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

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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.