The Value of Arterial Spin-Labeled Perfusion Imaging in Acute Ischemic Stroke – Comparison with Dynamic Susceptibility Contrast Enhanced MRI

Abstract

Background and Purpose

To evaluate the potential clinical value of arterial spin labeled (ASL) perfusion MRI in acute ischemic stroke (AIS) through comparison with dynamic susceptibility contrast (DSC) enhanced perfusion MRI.

Methods

Pseudo-continuous ASL with 3D background suppressed GRASE (Gradient and Spin Echo) readout was applied with DSC perfusion MRI on 26 AIS patients. ASL CBF and multi-parametric DSC perfusion maps were rated for image quality and lesion severity/conspicuity. Mean ASL CBF and DSC perfusion values were obtained in main vascular territories. Kendall’s coefficient of concordance was calculated to evaluate the reliability of ratings. Spearman correlation coefficients were calculated to compare ratings and quantitative perfusion values between ASL and DSC perfusion maps.

Results

ASL CBF and DSC perfusion maps provided largely consistent results in delineating hypoperfused brain regions in AIS. Hyperemic lesions, which also appeared frequently in the AIS cases studied, were more conspicuous on ASL CBF than on DSC CBF, Mean Transit Time (MTT) and Time to the maximum of the tissue residual function (Tmax) maps.

Conclusions

As a rapid, noninvasive and quantitative technique, ASL has clinical utility in detecting blood flow abnormalities in AIS patients.

Background

The role of perfusion neuroimaging in the management of acute ischemic stroke (AIS) is to confirm the presence of reduced regional blood flow and contribute to identification of the ischemic penumbra – regions of hypoperfusion that may be salvaged by thrombolytic and/or endovascular recanalization therapy ¹. Dynamic susceptibility contrast enhanced (DSC) techniques have been the main MR perfusion imaging method used in AIS. In particular, time to the maximum of the tissue residual function (Tmax) has been applied in large case series and clinical trials to define regions of hypoperfusion ^{2, 3}. The DEFUSE cohort study suggested that specific mismatch patterns between perfusion and diffusion lesions may predict clinical responses to thrombolytic therapy ^{4, 5}. Randomized trials, however, have yielded ambiguous findings showing only trends to benefit when using perfusion and diffusion mismatch as a patient selection criterion for thrombolysis ^{6, 7}. To date, the value for identifying the ischemic penumbra in the management of AIS remains less than firmly established. The fitful progress is undoubtedly related to the regionally heterogeneous and temporally evolving nature of AIS pathophysiology. However, apart from penumbral identification, there is still a clear utility for perfusion imaging with MRI or CT in AIS to confirm the presence of regional hypoperfusion, thereby ruling in acute ischemia and ruling out stroke mimics as the cause of acute deficits. While diffusion-weighted imaging is often used to confirm the diagnosis of AIS, it can be normal when ischemia is early and only moderate in degree. Perfusion imaging provides a direct indication of regional brain ischemia.

Arterial spin-labeled (ASL) techniques provide cerebral blood flow (CBF) measures without the use of contrast agent. Additional potential advantages of ASL versus DSC perfusion imaging include relative insensitivity to blood-brain barrier (BBB) permeability changes which occur frequently in AIS. Perfusion quantification using ASL generally does not rely on the selection of arterial input function. The main limitation of ASL is the short tracer half-life (blood T1 = 1–2 sec) resulting in limited sensitivity and potential underestimation of perfusion in the presence of prolonged transit delay resulting from arterial occlusion ⁸. Recent advances in MRI technology including higher magnetic fields, array receiver coils, pseudo-continuous ASL (pCASL) and rapid 3D acquisition techniques rendered it feasible to apply ASL in the setting of acute stroke ⁹. Preliminary studies have shown that ASL is able to detect both hypo- and hyper-perfusion lesions as well as delayed transit effects that may differentiate clinical outcomes in AIS ^10–13. However, the performance and potential clinical value of ASL versus that of the much more widely used DSC remains unclear. In order to address this issue, we conducted a systematic comparison of perfusion images obtained using ASL and DSC perfusion MRI in a retrospective cohort of 26 AIS patients.

Methods

Patient Selection

The present analysis was performed on data collected from June 2010 to Nov 2010 in an ongoing prospective registry of patients evaluated with diffusion–perfusion MRI at our academic medical center. Image data were included in this study if: (1) the patient presented with symptoms of AIS, (2) patients did not have history of previous stroke, (3) baseline MRI was performed within 24hr of symptom onset, (4) both ASL and DSC perfusion imaging were performed. The UCLA Institutional Review Boards approved the study.

MRI Protocols

All patients underwent MRI on Siemens 1.5 T Avanto or 3.0 T TIM Trio systems (Erlangen, Germany), using 12 channel head coils. The MRI protocol included diffusion weighted imaging (DWI), gradient recalled echo, fluid attenuated inversion recovery (FLAIR) and perfusion weighted imaging (PWI) sequences. ASL PWI scans were performed using a pCASL pulse sequence with background suppressed 3D GRASE (Gradient and Spin Echo) readout (labeling pulse duration=1.5s, post-labeling delay=2s, no flow crushing gradient, FOV=22cm, matrix=64×64, 26×5mm slices, rate-2 GRAPPA, TR=4s, TE=22ms, 30 pair of tag and control acquired in 4min)^{9, 14}. DSC PWI scans were acquired using a gradient-echo echo-planar imaging (EPI) sequence (TR=2.9/1.9s, TE=45/30ms for 1.5/3T, FOV=22cm, matrix=128×128, 26×5mm slices, scan time=2min) with an intravenous bolus injection of gadolinium contrast agent (0.1 mmol/kg).

Post-Processing and Evaluation

Data analysis was performed with Interactive Data Language (IDL (Boulder, CO, USA)) software programs developed in-house. ASL images were corrected for motion, pairwise subtracted between label and control images followed by averaging to generate the mean difference image (ΔM). Quantitative CBF (f) maps were calculated based on the following equation ¹⁴,

$$f=\frac{\lambda \mathrm{\Delta }M{R}_{1a}}{2\alpha M_0\left[exp\left(-{wR}_{1a}\right)-exp\left(-(\tau +w)R_{1a}\right)\right]}$$ [1]

where R_1a (=0.72/0.61sec⁻¹ at 1.5/3T) is the longitudinal relaxation rate of blood, M₀ is the equilibrium magnetization of brain tissue, α (=0.8) is the tagging efficiency, τ (=1.5sec) is the duration of the labeling pulse, w (=2sec) is the post-labeling delay time and λ (=0.9g/ml) is blood/tissue water partition coefficient. Equation [1] assumes that the labeled blood spins remain primarily in the vasculature rather than exchanging completely with tissue water, which is justified in stroke patients in whom arterial transit times are likely prolonged ¹³.

Post-processing of DSC images yielded multi-parametric perfusion maps including CBF, cerebral blood volume (CBV), Tmax and mean transit time (MTT), according to previously described analysis procedures ¹⁵. Two CBF values were calculated from DSC data, namely CBFr0 and CBFrm, based on the value at time 0 and Tmax of the tissue residual function (R(t)), respectively. The calculation of CBFr0 may not represent the standard processing of DSC perfusion MRI, but was used to inform the comparison with ASL CBF. In each case, all structural, diffusion and perfusion images were aligned using SPM8 (Wellcome Department of Cognitive Neurology, UCL, UK). Two neuroradiologists and one perfusion MRI expert blinded to treatment and clinical information independently and separately reviewed ASL and DSC perfusion maps, which were scored on a scale of 0–3 to rate image quality and lesion severity/conspicuity, respectively. Both hypo- and hyper-perfusion were noted.

ASL and DSC perfusion images were further normalized into the Montreal Neurological Institute (MNI) template space using SPM8. Subsequently, segmentation of ASL and DSC perfusion images into major vascular territories was performed using an automated region-of-interest (ROI) analysis based on a published template of vascular territories in both hemispheres ¹⁶. The vascular territories studied were anterior cerebral artery (ACA), posterior cerebral artery (PCA), and leptomeningeal and lenticulostriate (perforator) distributions of the middle cerebral artery (MCA). In addition, in AIS patients demonstrating hypoperfusion, ROIs defined by Tmax > 6s, 2s < Tmax < 6s and Tmax < 2s were used to extract corresponding ASL and DSC CBF values respectively. Manual restriction of the ROIs was applied when necessary.

Statistical Analysis

Statistical analysis was performed using STATA 10.0 software (College Station, TX, USA). Kendall’s coefficient of concordance was calculated to evaluate the reliability of ratings across three readers. Spearman correlation coefficients were calculated between average ratings of ASL and DSC perfusion maps, as well as between mean values of ASL CBF and multi-parametric DSC perfusion measures in major vascular territories. The Wilcoxon signed-rank test was applied to compare the mean ratings of ASL and DSC perfusion maps. The significance level was defined as p≤0.05 (2-sided).

Results

Demographic and Clinical Information

Image data from 26 patients (mean age 71.0±15.7 years; 14 men) with AIS were included. NIH Stroke Scale (NIHSS) scores at baseline ranged from 1 to 23, with a median of 9.5. The median time from stroke onset to imaging was 5.5 hr (range 47 min to 19 hr). Demographic and clinical information of the 26 AIS patients are provided in supplemental Table 1. Serial imaging (up to 3 time points within the subacute period) with combined ASL and DSC was obtained in a subset of 15 cases, resulting in a total of 44 image sets. In addition, 5 patients had repeated perfusion scans before and after endovascular therapies.

Ratings of Hypo-perfusion Lesions

Both ASL and DSC perfusion images were of high diagnostic quality (2.44 ± 0.56 and 2.39 ± 0.56 on scale of 0–3, respectively), without significant difference between the two modalities (p=0.38). However, image quality was significantly higher for both ASL (2.61 ± 0.41 vs. 2.03 ± 0.64, p=0.0018) and DSC images (2.56 ± 0.47 vs. 2.00 ± 0.59, p=0.0017) acquired at 3T versus 1.5T. Figure 1 shows a representative AIS case with co-registered DWI, ASL and multi-parametric DSC PWI. Both ASL and DSC PWI are of high quality with whole-brain coverage. Table 1 lists the Kendall’s coefficient of concordance (W) and associated p values for conspicuity ratings of ASL and DSC PWI across 3 readers. Excellent inter-rater reliability (W > 0.75) was achieved for ASL hypoperfusion, DSC Tmax and MTT prolongations. Fair to good inter-rater reliability (0.75 > W > 0.4) was achieved for ASL hyperperfusion and DSC hypoperfusion (CBFr0 and CBFrm images), while reliability was poor (W < 0.4) for hyperperfusion in DSC CBFr0 and CBFrm images as well as both hypo- and hyper-perfusion lesions in DSC CBV images.

Figure 1.

Representative AIS case (#25) with aligned DWI, ASL and multi-parametric DSC PWI. A 76-year-old male with history of untreated dyslipidemia presented with generalized fatigue, weakness in the left face and left arm. The patient was scanned before receiving any endovascular treatment. DWI shows infarcts in the right lentiform nucleus, right caudate nucleus and anterior left temporal lobe. ASL CBF shows hypoperfusion with delayed transit effects. DSC Tmax and MTT were prolonged with hypo-perfusion on CBFr0 images.

Table 1.

Mean and SD of conspicuity ratings of all 44 ASL and DSC perfusion scans, and Kendall’s coefficient of concordance (W) of ratings across 3 readers^*

	ASL CBF hypo-perfusion	ASL CBF hyper-perfusion	DSC CBFr0 hypo-perfusion	DSC CBFr0 hyper-perfusion	DSC CBFrm hypo-perfusion	DSC CBFrm hyper-perfusion	DSC CBV hypo-perfusion	DSC CBV hyper-perfusion	DSC Tmax increase	DSC MTT increase
Mean	1.30	0.87	0.75	0.40	0.50	0.37	0.34	0.41	1.34	1.32
SD	1.16	1.00	0.84	0.49	0.60	0.43	0.50	0.45	1.23	1.18
W	0.7597	0.5101	0.5298	0.3228	0.4419	0.2877	0.3192	0.2831	0.7868	0.7910
P value	<0.0001	0.0133	0.0077	0.5315	0.0725	0.7266	0.5521	0.7500	<0.000	<0.0001

^*Rating criteria are:

Conspicuity: Score 3, the perfusion lesion can be identified definitely; Score 2, relatively clear diagnosis of perfusion lesion can be drawn; Score 1, possible diagnosis of perfusion lesion can be obtained; Score 0, can’t afford any help to diagnosis.

Spearman correlation coefficients between average conspicuity ratings of hypoperfusion lesions on ASL CBF maps and multi-parametric DSC perfusion maps are listed in supplemental Table 2A. ASL was most consistent with DSC MTT (r = 0.79, p < 0.0001), Tmax (r = 0.77, p < 0.0001) and CBFr0 (r = 0.76, p < 0.0001) maps in demonstrating hypoperfusion. Note the above 4 parameters also demonstrated the highest inter-rater reliability in Table 1. The magnitude of correlations slightly reduced when comparing ASL with DSC CBFrm (r=0.62, p=0.0001) and CBV (r=0.61, p=0.0038) in delineating hypoperfusion. The mean rating of ASL hypoperfusion (1.30±1.16) was significantly higher than those of DSC CBFr0 (0.75±0.84), CBFrm (0.50±0.60) and CBV (0.34±0.43) hypoperfusion (p<0.0001), while not significantly different from the mean ratings of Tmax (1.34±1.23) and MTT (1.32±1.18). Figure 2 shows serial FLAIR, DWI, ASL and DSC PWI of representative AIS cases with primarily hypoperfusion lesions at baseline. By visual appearance, hypoperfusion lesions on ASL CBF maps match best with prolonged Tmax and MTT on DSC PWI. The severity of hypoperfusion lesions appear similar on ASL CBF and DSC CBFr0 maps, while the lesions are less conspicuous on DSC CBFrm and CBV maps. In addition, the correspondences between ASL and DSC ratings were stronger at 3T than 1.5T as shown in supplemental Table 2.

Figure 2. Representative AIS cases showing hypo-perfused lesions in baseline scans.

A. Case #16: 39-year-old male with no past stroke history presented with slurred speech, NIHSS=2. Scan performed 1.37 hrs after onset.

B. Case #13: 93-year-old female with no past stroke history presented with weakness in the left upper extremity and slurred speech, NIHSS=5. Scan performed 1.85 hrs after onset.

C. Case #19: 70-year-old male with history of hypertension presented with left-sided weakness and slurred speech, NIHSS=20. Scan performed 8.18 hrs after onset.

D. Case #7: 68-year-old male with past history of atrial fibrillation, hypertension and dyslipidemia presented with slurred speech, right-sided weakness and gait disturbance, NIHSS=18. Scan performed 1.38 hrs after onset. The patient received post-scan IV tPA.

Ratings of Hyperemic Lesions

Spearman correlation coefficients between conspicuity ratings of hyper-perfusion lesions on ASL CBF maps and multi-parametric DSC perfusion maps are listed in supplemental Table 2B. The ratings of hyperemic lesions on ASL images were consistent with those of DSC CBFr0 (r=0.47, p=0.0012), CBFrm (r=0.47, p=0.001) and CBV (r=0.39, p=0.0087) images. Nevertheless, ASL PWI (mean score = 0.87±1.00) was significantly more conspicuous than DSC PWI (CBFr0: 0.40±0.49, p=0.005; CBFrm: 0.37±0.43, p=0.005; CBV: 0.41±0.45, p=0.0087) in delineating hyperemic lesions. Figure 3 shows serial FLAIR, DWI, ASL and DSC PWI of representative AIS cases with hyperperfusion lesions at baseline. As can be clearly seen, hyperemic lesions were much more conspicuous on ASL CBF than DSC CBF or CBV maps. Furthermore, DSC Tmax and MTT maps performed poorly at delineating hyperemic lesions. Note 3 of the 4 cases shown in Fig. 3 were treated with rt-PA before first MRI scans and the hyperperfusion seen in ASL likely reflects hyperemia following thrombolytic reperfusion.

Figure 3. Representative AIS cases showing hyper-perfused lesions in baseline scans.

A. Case #17: 90-year-old female with history of atrial fibrillation and atrial flutter presented with slurred speech and right-sided weakness, NIHSS=16. IV tPA was administered before scan.

B. Case #23: 93-year-old female with history of hypertension and atrial fibrillation presented with right-sided numbness and weakness and slurred speech, NIHSS=23. IV tPA was administered before scan.

C. Case #10: 86-year-old male with history of hypertension presented with right-sided weakness, slurred speech and right lower facial droop. NIHSS=11. The patient received post-scan IV tPA.

D. Case #11: 75-year-old male with no past stroke history presented with left-sided weakness, NIHSS=18. IV tPA was administered before scan.

Serial ASL and DSC PWI

Serial ASL and DSC PWI were obtained in 5 AIS patients pre and post endovascular procedures. All patients demonstrated partial or full recanalization at angiography. As shown in Fig. 4, recanalization resulted in either normalization of perfusion or hyperemic responses within and/or around lesion areas. Again, ASL CBF was more conspicuous than DSC CBF and CBV maps in demonstrating hyperemic flow responses.

Figure 4. Serial FLAIR, DWI, ASL and DSC PWI prior to and after endovascular treatment.

A. Case #21: 57-year-old female with history of hypertension presented with left- sided weakness, left hand numbness and slurred speech. Baseline NIHSS=14. The patient received post-scan IV tPA and clot retrieval with final TICI score of 2b. Post-intervention NIHSS=0, mRS at discharge=2.

B. Case #2: 71-year-old female with past history of paroxysmal atrial fibrillation presented with slurred speech and right-sided weakness. Baseline NIHSS=16. The patient received post-scan IV tPA and clot retrieval with final TICI score of 2b. The symptoms remained unchanged after the intervention. mRS at discharge=4.

Quantitative Vascular Territory Analysis

Spearman correlation coefficients between mean values of ASL CBF and multi-parametric DSC perfusion parameters in the 4 major vascular territories are listed in supplemental Table 3. There were significant negative correlations between ASL CBF and DSC Tmax and MTT in the ACA, leptomeningeal MCA and perforator MCA territories (r≤−0.24, p<0.05)(supplemental Table 3A). There were significant associations between ASL CBF and DSC CBFr0 values in the perforator MCA territory (r=0.23, p=0.04). When only patients with predominately MCA strokes were considered, significant negative correlations between ASL CBF and DSC Tmax and MTT in the leptomeningeal and perforator MCA territories as well as a significant positive association between ASL CBF and DSC CBFr0 in the perforator MCA territory were preserved (supplemental Table 3B). The findings of quantitative vascular territory analysis are generally consistent with those based on subjective ratings, supporting the associations between ASL perfusion and DSC Tmax, MTT as well as CBFr0 measures across subjects.

Region-of-Interest Analysis

In the AIS cases demonstrating primarily hypoperfusion lesions, ASL and DSC CBF values within the ROIs of Tmax > 6s were significantly reduced compared to those of 2s < Tmax < 6s (Supplemental Table 4). When comparing the mean CBF values between the ROIs of 2s < Tmax < 6s and Tmax < 2s, ASL CBF and DSC CBFr0 values were significantly reduced in the former than the latter ROI while DSC CBFrm values were not significantly different.

Discussion

To summarize the main findings of the present study, ASL and DSC PWI provided largely consistent results in delineating hypoperfusion lesions in AIS. The most consistent associations, as demonstrated by both subjective ratings and quantitative vascular territory analyses, were between ASL CBF and DSC Tmax, MTT and CBFr0 measures which also demonstrated the highest inter-rater reliability. ASL techniques are limited by the relatively short tracer half-life determined by the T1 of blood. Even with advanced pCASL and 3D GRASE readout, the post-labeling delay (PLD) time is typically less than 3s in ASL experiments at field strengths of 3T or lower. In the present study, a PLD of 2s was used in pCASL scans as a tradeoff between maintaining adequate diagnostic quality while allowing sufficient delay to visualize tissue perfusion. Our findings suggest that hypoperfusion lesions on ASL CBF maps may reflect delayed transit effects as well as reduced CBF that are manifested as prolonged Tmax and MTT on DSC PWI. Furthermore, significant differences of ASL CBF values were demonstrated between the ROIs of Tmax > 6s, Tmax between 2 to 6s and Tmax < 2s, suggesting the potential of ASL to grade hypoperfusion lesions in AIS.

In the present study, two DSC CBF measurements, namely CBFr0 and CBFrm, were performed which represent DSC CBF calculation without and with consideration of delayed transit effects, respectively. ASL CBF values were more consistent with DSC CBFr0 than CBFrm or CBV measurements, further supporting that ASL hypoperfusion lesions reflect delayed transit effects in AIS. The CBFrm images are analogous to CBF images generated using circulant deconvolution (data not shown). Since existing clinical trials have mainly adopted prolonged Tmax to define hypoperfusion regions, the consistency between ASL CBF and Tmax (or MTT) may render ASL an alternative to DSC PWI in patients with renal diseases who cannot be exposed to gadolinium contrast agent. In this regard the availability of ASL may improve the timing of MRI assessment in AIS by eliminating the need for glomerular filtration rate (GFR) evaluation. To date, to ideally delineate the penumbra on ASL PWI remains challenging due to the inherent heterogeneity of CBF maps as well as the relatively low SNR. However, this study demonstrates that ASL provides a rapid contrast agent free and reliable assessment of the patient’s cerebral hemodynamic status. ASL may also complement DSC in CBF quantification, as indicated by a recent study ¹⁷.

The second major finding of the present study was that hyperemic lesions appeared more conspicuous on ASL CBF than on DSC PWI maps. The biophysical mechanism underlying this phenomenon is not clear, and may be related to differing effects of changes of BBB permeability on perfusion quantification using ASL and DSC. Hyperperfusion in acute ischemic stroke arises from spontaneous recanalization, therapeutic recanalization, and, less commonly, improved collateral flow without recanalization. All are present in the cohort studied. Existing ASL studies on stroke ^{10, 12} have linked hyperperfusion to the “luxury perfusion” seen on Positron Emission Tomographic (PET) CBF imaging studies and suggested that hyperperfusion may be associated with positive outcomes in AIS ¹⁸. Hyperperfusion following revascularization has been observed in both CT and DSC perfusion MRI studies ^{19, 20}. In contrast to regions showing normal perfusion after recanalization, regions presenting hyperperfusion mainly developed infarction and had greater bioenergetic compromise in pretreatment imaging measures ¹⁹.

Whether or not hyperperfusion is a useful prognostic feature of AIS has not been well established. As suggested by PET literature ^{21, 22}, luxury perfusion may indicate metabolic failures such as low oxygen extraction fraction, and therefore the concept of penumbra should include both hypo- and hyper-perfusion lesions. Hyperperfusion may reflect vasoparalysis and greater regional vulnerability to hemorrhagic transformation. If so, in the future its recognition might enable timely intervention to avert hemorrhagic complications, with blood pressure moderation and blood-brain barrier stabilizing therapies. Given its superior capability in delineating hyperperfusion lesions and high repeatability, ASL may have unique value in the management of AIS patients both pre-and post-treatment, and may be applied longitudinally to monitor treatment effects.

This study has several limitations. As a cross-sectional study to compare ASL and DSC PWI, the patient cohort was rather “heterogeneous” but represented typical patient population seen at an academic medical center. In 6 patients, the “baseline” ASL and DSC PWI were acquired after rt-PA treatments. Therefore, the correlation between perfusion values and clinical evaluations (NIHSS at baseline) could not be assessed. The patient cohort included both anterior and posterior circulation strokes. We performed statistical analyses based on data from all 26 AIS patients and the 19 patients with predominately MCA strokes, respectively. The results of vascular territory analysis were not affected (see Results). Lastly, correlation of perfusion MRI findings with clinical and neuroimaging outcomes was not feasible in this pilot study. Overall, the present study represents an initial step in exploring the clinical value of ASL in the management of AIS, through comparison with DSC perfusion MRI.

Summary

ASL has clinical utilities in detecting both hypo- and hyper-perfusion lesions in AIS patients, which may complement DSC perfusion MRI. The capability of ASL to provide noninvasive and quantitative CBF information without the use of contrast agent offers the potential to include ASL as part of standard neuroimaging protocol in the management of acute stroke both pre- and post-revascularization.