title: Signal Increase on Unenhanced T1-Weighted Images in the Rat Brain After Repeated, Extended Doses of Gadolinium-Based Contrast Agents: Comparison of Linear and Macrocyclic Agents.
abstract: OBJECTIVE
  In this prospective preclinical study, we evaluated T1-weighted signal intensity in the deep cerebellar nuclei (CN) and globus pallidus (GP) up to 24 days after repeated administration of linear and macrocyclic gadolinium-based contrast agents (GBCAs) using homologous imaging and evaluation methods as in the recently published retrospective clinical studies. In a second part of the study, cerebrospinal fluid (CSF) spaces were evaluated for contrast enhancement by fluid-attenuated magnetic resonance imaging (MRI).
  
  
  METHODS
  Sixty adult male Wistar-Han rats were randomly divided into a control and 5 GBCA groups (n = 10 per group). The administered GBCAs were gadodiamide, gadopentetate dimeglumine, and gadobenate dimeglumine (linear GBCAs) as well as gadobutrol and gadoterate meglumine (macrocyclic GBCAs) and saline (control). Over a period of 2 weeks, the animals received 10 intravenous injections at a dose of 2.5 mmol Gd/kg body weight, each on 5 consecutive days per week. Before GBCA administration, as well as 3 and 24 days after the last injection, a whole-brain MRI was performed using a standard T1-weighted 3-dimensional turbo spin echo sequence on a clinical 1.5 T scanner. The ratios of signal intensities in deep CN to pons (CN/Po) and GP to thalamus (GP/Th) were determined. For the evaluation of the CSF spaces, 18 additional rats were randomly divided into 6 groups (n = 3 per group) that received the same GBCAs as in the first part of the study. After MR cisternography for anatomical reference, a fluid-attenuated inversion recovery sequence was performed before and 1 minute after intravenous injection of a dose of 1 mmol Gd/kg body weight GBCA or saline.
  
  
  RESULTS
  A significantly increased signal intensity ratio of CN/Po was observed 3 and 24 days after the last injection of gadodiamide and gadobenate dimeglumine. No significant changes were observed between the 2 time points. Gadopentetate dimeglumine injection led to a moderately elevated but statistically not significant CN/Po signal intensity ratio. No increased CN/Po signal intensity ratios were determined in the MRI scans of rats that received macrocyclic GBCAs gadobutrol and gadoterate meglumine or saline. The ratio of signal intensity in GP/Th was not elevated in any group injected with GBCAs or saline. Enhanced signal intensities of CSF spaces were observed in the postcontrast fluid-attenuated inversion recovery images of all animals receiving GBCAs but not for saline.
  
  
  CONCLUSIONS
  In this animal study in rats, increased signal intensity in the CN was found up to 24 days after multiple, extended doses of linear GBCAs. However, in contrast to clinical reports, the signal enhancement in the GP was not reproduced, demonstrating the limitations of this animal experiment. The elevated signal intensities remained persistent over the entire observation period. In contrast, no changes of signal intensities in either the CN or the GP were observed for macrocyclic GBCAs. However, all GBCAs investigated were able to pass the blood-CSF barrier in rats to a certain, not yet quantified extent.
authors.affiliation: From the *MR and CT Contrast Media Research, Bayer Healthcare; †Institute of Vegetative Physiology, Charité; and ‡Clinical Project Management, Bayer Healthcare, Berlin, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Jost
authors.forename: Diana Constanze
authors.initials: DC
authors.lastname: Lenhard
authors.forename: Martin Andrew
authors.initials: MA
authors.lastname: Sieber
authors.forename: Jessica
authors.initials: J
authors.lastname: Lohrke
authors.forename: Thomas
authors.initials: T
authors.lastname: Frenzel
authors.forename: Hubertus
authors.initials: H
authors.lastname: Pietsch
mesh_terms: D000818:Animals; D001921:Brain / Q000033:anatomy & histology*; D003287:Contrast Media / Q000008:administration & dosage; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005682:Gadolinium / Q000008:administration & dosage*; D007089:Image Enhancement / Q000379:methods*; D047028:Macrocyclic Compounds / Q000008:administration & dosage; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D003287:Contrast Media; D047028:Macrocyclic Compounds; D005682:Gadolinium