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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

Robert, Philippe PhD; Lehericy, Stéphane MD, PhD; Grand, Sylvie MD, PhD; Violas, Xavier BS; Fretellier, Nathalie PhD; Idée, Jean-Marc PharmD, MS; Ballet, Sébastien PhD; Corot, Claire PharmD, PhD

doi: 10.1097/RLI.0000000000000181
Original Article

Objectives: To prospectively compare in healthy rats the effect of multiple injections of macrocyclic (gadoterate meglumine) and linear (gadodiamide) gadolinium-based contrast agents (GBCAs) on T1-weighted signal intensity in the deep cerebellar nuclei (DCN), including the dentate nucleus.

Materials and Methods: Healthy rats (n = 7/group) received 20 intravenous injections of 0.6 mmol of gadolinium (Gd) per kilogram (4 injections per week during 5 weeks) of gadodiamide, gadoterate meglumine, or hyperosmolar saline (control group). Brain T1-weighted magnetic resonance imaging was performed before and once a week during the 5 weeks of injections and during 5 additional weeks (treatment-free period). Gadolinium concentrations were measured with inductively coupled plasma mass spectrometry in plasma and brain. Blinded qualitative and quantitative evaluations of the T1 signal intensity in DCN were performed, as well as a statistical analysis on quantitative data.

Results: A significant and persistent T1 signal hyperintensity in DCN was observed only in gadodiamide-treated rats. The DCN-to-cerebellar cortex signal ratio was significantly increased from the 12th injection of gadodiamide (1.070 ± 0.024) compared to the gadoterate meglumine group (1.000 ± 0.033; P < 0.001) and control group (1.019 ± 0.022; P < 0.001) and did not significantly decrease during the treatment-free period. Total Gd concentrations in the gadodiamide group were significantly higher in the cerebellum (3.66 ± 0.91 nmol/g) compared with the gadoterate meglumine (0.26 ± 0.12 nmol/g; P < 0.05) and control (0.06 ± 0.10 nmol/g; P < 0.05) groups.

Conclusions: Repeated administrations of the linear GBCA gadodiamide to healthy rats are associated with progressive and persistent T1 signal hyperintensity in the DCN, with Gd deposition in the cerebellum in contrast with the macrocyclic GBCA gadoterate meglumine for which no effect was observed.

From the *Guerbet Research and Innovation Department, Aulnay-sous-Bois; †Institut du Cerveau et de la Moelle Epinière (ICM), Centre de Neuroimagerie de Recherche (CENIR), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie-Paris 6, INSERM UMR-S1127, CNRS 7225, Paris; Service de Neuroradiologie, Hôpital de la Pitié-Salpêtrière, Paris, France; and ‡INSERM, U836, Grenoble, France; Université Grenoble Alpes, Grenoble Institute of Neurosciences, Grenoble, France.

Received for publication April 13, 2015; and accepted for publication, after revision, May 2, 2015.

SL and SG report no conflicts of interest.

Reprints: Philippe Robert, PhD, Guerbet Research and Innovation Department, Postal Address Guerbet BP57400 95943 Roissy CDG Cedex France. E-mail: philippe.robert@guerbet-group.com.

Part of these data have been accepted for oral presentation during the next American Society of NeuroRadiology meeting: ASNR 53rd Annual Meeting and The Foundation of the ASNR Symposium 2015, Chicago, April 25–30, 2015

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