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Gadolinium Deposition in the Brain in a Large Animal Model

Comparison of Linear and Macrocyclic Gadolinium-Based Contrast Agents

Radbruch, Alexander MD, JD*,†; Richter, Henning PhD‡,§; Fingerhut, Stefanie PhD; Martin, Louise Francoise‡,§; Xia, Anna; Henze, Niklas; Paulus, Werner MD; Sperling, Michael PhD; Karst, Uwe PhD; Jeibmann, Astrid MD

doi: 10.1097/RLI.0000000000000575
Original Articles

Objective Recent studies reported a signal intensity increase in the deep cerebellar nuclei (DCN) on magnetic resonance images caused by gadolinium deposition after the injection of gadolinium-based contrast agents (GBCAs). There is an ongoing debate if the propensity of a GBCA to deposit gadolinium is primarily determined by its class as either linear or macrocyclic. In the current study, we aimed to compare the amount and the distribution of retained gadolinium of linear and macrocyclic GBCAs in the DCN after a single injection at a dose comparable to a human patient's in a large animal model.

Materials and Methods Eighteen sheep were randomly assigned in 6 groups of 3 animals, which received a single injection of 0.1 mmol/kg body weight of either the macrocyclic GBCAs gadobutrol, gadoteridol, or gadoterate meglumine; the linear GBCAs gadobenate dimeglumine or gadodiamide; or saline. Animals were euthanized 10 weeks after injection. Local distribution and concentration of gadolinium and colocalization to other metals (iron, zinc, copper) in the DCN was assessed by laser ablation-inductively coupled plasma-mass spectrometry.

Results Average gadolinium concentration for the macrocyclic GBCAs and the saline group was below the limit of quantification (5.7 ng/g tissue). In contrast, 14 (for gadobenate) and 27 (for gadodiamide) times more gadolinium than the limit of quantification was found for the linear GBCAs gadobenate (mean, 83 ng/g) or gadodiamide (mean, 155 ng/g brain tissue). Gadolinium distribution colocalized with other metals for linear GBCAs and a specific accumulation in the DCN was found.

Discussion The current study supports the hypothesis that the amount of gadolinium deposited in the brain is primarily determined by its class as either macrocyclic or linear. The accumulation of gadolinium in the DCN for linear GBCAs explains the hyperintensities in the DCN found in previous patient studies with linear GBCAs.

From the *Department of Diagnostic and Interventional Radiology and Neuroradiology, University Clinic Essen, Essen

German Cancer Research Center, Department of Radiology, Heidelberg, Germany

Diagnostic Imaging Research Unit, Clinic for Diagnostic Imaging, Department of Clinical Diagnostics and Services

§Clinic for Zoo Animals, Exotic Pets and Wildlife, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland

Institute of Inorganic and Analytical Chemistry, University of Münster

Institut of Neuropathology, Pottkamp 2, University Hospital Münster, Münster, Germany.

Received for publication January 26, 2019; and accepted for publication, after revision, March 27, 2019.

Alexander Radbruch and Henning Richter contributed equally to this study.

The study was not supported by any funding.

Alexander Radbruch lectures for Guerbet and Bayer, and he is also part of the Advisory Boards for GE, Bracco, and Guerbet. This study was supported by Bayer and Guerbet. For the remaining authors, no conflicts of interest are declared.

Correspondence to: Alexander Radbruch, MD, JD, Department of Diagnostic and Interventional Radiology and Neuroradiology, University Clinic Essen, Hufelandstraße 55, 45147 Essen, Germany. E-mail:

Online date: July 1, 2019

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