Abstract In December 2013, a groundbreaking study by Kanda et al. was published showing that the serial injection of gadolinium based contrast agents (GBCAs) is correlated with a signal intensity ...increase in the dentate nucleus (DN) and the globus pallidus (GP) on unenhanced T1 weighted MR images. Subsequent studies by Kanda et al. and McDonald et al. on brain tissue from deceased patients provided evidence that the reported signal intensity increase in the brain correlates with gadolinium deposits in the brain tissue. In the following, multiple retrospective patient studies and animal studies assessed the potential of the marketed GBCAs to cause hyperintensities or gadolinium deposits in the brain, respectively. This review summarizes the evidence provided by these studies and additionally takes into account data from in vitro studies on the stability of GBCAs. The author concludes that there is a body of evidence suggesting that the potential of a GBCA to cause hyperintensities or gadolinium deposition in the brain corresponds with its stability and is particularly depending on the group of the specific GBCA as either linear or macrocyclic.
Gadolinium (Gd) is one of the rare-earth elements. The properties of its trivalent cation (Gd3+) make it suitable to serve as the central ion in chelates administered intravenously to patients as a ...contrast agent in magnetic resonance imaging. Such Gd-chelates have been used for more than thirty years. During the past decades, knowledge has increased about potential harmful effects of Gd-chelates in patients with severe renal dysfunction. In such patients, there is a risk for a potentially disabling and lethal disease, nephrogenic systemic fibrosis. Restricting the use of Gd-chelates in persons with severely impaired renal function has decreased the occurrence of this toxic effect in the last decade. There has also been an increasing awareness of Gd-retention in the body, even in patients without renal dysfunction. The cumulative number of doses given, and the chemical structure of the chelate given, are factors of importance for retention in tissues. This review describes the chemical properties of Gd and its medically used chelates, as well as its toxicity and potential side effects related to injection of Gd-chelates.
Magnetic resonance imaging contrast agents are frequently used in clinics to enhance the contrast between diseased and normal tissues. The previously reported poly(acrylic acid) stabilized ...exceedingly small gadolinium oxide nanoparticles (ES‐GdON‐PAA) overcame the problems of commercial Gd chelates, but limitations still exist, i.e., high r2/r1 ratio, long blood circulation half‐life, and no data for large scale synthesis and formulation optimization. In this study, polymaleic acid (PMA) is found to be an ideal stabilizer to synthesize ES‐GdONs. Compared with ES‐GdON‐PAA, the PMA‐stabilized ES‐GdON (ES‐GdON‐PMA) has a lower r2/r1 ratio (2.05, 7.0 T) and a lower blood circulation half‐life (37.51 min). The optimized ES‐GdON‐PMA‐9 has an exceedingly small particle size (2.1 nm), excellent water dispersibility, and stability. A facile, efficient, and environmental friendly synthetic method is developed for large‐scale synthesis of the ES‐GdONs‐PMA. The weight of the optimized freeze–dried ES‐GdON‐PMA‐26 synthesized in a 20 L of reactor reaches the kilogram level. The formulation optimization is also finished, and the concentrated ES‐GdON‐PMA‐26 formulation (CGd = 100 mm) after high‐pressure steam sterilization possesses eligible physicochemical properties (i.e., pH value, osmolality, viscosity, and density) for investigational new drug application.
A polymaleic acid‐stabilized exceedingly small gadolinium oxide nanoparticle with superhigh r1 , ultralow r2/r1 and low blood circulation half‐life is developed to be a T1‐weighted magnetic resonance imaging contrast agent, which can be synthesized up to kilogram level by a facile, efficient and environmental friendly method and possesses eligible physicochemical properties for investigational new drug application.
Background and Purpose
Evidence of brain gadolinium retention has affected gadolinium‐based contrast agent usage. It is, however, unclear to what extent macrocyclic agents are retained and whether ...their in vivo detection may necessitate nonconventional MRI. Magnetization transfer (MT) could prove suitable to detect gadolinium‐related signal changes since dechelated gadolinium ions bind to macromolecules. Therefore, this study aimed to investigate associations of prior gadolinium administrations with MT and T1 signal abnormalities.
Methods
A cohort of 23 persons with multiple sclerosis (MS) (18 females, 5 males, 57 ± 8.0 years) with multiple past gadolinium administrations (median 6, range 3‐12) and 23 age‐ and sex‐matched healthy controls underwent 1.5 Tesla MRI with MT, T1‐weighted 2‐dimensional spin echo, and T1‐weighted 3‐dimensional gradient echo. The signal intensity index was assessed by MRI in gadolinium retention predilection sites.
Results
There were dose‐dependent associations of the globus pallidus signal on gradient echo (r = .55, p < .001) and spin echo (r = .38, p = .013) T1‐weighted imaging, but not on MT. Relative to controls, MS patients had higher signal intensity index in the dentate nucleus on T1‐weighted gradient echo (1.037 ± 0.040 vs. 1.016 ± 0.023, p = .04) with a similar trend in the globus pallidus on T1‐weighted spin echo (1.091 ± 0.034 vs. 1.076 ± 0.014, p = .06). MT detected no group differences.
Conclusions
Conventional T1‐weighted imaging provided dose‐dependent associations with gadolinium administrations in MS, while these could not be detected with 2‐dimensional MT. Future studies could explore newer MT techniques like 3D and inhomogenous MT. Notably, these associations were identified with conventional MRI even though most patients had not received gadolinium administrations in the preceding 9 years, suggestive of long‐term retention.
Gadolinium-based contrast agents (GBCAs) are frequently used in patients undergoing magnetic resonance imaging. In GBCAs gadolinium (Gd) is present in a bound chelated form. Gadolinium is a ...rare-earth element, which is normally not present in human body. Though the blood elimination half-life of contrast agents is about 90 minutes, recent studies demonstrated that some tissues retain gadolinium, which might further pose a health threat due to toxic effects of free gadolinium. It is known that the bone tissue can serve as a gadolinium depot, but so far only bulk measurements were performed. Here we present a summary of experiments in which for the first time we mapped gadolinium in bone biopsy from a male patient with idiopathic osteoporosis (without indication of renal impairment), who received MRI 8 months prior to biopsy. In our studies performed by means of synchrotron radiation induced micro- and submicro-X-ray fluorescence spectroscopy (SR-XRF), gadolinium was detected in human cortical bone tissue. The distribution of gadolinium displays a specific accumulation pattern. Correlation of elemental maps obtained at ANKA synchrotron with qBEI images (quantitative backscattered electron imaging) allowed assignment of Gd structures to the histological bone structures. Follow-up beamtimes at ESRF and Diamond Light Source using submicro-SR-XRF allowed resolving thin Gd structures in cortical bone, as well as correlating them with calcium and zinc.
Objectives
To evaluate the impact of previous administration of gadodiamide and neural tissue gadolinium deposition in patients who received gadobenate dimeglumine.
Methods
Our population included 62 ...patients who underwent at least three administrations of gadobenate dimeglumine, plus an additional contrast-enhanced last MRI for reference, divided into two groups: group 1, patients who in addition to gadobenate dimeglumine administrations had prior exposure to multiple doses of gadodiamide; group 2, patients without previous exposure to other gadolinium-based contrast agent (GBCAs). Quantitative analysis was performed on the first and last gadobenate dimeglumine MRIs in both groups. Dentate nucleus-to-middle cerebellar peduncle signal intensity ratios (DN/MCP) and relative change (RC) in signal over time were calculated and compared between groups using generalized additive model.
Results
Group 1 showed significant increase in baseline and follow-up DN/MCP compared to group 2 (
p
< 0.0001). The RC DN/MCP showed a non-statistically significant trend towards an increase in patients who underwent previous gadodiamide (
p
= 0.0735).
Conclusion
There is increased T1 signal change over time in patients who underwent gadobenate dimeglumine and had received prior gadodiamide compared to those without known exposure to previous gadodiamide. A potentiating effect from prior gadodiamide on subsequent administered gadobenate dimeglumine may occur.
Key Points
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Neural gadolinium deposition is associated with multiple administrations of less stable GBCAs.
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Less stable GBCA effect on subsequent more stable GBCA administrations is undetermined.
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Significant increase of DN/MCP was seen in patients with previous gadodiamide exposure.
•
RC DN/MCP showed a non-significant increase in patients who received previous gadodiamide.
•
Potentiating effects from prior gadodiamide on subsequent administered gadobenate dimeglumine may occur.
Gadolinium has been used as a base for contrast agents in MRI for the last three decades. Numerous studies over the last 4 years have reported increased signal intensity in deep brain nuclei in ...non-contrast MRI images following gadolinium-based contrast agent (GBCA) administration. Pathology studies performed on adults and children, and rodent necropsy studies have also shown gadolinium deposition in brain and other tissues after GBCA administration. The purpose of this review was to summarize and discuss the knowledge gained from these reports and the relevance for imaging pediatric patients.
OBJECTIVESThe aim of this study was to examine the effects of perinatal exposure to gadolinium (Gd)-based contrast agents (GBCAs) on the behavior of adulthood offspring.
MATERIALS AND METHODSPregnant ...Balb/C mice (n = 5 per group) were intravenously injected with gadoterate meglumine (Magnescope, macrocyclic GBCA), gadodiamide (Omniscan, linear GBCA), or vehicle from pregnancy day 15 to 19, corresponding to embryonic day 15 to 19 of the fetus, at 2 mmol/kg body weight per day. Brain samples from dams and pups were collected on postpartum day 28. The total Gd concentration was quantified by inductively coupled plasma-mass spectrometry (dams, n = 3; gadoterate meglumine-treated pups group, n = 9; and gadodiamide-treated pups group, n = 10). Behavioral testing of offspring was started on postpartum day 70 (control group, n = 22; gadoterate meglumine-treated group, n = 23; and gadodiamide-treated group, n = 20).
RESULTSHigher levels of Gd retention were observed in dams and pups in the gadodiamide-treated group. Perinatal exposure to GBCAs caused anxiety-like behavior, disrupted motor coordination, impaired memory function, stimulated tactile sensitivity, and decreased muscle strength, particularly in the gadodiamide-treated group.
CONCLUSIONSIn the present study, we showed that Gd was transferred to pups and was retained in their brain during postnatal development. Gadolinium retention may lead to impaired brain development. These findings indicate that the use of GBCAs in pregnant women should be avoided because it may have adverse effects on the fetus, particularly on brain development.
In current practice, gadolinium-based contrast agents have been considered safe when used at clinically recommended doses in patients without severe renal insufficiency. The causal relationship ...between gadolinium-based contrast agents and nephrogenic systemic fibrosis in patients with renal insufficiency resulted in new policies regarding the administration of these agents. After an effective screening of patients with renal disease by performing either unenhanced or reduced-dose-enhanced studies in these patients and by using the most stable contrast agents, nephrogenic systemic fibrosis has been largely eliminated since 2009. Evidence of in vivo gadolinium deposition in bone tissue in patients with normal renal function is well-established, but recent literature showing that gadolinium might also deposit in the brain in patients with intact blood-brain barriers caught many individuals in the imaging community by surprise. The purpose of this review was to summarize the literature on gadolinium-based contrast agents, tying together information on agent stability and animal and human studies, and to emphasize that low-stability agents are the ones most often associated with brain deposition.
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