Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: a potential pathway of entry into the brain tissue

Abstract

Objective: Signal hyperintensity on unenhanced MRI in certain brain regions has been reported after multiple administrations of some, but not all, gadolinium-based contrast agents (GBCAs). One potential initial pathway of GBCA entry into the brain, infiltration from blood into the cerebrospinal fluid (CSF), was systematically evaluated in this preclinical study.

Methods: GBCA infiltration and distribution in the CSF were investigated in healthy rats using repeated fluid-attenuated MRI up to 4 h after high-dose (1.8 mmol/kg) administration of six marketed and one experimental GBCA. Additionally, gadolinium measurements in CSF, blood and brain tissue samples (after 24 h) were performed using inductively coupled plasma mass spectrometry.

Results: Enhanced MRI signals in the CSF spaces with similar distribution kinetics were observed for all GBCAs. No substantial differences in the gadolinium concentrations among the marketed GBCAs were found in the CSF, blood or brain tissue. After 4.5 h, the concentration in the CSF was clearly higher than in blood but was almost completely cleared and lower than the brain tissue concentration after 24 h.

Conclusions: In contrast to the brain signal hyperintensities, no differences in penetration and distribution into the CSF of healthy rats exist among the marketed GBCAs.

Key points: • Gadolinium-based contrast agents can cross the blood-CSF barrier. • Fluid-attenuated MRI shows GBCA distribution with CSF flow. • GBCA structure and physicochemical properties do not impact CSF penetration and distribution. • GBCA clearance from CSF was almost complete within 24 h in rats. • CSF is a potential pathway of GBCA entry into the brain.

Keywords: Brain; Cerebrospinal fluid; Contrast media; Gadolinium; Magnetic resonance imaging.

Fig. 1

Experimental setup. The study was performed in two parts, each with six animals per experimental group. Part 1 (upper row) included MR-cisternography (MRC) and fluid-attenuated imaging (FLAIR) of the rat brain before and up to 240 min after injection of GBCA. After 270 min a blood and CSF sampling was performed. In part 2 (lower row) blood, CSF and samples from the cerebellum and pons were obtained 24 h after injection. No MRI was done in this part of the study. p.i. post injection

Fig. 2

Examples for region of interest (ROI) placement. For the quantitative analysis ROIs were placed around different CSF spaces using the MR-cisternography (MRC) images for anatomical reference

Fig. 3

Representative images. The CSF spaces were visualised by MR-cisternography (MRC), for example the fourth ventricle (arrowhead) and the subarachnoid space (arrow) (a). In the fluid-attenuated (FLAIR) images before GBCA injection the respective CSF signal is almost completely attenuated (b). After GBCA administration a clear signal enhancement of the CSF spaces was found in the FLAIR images up to 240 min post injection (p.i.) (c–e)

Fig. 4

Quantitative analysis of CSF signal intensity (SI). The analysis of the SI on fluid-attenuated (FLAIR) images over time in different CSF spaces was divided into two parts (a and b) because the SI for the baseline scans (t = 0 min) was significantly higher after servicing of the MRI scanner. However, each analysis includes a gadobutrol group to ensure comparability. gadopentetate = gadopentetate dimeglumine; gadobenate = gadobenate dimeglumine; gadoterate = gadoterate meglumine; error bars represent standard deviation

Fig. 5

Gadolinium (Gd) concentrations in CSF and blood. The gadolinium concentration determined in the CSF (b) and blood (b) samples obtained at 4.5 h and 24 h, respectively. gadopentetate = gadopentetate dimeglumine; gadobenate = gadobenate dimeglumine; gadoterate = gadoterate meglumine; error bars represent standard deviation

Fig. 6

Gadolinium (Gd) concentrations in the cerebellum and pons. The gadolinium concentration per gram tissue determined in the cerebellum (a) and pons (b) 24 h after administration. gadopentetate = gadopentetate dimeglumine; gadobenate = gadobenate dimeglumine; gadoterate = gadoterate meglumine; error bars represent standard deviation