Enabling accurate identification and quantification of brown adipose tissue mass by xenon enhanced computed tomography

项目摘要/摘要 在美国，超过36%的人患有肥胖症，9.4%的人患有糖尿病，其中大部分是2型糖尿病 由肥胖相关的胰岛素抵抗所驱动。目前的减肥策略已被证明在很大程度上是 为了阻止这一流行病，迫切需要不充分的、新的靶向疗法。在根本上 肥胖是由于能量摄入和能量消耗不平衡造成的。后者可以是 由棕色脂肪组织(BAT)的活动调节，这种组织不仅在能量上起着调节作用 平衡，也在葡萄糖的动态平衡中。因此，现在正在设计新的治疗方法来 靶向BAT治疗肥胖症和糖尿病。然而，这类发展的一个主要障碍是 治疗是准确检测和量化蝙蝠质量的能力。目前的技术要么是太 不敏感，或缺乏必要的特异性来区分这个组织和白色脂肪组织。这是 尤其是在超重/肥胖受试者--针对蝙蝠的介入治疗的目标人群中。 拟议的研究项目的目标是开发一种新的成像方法，该方法基于低剂量的氙气- 增强型CT(XECT)，可以检测BAT并准确测量其质量，独立于其 活动。这一建议建立在我们的初步结果的基础上，在这些结果中，我们已经表明，惰性和亲油性 气体氙气可作为CT造影剂用于检测和定量BAT质量。不管组织的 生热能力、水合状态和葡萄糖摄取能力，当刺激生热活性时， 氙气累积到蝙蝠体内的浓度高到足以显著改变其辐射密度。 组织，使蝙蝠在CT图像中可见。 我们在这项应用中的目标是：a)作为组织功能的BAT对Xe的摄取动力学的表征 瘦小和肥胖的非人类灵长类动物模型的水合作用和生热能力；b)表征 并优化用于人体纵向研究的低剂量XECT方案；以及c)建立低剂量XECT方案 与18F-FDG-PET/CT相比，剂量XECT能正确诊断BAT，具有更高的敏感性和特异性，最 广泛使用的测量蝙蝠体积的技术，以活组织检查为基础。 XECT将能够准确量化一般成年人口中的蝙蝠质量，同时提供 对肥胖发作期间该组织中发生的形态变化的新见解。这个项目是 预计会产生很大影响；这种新方法可以很容易地在标准的PET/CT平台上实施 并与BAT的其他功能措施相结合，通过减少局部体积来提高其准确性 效果。蝙蝠质量和活动的准确量化有望有助于更好地理解 由各种刺激和条件引起的这种组织的生长、进化和重塑。

PROJECT SUMMARY / ABSTRACT In the US, more than 36% of the population is obese and 9.4% has diabetes, most of which is type-2 diabetes driven by obesity-associated insulin resistance. Current anti-obesity strategies have been proven to be largely inadequate, and new-targeted therapies are desperately needed to stop this epidemic. At the fundamental level, obesity results from the imbalance between energy intake and energy expenditure. The latter can be regulated by the activity of brown adipose tissue (BAT), a tissue that plays a regulatory role not only in energy balance, but also in glucose homeostasis. As a result, new therapeutic approaches are now being devised to target BAT for the treatment of obesity and diabetes. However, a major roadblock to the development of such therapies is the ability to detect and quantify BAT mass accurately. Current techniques are either too insensitive, or lack the necessary specificity to differentiate this tissue from white adipose tissue. This is especially true in overweight/obese subjects - the target population for interventional therapies targeting BAT. The goal of the proposed research project is to develop a new imaging approach based on low-dose, xenon- enhanced CT (XECT) that can detect BAT and yield accurate measurements of its mass, independently of its activity. This proposal builds upon our preliminary results, in which we had shown that the inert and lipophilic gas xenon can be used as a CT contrast agent to detect and quantify BAT mass. Regardless of the tissue's thermogenic capacity, hydration status, and glucose uptake capacity, upon stimulation of thermogenic activity, xenon accumulates into BAT at a concentration high enough to significantly change the radiodensity of this tissue, making BAT visible in CT images. Our objectives in this application are: a) to characterize xenon uptake dynamics in BAT as a function of tissue hydration and thermogenic potency in lean and obese non human primates animal models; b) to characterize and optimize low-dose XECT protocols for use in longitudinal studies in humans; and c) to establish that low- dose XECT can correctly identify BAT with greater sensitivity and specificity than 18F-FDG-PET/CT, the most widely used technique for measurement of BAT volume, using biopsy as ground truth. XECT will enable accurate quantification of BAT mass in the general adult human population, while providing new insights into the morphological changes that occur in this tissue during the onset of obesity. This project is expected to have a high impact; this novel approach can be easily implemented on standard PET/CT platforms and combined with other functional measures of BAT to increase their accuracy by reducing partial volume effects. Accurate quantification of BAT mass and activity is expected to lead to a better understanding of the growth, evolution, and remodeling of this tissue resulting from various stimuli and conditions.