Gadolinium deposition in the brain: another concern regarding gadolinium-based contrast agents.

Nevzat Karabulut Life is continuously confronting us with new issues and sometimes breaking our routine. One case in point is the curious way radiologists’ knowledge about the benefits and risks of gadolinium-based contrast agents (GBCAs) continues to evolve. Significantly improving detection and characterization of lesions in a broad spectrum of diseases, GBCAs have become integral aides to magnetic resonance imaging (MRI) for almost three decades. Because free gadolinium is toxic, it needs to be chelated with a ligand ion to facilitate its excretion through the kidneys. Currently available GBCAs have different chemical properties primarily determined by the chelating ligand molecule. These agents had initially been believed to be risk-free with rapid elimination from the body, and administered to millions of patients somewhat indiscreetly for over a decade after the clinical approval of gadopentate dimeglumine in 1988. This naive belief was disproved by a string of studies revealing a relationship between the use of GBCAs and the development of nephrogenic systemic fibrosis (NSF) in 2006 (2, 3). The accrued data convincingly showed a causal link between GBCAs and the risk of NSF in patients with severely compromised renal function (glomerular filtration rate <30 mL/min). Due to insufficient excretion of GBCA in patients with poor renal function, the administered contrast material (gadolinium chelate) stays long enough in the body to pose the risk of dissociation (dechelation) which consequently triggers the cascade of events resulting in NSF. An editorial published in the December 2006 issue of this journal addressed the issue of NSF and provided some timely recommendations (4). Further studies revealed that the chemical structure of GBCAs matters in the development of NSF, and the risk is much higher with nonionic linear chelates, such as gadodiamide and gadoversetamide, due to rapid release of gadolinium (dechelation) in these agents. Conversely, macrocyclic GBCAs are more resistant to dechelation and considered to be more stable. These studies modified the practice of intravenous MRI contrast agent use and paved the way for the creation of new standards in the use of GBCAs. Many international and national authorities established guidelines for the use of GBCAs in MRI. These guidelines primarily categorized agents into three categories as low risk (macrocyclic agents), intermediate risk (ionic-linear chelates) and high risk (nonionic-linear chelates) for the development of NSF. Adherence to these guidelines and adoption of new contrast-enhanced MRI protocols, which restrict the administration of high-risk GBCAs only to subjects with normal renal function and replace these agents with more stable GBCAs in high-risk patients, resulted in a dramatic decline in the incidence of NSF (5). Nevertheless, it should be emphasized that there are considerable differences between GBCAs with similar structure. For instance, no unconfounded NSF case has been reported following administration of ionic-linear gadobenate dimeglumine whereas two NSF cases were reported after unconfounded administration of nonionic-macrocyclic gadobutrol (6). In 2014, radiologists (as well as clinicians) were in for another stunning report, this time of a study performed in Japan (7) implying deposition of gadolinium in the brain manifested as dose-related T1 shortening in the globus pallidus and the dentate nuclei in patients who had been administered repeated previous doses of gadodiamide and/or gadopentetate dimeglumine. This novel observation was subsequently confirmed by Errante et al. (8) who reported dose-dependent T1 shortening in the dentate nucleus in subjects with normal kidney and liver function who had serial prior administration of gadodiamide. Two recent studies performed on autopsy specimens proved that T1 shortening results from gadolinium retention in neuronal tissues of the global pallidus, thalamus, dentate nucleus, and pons (9, 10). It was shown that gadolinium deposition was detectable with as few as four lifetime