Experimental Studies of Endoscopic Third Ventriculostomy and Choroid Plexus Cauterization in Hydrocephalus

内镜下第三脑室造口术和脉络丛烧灼术治疗脑积水的实验研究

• 批准号: 10568647
• 负责人: David Delmar Limbrick
• 金额: $ 64.48万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-27 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568647
• 关键词: Ablation; Address; Adolescent; Affect; Africa South of the Sahara; Aftercare; Anatomy; Animal Model; Animals; Autopsy; Axon; Behavior; Biology; Brain; Caring; Cauterize; Cell Death; Cells; Cerebral Ventricles; Cerebrospinal Fluid; Child; Childhood; Choroid Plexus Epithelium; Clinical; Clinical Management; Cognition; Cognitive; Complex; Conflict (Psychology); Creation of ventriculo-peritoneal shunt; Cytology; Cytopathology; Data; Development; Diffusion Magnetic Resonance Imaging; Domestic Pig; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelial Cells; Exhibits; Family suidae; Flow Cytometry; Fluid Balance; Foundations; Goals; Gold; Hemorrhage; Hippocampus (Brain); Hospital Charges; Human; Hydrocephalus; IL8 gene; Immune; Impaired cognition; Impairment; Individual; Infant; Inflammation; Inflammatory; Injections; Interleukin-6; Intracranial Pressure; Kaolin; Knowledge; Lead; Length of Stay; Magnetic Resonance Imaging; Measures; Medical Device; Memory; Microglia; Molecular; NCAM1 gene; National Institute of Neurological Disorders and Stroke; Neuroanatomy; Neurobiology; Neurologic; Oligodendroglia; Operative Surgical Procedures; Organ; Outcome; Pediatric Hospitals; Physiological; Physiology; Pleocytosis; Procedures; Proteins; Proteomics; Publishing; Research; Risk; Role; Shunt Device; Signal Transduction; Structure of choroid plexus; Surgical Injuries; Techniques; Testing; Time; Tissues; United States National Institutes of Health; Ventricular; Ventriculostomy; Work; absorption; behavioral outcome; clinical practice; clinically relevant; cognitive testing; comparative; dysmyelination; evidence base; experimental study; extracellular vesicles; glial activation; immune activation; impaired brain development; improved; indexing; innovation; migration; nervous system disorder; neurobehavioral; neurodevelopment; neurodevelopmental effect; neurogenesis; novel; oligodendrocyte myelination; oligodendrocyte progenitor; porcine model; premature; prenatal; primary outcome; secondary analysis; single-cell RNA sequencing; spectrograph; standard care; stem cells; subventricular zone; tool; treatment effect; treatment group; white matter

Hydrocephalus (HC) is a common and debilitating neurological condition affecting up to 1 in 500 individuals. Ventriculoperitoneal shunting (VPS) has been the standard treatment for >60 years but shunts remain highly problematic, with an unacceptably high malfunction rate and often lead to a lifetime of complex neurosurgical care. Endoscopic third ventriculostomy (ETV) is an alternative to shunting but has limited efficacy in infants. Adding choroid plexus cauterization (CPC) to ETV seems to be a viable alternative to shunting infants. Despite conflicting outcomes, ETV-CPC is currently being offered routinely and globally, and with limited understanding of the risks or benefits of this procedure on brain development. The lack of knowledge about both the surgical and physiological consequences of ETV-CPC constitutes a significant barrier to broad acceptance of this procedure. For example, the impact of ablating the choroid plexus, a major homeostatic organ which regulates neurogenesis and neurodevelopment, has yet to be determined. Experimental studies are needed to determine the role of ETV and ETV-CPC in clinical practice, but the lack of appropriate, validated large animal models in which to test these techniques on brain physiology and, critically, on brain development, has never been studied. Our hypothesis-driven proposal builds on our foundational work that developed a large, clinically-relevant animal model of HC in juvenile domestic pigs and demonstrated feasibility of ETV+CPC, and VPS, thus continuing the goals of NIH PA-180-623, “Tools to Enhance the Study of Prenatal and Pediatric Hydrocephalus”. Three Specific Aims will test our Central Hypothesis that, compared with VPS, ETV+CPC impairs brain development through disruption of VZ/SVZ and PVWM precursor biology and CSF homeostasis with pro-inflammatory signaling: Aim 1 - compare the cytological effects of VPS and ETV+CPC on VZ/SVZ and PVWM; Aim 2 - determine the effect of VPS and ETV+CPC on choroid plexus and CSF profile; Aim 3 - compare neurobehavioral and cognitive outcomes in HC animals treated with VPS and ETV+CPC. Supporting these aims are published and preliminary data showing cytopathology in the subventricular zone (SVZ) and periventricular white matter (PVWM) following treatment with VPS and ETV+CPC, ventricular zone (VZ) disruption, SVZ/PVWM cell death, glial activation, and heterotopia, PVWM glial activation and reduced oligodendrocyte progenitors, flow cytometry and single cell RNA sequencing differences in microglia and precursor lineages, CSF cellular and protein alterations, and reduced cognitive assessments. Analyses will be performed at 30- and 90-days post-treatment. Pigs were chosen for studies for their close homology to human neuroanatomy and physiology and the ability to use standard clinical neurosurgical techniques. Successful completion of the proposed studies will fill a critical void in HC research through rigorous testing of emerging surgical procedures and injury mechanisms, which is essential to identifying best neurosurgical practices for the clinical management of HC.

脑积水 (HC) 是一种常见且令人衰弱的神经系统疾病，影响多达五百分之一的人。 脑室腹腔分流术 (VPS) 已成为标准治疗方法超过 60 年，但分流率仍然很高 存在问题，故障率高得令人无法接受，并且常常导致终生复杂的神经外科手术 内窥镜第三脑室造口术（ETV）是分流术的替代方法，但对婴儿的疗效有限。 尽管如此，在 ETV 中添加脉络丛烧灼术 (CPC) 似乎是分流婴儿的可行替代方案。 相互矛盾的结果，ETV-CPC 目前在全球范围内例行提供，但了解有限 该手术对大脑发育的风险或益处缺乏有关手术的知识。 ETV-CPC 的生理后果构成了广泛接受这一点的重大障碍 例如，消融脉络丛的影响，脉络丛是调节体内平衡的主要器官。 神经发生和神经发育，尚需实验研究才能确定。 ETV 和 ETV-CPC 在临床实践中的作用，但缺乏适当的、经过验证的大型动物模型 从未研究过如何在大脑生理学以及更重要的是大脑发育方面测试这些技术。 我们的假设驱动提案建立在我们开发大型临床相关动物的基础工作之上 建立了幼年家猪 HC 模型，并论证了 ETV+CPC 和 VPS 的可行性，从而继续研究 NIH PA-180-623“加强产前和儿童脑积水研究的工具”的目标。 目标将检验我们的中心假设，即与 VPS 相比，ETV+CPC 通过以下方式损害大脑发育： 促炎信号传导破坏 VZ/SVZ 和 PVWM 前体生物学和 CSF 稳态：目的 1 - 比较 VPS 和 ETV+CPC 对 VZ/SVZ 和 PVWM 的细胞学影响 目标 2 - 确定效果； VPS 和 ETV+CPC 对脉络丛和 CSF 特征的影响 目标 3 - 比较神经行为和认知； 使用 VPS 和 ETV+CPC 治疗的 HC 动物的结果已发表并初步支持这些目标。 数据显示脑室下区 (SVZ) 和脑室周围白质 (PVWM) 的细胞病理学 VPS 和 ETV+CPC 治疗、心室区 (VZ) 破坏、SVZ/PVWM 细胞死亡、神经胶质激活和 异位、PVWM 胶质细胞激活和少突胶质细胞祖细胞减少、流式细胞术和单细胞 RNA 小胶质细胞和前体谱系、脑脊液细胞和蛋白质改变的测序差异，并减少 认知评估将在治疗后 30 天和 90 天进行。 研究它们与人类神经解剖学和生理学的密切同源性以及使用标准临床的能力 神经外科技术的成功完成将填补 HC 研究的一个关键空白。 通过对新兴外科手术和损伤机制的严格测试，这对于识别 HC 临床管理的最佳神经外科实践。