Gadolinium Retention in the Brain: What Do We Need to Consider for Clinical Use?

G adolinium (Gd) retention in the body, especially in the brain, is a topic of ongoing debate since Kanda et al in 2013 first reported that hyperintensity in the brain on unenhanced brain magnetic resonance imaging scans might be related to the previous application of Gd-based contrast agents (GBCAs). It is the most recent clinical adverse impact reported in a chain of different observations beyond the clinical development of those agents that started with the observed pseudohypocalcemia followed by the debilitating effects of nephrogenic systemic fibrosis. Recently, various groups have shown that all commercially available GBCAs may show hyperintensities in the brain after application ofmultiple doses andmust therefore be retained to some extent in the body and especially the brain after intravenous application. This is possibly true for any substance entering the body, nomatter which route. All of the published reports only compared one linear to one macrocyclic, nonetheless proposing this as a class effect. Up to now, only a few postmortem studies have shown Gd in the brain in microscopy. These particles were located extracellularly in the perivascular space. The amount of Gd deposits found in these postmortem studies varies greatly between individuals, actually showing the highest Gd retention with one macrocyclic agent and the lowest retention rates with another macrocyclic agent. All other agents fall in between. No clear scientific evidence currently exists in which forms the agents are retained in the brain. Animal studies suggest that macrocyclic agents stay intact and are retained as the complete molecule. However, in some linear agents, the Gd dechelates from the ligand and appears retained bound to other ligands. However, the observed signal enhancement cannot be readily explained as insoluble Gd complexes such as GdPO4 or GdCO3 would have a negligible effect on signal intensity as the Gd is not exposed to the surrounding water molecules. Moreover, to measure the amount of Gd in these animal studies, the tissue has been homogenized rigorously so that it remains unknown if the Gd stays in the original form throughout the process. Now, radiologists around the world struggle to inform their patients correctly while they have to balance the possible, but clinically still unknown, adverse effects from Gd retention in the brain and therefore in the body with the clinical need to utilize GBCAs to establish a correct diagnosis, treatment plan, or response assessment. Patients on the other hand maybe very confused and potentially frightened leading to their refusal to the use of GBCAs even if it is necessary to diagnose life-threatening diseases such as malignant tumors and/or the real risk of alternative imaging approaches maybe truly higher.