Comprehensive noninvasive assessment of liver histopathology in nonalcoholic fatty liver disease (NAFLD) via magnetic resonance imaging, cytometry and elastography (MR-ICE)

项目总结/摘要 非酒精性脂肪性肝病（NAFLD）的日益普遍， 区分单纯性脂肪变性患者和非酒精性脂肪性肝炎（NASH）患者。 然而，肝脏炎症和细胞损伤的诊断通常需要侵入性肝活检， 组织病理学分期迫切需要安全可靠的非侵入性成像方法， 诊断NASH和纵向评估肝脏炎症和肝细胞损伤以监测 治疗效果脂肪变性和纤维化的存在和严重程度现在得到了很好的解决， 化学位移成像和磁共振弹性成像（MRE）。我们目前的研究周期 证实MRE评估的损耗模量是一种非常有前途的炎症生物标志物。在这次更新中， 应用，我们建议继续验证这种炎症生物标志物，并增加非侵入性 通过在MRE方案中引入新的MR细胞术修改来评估细胞损伤（气球样变）。 这项工作的总体目标是开发和验证多参数MR-ICE成像技术， 评估NAFLD演变过程中的疾病状态，特别是炎症和肝细胞损伤。 在目标1中，我们将开发MR-ICE成像协议。将使用6点狄克逊评价脂肪分数 法双频、自导航和混合径向-笛卡尔3D向量肝脏MRE技术将 可以优化表征粘弹性和非线性的多种机械性能。MRC 序列和重建将使用梯度波形和扩散信号拟合来开发， 专为肝细胞计数而设计，可同时采集或不采集MRE。 ·在目标2中，我们将在体内大鼠模型中进行MR-ICE的纵向应用（N=96，饮食诱导的 NASH）。将通过比较多个体内试验评估技术完整性和诊断性能 离体组织组成的成像生物标志物（脂肪分数、肝细胞大小、粘弹性、非线性） （水和脂肪含量）、动态力学分析（DMA）测试和组织学特征（脂肪变性， 炎症、气球样变、纤维化）。将训练统计模型以诊断NASH。 ·在初步临床评价之前，我们将评估5个对照组和5个对照组中MR-ICE生物标志物的可重复性。 临床患者使用测试-再测试策略。最后，在10名对照和40名患者中进行了初步临床评价。 将进行活检证实的NAFLD/NASH，以提供诊断的初步证据。 MR-ICE方案用于NAFLD/NASH分期的性能。 新兴的治疗干预措施可能需要终身治疗，因此需要更精确的非药物治疗。 用于识别需要此类干预的患者的侵入性方法。MR-ICE的发展将 使我们和其他研究人员能够推进NASH的精确无创评估。

PROJECT SUMMARY / ABSTRACT The growing prevalence of nonalcoholic fatty liver disease (NAFLD) creates an imperative to reliably distinguish between patients with simple steatosis and those with nonalcoholic steatohepatitis (NASH). However, hepatic inflammation and cellular injury diagnoses often require invasive liver biopsies for histopathologic staging. There is an urgent need for safe and reliable noninvasive imaging methods for diagnosing NASH and longitudinal assessing hepatic inflammation and hepatocellular injury to monitor treatment efficacy. The presence of and severity of steatosis and fiborosis are now well addressed with chemical shift imaging and magnetic resonance elastography (MRE). Our current cycle of research has confirmed that MRE-assessed loss modulus is a very promising biomarker for inflammation. In this renewal application, we propose to continue validation of this biomarker for inflammation and to add noninvasive assessment of cell injury (ballooning) by introducing a novel MR cytometry modification into the MRE protocol. The overall goal of this work is to develop and validate multiparametric MR-ICE imaging technologies for fully assessing disease states during NAFLD evolution, especially inflammation and hepatocellular injury. • In Aim 1, we will develop the MR-ICE imaging protocol. Fat fraction will be evaluated with a 6-point Dixon method. A dual-frequency, self-navigating, and hybrid radial-Cartesian 3D vector hepatic MRE technique will be optimized for characterizing multiple mechanical properties of viscoelasticity and nonlinearity. MRC sequence and reconstruction will be developed with gradient waveforms and diffusion signal fitting that are specifically designed for hepatocyte cytometry, with or without simultaneous MRE acquisition. • In Aim 2, we will perform longitudinal application of the MR-ICE in an in vivo rat model (N=96, diet-induced NASH). Technical integrity and diagnostic performance will be assessed by comparing multiple in vivo imaging biomarkers (fat fraction, hepatocyte size, viscoelasticity, nonlinearity) with ex vivo tissue composition (water and fat contents), dynamic mechanical analysis (DMA) testing and histologic features (steatosis, inflammation, ballooning, fibrosis), respectively. Statistical models will be trained to diagnose NASH. • Prior to pilot clinical evaluation, we will aseess the repeatability of MR-ICE biomarkers in 5 controls and 5 clinical patients using a test-retest strategy. Finally, a pilot clinical evaluation in 10 controls and 40 patients with biopsy-proven NAFLD/NASH will be performed to provide preliminary evidence of the diagnostic performance of the MR-ICE protocol for staging NAFLD/NASH. Emerging therapeutic interventions may require life-long treatment, creating the need for more precise non- invasive methods for identifying those patients who need such interventions. The development of MR-ICE will make it possible for us and other investigators to advance the precise noninvasive assessment of NASH.