Does Gadolinium deposition in the brain affect Hippocampal Neurogenesis?

Abstract

Background and Aims: Gadolinium-based contrast agents (GBCAs) are the only FDA approved agents that are used worldwide to enhance the visualization of internal body organs and tissues on MRI scans. Recent postmortem studies have shown that the exposure to linear and macrocyclic GBCAs result in Gadolinium (Gd) metal deposition in the brain and other organs. While the clinical significance of such metal deposition remains unsettled, it raises important questions concerning its long-term effects on learning and memory in developing brains undergoing multiple MRI scans. The purpose of this study is to investigate whether repeated exposure to linear and macrocyclic GBCAs at young age have an impact on the stem cell niche in the hippocampus, or affect the working memory performance. It also aims at investigating if exposure to GBCAs leads to Gd deposits in the spinal cord and peripheral nerves. Methods: Young male Sprague Dawley rats (140-150 g) were given serial daily intraperitoneal injections of two types of GBCAs: Gadoterate meglumine (Dotarem; macrocyclic GBCA) and Gadodiamide (Omniscan; Linear GBCA) at a dose of 2.5 mmol-kg for a period of 20 days. A control group received Saline injections. Along with GBCAs, animals received Bromodeoxyuridine injections every three days (total dose = 300 mg-kg; ip) to label newly formed cells in the brain. In order to assess the total number of proliferating cells in the dentate-gyrus of the hippocampus, one set of animals was sacrificed 48 hours after the last BrdU injection by cardiac perfusion. Furthermore, to determine the number of newly maturing neurons in the dentate gyrus, another set was sacrificed 29 days after the last BrdU injection. Hippocampal tissues were stained for BrdU+ and NeuN+ cells and quantified using confocal microscopy. The spontaneous alternation T-maze test was performed to assess the spatial working memory function at day 10, at day 20, and one month after the last GBCA exposure. Inductively Coupled Plasma Mass-Spectrometry (ICP-MS) analysis was use