|Year : 2015 | Volume
| Issue : 1 | Page : 26-37
Recent advances in magnetic resonance imaging for stroke diagnosis
Radhika Rastogi1, Yuchuan Ding1, Shuang Xia2, Meiyun Wang3, Yu Luo4, Hyun Seok Choi5, Zhaoyang Fan6, Meng Li7, Timothy D Kwiecien1, Ewart Mark Haacke8
1 Department of Neurological Surgery, Wayne State University, School of Medicine, Detroit, Michigan, USA
2 Department of Radiology, Tianjin First Central Hospital, Tianjin, China
3 Department of Radiology, Henan Provincial People's Hospital, Zhengzhou, China
4 Department of Radiology, The Branch of Shanghai First Hospital, Shanghai, China
5 Department of Radiology, The Catholic University of Korea, St. Mary's Hospital, Seoul, Korea
6 Department of Biomedical Sciences, Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
7 Department of Radiology, Wayne State University, School of Medicine, Detroit, Michigan, USA
8 Department of Radiology, Wayne State University, School of Medicine, Detroit, Michigan, USA; Department of Medical Imaging, University of Saskatchewan, Saskatoon, Canada; Department of Biomedical Engineering, Northeast University, Shenyang; Department of Physics, East China Normal University, Shanghai, China
|Date of Submission||26-May-2015|
|Date of Acceptance||02-Jul-2015|
|Date of Web Publication||30-Sep-2015|
Department of Neurological Surgery, School of Medicine, Wayne State University, 550 E Canfield, Detroit, Michigan - 48201, USA
Source of Support: None, Conflict of Interest: None
In stroke, diagnosis and identification of the infarct core and the penumbra is integral to therapeutic determination. With advances in magnetic resonance imaging (MRI) technology, stroke visualization has been radically altered. MRI allows for better visualization of factors such as cerebral microbleeds (CMBs), lesion and penumbra size and location, and thrombus identification; these factors help determine which treatments, ranging from tissue plasminogen activator (tPA), anti-platelet therapy, or even surgery, are appropriate. Current stroke diagnosis standards use several MRI modalities in conjunction, with T2- or T2*- weighted MRI to rule out intracerebral hemorrhage (ICH), magnetic resonance angiography (MRA) for thrombus identification, and the diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) mismatch for penumbral identification and therapeutic determination. However, to better clarify the neurological environment, susceptibility-weighted imaging (SWI) for assessing oxygen saturation and the presence of CMBs as well as additional modalities, such as amide proton transfer (APT) imaging for pH mapping, have emerged to offer more insight into anatomical and biological conditions during stroke. Further research has unveiled potential for alternative contrasts to gadolinium for PWI as well, as the contrast has contraindications for patients with renal disease. Superparamagnetic iron oxide nanoparticles (SPIONs) as an exogenous contrast and arterial spin labeling (ASL) as an endogenous contrast offer innovative alternatives. Thus, emerging MRI modalities are enhancing the diagnostic capabilities of MRI in stroke and provide more guidance for patient outcome by offering increased accessibility, accuracy, and information.
Keywords: Arterial spin labeling (ASL), cerebral microbleeds (CMBs), diffusion-weighted imaging (DWI), ischemic penumbra, magnetic resonance angiography (MRA), perfusion-weighted imaging (PWI), superparamagnetic iron oxide nanoparticles (SPIONs), susceptibility-weighted imaging (SWI)
|How to cite this article:|
Rastogi R, Ding Y, Xia S, Wang M, Luo Y, Choi HS, Fan Z, Li M, Kwiecien TD, Haacke EM. Recent advances in magnetic resonance imaging for stroke diagnosis. Brain Circ 2015;1:26-37
|How to cite this URL:|
Rastogi R, Ding Y, Xia S, Wang M, Luo Y, Choi HS, Fan Z, Li M, Kwiecien TD, Haacke EM. Recent advances in magnetic resonance imaging for stroke diagnosis. Brain Circ [serial online] 2015 [cited 2020 Jan 27];1:26-37. Available from: http://www.braincirculation.org/text.asp?2015/1/1/26/164996
| Introduction|| |
Stroke is the fourth leading cause of death within the United States (USA), with approximately 795,000 Americans suffering a stroke annually, and it remains a leading cause of permanent disability.  Stroke itself is characterized by a disruption of cerebral blood flow (CBF) due to either a thrombus/embolus blocking a vessel or hemorrhage. Current treatments favor thrombolytic therapy to dissolve clots using tissue plasminogen activator (tPA). This should generally be delivered within 3-4.5 hours from the onset of stroke for optimally safe function.  Outside this range, there is an increased risk of intracerebral hemorrhage (ICH) with reduced clinical benefits.  However, the use of this drug is still very dependent on the diagnostic capabilities of imaging. Computed tomography (CT) and magnetic resonance imaging (MRI) are the key modalities used in hospitals for the diagnosis of stroke and in determining whether tPA may be prescribed. Recent advances have driven the clinical use of MRI for the diagnosis of acute ischemic stroke for its precision, its capability for studying both anatomy and function, and its accurate early detection of tissue disruption. These characteristics of MRI provide a clear clinical picture that then guides thrombolytic and antiplatelet therapy. In light of this, the challenge is to differentiate salvageable ischemic tissue from tissue with irreversible loss, as well as those patients at continued risk for ICH. In this paper, the basic concepts of the various available MRI sequences, as applied to stroke, will be reviewed.
| Mri|| |
Stroke visualization has been radically altered with advances in MRI. MRI itself is a revolutionary technology that allows for high-resolution soft-tissue contrast within the body. MRI uses the magnetic properties of hydrogen nuclei (protons in particular) found throughout the body to generate a signal.  Generally, MRI utilizes a magnetic field to align the hydrogen spins along the main field. Radiofrequency (RF) pulses are then used to manipulate the spins to create a measurable bulk transverse magnetization. Over time, the signal decays in the transverse plane and regrows longitudinally along the main field, each behavior having its own characteristic time (T2 and T1, respectively).  Even with just the early MRI methods, there were already four tissue parameters to provide contrast: Spin density or the number of spins per voxel, and the relaxation times T1, T2, and T2 * . But over the decades since its inception, MRI has developed so that it can also be used to visualize and measure blood vessels and blood flow, diffusion, perfusion, iron content, and oxygen saturation, to name a few features.
| Stroke|| |
Stroke is a condition related to reduced blood flow and perfusion caused by a thrombus/embolus or hemorrhage. There are generally three territories associated with stroke: The ischemic core (less than 12 mL/100 g/min), the penumbra (12-20 mL/100 g/min), and oligemic tissue (greater than 20 mL/100 g/min); the first two are the most severely affected by the reduced perfusion, the penumbra being less hypoxic/ischemic. The ischemic tissue may not represent salvageable tissue unless the flow is recovered within a few hours, while the latter is associated more with secondary damage, being at risk if the blood flow is not returned to normal. In the ischemic region, the lack of oxygen supply reduces the availability of high-energy phosphates such as adenosine triphosphate (ATP) and elevates inorganic phosphates. Subsequent dysfunction of the Na + /K + channels results in an influx of Na + to cause osmotic disruption and cytotoxic edema.  On the other hand, the penumbra still has marginal blood supply from collateral sources and retains intact cellular metabolism. Thus, it has the potential to be restored under reperfusion conditions  and is vital in determining treatment options. The oligemic tissue is less at risk than the penumbral tissue. Ideally, it should also be possible to detect the size and age of the stroke.
| MRI in Stroke Diagnosis|| |
Today, CT remains the mainstay in evaluating acute stroke, although more and more sites are following CT with an MRI scan within the first day. CT can rapidly assess the presence of major intracranial hemorrhage and rule out giving tPA. However, CT fails to register smaller cerebral microbleeds (CMBs), an area that MRI is able to investigate very well, especially with susceptibility-weighted imaging  (SWI). This could have important consequences for follow-up treatment with antiplatelet therapy.  There is much more to studying stroke than just seeing the embolus. One wants to know the changes in function and the hemodynamics of the tissue. This is where the ability to study magnetic resonance angiography (MRA), and perfusion and diffusion with MRI plays a key role. CT can also perform perfusion-weighted imaging (PWI), but still remains unable to compete with MRI when it comes to studying CMBs and diffusion. ,, In fact, one of the critical elements in determining what tissue may still be viable lies in the concept of the diffusion/perfusion mismatch. There is evidence here that a larger perfusion abnormality relative to a diffusion-weighted imaging (DWI) abnormality is a marker of viable or penumbral tissue. This can affect the decision for treatment, with the mismatch indicating a higher chance of tissue recovery and perhaps extending the window of treatment for the patient. ,,
DWI was first explored in stroke using an animal model in the early 1990s. , These studies demonstrated that DWI could detect ischemia within 45 min after onset of stroke, while T2-weighted imaging failed to detect any ischemic core even after 3 hours.  In DWI, the contrast is dependent upon the apparent diffusion coefficient (ADC).  In ischemia, diffusion is limited (restricted) due to cytotoxic edema that occurs after stroke. With the Na + /K + channel dysfunction and influx of water, the cells swell (cytotoxic edema, restricted diffusion, and lower ADC) and the volume of the extracellular compartment is reduced (lower ADC) within the region of infarct. , The reduction in ADC occurs within minutes and can stay low for days, allowing for sensitive early detection of ischemia. On the other hand, conventional MRI could take 6-8 hours to reveal any tissue changes, much past the ideal period for thrombolytic treatment. In DWI, the ischemic core appears hyperintense, while on the ADC maps, it is darker; both of these effects are due to the decrease in diffusion.  See [Figure 1] parts d (DWI) and e (ADC) pretreatment; parts m (DWI) and n (ADC) posttreatment. In certain animal studies, DWI lesions have shown reversal of damage to the indicated region.  However, this reversibility is often temporary and abnormalities may reoccur up to a day later; however, the benefits of early diagnosis outweigh the potential reversal.  Practically, DWI data are collected using a rapid scanning technique, echo planar imaging (EPI), to avoid motion artifacts. EPI uses a train of echoes to encode a two-dimensional (2D) image rapidly and allows for whole-brain coverage in just 2-3 seconds. 
|Figure 1: Two MRI scans from the same patient were acquired at different time points. The fi rst and second rows are from the first scan in the acute stage. The third and fourth rows are from the second MRI scan 1 week later. The images shown here were: (a) MRA (magnetic resonance angiography), (b) T2-weighted, (c) SWI (susceptibility-weighted imaging), (d) DWI, (e) ADC, (f) rCBF (relative CBF), (g) rCBV (relative CBV), (h) MTT and (i) TTP; for the second MRI scan one week later, the correlating images are (j) MRA, (k) T2-weighting, (l) SWI, (m) DWI, (n) ADC, (o) rCBF, (p) rCBV, (q) MTT, and (r) TTP. Both DWI and ADC showed the stroke region in the fi rst scan, but each returned to normal in the second scan 1 week later. SWI showed much darker veins in the fi rst scan and these disappeared in the second scan|
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Dynamic susceptibility contrast perfusion (DSC PWI)
In DSC PWI, a bolus of an intravascular tracer, a contrast agent, is usually injected into the antecubital vein. This contrast agent, most commonly gadolinium diethylene triamine penta-acetic acid (Gd-DTPA), travels to the brain and subsequently washes out. During this process, T2*-weighted EPI data are collected every few seconds for roughly 90 seconds and the signal change is monitored over time to watch the effects of this bolus. As the contrast agent perfuses through the brain, the tissue experiences a signal drop due to the paramagnetic susceptibility effects of the gadolinium. The image then returns to normal as the contrast leaves the brain. Processing these images through time can provide for cerebral blood volume (CBV), CBF, mean transit time (MTT), and time to peak (TTP) maps.  The ischemic region should show little signal change over time, a decrease in CBV and an increase in MTT. See [Figure 1] parts f (CBF), g (CBV), h (MTT) and i (TTP) pretreatment; parts o (CBF), p (CBV), q (MTT), and r (TTP) posttreatment.
|Figure 2: An example of a PWI/DWI mismatch for an acute stroke patient. The images shown here were: (a) MRA; (b) T1; (c) SWI; (d) DWI; (e) ADC; (f) rCBF; (g) rCBV; (h) MTT; (i) TTP. DWI and ADC showed several tiny regions of the stroke affected area, but the PWI MTT map showed a much larger region with a perfusion abnormality. SWI showed much darker veins in the stroke region. MTT and TTP increased, and meanwhile rCBV also increased while rCBF appears to be maintained at the normal level in the stroke region|
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In comparing PWI and DWI, there have been cases of PWI lesions identified without any results seen in DWI.  Such cases, while rare, may cause confusion as to how to proceed with thrombolytic therapy, but Blondin et al.  determined in a retrospective study that the lack of a DWI lesion does not impact results of thrombolytic therapy and that sufficiently depressed perfusion is enough indication for such treatment. Our own experience suggests that several such cases may arise each year in a given center, especially within a 3 hour window when DWI may not show changes but PWI shows clear changes. These patients would still be treated by tPA, if possible. Therefore, PWI plays a key complementary role to DWI.
Arterial spin labeling (ASL) perfusion
Although DSC PWI has been well adopted, there are contraindications for the use of gadolinium in patients with kidney disease and kidney failure, and using it today requires glomerular filtration rate evaluation.  One contrast method being explored as an alternative is ASL, where the inflow of arterial blood that has been spatially labeled is used to both visualize and quantify blood flow.  ASL has little dependence on blood-brain barrier permeability changes, which is often compromised in stroke patients and affects the signal from exogenous contrast agents.  ASL has gained more momentum recently at high fields because of the increased signal-to-noise ratio (SNR), but it still requires several minutes and averaging to create sufficient-quality data. More recent innovations in the technique, such as background suppression, pseudocontinuous ASL (pcASL), and a standardized approach to its use have provided full brain coverage, improved SNR, and made it a more reliable technique. ,, With these innovations, ASL is capable of identifying regions of hypoperfusion consistent with exogenous contrasts. It also more clearly images regions of hyperperfusion, indicative of recanalization, compared to exogenous contrast, but has a less clear identification of the ischemic penumbra.  Overall, its ability to compete with DSC PWI in stroke studies is still being investigated but is increasingly promising. 
PWI and DWI mismatch
PWI and DWI both provide vital information regarding stroke diagnostics. PWI can show perfusion changes throughout the brain, while DWI shows local cytotoxic edema and hence the damaged tissue or infarct core. The difference between these two sets of images is referred to as the PWI/DWI mismatch see [Figure 1] PWI (parts h and i) shows a slightly larger perfusion deficit than DWI (d) or ADC (e). Early studies suggested that lesions with PWI-deficient regions (penumbra) larger than the infarct core as seen with DWI could determine which tissue was still salvageable.  The Diffusion and Perfusion Imaging Evaluation For Understanding Stroke Evolution (DEFUSE) study showed there were more favorable outcomes with early recanalization compared to subjects who lacked the PWI/DWI mismatch.  Furthermore, the mismatch allows clinicians to select thrombolytic therapies in the 3-6 hour window, as it indicates the presence of penumbra that will benefit from reperfusion. ,
The sensitivity of PWI to reduced perfusion, however, raises another issue. It is able to accurately identify regions of very mild hypoperfusion, regions that may still be receiving CBF and thus are not in danger of damage. Thus, when using it to identify the ischemic penumbra, certain regions may actually be benign oligemia, leading to an overestimation of the damage that will occur.  Continual refinements have been made to define the parameters of the penumbra, evolving through various studies such as DEFUSE and Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET), in order to better delineate the region from oligemia in PWI time-to-maximum (Tmax) maps. Toth et al.  found that using larger Tmax values (>4 seconds) and correcting PWI volumes with regard to the arterial input function allows for a more accurate assessment of the PWI volume. However, such corrections are not often clinically employed, as many MRI systems have lacked those capabilities until recently.  Thus, mismatch selection in therapeutic determination is sensitive to PWI volume selection methods.
An example of a severe PWI/DWI mismatch showing increases in CBV but significant losses in oxygen saturation is given in [Figure 2]. Here the brain tissue has successfully responded to the challenge from stroke in an attempt to compensate for the reduced perfusion. However, the opposite can also happen, in that CBV and CBF reduce, and this may not be a favorable prognostic factor for the patient. Such a case is shown in [Figure 3].
|Figure 3: A 70-year-old male with right limb weakness and unconsciousness 1.5 h after stroke. The images shown here were: (a) and (b) T2WI; (c) and (d) DWI; (e) and (f) ADC; (g) and (h) TTP; (i) and (j) MTT; (k) and (l) CBV; (m) and (n) CBF. T2WI, DWI, and ADC were negative (although there are subtle changes in DWI), but TTP and MTT showed obvious hypoperfusion in the bilateral cerebellar and left medial occipital lobes. Both rCBF and rCBV were slightly decreased in the same area|
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More recently, there have been a number of papers comparing signal changes with SWI in stroke and their implications. ,,,,,,,,,,,,,, In the presence of reduced flow, veins in SWI appear darker than usual because of increased levels of deoxyhemoglobin and are referred to as asymmetrically prominent cortical veins (APCV).  The presence of these cortical veins will usually match the MTT or TTP delays, and when treatment is successful, they will disappear in parallel with the reduction in MTT or TTP [see [Figure 1] parts c (SWI), h (MTT), and i (TTP) pretreatment; and parts l (SWI), q (MTT), and r (TTP) posttreatment.] However, sometimes an increase in MTT is seen but there is no concomitant increase in the visibility of the veins. This PWI/SWI mismatch may be due to the presence of collaterals and, therefore, be an indication that the tissue is still viable with only limited effects from reduced perfusion and normal levels of oxygen and, hence, is still treatable. (That is, SWI may be useful in differentiating hypoperfusion from delayed perfusion.)
SWI can also be used to detect CMBs. This may be important for those receiving antiplatelet therapy. It has been shown that those patients receiving antiplatelet therapy and having CMBs fare much more poorly than those patients with CMBs who are not on antiplatelet therapy. Further, the patients in the latter cohort demonstrated better recovery and stayed in the hospital for shorter periods of time. , It has also been suggested that patients with three or more CMBs, as seen with SWI, may also not fare well on antiplatelet therapy.  SWI has also been shown to better detect hemorrhagic transformation and CMBs than CT. 
Finally, the new multiecho SWI sequences  make it possible not only to detect microbleeds but also to show the thrombus clearly using short and long echo times [Figure 4]. SWI can often find the thrombus, which cannot be seen with conventional sequences, and this can help confirm which artery is responsible for the stroke. It can also be used to determine if there is thrombus resolution after tPA, which would provide a good prognosis for the patient. , Finally, SWI may be useful in conjunction with high-resolution MRA for recanalization via microcatheter extraction of the thrombus when necessary.
|Figure 4: An example of a double echo SWI evaluation of a stroke patient with an occlusion of the right MCA and a thrombus within the right MCA. (a) The short echo (TE = 7.5 ms) minimum intensity projection (mIP) SWI data show the thrombus clearly with limited signal from the veins; (b) The MRA shows the occlusion of the right MCA; (c) The quantitative susceptibility map again shows the thrombus clearly because of its high iron content while (d) the mIP SWI shows both the thrombus and numerous veins. The veins on the right side of the brain show the APCV effect indicating increased levels of deoxyhemoglobin in the veins and reduced fl ow to the tissue.|
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Comparison between SWI and PWI
Four different scenarios have been seen when comparing SWI and PWI. The first is that small lacunar acute infarction was found in DWI, while both SWI and T2-weighted imaging (T2WI) were normal. Although MTT was delayed, CBV and CBF still remained normal, and in some cases even increased. This phenomenon is called compensatory overperfusion after acute ischemic stroke [Figure 1]. The second is that multiple acute lacunar infarctions were found with DWI. Diffuse hemisphere APCV were detected on SWI and the area covered matched the delays seen in MTT and TTP. The CBF slightly decreased, but CBV remained within the normal range [Figure 2]. This phenomenon is called compensatory normal perfusion after acute ischemic stroke. The brain tissues pertaining to the previous two scenarios should still be viable and are likely to recover after treatment. The third is that a small acute lacunar infarction was seen on DWI, but there were no APCV, and the local delayed MTT and TTP combined with decreased CBV and CBF [Figure 3]. This lacunar brain tissue likely was compromised already and may well represent nonfunctioning tissue. The fourth was the presence of a large lobar hyperintensity on DWI, but no veins were seen with SWI in the corresponding area along with a consistent region of delayed MTT and TTP that matched a decreased CBV and CBF. This tissue has likely succumbed to prolonged hypoxic/ischemic conditions and has become necrotic.
MRA has long been a mainstay for the study of neurovascular diseases.  It can be acquired with or without contrast agents and provides high-resolution information about the major arteries in the brain. It is mainly used to look for stenosis and lack of flow. More recent results show that resolutions as high as 0.25 mm × 0.25 mm × 0.5 mm are possible with a contrast agent with superb small-vessel delineation.  Furthermore, with newer rephasing/dephasing methods, even 0.5 mm isotropic inplane resolution with 1 mm thick slices is possible without a contrast agent in reasonable clinical times.  MRA makes it possible to determine the source of the reduced perfusion by determining the responsible artery. That information then allows the physician to make a choice as to how to treat the patient, whether with thrombolytic therapy, antiplatelet therapy, or even intraarterial surgery. In conjunction with SWI and PWI, the clinician can then paint a complete picture of the status of the patient's neurovascular system. ,
Carotid vessel wall imaging
The carotid artery supplies the brain, eyes, and face with oxygen-rich blood. However, this critical blood vessel is a common site for atherosclerosis, a degenerative disease of the arterial wall caused by the buildup of fatty substances and cholesterol deposits.  The formation of atherosclerotic plaque can cause progressive narrowing of the arterial lumen that may eventually become severe enough to decrease or completely block blood flow. Advanced plaques may break off and obstruct blood flow, resulting in acute symptoms such as transient ischemic attack (TIA) and cerebral thromboembolic stroke. , The primary goal in treating carotid atherosclerotic disease is to reduce the risk of stroke. Each year, approximately 800,000 Americans sustain a stroke and 20% of ischemic strokes are associated with carotid atherosclerotic disease. , In addition to medical therapy, approximately 124,000 costly carotid revascularization procedures [89% carotid endarterectomy (CEA) and 11% carotid artery stenting (CAS)] are conducted each year in the USA to treat the disease and prevent stroke. 
Current management guidelines for carotid atherosclerotic disease are primarily based on the degree of luminal stenosis as determined by medical imaging, with high-grade (>70%) stenosis as an indication for CEA or CAS. , However, the degree of stenosis may not be an accurate indicator of the severity of disease. The European Carotid Surgery Trial reported that 43.8% of symptomatic patients had <30% stenosis.  Conversely, some patients with high-grade stenosis never develop symptoms but are likely over treated.  Hence, an accurate, reliable approach to risk stratification of carotid atherosclerotic lesions is highly desired for guiding treatment decisions.
Pathology studies revealed that atherosclerotic plaque destabilization followed by acute thromboembolic events is related to specific plaque characteristics, namely the presence of a large lipid-rich necrotic core (LRNC) with an overlying thin/ruptured fibrous cap (FC), intraplaque hemorrhage (IPH), and calcification (CA). , Characterization of such vulnerable plaque features may help better identify high-risk lesions. , In this regard, MRI has shown unique strengths over other commonly used diagnostic imaging modalities (i.e., x-ray angiography, duplex ultrasound, and CT) that merely provide information on luminal stenosis. Extensive research efforts have been devoted to the development of MRI techniques for carotid plaque characterization over the last two decades. Early interests were focused on lumen imaging (i.e., MRA) and wall morphological imaging (i.e., black-blood vessel wall imaging as shown in [Figure 5]a), both of which provide useful information on the presence of artery stenoses or atherosclerotic plaques as well as their distribution. However, plaque compositional imaging with MR is increasingly becoming more popular in the research community. The conventional MR approach identifies different plaque components based on their signal patterns on multicontrast-weighted images acquired typically with T1-, T2-, and proton density-weighted fast spin-echo (FSE), and time-of-flight (TOF) [Figure 5]b-e. , Using the protocol given above, high sensitivity and specificity for detecting various plaque components have been achieved.  To enhance the sensitivity and confidence for some specific plaque constituents, additional contrast weightings may be included. Delayed contrast-enhanced imaging creates sharp contrast between LRNC and FC, allowing for the identification of LRNC. , Furthermore, it has been shown to significantly overcome the low reproducibility in characterizing FC status associated with the noncontrast-enhanced protocol.  Recently, a heavily T1-weighted sequence, namely magnetization-prepared rapid acquisition with gradient echo (MP-RAGE),  was proved to be more sensitive to IPH than conventional T1-weighted FSE or TOF.  In addition, several novel techniques have been developed in an attempt to offer multiple capabilities with a single scan. For example, three-dimensional (3D) simultaneous noncontrast angiography and intraplaque hemorrhage (SNAP) imaging provides both noncontrast-enhanced MRA and IPH detection;  3D spoiled gradient recalled echo pulse sequence for hemorrhage assessment using inversion recovery and multiple echoes (SHINE) characterizes the age of IPH in addition to IPH detection;  and finally, multicontrast atherosclerosis characterization (MATCH) imaging is capable of detection of multiple plaque constituents with a single scan. 
|Figure 5: Representative carotid artery wall images acquired using 3D and 2D vessel wall imaging techniques from a symptomatic 43-year-old male patient. (a) 3D isotropic 0.78-mm images acquired with a 3D FSE sequence can be reformatted into a long axis view to better delineate the atherosclerotic lesions at the carotid bifurcation; (b.1-e.1) location-matched multicontrast images (0.63 × 0.63 × 2.0 mm3) acquired with TOF, pre-contrast T1- and T2-weighted FSE, and post-contrast T1-weighted FSE depict a plaque with large LRNC (arrows) and calcifi cation (arrowheads) at the carotid bifurcation (orange arrows in a.); (b.2-e.2) location-matched multicontrast images acquired with the same 2D imaging protocol depict normal vessel wall at the common carotid artery (blue arrows in a.)|
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As for carotid atherosclerosis MRI, black-blood techniques are the method of choice extensively utilized for vessel wall morphological imaging and plaque compositional imaging.  To make the vessel wall more conspicuous, luminal blood signals need to be suppressed. This is typically achieved by exploiting some flow properties such as in/outflow or fast flow velocity. However, blood suppression is often incomplete, particularly at locations involving complex flow.  As a result, residual juxtaluminal blood signals may be mistaken as part of carotid artery wall, thus leading to the overestimation of wall area or plaque burden. SWI may be a new approach to investigate the presence of hemorrhage or of calcium, which may not be seen if on the interior of the vessel wall and which are also important to recognize in the wall itself.  Today, it is possible to image the vessel wall with SWI to obtain full region of interest (ROI) coverage in three-dimension without the need to suppress the signal from the blood. Exquisite contrast on the SWI images should allow clear delineation between IPH and CA in plaques.
Intracranial vessel wall imaging
Atherosclerosis of the intracranial artery is also an important cause of stroke over and above the extracranial artery atherosclerosis. , Compared with extracranial atherosclerosis, intracranial artery atherosclerosis is more frequent in the Asian population than the Western population. ,, Previously, luminal stenosis of intracranial artery had been considered as a risk factor of stroke.  However, luminography cannot reveal the in situ pathology occurring at the arterial wall. Pathologically, intracranial arteries are different in terms of tight endothelial junction (blood-brain barrier), lack of vasa vasorum, and thin elastic lamina, compared with extracranial arteries.  However, vulnerable intracranial artery atherosclerosis shares with carotid artery atherosclerosis some common features such as presence of IPH, large LRNC, inflammation, and thin FC. Therefore, recent studies have focused on visualizing the in situ arterial wall using high-resolution multicontrast MRI. ,,,, Contrast enhancement at the intracranial arterial wall is considered pathologic and is correlated with inflammation  [Figure 6]. Several studies have suggested that enhancement of the intracranial arterial wall is a marker of histologically active disease and a potential marker for the culprit atherosclerotic lesion of the intracranial artery. It is still challenging to visualize the wall of intracranial arteries even using high field MRI because the thickness of the intracranial arterial wall is smaller than that of extracranial arteries. Further research should be performed to achieve suitable SNR, contrast-to-noise ratio, and methods of analysis on intracranial artery atherosclerosis.
|Figure 6: A 26-year-old male who suffered from transient weakness of the left limbs 8 days before being imaged. The T2WI was negative. The digital subtraction angiography (DSA) showed stenosis of the right MCA. The high-resolution MRI showed eccentric plaque of the MCA wall with vivid enhancement postcontrast|
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The current medical management of intracranial artery atherosclerosis consists of antiplatelets, anticoagulants, and statins. ,, Endovascular and surgical treatments are alternative treatment options in patients without response to best medical therapy.  However, in the previous studies on proper management of intracranial artery atherosclerosis, eligible patients were selected by means of luminography and clinical symptoms. Further clinical research is still needed to evaluate subclinical patients at risk for future stroke.
Amide proton transfer (APT) imaging and pH mapping
The ability to map the pH in the brain could allow direct measurements of physiological changes in stroke. This is through a chemical exchange saturation transfer technique called APT imaging, or pH-weighted MRI. More thoroughly explored in animal studies, APT has only recently been tested on human subjects in the more preliminary condition. In APT imaging, an RF pulse is used to label the water-exchangeable amide protons on endogenous mobile and tissue proteins.  These labeled protons are then tracked for contrast, with proton exchange rates with water indicative of pH; slow rates with lowered pH are due to increased proton concentrations. Thus, in stroke, the stroke volume appears as a hypointense region. , In rat models, the additional use of pH-MRI has allowed for the distinction between the benign oligemia and the penumbra, a distinction that was difficult to make with the PWI/DWI mismatch alone.  The region of lower pH was larger than DWI lesions but smaller than PWI lesions, allowing for a more accurate representation of the penumbra and potentially allowing for better prediction of outcome in terms of lesion growth during ischemia. 
Furthermore, after stroke, the lack of oxygen forces cells to turn to glycolysis for energy, which creates an excess of lactate. In such regions, the accumulation of lactate creates tissue acidosis, damaging the tissue and disrupting normal metabolism even when oxygen is returned. APT imaging correlates well with the lactic acidosis occurring post infarct within the brain, with further studies by Sun et al.  demonstrating pH correlation with lactate content. Harston et al.  performed proof-of-concept studies on human stroke subjects, showing that APT imaging provides a more accurate assessment and delineation of the ischemic penumbra and indicating which tissue will lead to infarction. APT imaging can be done within 3 minutes, ensuring that this could become a practical diagnostic tool.  An example image using this approach is shown in [Figure 7].
|Figure 7: Acute infarct in the corpus callosum. The infarct shows hypointensity on T1WI (a); hyperintensity on T2WI (b); hyperintensity on DWI (c); and hypointensity on the phase map using a length and offset varied saturation (LOVARS) scheme|
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| Novel Contrast Agents|| |
Other exogenous contrast agents have emerged for potential use with T2*-weighted MRI imaging as alternatives to current gadolinium (Gd)-based contrasts. One such method is the use of PEGylated superparamagnetic iron oxide nanoparticles (SPIONs) to identify specifically the leakage of the blood-brain barrier in stroke. Liu et al.  have explored this application within mice models. Because of their superparamagnetic properties, much smaller amounts of contrast are necessary for distinct contrast in imaging. SPIONs are injected and traced; they aggregate in areas where the blood-brain barrier is leaky, such as compromised ischemic tissue, creating a hypointense signal in the area due to their disruptive susceptibility effects. The nanoparticle had equivalent results when compared to Gd-DTPA in these models and allows for the unique capability of the compromised blood-brain barrier to be dynamically monitored for a 24 hour period after injection.  The long life of the contrast offers the potential for tracking tissue behavior after therapeutic intervention as well. Given the concern today about nephrogenic systemic fibrosis (NSF),  these iron-based agents may provide an alternative contrast agent for patients with compromised kidney function. 
| An Integrated MRI Stroke Protocol|| |
Current clinical usage favors the multimodal use of MRI.  This entails taking T2- or T2*-weighted imaging, and DWI and PWI imaging. The T2*-weighted imaging allows for accurate rule out or definition of ischemic hemorrhage, due to its susceptibility-weighted images. Meanwhile, the other modalities are used together. DWI and PWI mismatch are the most modern clinical applications of MRI in stroke. The presence of a mismatch (PWI > DWI) indicates the presence of a penumbra, which is currently utilized as an indication for thrombolytic therapy in the clinical arena. The mismatch, when accompanied by confirmed vessel occlusion in the middle cerebral artery (MCA), is a definite indication for recanalization and thrombolytic therapy.  Cases with a PWI/DWI match or a DWI lesion without hypoperfusion are less certain. In the former, it is difficult to determine if there is still salvageable tissue. In the latter, therapy is not needed, as it is indicative of spontaneous recanalization.  This may not be the case, however, if the time of arrival to the hospital is within a 3 hour time window (what might be called the superacute stage), and the patient may still require treatment. This is often the case when there is a stroke lesion in the medulla, brainstem, or basal ganglia with a mismatch.
Furthermore, using both PWI and DWI allows for accurate stroke identification in cases where there is a false negative DWI or no DWI lesion present.  All these features are well demonstrated by the data in [Figure 1].
Finally, the use of SWI will allow for the detection of microbleeds to assess the role of anti-platelet therapy and changes in oxygen saturation in the local venous structures. Both of these may have future treatment consequences, the former for determining if there are too many microbleeds for anti-platelet therapy and the latter in assessing the SWI/PWI mismatch and extending the window of treatment beyond the usual 4.5 to 6 hour window.
One of the advantages of multimodal MRI is the amount of information it offers within a limited amount of time, with complete examinations across DWI, PWI, T2*-weighted (preferably SWI), and conventional imaging completed within 10 minutes.  The immediacy and speed of such diverse imaging modalities make multimodal MRI very attractive in emergency situations such as acute stroke and allows for more immediate decision making, a vital point in stroke where "time is brain." 
| Conclusion|| |
Overall, noninvasive, nonionizing imaging methods such as MRI offer the potential to follow patients longitudinally and ascertain, perhaps, why some patients recover better than others and how the brain responds to treatment. Some questions that might be answered include: "Does perfusion recover immediately for all patients who do well or can a slow recovery of perfusion also be indicative of recovery for patients?"; "Should patients with CMBs be given antiplatelet therapy?"; "Does an SWI/MTT mismatch indicate collateral perfusion and hence suggest that the tissue is still viable?" More specifically, MRI is invaluable in its diagnostic capability for ischemia, in terms of stroke identification, prognostic capabilities, and therapeutic indications. Current standards involve the use of multiple sequences including T2-weighted, T2*-weighted, DWI, and PWI for stroke identification and therapeutic determination. Today, MRI is the key in determining who will do poorly if no intervention is employed. Emerging contrast mechanisms, such as SWI for monitoring oxygen saturation and detecting CMBs and APT for assessing tissue function, are increasing the information and predictive power that MRI can provide.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
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