On June 22, 2015, an article in Investigative Radiology was published online ahead of print.  The study by Robert et al, T1-Weighted Hypersignal in the Deep Cerebellar Nuclei After Repeated Administrations of Gadolinium-Based Contrast Agents in Healthy Rats – Difference Between Linear and Macrocyclic Agents”, describes for the first time “an animal model reproducing closely the recent clinical observations of cerebellum T1 signal hypersignal”.  “It also introduces an animal model to investigate the mechanism of the brain retention observed after repeated administrations of some GBCA.”

After 20 intravenous injections of 0.6 mmol of gadolinium per kilogram (4 injections per week for 5 weeks) of gadodiamide (Omniscan) or gadoterate meglumine (Dotarem) to healthy rats, they found that repeated injections of gadodiamide are associated with “progressive and persistent T1 signal hyperintensity in the deep cerebellar nuclei (DCN), with Gd deposition in the cerebellum in contrast with the macrocyclic GBCA gadoterate meglumine for which no effect was observed”.  Although repeated doses of gadoterate meglumine (Dotarem) did not cause signal increases, detectable concentrations of gadolinium were found in the cerebellum, cerebral cortex, and subcortical brain of the rats that were injected with it. 

The study included 21 healthy female Sprague-Dawley rats that were divided into 3 groups of 7 – gadodiamide group, gadoterate meglumine group, and a control group. One rat in the control group died at week 4.  The rats were injected 4 times a week for 5 weeks.  Brain T1-weighted MR imaging was performed before and once a week during the 5 weeks of injections, and during 5 additional weeks that were treatment-free.

The results show that repeated administrations of the linear GBCA gadodiamide (Omniscan) results in increased accumulation of gadolinium in brain tissues.  The cumulative effect of deposited gadolinium was “qualitatively observed in this animal model from the 8th injection of gadodiamide, which is close to the threshold 6 injections reported in humans to observe signal hyperintensity in the dentate nucleus”.  The signal hyperintensity did not resolve during the 5-week treatment-free period, “suggesting no washout effect”.  Once the gadolinium has been deposited in brain tissues, it appears that it might remain there for a long time.

Robert and colleagues noted that further studies are needed to determine whether the T1-weighted brain signal enhancement is related to dissociation of gadolinium from the chelate and to investigate the neurotoxicologic consequences of gadolinium deposited in the brain tissues.

This study raises some important questions.

While we are pleased that new research about gadolinium retention is being conducted, this study left me with more questions than answers.

Is it the increased signal or the gadolinium in the brain tissue that is the problem?  While the gadolinium concentrations were significantly lower in the Dotarem group than in the Omniscan group, the Gd concentration was not zero in any area of the brain tested – gadolinium from Dotarem (gadoterate meglumine) also remained in the brain.  I would think that should be of concern.

How much gadolinium can the brain tolerate?  How will it affect long-term cognitive function?

If gadolinium is being deposited in the brain, even at the lower concentrations seen with Dotarem, isn’t it logical to assume that gadolinium has been deposited elsewhere in the body too?

Does a hyperintense signal need to be seen on MR images before an alarm bell goes off?

If no amount of free gadolinium is allowed to be injected into humans, why is it acceptable to inject patients with Gadolinium-based Contrast Agents that are documented to leave residual gadolinium behind in the brain and other tissues?

While this study may have answered some questions for scientists, it has left me with many more questions that I believe need to be answered.

To learn more about the effects of retained gadolinium from GBCAs, see the Background section of our website.

Sharon Williams

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Robert, P., Lehericy, S., Grand, S., Violas, X., Fretellier, N., Idée, J.-M., … Corot, C. (2015). T1-Weighted Hypersignal in the Deep Cerebellar Nuclei After Repeated Administrations of Gadolinium-Based Contrast Agents in Healthy Rats: Difference Between Linear and Macrocyclic Agents. Investigative Radiology, 50(8). Retrieved from http://journals.lww.com/investigativeradiology/Fulltext/2015/08000/T1_Weighted_Hypersignal_in_the_Deep_Cerebellar.1.aspx