Fate of gadolinium in inflamed mouse brain: Release and phosphate interaction post-contrast agent administration

TL;DR

This study investigates how gadolinium from contrast agents behaves in inflamed mouse brains, revealing increased retention and release of Gd under neuroinflammatory conditions, with implications for MRI safety and chemical environment understanding.

Contribution

It introduces advanced spectroscopic techniques to directly detect and characterize Gd release and its environment in inflamed brain tissue, highlighting inflammation's role in Gd retention.

Findings

Inflammation increases Gd retention in brain tissue.

Linear GBCAs release Gd more than macrocyclic agents.

Conventional MRI may underestimate Gd accumulation.

Abstract

Mounting evidence for markedly increased cerebellar Gd retention under neuroinflammatory conditions after repeated linear gadolinium-based contrast agents (GBCA) administration in vivo, makes necessary a discrimination between Gd retained within the GBCA complex and forms dissociated form the complex and to characterize the chemical environment of the released Gd$^{3+}$. We employed electron paramagnetic resonance (EPR) and electron nuclear double resonance (ENDOR) spectroscopy, which enable direct detection of Gd$^{3+}$ release and evaluation of its molecular surroundings in intact cerebellar tissue from inflamed and non-inflamed brain sections exposed to either linear or macrocyclic GBCAs. The experiments were performed on sub-mm brain samples taken after administration of linear gadopentetate and macrocyclic gadobutrol in vivo in a murine multiple sclerosis model and ex vivo in organotypic hippocampal slice cultures under inflammatory conditions. EPR detected {\mu}M range Gd levels in intact cerebellar biopsies and slices and distinguished between complex-bound and released Gd following linear GBCA administration in vivo. In biopsies, we detected by ENDOR phosphorus-containing molecules in the microenvironment of released Gd. Complementary mass spectrometry (MS) and MRI calibration experiments on Gd-spiked homogenized mouse brain tissue were used to assess the relaxation-active fraction of retained Gd evidencing binding to inorganic ligands. Our findings demonstrate inflammation-promoted Gd retention, underscore the importance of integrating in vivo and ex vivo analyses to unravel mechanisms of long-term Gd retention, and suggest that conventional MRI may underestimate the true extent of Gd accumulation, especially under neuroinflammatory conditions.