REVIEW URRENT C OPINION
Arterial spin labeling magnetic resonance perfusion imaging in cerebral ischemia Nolan S. Hartkamp a, Matthias J.P. van Osch b, Jaap Kappelle c, and Reinoud P.H. Bokkers a,d
Purpose of review Arterial spin labeling (ASL) is a noninvasive magnetic resonance perfusion imaging method for visualizing and quantifying whole-brain perfusion that does not require exogenous contrast agents. The goal of this review article is to explain the principles of ASL perfusion imaging and review the strengths and limitations of different ASL methods. Recent findings There are several different approaches that vary mainly on the basis of the technique that is used to label the inflowing arterial blood. These methods can be used to assess perfusion at brain tissue level or the perfusion territories of the brain feeding arteries. In patients with acute ischemic stroke, ASL can be of clinical value by detecting brain regions with hypoperfusion and perfusion–diffusion mismatch. ASL has been used to detect decreased perfusion, delayed arrival of the arterial blood bolus and assessment of collateral blood flow in patients with extracranial large artery disease and moyamoya disease. Summary Recent evidence indicates that perfusion and territorial perfusion imaging of the brain feeding arteries with ASL can help to assess the extent of hemodynamic compromise and to customize medicinal and surgical treatment, both in patients with acute and with chronic cerebrovascular disease. Keywords arterial spin labeling, cerebral perfusion, cerebrovascular disease, magnetic resonance imaging
INTRODUCTION Cerebral perfusion is the basis for the delivery of oxygen and nutrients to the brain. Basic physiological functions such as synaptic transmission, the membrane ion pump and energy metabolism are disrupted when there is a disturbance in the supply of blood, leading to irreversible neuronal damage within minutes [1]. From the first method of measuring global brain perfusion in 1948 with nitrous oxide to the development of the first cross-sectional imaging method in the 1980s with PET in the human brain, there have been vast improvements in imaging brain perfusion [2,3]. In current clinical practice, the most commonly used techniques for brain perfusion imaging are computed tomography perfusion (CTP) and gadolinium-based dynamic susceptibility contrast (DSC)MRI [4]. Arterial spin labeling (ASL) is a new noninvasive alternative magnetic resonance perfusion imaging method for visualizing and quantifying cerebral perfusion at brain tissue level that does not require www.co-neurology.com
exogenous contrast agents. The goal of this review article is to explain the principles of perfusion imaging by ASL and to review the strengths and limitations of the different ASL perfusion imaging methods that are available. Furthermore, its potential in patients with cerebrovascular disease will be explored. Finally, literature concerning brain hemodynamics will be reviewed, and ASL will be compared with more traditional methods such as CTP, DSC-MRI and PET. a
Department of Radiology, University Medical Center Utrecht, Utrecht, Department of Radiology, C.J. Gorter Center for High Field MRI, Leiden University Medical Center, Leiden, cDepartment of Neurology and Neurosurgery, Brain Center Rudolf Magnus – Stroke Unit, University Medical Center Utrecht, Utrecht and dDepartment of Radiology, Gelre Hospitals, Apeldoorn, The Netherlands b
Correspondence to Reinoud P.H. Bokkers, MD, PhD, Department of Radiology, room E01.132, University Medical Centre Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands. Tel: +31 88 755 6687; fax: +31 30 258 1098; e-mail: [email protected] Curr Opin Neurol 2014, 27:42–53 DOI:10.1097/WCO.0000000000000051 Volume 27 Number 1 February 2014
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Perfusion imaging with ASL in cerebral ischemia Hartkamp et al.
KEY POINTS ASL is a noninvasive magnetic resonance perfusion imaging method that does not require exogenous contrast agents by means of magnetically labeling inflowing arterial blood. Depending on the labeling method, there are several different approaches for assessing perfusion at brain tissue level or the individual perfusion territories of the brain feeding arteries. ASL can help to assess the extent of hemodynamic compromise and to customize medicinal and surgical treatment, both in patients with acute and with chronic cerebrovascular disease.
ARTERIAL SPIN LABELING ASL was first introduced in 1992 by Williams and Detre as an alternative, noninvasive method for visualizing brain perfusion and quantifying cerebral blood flow [5,6]. The key innovative idea of this method is to employ arterial blood as an endogenous contrast agent by magnetically labeling the inflowing blood by means of radiofrequency pulses. It does not require injection of any contrast agent. After the initial radiofrequency labeling, a delay of 1–2.5 s allows the labeled arterial water protons to flow through the arterial vascular tree into the brain parenchyma. The experiment is subsequently repeated without labeling the arterial blood to acquire a so-called control image. Perfusion contrast is finally obtained by calculating the difference in magnetization between the labeled and unlabeled control image, thereby depicting the exchange of magnetization at brain tissue level. The difference is often in the order of 1% or less, and this intrinsic low signal-to-noise level has led to the development of a variety of alternative imaging techniques to maximize the ASL signal. Depending on the method used, cerebral perfusion can be assessed with whole brain coverage in 3–5 min. An advantage of ASL compared with some other techniques such as single-photon emission computed tomography (SPECT) and DSC-MRI is that it enables quantification of cerebral blood flow and that some variants are able to measure the arrival time of the labeled blood [7,8]. As multiple sequential measurements of perfusion are possible, ASL can also be utilized to assess the brain’s autoregulatory (or reserve) capacity by measuring the response in cerebral blood flow to a vasodilatory challenge [9,10]. Furthermore, perfusion territories of the different brain feeding arteries can be visualized by selectively labeling the inflowing blood of individual brain feeding arteries [11,12].
Labeling and imaging techniques There are several different ASL-MRI approaches that vary mainly on the basis of the technique that is used to label the inflowing arterial blood. Three main labeling strategies can be distinguished: pulsed ASL (PASL), in which the blood within a large spatial volume is inverted by a relatively short inversion pulse (typically 10–20 ms) [13]; continuous ASL (CASL), in which blood flowing through a specific plane is inverted for a labeling period of 1–3 s [9]; and, pseudo-continuous ASL (pCASL), which recently has been introduced as a more efficient and easy way to achieve such a labeling plane by means of a long train of small radiofrequency pulses [14,15]. Velocity selective ASL and acceleration selective ASL (AccASL) are novel labeling strategies, in which blood is selectively labeled according to a certain velocity or deceleration specific to blood within the capillary bed [16,17]. The main difference between velocity/AccASL and the other methods is that these also label blood within the imaging slices, whereas PASL and pCASL label only blood inferior from the imaging slices in the neck region. A severe limitation of ASL is that the created magnetic label decays with the longitudinal relaxation time of the compartment in which it resides. For most of the time, this will be in the arterial blood (water can cross the capillary wall almost unrestricted, and some label will, therefore, end up in the extravascular tissue compartment). As the T1 of arterial blood is approximately 1.65 s, this implies that after 3 s only 16% of the created label survives. This points to the fundamental compromise that needs to be solved in ASL: for a correct quantitative measurement of cerebral blood flow, one should wait long enough for all label to have arrived in the brain tissue; however, by waiting too long all signal will have decayed, and no label will be detected. This is especially difficult when applying ASL-MRI in patients with cerebrovascular disease in whom collateral blood flow can lead to prolonged transport times for the label to arrive in the brain tissues [18]. When the magnetic label has not yet reached the brain tissue at the moment of imaging, an underestimation of cerebral blood flow will occur. Furthermore, the presence of label with the arterial vasculature might lead to vascular artefacts, which will lead to bright focal spots with intravascular signal. By acquiring a series of perfusion weighted images at increasing delay times after labeling it is possible to visualize the arrival of the labeled blood dynamically, allowing the estimation of the transit delay and correction for the underestimation of cerebral blood flow due to long transit times [8].
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The kinetics of the labeled blood bolus can also be used as an additional physiological parameter [7]. For instance, the arrival time and the duration needed for the end of the labeled bolus to reach the brain tissue can be calculated through hemodynamic modeling and allows the identification of the vascular borderzones (Fig. 1) [19]. A main drawback of ASL perfusion imaging at multiple delay times, however, is that it has a considerably longer acquisition time in comparison to a single inversion time ASL perfusion sequence. To speed up imaging, a small flip angle gradient echo sampling strategy can be used in a manner similar to the Look–Locker technique used for fast T1 mapping [20]. A drawback of this imaging strategy is that the train of radiofrequency pulses during the readout decreases the perfusion signal, especially for the later phases. As a result of this signal loss and the natural T1 decay of the magnetized blood, the remaining signal from the ASL label is small, resulting in low signal-tonoise and diminished spatial resolution.
Territorial perfusion imaging Both PASL, CASL and pCASL labeling methods can each be utilized to selectively label one or multiple arteries of the individual extracranial brain feeding arteries and visualize the perfusion territories of the individual arteries [21 ]. The techniques based on PASL and CASL typically are heavily dependent on &&
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user interactions to plan the labeling region defined angulation of the labeling slabs in order to enclose only the specific arteries of interest [21 ]. In a clinical setting, the most convenient approach might be planning-free vessel-encoded pCASL. This technique requires only limited planning as the labeling slice is being locked at a fixed position in relation to the acquisition volume, thus providing robust and reproducible results within a clinically feasible time frame of less than 5-min scan time [21 ,22]. There are also superselective methods that can label the individual intracranial arteries. These methods are derived from pCASL and CASL-labeling techniques and are based on a rotating gradient that restricts the inversion to a circular or elliptical labeling spot [21 ]. Although territorial perfusion imaging ASL methods are currently not routinely available, they may provide valuable patient-specific knowledge for clinical practice, both from an anatomical and from a functional point (directional flow) of view. There are large variations in the individual cerebral vasculature, of which the most prominent are those in the circle of Willis [23]. The circle of Willis is fed from the internal carotid arteries (ICAs) and the basilar artery and supplies the anterior carotid artery (ACA), middle carotid artery (MCA) and posterior carotid artery (PCA) cerebral arteries. Only 65% of the healthy population has a nonvariant type circle of Willis, in which the ACA and MCA are fed from their &&
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FIGURE 2. Seventy-two-year-old male patient with left-sided internal carotid artery stenosis of more than 50%. MR angiogram images of the circle of Willis (a). 2D phase-contrast images (b, c) show blood flowing from right-to-left in white and left-to-right in black (b), and flowing from anterior-to-posterior in white and posterior-to-anterior in black (c). Fluid attenuation inversion recovery MR images (d) from cranial (top) to caudal (bottom) correspond with ASL perfusion images before (h) and after (f) administration of acetazolamide, cerebrovascular reactivity images (g) and territorial ASL perfusion maps (e) of the right (red), left (green) carotid arteries and the basilar artery (blue). A two-sided fetal-type variant of the posterior cerebral artery (a, below star) is shown. Both carotid arteries feed their ipsilateral posterior cerebral artery via its posterior communicating artery (b and c, besides star). There are old infarct lesions with gliosis in the left hemisphere, most prominently occipital (d and e, arrows) and frontal (d and e, arrows), with reduced baseline perfusion (h) and reduced cerebrovascular reactivity. Part of the perfusion territory of the left anterior cerebral artery is shown to be fed from the right carotid artery (e, bottom arrow). ASL, arterial spin labeling; MR, magnetic resonance.
ipsilateral ICA, and both PCAs are fed from the basilar artery [23]. About 30% of the population has a fetal-type configuration in which the PCA is supplied via the posterior communicating artery from the ICA (Fig. 2) [23]. Furthermore, in about 5% of the population both ACAs are fed via the anterior communicating artery from one ICA [23]. These variants of the circle of Willis will directly influence the ability of collateral flow in the case of
carotid occlusion and can often be deduced from clues on the presence or absence of certain vessel segments [24]. Also distal to the circle of Willis, on a subcortical level, there is variability in vascularization. For instance in the deep gray matter, the caudate nucleus may be fed by the ipsilateral or contralateral ICA depending on the origin of the medial striate artery [25]. The thalamic region is supplied by
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Cerebrovascular disease
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FIGURE 3. ASL and dynamic susceptibility perfusion, diffusion and FLAIR images of a 48-year old woman presenting within 6 h after symptom onset. Restricted diffusion and increased time-to-peak times can be appreciated in the flow territory of left posterior circulation on the DWI and DSC images. The corresponding ASL image shows a corresponding decrease in perfusion. Reproduced with permission from [36 ]. ASL, arterial spin labeling; DSC, dynamic susceptibility contrast; DWI, diffusion-weighted imaging; FLAIR, fluid attenuated inversion recovery. &&
branches of both the ACA and the PCA, which in turn can entirely or partly be supplied by either or both the ICA and basilar artery depending on the configuration of the circle of Willis [26]. The high variability in the cerebral perfusion territories may further be complicated by the presence of stenoocclusive artery disease, in which the presence of adequate collateral pathways play an important role in the pathogenesis of stroke [18,27]. In the case of an ICA occlusion, information on whether the affected hemisphere is supplied by the contralateral ICA or basilar artery is invaluable considering these collateral vessels may be subject to disease as well. 46
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ISCHEMIC STROKE IMAGING In patients suspected of stroke, classification of the underlying pathophysiology is critical for defining short and long-term treatment options. In current practice, noncontrast computed tomography (CT) is used as a fast and efficient imaging modality to differentiate ischemic from hemorrhagic stroke. Recent studies have indicated that additional brain perfusion imaging can help to depict brain tissue with reduced cerebral blood flow and to identify tissue that has not yet been permanently damaged [28]. This is of particular interest in the acute stage of stroke as the combination of anatomical and Volume 27 Number 1 February 2014
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FIGURE 4. ASL and dynamic susceptibility perfusion, diffusion and FLAIR images of a 53-year old man presenting within 10 h after symptom onset. Restricted diffusion and increased time-to-peak times can be appreciated in the right basal ganglia on the DWI and DSC images. The perfusion deficit was, however, not depicted with ASL. Reproduced with permission from [36 ]. ASL, arterial spin labeling; DSC, dynamic susceptibility contrast; DWI, diffusion-weighted imaging; FLAIR, fluid attenuated inversion recovery. &&
perfusion imaging might help to identify patients with salvageable brain tissue that may benefit from reperfusion therapy [29,30].
Perfusion imaging Magnetic resonance perfusion imaging has been postulated as a viable alternative to CTP in acute clinical care. Without much extra time from door to needle it can provide critical information on the extent of penumbra [31]. Despite current debate on the exact definition of penumbra, the concept of perfusion–diffusion mismatch provides a practical
and fast measure of the tissue at risk that has not yet developed irreversible cell injury as detected by diffusion-weighted imaging [29,30,32]. Both DSC and ASL imaging can be used for perfusion magnetic resonance imaging. In DSCMRI, a gadolinium contrast agent is injected, and a time series of fast T2-weighted images is acquired. Cerebral blood flow, transit time and time to peak can be computed from these dynamic inflow images. There are, however, serious concerns regarding the safety of gadolinium chelates in patients with poor renal function, as it has been reported to induce nephrogenic systemic fibrosis [33,34].
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FIGURE 5. Sixty-eight-year-old male patient with right-sided internal carotid artery occlusion. Images are depicted identically to Figure 2. Absence of blood flow in the right ICA can be appreciated (a and c, star); however, blood flow in the middle cerebral artery is distinctly flowing (b and c, star) and is presumed to be fed from the anterior communicating artery. An old ischemic infarct is seen in the left hemisphere (d, arrow) with absent perfusion (h and f, arrow) and reactivity (g, arrow); the area is within the territory of the left carotid artery. Perfusion artefact due to low perfusion and delayed arrival (h, f and e, star) can be appreciated in the right hemisphere. ICA, internal carotid artery.
Gadolinium is, therefore, often contraindicated in patients with an estimated glomerular filtration rate less than 30 ml/min and in those on hemodialysis. When ASL was first introduced two decades ago, initial studies showed its ability to detect hypoperfusion in acute stroke [35]. Practically, the use was limited because of the long acquisition time and low resolution of perfusion images. Fast imaging is, however, now possible with the introduction of pCASL and background suppression (Fig. 3) [36 ]. Two recent large studies demonstrated that ASL is largely consistent with DSC for depicting brain regions with hypoperfusion. In the first study, by Bokkers et al. [36 ], 156 patients suspected of ischemic stroke were included, and ALS was found to be &&
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able to depict large perfusion deficits and perfusiondiffusion mismatches correlating with DSC. They found that small ischemic lesions were more difficult to detect as the contrast-to-noise of the ASL perfusion-weighted maps is relatively low in comparison to DSC, in which increased mean transit times are predominantly used for lesion detection. An example of such a lesion is shown in Fig. 4 [36 ]. The second study, by Zaharchuk et al. [37 ], with 1.5 Tesla MRI, showed in 51 patients that the perfusion–diffusion mismatch detected with ASL correlates qualitatively with DSC, but also that ASL tends to overestimate the perfusion deficit due to over-sensitivity for delayed inflow. ASL has, therefore, a high negative predictive value for excluding &&
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FIGURE 6. Sixty-nine-year-old female patient with a stenosis of the right vertebral artery distal to the origin of the right PICA. Images (a–g) are depicted identically to Figure 2. Territorial perfusion images (e) of the right (red) and left (green) ICA and right (blue) and left (yellow) vertebral arteries are superimposed. MR angiogram source images reveal the presence of the right PICA with its origin from the right vertebral artery (a, besides star). The right vertebral artery is shown to effectively end into the right PICA revealing its territory (e, arrow). The circle of Willis has a normal distribution of blood flow (b and c). FLAIR images show no recent ischemic lesion (d, arrow) in the cerebellum. There is, however, reduced baseline perfusion (h, arrow), which increases after a vasodilatory stimulus with acetazolamide (f, arrow), showing a high cerebrovascular reactivity (g, arrow). FLAIR, fluid attenuated inversion recovery; ICA, internal carotid artery; MR, magnetic resonance; PICA, posterior inferior cerebellar artery.
mismatch, but when mismatch is detected the area of mismatch may be overestimated. This demonstrates an important limitation of ASL. As images are acquired after a fixed time point following the labeling, delayed inflow due to collateralization may lead to an underestimation of cerebral perfusion and overestimation of the perfusion-deficit mismatch. Faster multidelay multiparametric ASL approaches, such as recently introduced by Wang et al. [38],may partially provide a solution for this problem as both cerebral blood flow
and delayed arrival of the contrast bolus can be measured.
EXTRACRANIAL LARGE ARTERY DISEASE Current guidelines for the treatment of carotid artery stenosis and occlusion are based primarily on large randomized clinical trials in which cerebral perfusion was not taken into account [39]. Observational studies suggest strongly, however, that the risk of (recurrent) ischemic stroke is higher in
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FIGURE 7. Forty-five-year-old patient with both right and left-sided distal internal carotid artery stenosis and moyamoya disease. MR angiogram MIP in the axial (a), sagittal (b) and coronal (c) plane show the typical abundance of tiny moyamoya collaterals. The baseline perfusion images show apparent symmetrical perfusion in both cerebral hemispheres (h, star); although after a vasodilatory challenge there is no increase in perfusion in the right hemisphere (f, star) and generally reduced cerebrovascular reactivity (g, star). In the cerebellum, there is notable asymmetry in baseline perfusion against the left hemisphere (h, arrow). After the vasodilatory challenge, however, there is adequate increase in perfusion (f, arrow) and entirely symmetrical cerebrovascular reactivity is shown in the cerebellum (g, arrow). The affected right cerebral hemisphere and left cerebellar hemisphere is an example of crossed-cerebellar diaschisis. MIP, maximum intensity projection; MR, magnetic resonance.
patients with impaired cerebral perfusion in the hemisphere ipsilateral to a symptomatic or asymptomatic carotid stenosis than in those with normal perfusion [40,41]. The effect of extracranial–intracranial bypass surgery compared with best medical therapy was investigated in the Carotid Occlusion Surgery Study in patients with a hemodynamically compromised ICA occlusion as assessed with PET [42]. Despite excellent bypass graft patency and improved cerebral hemodynamics, patients did not, however, 50
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benefit from an extracranial-to-intracranial bypass, mainly because the surgical complication rates were too high. Assessment of cerebral autoregulation may prove to be important in large artery obstruction for the management of hypertension, as lowering the blood pressure may be dangerous in hemodynamically impaired areas. Studies with ASL have focused on detecting brain tissue with decreased perfusion, delayed arrival of the arterial blood bolus and assessment of collateral blood flow [43,44]. In patients with an Volume 27 Number 1 February 2014
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FIGURE 8. Forty-four-year-old patient with left-sided internal carotid artery occlusion and moyamoya disease. MR angiogram maximum intensity projections in the axial (a), sagittal (b) and coronal (c) plane show the typical abundance of tiny moyamoya collaterals. Images (d–e) are depicted identically to Figure 2. A recent ischemic infarct can be seen in the left hemisphere (d, star) with reduced baseline perfusion (h, star), and no increase in perfusion after a vasodilatory challenge with acetazolamide (f, star). There is generally low cerebrovascular reactivity against the left hemisphere (g, star). The perfusion territory of the left middle cerebral artery is fed from the right carotid artery (e, star). MR, magnetic resonance.
ICA occlusion, ASL can depict the presence and extent of regions with hypoperfusion comparable to PET [45,46]. By combining the unique ability of repeatable perfusion measurements with a vasodilatory challenge, studies have investigated autoregulatory impairment, both in patients with a stenosis and those with an occlusion [9,10,47]. As impairment of autoregulation is considered the first stage of hemodynamic compromise, in which cerebral perfusion is largely maintained through maximal vasodilatation of small arteries and arterioles, it may be potentially a sensitive tool for assessing the risk for developing ischemic stroke at brain tissue level [40].
Using perfusion-territory selective labeling techniques, ASL has also been used to provide information on shifts in the perfusion territories of the brain feeding arteries. When there is an obstructive lesion in one of the brain feeding arteries, collateral blood flow will be recruited through either the circle of Willis or secondary collaterals, such as the ophthalmic artery or leptomeningeal vessels, to sustain adequate oxygenation [18]. Studies indicate that hemodynamic and metabolic changes are more severe in patients with than in patients without primary collaterals and that the presence of secondary collateral flow is associated with an impaired hemodynamic status [48–50]. An example of a
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patient with a decreased autoregulatory reserve due to an ICA occlusion and inadequate collateralization through the anterior communicating artery is shown in Fig. 5. As shown in Fig. 6, this method can also be used to identify those patients that have decreased perfusion, but intact autoregulatory reserve due to adequate collateralization. This is in agreement with other studies that have used either transcranial Doppler to measure cerebrovascular reactivity in the intracranial arteries, or techniques such as PET and SPECT to measure cerebrovascular reactivity at the brain tissue level [51–54]. Diaschisis is another important hemodynamic change that may occur in patients with a large artery disease and areas with hemodynamic compromise. This phenomenon is caused by the loss of function on a distant but anatomically connected brain region [55]. Figure 7 shows an example of crossedcerebellar diaschisis due to deafferentation as a result of contralateral supratentorial disease in a 45-year-old patient with both right and left-sided distal internal carotid artery stenosis and moyamoya disease.
INTRACRANIAL ARTERIOPATHY Intracranial cerebral arteriopathies are a heterogeneous group of diseases that can be divided into large and small-vessel arteriopathies. Intracranial large-vessel arteriopathy is usually caused by atherosclerosis and in a small minority by inflammatory changes such as moyamoya disease. Moyamoya vasculopathy is characterized by an intracranial arteriopathy leading to progressive bilateral narrowing of the supraclinoid ICA and its branches. It leads to the formation of a vascular network of moyamoya vessels at the base of the brain. The majority of patients are children and young adults, presenting with symptoms of cerebral ischemia, seizures, cognitive deterioration and hemorrhagic stroke. Diagnosis is currently based on cerebral angiography. There is, however, a discrepancy between clinical symptoms and the angiographic severity. Perfusion and cerebrovascular reactivity measurements have been shown to identify those patients that may benefit from surgical revascularization [56,57]. Figure 8 shows an example of a patient with an ICA occlusion due to moyamoya disease. Despite extensive collateralization, a decreased autoregulatory reserve can be appreciated in the most affected hemisphere. The occurrence of prolonged arterial transit time artefacts due to obstruction of vessels or extensive collateralization is a severe limitation of ASL. In the case of a perfusion lesion, a careful consideration must be made whether the cause is hypoperfusion of 52
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the tissue or indeed an artefact due to prolonged transit time. The presence of these artefacts in certain locations in the brain may also offer additional hemodynamic information in patients who are suspected of having cerebrovascular disease known for extensive collateral formation [58]. Zaharchuk et al. [59] recently reported arterial transit time artefacts as an indicator of the presence and intensity of collateral flow.
CONCLUSION Over the last decade, there have been key improvements in ASL techniques which have made it a viable alternative to more established techniques such as DSC-MRI and CT perfusion imaging. Research is still ongoing to establish its value in clinical practice for diagnosing ischemic stroke and to determine whether perfusion imaging can help target revascularization therapy in patients with atherosclerotic large-vessel disease. As the use of ionizing radiation required for CT increases the risk of tumor induction and contrast agents can cause nephropathy and nephrogenic systemic fibrosis, ASL-MRI may prove to be a powerful noninvasive alternative. Perfusion and cerebral reactivity imaging with ASL can help assess the extent of hemodynamic compromise and may potentially be used to customize medicinal and surgical treatment. Acknowledgements N.S.H. receives support from the Dutch Heart Foundation (Grant 2010B274). M.J.P. van O. receives support from the Dutch Technology Foundation STW, Applied Science division of NWO and the Technology Program of the Ministry of Economic Affairs. R.P.H.B. receives support from the Dutch Heart Foundation (Grant 2013T047). Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Saver JL. Time is brain: quantified. Stroke 2006; 37:263–266. 2. Kety SS, Schmidt CF. The nitrous oxide method for the quantitative determination of cerebral blood flow in man; theory, procedure and normal values. J Clin Invest 1948; 27:476–483. 3. Phelps ME, Hoffman EJ, Mullani NA, et al. Application of annihilation coincidence detection to transaxial reconstruction tomography. J Nucl Med 1975; 16:210–224. 4. Wintermark M, Sesay M, Barbier E, et al. Comparative overview of brain perfusion imaging techniques. Stroke 2005; 36:e83–e99. 5. Williams DS, Detre JA, Leigh JS, et al. Magnetic resonance imaging of perfusion using spin inversion of arterial water. Proc Natl Acad Sci U S A 1992; 89:212–216.
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Perfusion imaging with ASL in cerebral ischemia Hartkamp et al. 6. Detre JA, Leigh JS, Williams DS, et al. Perfusion imaging. Magn Reson Med 1992; 23:37–45. 7. Buxton RB, Frank LR, Wong EC, et al. A general kinetic model for quantitative perfusion imaging with arterial spin labeling. Magn Reson Med 1998; 40:383–396. 8. Golay X, Hendrikse J, Lim TCC. Perfusion imaging using arterial spin labeling. Top Magn Reson Imaging 2004; 15:10–27. 9. Detre JA, Samuels OB, Alsop DC, et al. Noninvasive magnetic resonance imaging evaluation of cerebral blood flow with acetazolamide challenge in patients with cerebrovascular stenosis. J Magn Reson Imaging 1999; 10:870–875. 10. Bokkers RP, van Osch MJ, van der Worp HB, et al. Symptomatic carotid artery stenosis: impairment of cerebral autoregulation measured at the brain tissue level with arterial spin-labeling MR imaging. Radiology 2010; 256:201–208. 11. Paiva FF, Tannu´s A, Silva AC. 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37. Zaharchuk G, El Mogy IS, Fischbein NJ, et al. Comparison of arterial spin labeling and bolus perfusion-weighted imaging for detecting mismatch in acute stroke. Stroke 2012; 43:1843–1848. This study demonstrates the use of an ASL in acute stroke patients for depicting perfusion deficits and perfusion/diffusion mismatch. 38. Wang DJJ, Alger JR, Qiao JX, et al. The value of arterial spin-labeled perfusion imaging in acute ischemic stroke: comparison with dynamic susceptibility contrast-enhanced MRI. Stroke 2012; 43:1018–1024. 39. Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke – co-sponsored by the Council on Cardiovascular Radiology and Intervention – the American Academy of Neurology affirms the value of this guideline. Stroke 2006; 37:577– 617. 40. Markus H, Cullinane M. 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Effect of collateral blood flow and cerebral vasomotor reactivity on the outcome of carotid artery occlusion. Stroke 2001; 32:1552–1558. 50. Kluytmans M, van der Grond J, van Everdingen KJ, et al. Cerebral hemodynamics in relation to patterns of collateral flow. Stroke 1999; 30:1432–1439. 51. Imaizumi M, Kitagawa K, Hashikawa K, et al. Detection of misery perfusion with split-dose 123I-iodoamphetamine single-photon emission computed tomography in patients with carotid occlusive diseases. Stroke 2002; 33:2217– 2223. 52. Ogasawara K, Ogawa A, Yoshimoto T. Cerebrovascular reactivity to acetazolamide and outcome in patients with symptomatic internal carotid or middle cerebral artery occlusion: a xenon-133 single-photon emission computed tomography study. Stroke 2002; 33:1857–1862. 53. Hirano T, Minematsu K, Hasegawa Y, et al. Acetazolamide reactivity on 123IIMP single photon emission computed tomography in patients with major cerebral artery occlusive disease: correlation with positron emission tomography parameters. J Cereb Blood Flow Metab 1994; 14:763–770. 54. Vernieri F, Pasqualetti P, Passarelli F, et al. Outcome of carotid artery occlusion is predicted by cerebrovascular reactivity. Stroke 1999; 30:593–598. 55. Machado A, Baker KB. Upside down crossed cerebellar diaschisis: proposing chronic stimulation of the dentatothalamocortical pathway for poststroke motor recovery. Front Integr Neurosci 2012; 6:20. 56. Andaluz N, Choutka O, Vagal A, et al. Patient selection for revascularization procedures in adult Moyamoya disease based on dynamic perfusion computerized tomography with acetazolamide challenge (PCTA). Neurosurg Rev 2010; 33:225–232; discussion 232–233. 57. So Y, Lee H, Kim S, et al. Prediction of the clinical outcome of pediatric moyamoya disease with postoperative basal/acetazolamide stress brain perfusion SPECT after revascularization surgery. Stroke 2005; 36:1485– 1489. 58. Zaharchuk G, Bammer R, Straka M, et al. Arterial spin-label imaging in patients with normal bolus perfusion-weighted MR imaging findings: pilot identification of the borderzone sign. Radiology 2009; 252:797–807. 59. Zaharchuk G, Do HM, Marks MP, et al. Arterial spin-labeling MRI can identify the presence and intensity of collateral perfusion in patients with moyamoya disease. Stroke 2011; 42:2485–2491.
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Arterial spin labeling magnetic resonance perfusion imaging in cerebral ischemia Nolan S. Hartkamp a, Matthias J.P. van Osch b, Jaap Kappelle c, and Reinoud P.H. Bokkers a,d
Purpose of review Arterial spin labeling (ASL) is a noninvasive magnetic resonance perfusion imaging method for visualizing and quantifying whole-brain perfusion that does not require exogenous contrast agents. The goal of this review article is to explain the principles of ASL perfusion imaging and review the strengths and limitations of different ASL methods. Recent findings There are several different approaches that vary mainly on the basis of the technique that is used to label the inflowing arterial blood. These methods can be used to assess perfusion at brain tissue level or the perfusion territories of the brain feeding arteries. In patients with acute ischemic stroke, ASL can be of clinical value by detecting brain regions with hypoperfusion and perfusion–diffusion mismatch. ASL has been used to detect decreased perfusion, delayed arrival of the arterial blood bolus and assessment of collateral blood flow in patients with extracranial large artery disease and moyamoya disease. Summary Recent evidence indicates that perfusion and territorial perfusion imaging of the brain feeding arteries with ASL can help to assess the extent of hemodynamic compromise and to customize medicinal and surgical treatment, both in patients with acute and with chronic cerebrovascular disease. Keywords arterial spin labeling, cerebral perfusion, cerebrovascular disease, magnetic resonance imaging
INTRODUCTION Cerebral perfusion is the basis for the delivery of oxygen and nutrients to the brain. Basic physiological functions such as synaptic transmission, the membrane ion pump and energy metabolism are disrupted when there is a disturbance in the supply of blood, leading to irreversible neuronal damage within minutes [1]. From the first method of measuring global brain perfusion in 1948 with nitrous oxide to the development of the first cross-sectional imaging method in the 1980s with PET in the human brain, there have been vast improvements in imaging brain perfusion [2,3]. In current clinical practice, the most commonly used techniques for brain perfusion imaging are computed tomography perfusion (CTP) and gadolinium-based dynamic susceptibility contrast (DSC)MRI [4]. Arterial spin labeling (ASL) is a new noninvasive alternative magnetic resonance perfusion imaging method for visualizing and quantifying cerebral perfusion at brain tissue level that does not require www.co-neurology.com
exogenous contrast agents. The goal of this review article is to explain the principles of perfusion imaging by ASL and to review the strengths and limitations of the different ASL perfusion imaging methods that are available. Furthermore, its potential in patients with cerebrovascular disease will be explored. Finally, literature concerning brain hemodynamics will be reviewed, and ASL will be compared with more traditional methods such as CTP, DSC-MRI and PET. a
Department of Radiology, University Medical Center Utrecht, Utrecht, Department of Radiology, C.J. Gorter Center for High Field MRI, Leiden University Medical Center, Leiden, cDepartment of Neurology and Neurosurgery, Brain Center Rudolf Magnus – Stroke Unit, University Medical Center Utrecht, Utrecht and dDepartment of Radiology, Gelre Hospitals, Apeldoorn, The Netherlands b
Correspondence to Reinoud P.H. Bokkers, MD, PhD, Department of Radiology, room E01.132, University Medical Centre Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands. Tel: +31 88 755 6687; fax: +31 30 258 1098; e-mail: [email protected] Curr Opin Neurol 2014, 27:42–53 DOI:10.1097/WCO.0000000000000051 Volume 27 Number 1 February 2014
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Perfusion imaging with ASL in cerebral ischemia Hartkamp et al.
KEY POINTS ASL is a noninvasive magnetic resonance perfusion imaging method that does not require exogenous contrast agents by means of magnetically labeling inflowing arterial blood. Depending on the labeling method, there are several different approaches for assessing perfusion at brain tissue level or the individual perfusion territories of the brain feeding arteries. ASL can help to assess the extent of hemodynamic compromise and to customize medicinal and surgical treatment, both in patients with acute and with chronic cerebrovascular disease.
ARTERIAL SPIN LABELING ASL was first introduced in 1992 by Williams and Detre as an alternative, noninvasive method for visualizing brain perfusion and quantifying cerebral blood flow [5,6]. The key innovative idea of this method is to employ arterial blood as an endogenous contrast agent by magnetically labeling the inflowing blood by means of radiofrequency pulses. It does not require injection of any contrast agent. After the initial radiofrequency labeling, a delay of 1–2.5 s allows the labeled arterial water protons to flow through the arterial vascular tree into the brain parenchyma. The experiment is subsequently repeated without labeling the arterial blood to acquire a so-called control image. Perfusion contrast is finally obtained by calculating the difference in magnetization between the labeled and unlabeled control image, thereby depicting the exchange of magnetization at brain tissue level. The difference is often in the order of 1% or less, and this intrinsic low signal-to-noise level has led to the development of a variety of alternative imaging techniques to maximize the ASL signal. Depending on the method used, cerebral perfusion can be assessed with whole brain coverage in 3–5 min. An advantage of ASL compared with some other techniques such as single-photon emission computed tomography (SPECT) and DSC-MRI is that it enables quantification of cerebral blood flow and that some variants are able to measure the arrival time of the labeled blood [7,8]. As multiple sequential measurements of perfusion are possible, ASL can also be utilized to assess the brain’s autoregulatory (or reserve) capacity by measuring the response in cerebral blood flow to a vasodilatory challenge [9,10]. Furthermore, perfusion territories of the different brain feeding arteries can be visualized by selectively labeling the inflowing blood of individual brain feeding arteries [11,12].
Labeling and imaging techniques There are several different ASL-MRI approaches that vary mainly on the basis of the technique that is used to label the inflowing arterial blood. Three main labeling strategies can be distinguished: pulsed ASL (PASL), in which the blood within a large spatial volume is inverted by a relatively short inversion pulse (typically 10–20 ms) [13]; continuous ASL (CASL), in which blood flowing through a specific plane is inverted for a labeling period of 1–3 s [9]; and, pseudo-continuous ASL (pCASL), which recently has been introduced as a more efficient and easy way to achieve such a labeling plane by means of a long train of small radiofrequency pulses [14,15]. Velocity selective ASL and acceleration selective ASL (AccASL) are novel labeling strategies, in which blood is selectively labeled according to a certain velocity or deceleration specific to blood within the capillary bed [16,17]. The main difference between velocity/AccASL and the other methods is that these also label blood within the imaging slices, whereas PASL and pCASL label only blood inferior from the imaging slices in the neck region. A severe limitation of ASL is that the created magnetic label decays with the longitudinal relaxation time of the compartment in which it resides. For most of the time, this will be in the arterial blood (water can cross the capillary wall almost unrestricted, and some label will, therefore, end up in the extravascular tissue compartment). As the T1 of arterial blood is approximately 1.65 s, this implies that after 3 s only 16% of the created label survives. This points to the fundamental compromise that needs to be solved in ASL: for a correct quantitative measurement of cerebral blood flow, one should wait long enough for all label to have arrived in the brain tissue; however, by waiting too long all signal will have decayed, and no label will be detected. This is especially difficult when applying ASL-MRI in patients with cerebrovascular disease in whom collateral blood flow can lead to prolonged transport times for the label to arrive in the brain tissues [18]. When the magnetic label has not yet reached the brain tissue at the moment of imaging, an underestimation of cerebral blood flow will occur. Furthermore, the presence of label with the arterial vasculature might lead to vascular artefacts, which will lead to bright focal spots with intravascular signal. By acquiring a series of perfusion weighted images at increasing delay times after labeling it is possible to visualize the arrival of the labeled blood dynamically, allowing the estimation of the transit delay and correction for the underestimation of cerebral blood flow due to long transit times [8].
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The kinetics of the labeled blood bolus can also be used as an additional physiological parameter [7]. For instance, the arrival time and the duration needed for the end of the labeled bolus to reach the brain tissue can be calculated through hemodynamic modeling and allows the identification of the vascular borderzones (Fig. 1) [19]. A main drawback of ASL perfusion imaging at multiple delay times, however, is that it has a considerably longer acquisition time in comparison to a single inversion time ASL perfusion sequence. To speed up imaging, a small flip angle gradient echo sampling strategy can be used in a manner similar to the Look–Locker technique used for fast T1 mapping [20]. A drawback of this imaging strategy is that the train of radiofrequency pulses during the readout decreases the perfusion signal, especially for the later phases. As a result of this signal loss and the natural T1 decay of the magnetized blood, the remaining signal from the ASL label is small, resulting in low signal-tonoise and diminished spatial resolution.
Territorial perfusion imaging Both PASL, CASL and pCASL labeling methods can each be utilized to selectively label one or multiple arteries of the individual extracranial brain feeding arteries and visualize the perfusion territories of the individual arteries [21 ]. The techniques based on PASL and CASL typically are heavily dependent on &&
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user interactions to plan the labeling region defined angulation of the labeling slabs in order to enclose only the specific arteries of interest [21 ]. In a clinical setting, the most convenient approach might be planning-free vessel-encoded pCASL. This technique requires only limited planning as the labeling slice is being locked at a fixed position in relation to the acquisition volume, thus providing robust and reproducible results within a clinically feasible time frame of less than 5-min scan time [21 ,22]. There are also superselective methods that can label the individual intracranial arteries. These methods are derived from pCASL and CASL-labeling techniques and are based on a rotating gradient that restricts the inversion to a circular or elliptical labeling spot [21 ]. Although territorial perfusion imaging ASL methods are currently not routinely available, they may provide valuable patient-specific knowledge for clinical practice, both from an anatomical and from a functional point (directional flow) of view. There are large variations in the individual cerebral vasculature, of which the most prominent are those in the circle of Willis [23]. The circle of Willis is fed from the internal carotid arteries (ICAs) and the basilar artery and supplies the anterior carotid artery (ACA), middle carotid artery (MCA) and posterior carotid artery (PCA) cerebral arteries. Only 65% of the healthy population has a nonvariant type circle of Willis, in which the ACA and MCA are fed from their &&
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FIGURE 2. Seventy-two-year-old male patient with left-sided internal carotid artery stenosis of more than 50%. MR angiogram images of the circle of Willis (a). 2D phase-contrast images (b, c) show blood flowing from right-to-left in white and left-to-right in black (b), and flowing from anterior-to-posterior in white and posterior-to-anterior in black (c). Fluid attenuation inversion recovery MR images (d) from cranial (top) to caudal (bottom) correspond with ASL perfusion images before (h) and after (f) administration of acetazolamide, cerebrovascular reactivity images (g) and territorial ASL perfusion maps (e) of the right (red), left (green) carotid arteries and the basilar artery (blue). A two-sided fetal-type variant of the posterior cerebral artery (a, below star) is shown. Both carotid arteries feed their ipsilateral posterior cerebral artery via its posterior communicating artery (b and c, besides star). There are old infarct lesions with gliosis in the left hemisphere, most prominently occipital (d and e, arrows) and frontal (d and e, arrows), with reduced baseline perfusion (h) and reduced cerebrovascular reactivity. Part of the perfusion territory of the left anterior cerebral artery is shown to be fed from the right carotid artery (e, bottom arrow). ASL, arterial spin labeling; MR, magnetic resonance.
ipsilateral ICA, and both PCAs are fed from the basilar artery [23]. About 30% of the population has a fetal-type configuration in which the PCA is supplied via the posterior communicating artery from the ICA (Fig. 2) [23]. Furthermore, in about 5% of the population both ACAs are fed via the anterior communicating artery from one ICA [23]. These variants of the circle of Willis will directly influence the ability of collateral flow in the case of
carotid occlusion and can often be deduced from clues on the presence or absence of certain vessel segments [24]. Also distal to the circle of Willis, on a subcortical level, there is variability in vascularization. For instance in the deep gray matter, the caudate nucleus may be fed by the ipsilateral or contralateral ICA depending on the origin of the medial striate artery [25]. The thalamic region is supplied by
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Cerebrovascular disease
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FIGURE 3. ASL and dynamic susceptibility perfusion, diffusion and FLAIR images of a 48-year old woman presenting within 6 h after symptom onset. Restricted diffusion and increased time-to-peak times can be appreciated in the flow territory of left posterior circulation on the DWI and DSC images. The corresponding ASL image shows a corresponding decrease in perfusion. Reproduced with permission from [36 ]. ASL, arterial spin labeling; DSC, dynamic susceptibility contrast; DWI, diffusion-weighted imaging; FLAIR, fluid attenuated inversion recovery. &&
branches of both the ACA and the PCA, which in turn can entirely or partly be supplied by either or both the ICA and basilar artery depending on the configuration of the circle of Willis [26]. The high variability in the cerebral perfusion territories may further be complicated by the presence of stenoocclusive artery disease, in which the presence of adequate collateral pathways play an important role in the pathogenesis of stroke [18,27]. In the case of an ICA occlusion, information on whether the affected hemisphere is supplied by the contralateral ICA or basilar artery is invaluable considering these collateral vessels may be subject to disease as well. 46
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ISCHEMIC STROKE IMAGING In patients suspected of stroke, classification of the underlying pathophysiology is critical for defining short and long-term treatment options. In current practice, noncontrast computed tomography (CT) is used as a fast and efficient imaging modality to differentiate ischemic from hemorrhagic stroke. Recent studies have indicated that additional brain perfusion imaging can help to depict brain tissue with reduced cerebral blood flow and to identify tissue that has not yet been permanently damaged [28]. This is of particular interest in the acute stage of stroke as the combination of anatomical and Volume 27 Number 1 February 2014
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Perfusion imaging with ASL in cerebral ischemia Hartkamp et al.
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FIGURE 4. ASL and dynamic susceptibility perfusion, diffusion and FLAIR images of a 53-year old man presenting within 10 h after symptom onset. Restricted diffusion and increased time-to-peak times can be appreciated in the right basal ganglia on the DWI and DSC images. The perfusion deficit was, however, not depicted with ASL. Reproduced with permission from [36 ]. ASL, arterial spin labeling; DSC, dynamic susceptibility contrast; DWI, diffusion-weighted imaging; FLAIR, fluid attenuated inversion recovery. &&
perfusion imaging might help to identify patients with salvageable brain tissue that may benefit from reperfusion therapy [29,30].
Perfusion imaging Magnetic resonance perfusion imaging has been postulated as a viable alternative to CTP in acute clinical care. Without much extra time from door to needle it can provide critical information on the extent of penumbra [31]. Despite current debate on the exact definition of penumbra, the concept of perfusion–diffusion mismatch provides a practical
and fast measure of the tissue at risk that has not yet developed irreversible cell injury as detected by diffusion-weighted imaging [29,30,32]. Both DSC and ASL imaging can be used for perfusion magnetic resonance imaging. In DSCMRI, a gadolinium contrast agent is injected, and a time series of fast T2-weighted images is acquired. Cerebral blood flow, transit time and time to peak can be computed from these dynamic inflow images. There are, however, serious concerns regarding the safety of gadolinium chelates in patients with poor renal function, as it has been reported to induce nephrogenic systemic fibrosis [33,34].
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FIGURE 5. Sixty-eight-year-old male patient with right-sided internal carotid artery occlusion. Images are depicted identically to Figure 2. Absence of blood flow in the right ICA can be appreciated (a and c, star); however, blood flow in the middle cerebral artery is distinctly flowing (b and c, star) and is presumed to be fed from the anterior communicating artery. An old ischemic infarct is seen in the left hemisphere (d, arrow) with absent perfusion (h and f, arrow) and reactivity (g, arrow); the area is within the territory of the left carotid artery. Perfusion artefact due to low perfusion and delayed arrival (h, f and e, star) can be appreciated in the right hemisphere. ICA, internal carotid artery.
Gadolinium is, therefore, often contraindicated in patients with an estimated glomerular filtration rate less than 30 ml/min and in those on hemodialysis. When ASL was first introduced two decades ago, initial studies showed its ability to detect hypoperfusion in acute stroke [35]. Practically, the use was limited because of the long acquisition time and low resolution of perfusion images. Fast imaging is, however, now possible with the introduction of pCASL and background suppression (Fig. 3) [36 ]. Two recent large studies demonstrated that ASL is largely consistent with DSC for depicting brain regions with hypoperfusion. In the first study, by Bokkers et al. [36 ], 156 patients suspected of ischemic stroke were included, and ALS was found to be &&
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able to depict large perfusion deficits and perfusiondiffusion mismatches correlating with DSC. They found that small ischemic lesions were more difficult to detect as the contrast-to-noise of the ASL perfusion-weighted maps is relatively low in comparison to DSC, in which increased mean transit times are predominantly used for lesion detection. An example of such a lesion is shown in Fig. 4 [36 ]. The second study, by Zaharchuk et al. [37 ], with 1.5 Tesla MRI, showed in 51 patients that the perfusion–diffusion mismatch detected with ASL correlates qualitatively with DSC, but also that ASL tends to overestimate the perfusion deficit due to over-sensitivity for delayed inflow. ASL has, therefore, a high negative predictive value for excluding &&
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FIGURE 6. Sixty-nine-year-old female patient with a stenosis of the right vertebral artery distal to the origin of the right PICA. Images (a–g) are depicted identically to Figure 2. Territorial perfusion images (e) of the right (red) and left (green) ICA and right (blue) and left (yellow) vertebral arteries are superimposed. MR angiogram source images reveal the presence of the right PICA with its origin from the right vertebral artery (a, besides star). The right vertebral artery is shown to effectively end into the right PICA revealing its territory (e, arrow). The circle of Willis has a normal distribution of blood flow (b and c). FLAIR images show no recent ischemic lesion (d, arrow) in the cerebellum. There is, however, reduced baseline perfusion (h, arrow), which increases after a vasodilatory stimulus with acetazolamide (f, arrow), showing a high cerebrovascular reactivity (g, arrow). FLAIR, fluid attenuated inversion recovery; ICA, internal carotid artery; MR, magnetic resonance; PICA, posterior inferior cerebellar artery.
mismatch, but when mismatch is detected the area of mismatch may be overestimated. This demonstrates an important limitation of ASL. As images are acquired after a fixed time point following the labeling, delayed inflow due to collateralization may lead to an underestimation of cerebral perfusion and overestimation of the perfusion-deficit mismatch. Faster multidelay multiparametric ASL approaches, such as recently introduced by Wang et al. [38],may partially provide a solution for this problem as both cerebral blood flow
and delayed arrival of the contrast bolus can be measured.
EXTRACRANIAL LARGE ARTERY DISEASE Current guidelines for the treatment of carotid artery stenosis and occlusion are based primarily on large randomized clinical trials in which cerebral perfusion was not taken into account [39]. Observational studies suggest strongly, however, that the risk of (recurrent) ischemic stroke is higher in
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Cerebrovascular disease
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FIGURE 7. Forty-five-year-old patient with both right and left-sided distal internal carotid artery stenosis and moyamoya disease. MR angiogram MIP in the axial (a), sagittal (b) and coronal (c) plane show the typical abundance of tiny moyamoya collaterals. The baseline perfusion images show apparent symmetrical perfusion in both cerebral hemispheres (h, star); although after a vasodilatory challenge there is no increase in perfusion in the right hemisphere (f, star) and generally reduced cerebrovascular reactivity (g, star). In the cerebellum, there is notable asymmetry in baseline perfusion against the left hemisphere (h, arrow). After the vasodilatory challenge, however, there is adequate increase in perfusion (f, arrow) and entirely symmetrical cerebrovascular reactivity is shown in the cerebellum (g, arrow). The affected right cerebral hemisphere and left cerebellar hemisphere is an example of crossed-cerebellar diaschisis. MIP, maximum intensity projection; MR, magnetic resonance.
patients with impaired cerebral perfusion in the hemisphere ipsilateral to a symptomatic or asymptomatic carotid stenosis than in those with normal perfusion [40,41]. The effect of extracranial–intracranial bypass surgery compared with best medical therapy was investigated in the Carotid Occlusion Surgery Study in patients with a hemodynamically compromised ICA occlusion as assessed with PET [42]. Despite excellent bypass graft patency and improved cerebral hemodynamics, patients did not, however, 50
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benefit from an extracranial-to-intracranial bypass, mainly because the surgical complication rates were too high. Assessment of cerebral autoregulation may prove to be important in large artery obstruction for the management of hypertension, as lowering the blood pressure may be dangerous in hemodynamically impaired areas. Studies with ASL have focused on detecting brain tissue with decreased perfusion, delayed arrival of the arterial blood bolus and assessment of collateral blood flow [43,44]. In patients with an Volume 27 Number 1 February 2014
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Perfusion imaging with ASL in cerebral ischemia Hartkamp et al.
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FIGURE 8. Forty-four-year-old patient with left-sided internal carotid artery occlusion and moyamoya disease. MR angiogram maximum intensity projections in the axial (a), sagittal (b) and coronal (c) plane show the typical abundance of tiny moyamoya collaterals. Images (d–e) are depicted identically to Figure 2. A recent ischemic infarct can be seen in the left hemisphere (d, star) with reduced baseline perfusion (h, star), and no increase in perfusion after a vasodilatory challenge with acetazolamide (f, star). There is generally low cerebrovascular reactivity against the left hemisphere (g, star). The perfusion territory of the left middle cerebral artery is fed from the right carotid artery (e, star). MR, magnetic resonance.
ICA occlusion, ASL can depict the presence and extent of regions with hypoperfusion comparable to PET [45,46]. By combining the unique ability of repeatable perfusion measurements with a vasodilatory challenge, studies have investigated autoregulatory impairment, both in patients with a stenosis and those with an occlusion [9,10,47]. As impairment of autoregulation is considered the first stage of hemodynamic compromise, in which cerebral perfusion is largely maintained through maximal vasodilatation of small arteries and arterioles, it may be potentially a sensitive tool for assessing the risk for developing ischemic stroke at brain tissue level [40].
Using perfusion-territory selective labeling techniques, ASL has also been used to provide information on shifts in the perfusion territories of the brain feeding arteries. When there is an obstructive lesion in one of the brain feeding arteries, collateral blood flow will be recruited through either the circle of Willis or secondary collaterals, such as the ophthalmic artery or leptomeningeal vessels, to sustain adequate oxygenation [18]. Studies indicate that hemodynamic and metabolic changes are more severe in patients with than in patients without primary collaterals and that the presence of secondary collateral flow is associated with an impaired hemodynamic status [48–50]. An example of a
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Cerebrovascular disease
patient with a decreased autoregulatory reserve due to an ICA occlusion and inadequate collateralization through the anterior communicating artery is shown in Fig. 5. As shown in Fig. 6, this method can also be used to identify those patients that have decreased perfusion, but intact autoregulatory reserve due to adequate collateralization. This is in agreement with other studies that have used either transcranial Doppler to measure cerebrovascular reactivity in the intracranial arteries, or techniques such as PET and SPECT to measure cerebrovascular reactivity at the brain tissue level [51–54]. Diaschisis is another important hemodynamic change that may occur in patients with a large artery disease and areas with hemodynamic compromise. This phenomenon is caused by the loss of function on a distant but anatomically connected brain region [55]. Figure 7 shows an example of crossedcerebellar diaschisis due to deafferentation as a result of contralateral supratentorial disease in a 45-year-old patient with both right and left-sided distal internal carotid artery stenosis and moyamoya disease.
INTRACRANIAL ARTERIOPATHY Intracranial cerebral arteriopathies are a heterogeneous group of diseases that can be divided into large and small-vessel arteriopathies. Intracranial large-vessel arteriopathy is usually caused by atherosclerosis and in a small minority by inflammatory changes such as moyamoya disease. Moyamoya vasculopathy is characterized by an intracranial arteriopathy leading to progressive bilateral narrowing of the supraclinoid ICA and its branches. It leads to the formation of a vascular network of moyamoya vessels at the base of the brain. The majority of patients are children and young adults, presenting with symptoms of cerebral ischemia, seizures, cognitive deterioration and hemorrhagic stroke. Diagnosis is currently based on cerebral angiography. There is, however, a discrepancy between clinical symptoms and the angiographic severity. Perfusion and cerebrovascular reactivity measurements have been shown to identify those patients that may benefit from surgical revascularization [56,57]. Figure 8 shows an example of a patient with an ICA occlusion due to moyamoya disease. Despite extensive collateralization, a decreased autoregulatory reserve can be appreciated in the most affected hemisphere. The occurrence of prolonged arterial transit time artefacts due to obstruction of vessels or extensive collateralization is a severe limitation of ASL. In the case of a perfusion lesion, a careful consideration must be made whether the cause is hypoperfusion of 52
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the tissue or indeed an artefact due to prolonged transit time. The presence of these artefacts in certain locations in the brain may also offer additional hemodynamic information in patients who are suspected of having cerebrovascular disease known for extensive collateral formation [58]. Zaharchuk et al. [59] recently reported arterial transit time artefacts as an indicator of the presence and intensity of collateral flow.
CONCLUSION Over the last decade, there have been key improvements in ASL techniques which have made it a viable alternative to more established techniques such as DSC-MRI and CT perfusion imaging. Research is still ongoing to establish its value in clinical practice for diagnosing ischemic stroke and to determine whether perfusion imaging can help target revascularization therapy in patients with atherosclerotic large-vessel disease. As the use of ionizing radiation required for CT increases the risk of tumor induction and contrast agents can cause nephropathy and nephrogenic systemic fibrosis, ASL-MRI may prove to be a powerful noninvasive alternative. Perfusion and cerebral reactivity imaging with ASL can help assess the extent of hemodynamic compromise and may potentially be used to customize medicinal and surgical treatment. Acknowledgements N.S.H. receives support from the Dutch Heart Foundation (Grant 2010B274). M.J.P. van O. receives support from the Dutch Technology Foundation STW, Applied Science division of NWO and the Technology Program of the Ministry of Economic Affairs. R.P.H.B. receives support from the Dutch Heart Foundation (Grant 2013T047). Conflicts of interest There are no conflicts of interest.
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