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.

眼睛是脑积水患者大脑健康的窗口 项目摘要 脑积水是一种使人衰弱的疾病，由脑内脑脊液（CSF）过度积聚引起。 心室全球儿童脑积水的总患病率为10万分之88，死亡率为 未经治疗的脑积水比例高达87%。大多数小儿脑积水病例（>90%） 手术时，使用脑室分流术转移CSF。不幸的是，调车的时机是由总 测量颅内压（ICP）和大脑健康，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。有创ICP监测虽然更精确， 由于存在出血和脑损伤的风险，儿童不经常采用。这一提议将A 通过验证眼血流量作为ICP和脑缺血的精确生物标志物，在护理方面存在显著的临床差距 这就不需要有创颅内压监测了眼睛作为大脑的直接延伸， 研究ICP的一个窗口，但迄今为止，没有一种非侵入性方法评估眼部血流动力学 已被证明与侵入性ICP监测一样可靠。在我们提出的研究中，眼部超声造影 在高保真小儿猪模型中使用高速超声系统进行CEUS检查， 脑积水，以验证ICP和脑缺血的眼血流标志物。CEUS使用静脉内 注射2-3 µm大小的微泡，比红细胞小，可以在多个 使用先进的粒子跟踪方法（称为粒子图像和/或跟踪测速法 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技术是FDA批准的儿科 在临床应用中，特别是用于评价局灶性肝脏病变和膀胱输尿管反流，眼部CEUS是标签外使用。 研究团队随时准备根据该提议进行临床翻译，因为PI目前领导 首个FDA监管的、研究性新药（IND）批准的临床试验，将CEUS应用于患有脑血管疾病的婴儿 损伤和坏死性小肠结肠炎。该提案的中心假设是，眼部CEUS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 使用模拟眼成像的体模模型，改进PIV/PTV的准确性和再现性。 复杂的眼微血管网络和自发性眼球运动，2）验证眼CEUS指数， 使用建立的小儿脑积水猪模型和3）体内评估ICP和脑缺血 优化眼部CEUS方案的安全性。我们的工作将为临床翻译一种新的 无创工具，用于评估儿童脑积水的ICP和脑缺血，最终可以 影响受影响儿童的生存和长期结果。