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

点击翻译按钮获取中文摘要

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.