Two linear GBCAs and one macrocyclic GBCA were associated with significantly elevated gadolinium levels in neuronal, hepatic, splenic, and renal tissues in rats, compared with administration of a saline solution (Radiology, June 19, 2017).
"Our current findings refute current assumptions that gadolinium deposition in neural tissues is limited to linear GBCAs," wrote lead author Dr. Robert J. McDonald, PhD, a staff neuroradiologist at the Mayo Clinic in Rochester, MN. "While macrocyclic agents had diminished elemental gadolinium tissue deposition compared with linear agents, significant differences in tissue concentrations were noted between [two] macrocyclic agents."
Over the past several years, human and animal studies have shown the presence of minute traces of gadolinium in brain tissue and within the central nervous system long after repeated administration of various GBCAs. Naturally, there has been considerable concern and debate over the potential effects of the lingering deposits.
McDonald and colleagues at the Mayo Clinic have been researching both linear and macrocyclic GBCAs. Their March 2015 study discovered traces of gadolinium in four areas of the brain several years after the administration of MRI contrast.
More recently, in a June 2017 study, McDonald et al found that gadolinium retention in the brain may be more widespread than previous studies have shown, and it may not be limited to patients with brain abnormalities such as a tumor or infection. The findings challenged previous theories regarding the permeability and role of the blood-brain barrier in the accumulation of gadolinium within the neural tissues.
In the current study, the researchers divided 25 healthy rats into two groups. Over a 26-day period, the gadolinium group received 20 intravenous injections of 2.5 mmol gadolinium per kilogram, while the control group was injected with saline.
The researchers administered two linear GBCAs -- gadodiamide (Omniscan, GE Healthcare) and gadobenate dimeglumine (MultiHance, Bracco Imaging) -- and two macrocyclic GBCAs -- gadobutrol (Gadavist, Bayer HealthCare Pharmaceuticals) and gadoteridol (ProHance, Bracco). Unenhanced T1 signal intensities of the dentate nucleus were measured from MRI scans before GBCA injection and three days after the final injection.
Gadolinium deposition in brain tissue varied significantly based on GBCA type (p < 0.0001), with the two linear GBCAs having greater concentrations per gram of tissue than the two macrocyclic GBCAs, according to the researchers.
In fact, McDonald and colleagues noted that gadolinium concentration was two to four times greater with the two linear agents, gadodiamide and gadobenate dimeglumine, compared with the macrocyclic GBCA gadobutrol. There were no detectable levels of gadoteridol.
|Gadolinium deposition in rat brain tissue
||Median concentration (µg gadolinium per gram of tissue)
|Saline (6 rats)
|Gadoteridol (6 rats)
|Gadobutrol (5 rats)
|Gadobenate dimeglumine (3 rats)
|Gadodiamide (5 rats)
Compared with the controls, all gadolinium-exposed rats had significantly elevated levels of elemental gadolinium in their dentate nuclei, ranging from 0.1 to 6.9 µg gadolinium per gram of tissue (p = 0.0002). Gadolinium was also discovered in renal, hepatic, and splenic tissues at much higher tissue concentrations (p < 0.0001) and in the endothelial capillary walls and neural interstitium in GBCA-injected rats.
As one might expect, there was no detectable neural tissue gadolinium deposition or MRI signal in any of the six control rats.
MR images show dentate nucleus. (A) Wide view of hematoxylin-eosin-stained coronal slice of rat cerebellum with annotation of the dentate nucleus (red, DN), anterior interpositus nucleus (AIN), and fastigial nucleus (FN). Unenhanced axial T1-weighted MR images through posterior fossa at level of dentate nucleus (dashed circle) are shown for (B) saline-exposed rat and (C) gadodiamide-exposed rat (total cumulative dose, 50 mmol/kg). Images courtesy of Radiology.
"These findings suggest that organ tissue deposition is reduced but not eliminated following administration of macrocyclic GBCA chelates in lieu of linear chelates," the authors wrote. "Furthermore, our study utilized more extensive methods to characterize the location and distribution of gadolinium deposits in neural tissues and quantified tissue deposition in other organs. Such findings add to the collective knowledge of the evolving field of GBCA-mediated gadolinium tissue deposition."
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