, Volume 58, Issue 5, pp 433–441 | Cite as

Gadolinium deposition within the dentate nucleus and globus pallidus after repeated administrations of gadolinium-based contrast agents—current status

  • Dragan Stojanov
  • Aleksandra Aracki-Trenkic
  • Daniela Benedeto-Stojanov
Invited Review



Gadolinium-based contrast agents (GBCAs) have been used clinically since 1988 for contrast-enhanced magnetic resonance imaging (CE-MRI). Generally, GBCAs are considered to have an excellent safety profile. However, GBCA administration has been associated with increased occurrence of nephrogenic systemic fibrosis (NSF) in patients with severely compromised renal function, and several studies have shown evidence of gadolinium deposition in specific brain structures, the globus pallidus and dentate nucleus, in patients with normal renal function.


Gadolinium deposition in the brain following repeated CE-MRI scans has been demonstrated in patients using T1-weighted unenhanced MRI and inductively coupled plasma mass spectroscopy. Additionally, rodent studies with controlled GBCA administration also resulted in neural gadolinium deposits.


Repeated GBCA use is associated with gadolinium deposition in the brain. This is especially true with the use of less-stable, linear GBCAs. In spite of increasing evidence of gadolinium deposits in the brains of patients after multiple GBCA administrations, the clinical significance of these deposits continues to be unclear.


Here, we discuss the current state of scientific evidence surrounding gadolinium deposition in the brain following GBCA use, and the potential clinical significance of gadolinium deposition. There is considerable need for further research, both to understand the mechanism by which gadolinium deposition in the brain occurs and how it affects the patients in which it occurs.


Magnetic resonance imaging Gadolinium deposition Contrast media Globus pallidus Dentate nucleus 


Diagnosis and observation of neurological diseases frequently involve the use of contrast-enhanced magnetic resonance imaging (CE-MRI) [1]. CE-MRI impacts treatment strategy by providing morphological information with excellent sensitivity and specificity. In addition to morphological studies, functional CE-MRI is routinely used in neuroimaging. Techniques such as perfusion-weighted imaging (PWI) are used for evaluation and grading of brain lesions, as well as assessing of suitability for intra-arterial recanalization of patients with acute stroke. Additionally, GBCAs are used for contrast-enhanced MR angiography (CE-MRA).

One means of applying contrast for CE-MRI is via intravenous application of gadolinium-based contrast agents (GBCAs). The use of GBCAs enables detection of a wide variety of pathologic processes that would otherwise be undetectable with unenhanced MRI or other imaging modalities [2]. The use of GBCAs in CE-MRI is widespread, with more than 10 million intravenous administrations annually in the USA alone and in 40–50 % of all MRI examinations [2]. Most CE-MRI examinations utilize one of several available GBCAs that consist of the active constituent paramagnetic gadolinium (Gd) ion encased in a chelate molecule to minimize Gd3+ toxicity [3]. GBCAs can be classified according to their biochemical structure (linear or macrocyclic) or their charge (ionic or non-ionic).

Gadopentate dimeglumine was approved for clinical use in 1988, and GBCAs are generally considered to have an excellent safety profile. However, studies performed by Grobner [4] and Marckmann [5] in 2006 demonstrated an association between administration of GBCAs and the occurrence of nephrogenic systemic fibrosis (NSF) in patients with severely compromised renal function. Moreover, several recent studies have revealed indirect evidence of gadolinium deposition in specific brain structures, the globus pallidus and dentate nucleus, in patients with normal renal function [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18]. Two rodent studies by Robert et al. [19, 20] and Jost et al. [21] also demonstrated neural gadolinium deposition following controlled, repeated GBCA administration.

The exact mechanism and clinical significance of gadolinium deposition remain unclear, and the United States Food and Drug Administration (FDA) recently announced that it will investigate the risk of brain deposits following repeated use of GBCAs for CE-MRI [22]. This report aims to present the current status of research into gadolinium deposition in the dentate nucleus and globus pallidus after repeated administrations of GBCAs, including clinical significance, recommendations, and review of relevant literature.


GBCAs are diagnostic pharmaceutical compounds containing paramagnetic gadolinium ions that affect the MR signal properties of surrounding tissue. GBCAs are most commonly used in clinical practice as contrast agents for CE-MRI due to their fundamental ability to selectively decrease T1 relaxation time within a lesion rather than in normal tissue. The following GBCAs are available internationally: gadopentetate dimeglumine (linear and ionic), gadodiamide (linear and non-ionic), gadoterate meglumine (macrocyclic and ionic), gadobenate dimeglumine (linear and ionic), gadobutrol (macrocyclic and non-ionic), and gadoteridol (macrocyclic and non-ionic). Gadoversetamide is available in the USA only. These compounds are approved specifically for CE-MRI in the central nervous system (CNS). There are two GBCAs not approved for CE-MRI of the CNS—gadofosveset trisodium and gadoxetic acid. Gadofosveset trisodium is an intravascular “blood-pool” agent approved for MR angiography of aortoiliac vessels. It binds to serum albumin, resulting in large molecule size, which restricts permeability across the open blood-brain barrier. Gadoxetic acid is an approved liver-specific GBCA. One half of the administered dose is taken up and eliminated by hepatocytes.

Mechanisms of action

GBCA function is attributed to short-range dipolar interactions dominated by the high magnetic moment of seven unpaired electrons of gadolinium. At the molecular level, the strong paramagnetism of gadolinium alters the relaxation of nearby water protons, causing reduction of the T1, T2, and T2* relaxation times and a concomitant increase in tissue signal intensity on T1-weighted images (positive enhancement) [23, 24]. Though both T1 and T2 relaxation times are affected by GBCAs, the effects on T1 relaxation times are stronger with the concentrations used in clinical practice.

As a heavy metal in the lanthanide series, elemental free gadolinium is toxic to humans [1]. Organic ligands serve as physiological chaperones, allowing otherwise toxic gadolinium to be safely administered intravenously to humans and subsequently excreted [3, 25, 26, 27]. Structural design differences between GBCAs result in differing physicochemical properties. GBCAs can be structurally divided into two distinct categories: (1) linear or open chain molecules and (2) macrocyclic molecules in which the Gd3+ ion is caged within the cavity of the ligand [24, 25]. In addition to their structural classes, GBCAs can be further classified according to their charge, either ionic or non-ionic. The different classes, as well as different agents within each class, have different stabilities, i.e., different propensities to retain the toxic Gd3+ ion within the complex [28]. Generally, macrocyclic chelates are more stable than linear chelates, and work is ongoing to determine what, if any, clinical relevance is associated with the increased stability.


All GBCAs have nearly identical pharmacokinetic profiles. Gadolinium complexes are called non-specific as they are hydrophilic and do not bind to proteins or receptors. Gadobenate dimeglumine, which interacts weakly and transiently with serum albumin in vivo, is the only exception. Additionally, GBCAs are considered extracellular fluid markers. Gd chelates have low molecular masses (approximately 500 Da), and because of their small size, they are rapidly cleared from the intravascular space after injection. This results in a non-specific biodistribution. Interstitial space contrast agents diffuse freely into and out of the extracellular space but do not enter tissues with specialized vascular barriers or cross an intact blood-brain barrier.

GBCAs have similar clearance pathways, almost exclusively leaving the body through the kidneys. Gadolinium chelates are excreted in an unmetabolized form by passive glomerular filtration. Again, only gadobenate dimeglumine differs in that a small fraction of the injected dose (approximately 3–5 %) is taken up by normally functioning hepatocytes and excreted into the bile. Though the vast majority of GBCAs are eliminated from the body, trace amounts of gadolinium may remain in the body long term [22].


Free-ion Gd3+ is toxic due to its tendency to precipitate and be deposited in the liver, lymph nodes, and bones, prolonging its half-life [2, 4]. Gd3+ ions may also arrest neuromuscular transmission by obstructing calcium-ion passage through muscle cells and blocking the flow of calcium in bone epiphyses and nerve tissue cells. Transmetallation, wherein Gd replaces some endogenous metals, especially zinc, is a primary factor in the toxicity of Gd complexes. Gd toxicity is also partially governed by the stability of the complex; high stability is necessary to avoid any in vivo decomplexation. Decomplexation is an equilibrium characterized by a thermodynamic stability constant (LogK therm). Macrocyclic GBCAs have the highest thermodynamic stability constants [1]. Moreover, at physiological pH, a study of the conditional stability constant (LogK cond) showed that non-ionic structures are the most stable. Importantly, though, these differences in stability constants do appear to be of minor clinical importance [2].


Following the recognition of the association between GBCAs and NSF in 2006, there has been an increased focus on GBCA safety. NSF is a rare, potentially life-threatening disease that has been linked to the administration of some GBCAs in patients with severe renal impairment. Due to insufficient excretion of GBCAs in patients with poor renal function, the administered gadolinium chelate remains in the body long enough to pose a risk of dissociation (dechelation), which consequently triggers a cascade of events resulting in NSF. In peer-reviewed literature, approximately 78 % of all unconfounded, single-agent cases of NSF have been associated with gadodiamide, while a further 20 % with gadopentetate dimeglumine and ∼2 % with gadoversetamide [29]. Very few single-agent cases (0.5 %) have been associated with the macrocyclic agent gadobutrol, while no unconfounded cases have been reported for gadoterate meglumine, gadobenate dimeglumine, or gadoteridol [29].

Further studies revealed that the chemical structures of GBCAs matter in the development of NSF, and the risk is much higher with non-ionic-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. GBCAs are primarily categorized into three categories: low risk (macrocyclic agents), intermediate risk (ionic-linear chelates), and high risk (non-ionic-linear chelates) for the development of NSF [30]. Guidelines were introduced that called for patient prescreening for renal disease, contraindication of high-risk GBCAs (gadopentetate dimeglumine, gadodiamide, and gadoversetamide) in patients with renal disease, and restriction of GBCA use to a single administration of the lowest necessary dose. Adherence to these guidelines and adoption of new contrast-enhanced MRI protocols, which restrict the administration of high-risk GBCAs 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 [26]. Indeed, these measures have resulted in a reduction of new NSF cases related to GBCA administration to nearly zero [31].

In general, patients tolerate GBCAs well, although adverse reactions are sometimes observed after the administration of all agents as reported in the prescribing information and approved by regulatory authorities. Published data indicates that adverse reactions following GBCA administration occur at a rate of 0.03 to 2.4 % [32, 33, 34, 35, 36, 37, 38, 39, 40, 41]. Of these reactions, 74 % are transient and mild. Moderate to severe reactions have been reported in ∼1 to 19 % of cases [32, 34, 37, 38, 39, 40, 41, 42]. Life-threatening and fatal reactions are extremely rare, with only 40 deaths reported in 51 million GBCA doses administered between 2004 and 2009 [41].

Adverse drug reactions fall into two categories: those that can occur in any patient, such as overdose or drug interactions, and those that are only found in patients with an existing susceptibility like drug toxicity and augmented effects or hypersensitivity due to an allergic or pseudoallergic reaction [43]. These latter two reactions present with similar clinical symptoms though they have different mechanistic causes. Though some true allergic reactions to GBCAs have been reported [44, 45], current evidence suggests that most adverse reactions to GBCAs are pseudoallergic and not associated with immunologic specificity [33]. Adverse and allergic reactions to gadobenate dimeglumine have been reported in 0.18 % of patients who were treated over a 7.5-year period [46]. Approximately half of those cases required some form of treatment, and only a few were considered serious [46].

Gadolinium deposition in dentate nuclei and globus pallidus

The initial concerns about GBCA safety were related to incidence of NSF; however, recent evidence suggests that there is a risk of gadolinium deposits in the brain following repeated GBCA administrations (reviewed in [47, 48, 49]). Based on a number of recent studies, the FDA, in conjunction with the research and clinical community, is investigating this risk [22]. These studies demonstrated that GBCA deposits are found in the brains of some patients who have been subjected to repeated CE-MRI scans, even well after the last administration. Moreover, animal studies have contributed to our understanding of how the use of GBCAs affects the likelihood of gadolinium deposition in the mammalian brain.


In the last 2 years, multiple independent research groups have demonstrated evidence of gadolinium deposition and hyperintensity in the dentate nucleus and/or globus pallidus in the brains of patients who previously received GBCAs for CE-MRI. In these studies, researchers evaluated the signal intensity (SI) ratios between the dentate nucleus and globus pallidus compared to control regions [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18], usually the pons and thalamus, respectively. Retrospective analysis was performed on T1-weighted MR images in each study. The mean SI was calculated in each brain region, and SI ratios were determined by dividing the mean dentate nucleus SI by mean central pons SI or mean globus pallidus SI by mean thalamus SI [12]. The amount and type of GBCA used in each clinical population varied, as did the clinical diagnosis of the patients included in the study. These differences and their relevance will be discussed below.

While these retrospective patient studies strongly suggest a correlation between use of GBCAs for CE-MRI and hyperintensity in the dentate nucleus and globus pallidus, they stop short of demonstrating direct evidence of gadolinium deposition in the brain. Recently, researchers have begun to address this shortcoming through postmortem and animal studies. In 2015, studies by McDonald et al. [11] and Kanda et al. [13] used inductively coupled plasma mass spectrometry (ICP-MS) to evaluate the levels of gadolinium in postmortem neural tissue. In these studies, postmortem tissue was fixed with formalin, digested, and prepared for MS analysis; then, stable gadolinium isotopes (157 and 160 Ga) were quantified using an inductively coupled plasma mass spectrometer. Gadolinium concentrations were calculated by multiplying the weight of gadolinium in the tissue by the dilution factor, then dividing by the tissue sample weight [11]. Both of these studies detected significant levels of gadolinium in postmortem neural tissue of patients who received GBCAs for CE-MRI [11, 13], providing additional evidence of gadolinium deposition in the brain following GBCA administration.

In addition to ICP-MS, McDonald et al. [11] used transmission electron microscopy (TEM) with electron probe microanalysis to further define the localization of gadolinium deposits in postmortem brain tissue. This technique allows for highly accurate determination of the elemental composition of structures viewed by TEM. This analysis also showed extensive gadolinium deposition in the brain of patients who received gadodiamide, which suggests that gadolinium is able to cross an otherwise intact blood-brain barrier and be deposited in the neural tissue interstitium [11].

In 2015, Robert et al. [19] published the first animal study of linear GBCA gadodiamide administration and its effects on gadolinium deposition in the brain. As opposed to the human studies described above, which are retrospective in nature, their study, in rats, involved 20 GBCA administrations over 5 weeks, with a consistent interval between injections and MR image collection once per week for the 5 weeks of treatment, as well as 5 weeks following the completion of treatment. Subjects were sacrificed 5 weeks after the last GBCA administration and analyzed by ICP-MS in both plasma and brain. Increased SI in the deep cerebellar nuclei was qualitatively observed after eight GBCA injections and confirmed quantitatively after 12. The increased SI remained even following 5 weeks of no treatment, and increased gadolinium concentration was observed in the cerebellum by ICP-MS, indicating that the effects of GBCA administration persist in the absence of GBCA administration [19]. This study confirmed the relationship between deep cerebellar nuclei T1W hyperintensity and local gadolinium accumulation after gadodiamide administration. A further study by the same group confirmed these findings and demonstrated that macrocyclic GBCA administration did not result in a similar increase in SI [20]. In addition, Jost et al. [21] evaluated gadolinium deposition in the cerebellar nuclei and globus pallidus following injection of both linear and macrocyclic GBCAs. They found that injection of linear GBCAs resulted in increased neural gadolinium deposition in the cerebellar nuclei, though not the globus pallidus. No gadolinium deposition was observed following injection of macrocyclic GBCAs or saline, though all GBCAs (both linear and macrocyclic) caused an increase in signal intensity in the cerebrospinal fluid, indicating that both classes of GBCA were able to cross the blood-brain barrier [21].

GBCA type and T1W hyperintensity

As described above, GBCAs are classified according to their chemical characteristics: linear vs macrocyclic and ionic vs non-ionic. Beyond that, there are multiple brands of GBCA within each class considering evidence suggests that GBCA type, and potentially even the specific GBCA compound, may have an effect on the likelihood of gadolinium deposition in the brain after GBCA administration. The first study described T1W hyperintensity in the dentate nucleus and globus pallidus [6]. Additional subsequent ones have demonstrated evidence of increase of SI in the brain using various linear GBCAs: gadopenetate dimeglumine [6, 8, 10, 13, 16, 18], gadodiamide [6, 9, 13, 14, 19], and gadobenate dimeglumine [14, 15]. Ramalho et al. [14] evaluated the differences between linear ionic (gadobenate dimeglumine) and linear non-ionic (gadodiamide) GBCAs. While they found evidence of gadolinium deposition with both compounds, the linear non-ionic GBCA had a greater effect than the linear ionic one [14].

Researchers have recently begun investigating the influence of macrocyclic GBCAs on neural gadolinium deposition as well. Though Kanda et al. [8], Radbruch et al. [10, 17], Cao et al. [18], and Robert et al. [19, 20] did not find evidence of gadolinium deposition in humans or rats following administration of the macrocyclic GBCAs gadoteridol [8], gadoterate meglumine [10, 19, 20], or gadobutrol [17, 18] at similar levels to linear GBCA administration, Stojanov et al. [12] did show a small increase in both dentate nucleus and globus pallidus SI in patients who were given gadobutrol. The correlation found in this study was very small, and both Runge [50] and Agris et al. [51] have pointed out some of its critical limitations, as well as those in other studies, which may compromise the scientific interpretation of the data presented [45]. Therefore, further prospective studies with larger patient populations and follow-up periods, more comprehensive controls, comparison between macrocyclic GBCAs, and autopsy specimen or animal model evaluation are warranted [52]. In spite of these limitations, these findings are consistent with those from a previous animal study that showed presence of gadolinium in the brains of rats treated with both macrocyclic and linear GBCAs, though the concentration of gadolinium following treatment with gadobutrol and gadobenate dimeglumine was at a much lower level than with the linear GBCA gadodiamide [53].

The current prevailing theory is that multiple agents can cause gadolinium deposition and the degree of deposition depends on the molecular structure of the GBCA used (linear vs macrocyclic). Neural deposition may occur due to gradual dissociation of accumulated GBCAs in the brain [19]. After dissociation, soluble gadolinium may bind to proteins and macromolecules following transmetallation with brain metals. Moreover, gadolinium deposits have been associated with deposits of calcium, phosphorus, iron, or zinc [54]. The likelihood of dissociation of GBCAs depends on their kinetic and thermodynamic stability. This is a key to understanding the differences between the effects of linear and macrocyclic GBCAs, as macrocyclic GBCAs have increased thermodynamic and kinetic stability compared to linear GBCAs [55, 56]. This may explain why larger effects of gadolinium administration are found when linear GBCAs are used. Hyperintensity in the brain may be associated with both protein-bound and insoluble gadolinium, and further research is needed to precisely determine how gadolinium deposition in the brain occurs and how the relatively stability of GBCA compounds affects this process.

Mechanism of GBCA deposition

At this point, it’s clear that the type of GBCA used for CE-MRI and the chemical and biophysical characteristics of that compound have a strong effect on the likelihood of gadolinium deposition in the brain following GBCA administration. However, the mechanism by which GBCA use leads to neural gadolinium deposits remains unknown. White et al. [57] and Darrah et al. [58] demonstrated sequestration of gadolinium in bone matrix following intravenous GBCA administration, indicating that bone matrix may absorb a small amount of GBCA and slowly release the associated gadolinium over time, resulting in it being taken up by other tissues. In bone and other tissues, gadolinium deposition may be explained by the presence of fenestrated capillary system. Importantly, the presence of gadolinium deposition in the brain indicates that gadolinium can cross the blood-brain barrier, even in the absence of evidence that the barrier has been compromised [11]. This is supported by the presence of punctate gadolinium in neuronal capillary endothelium, although the distribution seen by McDonald et al. may be due to cellular responses to gadolinium rather than the localization of the gadolinium itself [11]. Exact mechanism of gadolinium deposition in the brain, including whether the gadolinium detected in the brain is chelated or free, remains to be determined. No histologic lesions were found in brain tissues of patients with T1W signal hyperintensity [11]. Dentate nuclei and deep gray nuclei may be uniquely susceptible to metal deposition as T1W hyperintensity has also been found in patients with multiple sclerosis, neurofibromatosis, hypoparathyroidism, inherited metabolic disorders, and Fahr disease [6, 7, 11, 59]. Researchers have begun using animal models to investigate biological factors that influence neural gadolinium deposition, and recently, Tabanor et al. [60] provided evidence that the HAV6 peptide, when co-injected with gadolinium-diethylenetriaminepentaacetate, increases the amount of gadolinium deposited in the brain.

Patient clinical characteristics

As when clinicians discovered that GBCA administration could cause NSF in patients with chronic kidney disease, many studies over a short period of time have demonstrated that GBCA use, though previously thought safe for repeated administration, is associated with neural gadolinium deposition [61]. Researchers are not yet certain, however, of which types of patients are particularly vulnerable to gadolinium deposition. A number of pre-existing clinical factors can affect gadolinium deposition in the brain and/or hyperintensity on MRI in the deep cerebellar nuclei. The first of these is poor renal function. Gadolinium is cleared from the body almost entirely through the kidneys [22], and GBCA use was associated with increased incidence of a kidney disease, NSF [4, 5]. Gadolinium deposits have been reported in the brain of a patient who developed NSF related to GBCA use [62]. Therefore, it is critical that studies of the effect of GBCA administration in the brain take into account any potential abnormalities in kidney function. The studies described here conducted a variety either used abnormal kidney function as an exclusionary factor in their analysis or conducted careful controls of kidney function to ensure that any gadolinium deposition in the brain was not caused by inefficient clearance of GBCAs by the kidneys [6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17].

In addition to controlling for kidney function, some critical inclusion and exclusion criteria were used to define the patient populations investigated for gadolinium deposition in the brain. Firstly, patients with brain lesions in the deep cerebellar nuclei unrelated to GBCA administration were excluded from analysis [6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17]. In addition, patient populations were controlled for pre-existing diseases that are known to effect SI in the dentate nucleus or globus pallidus, such as Langerhans cell histiocytosis or multiple sclerosis (MS). The presence of MS is particularly interesting, as hyperintensity in the dentate nucleus has previously been reported in patients with secondary progressive MS (SPMS) [63], though this finding is potentially confounded by the fact that patients with SPMS tend to receive more GBCA administrations than patients with other neurological disorders [50]. Some researchers eliminated patients with MS from their studies [6, 8, 11], while others [7, 12] examined MS patients as a selected patient group. Errante et al. [7] examined patients with either MS or brain metastases who had received at least two CE-MRI exams using GBCAs and found that both groups of patients exhibited a progressive increase in SI that correlated to the number of GBCA administrations received. Furthermore, Stojanov et al. [12] investigated the effect of gadobutrol (a macrocyclic GBCA) administration on patients with relapsing remitting MS (RRMS).

Differential diagnosis of T1W hyperintensities within the dentate nucleus and globus pallidus

There is a broad differential diagnosis of T1W hyperintensities within the dentate nucleus and globus pallidus. In patients with MS, hyperintensity within the dentate nucleus on T1W MR images can be caused by reactive, iron-containing micro- and macroglia affected by MS [64, 65]; accumulation of ferric iron, ferritin with lipid peroxidation, hemosiderin, manganese, and manganese-binding enzymes [66, 67, 68, 69, 70, 71]; infiltration of macrophages and paramagnetic free radicals resulting from macrophage activity [72]; or remyelination [73]. Other factors, unrelated to MS, such as high concentrations of proteins [74], tissue calcifications [75, 76, 77], lipids [71], paramagnetic compounds [78], metal ions [71, 74], or molecular oxygen [79], may also cause T1W hyperintensity within the dentate nucleus. T1W hyperintensity in the globus pallidus has been linked to many conditions, including Wilson disease [80, 81, 82, 83], hepatic dysfunction [80, 82, 83, 84, 85], Rendu-Osler-Weber disease [86], neural calcifications [83], manganese toxicity [83, 86], total parenteral nutrition [87], hemodialysis [88], and neurofibromatosis type 1 [89].

Clinical significance and recommendations

In addition to the biological mechanism of gadolinium retention in the brain, further research is needed to determine its clinical significance. Currently, there is no evidence of adverse health effects specifically related to neural gadolinium deposits. Due to the recent findings that demonstrate gadolinium deposition and the lack of conclusive evidence regarding its potential long-term consequences, the US FDA currently recommends that clinicians carefully evaluate the necessity of GBCA use and limit it only to those cases where the additional information provided is clinically significant [22]. Doctors have an imperative to provide the best possible and least invasive care to their patients, and careful evaluation of the potential benefits and risks of treatment or diagnostic intervention is critical to clinical success. It is also important to consider the trade-off between an increase in our understanding of the mechanism and clinical significance of gadolinium deposition following linear GBCA use and the decreased risk associated with using macrocyclic GBCAs preferentially in the clinic.


In spite of many years of clinical use with a robust safety record, recent evidence has demonstrated that use of GBCAs as contrast agents for CE-MRI may be associated with increased gadolinium deposition in the brain, in particular in the globus pallidus and dentate nucleus. This is especially true with the use of less-stable, linear GBCAs and occurs in spite of normal renal function in the patients receiving GBCA. As the biological characteristics of this phenomenon have only recently been described, the clinical significance continues to be unclear. Further research is needed, both to understand the mechanism by which gadolinium deposition in the brain occurs and how it affects the patients in which it occurs.


Compliance with ethical standards

We declare that this manuscript does not contain clinical studies or patient data.

Conflict of interest

We declare that we have no conflict of interest.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Faculty of MedicineUniversity of NisNisSerbia
  2. 2.Center for RadiologyNisSerbia

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