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: 10710213
• 负责人: David Delmar Limbrick
• 金额: $ 62.81万
• 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/10710213
• 关键词: Ablation; Adolescent; Affect; Africa South of the Sahara; Aftercare; Anatomy; Animal Model; Animals; Autopsy; Axon; Behavior; Biology; Brain; Caring; Cauterize; Cell Death; Cells; Cephalic; Cerebral Ventricles; Cerebrospinal Fluid; Child; Childhood; Choroid Plexus Epithelium; Clinical; Clinical Management; Cognition; Cognitive; Complex; Creation of ventriculo-peritoneal shunt; Cytology; Cytopathology; Data; Development; Diffusion Magnetic Resonance Imaging; Domestic Pig; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Epithelium; Exhibits; Family suidae; Flow Cytometry; Fluid Balance; Goals; Hemorrhage; Hippocampus; Hospital Charges; Human; Hydrocephalus; IL8 gene; Immune; Impaired cognition; Impairment; Individual; Infant; Inflammation; Inflammatory; Injections; Interleukin-6; Intracranial Pressure; Kaolin; Knowledge; 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; myelination; nervous system disorder; neurobehavioral; neurodevelopment; neurodevelopmental effect; neurogenesis; neurosurgery; novel; 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状况，影响了500个人中有1个。 心室旋转分流（VPS）已成为60年以上的标准治疗方法 有问题的，出现高功能率的高功能率，通常会导致复杂的神经外科治疗寿命 关心。内窥镜第三室造口术（ETV）是分流的替代方法，但婴儿的效率有限。 将脉络丛烧伤（CPC）添加到ETV中似乎是分类婴儿的可行替代品。尽管 相互矛盾的结果，目前正在定期和全球提供ETV-CPC，并且有限的理解 该程序对大脑发育的风险或好处。缺乏有关手术的知识 ETV-CPC的身体后果构成了广泛接受此事的重大障碍 程序。例如，消融脉络丛的影响，脉络丛，这是一种调节的主要稳态器官 神经发生和神经发育尚未确定。需要实验研究来确定 ETV和ETV-CPC在临床实践中的作用，但是缺乏适当的，有验证的大型动物模型 这些技术在脑生理学上测试这些技术，并在批判性地对大脑发育进行了研究。 我们的假设驱动的提案建立在我们发展出大型临床动物的基础工作的基础上 少年家猪中的HC模型，并且表现出ETV+CPC和VP的可行性，因此继续 NIH PA-180-623的目标，“增强产前和小儿脑积水研究的工具”。三个具体 AIMS将检验我们的中心假设，即与VPS相比，ETV+CPC通过 VZ/SVZ和PVWM前体生物学的破坏以及促炎信号的CSF稳态：AIM 1-比较VPS和ETV+CPC对VZ/SVZ和PVWM的细胞学效应；目标2-确定效果 脉络丛和CSF轮廓上的VPS和ETV+CPC的;目标3-比较神经行为和认知 用VPS和ETV+CPC处理的HC动物的结果。支持这些目标是发布和初步的 数据显示了脑室内区域（SVZ）和周围白质（PVWM）的细胞病理学 用VP和ETV+CPC，心室区（VZ）破坏，SVZ/PVWM细胞死亡，神经胶质激活和 杂质，PVWM神经胶质激活和少突胶质祖细胞，流式细胞术和单细胞RNA的降低 测序小胶质细胞和前体谱系，CSF细胞和蛋白质改变的差异，并减少 认知评估。分析将在处理后30天和90天进行。选择猪 研究与人类神经解剖学和生理学以及使用标准临床的能力的研究 神经外科技术。成功完成拟议的研究将填补HC研究中的关键空隙 通过对新兴手术程序和伤害机制进行严格的测试，这对于识别至关重要 HC临床管理的最佳神经外科实践。

项目成果

Impaired neurogenesis with reactive astrocytosis in the hippocampus in a porcine model of acquired hydrocephalus.

在获得性脑积水的猪模型中，海马反应性星形细胞增多症神经发生受损。

• DOI: 10.1016/j.expneurol.2023.114354
• 发表时间: 2023
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Garcia-Bonilla,Maria;Nair,Arjun;Moore,Jason;Castaneyra-Ruiz,Leandro;Zwick,SarahH;Dilger,RyanN;Fleming,StephenA;Golden,RebeccaK;Talcott,MichaelR;Isaacs,AlbertM;LimbrickJr,DavidD;McAllister2nd,JamesP
• 通讯作者: McAllister2nd,JamesP

A novel model of acquired hydrocephalus for evaluation of neurosurgical treatments.

• DOI: 10.1186/s12987-021-00281-0
• 发表时间: 2021-11-08
• 期刊: Fluids and barriers of the CNS
• 影响因子: 7.3
• 作者: McAllister JP 2nd;Talcott MR;Isaacs AM;Zwick SH;Garcia-Bonilla M;Castaneyra-Ruiz L;Hartman AL;Dilger RN;Fleming SA;Golden RK;Morales DM;Harris CA;Limbrick DD Jr
• 通讯作者: Limbrick DD Jr

Acquired hydrocephalus is associated with neuroinflammation, progenitor loss, and cellular changes in the subventricular zone and periventricular white matter.

• DOI: 10.1186/s12987-022-00313-3
• 发表时间: 2022-02-22
• 期刊: Fluids and barriers of the CNS
• 影响因子: 7.3
• 作者: Garcia-Bonilla M;Castaneyra-Ruiz L;Zwick S;Talcott M;Otun A;Isaacs AM;Morales DM;Limbrick DD Jr;McAllister JP 2nd
• 通讯作者: McAllister JP 2nd