Gadolinium-based Contrast Media, Cerebrospinal Fluid and the Glymphatic System: Possible Mechanisms for the Deposition of Gadolinium in the Brain

Toshiaki Taoka, Shinji Naganawa, Toshiaki Taoka, Shinji Naganawa

Abstract

After Kanda's first report in 2014 on gadolinium (Gd) deposition in brain tissue, a considerable number of studies have investigated the explanation for the observation. Gd deposition in brain tissue after repeated administration of gadolinium-based contrast medium (GBCM) has been histologically proven, and chelate stability has been shown to affect the deposition. However, the mechanism for this deposition has not been fully elucidated. Recently, a hypothesis was introduced that involves the 'glymphatic system', which is a coined word that combines 'gl' for glia cell and 'lymphatic' system. According to this hypothesis, the perivascular space functions as a conduit for cerebrospinal fluid to flow into the brain parenchyma. The perivascular space around the arteries allows cerebrospinal fluid to enter the interstitial space of the brain tissue through water channels controlled by aquaporin 4. The cerebrospinal fluid entering the interstitial space clears waste proteins from the tissue. It then flows into the perivascular space around the vein and is discharged outside the brain. In addition to the hypothesis regarding the glymphatic system, some reports have described that after GBCM administration, some of the GBCM distributes through systemic blood circulation and remains in other compartments including the cerebrospinal fluid. It is thought that the GBCM distributed into the cerebrospinal fluid cavity via the glymphatic system may remain in brain tissue for a longer duration compared to the GBCM in systemic circulation. Glymphatic system may of course act as a clearance system for GBCM from brain tissue. Based on these findings, the mechanism for Gd deposition in the brain will be discussed in this review. The authors speculate that the glymphatic system may be the major contributory factor to the deposition and clearance of gadolinium in brain tissue.

Keywords: cerebrospinal fluid; gadolinium-based contrast media; glymphatic system; magnetic resonance imaging; tissue deposition.

Conflict of interest statement

Conflicts of Interest

Toshiaki Taoka received lecture fees from Bayer Yakuhin, Ltd., Fuji Pharma Co., Ltd., Daiichi-Sankyo Co. Ltd., and Eisai Co. Ltd.

Shinji Naganawa received lecture fees from Bayer Yakuhin, Ltd., Fuji Pharma Co., Ltd., Daiichi-Sankyo Co. Ltd., and Eisai Co. Ltd, and non-purpose research funds from Daiichi-Sankyo Co. Ltd. and Eisai Co. Ltd.

Figures

Fig. 1
Fig. 1
Deposition of gadolinium in the dentate nucleus. A case with multiple sclerosis between an initial MRI performed in 2009 (a) and an MRI performed in 2017 (b), repeated contrast-enhanced MRI examinations were performed 17 times using linear-type gadolinium-based contrast medium (GBCM) five times and macrocyclic GBCM 12 times. On the T1-weighted image obtained with fast spin echo imaging in 2017 (b: arrow), the bilateral dentate gyrus shows high-signal intensity. The signal intensity ratio between the pons and dentate nucleus was 1.02 in 2009 and 1.08 in 2017.
Fig. 2
Fig. 2
Outline of the glymphatic system. This figure illustrates that perivascular clearance comprises perivascular drainage and glymphatic pathways. (1) Cerebrospinal fluid flows into the brain parenchyma via the periarterial space, which is the perivascular space surrounding the parenchymal arteries. From this perivascular space surrounding the artery, cerebrospinal fluid enters the interstitium of the brain tissue via aquaporin 4 (AQP4)-controlled water channels. These are distributed in the end feet of astrocytes that constitute the outer wall of the perivascular space. (2) Cerebrospinal fluid entering the interstitial fluid flows by convection, and the cerebral spinal fluid (CSF)– interstitial fluid (ISF) exchange within the brain parenchyma. (3) After washing the waste proteins from the tissue, it flows into the perivenous space, which is the perivascular space around the deep-draining vein, and is subsequently discharged outside the brain., (Reprinted by permission from Macmillan Publishers Ltd: Nat Rev Neurol [11:457–470], copyright [2015]).
Fig. 3
Fig. 3
Distribution of gadolinium-based contrast medium (GBCM) over time after intravenous injection. Heavily T2-weighted fluid attenuated inversion recovery (FLAIR) imaging over time after GBCM administration to normal volunteers. Images at 30 minutes (a and e), 1.5 h (b and f), 3 h (c and g), and 6 h (d and h) after administration are shown. Signal enhancement was observed in the anterior eye segment (empty arrow head), the perilymph of the inner ear (white arrow head), the cerebrospinal fluid in the internal auditory canal (arrow), Meckel’s cave, and the suprasellar cistern to the ambient cistern (empty arrow), indicating the distribution of GBCM. The peak enhancement after administration was 1.5 h in the anterior eye segment and Meckel’s cave, 3 h in the internal auditory canal and ambient cistern, and 4.5 h (not shown) in the perilymph in the inner ear and optic nerve sheath.
Fig. 4
Fig. 4
Distribution of gadolinium-based contrast medium (GBCM) to the perivascular space. Heavily T2-weighted fluid attenuated inversion recovery (FLAIR) 4 h after intravenous GBCM administration. As in Fig. 3, in addition to the internal auditory canal (a), Meckel’s cave (a), anterior eye segment (b), and optic nerve sheath (b), a wide range of the cerebrospinal fluid space shows high-signal intensity indicating the distribution of GBCM. Markedly high-signal intensity is seen in the enlarged perivascular space of the basal ganglia (c: arrow) compared to the other cerebrospinal fluid cavities.
Fig. 5
Fig. 5
Hypothesis of the mechanism for gadolinium deposition via the glymphatic system. Introducing our hypothesis for gadolinium deposition. Compared with gadolinium-based contrast medium (GBCM) in the systemic circulation, GBCM distributed into the cerebrospinal fluid cavity via glymphatic system can remain in brain tissue for a long time. The authors of this review speculate that the glymphatic system may be involved in the tissue deposition of gadolinium.

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