Gadolinium Accumulation in the Deep Cerebellar Nuclei and Globus Pallidus After Exposure to Linear but Not Macrocyclic Gadolinium-Based Contrast Agents in a Retrospective Pig Study With High Similarity to Clinical Conditions

OBJECTIVE: The aim of this retrospective study was to determine the gadolinium (Gd) concentration in different brain areas in a pig cohort that received repeated administration of Gd-based contrast agents (GBCAs) at standard doses over several years, comparable with a clinical setting. MATERIAL AND METHODS: Brain tissue was collected from 13 Göttingen mini pigs that had received repeated intravenous injections of gadopentetate dimeglumine (Gd-DTPA; Magnevist) and/or gadobutrol (Gadovist). The animals have been included in several preclinical imaging studies since 2008 and received cumulative Gd doses ranging from 7 to 129 mmol per animal over an extended period. Two animals with no history of administration of GBCA were included as controls. Brain autopsies were performed not earlier than 8 and not later than 38 months after the last GBCA application. Tissues from multiple brain areas including cerebellar and cerebral deep nuclei, cerebellar and cerebral cortex, and pons were analyzed for Gd using inductively coupled plasma mass spectrometry. RESULTS: Of the 13 animals, 8 received up to 48 injections of gadobutrol and Gd-DTPA and 5 received up to 29 injections of gadobutrol only. In animals that had received both Gd-DTPA and gadobutrol, a median (interquartile range) Gd concentration of 1.0 nmol/g tissue (0.44-1.42) was measured in the cerebellar nuclei and 0.53 nmol/g (0.29-0.62) in the globus pallidus. The Gd concentration in these areas in gadobutrol-only animals was 50-fold lower with median concentrations of 0.02 nmol/g (0.01-0.02) for cerebellar nuclei and 0.01 nmol/g (0.01-0.01) for globus pallidus and was comparable with control animals with no GBCA history. Accordingly, in animals that received both GBCAs, the amount of residual Gd correlated with the administered dose of Gd-DTPA (P ≤ 0.002) but not with the total Gd dose, consisting of Gd-DTPA and gadobutrol. The Gd concentration in cortical tissue and in the pons was very low (≤0.07 nmol/g tissue) in all animals analyzed. CONCLUSION: Multiple exposure to macrocyclic gadobutrol is not associated with Gd deposition in brain tissue of healthy pigs. A single additional administration of linear Gd-DTPA is sufficient for Gd accumulation in the nucleus dentatus and globus pallidus, underlining the importance of obtaining a complete GBCA history in clinical studies.