Contrast media in magnetic resonance imaging (MRI)

In the early years of clinical MRI it was believed that the natural contrast between different soft tissues would exclude the need for contrast media. It was soon found (just as in computed tomography) that the signal differences between the different tissues, i.e. the contrast resolution in the MR-image, could be profoundly improved by different contrast media. It was not until the first MRI contrast medium (Gd-DTPA, based on the paramagnetic gadolinium ion inside the chelate DTPA) became commercially available that MRI became equal to or better than computerized tomography in certain applications.

Mechanisms behind MR contrast media

For information on the T1- and T2-weighted images in MRI, we refer the reader to the chapters on "Radiophysics" and on "Modalities".
The signal intensity from a small volume unit (a voxel) in a patient undergoing MRI depends on several factors. Among the machine-related factors are the strength of the magnetic field and gradient coils, the sequences of proton-exciting radio waves from the transmitting antenna and the timing for signal registration in the receiving antenna. Among patient factors are the proton spin density inside a voxel and the T1- and T2-relaxation times of the protons inside those voxels. It is known that

Figure 6. lnfluence of paramagnetic and ferromagnetic contrast media on the intensity of the MR-signal.

some substances may influence the relaxation times of protons in their vicinity. The MR contrast medium inside a voxel can influence the proton relaxations times T1 and T2 or the proton dens it y inside that voxel. Depending on different magnetic properties, the MR contrast media are divided into paramagnetic and super-paramagnetic media.

Paramagnetic contrast media

Atoms with one or several unpaired electrons have paramagnetic properties. The most common MRI contrast media are paramagnetic metal ions with a large magnetic moment. Examples of such ions are gadolinium, chromium, manganese, nickel and iron. Gadolinium compounds have hitherto enjoyed the largest clinical use. The large arrows in Fig. 6 illustrate that the MR signals from a voxel become stronger with higher proton density, shorter T l-time and longer T2-time. The small arrows in Fig. 6 illustrate how a paramagnetic contrast medium, in clinical doses, may increase the signal intensity through a shortening of T1-time, while the super-paramagnetic contrast media mainly decrease the MR-signal through a shortening of T2-time. The contrast medium effect of the gadolinium ions is a reduction in T1- and T2-relaxation times. In low doses it is mainly a T1-effect which increases the signal intensity, illustrated in Fig. 6. In high doses it is more a T2-effect with a reduction of the signal.

Superparamagnetic contrast media

Superparamagnetic iron oxide is used as contrast medium. Its dominating effect is a reduction of T2-relaxation time. With an increasing dose there is a reduction of signal intensity (Fig. 6).

Depending on the above mentioned mechanisms the T1-weighted images are mainly influenced by paramagnetic contrast media, while T2-weighted images are mainly influenced by superparamagnetic contrast media (Figure 6).

Water soluble extracellular contrast media

The first registered contrast medium is a gadolinium chelate, gadopentatedimeglumine (MagnevistR). Chelate means "claw" and describes how the gadolinium ion (Gd³⁺) with three positive "unit charges" is trapped in a negatively charged chelate (claw or cage) consisting of the dimeglumine salt of diethylene-triamine-penta-acetic-acid (DTPA), which has 5 negatively charged carboxyl groups (5 "unit charges"). The Gd-DTPA ion has 2 negative "charges" (+3 -5 =-2) and is accompanied by 2 positively charged meglumine ions for electroneutrality. The benefit gained by enclosing the Gd-ion in DTPA is that the Gd-DTPA ion has a ten times lower toxicity than the free or non-chelated Gd-ions. This DTPA detoxifying effect on the Gd-ion toxicity causes slight shielding of the magnetic field of the 7 unpaired electrons of the Gd-ion with some decrease of its effects on protons in the body. The pharmacokinetic properties of Gd-DTP A resemble those of the intravenous water soluble iodine contrast media. It has a high water solubility, a small binding affinity for proteins and a low intracellular penetration. It is distributed almost exclusively in the extra-cellular space and excreted by the glomeruli. At normal glomerular filtration rate its plasma half-life is 90 minutes and over 75% of the dose is excreted via the kidneys in 3 hours.

Gd-DTP A, like the iodine contrast media, does not cross the normal blood brain barrier when injected intravascularly. When there is a blood brain barrier damage, e.g. in patients with cerebral tumors or vascular lesions, Gd-DTP A leaks out into the interstitial fluid of the CNS (within the tumor or vascular lesion). The higher the Gd concentration gets in a tissue (compartment) the shorter the T1-time in that tissue. The Gd-DTPA concentration may be different in normal brain parenchyma, edema and tumor tissue and this increases the ability to differentiate between these structures.

The clinically recommended doses vary between 0.1 and 0.2 mmol/kg body weight. Sometimes a feeling of warmth and headache can occur (12 %). Gd-DTP A (Magnevist) is extremely safe and has in clinical doses an even lower frequency of pseudoallergic reactions than the non-ionic iodine contrast media.

New Gd contrast media for the extracellular space are being developed and some have been introduced into clinical practise. Some examples follow: Gd-DTPA is a linear ionic Gd-chelate, while Gd-DOTA is a cyclic ionic chelate. Gd-DTP A-BMA (Omniscan) and Gd-HP-D03A (Prohance) are neutral or nonionic linear and cyclic chelates, respectively. Their clinical use has just started and their exact roles will be defined in the future.

Macromolecular Gd-chelates (Albumin-Gd-DTP A, Dextran-GdDTPA, Polylysin-Gd-DTPA) and paramagnetic liposomes have been tried as blood pool agents. The liposomes are taken up by the reticuloendothelial cells (RES) and may be used as media to image the reticuloendothelial system, for instance, Kupffer cells. Water soluble paramagnetic contrast media with lipophilic components in the chelate host are taken up by the liver and have been designed as contrast media for the liver parenchyma. Some examples of these are: Mn-DPDP, GdBOPTA, and Gd-EOB-DTPA.

Oral contrast media

Just as in computerized tomography the oral contrast media are used mainly in abdominal imaging, in order to differentiate between intestine and surrounding normal and pathological tissues. Demarcation of the small intestine is particularly important in abdominal diagnosis.

Magnetite, Fe₃O₄ is a contrast medium which has been used in the gastrointestinal tract. This is a superparamagnetic contrast medium with its main effect on the T2 relaxation and it works as a negative contrast medium. This means that it decreases the signal intensity. Other negative contrast media in the gastrointestinal tract are gases and perfluor compounds which in principle do not contain any hydrogen atoms and therefore do not give any signal.

Contrast media for ultrasound

In ultrasound, sound waves with a frequency of 3-15 MHz are used. These sound waves are generated by the piezoelectric crystal in the ultrasound transducer. Ultrasound energy penetrates different tissues and is attenuated both by reflection and absorption. In contrast to the roentgenogram which is created by X-rays transmitted by different structures of the body, the ultrasound image is created by ultrasound energy reflected by different structures of the body: "echoes".

The extent to which sound is reflected by a tissue depends on the acoustic impedance of the tissue or the tissue components. The larger the difference in acoustic impedance between two tissue types, the larger the reflection of the ultrasound from the interface between those two tissues.

Except for air, fat and bone, the natural differences in acoustic impedance between different soft tissues in the body are small. The differences that exist between different tissues with regard to reflectivity of ultrasound depend on the different amounts of components such as collagen, fat and fibro-elastic tissue. Presently, contrast media are developed which increase the differences in the amount of ultrasound energy reflected by different structures of the body. An ultrasound contrast medium can thus be described as an echogenic substance which is introduced into a vessel or organ system in order to induce an increased echogenicity - increased ability to reflect ultrasound energy. Such media may be injected intravenously and examples are - suspensions of solid particles, emulsions of fluid droplets, micro bubbles of pure gas, gas bubbles encapsulated in various structures or liquids that release micro bubbles. Like other contrast media, ultrasound media should have low toxicity and fast excretion.

Examples of ultrasound contrast media, in different stages of development and/or clinical introduction, are:
- Suspensions in water of solid particles of, for instance, an ethylester of the biliary medium iodipamide, which, in blood, functions as a blood pool agent and increases the reflectivity of blood and which, after being phagocytosed in the liver, increases the echogenicity (reflectivity) of the liver.
- Droplets of perfluorocarbon compounds, oily liquid media, which similarly first act as a blood pool medium and then as a liver parenchyma medium.
- Micro bubbles of gas encapsulated in albumin (Albunex). - Micro bubbles of gas encapsulated by galactose (Echovist) or entrapped in galactose/fatty acids (Levovist).
- Liquid which is injected into the blood and then inside the blood releases micro bubbles of gas (EchoGen).

While Echovist is trapped in the lungs and therefore used only for cardiac diagnosis and for the large veins, several of the other ultrasound media pass through the lung capillaries and other capillaries and can therefore be used for a larger number of organs.
The usefulness of an ultrasound medium is that it may increase the contrast resolution between normal and diseased tissue and may improve the identification of deep lying vessels and help in identifying tumorsor tumor vessels. Other possible advantages are the improved visualization of stenotic arterial segments, e.g. renal arteries and the increased ability to detect areas of infarction or ischemia. The possibility of tissue characterization might also increase with different ultrasound contrast media.

Torsten Almén and Peter Aspelin