Histology and Gadolinium Distribution in the Rodent Brain After the Administration of Cumulative High Doses of Linear and Macrocyclic Gadolinium-Based Contrast Agents

Lohrke, Jessica; Frisk, Anna-Lena; Frenzel, Thomas; Schöckel, Laura; Martin, Rachel W.; Jošt, Gregor; Lenhard, Diana C.; Sieber, Martin; Nischwitz, Volker; Küppers, Astrid; Pietsch, Hubertus

doi:10.1097/rli.0000000000000344

Cited by 159 publications

(229 citation statements)

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“…Whereas several studies in animals have looked at gadoterate and gadobutrol in terms of Gd accumulation in the brain and other organs, comparatively few studies have evaluated gadoteridol after a prolonged off‐dose period. In one recent study aimed at investigating the differential effects on histology between macrocyclic and linear GBCAs, Lohrke et al found only minimally different levels of Gd in the brains of animals administered gadobutrol compared with animals administered gadoteridol (0.7 ± 0.4 vs. 0.5 ± 0.2 nmol Gd/g tissue, respectively; evaluation of significance not presented). Conversely, a more recent independent study by McDonald et al found higher median concentrations of Gd in brain tissue of gadobutrol‐injected rats than in brain tissue of gadoteridol‐injected rats (1.6 vs. 0 mg/g tissue, respectively).…”

Section: Discussionmentioning

confidence: 99%

“…Notably, McDonald et al further corroborated our findings in demonstrating markedly higher median concentrations of Gd also in the kidney, liver, and spleen of rats administered gadobutrol than in rats administered gadoteridol. Of note, however, is that whereas Lohrke et al allowed 8 weeks' recovery after the last GBCA administration before animal sacrifice, McDonald et al allowed only 7 days. However, this again points to a more rapid and efficient elimination mechanism for gadoteridol, possibly reflecting advantageous physicochemical properties.…”

Section: Discussionmentioning

confidence: 99%

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Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats

Bussi

Coppo

Botteron

et al. 2017

Magnetic Resonance Imaging

110

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PurposeTo compare the levels of gadolinium in the blood, cerebrum, cerebellum, liver, femur, kidneys, and skin after multiple exposure of rats to the macrocyclic gadolinium‐based contrast agents (GBCAs) gadoterate, gadobutrol, and gadoteridol.Materials and MethodsFifty male Wistar Han rats were randomized to three exposure groups (n = 15 per group) and one control group (n = 5). Animals in the exposure groups received a total of 20 GBCA administrations (four administrations per week for 5 consecutive weeks) at a dose of 0.6 mmol/kg bodyweight. After a 28‐day recovery period animals were sacrificed and the blood and tissues harvested for determination of gadolinium (Gd) levels. Gd determination was performed by inductively coupled plasma mass spectrometry (ICP‐MS).ResultsAfter 28 days' recovery no Gd was found in the blood, liver, or skin of any animal in any group. Significantly lower levels of Gd were noted with gadoteridol compared to gadoterate and gadobutrol in the cerebellum (0.150 ± 0.022 vs. 0.292 ± 0.057 and 0.287 ± 0.056 nmol/g, respectively; P < 0.001), cerebrum (0.116 ± 0.036 vs. 0.250 ± 0.032 and 0.263 ± 0.045 nmol/g, respectively; P < 0.001), and kidneys (25 ± 13 vs. 139 ± 88 [P < 0.01] and 204 ± 109 [P < 0.001], respectively). Higher levels of Gd were noted in the femur (7.48 ± 1.37 vs. 5.69 ± 1.75 and 8.60 ± 2.04 nmol/g, respectively) with significantly less Gd determined for gadoterate than for gadobutrol (P < 0.001) and gadoteridol (P < 0.05).ConclusionDifferences exist between macrocyclic agents in terms of their propensity to accumulate in tissues. The observed differences in Gd concentration point to differences in GBCA washout rates in this setting and in this experimental model, with gadoteridol being the GBCA that is most efficiently removed from both cerebral and renal tissues. Level of Evidence: 2 Technical Efficacy: Stage 5J. Magn. Reson. Imaging 2018;47:746–752.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats

Bussi

Coppo

Botteron

et al. 2017

Magnetic Resonance Imaging

110

View full text Add to dashboard Cite

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“…36 In an additional study, after repeated high dosing in rats with normal renal function, NSF like macroscopic and microscopic lesions in the skin were only seen with gadodiamide. 37 These were not seen with gadopentetate dimeglumine and the 2 evaluated macrocyclic GBCAs, gadobutrol and gadoteridol. No histologic changes were observed with any agent in the brain.…”

Section: Recent Animal Investigationsmentioning

confidence: 99%

Critical Questions Regarding Gadolinium Deposition in the Brain and Body After Injections of the Gadolinium-Based Contrast Agents, Safety, and Clinical Recommendations in Consideration of the EMA's Pharmacovigilance and Risk Assessment Committee Recommendation for Suspension of the Marketing Authorizations for 4 Linear Agents

2017

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For magnetic resonance, the established class of intravenous contrast media is the gadolinium-based contrast agents. In the 3 decades since initial approval, these have proven in general to be very safe for human administration. However, in 2006, a devastating late adverse reaction to administration of the less stable gadolinium-based contrast agents was identified, nephrogenic systemic fibrosis. The result of actions taken by the European Medicines Agency and the US Food and Drug Administration, stratifying the agents by risk and contraindicating specific agents in severe renal dysfunction, has led to no new cases being identified in North America or Europe. Subsequently, in 2014, long-term deposition in the brain of gadolinium was first shown, after administration of 2 nonionic linear chelates, gadodiamide, and gadopentetate dimeglumine. This has led to an intense focus on the question of in vivo distribution, possible dechelation, and subsequent deposition of gadolinium, together with substantial clarification of the phenomenon as well as stratification of the agents on this basis. This review focuses on 8 critical questions regarding gadolinium deposition in the brain and body, with the answers and discussion therein important for future regulatory decisions and clinical practice. It is now clear that dechelation of gadolinium occurs in vivo with the linear agents and is responsible for this phenomenon, with key experts in the field recommending, except where there is no suitable alternative, a shift in clinical practice from the linear to macrocyclic agents. In addition, on March 10, 2017, the Pharmacovigilance and Risk Assessment Committee of the European Medicines Agency recommended suspension of the marketing authorization for 4 linear gadolinium contrast agents-specifically Omniscan, Optimark, Magnevist, and MultiHance (gadodiamide, gadoversetamide, gadopentetate dimeglumine, and gadobenate dimeglumine)-for intravenous injection. Cited in the report was convincing evidence of gadolinium deposition in the brain months after injection of these linear agents. Primovist/Eovist (gadoxetic acid disodium) will remain available, being used at a lower dose for liver imaging, because it meets an important diagnostic need. In addition, a formulation of Magnevist for intra-articular injection will remain available because of its very low gadolinium concentration.

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“…HIGH SIGNAL INTENSITY of deep cerebellar and deep brain nuclei on unenhanced T 1 ‐weighted images as well as changes of T 1 relaxometry values may reflect the presence of long‐term retained or deposited gadolinium in the brain in patients exposed to cumulative doses of gadolinium‐based contrast agents (GBCAs). In the cerebellum, the dentate nuclei (DN) and the cortex are the areas where gadolinium predominantly retains and/or accumulates …”

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confidence: 99%

Absence of dentate nucleus resting‐state functional connectivity changes in nonneurological patients with gadolinium‐related hyperintensity on T₁‐weighted images

Mallio

Piervincenzi

Gianolio

et al. 2019

Magnetic Resonance Imaging

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Background The dentate nuclei of the cerebellum are the areas where gadolinium predominantly accumulates. It is not yet known whether gadolinium deposition affects brain functions. Purpose/Hypothesis To assess whether gadolinium‐dependent high signal intensity of the cerebellum on T1‐weighted images of nonneurological adult patients with Crohn's disease is associated with modifications of resting‐state functional connectivity (RSFC) of the cerebellum and dentate nucleus. Study Type Observational, cross‐sectional. Population Fifteen patients affected by Crohn's disease were compared with 16 healthy age‐ and gender‐matched control subjects. All participants underwent neurological, neurocognitive‐psychological assessment, and blood sampling. Field Strength/Sequence 1.5‐T magnet blood oxygenation level‐dependent (BOLD) functional MRI. Assessment High signal intensity on T1‐weighted images, cerebellum functional connectivity, neurocognitive performance, and blood circulating gadolinium levels. Statistical Tests An unpaired two‐sample t‐test (age and sex were nuisance variables) was used to investigate between‐group differences in cerebellar and dentate nucleus functional connectivity. Z‐statistical images were set using clusters determined by Z > 2.3 and a familywise error (FWE)‐corrected cluster significance threshold of P = 0.05. Results Dentate nuclei RSFC was not different (P = n.s.) between patients with gadolinium‐dependent high signal intensity on T1‐weighted images and controls. Pre‐ and postcentral gyrus bilaterally and the right supplementary motor cortex showed a decrease of RSFC with the cerebellum hemispheres (P < 0.05 FWE‐corrected) and was related to disease duration but not to gadodiamide cumulative doses (P = n.s.). Data Conclusion Crohn's disease patients with gadolinium‐dependent hyperintense dentate nuclei on unenhanced T1‐weighted images do not show dentate nucleus RSFC changes. Level of Evidence: 2 Technical Efficacy Stage: 5 J. Magn. Reson. Imaging 2019;50:445–455.

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Histology and Gadolinium Distribution in the Rodent Brain After the Administration of Cumulative High Doses of Linear and Macrocyclic Gadolinium-Based Contrast Agents

Abstract: Supplemental digital content is available in the text.

Cited by 159 publications

References 52 publications

Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats

Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats

Absence of dentate nucleus resting‐state functional connectivity changes in nonneurological patients with gadolinium‐related hyperintensity on T₁‐weighted images

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Histology and Gadolinium Distribution in the Rodent Brain After the Administration of Cumulative High Doses of Linear and Macrocyclic Gadolinium-Based Contrast Agents

Abstract: Supplemental digital content is available in the text.

Cited by 159 publications

References 52 publications

Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats

Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats

Absence of dentate nucleus resting‐state functional connectivity changes in nonneurological patients with gadolinium‐related hyperintensity on T1‐weighted images

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Absence of dentate nucleus resting‐state functional connectivity changes in nonneurological patients with gadolinium‐related hyperintensity on T₁‐weighted images