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| Item Type: | Preprint |
|---|---|
| Title: | Fate of gadolinium in inflamed mouse brain: release and phosphate interaction post-contrast agent administration |
| Creators Name: | Anderhalten, Lina, Höfer, Nicole, Dymnikova, Daria, Hahndorf, Julia, Taupitz, Matthias, Traub, Heike, Teutloff, Christian, Infante-Duarte, Carmen and Bittl, Robert |
| Abstract: | OBJECTIVES: In view of the mounting evidence for markedly increased cerebellar Gd retention under neuroinflammatory conditions after repeated linear GBCA administration in vivo, we aimed to discriminate between Gd retained within the GBCA complex and forms dissociated form the complex within the CNS and to characterize the chemical environment of the released Gd(3+). For this purpose, we employed electron paramagnetic resonance (EPR) spectroscopy, which enables 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. MATERIALS AND METHODS: We performed EPR and electron nuclear double resonance (ENDOR) experiments 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. Complementary mass spectrometry (MS) and MRI calibration experiments on Gd-spiked homogenized mouse brain tissue were used to identify potential Gd bindings and assess the relaxation-active fraction of retained Gd. RESULTS: EPR detected µM 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. Binding to inorganic ligands was evidenced using MS and MRI calibration experiments in homogenized mouse brain tissue. CONCLUSIONS: EPR and ENDOR proved to be sensitive methods for detecting Gd(3+) release and characterizing retained Gd species within intact brain tissue. 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. |
| Keywords: | Electron Paramagnetic Resonance, Experimental Autoimmune Encephalomyelitis, Gadoliniumbased Contrast Agents, Gadolinium Retention, Laser Ablation Inductively Coupled Plasma Mass Spectrometry, Magnetic Resonance Imaging, Multiple Sclerosis, Neuroinflammation, Organotypic Hippocampal Slice Cultures, Phosphate Interaction, Animals, Mice |
| Source: | arXiv |
| Publisher: | Cornell University |
| Article Number: | 2512.05615 |
| Date: | 5 December 2025 |
| Official Publication: | https://doi.org/10.48550/arXiv.2512.05615 |
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