Gadolinium-based contrast agents (GBCAs) have revolutionized magnetic resonance imaging (MRI) by increasing the clinical utility and detection sensitivity of these exams. GBCA-enhanced MRI exams often provide clinical information that cannot be obtained from an unenhanced MRI or any other diagnostic imaging exam. In this way, GBCAs have profoundly improved medical care worldwide by improving the accuracy and expediency in obtaining relevant information that can be used to diagnose, treat, and cure human disease. Approximately 50% of all MRIs are performed with intravenous GBCA administration. Since initial approval from the U.S. Food and Drug Administration (FDA) in 1988, more than 450 million GBCA doses have been administered worldwide.

A patient is examined via MRI on the Charlton 7 Radiology Unit at Mayo Clinic in Rochester, Minnesota.

GBCAs all contain gadolinium, a rare earth metal with unique chemical properties that increases the conspicuity of diseased tissues. However, the recent discovery of small amounts of retained gadolinium in human brain tissues following intravenous administration of GBCAs used during routine MRI exams has caused concern among patients, physicians, scientists, and regulatory agencies. These findings have attracted a great deal of media attention and have focused on the potential adverse health effects to chronic gadolinium exposure.

The recent concern coincides with an FDA announcement in December 2017, when the agency recommended a new class warning and other safety measures for all GBCAs used for MRI exams. This warning was fueled by recent evidence that gadolinium can be retained in the brain (and other body tissues) for months to years after exposure.

It was a Mayo Clinic research team that, in a 2015 study published in Radiology, retrieved archived tissues from the Mayo Clinic Biorepository within Mayo’s Biobank (one of the largest resources of its kind) to determine whether or not repeated doses of gadolinium from MRIs caused any type of accrual of the metal in neuronal tissue.

Figure 1: Tissue localization and cellular response to gadolinium deposition. (Image Credit: McDonald RJ, McDonald JS, Kallmes DF, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. "Radiology." 2015;275:772-782. By permission of the Radiological Society of North America.)

Mayo Clinic’s Bioservices offers a unique resource that allowed us to rapidly carry out this study,” says Robert McDonald, M.D., Ph.D., a neuroradiologist and scientist at Mayo in Rochester, Minnesota, and lead investigator on the study. “We found that gadolinium accumulates in a dose-dependent fashion in the brain. It also accumulates in every tissue in the body over time.”

The FDA endorsed the study findings during its review process.

“We didn’t anticipate what a tidal wave these findings would cause,” adds Dr. McDonald. “And so now, over two years later, it’s driven a lot of safety concerns because gadolinium was never expected to be retained in the brain tissue.”

Since then, Mayo has done a series of groundbreaking studies on gadolinium retention, led by Dr. McDonald. For the most recent 2017 study (presented at the Radiological Society of North America’s 2017 conference), researchers wanted to create very practical parameters that represent the typical patient. Hence, their study asked the question . . .

What Happens in MRI Patients after Several Doses of Gadolinium?

Whether or not patients are exposed to GBCAs for an MRI scan is based on clinical assessment of each individual’s risk and tolerance profile.

“Patients who receive huge doses of gadolinium—20 to 30 doses, because of an obvious brain tumor that needs monitoring, for example—represent only a small subset of patients,” says Dr. McDonald. “The majority of patients only get a few gadolinium-enhanced MRIs over the course of their lifetime. With these lower doses, the risk-benefit ratio is much different when compared to a patient with a known malignancy who needs the GBCA for clinical surveillance. We wanted to focus on patients who receive lower GBCA doses because it mimics a more real-world scenario and represents a larger patient population.”

To conduct this investigation, the team took advantage of the Mayo Clinic Study of Aging (MCSA), a longitudinal population-based study on cognitive changes related to aging. It is the largest and most comprehensive study on aging in the world.

Figure 2: Axial T1-weighted MR images through, A, C, E, basal ganglia and, B, D, F, posterior fossa at level of dentate nucleus. Images are shown for, A, B, control group patient 4, and the, C, D, first and, E, F, last examinations performed in contrast group patient 13. Regions of interest used in quantification of signal intensity are shown as dashed lines for globus pallidus (green), thalamus (blue), dentate nucleus (yellow), and pons (red). (Photo Credit: McDonald RJ, McDonald JS, Kallmes DF, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. "Radiology." 2015;275:772-782. By permission of the Radiological Society of North America.)

“We realized this was the perfect study to determine if chronic GBCA exposure was detrimental to neurologic function because it was a longitudinal population-based study, unlike any other in the world, with a comprehensive neurologic exam performed on thousands of patients at regular intervals. Fortunately for us, the MCSA happened to be inadvertently studying gadolinium deposition as well,” says Dr. McDonald.

He adds, “Since it’s a population-based study, the MCSA is looking at thousands and thousands of patients, and some of them have had MRIs for reasons unrelated to cognitive decline or a brain tumor. We focused our attention on this very patient group to understand if incidental gadolinium exposure is associated with excess risk of cognitive decline.”

By separating out these particular MCSA patients, Dr. McDonald’s team was able to study 4,261 cognitively normal men and women, between the ages of 50 and 90, with a mean age of 72. All of them underwent extensive neurologic evaluation and neuropsychological testing. Their scores were compared using standard methods between MCSA patients with no history of prior gadolinium exposure and those who underwent prior MRI with GBCAs.

The mean length of study participation was 3.7 years, and the median time since first gadolinium exposure was 5.6 years.

The results?

“We view this as a preliminary study, but so far, we’ve found no evidence that gadolinium retention in the brain is associated with cognitive decline or adverse clinical outcomes,” says Dr. McDonald.

“Our study is ongoing because the burden is still on our field to better understand this retention phenomenon. We need to foster collaborative efforts abroad to better understand the safety of all commercially available GBCAs to render the best and safest care to all patients. That’s what really drives us to do these studies,” he adds.

Patients Retain Gadolinium Regardless of Age

Because prior investigations on gadolinium exposure by the FDA and the European Medicines Agency have been largely limited to adults, Mayo also conducted a smaller case-control study in 2017 on a cohort of pediatric patients (under age 18) who had received at least four gadolinium-enhanced MRI exams. The study wanted to determine if young patients also retain gadolinium, or if perhaps their youth made them more immune to it—given that gadolinium is suspected to enter the brain by circumventing the blood-brain barrier, which breaks down as individuals age.

Unfortunately, youth doesn’t seem to confer an advantage. The study confirmed the presence of intracranial gadolinium deposits in pediatric patients with normal renal function. And, as with the adult population, the gadolinium deposition seems to follow a dose-dependent trend.

“It appears that every patient exposed to gadolinium, regardless of age, or disease, is going to have a small amount accumulate in their bodies,” says Dr. McDonald, who co-authored the study paper. “We need to continue research on vulnerable populations such as pediatric patients as they are at higher potential risk of harm from gadolinium retention given their long life spans and developing brain tissues.”

Why Do Some Patients Retain Gadolinium While Others Do Not?

Diluting patient samples for analysis.

“Anecdotally, we’ve tested and seen patients with normal renal function, who have shown prolonged elimination of gadolinium—that is, we’ve found detectable levels in patients’ urine, several weeks and even months after initial exposure to GBCAs,” says Paul Jannetto, Ph.D., DABCC, FAACC, Co-Director of Mayo’s Metals Laboratory, which collaborates with Dr. McDonald’s team and can measure levels of gadolinium and other elements in the body. “We still don’t understand the clinical significance of these findings, and just because we can measure levels of gadolinium retained in the body, it doesn’t mean it directly correlates to increased risk or toxicity.”

The Metals Laboratory has one of the few ISO 7 class cleanrooms for trace metal analysis of its kind, which minimizes potential contamination to a patient sample. And the lab’s inductively coupled plasma mass spectrometer (ICP-MS) technology provides greater sensitivity, dynamic range, and specificity for elemental analysis compared to traditional atomic absorption techniques.

Although the laboratory offers the measurement of gadolinium levels in the body—via serum, urine, and dermal tissue—there is still no definitive or diagnostic test for gadolinium toxicity. In other words, the presence of gadolinium in serum or urine only confirms past exposure and/or prolonged elimination of gadolinium by the renal system. (For an FAQ on gadolinium testing, read this article from Dr. Jannetto and his colleague Joshua Bornhorst, Ph.D.)

Because of the recent FDA and media attention, the Metals Laboratory has seen a sharp uptick in demand for gadolinium testing. The lab continues to collect data from living subjects who are being exposed to gadolinium, which can be studied to further the literature. It is also supporting tissue studies from Dr. McDonald’s team.

“A systemic exploration of the pharmacokinetics of long-term gadolinium retention is needed,” says Joshua Bornhorst, Ph.D., DABCC, FAACC, who co-directs the Metals Laboratory with Dr. Jannetto.

“Our lab is in a unique position to support that, either with collaborative studies here at Mayo, or with other institutions. We want to help facilitate these studies, so we have a better understanding of the science behind gadolinium and can provide better patient care and treatment in the future,” Dr. Bornhorst adds.

Instrument sampling for analysis.

The Two Types of Gadolinium Agents

Currently, there are two types of GBCAs used to enhance MRIs: linear and macrocyclic, and each has their own type of organic molecule that binds (or chelates) with the gadolinium metal. Of the two, linear agents bind less tightly to the metal, resulting in more retention of gadolinium in patients, versus the newer, more stable macrocyclic GBCAs.

“Right now, both linear and macrocyclic agents still allow some gadolinium deposition in the body,” says Dr. Jannetto. “It was once thought that these agents wouldn’t disassociate from the gadolinium, but studies like Dr. McDonald’s have shown otherwise.”

“The newer macrocyclic agents bind tighter, so they release less gadolinium into the body, but you still have some release, at detectable levels, in patients who have only had macrocyclic compounds,” says Dr. Bornhorst. “This is why institutions like Mayo have switched from linear to the macrocyclic agents because they seem to have a tighter binding, which means less release, and this reduces potential risk.”

Regardless of which compound an institution chooses, the FDA has approved the use of both linear and macrocyclic agents as safe and effective with MRIs—which means the agency does not recommend one agent over the other.

Dr. McDonald believes that both agents are safe.

“Although greater gadolinium retention is associated with linear GBCA administration, the amounts retained are so incredibly small that some of the most sensitive analytical instrumentation in the world is needed to detect the traces that are left in the body.”

The Benefits of MRI Far Outweigh Potential Risk

As noted earlier, since 1988, more than 450 million doses of gadolinium have been administered for MRIs throughout the world. On one hand, a person could say that the big population experiment has already been performed, what with that many doses spanning three decades without any proven adverse effects. Further, gadolinium is present in many municipal water sources, which means some of us may have low concentrations of this metal already in our bodies.

Given these facts, coupled with the historical data, “It’s fair to say that GBCAs are well-tolerated and very safe agents,” says Dr. McDonald. “GBCAs actually have safety profiles that are far better than most currently approved pharmaceutical agents, and this is an important point because there’s been a lot of fear-mongering, some of which has been driven by competition between GBCA manufacturers.”

In other words, people shouldn’t avoid having a contrast-enhanced MRI. The benefits are profound compared to any potential theoretical risk.

“Gadolinium has revolutionized and literally driven MRI imaging into the 21st century,” says Dr. McDonald. “It has saved millions of lives, and its loss from our imaging armamentarium would be a cataclysmic loss to diagnostic medicine in general because MRI scans provide such useful information to all physicians, and gadolinium is essential to that role. Without GBCAs, we would not be able to render as high quality of care to our patients.”

Christoph Bahn

Christoph Bahn

Christoph Bahn covers emerging research and discovery for Mayo Clinic Laboratories. His writing has also appeared in The New York Times, Los Angeles Times, and Smithsonian Air & Space. He divides his time between Southern California and Northwest Ohio.