Ultrasound Targeted Molecular Imaging in Large Arteries to Diagnose Stroke Risk

描述（由申请人提供）：每年约有110万人死于颈动脉粥样硬化栓塞。如果在斑块形成之前检测到动脉粥样硬化的发展，这些死亡是高度可预防的，通过改变生活方式或药物治疗。同样，如果颈动脉斑块能够充分表征（即易损斑块与稳定斑块），则介入治疗和疗法在疾病的后期阶段具有良好的临床疗效。基于超声的靶向分子成像代表了一种新兴技术，具有提供颈动脉粥样硬化的早期检测和颈动脉斑块的更特异性诊断和表征的潜力。然而，基于微泡的超声成像在临床中的当前使用仅限于一组狭窄的适应症（例如，肝结节诊断），并且靶向微泡成像的当前临床使用在很大程度上由于与大动脉中的成像相关的技术挑战而不存在。该项目的总体目标是打破目前阻碍基于超声的靶向分子成像用于预防中风的临床实用性的技术障碍。这一目标的成功实现将涉及一种新的靶向分子成像技术的体内演示，称为基于奇异谱的靶向分子（SiSTM）成像，具有超过95%的灵敏度和特异性检测兔主动脉粥样硬化的早期分子标志物。针对SiSTM成像的射束序列将进行优化，以增强灵敏度和特异性，包括自适应血流速度校正技术。此外，双频1.5D分子成像探针将被设计，制造，并在研究扫描仪上实现。将使用表现出极端高胆固醇血症和晚期动脉粥样硬化的遗传倾向的Watanabe遗传性高胆固醇血症品系（WHHL）兔评估大动脉中SSTM成像的体内灵敏度和特异性。疾病标志物的免疫组织化学结果将与SiSTM成像数据相关。 公共卫生相关性：中风是世界上主要的死亡原因，每年估计有720万人死亡。基于超声的分子成像策略是一种新兴技术，通过使用更简单、风险更低、成本更低的方法实现颈动脉粥样硬化的早期或及时治疗，具有早期检测和预防卒中的潜力。该项目将开发一种新的基于超声的分子成像技术，称为基于奇异谱的靶向分子（SiSTM）成像，并在体内兔子研究中验证检测心血管疾病早期标志物的技术。

DESCRIPTION (provided by applicant): Approximately 1.1 million deaths each year are a result of emboli from carotid artery atherosclerosis. These deaths are highly preventable through lifestyle changes or drug therapy if the development of atherosclerosis is detected prior to plaque formation. Similarly, interventional treatment and therapy is available with good clinica efficacy at later stages of the disease if carotid plaques can be adequately characterized (i.e. vulnerable versus stable plaques). Ultrasound-based targeted molecular imaging represents an emerging technology with potential to provide both earlier detection of carotid atherosclerosis and more specific diagnosis and characterization of carotid plaques. However, current use of microbubble-based ultrasound imaging in the clinic is limited to a narrow set of indications (e.g. liver nodule diagnosis) and current clinical use of targeted microbubble imaging is non-existent largely due to technical challenges associated with imaging in large arteries. The overarching goal of this project is to break down the technological barriers currently preventing clinical utilty of ultrasound-based targeted molecular imaging for prevention of stroke. Successful achievement of this goal will involve in vivo demonstration of a novel targeted molecular imaging technology, called singular spectrum-based targeted molecular (SiSTM) imaging, with greater than 95% sensitivity and specificity for detection of early molecular markers for atherosclerosis in rabbit aorta arteries. Beam sequences specific to SiSTM imaging will be optimized for enhanced sensitivity and specificity including an adaptive blood velocity correction technique. Additionally, a dual frequency 1.5D molecular imaging probe will be designed, fabricated, and implemented on a research scanner. In vivo sensitivity and specificity of SiSTM imaging in large arteries will be assessed using Watanabe heritable hyperlipidemic strain (WHHL) rabbits exhibiting genetic predisposition for extreme hypercholesterolemia and advanced atherosclerosis. Immunohistochemistry results for disease markers will be correlated with SiSTM imaging data. PUBLIC HEALTH RELEVANCE: Stroke is a leading cause of death in the world representing an estimated 7.2 million deaths annually. Ultrasound-based molecular imaging strategies are an emerging technology with potential for early detection and prevention of stroke by enabling early or prompt therapy of carotid atherosclerosis using simpler, lower risk, and lower cost approaches. This project will develop a new ultrasound-based molecular imaging technology, called singular spectrum-based targeted molecular (SiSTM) imaging, and validate the technique for detection of early markers for cardiovascular disease in in vivo rabbit studies.