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

• 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
• 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

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.

眼睛作为脑海中大脑健康的窗口 项目摘要 脑积水是一种令人衰弱的疾病 心室。儿童脑积水的整体全球流行率为100,000分之88，死亡率率为死亡率 未经处理的脑积水高达87％。大多数儿科脑积水病例（> 90％）是管理的 操作，使用心室分流转移CSF。不幸的是，分流的时机是由毛茸茸的指导 颅内压（ICP）和大脑健康的度量，包括心室大小和临床体征。延迟 CSF转移会导致ICP升高和不可逆的脑损伤。侵入性ICP监视，虽然更精确，但 由于出血和脑损伤的风险，在儿童中不常规采用。该提议桥接 通过验证眼血流作为ICP和脑缺血的精确生物标志物，通过验证眼血流的显着临床差距 这可以消除对ICP监测的需求。作为大脑的直接延伸，眼睛已成为 研究ICP的窗口，但迄今为止没有评估眼动力学的无创方法 事实证明，与侵入性ICP监测一样可靠。在我们提出的研究中，眼对比增强超声 （CEU）使用高速超声系统在高保真的儿科猪模型中进行 脑积水以验证ICP和脑缺血的眼血流量标记。 CEU静脉内使用 注入2-3 µm大小的微泡，比红细胞小，可以在多个上跟踪 使用高级粒子跟踪方法的超声帧（称为粒子图像和/或跟踪赛车测定法 或PIV/PTV）。结果，可以量化眼微循环的空间和临时变化 评估ICP升高和脑缺血的评估。而CEU技术是FDA批准的小儿 Ocular CEUS的应用，专门用于评估局灶性肝病变和囊泡级反射X的应用。 调查团队准备根据此提案进行临床翻译准备，因为PI目前领导 第一次由FDA调节的研究新药（IND）批准了脑CEUS的临床试验 损伤和坏死性小肠结肠炎。该提案的中心假设是眼CEU将提供 ICP和脑缺血的准确生物标志物。因此，该提案的总体目标是1）验证和 使用模仿模拟的PHANTOM模型来完善PIV/PIV/PTV对眼部成像的准确性和可重复性 复杂的眼部微血管网络和赞助眼运动，2）验证眼CEUS指数 ICP和脑缺血使用已建立的脑积水的小儿猪模型和3）体内评估 优化的眼CEUS协议的安全性。我们的工作将为新的临床翻译奠定基础 用于评估小儿脑积水中ICP和脑缺血的无创工具，最终可以 影响受影响儿童的生存和长期结局。