Effect of Long-Term Retention of Gadolinium on Metabolism of Deep Cerebellar Nuclei After Repeated Injections of Gadodiamide in Rats

Abstract

Objectives: To determine potential metabolism and histological modifications due to gadolinium retention within deep cerebellar nuclei (DCN) after linear gadolinium based contrast agent injection (gadodiamide) in rats at 1 year after the last injection. Materials and Methods: Twenty rats received 20 doses of gadodiamide (0.6 mmol of gadolinium per kilogram each) over 5 weeks. They were followed at 1 week (M0), 6 weeks (M1) and 54-55 weeks (M13) post-injections to evaluate hypersignal on unenhanced T1weighted MRI and metabolic alterations by 1 H MRS. At 1 year post-injections, brains were sampled to determine the localization of gadolinium within cerebellum by laser ablation inductively coupled mass spectroscopy (LA-ICP-MS) and to evaluate morphological changes by semi-quantitative immunofluorescence analysis. Results: There is a significant increase of the ratio DCN/brainstem for the gadodiamide group at M0 (+7.2% vs control group=0.989±0.01), M1 (+7.6% vs control group=1.002±0.018) and it lasted up to M13 (+4.7% vs control group=0.9862±0.008). No variation among metabolic markers (cellular homeostasis, excitatory neurotransmitter and metabolites specific to a cellular compartment) were detected by 1 H MRS between gadodiamide and saline groups at M0, M1 and M13. At M13, LA-ICP-MS demonstrated that long-term gadolinium retention occurred preferentially in DCN. No histological abnormalities (including analysis of astrocytes, neurons and microglial cells) were found in the rostral part of DCN. Conclusion: Repeated administration of gadodiamide lead to a retention of gadolinium preferentially within DCN until 1-year post-injections. This retention did not lead to any detectable changes of metabolic biomarkers nor histological alterations.

Effect of Exposure to Gadodiamide and Brain Irradiation on T1‐Weighted Images and ADC Maps of the Dentate Nucleus

“…Indeed, no proof of tissue damage related to gadolinium deposition has been demonstrated so far by MRI studies using different techniques, 21,27 as well as by histological postmortem studies conducted on humans and animal models 5,15,17,18 . Furthermore, a recent study on a murine model by El Hamrani et al showed that retention of gadolinium after 20 intravenous doses of gadodiamide, mostly within DN, was not associated with detectable changes of metabolic biomarkers and histological abnormalities 19 . However, another preclinical in vitro study performed on a cellular line of human basal ganglia neurons demonstrated cell death at clinically relevant doses for GBCAs with lower kinetic stability (ie, linear), due to neurotoxic effects 28 …”

“…5,15,17,18 Furthermore, a recent study on a murine model by El Hamrani et al showed that retention of gadolinium after 20 intravenous doses of gadodiamide, mostly within DN, was not associated with detectable changes of metabolic biomarkers and histological abnormalities. 19 However, another preclinical in vitro study performed on a cellular line of human basal ganglia neurons demonstrated cell death at clinically relevant doses for GBCAs with lower kinetic stability (ie, linear), due to neurotoxic effects. 28 This difference between preclinical animal and in vitro studies might depend on the poorly understood complexities of cellular and extracellular in vivo microenvironment that needs to be further investigated.…”

“…Gadolinium deposited within the central nervous system structures, especially the DN, has been confirmed with analytical techniques in animal models as well as in autopsy studies 15–19 and the high SI on T 1 ‐weighted imaging is considered an in vivo indicator of gadolinium deposition.…”

Role of gadolinium-based contrast agents in neurological disorders

“…After 20 weeks from linear administration to a group of healthy rats, neurotoxicity was not detectable [47]. Moreover, an analysis of chosen metabolic markers (cellular homeostasis, excitatory neurotransmitter, and metabolites specific to a cellular compartment) with 1H-magnetic resonance spectroscopy (1H-MRS) and laser ablation ICP-MS revealed no significant metabolism and histological changes between gadodiamide and a control group [57]. On the other hand, some studies have found relevant alterations after GBCA administration in animal models.…”

Effects of Gadolinium Deposits in the Cerebellum: Reviewing the Literature from In Vitro Laboratory Studies to In Vivo Human Investigations

“…Res. Public Health 2021, 18, 7214 2 of 12 of incubation [6]. Such transmetalation and the release of Gd 3+ may cause toxicity in GBCA-deposited tissues, although the GBCA itself may also possibly cause toxicity.…”