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Invest Radiol
2022 May 01;575:283-292. doi: 10.1097/RLI.0000000000000846.
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Comprehensive Speciation Analysis of Residual Gadolinium in Deep Cerebellar Nuclei in Rats Repeatedly Administered With Gadoterate Meglumine or Gadodiamide.
Strzeminska I
,
Factor C
,
Jimenez-Lamana J
,
Lacomme S
,
Subirana MA
,
Le Coustumer P
,
Schaumlöffel D
,
Robert P
,
Szpunar J
,
Corot C
,
Lobinski R
.
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PURPOSE: Several preclinical studies have reported the presence of gadolinium (Gd) in different chemical forms in the brain, depending on the class (macrocyclic versus linear) of Gd-based contrast agent (GBCA) administered. The aim of this study was to identify, with a special focus on insoluble species, the speciation of Gd retained in the deep cerebellar nuclei (DCN) of rats administered repeatedly with gadoterate or gadodiamide 4 months after the last injection.
METHODS: Three groups (N = 6/group) of healthy female Sprague-Dawley rats (SPF/OFA rats; Charles River, L'Arbresle, France) received a cumulated dose of 50 mmol/kg (4 daily intravenous administrations of 2.5 mmol/kg, for 5 weeks, corresponding to 80-fold the usual clinical dose if adjusted for man) of gadoterate meglumine (macrocyclic) or gadodiamide (linear) or isotonic saline for the control group (4 daily intravenous administrations of 5 mL/kg, for 5 weeks). The animals were sacrificed 4 months after the last injection. Deep cerebellar nuclei were dissected and stored at -80°C before sample preparation. To provide enough tissue for sample preparation and further analysis using multiple techniques, DCN from each group of 6 rats were pooled. Gadolinium species were extracted in 2 consecutive steps with water and urea solution. The total Gd concentrations were determined by inductively coupled plasma mass spectrometry (ICP-MS). Soluble Gd species were analyzed by size-exclusion chromatography coupled to ICP-MS. The insoluble Gd species were analyzed by single-particle (SP) ICP-MS, nanoscale secondary ion mass spectroscopy (NanoSIMS), and scanning transmission electron microscopy with energy-dispersive X-ray spectroscopy (STEM-EDX) for elemental detection.
RESULTS: The Gd concentrations in pooled DCN from animals treated with gadoterate or gadodiamide were 0.25 and 24.3 nmol/g, respectively. For gadoterate, the highest amount of Gd was found in the water-soluble fractions. It was present exclusively as low-molecular-weight compounds, most likely as the intact GBCA form. In the case of gadodiamide, the water-soluble fraction of DCN was composed of high-molecular-weight Gd species of approximately 440 kDa and contained only a tiny amount (less than 1%) of intact gadodiamide. Furthermore, the column recovery calculated for this fraction was incomplete, which suggested presence of labile complexes of dissociated Gd3+ with endogenous molecules. The highest amount of Gd was detected in the insoluble residue, which was demonstrated, by SP-ICP-MS, to be a particulate form of Gd. Two imaging techniques (NanoSIMS and STEM-EDX) allowed further characterization of these insoluble Gd species. Amorphous, spheroid structures of approximately 100-200 nm of sea urchin-like shape were detected. Furthermore, Gd was consistently colocalized with calcium, oxygen, and phosphorous, strongly suggesting the presence of structures composed of mixed Gd/Ca phosphates. No or occasional colocalization with iron and sulfur was observed.
CONCLUSION: A dedicated analytical workflow produced original data on the speciation of Gd in DCN of rats repeatedly injected with GBCAs. The addition, in comparison with previous studies of Gd speciation in brain, of SP element detection and imaging techniques allowed a comprehensive speciation analysis approach. Whereas for gadoterate the main fraction of retained Gd was present as intact GBCA form in the soluble fractions, for linear gadodiamide, less than 10% of Gd could be solubilized and characterized using size-exclusion chromatography coupled to ICP-MS. The main Gd species detected in the soluble fractions were macromolecules of 440 kDa. One of them was speculated to be a Gd complex with iron-binding protein (ferritin). However, the major fraction of residual Gd was present as insoluble particulate species, very likely composed of mixed Gd/Ca phosphates. This comprehensive Gd speciation study provided important evidence for the dechelation of linear GBCAs and offered a deeper insight into the mechanisms of Gd deposition in the brain.
Davies,
Repeat and single dose administration of gadodiamide to rats to investigate concentration and location of gadolinium and the cell ultrastructure.
2021, Pubmed
Davies,
Repeat and single dose administration of gadodiamide to rats to investigate concentration and location of gadolinium and the cell ultrastructure.
2021,
Pubmed
El Hamrani,
Effect of Long-Term Retention of Gadolinium on Metabolism of Deep Cerebellar Nuclei After Repeated Injections of Gadodiamide in Rats.
2020,
Pubmed
Frenzel,
Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37 degrees C.
2008,
Pubmed
Frenzel,
Quantification and Assessment of the Chemical Form of Residual Gadolinium in the Brain After Repeated Administration of Gadolinium-Based Contrast Agents: Comparative Study in Rats.
2017,
Pubmed
Gelli,
The importance of being amorphous: calcium and magnesium phosphates in the human body.
2019,
Pubmed
Gianolio,
Gadolinium Retention in the Rat Brain: Assessment of the Amounts of Insoluble Gadolinium-containing Species and Intact Gadolinium Complexes after Repeated Administration of Gadolinium-based Contrast Agents.
2017,
Pubmed
Grobner,
Gadolinium--a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?
2006,
Pubmed
HALLGREN,
The effect of age on the non-haemin iron in the human brain.
1958,
Pubmed
Idée,
The role of gadolinium chelates in the mechanism of nephrogenic systemic fibrosis: A critical update.
2014,
Pubmed
Jost,
Long-term Excretion of Gadolinium-based Contrast Agents: Linear versus Macrocyclic Agents in an Experimental Rat Model.
2019,
Pubmed
Kanda,
High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material.
2014,
Pubmed
Kanda,
Gadolinium-based Contrast Agent Accumulates in the Brain Even in Subjects without Severe Renal Dysfunction: Evaluation of Autopsy Brain Specimens with Inductively Coupled Plasma Mass Spectroscopy.
2015,
Pubmed
Karamanos,
Extraction and fractionation of proteoglycans from squid skin.
1988,
Pubmed
Lancelot,
Gadolinium Retention as a Safety Signal: Experience of a Manufacturer.
2020,
Pubmed
Le Fur,
The biological fate of gadolinium-based MRI contrast agents: a call to action for bioinorganic chemists.
2019,
Pubmed
Malherbe,
A New Radio Frequency Plasma Oxygen Primary Ion Source on Nano Secondary Ion Mass Spectrometry for Improved Lateral Resolution and Detection of Electropositive Elements at Single Cell Level.
2016,
Pubmed
McDonald,
Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging.
2015,
Pubmed
Neburkova,
Formation of gadolinium-ferritin from clinical magnetic resonance contrast agents.
2020,
Pubmed
Port,
Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review.
2008,
Pubmed
Rasschaert,
Multimodal Imaging Study of Gadolinium Presence in Rat Cerebellum: Differences Between Gd Chelates, Presence in the Virchow-Robin Space, Association With Lipofuscin, and Hypotheses About Distribution Pathway.
2018,
Pubmed
,
Echinobase
Rasschaert,
Gadolinium Retention, Brain T1 Hyperintensity, and Endogenous Metals: A Comparative Study of Macrocyclic Versus Linear Gadolinium Chelates in Renally Sensitized Rats.
2018,
Pubmed
Rasschaert,
Retention of Gadolinium in Brain Parenchyma: Pathways for Speciation, Access, and Distribution. A Critical Review.
2020,
Pubmed
Robert,
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.
2015,
Pubmed
Robert,
Linear Gadolinium-Based Contrast Agents Are Associated With Brain Gadolinium Retention in Healthy Rats.
2016,
Pubmed
Robert,
Methodological Aspects for Preclinical Evaluation of Gadolinium Presence in Brain Tissue: Critical Appraisal and Suggestions for Harmonization-A Joint Initiative.
2018,
Pubmed
Robert,
One-year Retention of Gadolinium in the Brain: Comparison of Gadodiamide and Gadoterate Meglumine in a Rodent Model.
2018,
Pubmed
Runge,
Safety of the Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging, Focusing in Part on Their Accumulation in the Brain and Especially the Dentate Nucleus.
2016,
Pubmed
Sieber,
A preclinical study to investigate the development of nephrogenic systemic fibrosis: a possible role for gadolinium-based contrast media.
2008,
Pubmed
Strzeminska,
Speciation Analysis of Gadolinium in the Water-Insoluble Rat Brain Fraction After Administration of Gadolinium-Based Contrast Agents.
2021,
Pubmed
Thakral,
Gadolinium-induced nephrogenic systemic fibrosis is associated with insoluble Gd deposits in tissues: in vivo transmetallation confirmed by microanalysis.
2009,
Pubmed
Tweedle,
Gadolinium deposition: Is it chelated or dissociated gadolinium? How can we tell?
2016,
Pubmed