Magnetic Field

Due to the intrinsic low signal-to-noise ratio (SNR) of ASL techniques, using a high magnetic field strength can improve the SNR. ^{15 ,​ 16} In addition, lengthening of T1 is another factor that allows more spins to reach and accumulate in the image slab. Previous studies have shown doubling of signal performing CASL/PASL at 3 and 4 T, compared to 1.5 T. ^{15 ,​ 16}

Phased Array Receiver Coils and Parallel Imaging

Another approach to increase SNR is to use a phased array of receiver coils. Use of these coils is associated with inhomogeneity of received signal; however, calibration steps involved in perfusion quantification leave the final cerebral blood flow (CBF) maps unaffected, ¹⁷ and SNR will be increased not only in the regions close to the coil but in the entire image. Another advantage of phase array coils is the potential for using parallel imaging, which can also be helpful by shortening the imaging time and reducing image distortion from susceptibility artifacts. ¹⁷

Crusher Gradients

Crusher gradients are an option with most clinical releases, but they have a significant influence on the appearance of pathology with ASL. Crusher gradients are applied prior to image acquisition to null the signal from intravascular moving spins. If these spins are not eliminated, quantification of CBF derived from ASL will be artificially high in slow-flow states where the ASL signal is predominantly intravascular. Ye et al ¹⁸ proposed the use of bipolar crusher gradients to eliminate the signal from large arteries by dephasing the moving spins. These crusher gradients have more significant implications with stroke or slow-flow imaging; however, when quantification of CBF in tumors is considered, a consistent technique should be employed to decrease variability when tracking blood flow in tumors over time, especially in regard to tumor response.

Readout Strategies

A two-dimensional (2D) echoplanar imaging (EPI) readout is commonly used in ASL imaging due to high SNR and rapid acquisition time; however, EPI suffers from susceptibility artifact with the potential for signal loss and image distortion, especially when the lesion is near the skull base, orbit, or sinuses, or in the presence of blood products. Three-dimensional (3D) techniques with spin-echo (GRASE) or rapid acquisition with relaxation enhancement (RARE)-based readout strategies for ASL can be of particular benefit to improve the image quality for several reasons. They improve SNR secondary to slab excitation and a prolonged image acquisition window and are also associated with less image distortion and susceptibility artifact. Furthermore, 3D imaging is associated with more effective background suppression, ¹⁹ which can significantly increase the measured signal. ²⁰ 3D techniques such as GRACE or RARE-based readout strategies are also less affected by susceptibility artifacts. ^{21 ,​ 22 ,​ 23}

Absolute versus Relative Cerebral Blood Flow

The absolute CBF value could be theoretically determined by using ASL ^{24 ,​ 25} ; however, there are several factors that can potentially affect quantitative CBF measurement. These include dependence on transit time of the labeled blood, the local relaxation times of tissue and blood, and the assumption of a constant T1 relaxation time of arterial blood regardless of variable factors, such as vessel size or level of oxygenation. ²⁶ In addition there are large interindividual differences in perfusion ²⁷ that can affect estimation of CBF. The accuracy of absolute perfusion measurement by using Q2TIPS has not been fully established, especially in pathological conditions ^{28 ,​ 29} ; therefore most of the authors used relative perfusion index rather than the absolute blood flow value. In most of the studies, the average signal intensity of gray matter was used as a reference for relative perfusion instead of white matter. This is mainly because the arterial transit time of white matter is much longer than that of gray matter, resulting in a substantial underestimation of the blood flow in white matter. ^{30 ,​ 31}

Comparison of ASL to Contrast-Based MR Perfusion Methods

Numerous studies demonstrated positive correlation of relative cerebral blood volume (rCBV) measured by DSC-MRI with histological measurements of tumor neovascularization. ^{32 ,​ 33 ,​ 34} Compared to MR perfusion methods based on contrast injection (DSC and DCE), ASL is capable of measuring absolute CBF values. Other advantages of ASL include noninvasiveness, repeatability, utility in patients with renal failure who are at risk of related nephrogenic systemic fibrosis, and utility in young children in whom the rapid bolus injection of contrast materials into the vein may be problematic. Despite these advantages, ASL suffers from lower SNR and requires multiple signal acquisitions, which increase the imaging time.

Numerous studies have compared ASL and DSC perfusion in various aspects of brain tumor imaging. Weber et al evaluated normal brain tissue in 62 patients with brain metastases who were treated with stereotactic radiosurgery using PASL and DSC perfusion and demonstrated good correlation between perfusion values, which remained unchanged after stereotactic radiosurgery. ³⁵ A study by Lehmann et al ³⁶ that evaluated 27 patients included 9 gliomas, 10 metastases, and 8 meningiomas. They used PASL and DSC T2* perfusion sequence and found a significant correlation between rCBF calculated from the two perfusion sequences. Warmuth et al showed a high correlation for rCBF measurements on ASL and DSC perfusion maps using 1.5 T using single TI PASL. ²⁶ Lüdemann et al ³⁷ used different perfusion techniques (DCE-MRI/DSC-MRI, PASL, and H₂ ¹⁵O positron-emission tomography) in 12 patients with brain tumors, and demonstrated a linear relationship between all five imaging modalities regarding the perfusion signal of normal brain tissue and tumor; however, the perfusion ratios between tumor and brain differed significantly with the method applied. This suggested that relative tumor perfusion values determined with different techniques cannot be directly compared. ³⁷ Hirai et al compared ASL MRI using QUASAR and DSC-MRI on 3 T scanners ³⁸ in 24 patients with histologically proved glioma. They demonstrated good to excellent intermodality agreement for maximum rCBF between ASL and DSC.

Very few studies have been performed to compare ASL with DCE-MRI. Roy et al evaluated 64 patients with glioma using 3D-PCASL and DCE-MRI and demonstrated a weak correlation in rCBF values between the two methods. They also did not find a significant difference in absolute or relative CBF values between high- and low-grade gliomas using ASL, whereas DCE indices were significantly higher in high-grade gliomas. ³⁹

Van Westen et al ⁴⁰ used the QUASAR method at 3 T to measure aBV in 11 brain tumors (grade III gliomas, glioblastomas, and meningiomas), and compared measurement of aBV from arterial spin labeling with CBV from DSC-MRI. They demonstrated a positive correlation between ASL-based aBV tumor-to-gray matter(GM) ratios and DSC-MRI-based CBV tumor-to-GM ratios.

Diagnostic Impact

A few studies have evaluated the diagnostic impact of adding ASL imaging in patients with brain tumors. Geer et al ⁴¹ evaluated 59 patients with glial tumors and demonstrated that the addition of perfusion to the standard imaging protocol was associated with a change in management plan in 8.5% of patients and an increase in the treatment team’s confidence in their management plan in 57.6% of patients. Kim et al in a prospective study evaluated the added value of pulsed ASL and apparent diffusion coefficients in the grading of gliomas. In this study, two observers made the correct diagnosis in 23 of 33 (70%) lesions in the first review and in 29 of 33 (88%) of lesions in the second review. ⁴²

Quantitative vs. Qualitative Techniques of ASL Image Interpretation in Brain Tumors

Although quantitative analysis of ASL imaging is more valuable and gives investigators the potential to compare perfusion values between patients and during the course of the disease, quantitative analysis is more practical in the research setting with a limited number of patients. On the other hand qualitative methods are very fast and more applicable in routine clinical practice. In a prospective study, Järnum et al used PCASL and DSC perfusion to evaluate 28 patients with contrast-enhancing brain tumors at 3 T with whole-brain coverage. ⁴³ They used a qualitative scoring system to evaluate signal enhancement and susceptibility artifact in the tumor. They also performed a quantitative analysis with normalized tumor blood flow (TBF) values. Results of this study showed no difference in total visual score for signal enhancement between PCASL and DSC relative to CBF, and a good correlation between normalized CBF between both perfusion methods. Not surprisingly, ASL had a lower susceptibility-artifact score than DSC-MRI. Studies using ASL imaging in distinguishing predominantly recurrent high-grade glioma from radiation necrosis also demonstrated that both qualitative (based on visual inspection) and quantitative techniques were effective in differentiation of radiation necrosis from tumor recurrence. ⁴⁴ Kim and Kim also did not find a significant difference between the quantitative and qualitative ASL parameters in glioma grading. ⁴²

Gliomas

Neovascularization is one of the hallmarks of malignancy along with mitosis, pleomorphism, and necrosis. ⁵⁸ A direct correlation between glioma grade and angiogenesis has been well established. ^{59 ,​ 60} DSC perfusion has been proved to increase the sensitivity in determining glioma grade, compared with conventional MRI. ⁶¹ In addition, DSC perfusion has been shown to be a better predictor of tumor progression and patient outcome compared with initial histopathological interpretation. ⁶² ASL was first used in 1996 to evaluate perfusion in a heterogeneous group of brain tumors, and demonstrated elevated perfusion in high-grade astrocytomas with marked regional heterogeneity compared with low perfusion in low-grade astrocytomas and lymphomas. ⁶³ More recently Wolf et al using CASL at 3 T demonstrated that maximum CBF normalized to the global mean CBF in the brain provided the best distinction between high- and low-grade gliomas (Fig. 6.2). ⁴⁷ They also showed that low-grade gliomas with oligodendroglial components demonstrated high CBF. This confounding effect of oligodendrogliomas in glioma grading has also been encountered in DSC perfusion imaging. ⁶⁴ As a solution Chawla et al showed that ASL-guided voxelwise analysis of proton MR spectroscopy of regions of high blood flow may be helpful in distinguishing low-grade from high-grade oligodendrogliomas (Fig. 6.3). ⁶⁵

Different thresholds have been proposed for glioma grading. Weber et al, ²⁹ using a relative CBF of 1.4 for discrimination of glioblastomas from grade III gliomas, showed sensitivity was 97%, specificity was 50%, positive predictive value (PPV) was 84%, and negative predictive value (NPV) was 86%. In the same study, using an rCBF value of 1.6 for discrimination of glioblastomas from grade II gliomas, sensitivity was 94%, specificity was 78%, PPV was 94%, and NPV was 78%. In Warmuth et al’s study, the mean rCBF values in high- and low-grade gliomas were 1.54 and 0.64, respectively. ²⁶

Typically, based on T1 decay of blood, ASL measurements are acquired at an inversion time, which is approximately 1,200 ms at 1.5 T and 1,600 ms at 3 T. ^{66 ,​ 67} In a study of healthy volunteers MacIntosh et al ⁶⁸ showed that the mean arterial transit time is approximately 641 to 935 ms, depending on the brain region. Furtner et al used PASL at eight different inversion times from 370 ms to 2,114 ms in order to find the largest difference in normalized intratumoral signal intensity between high-grade and low-grade astrocytomas, and demonstrated that inversion time of 370 ms best differentiated high-grade and low-grade astrocytomas. They suggested that, at this short inversion time, the labeled spins are located primarily within the vessel and mainly reflect the labeled intra-arterial blood bolus, and they called it normalized vascular intratumoral signal intensity (nVITS). ⁶⁹