures will be acquired to identify factors that affect MRE performance and develop hypotheses for future studies. !