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

胎儿发病脑积水是最常见的需要手术干预的儿科疾病， 大脑皮层发育异常和终生神经功能缺损一个持续的挑战，提供“非表面， 胎儿发病脑积水的“手术治疗”是为了阐明glym的潜在调节机制， 社交功能障碍特别是，星形胶质细胞活化和血管旁透明细胞的功能动态相互作用， 在脑积水的大脑中仍然是难以捉摸的。该提案的目标是开发一种多模态MRI 产前/产后阶段确定CSF动态异常和血管旁清除受损的方法 并表征胎儿发病脑积水幼年期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（即血管旁）中的Mn分布和清除动力学 清除）和心室（CSF流动动力学）作为出生前/出生后小鼠胶质淋巴循环的标志物。还有， 我们将应用基于平衡稳态自由进动（bSSFP）的单血管fMRI方法来识别 幼龄小鼠血管特异性静息态血流动力学相关性变化。改变的血管血- 脑积水脑的动力学和血管旁清除特征将结合 GCaMP 6介导的皮层和海马星形胶质细胞Ca ~（2+）纤维记录。我们将解决 该提案有两个目的：1）。确定术前/术后CSF动态异常和血管旁清除受损 GFAP/TGF-β1转基因小鼠胎仔期脑积水模型。我们将开发基于MDEFT的MEMRI， 绘制Mn增强的CSF和实质信号在出生前/出生后阶段的分布和清除图， 脑积水小鼠。2.将星形胶质细胞介导的血管血流动力学与异常的旁动脉相关联- 胎儿发病脑积水的眼清除率。我们将联合收割机与同步单血管功能磁共振成像结合， 光纤介导的星形胶质细胞Ca 2+记录，以阐明星形胶质细胞功能障碍的动态联系， 配对血管旁清除率和脑积水中的病理性血管血流动力学。使用新颖 多模态MRI方法，我们期望识别胶质淋巴功能障碍的特异性标志物，其可以是反式的， 旨在指导和优化胎儿发病脑积水的胶质淋巴功能障碍的治疗。

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.