High-Resolution MR Imaging of the Cervical Arterial Wall: What the Radiologist Needs to Know 1

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1 Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at EDUCATION EXHIBIT High-Resolution MR Imaging of the Cervical Arterial Wall: What the Radiologist Needs to Know TEACHING POINTS See last page Catherine Oppenheim, MD, PhD Olivier Naggara, MD Emmanuel Touzé, MD, PhD Jean-Christophe Lacour, MD Emmanuelle Schmitt, MD Fabrice Bonneville, MD, PhD Sophie Crozier, MD Evelyne Guégan-Massardier, MD Emmanuel Gerardin, MD, PhD Xavier Leclerc, MD, PhD Jean-Philippe Neau, MD Marc Sirol, MD, PhD Jean-François Toussaint, MD, PhD Jean-Louis Mas, MD Jean-François Méder, MD, PhD The emergence of high-resolution rapid imaging methods has enabled magnetic resonance (MR) imagers to noninvasively image the fine internal structure of cervical arterial walls. In this article, a comprehensive guide to performing high-resolution MR imaging of cervical arteries is provided, including the choice of coils, sequences, and imaging parameters, as well as tips for optimal image quality. Explanations and illustrations are given of using high-resolution MR imaging to quantify plaque volume, determine atherosclerotic plaque burden, depict plaque composition, and ultimately identify unstable plaque before it leads to a clinical event. Finally, the role of high-resolution MR imaging in the diagnosis of cervical dissection and inflammatory disease of the arterial wall is emphasized. RSNA, 2009 radiographics.rsna.org Abbreviations: IR = inversion-recovery, PD = proton density, TOF = time-of-flight, USPIO = ultrasmall superparamagnetic iron oxide RadioGraphics 2009; 29: Published online /rg Content Codes: 1 From the Departments of Imaging (C.O., O.N., J.F.M.) and Neurology (E.T., J.L.M.), Université Paris Descartes, EA 4055, Centre Hospitalier Sainte-Anne, 1, Rue Cabanis, Paris Cedex 14, France; Departments of Imaging (E.S.) and Neurology (J.C.L.), CHU de Nancy, Nancy, France; Departments of Imaging (F.B.) and Neurology (S.C.), GH Pitié-Salpêtrière, Paris CHRU de Lille, Lille, France; Departments of Imaging (E.G.) and Neurology (E.G.M.), Hôpital Charles Nicolle, Rouen, France; Department of Imaging, Hôpital Roger Salengro, CHRU de Lille, Lille, France (X.L.); Department of Neurology, Hôpital Jean Bernard, Poitiers, France (J.P.N.); Department of Cardiology, Hôpital Lariboisière, Paris, France (M.S.); and Center for Imaging and Functional Explorations, Hôtel-Dieu, Paris, France (J.F.T.). Presented as an education exhibit at the 2007 RSNA Annual Meeting. Received July 24, 2008; revision requested September 9; final revision received May 29, 2009; accepted June 4. Study supported by a grant from the Programme Hospitalier de Recherche Clinique of the French Ministry of Health (No. AOR ). All authors have no financial relationships to disclose. Address correspondence to C.O. ( c.oppenheim@ch-sainte-anne.fr). RSNA, 2009

2 1414 September-October 2009 radiographics.rsna.org Teaching Point Introduction Magnetic resonance (MR) imaging is an attractive tool for the assessment of carotid and vertebral artery diseases. It allows imaging of the arterial lumen by using MR angiography; and at the same time, by using dedicated surface radiofrequency coils, it provides high-resolution images of the arterial wall in vivo. Optimal image quality relies on correct preparation of the patient, adequate coil positioning, and the use of pulse sequences with signal suppression of the flowing blood. High-resolution MR imaging has initially been applied for the in vivo analysis of carotid atherosclerosis. Solid evidence now exists that high-resolution MR imaging can be used to identify the major components of atherosclerotic plaque, that is, the lipid core, mural hemorrhage, calcifications, and the fibrous cap (1). This identification enables one to differentiate between stable and unstable atherosclerotic plaques by using high-resolution MR imaging (2). Beyond atherosclerosis, high-resolution MR imaging can be used in the case of suspicion of cervical artery dissection, providing excellent depiction of the cervical arterial mural hematoma in both carotid and vertebral arteries (3,4). High-resolution MR imaging can also be used to image other rare arterial diseases, such as inflammatory diseases, for diagnostic purposes or to improve our understanding of their physiopathology (5). The aim of this article is to (a) present a comprehensive guide to performing high-resolution MR imaging of cervical arteries, (b) explain how to differentiate between stable and unstable atherosclerotic plaques on high-resolution MR images, and (c) provide an overview of the MR imaging patterns associated with various diseases of the cervical arterial wall. How to Image the Arterial Wall The aim of MR imaging of the arterial wall of cervical arteries is to obtain in-plane submillimeter voxels. The decrease in the signal-to-noise ratio induced by reducing the voxel size (500 µm Figure 1. Photograph of phased-array surface coil for carotid wall imaging. The coils are positioned bilaterally around the neck, allowing the imaging of both sides simultaneously. (Reprinted, with permission, from reference 6.) 500 µm 2 3 mm) is compensated for by the use of phased-array surface coils, which increases the signal-to-noise ratio by 40%. The so-called high-resolution MR imaging corresponds to images with submillimeter voxels that imply the use of dedicated surface coils. Such coils are commercially available (Machnet, Eelde, the Netherlands; and are compatible with most MR manufacturers equipment. The coils consist of a pair of multichannel coils that collect data simultaneously over a 10-cm height. The coils, which are made of flexible material, are placed bilaterally around the neck (Fig 1) (6). Because the carotid arteries are superficial structures, they are well suited for surface coil imaging. Image Quality The preparation of the patient is one of the keys to obtaining good-quality images. The patient has to be aware that the MR imaging examination might last 30 minutes and that swallowing is the worst enemy of image quality (7) (Fig 2). To prevent head movement and improve patient comfort, a custom-made or a commercially available head holder is used to provide support for the occiput and the head.

3 RG Volume 29 Number 5 Oppenheim et al 1415 Figure 2. Image quality. (a) Considering the limited height coverage of the neck coils (<3 cm), it is important to precisely locate the qualifying stenosis on the MR angiographic image (at left) before performing the high-resolution MR examination. Black-blood MR image (at right) corresponds to black-blood native axial sections acquired in the axial plane, reformatted along the axis of the carotid artery. (b) Axial T1-weighted black-blood MR image shows swallowing artifacts. (c) Axial fat-suppressed PD-weighted MR image shows that an erroneous positioning of the coil (too posterior) results in a decrease in signal-to-noise ratio. (d) Axial fat-suppressed PD-weighted MR image obtained after coil repositioning for the same patient as in c shows that repositioning the coil improves the signal-tonoise ratio. (Adapted and reprinted, with permission, from reference 6.) The next step is the coil positioning. The carotid bifurcation should be searched for, either manually or by using ultrasonography (US). A mark on the skin can be placed at the level of the carotid bifurcation to guide the placement of the coils. On the MR imaging scout view, the operator must check that the superficial brightness induced by the coils is at the level of the carotid stenosis. If not, the coil must be repositioned to improve the signal-to-noise ratio (Fig 2). Image quality also depends on the shape of the neck, being best for those patients with a longilineal neck. Similarly, obtaining optimal images can be difficult when the carotid artery is deeply located or when it bifurcates at the C2 vertebral level. In such a case, the radiologist should ensure that the coil is at the level of the carotid bifurcation and should increase the number of signals acquired to compensate for the decrease of the signal-tonoise ratio. Investigators of multicenter studies have reported rates of 85% (2) to 95% (8) for interpretable MR imaging examinations, but these rates are likely overestimated compared with the

4 1416 September-October 2009 radiographics.rsna.org Figure 3. High-resolution black-blood PD-weighted MR images obtained from three different patients on MR imaging units from three different manufacturers. By using dedicated surface coils, similar image quality (for black-blood PD-weighted sequences) can be obtained with 1.5-T MR units from different manufacturers: Siemens (a), Philips (b), and General Electric (c). rate for interpretable MR imaging examinations performed in a clinical setting. Finally, for a given magnetic field when using the same surface coil, image quality seems stable across different manufacturers platforms (C.O., E.T., unpublished data, 2007) (Fig 3). This suggests that multicenter studies can be conducted without taking major interplatform variability into account. Teaching Point Pulse Sequences The MR imaging protocol comprises multiple pulse sequences in the axial plane, covering about 3 cm in height (Fig 2). Consequently, the sections must be focused on the index artery. This can be done either (a) with a two-dimensional time-of-flight (TOF) or phase-contrast MR angiographic scout view to find the coordinates of the stenosis or (b) by placing the sections graphically. The current recommendation is to combine MR images obtained with multiple MR pulse sequences in order to fully characterize plaque morphology and composition (1). Pulse sequences designed for vascular imaging are classified as bright blood or black blood, depending on the signal of flowing blood. Both of these Figure 4. Diagram of double-ir pulse sequence. The aim is to cancel the signal of flowing blood to improve the contrast between the lumen (in red at left and in black at right) and the arterial wall. The first nonselective IR pulse inverts the magnetization of the entire body, including the blood. The second IR pulse, which is section selective, is immediately applied and re-inverts the imaging section (shown in yellow). The magnetization from outside the imaging section, notably that of the blood, is inverted, and magnetization within the section is unchanged. A rapid spin-echo sequence is used after a delay time in which the blood that was originally in the imaging section which was re-inverted flows out of the imaging section, and the inverted blood becomes null (shown in black) and flows into the imaging section. (Adapted and reprinted, with permission, from reference 6.)

5 RG Volume 29 Number 5 Oppenheim et al 1417 Figure 5. Diagram of a cardiac-gated black-blood sequence with double IR shows cardiac synchronization (red line), signal (yellow line), and radiofrequency pulses (green line). The preparation (double IR) takes place during diastole. The rapid spin-echo acquisition starts after the inversion time, when the vessel s motions are minimal (diastole). (Adapted and reprinted, with permission, from reference 6.) types of sequences provide good contrast between the lumen and the arterial wall (Fig 3). Black-Blood Sequences. The aim is to cancel the signal of the flowing blood so as to increase the contrast between the lumen (depicted as black) and the wall. For that reason, the acquisition rate is synchronized to the heart beat and is preceded by a double inversion-recovery (IR) magnetization preparation pulse (Fig 4). This double IR ensures that the signal from flowing blood is adequately suppressed (9). The first nonselective IR pulse inverts the magnetization of the entire body, including the blood. The second section-selective IR pulse re-inverts the magnetization in the imaging section. As a result, the magnetization from outside the imaging section (including that of the blood) is inverted, and magnetization within the section is unchanged. After a time lapse, during which the re-inverted blood originally in the imaging section flows out of this section and the inverted blood becomes null and flows into the imaging section, a standard rapid spin-echo sequence is performed. The double flow-ir pulse is placed before the period of fast flow, and data acquisition occurs during the period of slow flow (Figs 4, 5). This process maximizes flow suppression that is due to outflow and minimizes artifacts that are due to vessel motion. The inversion time for the double-ir preparatory pulse is fixed as close to the null point of the blood signal as possible. The double-ir preparation and rapid spinecho acquisition are typically repeated by using cardiac gating at two times the R-R interval (2 RR) until all of the rapid spin-echo images are acquired (Fig 5). A black-blood sequence can be T2 or proton density (PD) weighted (2 RR), or T1 weighted (1 RR). By applying the double- IR preparation just after the cardiac trigger, the section-selective re-inversion pulse is placed in the end-diastolic part of the cardiac cycle. Because the inversion time is usually close to 650 msec, the rapid spin-echo acquisition is also played out during diastole (Fig 5). A third inversion pulse can be added for fat suppression. Bright-Blood Sequence. The bright-blood sequence corresponds to three-dimensional TOF gradient-echo sequences used for MR angiography. With this sequence, the signal of flowing blood is enhanced, and the lumen is brighter than the vessel s wall. The lack of a 180 refocusing pulse creates T2* sensitive signal. Consequently, this sequence is best suited for the depiction of calcifications. It is a mix of T1 and PD weighting. MR Imaging Protocol Several principles should be followed when designing an MR protocol for imaging the cervical arterial wall: (a) acquire an oblique scout view (three-dimensional phase contrast, two-dimensional TOF, 1 minute) of the entire index artery so as to visualize the plaque distribution and the level of the carotid bifurcation; (b) acquire highresolution images (voxel = 500 µm 500 µm in plane or 250 µm 250 µm after zero filling interpolation); (c) use multiple pulse sequences, by combining black- and bright-blood sequences, to identify the different plaque components (see subsequent sections about assessment of plaque components); and (d) keep the total acquisition

6 1418 September-October 2009 radiographics.rsna.org Table 1 Example of a Set of Imaging Parameters for 1.5-T High-Resolution MR Imaging of Plaque by Using Dedicated Surface Coils Parameter 3D TOF T1-weighted Black Blood* PD-weighted Black Blood* T2-weighted Black Blood* TR (msec) 30 1 RR 2 RR 2 RR TE (msec) FOV (mm) Section thickness (mm) Matrix Number of signals acquired Synchronization NA Cardiac Cardiac Cardiac Number of sections Scan time (min) Note. Adapted and reprinted, with permission, from reference 6. NA = not applicable, RR = R-R interval, 3D = three-dimensional. *Black-blood sequence with double-ir preparation pulse. In-plane resolution after zero filling interpolation: µm. Reported scan times are based on a heart rate of 70 beats per minute. Times shorten with faster rates. time less than 30 minutes. Table 1 provides an example of a set of imaging parameters that can be used at 1.5-T imaging. Imaging at 3 T Although most of the plaque studies have been performed on 1.5-T MR units, 3-T units are now more widely available. Surface coils for carotid imaging are commercially available for 3-T MR units. These coils are slightly different from those used with 1.5-T units (tuned to a different frequency and adapted to the 3-T connectors and/or interfacing). The coils provide marked improvement in signal-to-noise and contrastto-noise ratios (10), allowing reduction in both the acquisition time and the in-plane resolution. For a given acquisition time, thinner sections or larger anatomic coverage in the z-axis can be obtained (11,12). At 3 T, longer repetition times are advised for PD- and T2-weighted images to avoid unwanted T1 weighting (13). Such adjustment is not necessary for T1-weighted and three-dimensional TOF images because the enhancement of T1 contrast at 3 T is beneficial to these images. Double-IR blood-suppression techniques are available at 3 T, but they require an adjustment of the inversion time for the blood T1 at 3 T (ie, slightly longer inversion time for 3 T compared with that used for 1.5 T) (10). Figure 6. Schematic diagram (at right) shows the atherosclerotic plaque components of a moderate carotid stenosis seen on the MR angiographic image (at left) obtained after administration of gadoterate meglumine (Dotarem; Guerbet, Roissy, France). According to a recent article, there is a strong agreement between 3- and 1.5-T high-resolution MR imaging of carotid plaques, both in quantitative measures of plaque morphology and in the identification of plaque composition, including calcification, lipid core, and hemorrhage (13). This agreement supports the translation of histologically validated 1.5-T criteria to 3-T carotid

7 RG Volume 29 Number 5 Oppenheim et al 1419 Table 2 Signal Intensity of Carotid Plaque Components at 1.5-T High-Resolution MR Imaging with Various Pulse Sequences Plaque Component 3D TOF Sequence T1-weighted Sequence PD-weighted Sequence T2-weighted Sequence Hypointense Isointense/hyperintense Lipid core Isointense Isointense/hyperintense Isointense/hyperintense Fibrous tissue Isointense Isointense/hyperintensintense Isointense/hyper- Hemorrhage Fresh (<1 wk) Hyperintense Hyperintense Isointense/hypointense Isointense/hypointense Recent (1 6 wk) Hyperintense Hyperintense Hyperintense Hyperintense Calcification Markedly hypointense Markedly hypointense Note. Signal intensity is compared with that of adjacent muscles. Markedly hypointense Markedly hypointense in serial prospective trials should be imaged at the same field strength to minimize interstudy errors during analysis of plaque composition. Figure 7. Four main components of atherosclerotic plaque. Axial MR images obtained with four pulse sequences show that the calcifications have low signal intensity with all four sequences. Recent hemorrhage demonstrates high signal intensity with all four sequences. The lipid core corresponds to an area that shows a decrease in signal intensity from PD- to T2- weighted images in areas without calcifications or hemorrhage. The remaining part of the plaque corresponds to the fibrous component. (Adapted and reprinted, with permission, from reference 6.) images. However, there are differences in the measured size of particular components between 1.5- and 3-T images. Hemorrhage measures larger at 1.5 T, while calcifications measure larger at 3 T because of prominent susceptibility effects. No significant differences in the size of the lipid core without hemorrhage were reported (13). These observations suggest that patients enrolled Atherosclerotic Plaque Because high-resolution MR imaging can be used to provide images of the fine internal structure of the atherosclerotic arterial wall, clinicians and radiologists see this technique as an opportunity to assess disease severity according to the characteristics of atherosclerotic lesions themselves, rather than according to their indirect effects on the vessel lumen. MR imaging of atherosclerosis could be used in medical treatment decisions or to assess the effects of treatment options. A number of research groups have shown that such imaging can be used to depict the atherosclerotic plaque burden, to depict and quantify key plaque components, and, ultimately, to identify vulnerable plaque before it leads to a clinical event. Plaque Components As shown in Figure 6, a typical atherosclerotic plaque contains several components, including a fibrous cap separating the lumen from the wall. This fibrous cap may be intact, thin, or ruptured. The atherosclerotic plaque can also contain calcifications, a necrotic lipid core, hemorrhagic areas, and a fibrous component. The MR signal intensity of these components has been described on 1.5-T MR images (Table 2) (Fig 7) and, more recently, on 3-T images (13).

8 1420 September-October 2009 radiographics.rsna.org Figure 8. Calcifications on MR and computed tomographic (CT) images of two different patients. * indicates lumen of the artery. (a) Axial MR image (native TOF section) and axial CT angiographic image both show juxtaluminal and adventitial calcifications. (b) Axial T1-weighted MR image and axial CT angiographic image show calcification (arrow). Figure 9. Unstable plaque in a patient with recurrent ischemic strokes ipsilateral to the carotid plaque. MR angiographic image and axial diffusion-weighted MR image of brain (large panel at right) show moderate stenosis with ulceration; inset shows similar images obtained 1 year earlier. Axial high-resolution T2- and T1-weighted MR images obtained at two levels (levels A and B) show that the plaque is hyperintense on T1-weighted and TOF images (A), and therefore hemorrhagic, and is without calcifications but with an ulceration (arrow in B). The carotid plaque is likely to be symptomatic, given that (a) recurrent strokes occurred ipsilateral to the carotid plaque; (b) its morphology changed during the year after the initial MR imaging; (c) the MR characteristics (hemorrhage, ulceration) corresponded to unstable plaques; and (d) the findings from the remaining etiologic work-up were normal. The patient underwent carotid surgery and has been free of new ischemic events during the 2 years since treatment. (Adapted and reprinted, with permission, from reference 6.)

9 RG Volume 29 Number 5 Oppenheim et al 1421 Figure 10. Complex plaque. Axial diffusion-weighted MR image of the brain (top right) and MR angiographic image (bottom right) show high-grade carotid stenosis with ipsilateral recent ischemic event. Axial MR images obtained with four pulse sequences show that the plaque contains four components. A large recent hemorrhage (arrowhead) is hyperintense on T1-weighted and TOF MR images, a small lipid core shows loss of signal intensity between PD- and T2-weighted MR images, and calcifications (arrows) are hypointense with all sequences. The remaining part of the plaque is considered fibrous. Teaching Point Calcifications. The calcifications are composed of calcium hydroxyapatite. Because of their low PD and susceptibility effects, these calcifications are hypointense with all pulse sequences. Calcifications may be adjacent to the lumen or may cover the entire wall in the case of macrocalcifications (Fig 8). Intraplaque Hemorrhage. The signal of intraplaque hemorrhage depends on the structure of the hemoglobin and its oxidative state. The signal of intraplaque hemorrhage is more complex than that of cerebral hematoma because the blood mixes up with the other components of atherosclerosis. It is, however, possible to identify recent and fresh intraplaque hemorrhage. Recent intraplaque hemorrhage (1 6 weeks), which corresponds to extracellular methemoglobin, is hyperintense with all four sequences, notably with native TOF and T1-weighted sequences (14 16) (Figs 9, 10). Fresh hemorrhage (<1 week) corresponds to early subacute cerebral hemorrhage (intracellular methemoglobin) and appears hyperintense on T1-weighted and TOF images and isointense or hypointense on T2- and PD-weighted images. At the chronic stage (>6 weeks), the signal intensity decreases with all four sequences. Recent and fresh hemorrhage can be reliably identified by using high-resolution MR imaging, as shown by histologic validation studies: A high-signal-intensity area within the plaque around the carotid artery on TOF images, compared with histopathologic findings, demonstrates a sensitivity of 91% and a specificity of 83% in the depiction of an intraplaque hemorrhage (16). Similarly, using a T1-weighted sequence, another group reported excellent agreement for the distinction between fresh and recent hemorrhage on histologic and MR imaging findings (17).

10 1422 September-October 2009 radiographics.rsna.org Figure 11. Comparison of histopathologic and MR images in an animal model. (a c) Highresolution in vivo MR images of a rabbit artery, including T1-weighted (a), PD-weighted (b), and T2-weighted (c) images, were used to characterize the plaque. Two different areas of the atherosclerotic plaque are seen: fibrous cap (arrow in a) on the T1-weighted image and large lipid core (arrow in c) on the T2-weighted image. (d) Photomicrograph (original magnification, 4; combined Masson-elastic trichrome stain) of the histopathologic section of the artery, corresponding to that seen in the MR images, shows the atherosclerotic plaque. Ad = adventitia, FC = fibrous cap, L = lumen, LC = lipid core. Lipid Core. The predominant lipids are cholesterol and ester of cholesterol. Because the lipid core does not contain triglycerides, it is not suppressed with fat-suppression techniques, which are often coupled with black-blood techniques. The lipid core has a short T2 (18), which is due to the micellar structure of the lipoproteins, their destruction by oxidation, and exchanges between ester of cholesterol and water. The lipid core, which has intermediate signal intensity on PD-weighted images that decreases on T2-weighted images (6,18), corresponds to an area with a decrease in signal intensity between PD- and T2-weighted images (Figs 7, 10). In 2001, Yuan et al (1) were the first to report a high sensitivity (87%) and specificity (92%) of multisequence ( multispectral ) MR imaging (ie, comparison of four matched MR images: T1-, T2-, and PD-weighted and threedimensional TOF images) for the identification of the lipid core. Since then, several studies have confirmed the ability to use high-resolution MR imaging to identify the lipid core on the basis of the decrease in the lipid transverse relaxation time (T2) (19) (Figs 11, 12). Fibrous Component. The fibrous component corresponds to an extracellular matrix, which modifies the water-protein interactions and reduces the T1. This results in a moderate T1 hyperintensity. The fibrous component is described as an area of isointensity or moderate hyperintensity relative to the adjacent muscles on T1-, T2-, and PD-weighted images, with an isointense area on native TOF sections (Figs 7, 10). Qualitative MR imaging Assessment of the Plaque Components For the qualitative identification of these components, the following reading scheme can be proposed (8): (a) search for calcifications (ie, loss of signal intensity with all four sequences); (b) search for recent hemorrhage (ie, hyperintensity with all sequences); (c) search for a lipid core (ie, focal decrease in signal intensity from PD- to T2-weighted images) in areas without calcifications or hemorrhage; and (d) assign a fibrous component to the remaining areas. As indicated on Figure 7, a T1 hyperintensity corresponds to lipid core, fibrous component, or recent hemorrhage. The native TOF sections allow one to distinguish among these three components (1): The hyperintensity is no longer seen on TOF images for lipid core and, conversely, persists on T1-weighted images in the case of recent hemorrhage. Similarly, a focal decrease in signal intensity from PD- to T2-weighted images is observed for lipid core but not for fibrous components (20) (Fig 7). By using high-resolution MR imaging, it is possible to classify atherosclerotic plaques into categories defined by the American Heart Association, which have been recently adapted for MR imaging (21). The modified American Heart Association criteria are as follows: (a) type I-II corresponds to near-normal wall thickness without calcification; the combination of type I and II is due to the impossibility of using high-resolution MR imaging to differentiate discrete foam cells in type I from multiple foam cell layers of the fatty streaks in type II; (b) type III corresponds to diffuse wall thickening or small eccentric plaque without calcification; (c) type IV-V corresponds

11 RG Volume 29 Number 5 Oppenheim et al 1423 Figure 12. Comparison of T2-weighted MR image of a human carotid artery with corresponding histopathologic section. (a) Axial high-resolution black-blood T2-weighted MR image of the right carotid artery obtained at 1.5 T in a 68-year-old patient with a history of previous stroke allows depiction of the lipid core (orange arrow) within atherosclerotic plaque and the intact thick fibrous cap (yellow arrow). (b) Photomicrograph (original magnification, 2.5; hematoxylin-eosin stain) shows rupture of the intact and thick fibrous cap (FC) that occurred during histologic preparation, with part of the lipid core (LC) extruding into the lumen. to a plaque with a lipid-rich necrotic core surrounded by fibrous tissue with possible calcification; this latter combination is due to the inability to use high-resolution MR imaging to distinguish between the proteoglycan composition of the type IV cap and the dense collagen of the type V cap; (d) type VI is complex plaque with a possible surface defect, hemorrhage, or thrombus; (e) type VII is calcified plaque; and (f) type VIII is fibrotic plaque without a lipid core and with possible small calcifications. This high-resolution MR imaging classification shows good agreement with the American Heart Association classification of histologic specimens in both animal models (22) and human plaque (21). However, moderate interreader agreement between type I-II and III lesions has been reported (23). Quantitative Assessment of the Plaque Components The first step toward quantification of plaque morphology is delineation of the inner and outer boundaries of the vessel wall. A number of segmentation approaches, from manual outlining (8) to edge-based or model-based segmentations, have been proposed. Manual outlining offers high interobserver reproducibility for quantitative measurements of vessel, lumen, plaque, lipid core, and fibrous components, with intraclass correlation coefficients ranging from 0.73 to 0.99 (8). Automatic segmentation of the plaque is increasingly used and allows reproducible volume measurements of the plaque (24 26). Automatic identification of the plaque components is the focus of active research (24,26), as an alternative to the time-consuming manual outlining. To date, however, none of the commercially available software has been validated in the human clinical setting for the automatic depiction of plaque components. Fibrous Cap The fibrous cap can be depicted with a 1.5-T MR unit. According to Yuan et al (27), threedimensional TOF native sections, based on a gradient-echo sequence with a low flip angle, show the hyperintense lumen, the soft tissue, and the fibrous cap. Hypothesizing that the layered nature of the fibrous cap was responsible for the relative decrease in signal intensity on the threedimensional TOF native section, Hatsukami et al (28) were able to characterize the state of the fibrous cap as being (a) intact and thick, (b) intact and thin, or (c) ruptured. An intact and thick cap corresponds to a hypointense rim between the lumen and the plaque burden. The cap is considered as intact and thin when this hypointensity

12 1424 September-October 2009 radiographics.rsna.org Figure 13. Characterization of the fibrous cap with three-dimensional TOF MR imaging. On native axial three-dimensional TOF MR images, an intact and thick cap corresponds to a continuous hypointense rim (thin arrow) between the lumen (*) and the plaque burden. The cap is considered as intact and thin when this hypointensity is lacking, and the cap is considered ruptured when the dark band is absent, with an ulceration (thick arrow). Figure 14. Ruptured fibrous cap in a patient with moderate stenosis of the right internal carotid artery associated with recurrent ipsilateral ischemic stroke. (a) MR angiographic image shows moderate stenosis. Brain diffusion-weighted MR image (inset) shows a hyperintense acute (black *) and a hypointense chronic (white *) ischemic stroke, ipsilateral to the carotid plaque. (b) Axial high-resolution PDweighted MR image of the internal carotid artery shows a ruptured fibrous cap (white arrow). On TOF MR image, the dark band between the lumen and the plaque is not depicted, and the lumen boundary is slightly irregular (black arrow). Images at bottom are magnified views of the boxed area in the top image. is lacking; and the cap is considered as ruptured when the dark band is absent and, instead, a hyperintense region is seen adjacent to the lumen (Fig 13). This hyperintense region corresponds to an intraplaque hemorrhage or a fresh luminal thrombus (27). The fibrous cap can also be seen on T2-weighted images and with short inversion time inversion-recovery (STIR) sequences as a hyperintensity located between the dark lumen and the plaque (29,30). In this case, the cap rupture corresponds to a loss of the periluminal hyperintensity on T2-weighted images (Fig 14). Compared with histologic findings, the preoperative MR imaging appearance of the fibrous cap has a high test sensitivity (0.81) and specificity (0.90) for identifying an unstable cap in vivo (31). However, the analysis of the state of the fibrous cap is not straightforward (8). Some plaque components produce misleading images: Juxtaluminal calcifications that induce a decrease in signal intensity on T2-weighted images may be confounded with the dark lumen and mimic cap rupture on T2-weighted images or may be misinterpreted as thick intact cap on TOF images. Old hemorrhage, containing hemosiderin, can be hard to distinguish from the cap. The availability of different pulse sequences facilitates image interpretation when intimal calcifications or flow artifacts obscure the inner arterial lining (31). Recently, it has been shown that the fibrous cap enhances more than the lipid core. For that reason, the use of a gadolinium-based contrast agent may also enhance the differences between various plaque components (Fig 15). Interestingly, reader reproducibility for the quantification of lipid core size is improved by the administration of a gadolinium-based contrast agent (32). Stable and Unstable Plaques The degree of luminal stenosis is the traditional measure of atherosclerotic disease severity. However, there is growing evidence that it is not

13 RG Volume 29 Number 5 Oppenheim et al 1425 Figure 15. Use of gadoliniumbased contrast agent for plaque characterization. (a) MR angiographic image of right carotid artery shows no high-grade stenosis. (b) Axial PD-, T2-, and T1-weighted and TOF MR images show plaque that looks mainly fibrous except for a small area with decrease in signal intensity (arrow) on T2-weighted image. (c) Axial T1-weighted MR images obtained before and after administration of gadoterate meglumine (Dotarem; Guerbet) show that on the gadolinium-enhanced image, the fibrous cap enhances while a large area remains isointense, which corresponds to the lipid core. * indicates lumen. Figure 16. Schematic diagram of stable and unstable atherosclerotic plaques. Unstable plaques contain (a) a large lipid core or intraplaque hemorrhage that is separated from the lumen by an unstable (thin or ruptured) cap and (b) a marked inflammatory component. Conversely, stable plaques are typically described as mainly fibrous, with a small or no lipid core, little sign of inflammation, and a thick continuous fibrous cap. Teaching Point the only predictive parameter of neurovascular events in patients with carotid atherosclerosis (33). High-resolution MR imaging can be used to identify the features of unstable plaques, which helps in determining if a neurologic ischemic event is attributable to an ipsilateral carotid plaque, even in the case of moderate stenosis. It further helps in predicting the risk of vascular recurrence or neurologic event in the case of asymptomatic plaque. Unstable plaques are typically described as containing a large lipid core or intraplaque hemorrhage that is separated from the lumen by an unstable (thin or ruptured) cap. Infiltration by inflammatory cells is also a marker of instability. Conversely, stable plaques are typically described as mainly fibrous, with a small or no lipid core, little sign of inflammation, and a thick continuous fibrous cap (Fig 16). High-resolution MR imaging is currently considered as the best tool to distinguish stable from unstable plaques. There is an association between the fibrous cap characteristics and a recent ischemic stroke: 70% of the patients with a ruptured cap, 50% of those with a thin cap, and only 9% of those with a thick intact cap have a history of ischemic stroke. Overall, when compared with patients with a thick fibrous cap, patients with a ruptured cap were 23 times more likely to have had a recent neurovascular event (27). In a longitudinal study including 154 patients with asymptomatic moderate stenosis of 50% 79% (NASCET [North American Symptomatic Carotid Endarterectomy Trial]), the risk of a neurovascular event (n = 12) was associated with a large plaque, the presence of a thin or ruptured cap, and intraplaque hemorrhage (2). Some data exist to support the notion that this intraplaque high signal intensity, which corresponds to recent intraplaque hemorrhage, is a clinically valid biomarker of further transient ischemic attack and/or stroke (34). It predicts those symptomatic patients with high-grade carotid stenosis who develop recurrent ipsilateral neurologic events while awaiting a carotid endarterectomy (34), and it is associated with increased ipsilateral microembolization (as detected with

14 1426 September-October 2009 radiographics.rsna.org Figure 17. Carotid artery dissection. Axial high-resolution T2- and PDweighted and TOF MR images (at right) show crescent mural hematoma of the subpetrous right carotid artery that is responsible for stenosis seen on MR angiographic image (at left). transcranial Doppler US) during carotid endarterectomy (35). Furthermore, in symptomatic arteries, MR imaging detected intraplaque hemorrhage predicted the risk of further neurologic events better than the degree of luminal stenosis did (hazard ratios: 9.8 and 1.5, respectively) (36). High-resolution MR imaging also affords the opportunity to image both carotid arteries at the same time. In the same patient, symptomatic plaques have a higher incidence of cap rupture, juxtaluminal thrombus, complicated American Heart Association type VI plaques, and larger areas of intraplaque hemorrhage than asymptomatic plaques do (37). Other prognostic longitudinal multicenter studies are ongoing to validate the ability to distinguish stable from unstable plaque by using MR imaging (8). Plaque Progression and Regression High-resolution MR imaging can be used to evaluate the natural history of plaque progression or to monitor the response to pharmacologic treatment. In an 18-month natural history longitudinal study (n = 68), Saam et al (38) showed a mean wall area increase of 2.2%/year and a mean luminal area decrease of 1.9%/year. In this study, the disease progression was about four times greater in patients who were not treated with statins compared with patients who were treated. In another study, investigators showed that intraplaque hemorrhage stimulates the progression of the plaque (39). The ability to use high-resolution MR imaging to monitor plaque regression in response to therapy was first shown by Corti et al (40), who demonstrated a decrease in plaque burden after 2 years of therapy with simvastatin. In several clinical trials, investigators have used high-resolution MR imaging findings (lipid core or plaque volume) as end points to assess the effect of therapy with statins or to monitor the effect of different doses on plaque volume and composition (41,42). Plaque Inflammation Inflammation is one of the major components of the plaque physiopathology that has been shown to be related to plaque vulnerability. There is a correlation between the degree of enhancement after gadolinium-based contrast agent administration and the degree of neovascularization, which is itself linked to plaque inflammation on histologic findings. Wasserman et al (43) showed that the wash-in kinetics of gadolinium into the fibrous cap and lipid core may be correlated with the degree of neovascularization. To improve the depiction of plaque inflammation, several targeted MR imaging agents have been developed. The agents most used are ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, which consist of a ferrous core surrounded by a dextran coating. This coating allows the USPIO particles to be phagocytosed by the macrophages. The inflammation within the atheroma is a dynamic process, with macrophages migrating to the plaque, replacing dying cells in

15 RG Volume 29 Number 5 Oppenheim et al 1427 Other Cervical Wall Disease Figure 18. Vertebral artery dissection. Axial highresolution PD-weighted MR image shows that the mural hematoma (arrow) can easily be distinguished from the adjacent perivertebral venous structures. the lipid core, after approximately hours. The USPIO particles emit a tiny magnetic field around them, which dephases the MR signal and leads to a susceptibility artifact clearly seen on T2*-weighted images. Thus, USPIO-laden macrophages produce a region of decreased signal intensity on T2*-weighted images (44,45). Because other plaque components, such as calcifications, also produce decreased signal intensity on T2*-weighted images, a pre-uspio baseline image needs to be obtained to ensure that the decrease in signal intensity is due to the injection of USPIO particles. A decrease in signal intensity after administration of USPIO nanoparticles is more frequently observed in the carotid plaques of symptomatic patients than in those of asymptomatic patients (46). However, some asymptomatic plaques can also have focal areas of signal intensity decrease, which is suggestive of an occult macrophage burden. If the use of USPIO particles is validated with larger studies, these particles may be a useful dual contrast agent able to improve the risk stratification of patients with carotid stenosis. Currently, smart MR contrast agents, which are much more targeted than the first-generation agents such as gadolinium-based contrast agents or USPIO particles, are being developed. Molecular targeting of contrast agents to either membrane-bound receptors or free proteins will allow in vivo microscopy with the use of high-fieldstrength MR units. An exhaustive description of molecular imaging markers is beyond the scope of this review; however, some challenging applications and recent clinical data suggest a growing interest in the assessment of vulnerable plaque by using these methods. Cervical Arterial Dissection Cervical arterial dissection is the most frequent cause of stroke in young adults, accounting for nearly 20% of the cases (47). MR imaging has become the reference method for evaluating patients who are suspected of having cervical arterial dissection, by using cervical axial T1- weighted images with fat suppression and cervical contrast-enhanced MR angiography. This method allows clinicians to almost completely forego invasive digital subtraction angiography. However, an early and reliable identification of acute cervical arterial dissection might be impaired by the limited spatial resolution, the tortuous course of the arteries, the great variability in normal vessel caliber, the presence of a thick bone covering, and adjacent veins. This is the case for dissection of the upper portions of the vertebral arteries and for dissection of the petrous internal carotid artery. In some cases, the diagnosis of cervical arterial dissection is presumptive and is further confirmed by sequential follow-up MR images showing signs of healing or progression in response to treatment. High-resolution MR imaging has recently been demonstrated to be useful for the assessment of cervical arterial dissection (3,4,48) and to permit excellent depiction of the structural characteristics of the vessel wall and the vessel lumen in acute cervical arterial dissection (Figs 17, 18). The coil positioning is of importance and should be guided by luminal abnormalities seen at contrast-enhanced MR angiography or US examination. The surface coils should be placed posterior and under the mastoid for the upper segment of the vertebral artery. Alternatively, the coils should be positioned anterior and lateral, facing the mandibular bone, for the petrous portion of the internal carotid artery. The eccentric vessel lumen (occlusion, stenosis, luminal thrombus) and the vessel wall (crescent mural hematoma, pseudoaneurysm, double lumen, intimal tear) of the dissected artery can then be exquisitely analyzed by using high-resolution MR imaging (4). The mural hematoma is well defined between the intimal and adventitial wall boundary. The signal intensity of mural hematoma varies with the time elapsed since the onset of symptoms. Initially, the mural hematoma is hyperintense

16 1428 September-October 2009 radiographics.rsna.org Figure 19. Vertebral artery dissection. (a) Initial MR angiographic image shows irregularity of the right vertebral artery (arrow), which is suggestive of a stenosis. (b) Axial fat-suppressed T1-weighted MR image from 5-mm axial section obtained with head/neck coils does not allow a definite diagnosis of dissection. (c) Axial high-resolution T2-weighted MR image shows the mural hematoma (arrow) surrounded by venous structures at the C3 vertebral level. (d) Follow-up MR angiographic image at 3 months shows regression of the right vertebral stenosis. with all pulse sequences. Progressively, the signal decreases with all pulse sequences because of susceptibility effects. One of the pitfalls of using MR imaging to diagnose vertebral artery dissection is that the flow-related enhancement of the vertebral venous plexus surrounding the artery in the transverse canal can mimic the high signal intensity of mural hematoma on T1-weighted spin-echo images (Fig 19). The distinction between the vertebral artery wall and perivertebral venous structures is easily made at high-resolution MR imaging (Figs 18, 19) because the venous lumen is hyperintense on T2- and PD-weighted images and isointense to the sternocleidomastoid muscle on both TOF and T1-weighted images (3). Finally, high-resolution MR imaging can be used to help distinguish between dissection and atherosclerosis in the case of cervical artery occlusion. The signal of the mural hematoma is usually homogeneous in cervical arterial dissection while being heterogeneous in hemorrhagic atherosclerotic plaques. Inflammatory Arterial Diseases Although atherosclerosis has been the main focus of interest, there is growing evidence that highresolution MR imaging may serve other pur- poses. It could allow one to distinguish between atherosclerosis and other rare causes of arterial stenosis or occlusion. High-resolution MR imaging also provides new insight into the physiopathology of inflammatory arterial disorders. This technique has been used to image carotid stenosis in patients with Erdheim-Chester disease (5) or in those with chronic granulomatous vasculitis, such as Takayasu arteritis (49) or giant cell arteritis (50,51). The imaging pattern of the arterial wall is different from that of atherosclerosis, with a prominent inflammatory component (Fig 20), thus allowing differential diagnosis to be made in difficult cases. In inflammatory disorders, highresolution MR imaging with contrast enhancement may also be useful for the detection of early arterial wall changes and may be helpful for routine monitoring and evaluation of disease activity at a more treatable stage (ie, before morphologic changes are detected with other imaging studies). Conclusions Because of technical advances, high-resolution MR imaging allows depiction of the wall of cervical arteries, especially carotid atherosclerosis. High-resolution MR imaging allows depiction of the different components of atherosclerosis: the necrotic lipid core, intraplaque hemorrhage, calcifications, and the fibrous cap. Global plaque volume, as well as the volumes of individual plaque

17 RG Volume 29 Number 5 Oppenheim et al 1429 Figure 20. Takayasu arteritis. (a) MR angiographic image shows proximal stenoses (arrows) involving the left subclavian artery and the ostium of the left common carotid artery. (b d) Axial high-resolution nonenhanced T1-weighted (b), gadolinium-enhanced T1-weighted (c), and gadolinium-enhanced fat-saturated T1- weighted (d) MR images at the level of the distal common carotid artery show a circumferentially thickened arterial wall with strong contrast enhancement after administration of gadoterate meglumine (Dotarem; Guerbet). This supports a diffuse inflammatory process of the arterial wall. * indicates lumen. Teaching Point components, can be calculated. Analysis of the structure of atherosclerotic plaque and measurement of stenosis contribute to the stratification of the risk of stroke. High-resolution MR imaging can also be used to assess the efficacy of treatment aimed at stabilizing or reducing plaque progression. High-resolution MR imaging of the wall of cervical arteries can be successfully performed in the clinical setting, provided (a) the patient is properly prepared and (b) dedicated surface coils and combined black-blood and bright-blood MR sequences are used. High-resolution MR imaging can also be used to depict vertebral arteries and can be used for the diagnosis of dissection or inflammatory arterial diseases. References 1. Yuan C, Mitsumori LM, Ferguson MS, et al. In vivo accuracy of multispectral magnetic resonance imaging for identifying lipid-rich necrotic cores and intraplaque hemorrhage in advanced human carotid plaques. Circulation 2001;104: Takaya N, Yuan C, Chu B, et al. Association between carotid plaque characteristics and subsequent ischemic cerebrovascular events: a prospective assessment with MRI initial results. Stroke 2006;37: Naggara O, Oppenheim C, Toussaint JF, et al. Asymptomatic spontaneous acute vertebral artery dissection: diagnosis by high-resolution magnetic resonance images with a dedicated surface coil. Eur Radiol 2007;17: Bachmann R, Nassenstein I, Kooijman H, et al. High-resolution magnetic resonance imaging (MRI) at 3.0 tesla in the short-term follow-up of patients with proven cervical artery dissection. Invest Radiol 2007;42: Gauvrit JY, Oppenheim C, Girot M, et al. Images in cardiovascular medicine: high resolution images obtained with ultrasound and magnetic resonance imaging of pericarotid fibrosis in Erdheim-Chester disease. Circulation 2004;110:e443 e ahajournals.org/cgi/content/full/110/15/e443. Published October 12, Accessed June 24, Oppenheim C, Touze E, Leclerc X, et al. High resolution MRI of carotid atherosclerosis: looking beyond the arterial lumen [in French]. J Radiol 2008;89: Boussel L, Herigault G, de la Vega A, Nonent M, Douek PC, Serfaty JM. Swallowing, arterial pulsation, and breathing induce motion artifacts in carotid artery MRI. J Magn Reson Imaging 2006;23: Touze E, Toussaint JF, Coste J, et al. Reproducibility of high-resolution MRI for the identification and the quantification of carotid atherosclerotic plaque components: consequences for prognosis studies and therapeutic trials. Stroke 2007;38: Edelman RR, Chien D, Kim D. Fast selective black blood MR imaging. Radiology 1991;181: Yarnykh VL, Terashima M, Hayes CE, et al. Multicontrast black-blood MRI of carotid arteries: comparison between 1.5 and 3 tesla magnetic field strengths. J Magn Reson Imaging 2006;23: