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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 P, Lehericy S, Grand S, Violas X, Fretellier N, Idée JM, Ballet S, Corot C - Invest Radiol (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

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.

No MeSH data available.


Total Gd concentrations in the cerebellum (A), cerebral cortex (B), subcortical brain (C), and plasma (D) at completion of the treatment-free period (week 10). Individual values, mean, and SD are given.
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Figure 9: Total Gd concentrations in the cerebellum (A), cerebral cortex (B), subcortical brain (C), and plasma (D) at completion of the treatment-free period (week 10). Individual values, mean, and SD are given.

Mentions: Normality test was positive for cerebral cortex and subcortical brain Gd concentration, enabling a parametric ANOVA test. The Gd concentration in the cerebellum was analyzed with nonparametric Kruskal-Wallis test because of the negative normality test. The total Gd concentration was 8- to 52-fold higher in the brain after gadodiamide compared to gadoterate meglumine or control: total Gd concentrations were higher in the cerebellum (3.66 ± 0.91 nmol/g), cerebral cortex (2.32 ± 0.46 nmol/g), and subcortical brain (2.47 ± 0.62 nmol/g) in the gadodiamide group versus the control group (0.07 ± 0.10 nmol/g, P < 0.05; 0.17 ± 0.20 nmol/g, P < 0.001; 0.08 ± 0.06 nmol/g, P < 0.001) and the gadoterate meglumine group (0.26 ± 0.12 nmol/g, P < 0.05; 0.30 ± 0.08 nmol/g, P < 0.001; 0.30 ± 0.10 nmol/g, P < 0.001) (Fig. 9). Gadolinium concentration in subcortical brain was significantly higher in the gadoterate meglumine group than in the control group (0.30 ± 0.10 vs 0.08 ± 0.06 nmol/g, respectively; P < 0.01). Plasma total Gd concentrations could not be determined in any of the test groups (values below the lower limit of quantification).


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 P, Lehericy S, Grand S, Violas X, Fretellier N, Idée JM, Ballet S, Corot C - Invest Radiol (2015)

Total Gd concentrations in the cerebellum (A), cerebral cortex (B), subcortical brain (C), and plasma (D) at completion of the treatment-free period (week 10). Individual values, mean, and SD are given.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494686&req=5

Figure 9: Total Gd concentrations in the cerebellum (A), cerebral cortex (B), subcortical brain (C), and plasma (D) at completion of the treatment-free period (week 10). Individual values, mean, and SD are given.
Mentions: Normality test was positive for cerebral cortex and subcortical brain Gd concentration, enabling a parametric ANOVA test. The Gd concentration in the cerebellum was analyzed with nonparametric Kruskal-Wallis test because of the negative normality test. The total Gd concentration was 8- to 52-fold higher in the brain after gadodiamide compared to gadoterate meglumine or control: total Gd concentrations were higher in the cerebellum (3.66 ± 0.91 nmol/g), cerebral cortex (2.32 ± 0.46 nmol/g), and subcortical brain (2.47 ± 0.62 nmol/g) in the gadodiamide group versus the control group (0.07 ± 0.10 nmol/g, P < 0.05; 0.17 ± 0.20 nmol/g, P < 0.001; 0.08 ± 0.06 nmol/g, P < 0.001) and the gadoterate meglumine group (0.26 ± 0.12 nmol/g, P < 0.05; 0.30 ± 0.08 nmol/g, P < 0.001; 0.30 ± 0.10 nmol/g, P < 0.001) (Fig. 9). Gadolinium concentration in subcortical brain was significantly higher in the gadoterate meglumine group than in the control group (0.30 ± 0.10 vs 0.08 ± 0.06 nmol/g, respectively; P < 0.01). Plasma total Gd concentrations could not be determined in any of the test groups (values below the lower limit of quantification).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

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.

No MeSH data available.