Quantification and Assessment of the Chemical Form of Residual Gadolinium in the Brain After Repeated Administration of Gadolinium-Based Contrast Agents

Abstract

Supplemental digital content is available in the text.

Gadolinium retention after administration of contrast agents based on linear chelators and the recommendations of the European Medicines Agency

“…The increased signal intensity in the brain on MRI scans is not always reliable and comparable due to different field strengths (1.5 Tesla and 3.0 Tesla), and the use of different T1-weighted sequences or sequence parameters. Moreover, the proton T1 relaxivity also depends on the molecular weight of the molecule to which the Gd-ions or Gd-contrast media molecules are attached (either soluble macromolecules or insoluble cell components), the water residence time of the coordinated water molecules, and, for some GCCAs, the presence of albumin [15,16]. It is therefore unclear to what extent the increased signal intensity in the brain truly reflects higher gadolinium concentrations [17].…”

Critical Questions Regarding Gadolinium Deposition in the Brain and Body After Injections of the Gadolinium-Based Contrast Agents, Safety, and Clinical Recommendations in Consideration of the EMA's Pharmacovigilance and Risk Assessment Committee Recommendation for Suspension of the Marketing Authorizations for 4 Linear Agents

“…15 For all 3 linear agents evaluatedgadodiamide, gadopentetate dimeglumine, and gadobenate dimegluminethe residual Gd was present in at least 3 distinctive forms-soluble small molecules (likely the intact chelate), soluble macromolecules, and insoluble Gd, with no relevant differences between these agents. The authors hypothesized that the latter 2 forms were most likely responsible for the residual T1 high signal intensity seen in clinical patients in the dentate nucleus and other structures.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13] Stability both in in vitro and in vivo, relative to the release of gadolinium (which depends upon both thermodynamic and kinetic stability), has been shown to be markedly superior for the macrocyclic agents when compared with the linear agents. [14][15][16][17] The linear nonionic agents (specifically gadodiamide and gadoversetamide) are also markedly less stable by this measure than the linear ionic ones. 18 All GBCAs cause, in a small percent of patients, mild adverse reactions, including nausea and hives, with a large number of articles in the scientific literature debating the relative percent of such with the different agents.…”

The Effects of Gadolinium-Based Contrast Agents on the Cerebellum: from Basic Research to Neurological Practice and from Pregnancy to Adulthood

“…Furthermore, the Gd deposition has also been observed in the cerebellar cortex [3,7]. Gd compounds deposited in the cerebellum consist of both soluble and insoluble forms [1,2]. Soluble form may be intact GBCA, whereas insoluble form may be Gd bound with organic or inorganic anions, although the exact chemical nature of insoluble form has not yet fully clarified.…”

“…Studies using animal models have shown that GBCAs may be deposited in the brain after repeated injections [1][2][3]. Tissue depositions of linear GBCAs are much higher than those of macrocyclic GBCA.…”