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

通过磁共振成像、细胞计数和弹性成像 (MR-ICE) 对非酒精性脂肪性肝病 (NAFLD) 的肝脏组织病理学进行综合无创评估

• 批准号: 10517042
• 负责人: Meng Yin
• 金额: $ 35.78万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517042
• 关键词: 3-Dimensional; Address; Adult; Affect; Assessment tool; Biological Markers; Biopsy; Cell Size; Chemical Shift Imaging; Cirrhosis; Clinical; Clinical Research; Clinical Trials; Cytometry; Development; Diagnosis; Diagnostic; Diet; Diffusion; Disease; Ensure; Evaluation; Evolution; Fatty acid glycerol esters; Fibrosis; Frequencies; Goals; Hepatic; Hepatocyte; Histologic; Histopathology; Hybrids; Image; Image Cytometry; Imaging technology; Inflammation; Intercellular Fluid; Intervention; Iron; Knowledge; Life; Liver; Liver Fibrosis; Liver diseases; Magnetic Resonance Elastography; Magnetic Resonance Imaging; Measurement; Mechanics; Methods; Modeling; Modification; Modulus; Monitor; Motion; Patients; Performance; Phase; Prevalence; Protocols documentation; Radial; Rattus; Research; Research Personnel; Risk; Scheme; Severities; Signal Transduction; Staging; Statistical Models; Steatohepatitis; Techniques; Technology; Testing; Therapeutic Intervention; Tissues; Training; Treatment Efficacy; United States; Water; Work; advanced disease; base; biomarker validation; cell injury; clinical practice; design; elastography; hepatocellular injury; high risk; imaging biomarker; imaging modality; in vivo; in vivo imaging; liver biopsy; liver inflammation; liver stiffness; mechanical properties; multiparametric imaging; non-alcoholic fatty liver disease; non-invasive imaging; nonalcoholic steatohepatitis; novel; preclinical study; primary endpoint; reconstruction; research clinical testing; secondary endpoint; simple steatosis; success; treatment effect; vector; virtual; viscoelasticity

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.

项目摘要 /摘要 非酒精性脂肪肝疾病（NAFLD）的越来越多的患病率使必要 简单脂肪变性的患者与非酒精性脂肪性肝炎（NASH）的患者不同。 但是，肝炎感染和细胞损伤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无创成像方法 诊断纳什和纵向评估肝注射和肝细胞损伤以监测 治疗效率。现在，脂肪变性和纤维病的存在和严重程度已得到很好的解决 化学移位成像和磁共振弹性图（MRE）。我们目前的研究周期 确认，MRE评估的损失模量是炎症的非常有希望的生物标志物。在此续约中 应用程序，我们建议继续验证该生物标志物进行创新并添加无创的 通过在MRE方案中引入新的MR细胞仪修饰来评估细胞损伤（气球）。 这项工作的总体目标是开发和验证多参数MR-ICE成像技术以完全 评估NAFLD进化期间疾病状态，尤其是炎症和肝细胞损伤。 •在AIM 1中，我们将开发MR-ICE成像协议。脂肪分数将使用6分dixon评估 方法。双频，自动化和混合径向radial-cartesian 3D矢量肝MRE技术 优化以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开发 专门为肝细胞细胞术而设计，无论是否同时获得MRE。 •在AIM 2中，我们将在体内大鼠模型中执行MR-ICE的纵向应用（n = 96，饮食诱导 纳什）。技术完整性和诊断性能将通过比较多个体内评估 具有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），动态机械分析（DMA）测试和组织学特征（脂肪变性， 炎症，气囊，纤维化）。统计模型将接受培训以诊断NASH。 •在进行试点临床评估之前，我们将在5个对照和5个对照中的MR-ICE生物标志物的重复性 使用重测策略的临床患者。最后，对10个对照和40例患者进行了试点临床评估 将进行活检证实的NAFLD/NASH，以提供诊断的初步证据 MR-ICE协议的性能进行了NAFLD/NASH。 新兴疗法的干预措施可能需要终身治疗，从而需要更精确的非 - 识别需要此类干预措施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有可能进步对NASH的精确无创评估。