There are a number of limitations of DSC-MRI techniques which include the effects of contrast medium recirculation, contrast medium leakage and subsequent tissue enhancement and bolus dispersion (7).

Analysis of the contrast bolus passage assumes that the bolus passes through the tissue, and that the signal intensity (i.e., concentration of contrast medium) then returns to zero. In practice, the contrast medium recirculates through the body and a second recirculation peak is always seen (Figs. 2 and 3). With bolus dispersion, the second peak is lower and broader than the first pass, and by the time of the third recirculation the intravascular contrast has mixed evenly throughout the blood volume. Measurement of kinetic parameters is, therefore, subjected to errors due to the presence of both first pass and recirculating contrast in the vessels during the later part of the bolus passage. One way of overcoming this limitation is to use an idealized model to the observed data (Fig. 4). This relies on the fact that the shape of the contrast concentration curve during the passage of the first bolus can be shown theoretically to always conform to a specific shape known as a gamma variate (25). The use of curve fitting also smoothes the data effectively reducing noise, and eliminates the contamination of the first pass bolus due to contrast agent recirculation.

Loss of contrast medium compartmentalization during the first pass into the interstitial space will cause aberrant signal intensity changes by the end of the experiment (either enhancement or failure of the signal intensity to return to baseline). Recirculation and contrast leakage into the extracellular space during the first pass of contrast medium are the principle causes of falsely lower blood volume values. Furthermore, the T1 signal-enhancing effects of contrast medium leaking from blood vessels can counteract T2* signal-lowering effects. Quantitative imaging is thus most reliably used for normal brain and nonenhancing brain lesions because the contrast medium is completely or largely retained within the intravascular space.

Solutions for counteracting the T1-enhancing effects of gadolinium chelates include optimization of sequences by using dual or multiecho sequences that minimize T1 sensitivity and pre-dosing with contrast medium to saturate the leakage space (26). (i) The use of techniques with reduced T1 sensitivity, such as low flip angle gradient-echo-based sequences, effectively removes relaxivity effects although some workers have observed residual effects in rapidly enhancing tumors (27,28). The major problem with this method is the lowering of SNR produced by the reduction in flip angle, although this can be partially compensated by increasing contrast agent doses. (ii) Another approach to reducing Ti sensitivity is to use a dual echo technique in which the T1-weighted first echo is used to correct the predominantly T2-weighted second echo (26,29). The dual echo technique is technically challenging for most machines, and reducing the sampling time inevitably restricts the number of samples and therefore, the slices which can be obtained. (iii) The third approach is to use pre-enhancement with an additional dose of contrast agent. Saturating the extracellular space with contrast medium induces maximum T1 shortening, and the arrival of further contrast medium given during the susceptibility experiment causes little additional relaxivity-based signal intensity responses. Recently, Johnson et al. (30), have shown that it is possible to phar-macokinetically model the first pass effect in the presence of leaking capillaries, and to obtain an estimate of blood volume, vascular transfer constant, and EES volume. Other solutions for overcoming some of these problems include the use of nongadolinium-susceptibility contrast agents based on the element dysprosium or ultrasmall, superparamagnetic iron oxide particles (USPIOs), which have strong T2* effects but weak T1 effects (31,32). Preliminary results have indicated that dysprosium-based relative cerebral blood volume (rCBV) maps are superior to those obtained with gadolinium chelates (33,34). USPIOs designed for bolus injection have the advantage of being retained within the vascular space during the first pass owing to their larger size (35,36).

As noted above, the measurement of CBF requires an accurate estimation of MTT which is extracted from the width of the contrast bolus. The width of the contrast bolus is actually affected by a combination of the following three factors:

(i) the width of the bolus at the tissue level [the arterial input function (AIF)],

(ii) changes in bolus width due to regional alterations in flow related to nonlaminar flow (which arises from the presence of irregular caliber vessels), nondichotomous branching and high vascular permeability (which leads to increased blood viscosity from hemoconcentration), and variations in the hematocrit fraction as blood passes through a vascular bed, and (iii) physical bolus broadening due to dispersive effects which are unrelated to flow. Additionally, the width of the bolus is strongly affected by individual variations in injection technique, contrast dose, and cardiovascular functioning and structural architecture including upstream vascular stenoses.

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