Issues related to perfusion quantification

In this section, the principal systematic errors that are associated w ith flow determ ination using the A SL techniques are described. Experim ental m ethods of correction are also presented.

3.5.1 The transit time

The transit time effect essentially describes a loss of the m agnetic label due to the physical extent of the tagging procedure. The transit time, Ô, representing the delay between the creation of the tag and its arrival at the im aging slice, is expected to be especially significant for the C A SE techniques since the tagging plane is norm ally placed in the neck in order to intersect a major artery. By way of contrast, in the case of the pulsed techniques such as EPISTA R, the inversion slab is positioned close to the im aging slice. N evertheless, the degree of proxim ity is still lim ited by the introduction of system atic errors due to the im perfect slice profiles. In an analogous m anner, for practical im plem entations o f the FAIR technique, the width of the inversion slice m ust be increased with respect to the im aging slice in order to elim inate effects from im perfect edges of the inversion profiles. D uring the resultant Ô time, inflow ing blood moves into the im aging plane but will not contribute to the flow signal since these spins are w ithin the inversion slice. The transit tim e effect reduces the intrinsic sensitivity of the A SL techniques especially to low er levels of flow. Errors will be introduced into the CBF m easurem ents if the effect is not considered in the analysis of the perfusion model (see Section 4.6). Furtherm ore, it is likely that the transit time will vary significantly across the im aging plane, resulting in a variable attenuation of the A SL signal and this will exacerbate the errors in the quantification process.

3.5.1.1 Re duc ed transit time modificatiofis

A nalogous m odifications of the continuous and pulsed methods have been proposed in order to decrease the transit time sensitivity of the techniques. A post-labelling delay is em ployed that has a dual effect; the delay allows the tagged blood w ater to reach the tissue com partm ent and, thereby, reduces the significance o f the vascular signal (see the next section) and m inim ises the effects of variable transit delays. It also allow s tim e for the tagged blood that is flow ing through the im aging voxel w ithout exchange, to do so before the time of image acquisition. These blood spins should only contribute to the signal in the distal voxels which contain the capillary exchange sites that are" their

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eventual destination. This corrective scheme is im plem ented in the CA SL m ethod by sim ply delaying the image acquisition after the continuous RF irradiation (Alsop, 1996). In the case of the pulsed m ethods, a delay (the TI tim e) after the inversion pulse is inherent to the procedure o f these techniques but the tagged bolus possesses an undefined width due to the geom etric spread and the dispersion of the transit tim es from the distal end of the inversion slab to the tissue. A slightly different approach is, therefore, needed to reduce the transit time sensitivity for the PA SL methods. The m odification is known as Q uantitative Im aging of Perfusion U sing a Single Subtraction (QUIPSS II) and creates a slab of known time width by saturating the tagging region at a tim e T I| after the inversion pulse. An additional delay, TU, before the im age acquisition then reduces the sensitivity of the m ethod to the transit tim e in the same m anner as the modified continuous technique (W ong, 1997).

5.5.2 Intravascular contamination

The significance of the vascular signal to the m agnetisation difference is closely related to the discussion of the previous section since the transit delay determ ines the tim e spent by the water spins in the vasculature before entering the tissue com partm ent at the capillary exchange sites. Tw o principal sources of intravascular contam ination need to be considered; the blood in the m ajor arteries, and the com ponent that is in closer contact with the tissue bed w ithin the arterioles and capillaries.

3.5.2.1 A rteria l signal

The m ost obvious illustration o f the vascu lar a rtefa ct is the observation of bright focal anom alies in the perfusion im ages (see Fig. 3.3). The m acroscopic blood flow violates the assumption of a w ell-m ixed com partm ent (Section 3.2.1) and should, therefore, be elim inated from the m easured signal. A m inim al am ount of diffusion w eighting (b < 2 sec/mm^) such as that provided by the EPI im aging gradients, should dephase the m ajority of this signal com ponent.

3.5 .2 .2 The vascular sign al in the sm aller vessels

The initial descriptions of the perfusion T | model (for exam ple Zhang, 1992) assum ed that only the tissue com partm ent is contributing to the observed signal difference. The com bination of im aging and diffusion gradients and the inherently small volum e of the vascular com partment (approxim ately 5% in the rat (Sandor, 1986)) was expected to

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reduce the contribution of the blood signal to an insignificant level. The observed tissue-based m agnetisation difference then provides a direct m easurem ent o f the

irrigating blood flow after back-correction with the partition coefficient (i.e.

M v = M ( t) /^ ) . In this sense, the A S L m ethods m easure perfusion as the biologically relevant - useful - blood delivered to the voxel since only the exchanged blood w ater should be considered in the analysis. W ith the further developm ent of these techniques, the system atic errors associated with the vascular signal have becom e better understood and characterised. It has becom e clear that the em pirical adjustm ent o f diffusion gradients w ithin the perfusion sequence to dephase the vascular signal (Ye, 1997a), is a sub-optim al procedure. It is also probable that a substantial fraction o f the blood spins m ay not be dephased by these gradients (Henkelm an, 1994). It must, therefore, be accepted that the A S L signal is principally sensitised to the exchanged tissue w ater but w ill also contain a contribution from the vascular com partm ent. It can be argued that the blood spins m ay be justifiably included in the m easurem ent of tissue perfusion as long as they w ill exchange or have already exchanged across the capillary bed in that voxel (B uxton, 1998). The vascular signal at the capillary level is, thereby, considered as biologically relevant blood signal and should be incorporated in the overall m easurem ent o f perfusion in the im aging voxel. The inclusion of this com ponent o f the

A S L signal m ust, however, be reflected in a m odified analysis o f the perfusion model. T his is discussed in the next sub-section.

T he nature o f a particular w ater spin will be characterised by the N M R param eters that are associated w ith its environm ent. The different longitudinal relaxation tim es o f the tissue and vascular com partm ents can be incorporated into the perfusion m odel and analysis. The general model has dem onstrated that the perfusion m easurem ent is especially sensitive to the tim e spent by a water spin in the different environm ents (B uxton, 1998). The differing transverse relaxation rates of the tw o com partm ents m ust also be considered since the relatively long echo times of the com m only used EPI m ethod o f im age acquisition, will w eight the signal towards the blood com ponent

(T2[blood] ~ 200 ms; T2[tissue] ~ 80 ms at 1.5T (Wong, 1998a)). M oreover, when

collecting data at a num ber o f TI delays, the deleterious effect of this resultant bias will be intensified with increasing T I as the influence of the vascular com ponent becom es less significant due to exchange and outflow. This T2 effect has not been considered in

the existing treatm ents of the A SL m ethods but will require analysis as the SN R and, hence, the precision of the techniques improve.

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3 .5 .2 3 Quantification o f the vascular component

Several authors have attem pted to incorporate the blood signal into their analysis o f the Ti model (St. Lawrence, 1997). Alsop et al. described the vascular com partm ent in its role as the arterial input to the tissue exchange sites (Alsop, 1996). H ow ever, this treatm ent neglects the blood water associated with the vascular output of the tissue com partm ent that does not exchange in the voxel and the tissue w ater that diffuses back into the vascular pool. Silva et al. have attem pted to include this signal contribution in their analysis o f the continuous technique (Silva, 1997a). The existence of unexchanged blood spins in the outflow of the vascular com partm ent is intrinsically related to the assum ption o f a freely diffusable tracer. The extraction fraction, E(f), describes the flow -dependent com petitive partition of w ater spins between the vascular and tissue com partm ents after equilibrium has been reached. The com m on assum ption o f E (f)= l in the perfusion m odel has been shown to be invalid for higher flow rates using both tracer kinetics and M R I approaches (Eichling, 1974; Go, 1981; Silva, 1997a; Silva 1997b; Zaharchuk, 1998).

In the follow ing theoretical analysis, an original com bined approach was taken in order to model the contribution of both the arterial/tissue interface (input) and tissue/venous interface (output) com ponents o f the vascular signal in the sm aller blood vessels w ithin the tissue volum e. Figure 3.7 depicts a schematic representation o f the m odified m odel that can be com pared with the standard form shown in Fig. 3.1. This treatm ent was carried out for the FAIR experim ent assum ing the follow ing form for the total signal, Stot(0> from an im aging voxel with a unit volume