Quantitative Blood Flow Measurements in Gliomas Using Arterial Spin-Labeling at 3T: Intermodality Agreement and Inter- and Intraobserver Reproducibility Study

Discussion

ASL is a promising tool for assessing tumor angiogenesis and for glioma grading.^{12⇓⇓–15} However, for ASL to be practical in determining changes in tumor rCBF values, the reproducibility of rCBF measurements must be ascertained. We found that the maximum sTBF values measured with ASL by using QUASAR agreed well with the values obtained by DSC perfusion MR imaging; the difference in sTBF values acquired by the 2 methods was within a similar range. Thus, ASL by using QUASAR may represent a reliable technique for evaluating brain tumor perfusion and an alternative to the DSC method in the quantitative evaluation of glioma perfusion. We attribute the good intermodality agreement to the high quality of data obtained with the QUASAR technique.

An earlier study that used 1.5T pulsed ASL performed at a single TI point also showed a high correlation for sTBF measurements on ASL and DSC perfusion maps.¹² However, pulsed ASL with a single TI point may lead to serious errors in the estimation of perfusion due to its sensitivity to the transit time.¹⁶ To render ASL less transit-time sensitive, bolus saturation sequences such as QUIPSS II²⁰ were developed. The principle of these techniques is to saturate the part of the label that remains within the labeling slab at a time delay that is short enough for the trailing edge of the fastest blood to remain within the inversion slab. However, if the transit-time distribution is wide (as in patients with atherosclerosis), these methods would not work. This problem can be solved by acquiring images at multiple TIs.

The bolus saturation techniques and the acquisition of images at multiple time points as used in the QUASAR sequence render ASL less sensitive to the transit time. In addition, the QUASAR sequence can quantify rCBF user-independently because AIF is calculated automatically voxel-by-voxel based on crushed and noncrushed control-label pairs.¹⁶ The high signal intensity–to-noise ratios on 3T may have also affected our results.

Our data suggest that the 95% limit of agreement in sTBF measurements is slightly greater for interobserver than intraobserver assessments. Despite our attempts for consistent region-of-interest placement, a change in sTBF measurements between 2 observers, amounting to less than approximately 89% of the mean sTBF (ie, 95% limit of agreement), was within the limit of error on ASL images. The change in sTBF between 2 observers on DSC images was also approximately 83% of the mean sTBF values. Wetzel et al,²⁷ who reported that the limit of error in sTBF on DSC images was relatively high, attributed the relatively large differences between observers in part to noise in both the lesions and the reference regions of interest. Thus, the error limit in our study may also be due to the effect of noise on the measurements.

For both observers, the mean-maximum and average sTBF values were higher on DSC than on ASL images. In 1 observer, there was a significant difference in average sTBF measurements on DSC and ASL images. While we cannot readily explain this, the difference in sTBF measurements between the 2 modalities may be attributable to differences in the characteristics of perfusion MR imaging. Because we used the gradient echo−type echo-planar imaging sequence in our DSC study, large arteries would not have been suppressed.²⁸ On the other hand, on ASL images, large arteries were suppressed by the crusher gradients.¹⁶ Although the observers carefully placed the region of interest inside the solid portion of the tumor while avoiding volume averaging with normal vessels, the signal intensity from large arteries could have affected the results obtained with DSC images.

Although a constant region-of-interest size was used in this study, differences in the section thickness may have affected our results. The section thickness was 6 mm for ASL and 5 mm for DSC images. The partial volume effect of normal brain tissue can be expected to exert a greater effect on ASL images, resulting in a lower signal intensity than on DSC images. Because this effect may be exacerbated with the average sTBF method, for the evaluation of sTBF in gliomas on ASL images, the maximum sTBF method may be more suitable than the average sTBF method.

Although the rCBV is usually used for evaluating the perfusion of gliomas, we used rCBF values. DSC perfusion MR imaging can provide both rCBF and rCBV of the brain. In contrast to DSC perfusion MR imaging, ASL methods measure CBF only.²⁹ Although attempts have been made to determine CBV with ASL techniques in animal models, they cannot yet be applied in clinical practice.^30,31 Because earlier reports by using DSC perfusion MR imaging showed a strong correlation between the rCBV and rCBF ratios in high- and low-grade gliomas,^32,33 we used rCBF ratios to compare tumor perfusion obtained by DSC and ASL methods. On the basis of our finding that ASL at 3T yielded measurements similar to those of DSC perfusion MR imaging, we suggest that measuring rCBF ratios with ASL at 3T is useful for evaluating the perfusion of gliomas.

ASL is thought to be capable of measuring absolute CBF values. The absolute CBF values obtained with ASL may allow the comparison of different patients and of values obtained during the course of treatment in individual patients. To our knowledge, no systematic investigations by using the absolute CBF values obtained with ASL in patients with glioma have been reported. On the other hand, because there are several reports that used standardized CBF values with ASL,^12,14 we used standardized values in our study.

ASL has the advantage of being noninvasive; because it also does not require the administration of an extrinsic tracer, there is no contrast medium to affect the physical, chemical, or physiologic properties of the blood. Therefore, ASL may be especially useful in patients with glioma with renal dysfunction because they may be at risk for contrast-related nephrogenic systemic fibrosis³⁴ and in children in whom the rapid bolus injection of contrast materials into the vein may be difficult.

There are some limitations to this study. First, leakage of gadolinium, which occurs in most high-grade gliomas, may underestimate the rCBF at DSC perfusion MR imaging.¹⁹ Therefore, we used the preload-correction approach, and we posit that the effect of contrast leakage on our DSC perfusion MR imaging was small. Second, CBF quantification on DSC perfusion MR imaging scans depends on the selection of the proper AIF. Although 1 experienced neuroradiologist and 1 technologist carefully selected the AIF manually, its selection on DSC images may have affected the TBF measurements. Third, we cannot rule out bias in the selection of our patients. Although our study population comprised 24 consecutive patients with histologically proved supratentorial gliomas, only 1 patient had a low-grade glioma and 4 lesions were not contrast-enhanced. Consequently, patient selection might have affected our results. Fourth, our study population was relatively small. Nevertheless, because our results were promising, further clinical studies with a larger number of patients with glioma would clarify the value of this technique in a clinical setting.

In conclusion, for the quantitative evaluation of blood flow in gliomas, ASL by using QUASAR at 3T yielded measurements and reproducibility similar to those in DSC perfusion MR imaging. Although the reproducibility of sTBF measurements by maximum and average methods was similar, the measurement method applied may affect the sTBF values of gliomas on ASL images.