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

胎儿发作性脑积水是最常见的儿科疾病，需要手术治疗，可导致 大脑皮层发育异常和终生神经缺陷。一个持续不断的挑战是提供“非苏尔-- “胎儿性脑积水的外科治疗”是为了阐明Glym-2的潜在调节机制。 神经性功能障碍。尤其是星形胶质细胞激活和血管旁清除的功能动态相互作用。 脑积水的脑部异常反应仍然难以捉摸。该方案的目标是开发一种多模式磁共振成像 产前/产后脑脊液动力学异常和血管旁清除受损的识别方法 并对胎儿期脑积水幼年阶段星形胶质细胞的病理生理功能进行了表征， 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)的锰增强磁共振成像 (MEMRI)方法估计MN在两个实质(即血管旁)的分布和清除动力学 脑室(脑脊液血流动力学)和脑室(脑脊液血流动力学)作为出生前/出生后小鼠淋巴循环的标志物。另外， 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 幼年小鼠血管特异性静息状态血流动力学相关性变化。改变的血管血液- 脑积水的动力学和血管旁清除特征将结合 GCaMP6介导的大脑皮质和海马区星形胶质细胞钙离子纤维记录我们将解决 该建议的目的有两个：1)。识别脑脊液动力学异常和血管旁清除受损 胎儿性脑积水胎鼠GFAP/转化生长因子-β1转基因小鼠。我们将开发基于MDEFT的MEMRI来 脑脊液和脑实质锰强化信号在出生前后的分布和清除 脑积水的小鼠。2.星形胶质细胞介导的血管血流动力学与异常脑室旁 胎儿发作性脑积水的循环清除。我们将把并发的单血管功能磁共振成像与 光纤介导的星形胶质细胞钙离子记录用于阐明星形胶质细胞功能障碍的动态联系 脑积水中成对的血管旁清除和病理血管血流动力学。使用小说 多模式MRI方法，我们希望找到淋巴功能障碍的特异性标记物，这些标记物可以反式 目的：指导和优化胎儿发作性脑积水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.