Development of a Multi-Modal MRI Methodology to Map Paravascular Clearance Linked to Astrocyte Dysfunction in Fetal-Onset Hydrocephalus

开发多模态 MRI 方法来绘制与胎儿发病脑积水的星形胶质细胞功能障碍相关的血管旁间隙

• 批准号: 10370865
• 负责人: Xin Yu
• 金额: $ 46.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370865
• 关键词: 1 year old; 3-Dimensional; Address; Adolescent; Age; Anatomy; Animal Model; Astrocytes; Autopsy; Blood Vessels; Brain; Brain region; Cerebrospinal Fluid; Cerebrospinal fluid shunts procedure; Child; Childhood; Development; Diagnostic; Disease; Echo-Planar Imaging; Economic Burden; Embryo; Equilibrium; Failure; Fiber; Fiber Optics; Fourier Transform; Functional Magnetic Resonance Imaging; Functional disorder; Future; Glial Fibrillary Acidic Protein; Goals; Healthcare; Hip region structure; Hippocampus (Brain); Hydrocephalus; Imaging technology; Impairment; Lead; Life; Link; Magnetic Resonance Imaging; Manganese; Maps; Mediating; Methodology; Methods; Multimodal Imaging; Mus; Neurologic; Neurologic Deficit; Newborn Infant; Operative Surgical Procedures; Pathologic; Photometry; Play; Prognostic Factor; Regulation; Reporting; Rest; Role; Sampling; Shunt Device; Signal Transduction; Symptoms; Therapeutic; Time; To specify; Transgenic Mice; Translating; Ventriculostomy; absorption; arachnoid villi; arteriole; base; cerebral blood volume; effective therapy; fetal; glymphatic dysfunction; glymphatic flow; glymphatic system; hemodynamics; improved; in utero; multimodality; neonate; novel; novel marker; optical fiber; overexpression; postnatal; prognostic; response; treatment optimization; vasomotion

Fetal-onset hydrocephalus is the most frequent pediatric disease requiring surgical intervention, which can lead to abnormal cortical development and life-long neurological deficits. An ongoing challenge to provide “non-sur- gical treatment” of the fetal-onset hydrocephalus is to elucidate the underlying regulatory mechanism of glym- phatic dysfunction. In particular, the functional dynamic interaction of astrocyte activation and paravascular clear- ance in the hydrocephalus brain remains elusive. The goal of this proposal is to develop a multi-modal MRI methodology to identify CSF dynamic abnormality and impaired paravascular clearance at pre/postnatal stages and characterize the pathophysiological astrocyte function at the juvenile stage of fetal-onset hydrocephalus, aiming to provide novel biomarkers with diagnostic, prognostic, and therapeutic value. We will implement a 3- dimensional Modified-Driven-Equilibrium Fourier Transform (3D-MDEFT)-based Manganese-enhanced MRI (MEMRI) method to estimate the Mn distribution and clearance dynamics in both parenchyma (i.e. paravascular clearance) and ventricles (CSF flow dynamics) as markers of glymphatic circulation in pre/postnatal mice. Also, we will apply the balanced steady-state free precession (bSSFP)-based single-vessel fMRI method to identify the vessel-specific resting-state hemodynamic correlation changes in juvenile mice. The altered vascular hemo- dynamics and paravascular clearance features of the hydrocephalic brain will be mapped in combination with the GCaMP6-mediated astrocytic Ca2+ fiber optic recordings in both cortex and hippocampus. We will address the proposal in two aims: 1). Identify CSF dynamic abnormality and impaired paravascular clearance in pre/post- natal GFAP/TGF-β1 transgenic mice with fetal-onset hydrocephalus. We will develop MDEFT-based MEMRI to map the distribution and clearance of Mn-enhanced CSF and parenchyma signals cross pre/postnatal stages of the hydrocephalic mice. 2. Correlate the astrocyte-mediated vascular hemodynamics to the abnormal paravas- cular clearance of the fetal-onset hydrocephalic brain. We will combine the concurrent single-vessel fMRI with optical fiber-mediated astrocytic Ca2+ recording to elucidate the dynamic linkage of astrocytic dysfunction, im- paired paravascular clearance, and pathological vascular hemodynamics in the hydrocephalic brain. Using novel multi-modal MRI methods, we expect to identify specific markers for glymphatic dysfunction, which can be trans- lated to guide and optimize treatments of glymphatic dysfunction of fetal-onset hydrocephalus.

胎儿发病的脑积水是最常见的需要手术干预的儿科疾病，这可能导致 皮质发育异常和终生神经功能缺陷是提供“非补充”的持续挑战。 胎儿发病脑积水的“药物治疗”的目的是阐明血糖的潜在调节机制 特别是星形胶质细胞激活和血管旁透明质酸的功能动态相互作用。 脑积水的脑部疾病仍然难以捉摸。该提案的目标是开发多模态 MRI。 产前/产后阶段识别脑脊液动态异常和血管旁清除受损的方法 并表征胎儿发病的脑积水幼年阶段的病理生理星形胶质细胞功能， 旨在提供具有诊断、预后和治疗价值的新型生物标志物，我们将实施3-。 基于三维修正驱动平衡傅立叶变换 (3D-MDEFT) 的锰增强 MRI (MEMRI) 方法来估计两个实质中的 Mn 分布和间隙动态（即血管旁组织） 清除率）和心室（脑脊液流动动力学）作为产前/产后小鼠类淋巴循环的标志物。 我们将应用基于平衡稳态自由进动（bSSFP）的单血管功能磁共振成像方法来识别 幼年小鼠血管特异性静息态血流动力学相关性变化。 脑积水大脑的动力学和血管旁间隙特征将结合 我们将讨论皮层和海马体中 GCaMP6 介导的星形细胞 Ca2+ 光纤记录。 该提案有两个目标：1）识别脑脊液动态异常和血管旁间隙受损。 我们将开发基于 MDEFT 的 MEMRI 来治疗患有胎儿期脑积水的出生 GFAP/TGF-β1 转基因小鼠。 绘制 Mn 增强的 CSF 和实质信号在产前/产后阶段的分布和清除图 2.将星形胶质细胞介导的血管血流动力学与异常的paravas-相关联 我们将同时进行单血管功能磁共振成像和胎儿脑积水的眼部清除。 光纤介导的星形细胞 Ca2+ 记录阐明星形细胞功能障碍的动态联系，im- 使用新颖的方法对脑积水脑中的血管旁间隙和病理血管血流动力学进行配对。 多模态 MRI 方法，我们期望识别类淋巴功能障碍的特定标记物，这些标记物可以是反式的 与指导和优化胎儿发病性脑积水的类淋巴功能障碍的治疗有关。