MRI contrast agents are a group of contrast media used to improve the visibility of internal body structures in magnetic resonance imaging (MRI). The most commonly used compounds for contrast enhancement are gadolinium-based. MRI contrast agents alter the relaxation times of tissues and body cavities where they are present. Depending on the image weighting, this can give a higher or lower signal.
Gadolinium-chelate MRI contrast agents, when used in patients with renal failure, have been associated with a rare systemic fibrosing disease called nephrogenic systemic fibrosis. This has been associated with use of at least four different gadolinium-containing agents, which share only the presense of gadolinium, which is already known to be toxic when in the free soluble ionic state. Newer agents which chelate gadolinium more strongly are under development.
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Most clinically used MRI contrast agents work through shortening the T1 relaxation time of protons located nearby. The T1 shortening is due an increase in rate of stimulated emission from high energy states (spin anti-aligned with the main field) to low energy states (spin aligned). The source of the stimulation is thermal vibration of the strongly magnetic metal ions, which create oscillating electromagnetic fields at frequencies corresponding to the energy difference between the spin states (via E = hν).
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 G.I. tract scans, while intravascular administration proves more useful for most other scans. A variety of agents of both types enhance scans routinely.
MRI contrast agents delivered through the blood stream are chelated metals.
Gadolinium(III) contrast MRI contrast agents (in a complex) 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. For large vessels such as the aorta and its branches, the gadolinium(III) dose can be as low as 0.1 mmol per kg body mass. Higher concentrations are often used for finer vasculature.[1] Due to their hydrophilic character, Gd(III) chelates do not pass the blood-brain barrier. Thus, these are useful in enhancing lesions and tumors where the Gd(III) leaks out. In the rest of the body, the Gd(III) initially remains in the circulation but then distributes into the interstitial space or is eliminated by the kidneys.
Gadolinium MRI contrast agents have proved safer than the iodinated contrast agents used in X-ray radiography or computed tomography. Anaphylactoid reactions are rare, occurring in approx. 0.03–0.1%.[2]
As a free solublized aqueous ion, gadolinium is highly toxic, but was generally regarded as safe when administered as a chelated compound. Then, the use of some Gd chelates in persons with renal disease was linked to a rare but severe complication, nephrogenic fibrosing dermopathy[3], also known as nephrogenic systemic fibrosis (NSF).[4][5][6] This systemic disease resembles scleromyxedema and to some extent scleroderma. It may occur months after contrast has been injected. [7] Patients with poorer renal function are more at risk for NSF, with dialysis patients being more at risk than patients with renal insufficiency.[8][9] At present, NSF has been linked to the use of four gadolinium-containing MRI contrast agents. Its association with gadolinium and not the carrier molecule is confirmed by its occurrence in from contrast materials in which gadolinium is carried by very different carrier molecules.
The carrier molecule compounds can be classified by whether they are macro-cyclic or have linear geometry and whether they are ionic or not. Cyclical ionic Gd compounds are considered the least likely to release the Gd ion and hence the safest.[10]
Presently, different types of gadolinium-containing contrast agents are available in different territories. In the United States of America, Gd chelated contrast agents approved by the U.S. Food and Drug Administration (FDA) include:[11]
Apart from the gadolinium-containing contrast agents that have been approved by the FDA and other regulatory bodies for marketing, there are some others that have been assigned international non-proprietary ("generic") names by the World Health Organization:[12]
The use of present agents has resulted in lawsuits. After several years of controversy during which up to 100 Danish patients have been gadolinium poisoned (and some died) after use of the contrast agent Omniscan, it was admitted by the Norwegian medical company Nycomed that they were aware of some dangers of using gadolinium-based agents for their product.[13]
Several academic research groups are working to develop the next generation of MRI contrast agents, including A. Dean Sherry (University of Texas, Dallas),[14] Thomas Meade (Northwestern),[15] Ken Raymond (University of California, Berkeley), [16] Peter Caravan (Harvard Medical School), [17] Christopher Chang (University of California, Berkeley), [18]
Two types 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 tumor enhancement.[19] It appears that most of the agents listed below are no longer available. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/01/WC500067464.pdf http://www.wellsphere.com/cancer-article/the-demise-of-combidex-160-sinerem/1058235
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. [20]. These are, however, investigational agents which have not yet been tried in humans.
Manganese chelates such as Mn-DPDP enhance the T1 signal and have been used for the detection of liver lesions. The chelate dissociates in vivo into manganese and DPDP where the former is absorbed intra-cellularly and excreted in bile, while the latter is eliminated via the renal filtration.[21]
A wide variety of oral contrast agents can be used for enhancement 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.[22]
Perflubron, a type of perflorocarbon, has been used as a gastrointestinal MRI contrast agent for pediatric imaging.[23] This contrast agent works by reducing the amount of protons (as hydrogen) in a body cavity, thus causing it to appear dark in the images.
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