Gadolinium : An MRI Contrast Agent

Gadolinium: An MR Contrast Agent

MRI is based on the response of proton spin in the presence of an external magnetic field when triggered with a radio frequency (RF) pulse. Under the influence of an external magnetic field, protons align in one direction. On application of the RF pulse, aligned protons are perturbed and subsequently relax to their original state. There are two independent relaxation processes: longitudinal (T1) and transverse (T2) relaxation, which are typically used to generate the MR images.¹

In order for an excited spin system to return to its equilibrium magnetization, energy must be transferred from the spin system to the lattice (surrounding). The return to equilibrium is described by the spin-lattice relaxation time (T1). When T1 weighted sequences are used, the magnitude of the MR signal increases with decreasing T1 relaxation times. Further, the contrast between two tissues will of course also increase with increasing difference in T1 relaxation times between the two tissues. We know MRI creates images capable of differentiating among different tissues based on their T1 and T2 properties. However, the inherent difference in T1 relaxation time between biological tissues, or between normal and pathologic tissue is not always large enough to obtain a detectable contrast in the MR image. Sufficient contrast is of particular importance in differentiating pathological tissue from normal surrounding tissue. Exogenous MR contrast agents were therefore developed shortly after the first commercial MR systems became available in the early 1980’s. Today, MR contrast agents are typically in a significant proportion of MR examinations; with the highest usage in CNS applications (tumor diagnosis). MR contrast agents are widely used in MR angiography (MRA), they are injected into the bloodstream, and strongly T1 weighted images are acquired. Blood vessels appear much brighter than any other tissue that highlights the vessels.³

All biological systems are composed of various molecules and organisms which have different proton concentrations and different T1 relaxation times. The presence of paramagnetic ions (e.g., Gd⁺³ and Mn⁺²) near the tissue enhances its relaxation and shortens the T1 relaxation time. Contrast agents with T1 weighted enhancing ability produce bright positive signal intensity in images and increase the conspicuousness of cells, facilitating easy tracking of cells in low signal tissues. Among, those paramagnetic ions, Gd⁺³ are the most effective T1 weighted contrast agent for clinical use.¹

Paramagnetic contrast agents, which have unpaired electrons in the outer electron shell and thus also a magnetic momentum, are used to improve imaging. Electrons affect the protons since they have a 657 times stronger magnetic momentum than protons. As a result, both the proton density in the tissue is changed directly and the local magnetic field is changed indirectly by the interaction between the electron spin of the contrast agent and the surrounding hydrogen nuclei. Apart from the paramagnetic elements manganese and iron, the lanthanide gadolinium, with its seven unpaired electrons in the outer electron shell, interact with protons in nearby water molecules to dramatically shorten the T1 relaxation time and is one of the metals most commonly used in MRI contrast agents. The appearance of tissue in which the contrast agent penetrates appears brighter on T1 weighted imaging relative to non-contrast enhanced tissues. Because of its intrinsic toxicity, however, gadolinium cannot be used in the free ionic (Gd⁺³), but only in the form of its water soluble chelate complexes. In particular, the derivatives of diethylenetriamine pentacetic acid (DTPA) have proved useful as MRI contrast enhancing agents.⁴

MR contrast agents act by selectively reducing T1 (and T2) relaxation times of tissue water through spin-interaction between electron spins of the metal containing contrast agent and water protons in tissue. However, here, we are only discussing about Gadolinium based contrast agents. In the presence of the contrast agent, the observed relaxation rate (R1=1/T1) can be split up in an intrinsic tissue contribution and a contribution from the contrast agent, according to

R1^obs = R1^tissue + R1^ca,

Where R1^tissue is the intrinsic relaxation of the tissue without the contrast agent and R1^ca is a paramagnetic contribution of the contrast agent. The contribution of the contrast agent can be written as

R1^ca = r1. (CA),

In which r1 is the relaxivity (in mM^-1s^-1) and (CA) the concentration of the contrast agent. Using R1 =1/T1, this leads to the well-known equation,

,

which shows that the shortening of the relaxation rate R1 is linear with contrast agent concentration and that contrast in the MR images can be enhanced either by using a contrast agent with a high relaxivity r1 and/or by increasing the local contrast agent concentration. It should be noted that the relaxivity apart from being a contrast agent specific parameter, also depends on the solvent and distribution, which could vary considerably in vivo, e.g. when the contrast agent is confined to the blood pool or compartmentalized in the cytoplasm of cells. This means that the contrast agent may not affect all water protons in the tissue equally. Linearity of R1 with concentration can therefore not be guaranteed under all circumstances.²

The paramagnetic contribution from the contrast agent is generally understood to originate from relaxation in two pools of water coordinated either directly with the Gd⁺³, called the inner sphere, or located in the second coordination sphere and the bulk, referred to as the outer sphere. The detailed interactions between the ion and the water can be understood in terms of the Solomon-Bloembergen-Morgen (SBM) theory.²

At higher concentrations, signal saturation occur meaning that a further reduction in T1 does not result in a further increase in signal intensity since the longitudinal magnetization is fully recovered. Further, when the concentration becomes very high (depending on TE) the signal will start to fall with further increase in concentration since the T2 effects of the contrast agent will start to dominate the signal behavior.⁵

Note that the contrast agent does not leak out from the intravascular space in normal brain tissue due to the presence of a blood brain barrier (BBB) which prevents even small molecular weight molecules like Gd chelates to enter the interstitial. Since the intravascular volume in the brain is small (<5%), little enhancement is thus seen in healthy brain tissue. In brain tumors however, the BBB can often be disrupted due to various pathological processes, resulting in a selective accumulation in the extravascular space in the tumor. The fact that many pathological processes alter the permeability of the BBB, resulting in selective accumulation of MR contrast agents is, in fact, the main reason why these agents are so useful for CNS imaging since the absence/presence of CA leakage as well as the pattern of contrast enhancement can give important indications as to the type of pathology present. Therefore, MR contrast agents not only increase the sensitivity (the ability to detect) but also the specificity (the ability to differentiate) of the diagnostic procedure.⁵

In most organs it passes from the vasculature into the interstitial space relatively quickly. After the initial redistribution into the extracellular fluid space with a half-life of about 11 min, Gd is gradually excreted via kidneys with a biological half-life of approximately 90 min, so in most patients it is not detectable in tissues after about 6 h although it may linger in the urine and bladder for a day. At low concentrations such as those used in normal clinical practice the major effect is the T1 shortening, and tissues which take up the agent have enhanced signal intensity on T1WI. Most clinical sites use a standard dose of 10 or 15 ml for adult patients, who approximates to 0.1mmol Gd per kg body wt. Double and even triple dose injections are routinely used for MRA and perfusion imaging and have been shown to improve the conspicuity of lesions in multiple sclerosis and metastatic disease. At concentrations higher than about 1mmol Gd Kg^-1, ten times the standard dose, the effect on T2 begins to dominate and a loss of signal occurs.⁶

Fig: Signal Intensity vs concentration of Gd, calculated using T1W SEQ (TR=400ms, TE=15ms) and a tissue with T1=800ms and T2=75ms

Magnetic resonance is one of the leading diagnostic imaging modalities, since it excels in depicting tissues with high spatial resolution and has superior soft tissue contrast. Nevertheless, MRI can considerably gain from the use of contrast agents. Contrast enhanced MR angiography is now routinely used in the non-invasive evaluation of vascular diseases. Dynamic contrast enhanced MRI receives considerable attention in the assessment of stroke and tumor vascularity. MRI applications are becoming more and more dependent on contrast agents. Traditionally MR contrast agents are based on their ability to lower T1 and T2 of water. Nowadays, nanoparticle based contrast seems to be a powerful technology in both basic science as well as clinical settings. Chemical Exchange Saturation Transfer (CEST) agents, based on magnetization transfer methods have also been developed where contrast can be switched on and off at will, which facilitates localization and detection of contrast agents in living organism without the need for exact co-registration of pre and post contrast MR images. The sensitivity of CEST has increased with the invention of (liposome based) LIPOCEST agents. Researches are going on to study subcellular processes from bimodal imaging combining fluorescent markers, such as quantum dots, with MR contrast agents.^1,2,5

Reference:

1.      Zhu et al, Nanoparticle-based systems for T1-weighted Magnetic Resonance Imaging Contrast Agents, Int.J.Mol.Sci.2013.

2.      Strijkers et al, MRI Contrast Agents: Current Status and Future Perspectives, Anti-Cancer Agents in Medicinal Chemistry, 2007.

3.      Image Contrast, International Center for Postgraduate Medical Education, 2009.

4.      Peter et al, Gadolinium based contrast agents, Metrohm International Headquaters, Herisau, Switzerland.

5.      MR Contrast Agents, FYS-KJM 4740 – The Physics of MRI.

6.      McRobbie et al, MRI from picture to proton, Cambridge University Press, Second Edition, 2006.