title: 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.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.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.
authors.forename: Philippe
authors.initials: P
authors.lastname: Robert
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lehericy
authors.forename: Sylvie
authors.initials: S
authors.lastname: Grand
authors.forename: Xavier
authors.initials: X
authors.lastname: Violas
authors.forename: Nathalie
authors.initials: N
authors.lastname: Fretellier
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Idée
authors.forename: Sébastien
authors.initials: S
authors.lastname: Ballet
authors.forename: Claire
authors.initials: C
authors.lastname: Corot
mesh_terms: D000818:Animals; D002529:Cerebellar Nuclei / Q000187:drug effects / Q000378:metabolism*; D003287:Contrast Media / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D005500:Follow-Up Studies; D019786:Gadolinium DTPA / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008279:Magnetic Resonance Imaging; D008536:Meglumine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003287:Contrast Media; D009942:Organometallic Compounds; D008536:Meglumine; C064925:gadodiamide; D019786:Gadolinium DTPA; C072417:gadoterate meglumine