MRI contrast agent

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MRI contrast agents are contrast agents used to improve the visibility of internal body structures in magnetic resonance imaging (MRI). [1] The most commonly used compounds for contrast enhancement are gadolinium-based contrast agents (GBCAs). Such MRI contrast agents shorten the relaxation times of nuclei within body tissues following oral or intravenous administration.

Contents

Theory of operation

In MRI scanners, sections of the body are exposed to a strong magnetic field causing primarily the hydrogen nuclei ("spins") of water in tissues to be polarized in the direction of the magnetic field. An intense radiofrequency pulse is applied that tips the magnetization generated by the hydrogen nuclei in the direction of the receiver coil where the spin polarization can be detected. Random molecular rotational oscillations matching the resonance frequency of the nuclear spins provide the "relaxation" mechanisms that bring the net magnetization back to its equilibrium position in alignment with the applied magnetic field. The magnitude of the spin polarization detected by the receiver is used to form the MR image but decays with a characteristic time constant known as the T1 relaxation time. Water protons in different tissues have different T1 values, which is one of the main sources of contrast in MR images. A contrast agent usually shortens, but in some instances increases, the value of T1 of nearby water protons thereby altering the contrast in the image.

Most clinically used MRI contrast agents work by shortening the T1 relaxation time of protons inside tissues via interactions with the nearby contrast agent. Thermally driven motion of the strongly paramagnetic metal ions in the contrast agent generate the oscillating magnetic fields that provide the relaxation mechanisms that enhance the rate of decay of the induced polarization. The systematic sampling of this polarization over the spatial region of the tissue being examined forms the basis for construction of the image.

MRI contrast agents may be administered by injection into the blood stream or orally, depending on the subject of interest. Oral administration is well suited to gastrointestinal tract scans, while intravascular administration proves more useful for most other scans.

MRI contrast agents can be classified [2] by their:

Gadolinium(III)

Effect of contrast agent on images: Defect of the blood-brain barrier after stroke shown in MRI. T1-weighted images, left image without, right image with contrast medium administration Bluthirnschranke nach Infarkt nativ und KM.png
Effect of contrast agent on images: Defect of the blood–brain barrier after stroke shown in MRI. T1-weighted images, left image without, right image with contrast medium administration

Gadolinium(III) containing MRI contrast agents (often termed simply "gado" or "gad") are the most commonly used for enhancement of vessels in MR angiography or for brain tumor enhancement associated with the degradation of the blood–brain barrier (BBB). [3] [4] Over 450 million doses have been administered worldwide from 1988 to 2017. [5] For large vessels such as the aorta and its branches, the dose can be as low as 0.1 mmol/kg of body mass. Higher concentrations are often used for finer vasculature. [6] At much higher concentration, there is more T2 shortening effect of gadolinium, causing gadolinium brightness to be less than surrounding body tissues. [7] However at such concentration, it will cause greater toxicity to bodily tissues. [8]

Gd3+ chelates are hydrophilic and do not readily cross the intact blood–brain barrier. Thus, they are useful in enhancing lesions and tumors where the blood–brain barrier is compromised and the Gd(III) leaks out. [9] [lower-alpha 1] In the rest of the body, the Gd3+ initially remains in the circulation but then distributes into the interstitial space or is eliminated by the kidneys.

Available gadolinium-based contrast agents (GBCAs) (brand names, approved for human use by EMA [10] [ when? ] and by the FDA in 1988; [11] [12] (standard dose [13] )):

Extracellular fluid agents

Blood pool agents

Hepatobiliary (liver) agents

Safety

The use of Gd3+ chelates in persons with acute or chronic kidney disease can cause nephrogenic systemic fibrosis (NSF), [17] [18] [19] a rare but severe systemic disease resembling scleromyxedema and to some extent scleroderma. It may occur months after contrast injection. [20] Patients with severely deteriorated kidney function are more at risk for NSF, with dialysis patients being more at risk than patients with mild chronic kidney disease. [21] [22] NSF can be caused by linear and macrocyclic [23] [24] (macrocyclic ionic compounds have been found the least likely to release the Gd3+), [25] [17] gadolinium-containing MRI contrast agents although much more frequently by linear ones.

While NSF is a severe form of disease, gadolinium deposition disease (GDD) is a mild variant with pain (e.g. headache), fatigue, and / or gadolinium depositions. [26]

As a free solubilized aqueous ion, gadolinium(III) is highly toxic, but the chelated compounds are generally regarded as safe for individuals without kidney disease. Free Gd3+ has a median lethal dose of 0.34 mmol/kg (IV, mouse) [27] or 100–200 mg/kg, but the LD50 is increased by a factor of 31 times [28] when Gd3+ is chelated. [29]

The spectrum of adverse drug reactions is greater with gadolinium-based contrast agents than with iodinated contrast agents (radiocontrast agents). [30]

Gadolinium has been found to remain in the brain, heart muscle, kidney, liver, and other organs after one or more injections of a linear or macrocyclic gadolinium-based contrast agents, even after a prolonged period of time. [31] [32] The amount differs with the presence of kidney injury at the moment of injection, the molecular geometry of the ligand, and the dose administered.[ citation needed ]

In vitro studies have found gadolinium-based contrast agents to be neurotoxic, [33] and a study found signal intensity in the dentate nucleus of MRI (indicative of gadolinium deposition) to be correlated with lower verbal fluency. [34] Confusion is often reported as a possible clinical symptom. [33] The FDA has asked doctors to limit the use of gadolinium contrast agents to examinations where necessary information is obtained only through its use. [35] Intrathecal injections of doses higher than 1 mmol are associated with severe neurological complications and can lead to death. [36] [37] The glymphatic system could be the main access of GBCA to the brain in intravenous injection. [38] [39]

Continuing evidence of the retention of gadolinium in brain and other tissues following exposure to gadolinium containing contrast media, led to a safety review by the Committee for Medicinal Products for Human Use (CHMP) which led the EMA to restrict or suspend authorization for the intravenous use of most brands of linear gadolinium-based media, in which Gd3+ has a lower binding affinity, in 2017. [16] [40]

In the United States, the research has led the FDA to revise its class warnings for gadolinium-based contrast media. It is advised that the use of gadolinium-based media should be based on careful consideration of the retention characteristics of the contrast, with extra care being taken in patients requiring multiple lifetime doses, pregnant, and paediatric patients, and patients with inflammatory conditions. Minimizing repeated GBCA imaging studies when possible, particularly closely spaced MRI studies. However, do not avoid or defer necessary GBCA MRI scans. [41]

In December 2017, the FDA announced that it was requiring these warnings to be included on all GBCAs. The FDA also called for increased patient education and requiring gadolinium contrast vendors to conduct additional animal and clinical studies to assess the safety of these agents. [42]

The French health authority recommends to use the lowest possible dose of a GBCA and only when essential diagnostic information cannot be obtained without it. [43]

The World Health Organization issued a restriction on use of several gadolinium contrast agents in November 2009 stating that "High-risk gadolinium-containing contrast agents (Optimark, Omniscan, Magnevist, Magnegita, and Gado-MRT ratiopharm) are contraindicated in patients with severe kidney problems, in patients who are scheduled for or have recently received a liver transplant, and in newborn babies up to four weeks of age." [44]

In magnetic resonance imaging in pregnancy, gadolinium contrast agents in the first trimester is associated with a slightly increased risk of a childhood diagnosis of several forms of rheumatism, inflammatory disorders, or infiltrative skin conditions, according to a retrospective study including 397 infants prenatally exposed to gadolinium contrast. [45] In the second and third trimester, gadolinium contrast is associated with a slightly increased risk of stillbirth or neonatal death, by the same study. [45]

Anaphylactoid reactions are rare, occurring in about 0.03–0.1%.[ medical citation needed ]

Iron oxide: superparamagnetic

Two types of iron oxide contrast agents exist: superparamagnetic iron oxide (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO). These contrast agents consist of suspended colloids of iron oxide nanoparticles and when injected during imaging reduce the T2 signals of absorbing tissues. SPIO and USPIO contrast agents have been used successfully in some instances for liver lesion evaluation. [46] [47]

Iron platinum: superparamagnetic

Superparamagnetic iron–platinum particles (SIPPs) have been reported and had significantly better T2 relaxivities compared with the more common iron oxide nanoparticles. SIPPs were also encapsulated with phospholipids to create multifunctional SIPP stealth immunomicelles that specifically targeted human prostate cancer cells. [56] These are, however, investigational agents which have not yet been tried in humans. In a recent study, multifunctional SIPP micelles were synthesized and conjugated to a monoclonal antibody against prostate-specific membrane antigen. [56] The complex specifically targeted human prostate cancer cells in vitro, and these results suggest that SIPPs may have a role in the future as tumor-specific contrast agents.[ citation needed ]

Manganese

Manganese(II) chelates such as Mn-DPDP (mangafodipir) enhance the T1 signal. [57] The chelate dissociates in vivo into manganese and DPDP; the manganese is excreted in bile, while DPDP is eliminated via kidney filtration. [58] Mangafodipir has been used in human neuroimaging clinical trials, including for neurodegenerative diseases such as multiple sclerosis. [59] [60] Manganese(II) ions are often used as a contrast agent in animal studies, often called MEMRI (manganese-enhanced MRI). [61] Because Mn2+ ions can enter cells through calcium transport channels, it has been used for functional brain imaging. [62]

Manganese(III) chelates with porphyrins and phthalocyanines have also been studied. [57]

Unlike the other well-studied iron oxide-based nanoparticles, research on Mn-based nanoparticles is at a relatively early stage. [63]

Oral administration

A wide variety of oral contrast agents can enhance images of the gastrointestinal tract. They include gadolinium and manganese chelates, or iron salts for T1 signal enhancement. SPIO, barium sulfate, air and clay have been used to lower T2 signal. Natural products with high manganese concentration such as blueberry and green tea can also be used for T1 increasing contrast enhancement. [64]

Perflubron, a type of perfluorocarbon, has been used as a gastrointestinal MRI contrast agent for pediatric imaging. [65] This contrast agent works by reducing the number of hydrogen ions in a body cavity, thus causing it to appear dark in the images.

Protein-based MRI contrast agents

Newer research suggests the possibility of protein based contrast agents, based on the abilities of some amino acids to bind with gadolinium. [66] [67] [68] [69]

See also

Footnotes

  1. ↑ "Disruption of the BBB tight junctions is thought to be an early or initiating event in new MS lesion formation. T1-w MRI in combination with low molecular weight gadolinium-based contrast agents (GBCA) is most typically used to characterize BBB compromise in MS. MRI GBCAs do not readily cross cellular membranes, are avid extracellular space markers, and are thought to enter the brain from the blood by diffusive transport between endothelial cells (ie, via intercellular pathways). Although it is widely believed that the MRI GBCAs do not cross the BBB under homeostatic conditions, there is substantial evidence that they do, albeit with very small volume transfer rate constants." — Bagnato, Gauthier, Laule, et al. (2020) [9]

Related Research Articles

<span class="mw-page-title-main">Gadolinium</span> Chemical element with atomic number 64 (Gd)

Gadolinium is a chemical element; it has symbol Gd and atomic number 64. Gadolinium is a silvery-white metal when oxidation is removed. It is a malleable and ductile rare-earth element. Gadolinium reacts with atmospheric oxygen or moisture slowly to form a black coating. Gadolinium below its Curie point of 20 °C (68 °F) is ferromagnetic, with an attraction to a magnetic field higher than that of nickel. Above this temperature it is the most paramagnetic element. It is found in nature only in an oxidized form. When separated, it usually has impurities of the other rare earths because of their similar chemical properties.

<span class="mw-page-title-main">Magnetic resonance imaging</span> Medical imaging technique

Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves to generate images of the organs in the body. MRI does not involve X-rays or the use of ionizing radiation, which distinguishes it from computed tomography (CT) and positron emission tomography (PET) scans. MRI is a medical application of nuclear magnetic resonance (NMR) which can also be used for imaging in other NMR applications, such as NMR spectroscopy.

<span class="mw-page-title-main">Gadolinium(III) chloride</span> Chemical compound

Gadolinium(III) chloride, also known as gadolinium trichloride, is GdCl3. It is a colorless, hygroscopic, water-soluble solid. The hexahydrate GdCl3∙6H2O is commonly encountered and is sometimes also called gadolinium trichloride. Gd3+ species are of special interest because the ion has the maximum number of unpaired spins possible, at least for known elements. With seven valence electrons and seven available f-orbitals, all seven electrons are unpaired and symmetrically arranged around the metal. The high magnetism and high symmetry combine to make Gd3+ a useful component in NMR spectroscopy and MRI.

<span class="mw-page-title-main">Magnetic resonance angiography</span> Group of techniques based on magnetic resonance imaging (MRI) to image blood vessels.

Magnetic resonance angiography (MRA) is a group of techniques based on magnetic resonance imaging (MRI) to image blood vessels. Magnetic resonance angiography is used to generate images of arteries in order to evaluate them for stenosis, occlusions, aneurysms or other abnormalities. MRA is often used to evaluate the arteries of the neck and brain, the thoracic and abdominal aorta, the renal arteries, and the legs.

A contrast agent is a substance used to increase the contrast of structures or fluids within the body in medical imaging. Contrast agents absorb or alter external electromagnetism or ultrasound, which is different from radiopharmaceuticals, which emit radiation themselves. In X-ray imaging, contrast agents enhance the radiodensity in a target tissue or structure. In magnetic resonance imaging (MRI), contrast agents shorten the relaxation times of nuclei within body tissues in order to alter the contrast in the image.

<span class="mw-page-title-main">Gadopentetic acid</span> Complex of gadolinium by DTPA

Gadopentetic acid, sold under the brand name Magnevist, is a gadolinium-based MRI contrast agent.

<span class="mw-page-title-main">Pentetic acid</span> DTPA: aminopolycarboxylic acid

Pentetic acid or diethylenetriaminepentaacetic acid (DTPA) is an aminopolycarboxylic acid consisting of a diethylenetriamine backbone with five carboxymethyl groups. The molecule can be viewed as an expanded version of EDTA and is used similarly. It is a white solid with limited solubility in water.

<span class="mw-page-title-main">Mangafodipir</span> Chemical compound

Mangafodipir is a contrast agent delivered intravenously to enhance contrast in magnetic resonance imaging (MRI) of the liver, and has potential to serve as an adjunct for various chemotherapeutic agents and during coronary intervention. It has two parts, a paramagnetic manganese(II) ion and the fodipir chelating agent. When freed from the organic ligand, the manganese shortens the longitudinal relaxation time (T1) in an MRI scan. Normal liver tissue absorbs the manganese more than abnormal or cancerous tissue, which makes the normal tissue appear brighter in MRIs. This enhanced contrast allows lesions to be more easily identified.

<span class="mw-page-title-main">Breast MRI</span> Form of breast imaging

One alternative to mammography, breast MRI or contrast-enhanced magnetic resonance imaging (MRI), has shown substantial progress in the detection of breast cancer.

<span class="mw-page-title-main">Gadodiamide</span> Chemical compound

Gadodiamide, sold under the brand name Omniscan, is a gadolinium-based MRI contrast agent (GBCA), used in magnetic resonance imaging (MRI) procedures to assist in the visualization of blood vessels.

Nephrogenic systemic fibrosis is a rare syndrome that involves fibrosis of the skin, joints, eyes, and internal organs. NSF is caused by exposure to gadolinium in gadolinium-based MRI contrast agents (GBCAs) in patients with impaired kidney function. Epidemiological studies suggest that the incidence of NSF is unrelated to gender or ethnicity and it is not thought to have a genetic basis. After GBCAs were identified as a cause of the disorder in 2006, and screening and prevention measures put in place, it is now considered rare.

<span class="mw-page-title-main">Gadobutrol</span> Chemical compound

Gadobutrol (INN) (Gd-DO3A-butrol) is a gadolinium-based MRI contrast agent (GBCA).

<span class="mw-page-title-main">Gadoteric acid</span> Chemical compound

Gadoteric acid, sold under the brand name Dotarem among others, is a macrocycle-structured gadolinium-based MRI contrast agent (GBCA). It consists of the organic acid DOTA as a chelating agent, and gadolinium (Gd3+), and is used in form of the meglumine salt (gadoterate meglumine). The paramagnetic property of gadoteric acid reduces the T1 relaxation time (and to some extent the T2 and T2* relaxation times) in MRI, which is the source of its clinical utility. Because it has magnetic properties, gadoteric acid develops a magnetic moment when put under a magnetic field, which increases the signal intensity (brightness) of tissues during MRI imaging.

<span class="mw-page-title-main">Cardiac magnetic resonance imaging perfusion</span>

Cardiac magnetic resonance imaging perfusion, also known as stress CMR perfusion, is a clinical magnetic resonance imaging test performed on patients with known or suspected coronary artery disease to determine if there are perfusion defects in the myocardium of the left ventricle that are caused by narrowing of one or more of the coronary arteries.

<span class="mw-page-title-main">Gadofosveset</span> Chemical compound

Gadofosveset is a gadolinium-based MRI contrast agent. It was used as the trisodium salt monohydrate form. It acts as a blood pool agent by binding to human serum albumin. The manufacturer discontinued production in 2017 due to poor sales.

Blood pool agents (BPAs) are a class of magnetic resonance angiography contrast agents. Blood pool agents are differentiated from other contrast agents due to their high molecular weight and higher relaxivities. Their large size prevents diffusion through the vascular epithelium and leakage into the interstitial space, and because of this they stay in the vascular system for a longer time period. Most contrast agents, leave the vascular system within a few minutes, however blood pool agents remain in the circulation for up to an hour, extending the window available for imaging. Longer image acquisition times allow better signal-to-noise ratio and improved image resolution.

<span class="mw-page-title-main">Val Murray Runge</span> American professor of radiology

Val Murray Runge is an American and Swiss professor of radiology and the editor-in-chief of Investigative Radiology. Runge was one of the early researchers to investigate the use of gadolinium-based contrast agents for magnetic resonance imaging (MRI), giving the first presentation in this field, followed two years later by the first presentation of efficacy. His research also pioneered many early innovations in MRI, including the use of tilted planes and respiratory gating. His publication on multiple sclerosis in 1984 represented the third and largest clinical series investigating the role of MRI in this disease, and the first to show characteristic abnormalities on MRI in patients whose CT was negative.

<span class="mw-page-title-main">Perfusion MRI</span>

Perfusion MRI or perfusion-weighted imaging (PWI) is perfusion scanning by the use of a particular MRI sequence. The acquired data are then post-processed to obtain perfusion maps with different parameters, such as BV, BF, MTT and TTP.

<span class="mw-page-title-main">MRI pulse sequence</span> A pulse sequence during a medical test

An MRI pulse sequence in magnetic resonance imaging (MRI) is a particular setting of pulse sequences and pulsed field gradients, resulting in a particular image appearance.

<span class="mw-page-title-main">Gadopiclenol</span> MRI contrast agent

Gadopiclenol, sold under the brand name Elucirem among others, is a contrast agent used with magnetic resonance imaging (MRI) to detect and visualize lesions with abnormal vascularity in the central nervous system and in the body. Gadopiclenol is a paramagnetic macrocyclic non-ionic complex of gadolinium.

References

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