A new animal study published online June 22 in Investigative Radiology has linked one class of gadolinium-based contrast agents (GBCAs) to increased deposits of the element in the brains of rats, highlighting recent safety concerns about the use of the MRI contrast medium.
French researchers found that over time "significant and persistent" MRI abnormalities developed in the brains of rats receiving gadodiamide (Omniscan, GE Healthcare), while no such T1-weighted hyperintensities were evident in the brains of rats injected with gadoterate meglumine (Dotarem, Guerbet) or a saline solution.
The results showed high total gadolinium concentrations in the deep cerebellar nuclei of rats given gadodiamide, which corresponded with the location of the T1-weighted hyperintensities.
Raising awareness
The study, led by Philippe Robert, PhD, from the French pharmaceutical company Guerbet, comes as interest in the potential long-term effects of gadolinium-based contrast agents has been renewed in light of new research.
In December 2013, researchers from Teikyo University in Tokyo, led by Dr. Tomonori Kanda, PhD, found a connection between gadolinium-based MRI contrast and abnormalities in two regions of the brain, which could represent a reaction to gadolinium's toxicity. The results suggested the possibility that a toxic component of the contrast agent may remain in the body long after it is injected, even in patients with normal renal function.
In May of this year, Kanda and colleagues confirmed their previous findings that traces of gadolinium contrast remain in the brain years after contrast-enhanced MRI scans. The results raised new questions about the safety of gadolinium-based contrast, such as whether the deposits are harmful.
In another related paper, McDonald et al from the Mayo Clinic in Rochester, MN, were unable to explain gadolinium traces they found in four areas of the brain several years after the administration of MRI contrast.
Finally, Radbruch and colleagues discovered greater signal intensity in the dentate nucleus and globus pallidus of patients who had received gadopentetate dimeglumine (Magnevist, Bayer HealthCare), while there was no such escalation in patients who had received gadoterate meglumine -- despite the fact that a substantially larger dose of contrast was used in the latter group (Radiology, June 2015, Vol. 275:3, pp. 783-791).
Exploring the mystery
For their investigation, Robert and colleagues examined healthy female rats that weighed 210 g (± 29 g) at the beginning of the study. The animals received 20 intravenous injections of 0.6 mmol of gadolinium per kilogram (1.2 mL/kg) over a period of five weeks, with four daily and consecutive injections per week. Injections were administered while the rats were anesthetized.
The gadolinium dose of 0.6 mmol/kg is equivalent to the usual human dose of 0.1 mmol/kg, after adjusting for a patient's size as recommended by the U.S. Food and Drug Administration (FDA).
The rats were divided into three groups of seven each. One group was given gadodiamide, the second group was given gadoterate meglumine, and a control group received a saline solution. The rats were scanned under general anesthesia with T1-weighted MRI on a 2.35-tesla preclinical magnet (BioSpec 24/40, Bruker) with a dedicated quadrature brain coil.
Scans were performed before the first GBCA administration, once a week during the five weeks of injections, and for five additional weeks during which no contrast injections were given. MR images were obtained after the fourth, eighth, 12th, 16th, and 20th injections, and also three days after the last administration. Twenty rats completed the protocol. A behavioral examination was also performed daily, the researchers noted.
At the end of the study protocol, the animals were sacrificed, and the total gadolinium concentration in the brains of the rats was measured and compared.
Comparing the agents
The total gadolinium concentration was eight- to 52-fold greater in the brains of rats injected with gadodiamide, compared with the rats given gadoterate meglumine or the saline control, Robert and colleagues found.
| Gadolinium concentration in brain regions | |||
| Region | Gadodiamide | Gadoterate meglumine | Control |
| Cerebellum | 3.66 ± 0.91 nmol/g | 0.26 ± 0.12 nmol/g | 0.07 ± 0.10 nmol/g |
| Cerebral cortex | 2.32 ± 0.46 nmol/g | 0.30 ± 0.08 nmol/g | 0.17 ± 0.20 nmol/g |
| Subcortical brain | 2.47 ± 0.62 nmol/g | 0.30 ± 0.10 nmol/g | 0.08 ± 0.06 nmol/g |
In addition, gadolinium concentration was significantly higher in subcortical regions among rats given gadoterate meglumine (0.30 ± 0.10 nmol/g) compared with the control group (0.08 ± 0.06 nmol/g).
The T1 signal hyperintensity in the deep cerebellar nuclei of rats receiving gadodiamide remained at a high level and stable during the treatment-free period, and it was qualitatively equivalent after five weeks and after 10 weeks. T1 signal hyperintensity was lower and showed no difference between the gadoterate meglumine and control groups at any time point.
The researchers also looked at the ratio of the deep cerebellar nuclei signal to the cerebellar cortex signal for the three groups at each time point. A significant increase in the ratio was seen only in the gadodiamide group beginning at the 12th injection. The maximum value was reached for each rat given gadodiamide from the 12th to the 20th injection, with the deep cerebellar nuclei/cerebellar cortex ratio staying the same for five weeks after the last injection.
The finding indicates "no washout effect and the persistence of this phenomenon for a long time after the last administration of gadodiamide," the authors wrote.
"Our results suggest that delayed T1-weighted signal hyperintensity in rat deep cerebellar nuclei depends on the molecular structure of GBCA (macrocyclic vs. linear), since this effect was observed only in animals treated with the linear GBCA gadodiamide," they concluded. "Additional studies including other GBCAs are warranted."
No notable abnormal behavior was seen in any of the rats during the treatment period, they added. The authors recommended additional studies to explore whether long-term gadolinium deposits in the cerebellum could cause any adverse clinical consequences.
