Signal Increase on Unenhanced T1-Weighted Images in the Rat Brain After Repeated, Extended Doses of Gadolinium-Based Contrast Agents: Comparison of Linear and Macrocyclic Agents

Abstract

Objectives: In this prospective preclinical study, we evaluated T1-weighted signal intensity in the deep cerebellar nuclei (CN) and globus pallidus (GP) up to 24 days after repeated administration of linear and macrocyclic gadolinium-based contrast agents (GBCAs) using homologous imaging and evaluation methods as in the recently published retrospective clinical studies. In a second part of the study, cerebrospinal fluid (CSF) spaces were evaluated for contrast enhancement by fluid-attenuated magnetic resonance imaging (MRI).

Materials and methods: Sixty adult male Wistar-Han rats were randomly divided into a control and 5 GBCA groups (n = 10 per group). The administered GBCAs were gadodiamide, gadopentetate dimeglumine, and gadobenate dimeglumine (linear GBCAs) as well as gadobutrol and gadoterate meglumine (macrocyclic GBCAs) and saline (control). Over a period of 2 weeks, the animals received 10 intravenous injections at a dose of 2.5 mmol Gd/kg body weight, each on 5 consecutive days per week. Before GBCA administration, as well as 3 and 24 days after the last injection, a whole-brain MRI was performed using a standard T1-weighted 3-dimensional turbo spin echo sequence on a clinical 1.5 T scanner. The ratios of signal intensities in deep CN to pons (CN/Po) and GP to thalamus (GP/Th) were determined. For the evaluation of the CSF spaces, 18 additional rats were randomly divided into 6 groups (n = 3 per group) that received the same GBCAs as in the first part of the study. After MR cisternography for anatomical reference, a fluid-attenuated inversion recovery sequence was performed before and 1 minute after intravenous injection of a dose of 1 mmol Gd/kg body weight GBCA or saline.

Results: A significantly increased signal intensity ratio of CN/Po was observed 3 and 24 days after the last injection of gadodiamide and gadobenate dimeglumine. No significant changes were observed between the 2 time points. Gadopentetate dimeglumine injection led to a moderately elevated but statistically not significant CN/Po signal intensity ratio. No increased CN/Po signal intensity ratios were determined in the MRI scans of rats that received macrocyclic GBCAs gadobutrol and gadoterate meglumine or saline. The ratio of signal intensity in GP/Th was not elevated in any group injected with GBCAs or saline. Enhanced signal intensities of CSF spaces were observed in the postcontrast fluid-attenuated inversion recovery images of all animals receiving GBCAs but not for saline.

Conclusions: In this animal study in rats, increased signal intensity in the CN was found up to 24 days after multiple, extended doses of linear GBCAs. However, in contrast to clinical reports, the signal enhancement in the GP was not reproduced, demonstrating the limitations of this animal experiment. The elevated signal intensities remained persistent over the entire observation period. In contrast, no changes of signal intensities in either the CN or the GP were observed for macrocyclic GBCAs. However, all GBCAs investigated were able to pass the blood-CSF barrier in rats to a certain, not yet quantified extent.

Conflict of interest statement

Conflicts of interest and sources of funding: HP, GJ, JL, MAS, and TF are empoyees of Bayer Pharma AG. DCL received a research grant from Bayer Pharma.

Figures

FIGURE 1

A, Study setup and application scheme for GBCAs. Five consecutive daily intravenous injections (blue arrows) per week of 2.5 mmol GBCA/kg b.w. for 2 weeks were given to 10 animals per GBCA group. MRI scans (red arrows) were performed before (BL) GBCA application, and on day 15 (3 days p.i.) for 10 rats per group and on day 36 (24 days p.i.) of study initiation on 5 animals per group. On day 15 and on day 36, 5 rats each per GBCA group were euthanized for dissection. B and C, Examples of the positioning of the ROI for the signal intensity evaluation of deep CN and pons (Po) in B and of GP and thalamus (Th) in C.

FIGURE 2

Representative T1w MRI scans of CN in the cerebellum before (baseline, left column), at day 3 p.i. (middle column) and at day 24 p.i. (right column) with saline, gadobutrol, gadoterate meglumine, gadopentetate dimeglumine, gadobenate dimeglumine, and gadodiamide. Increased signal intensities of the CN are indicated by white arrows.

FIGURE 3

A, Change over time for signal intensity ratios between deep CN and pons (CN/Po) compared with baseline after injection of saline, gadobutrol, gadoterate meglumine, gadopentetate dimeglumine, gadobenate dimeglumine, and gadodiamide. *P < 0.05 and **P < 0.01 indicate statistical significance of CN/Po compared with baseline. B, Percent change of CN/Po for day 3 and day 24 p.i. compared with baseline. *P < 0.05 and **P < 0.01 indicate statistical significance of GBCA group compared with saline.

FIGURE 4

Percent change of GP/thalamus signal intensity ratio (GP/Th) for day 3 and day 24 p.i. compared with baseline.

FIGURE 5

Representative transversally acquired MRCs (left column) of the rat brains at a level showing the dorsal (das) and lateral arachnoid space (las) as well as the aqueduct (aq) and inner auditory canal (iac). The middle column illustrates the respective slices acquired with FLAIR before GBCA administration. The right column represents FLAIR images acquired 1 minute p.i. of saline, gadobutrol, gadoterate meglumine, gadopentetate dimeglumine, gadobenate dimeglumine, and gadodiamide.