Impaired Glymphatic Transport in Spontaneously Hypertensive Rats.

The glymphatic system is a brainwide CSF transport system that uses the perivascular space for fast inflow of CSF. Arterial pulsations are a major driver of glymphatic CSF inflow, and hypertension that causes vascular pathologies, such as arterial stiffening and perivascular alterations, may impede the inflow. We used dynamic contrast-enhanced MRI to assess the effect of hypertension on glymphatic transport kinetics in male young and adult spontaneously hypertensive (SHR) rats compared with age-matched normotensive Wistar-Kyoto rats (WKY). We anesthetized the rats with dexmedetomidine/isoflurane and infused paramagnetic contrast (Gd-DOTA) into the cisterna magna during dynamic contrast-enhanced MRI to quantify glymphatic transport kinetics. Structural MRI analysis showed that cerebroventricular volumes are larger and brain volumes significantly smaller in SHR compared with WKY rats, regardless of age. We observed ventricular reflux of Gd-DOTA in SHR rats only, indicating abnormal CSF flow dynamics secondary to innate hydrocephalus. One-tissue compartment analysis revealed impeded glymphatic transport of Gd-DOTA in SHR compared with WKY rats in both age groups, implying that glymphatic transport, including solute clearance from brain parenchyma, is impaired during evolving hypertension in young SHR, an effect that worsens in states of chronic hypertension. The study demonstrates the suppression of glymphatic clearance in SHR rats and thus offers new insight into the coexistence of hypertension and concomitant vascular pathologies in Alzheimer's disease. The study further highlights the importance of considering the distribution of tracers in the CSF compartment in the analysis of the glymphatic system.SIGNIFICANCE STATEMENT The glymphatic system contributes to the removal of amyloid ß from the brain and is disrupted in Alzheimer's disease and aging. Using a rat model of hypertension, we measured gross CSF flow and tracked glymphatic influx and efflux rates with dynamic contrast-enhanced MRI, showing that glymphatic transport is compromised in both early and advanced stages of hypertension. The study provides a new perspective on the importance for brain metabolite and fluid homeostasis of maintaining healthy blood vessels, an increasingly pertinent issue in an aging population that in part may explain the link between vascular pathology and Alzheimer's disease.

Quantitative Gd-DOTA uptake from cerebrospinal fluid into rat brain using 3D VFA-SPGR at 9.4T.

PURPOSE: We propose a quantitative technique to assess solute uptake into the brain parenchyma based on dynamic contrast-enhanced MRI (DCE-MRI). With this approach, a small molecular weight paramagnetic contrast agent (Gd-DOTA) is infused in the cerebral spinal fluid (CSF) and whole brain gadolinium concentration maps are derived. METHODS: We implemented a 3D variable flip angle spoiled gradient echo (VFA-SPGR) longitudinal relaxation time (T1) technique, the accuracy of which was cross-validated by way of inversion recovery rapid acquisition with relaxation enhancement (IR-RARE) using phantoms. Normal Wistar rats underwent Gd-DOTA infusion into CSF via the cisterna magna and continuous MRI for approximately 130 min using T1-weighted imaging. Dynamic Gd-DOTA concentration maps were calculated and parenchymal uptake was estimated. RESULTS: In the phantom study, T1 discrepancies between the VFA-SPGR and IR-RARE sequences were approximately 6% with a transmit coil inhomogeneity correction. In the in vivo study, contrast transport profiles indicated maximal parenchymal retention of approximately 19% relative to the total amount delivered into the cisterna magna. CONCLUSION: Imaging strategies for accurate 3D contrast concentration mapping at 9.4T were developed and whole brain dynamic concentration maps were derived to study solute transport via the glymphatic system. The newly developed approach will enable future quantitative studies of the glymphatic system in health and disease states. Magn Reson Med 79:1568-1578, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Serial scans in healthy volunteers following intravenous administration of gadoteridol: time course of contrast enhancement in various cranial fluid spaces.

PURPOSE: Heavily T2-weighted, 3-dimensional, fluid-attenuated inversion recovery (hT2W-3D-FLAIR) imaging has been reported to detect low concentrations of gadolinium-based contrast media (GBCM) in the anterior eye segment (AES), subarachnoid space (SAS), and labyrinthine perilymph as well as in the cerebrospinal fluid (CSF) of the internal auditory canal (IAC) 4 hours after intravenous administration of a single dose (IV-SD-GBCM) in patients with inner ear disorders. To elucidate the time course of contrast enhancement in healthy volunteers, we obtained hT2W-3D-FLAIR serially after IV-SD-GBCM. MATERIALS AND METHODS: We obtained hT2W-3D-FLAIR before and 0.5, 1.5, 3, 4.5 and 6 hours after IV-SD-GBCM in 6 healthy volunteers and measured signal intensity of the AES, SAS surrounding the optic nerve (SAS-ON), SAS in Meckel's cave (SAS-MC), pontine parenchyma, CSF in the IAC (CSF-IAC), CSF in the ambient cistern (CSF-AC), CSF in the lateral ventricles (CSF-LV), perilymph (PL), and endolymph (EL) in the labyrinth. We then compared averaged values among all time points using analysis of variance (ANOVA). RESULTS: After IV-SD-GBCM, we observed no change in signal intensity in the pontine parenchyma, CSF-LV, or EL and significant enhancement in all other structures. Maximum enhancement was most frequent at 4.5 hours after IV-SD-GBCM in the SAS-ON and PL, at 1.5 hours in the AES and SAS-MC, and at 3 hours in the CSF-IAC and CSF-AC. CONCLUSIONS: Contrast enhancement can be detected by hT2W-3D-FLAIR in the AES, SAS-ON, SAS-MC, PL, CSF-IAC, and CSF-AC in healthy volunteers after IV-SD-GBCM. Timing of maximum enhancement differed among locations. These data might serve as basic knowledge for future clinical research.