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.

眼睛是了解脑积水大脑健康的窗口 项目概要 脑积水是一种因大脑中脑脊液 (CSF) 积聚过多而导致的衰弱性疾病。 心室。全球儿童脑积水的总体患病率为十分之八，死亡率为 未经治疗的脑积水率高达 87%。大多数儿科脑积水病例 (>90%) 得到管理 手术上，使用脑室分流术转移脑脊液。不幸的是，分流的时间是根据总的 颅内压 (ICP) 和大脑健康的测量，包括脑室大小和临床体征。延迟 脑脊液分流可导致颅内压升高和不可逆的脑损伤。侵入式ICP监测虽然更精确， 由于存在出血和脑损伤的风险，不常用于儿童。该提案弥合了 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 这可以消除侵入性 ICP 监测的需要。作为大脑的直接延伸，眼睛充当了 研究 ICP 的一个窗口，但迄今为止还没有评估眼部血流动力学的非侵入性方法 已被证明与侵入性 ICP 监测一样可靠。在我们提出的研究中，眼部对比增强超声 (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。 CEUS 静脉注射使用 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 ICP 升高和脑缺血的评估。虽然 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建议进行临床转化，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 损伤和坏死性小肠结肠炎。该提案的中心假设是眼部超声造影将提供 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 使用模拟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 优化的眼部 CEUS 方案的安全性。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。