Safety of the Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging, Focusing in Part on Their Accumulation in the Brain and Especially the Dentate Nucleus

Abstract

The established class of intravenous contrast media for magnetic resonance imaging is the gadolinium chelates, more generally referred to as the gadolinium-based contrast agents (GBCAs). These can be differentiated on the basis of stability in vivo, with safety and tolerability of the GBCAs dependent upon chemical and biologic inertness. This review discusses first the background in terms of development of these agents and safety discussions therein, and second their relative stability based both on in vitro studies and clinical observations before and including the advent of nephrogenic systemic fibrosis. This sets the stage for the subsequent focus of the review, the current knowledge regarding accumulation of gadolinium in the brain and specifically the dentate nucleus after intravenous administration of the GBCAs and differentiation among agents on this basis. The information available to date, from the initial conception of these agents in 1981 to the latest reports concerning safety, demonstrates a significant difference between the macrocyclic and linear chelates. The review concludes with a discussion of the predictable future, which includes, importantly, a reassessment of the use of the linear GBCAs or a subset thereof.

Histology and Gadolinium Distribution in the Rodent Brain After the Administration of Cumulative High Doses of Linear and Macrocyclic Gadolinium-Based Contrast Agents

“…2,6 Currently, there is a growing body of evidence from clinical 9,11,13–17,51 and preclinical studies 21–23,35,36 suggesting that the potential of a GBCA to increase SI and presumably Gd retention in the brain depends on its specific stability. 52,53 Nevertheless, further scientific investigations are needed to elucidate the precise mechanism of how GBCAs enter the brain.…”

Moderate Renal Failure Accentuates T1 Signal Enhancement in the Deep Cerebellar Nuclei of Gadodiamide-Treated Rats

“…Indeed, it has clearly been shown that repeated administrations of linear GBCA (LGBCA) lead to T1 signal enhancement in specific brain structures, in particular, the globus pallidus (GP) and dentate nuclei (DN). 1–4 Although it was previously thought that GBCAs do not cross a healthy blood-brain barrier, 5 the presence of Gd has been demonstrated in these structures, and puncture Gd deposits have even been found within brain endothelial cells and the interstitium of DN of postmortem specimens. 6 This is raising important questions concerning the potential neurotoxic consequences of such accumulation.…”

Distribution and clearance of retained gadolinium in the brain: differences between linear and macrocyclic gadolinium based contrast agents in a mouse model

“…1,2 In the field of neuroradiology, GBCAs are particularly useful for detecting aggressive or metastatic brain tumours and vascular lesions. 3,4 However, recent studies demonstrated gadolinium (Gd) retention in the brain after multiple GBCA administrations.…”