MRI Contrast Agent Kinetics

When a bolus of paramagnetic, low-molecular weight contrast agent passes through a capillary bed, it is transiently confined within the vascular space. Concentrated contrast media within the vessels and in the immediate vicinity, cause magnetic field (Bo) inhomogeneities that result in a decrease in the signal intensity of surrounding tissues (susceptibility effects). In most tissues except the brain, testes, and retina, the contrast agent rapidly passes into the extravascular-extracellular space (EES, also called leakage space -ve) at a rate determined by the blood flow (which determines contrast medium delivery), and the permeability and surface area of the microvessels

Figure 1 Body compartments accessed by low-molecular weight, gadolinium-containing contrast media injected intravenously.

(Fig. 1). When low molecular weight contrast agents are used, typically 12% to 45% of the contrast media leaks into the EES during the first pass in tumors (11). The transfer constant (Ktrans) describes the transendothelial transport of the contrast medium. Three major factors determine the behavior of the contrast media during the first few minutes after injection; contrast medium delivery by blood perfusion, transport of contrast agent across vessel walls, and diffusion of contrast medium in the interstitial space. If the delivery of the contrast medium to a tissue is insufficient with respect to maintaining a high enough concentration to continually supply the extracellular space (flow-limited situations or where vascular permeability is greater than inflow), then perfusion will determine contrast agent distribution and Ktrans approximates to tissue blood flow per unit volume (12); this is a situation commonly found in tumors and in many normal tissues. If transport out of the vascula-ture does not deplete intravascular contrast medium concentration (nonflow-limited situations), then Ktrans approximates to permeability surface area product-PS. The latter circumstance occurs in some tumors that have a low blood supply such as lobular carcinoma, carcinoma in situ, and in some brain tumors (which have a largely intact blood-brain barrier), but can also occur in extracranial tumors usually after treatment (including chemotherapy and radiation), in fibrotic lesions and in some normal tissues.

As low-molecular weight contrast media do not cross cell membranes, the volume of distribution is effectively the EES (ve). After a variable time, the contrast agent diffuses back into the vasculature (described by the rate constant or kep) from where it is excreted principally by the kidneys, although some contrast media have significant hepatic excretion. When capillary permeability is very high, the return of contrast medium is typically rapid resulting in faster washout as plasma contrast

Table 1 Comparison of T2*- and Trweighted DCE-MRI Techniques

Tissue signal intensity change Duration of effect and optimal data acquisition Magnitude of effect Optimal contrast medium dose Quantification method used Physiological property determining effects

Kinetic parameters derived

Pathological correlates

Clinical usage

T2*W imaging (susceptibility methods)

Darkening Seconds/subsecond

Small

>0.2mmol/kg

Relative, more than absolute Perfusion/blood volume

Blood volume and flow, transit time

Various, including tumor grade and microvessel density Lesion characterization -breast, liver and brain Noninvasive brain tumor grading Directing brain tumor biopsy Determining brain tumor prognosis Monitoring treatment e.g., radiotherapy

TiW imaging (relaxivity methods)

Enhancement Minutes/2-25 sec

Larger

0.1-0.2mmol/kg Relative and absolute Perfusion, transendothelial permeability, capillary surface area, lesion leakage space Transfer and rate constants, leakage space Various, including microvessel density and VEGF expression Lesion detection and characterization Improving accuracy of tumor staging Predicting response to treatment Monitoring response to treatment Novel therapies including antiangiogenic drugs Detecting tumor relapse

Abbreviations: DCE-MRI, dynamic contrast medium enhanced magnetic resonance imaging; VEGF, vascular endothelial growth factor.

agent concentrations fall. Contrast medium elimination from very slow-exchange tissues, such as those with fibrosis and necrosis, occurs more slowly, and contrast media may occasionally be retained for a day or two.

MRI sequences can be designed to be sensitive to the vascular phase of contrast medium delivery (so-called T2* or susceptibility-based methods) which reflect on tissue perfusion and blood volume (13,14). Trweighted sequences are sensitive to the presence of diluted contrast medium in the EES and thus reflect microvessel perfusion, permeability, and extracellular leakage space volume (so-called T1 or relaxivity-based methods). These two methods are compared in Table 1.

t2-weighted dsc-mri

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