Mapping of CSF transport using high spatiotemporal resolution dynamic contrast-enhanced MRI in mice: Effect of anesthesia.

PURPOSE: Dynamic contrast-enhanced MRI (DCE-MRI) represents the only available approach for glymphatic cerebrospinal fluid (CSF) flow 3D mapping in the brain of living animals and humans. The purpose of this study was to develop a novel DCE-MRI protocol for mapping of the glymphatic system transport with improved spatiotemporal resolution, and to validate the new protocol by comparing the transport in mice anesthetized with either isoflurane or ketamine/xylazine. METHODS: The contrast agent, gadobutrol, was administered into the CSF of the cisterna magna and its transport visualized continuously on a 9.4T preclinical scanner using 3D fast-imaging with a steady-state free-precession sequence (3D-FISP), which has a spatial resolution of 0.001 mm3 and a temporal resolution of 30 s. The MR signals were measured dynamically for 60 min in multiple volumes of interest covering the entire CSF space and brain parenchyma. RESULTS: The results confirm earlier findings that glymphatic CSF influx is higher under ketamine/xylazine than with isoflurane anesthesia. This was extended to account for new details about the distinct CSF efflux pathways under the two anesthetic regimens. Dynamic contrast MR shows that CSF clearance occurs mainly along the vagus nerve near the jugular vein under isoflurane and via the olfactory bulb under ketamine/xylazine. CONCLUSION: The improved spatial and temporal sampling rates afforded by 3D-FISP shed new light on the pharmacological modulation of CSF efflux paths. The present observations may have the potential to set a new standard for future experimental DCE-MRI studies of the glymphatic system.

The orthotopic xenotransplant of human glioblastoma successfully recapitulates glioblastoma-microenvironment interactions in a non-immunosuppressed mouse model.

BACKGROUND: Glioblastoma (GBM) is the most common primary brain tumor and the most aggressive glial tumor. This tumor is highly heterogeneous, angiogenic, and insensitive to radio- and chemotherapy. Here we have investigated the progression of GBM produced by the injection of human GBM cells into the brain parenchyma of immunocompetent mice. METHODS: Xenotransplanted animals were submitted to magnetic resonance imaging (MRI) and histopathological analyses. RESULTS: Our data show that two weeks after injection, the produced tumor presents histopathological characteristics recommended by World Health Organization for the diagnosis of GBM in humans. The tumor was able to produce reactive gliosis in the adjacent parenchyma, angiogenesis, an intense recruitment of macrophage and microglial cells, and presence of necrosis regions. Besides, MRI showed that tumor mass had enhanced contrast, suggesting a blood-brain barrier disruption. CONCLUSIONS: This study demonstrated that the xenografted tumor in mouse brain parenchyma develops in a very similar manner to those found in patients affected by GBM and can be used to better understand the biology of GBM as well as testing potential therapies.