High-resolution High-speed Photoacoustic and Ultrasound Imaging of SmallVessel Functions in Ischemic Stroke

摘要： 缺血性中风仍然是世界范围内死亡和长期残疾的主要原因。这是 随着人口日益老龄化，这一问题变得更加明显。包括我们在内的许多研究都揭示了 年轻人和老年人大脑的显著差异，包括与年龄相关的大脑变化 血管形态和血液氧合。治疗中风后脑的首要任务是恢复血液 脑实质的灌注，这依赖于脑血管网络的完整性。它已经被证明了 小血管(直径小于100微米)在缺血性中风后损失最多，结果 阻碍血液再灌流和延缓脑部重塑。此外，在缺血性中风后，有两个 主要的血管修复过程，急性期的动脉生成和延迟期的血管生成 主要在小血管层面被激活。血管损伤和再滴定都是不同的。 受缺血影响的不同脑区。因此，促进局部微血管的发展具有 被认为是一种特别有前途的治疗策略。然而，有针对性的血管建模尚未得到 在临床卒中治疗中取得成功，主要是因为我们对中风患者的微血管功能了解有限 中风后的大脑，尤其是老年人的大脑。目前的脑成像技术，特别是光学显微镜， 不同程度地受到低分辨率、低速度和/或浅渗透深度的影响，因此无法满足所需的需求 知识鸿沟。在这里，依托快速多边形扫描和超宽带等技术创新 在超声检测方面，我们建议开发一种真正相互作用的光声和紫外线成像系统 (IPAUSI)，这将比其他成像方式提供明显的优势。IPAUSI将提供纵向 小血管的结构和功能测量，包括血管形态(密度、体积、 曲折)、血液流动和血液氧合，具有高度的空间和时间细节。通过以下方式实现 能力，我们将执行一个全面的分析小血管损伤和重塑在 中风后小鼠的大脑。最终，我们期望获得关于小鼠侧支重构的详细信息。 老年卒中患者急性期血管和延迟期血管生成。我们将完成 我们的总体目标通过追求以下具体目标：(1)目标1：发展和优化综合 具有高时空分辨率的光声和超声成像系统。(2)目标2：发展 一套新的成像方法精确定量深部小血管的氧合和血流量 大脑。(3)目的3：研究年龄特异性对幼年小鼠缺血性卒中小血管重构的影响 和年龄。如果成功，我们的结果有望对中风后老化的大脑产生新的见解，这 将为针对老年中风患者的小血管重塑的新策略的开发提供信息。

Abstract: Ischemic stroke continues to be a leading cause of both mortality and long-term disability worldwide. This is becoming more pronounced with an increasingly aging population. Many studies, including ours, have revealed substantial differences between the young and aged brains, including age-associated changes in cerebral vasculature morphology and blood oxygneation. The first task in treating poststroke brain is to restore the blood perfusion to the parenchyma, which relies on the integrity of the cerebral vascular network. It has been shown that small blood vessels (diameters less than 100 µm) experience the most loss after ischemic stroke, resulting in the impediment of blood reperfusion and a delay in brain remodeling. Moreover, after ischemic stroke, two major vascular repair processes, arteriogenesis in the acute phase and angiogenesis in the delayed phase, are activated mostly at the small vessel levels. Both the vascualr impairment and resotration are heterogeneous at different brain regions affected by ischemia. Therefore, promoting the development of local microvessels has been recognized as a particularly promising therapeutic strategy. Yet, targeting vascular modeling has not been successful in clinical stroke mangement, primarily due to our limited understanding of microvascular functions in poststroke brains, especially in aged brains. Current brain imaging technologies, especially optical microscopy, variously suffer from low resolution, low speed, and/or shallow penetration depth, and thus cannot fill the needed knowledge gap. Here, relying on the tehnical innovations such as the fast polygon scanning and ultra-wideband ultrasound detection, we propose to develop a truly interagred photoacoustic and utlrasound imaging system (iPAUSI) that will provide clear advantages over other imaging modalities. iPAUSI will offering longitudinal structural and functional measurements of small vessels, including vascular morphology (density, volume, tortuosity), blood flow, and blood oxygenation, with high spatial and temporal details. Enabled by these capabilities, we will perform a comprehensive analysis of small vascular impairment and remodeling in the poststroke mouse brain. Ultimiately, we expect to obtain detailed information of collateral remodeling of small vessels in the acute phase and angiogenesis in the delayed phase, in the aged stroke brains. We will accomplish our overall objective by pursuing the following specific aims: (1) Aim1: Develop and optimize an integrated photoacoustic and ultrasound imaging system with high spatial and temporal resolutions. (2) Aim 2: Develop a set of novel imaging methods to accurately quantify the oxygenation and blood flow of small vessels in deep brain. (3) Aim 3: Study the age specific effects on small vessel remodeling in ischemic stroke in mice at young and age. If successful, our results are expected to generate new insights on the aged brains after stroke, which will inform development of new strategies targeting small vascular remodeling for elderly stroke patients.