Eye as a Window into Brain Health in Pediatric Hydrocephalus

眼睛是了解小儿脑积水大脑健康的窗口

基本信息

批准号：
10659299
负责人：
Misun Hwang
金额：
$ 69.46万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659299
关键词：
3-Dimensional Acoustics Adopted Affect Age Algorithms Assessment tool Biological Markers Blood Vessels Blood flow Brain Brain Injuries Brain Ischemia Calibration Caring Cerebral Ventricles Cerebrospinal Fluid Child Childhood Clinical Clinical Trials Compensation Complex Contrast Media Doppler Ultrasound Erythrocytes Evaluation Eye Eye Movements Eye diseases FDA approved Family suidae Goals Hemorrhage Histologic Histopathology Hydrocephalus Image Infant Infection International Intracranial Hypertension Intracranial Pressure Intravenous Investigational Drugs Ischemia Label Lesion Liquid substance Liver Location Maps Measures Mechanics Mediating Methods Microbubbles Microcirculation Microdialysis Modeling Monitor Motion Necrotizing Enterocolitis Ocular Pathology Operative Surgical Procedures Ophthalmologist Ophthalmology Optical Methods Optics Outcome Pathology Patients Peripheral Preparation Prevalence Procedures Protocols documentation Reproducibility Retina Risk Safety Shunt Device Speed Structure of fontanel of skull System Techniques Technology Ultrasonography Velocimetries Ventricular Vesico-Ureteral Reflux Visualization Work biomarker development brain health clinical translation contrast enhanced experience hemodynamics hypoxic ischemic injury in vivo indexing insight meter mortality multidisciplinary nervous system disorder neuropathology non-invasive monitor novel particle phantom model porcine model prevent prognostication spatiotemporal statistics therapeutic target tool ultrasound

项目摘要

Eye as a Window into Brain Health in Hydrocephalus Project Summary Hydrocephalus is a debilitating condition caused by excess buildup of cerebrospinal fluid (CSF) in the cerebral ventricles. The overall global prevalence of hydrocephalus in children is 88 out of 100,000, with the mortality rate of untreated hydrocephalus reaching up to 87%. Most pediatric hydrocephalus cases (>90%) are managed operatively, using a ventricular shunt to divert CSF. Unfortunately, timing of shunting is guided by gross measures of intracranial pressure (ICP) and brain health including ventricular size and clinical signs. Delaying CSF diversion can lead to elevated ICP and irreversible brain injury. Invasive ICP monitoring, while more precise, is not routinely adopted in children due to the risks of hemorrhage and brain injury. This proposal bridges a significant clinical gap in care by validating ocular blood flow as a precise biomarker of ICP and brain ischemia that can negate the need for invasive ICP monitoring. As a direct extension of the brain, the eye has served as a window into studying ICP, but to date none of the noninvasive approaches evaluating ocular hemodynamics has proven as reliable as invasive ICP monitoring. In our proposed study, ocular contrast-enhanced ultrasound (CEUS) using a high-speed ultrasound system is performed in a high-fidelity pediatric porcine model of hydrocephalus to validate ocular blood flow markers of ICP and brain ischemia. CEUS uses intravenously injected microbubbles of 2-3 µm in size, smaller than red blood cells, that can be tracked across multiple ultrasound frames using an advanced particle tracking method (called particle image and/or tracking velocimetry or PIV/PTV). As a result, spatial and temporal changes in ocular microcirculation can be quantified for assessment of elevated ICP and brain ischemia. While the CEUS technology is FDA-approved for pediatric applications, specifically for evaluation of focal liver lesions and vesicoureteral reflux, ocular CEUS is off-label. The investigative team stands ready for clinical translation following this proposal, as the PI currently leads the first FDA-regulated, Investigational New Drug (IND)-approved clinical trials applying CEUS in infants with brain injury and necrotizing enterocolitis. The central hypothesis of the proposal is that ocular CEUS will provide accurate biomarkers of ICP and brain ischemia. The overall goal of the proposal is therefore to 1) validate and refine the accuracy and reproducibility of the PIV/PTV for eye imaging using phantom models mimicking the complex ocular microvascular networks and spontaneous eye movement, 2) validate ocular CEUS indices of ICP and brain ischemia using an established pediatric porcine model of hydrocephalus and 3) assess in vivo safety of the optimized ocular CEUS protocol. Our work will set the stage for clinical translation of a new noninvasive tool for assessment of ICP and brain ischemia in pediatric hydrocephalus, which could ultimately impact survival and long-term outcomes of affected children.

眼睛是了解脑积水大脑健康的窗口项目概要脑积水是一种使人衰弱的疾病，由脑部脑脊液 (CSF) 过多积聚引起全球儿童脑积水的总体患病率为每 10 万人中就有 88 人患有脑积水，死亡率为未经治疗的脑积水率高达 87%，大多数儿童脑积水病例 (>90%) 得到了治疗。在手术上，使用脑室分流术来转移脑脊液，不幸的是，分流的时间是由粗略指导的。颅内压 (ICP) 和大脑健康的测量，包括脑室大小和临床症状。脑脊液转移可导致 ICP 升高和不可逆的脑损伤，同时更精确。由于存在出血和脑损伤的风险，该建议并未在儿童中常规采用。通过验证眼部血流作为 ICP 和脑缺血的精确生物标志物，在护理方面存在显着的临床差距眼睛作为大脑的直接延伸，可以消除侵入性ICP监测的需要。研究 ICP 的一个窗口，但迄今为止还没有评估眼血流动力学的非侵入性方法在我们提出的研究中，眼部对比增强超声已被证明与侵入性 ICP 监测一样可靠。 (CEUS) 使用高速超声系统在高保真儿科猪模型中进行脑积水以验证 ICP 和脑缺血的眼部血流标志物静脉内使用。注射的微泡尺寸为 2-3 µm，小于红细胞，可以在多个使用先进粒子跟踪方法（称为粒子图像和/或跟踪测速法）的超声帧或 PIV/PTV）因此，可以量化眼部微循环的空间和时间变化。评估 ICP 升高和脑缺血，而 CEUS 技术已获得 FDA 批准用于儿科。应用，特别是对于评估局灶性肝脏病变和膀胱输尿管反流，眼部超声造影是标签外的。研究团队已准备好按照该提案进行临床转化，因为 PI 目前正在领导该研究第一个 FDA 监管、研究性新药 (IND) 批准的临床试验，在患有脑部疾病的婴儿中应用 CEUS 该提案的中心假设是眼部超声造影将提供预防损伤和坏死性小肠结肠炎的能力。因此，该提案的总体目标是 1) 验证和确定。使用模仿眼睛的模型模型来提高 PIV/PTV 眼部成像的准确性和再现性复杂的眼部微血管网络和自发眼球运动，2) 验证眼部 CEUS 指数使用已建立的儿科猪脑积水模型进行 ICP 和脑缺血，并 3) 进行体内评估我们的工作将为新的临床转化奠定基础。用于评估儿科脑积水 ICP 和脑缺血的无创工具，最终可能影响受影响儿童的生存和长期结果。