Impact of the Glymphatic System on the Kinetic and Distribution of Gadodiamide in the Rat Brain: Observations by Dynamic MRI and Effect of Circadian Rhythm on Tissue Gadolinium Concentrations

Objectives The glymphatic system is a recently hypothesized waste clearance system of the brain in which perivascular space constitutes a pathway similar to the lymphatic system in other body regions. Sleep and anesthesia are reported to influence the activity of the glymphatic system. Because rats are nocturnal animals, the glymphatic system is expected to be more active during the day. We attempted to elucidate the influence of the glymphatic system for intravenously injected gadodiamide in the rat brain by 2 experiments. One was a magnetic resonance imaging (MRI) experiment to evaluate the short-term dynamics of signal intensity changes after gadodiamide administration. The other was a quantification experiment to evaluate the concentration of retained gadolinium within the rat brain after repeated intravenous administration of gadodiamide at different times of day and levels of anesthesia. Materials and Methods The imaging experiment was performed on 6 rats that received an intravenous injection of gadodiamide (1 mmol/kg) and dynamic MRI for 3 hours at 2.4-minute intervals. The time course of the signal intensity changes was evaluated for different brain structures. The tissue quantification experiment was performed on 24 rats divided into 4 groups by injection time (morning, late afternoon) and anesthesia (none, short, long) during administration. All animals received gadodiamide (1.8 mmol/kg, 8 times over 2 weeks). Gadolinium concentration of dissected brain tissues was quantified 5 weeks after the last administration by inductively coupled plasma mass spectrometry. Results In the imaging experiment, muscle and the fourth ventricle showed an instantaneous signal intensity increase immediately after gadodiamide injection. The signal curve of the cerebral cortex and deep cerebellar nuclei reached the peak signal intensity later than the fourth ventricle but earlier than that of the prepontine cistern. In the gadolinium quantification experiment, the concentration in the group with the morning injection showed a significantly lower concentration than the late afternoon injection group. The lowest tissue gadolinium concentrations were found in the groups injected in the morning during long anesthesia. Conclusions Instantaneous transition of gadodiamide from blood to cerebrospinal fluid was indicated by dynamic MRI. The gadodiamide distribution to the cerebral cortex and deep cerebellar nuclei seemed to depend on both blood flow and cerebrospinal fluid. This confirms previous studies indicating that the cerebrospinal fluid is one potential pathway of gadolinium-based contrast agent entry into the brain. For the distribution and clearance of the gadodiamide from brain tissue, involvement of the glymphatic system seemed to be indicated in terms of the influence of sleep and anesthesia. Received for publication January 30, 2018; and accepted for publication, after revision, February 28, 2018. Conflicts of interest and sources of funding: Gregor Jost, Thomas Frenzel and Hubertus Pietsch are employees of Bayer AG. Correspondence to: Toshiaki Taoka, MD, PhD, Department of Radiology, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466–8550, Japan. E-mail: ttaoka@med.nagoya-u.ac.jp. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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