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1 EURA MEDICOPHYS 2007;43: Diffusion and perfusion-weighted magnetic resonance imaging techniques in stroke recovery Most of the functional recovery after stroke takes place during the first three months after the insult. The neuronal mechanisms underlying this recovery are presently mostly unknown. However, in order to create efficient rehabilitation programs, it is of great importance to uncover these mechanisms. Multiple imaging techniques have been employed for the detection and characterization of ischemic lesions in the brain as well as monitoring of processes associated with stroke recovery. Diffusion and perfusion-weighted magnetic resonance imaging techniques are easy and fast to perform and provide significant information about the ischemic lesion and the hypoperfusion surrounding the lesion at both micro and macrovascular level. More sensitive detection and accurate characterization of the lesion will help in choosing the therapeutic strategies. Methods for monitoring brain function recovery will provide a better understanding of the basic mechanisms of plasticity in the brain, and will serve as a tool for the evaluation of therapeutic interventions, which may eventually include, for example, stem cell transplantation. With the help of these diagnostic tools it may become possible to tailor individual rehabilitation programs. KEY WORDS: Magnetic resonance imaging - Stroke - Rehabilitation. H. J. ARONEN 1, 2, 3, M. P. LAAKSO 4, 5, M. MOSER 3, J. PERKIÖ 3, 6 The acute reduction of blood supply, acute stroke, is one of the major causes of adult neurological Fundings. This work was supported by the Academy of Finland, the State Subsidy for University Hospitals (Helsinki University Central Hospital), and the Sigrid Jusélius Foundation. Acknowledgments. The authors thank Dr. Y. Liu, and Dr. J. Karonen, for comments and Figures. Address reprint requests to: H. J. Aronen, Department of Radiology, Turku University Central Hospital Kiinamyllynkatu 4-8, FIN Turku. hannu.aronen@utu.fi 1Department of Radiology Turku University Central Hospital, Turku, Finland 2The Centre of Military Medicine, Helsinki, Finland 3Functional Brain Imaging Unit Helsinki Brain Research Center, Helsinki, Finland 4Department of Neurology Kuopio University Hospital, Kuopio, Finland 5Department of Radiology Kuopio University Hospital, Kuopio, Finland 6Department of Child Neurology Helsinki University Central Hospital, Helsinki, Finlan disability and one of the leading causes of death in the developed countries. In four of five strokes, the abrupt decline in oxygen delivery is due to a local blockage of blood flow and referred to as ischemic stroke. 1 One of every five strokes is due to a weakened vessel that ruptures and bleeds into the surrounding brain a hemorrhagic stroke. Whereas, hemorrhagic stroke is untreatable, luckily the progression of ischemic stroke can, in many instances, be inhibited by thrombolytic therapy targeted at dissolving the clot, which blocks blood flow. This treatment effect is most optimal if administered within 3 or 6 h after the onset of symptoms. 2, 3 However, thrombolytic therapy can lead to complications, such as intracranial hemorrhage, and is contraindicated by initial hemorrhage. Hence, it is necessary to assess the risks involved with thrombolytic therapy for each individual case of ischemic stroke. To date, several imaging methodologies are used to assess these risks and the size and extent of ischemic Vol No. 2 EUROPA MEDICOPHYSICA 271

2 ARONEN DIFFUSION AND PERFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING TECHNIQUES IN STROKE RECOVERY Figure 1. Time series of a dynamic susceptibility contrast magnetic resonance imaging sequence obtained by echo-planar spin echo imaging. Time evolves row-wise from top left to bottom right. As the contrast agent passes through the brain, the imaging voxels experience a signal loss in T2 weighted images. As the contrast agent has made its first-pass through the brain the signal is restored near the original level. brain tissue in stroke in an attempt to characterize and classify patients for potential thrombolytic therapy. In this review, we discuss the current research surrounding changes and improvements in using diffusion- and perfusion-weighted magnetic resonance imaging (MRI) in the assessment of ischemic stroke. The techniques: diffusion and perfusion-weighted magnetic resonance imaging Diffusion-weighted MRI (DWI) is based on the diffusion of tissue water molecules within the time-frame of a tailored spin echo pulse sequence. 4 The higher the diffusion, the lower the signal in DWI. In human tissue, the diffusion is highly more restricted in the intracellular space than in the extracellular space due to limiting structures such as microparticles and membranes. The cytotoxic edema, associated with ischemic stroke within minutes of the insult, increases significantly the proportion of intracellular space in the imaging voxel. As a result, the signal detected by DWI is decreased and the area susceptible to ischemia is pinpointed as bright. DWI is a part of clinical stroke imaging in many centers. Diffusion is measured by the apparent diffusion coefficient (ADC), which is determined by acquiring 272 EUROPA MEDICOPHYSICA June 2007

3 DIFFUSION AND PERFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING TECHNIQUES IN STROKE RECOVERY ARONEN TABLE I. Summary of the most common MR perfusion/diffusion related parameters used to characterize ischemia and hypoperfusion in the brain. Parameter Physiological meaning Rationale in the evaluation of ischemia and hypoperfusion Apparent diffusion coefficient (ADC) Cerebral blood volume (CBV) Cerebral blood flow (CBF) Contrast agent mean transit time (MTT) Cerebral blood flow heterogeneity (FH) Quantitative measure of tissue water diffusion, different for gray and white matter The blood volume of perfused microvessels The mean microvascular blood flow The time it takes for blood to move from artery side to venous side (cerebral blood volume: cerebral blood flow) Intravoxel blood flow distribution at leaset two different diffusion weighted images. Utilizing echo-planar imaging (EPI) in DWI results in an intrinsic sensitivity to magnetic field inhomogeneities in the form of susceptibility artefact. Although the higher field strength provides a higher signal-tonoise ratio (SNR), the rise in susceptibility artefact counteracts the benefits. However, parallel acquisition techniques reduce the sensitivity to susceptibility effects by shortening the EPI readout train and will become more important in higher field strengths. Perfusion weighted imaging (PWI) by dynamic susceptibility contrast (DSC) MRI utilizes the susceptibility effect of an external paramagnetic contrast agent, which is injected as a concise bolus and compartmentalized in extracellular intravascular space. This agent induces a temporary signal change during its first-pass through the neuronal vasculature 5-9 (Figure 1). By capturing the first-pass by a T2 or T2* weighted imaging sequence, a signal-time curve is obtained and subsequently used to calculate several parameters describing tissue perfusion. The most common parameters describing tissue perfusion are cerebral blood volume (CBV), cerebral blood flow (CBF), contrast agent mean transit time (MTT), and cerebral blood flow heterogeneity (FH). These parameters and the rationale for their usage in the characterization of brain ischemia is summarized in Table I. The postprocessing steps for obtaining these parameters are shown schematically in Figure 2. Although, both spin and gradient echo measurements can be used to capture the signal-time curve, spin echo measurements are more sensitive to microvasculature (vessel size <20 µm), whereas gradient echo measurements are less dependent on the vessel size The accuracy and precision of the parameter estimates depend on the SNR of the concentration-time curve which, again, is directly associated with the signal change during the first-pass of the contrast agent. The signal change can be increased by any method that amplifies the susceptibility effect, such as increasing the main magnetic field strength or increasing the dose of the contrast agent. The signal change has been shown to be approximately linearly proportional to the amount of the injected contrast agent 9, meaning that the higher the contrast agent concentration the higher the signal drop during the first pass of the agent and, consequently, the better quality of the postprocessed perfusion maps. 15 Sensitive marker of ischemic tissue, although not always irreversible Diffusion is decreased in the acute phase and increased in the chronic phase of infarction Initial hypoperfusion volume on CBV map roughly predicts final infarct size Decreased CBV in the acute phase suggests permanent damage CBF may provide information about changed hemodynamics not directly reflected by CBV A CBF defect larger than a CBV defect suggests tissueat-risk Most sensitive measure for tissue hypoperfusion Usually shows the largest hypoperfusion volume surrounding the ischemic lesion Flow heterogeneity is decreased in the acute phase as the high-flow components are reduced to maximize oxygen extraction Cerebral blood volume CBV describes tissue perfusion from the point of view of capillary density and was originally the para- Vol No. 2 EUROPA MEDICOPHYSICA 273

4 ARONEN DIFFUSION AND PERFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING TECHNIQUES IN STROKE RECOVERY Figure 2. Schematic illustration of the postprocessing of dynamic susceptibility contrast magnetic resonance imaging study. A signal-timecurve is obtained from each voxel of the T2-weighted images. Integration of the signal-time curve gives a measure of the cerebral blood volume (CBV) in each voxel. The arterial input function (AIF) is obtained from the territory of the middle cerebral artery and is deconvolved with the signal-time curve in each voxel to produce the tissue impulse response function. The tissue impulse response function yields a measure of the cerebral blood flow (CBF) and the intravoxel flow distribution, flow heterogeneity (FH). Finally, the contrast agent mean transit time (MTT) is obtained as the CBV:CBF ratio. meter of interest 16 being applied to cerebral neoplasms. 17, 18 Assuming the whole amount of contrast agent passes through the region of interest during the time of measurement and each molecule is observed only once, the measured concentration time curve is an indication of the amount of contrast agent particles that have passed through the region. By calculating the area under the concentration time curve, the whole amount of contrast agent that has passed through the region can be determined. This measure is an indication of the capability of the region to pass contrast agent, and thus also blood, through it, 19, 20 thus being a measure of capillary density or microvascular blood volume. The CBV can be calculated in several ways and the method of choice should be optimized with respect to postprocessing time, computing requirements and depending on whether relative or absolute values are required. 21 Cerebral blood flow The determination of CBF is not straightforward, but requires knowledge of the arterial input function (AIF), which is inherently difficult to determine with 274 EUROPA MEDICOPHYSICA June 2007

5 DIFFUSION AND PERFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING TECHNIQUES IN STROKE RECOVERY ARONEN DSC MRI. Although, the temporal resolution of DSC MRI, typically around 1.5 s, is insufficient to capture the AIF reliably as the absolute concentration levels may be missed, CBF can be reliably estimated with DSC MRI. 22, 23 The complex convolution of the AIF and tissue impulse response can be solved fairly independently from the underlying vascular structure by nonparametric deconvolution of a tissue concentration time curve with a noninvasively determined AIF. Although this methodology as such does not enable the determination of the absolute CBF values, it has been shown to yield gray matter to white matter CBF ratios in excellent agreement with PET studies. 22, 23 Cerebral blood flow heterogeneity In normal human cerebral capillaries, CBF is markedly heterogeneous. 24 This heterogeneity of CBF is believed to be linked to a mechanism that helps regulate tissue oxygen metabolism. 24, 25 In states of altered cerebral hemodynamics, such as functional activation or lowered perfusion pressure due to a pathology, the flow velocities show a more homogeneous distribution, 26 which is believed to improve oxygen delivery. 24, 27 This ability to change CBF provides a regulatory mechanism for the tissue to adapt to a situation with altered hemodynamics. The heterogeneity of CBF, the FH, has been shown to be assessable by DSC MRI. 28 The method is based on observing the distribution of transit times by DSC MRI and converting that to a distribution of flow values 28 utilizing tools originally developed for describing major vessel transport and microvascular tracer retention. 29 The FH determined by DSC MRI has been shown to confirm the heterogeneous flow distribution in normal cerebrovascular circulation 28 and homogenization of the flow distribution in the setting of compromised circulation in acute stroke 27, 30 (Figure 3). Contrast agent mean transit time The time that it takes for blood to move from the arterial to the venous side of the circulation, i.e. the time blood spends in the capillary bed, is characterized by the MTT of the contrast agent. Due to the inherent differences of MRI and nuclear medicine imaging techniques, the methodology for determining MTT, as the normalized first moment of the contrast Figure 3. The development of the ischemic lesion and the perfusion abnormalities in a 67-year-old woman (patient 10) during the first week of ischemic stroke. The abnormalities on flow heterogeneity (FH) maps [FH(01) and FH(05)] are presented as color-coded overlays of the voxelbased probability value onto the corresponding CBF map. The ischemic lesion on diffusion-weighted images increases from the hyperacute phase to 24 h, and further to 1 week, with simultaneous decrease in the sizes of the perfusion abnormalities on FH01, FH05, CBV, CBF, and MTT maps. At the hyperacute phase and at 24 h, the size of the FH abnormality [both FH(01) and FH(05)] exceeds that of CBV and CBF, but no difference is observed at 1 week. The size of the FH [both FH(01) and FH(05)] abnormality remains smaller than MTT during the whole week. (From Perkiö J et al. Abnormal intravoxel cerebral blood flow heterogeneity in human ischemic stroke determined by dynamic susceptibility contrast magnetic resonance imaging. Stroke 2005;36:44-49; with permission). 30 agent efflux curve, cannot be utilized with DSC MRI. 31 However, utilizing the methodology to determine CBF, 22, 23 MTT can be determined by the central volume theorem as the ratio CBV:CBF. 32 Vol No. 2 EUROPA MEDICOPHYSICA 275

6 ARONEN DIFFUSION AND PERFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING TECHNIQUES IN STROKE RECOVERY Characterization of diffusion lesion and hypoperfusion lesions Diffusion lesion The ADC decreases rapidly in acute ischemia 33, 34 followed by a reversal in ADC in 5 to 10 days, first returning to a healthy level 33, 35, 36 and subsequently rising above normal in the chronic phase 33, 34 due to cavitation and replacement of brain tissue with water in necrotic tissue. Due to the temporal evolution of the ADC values from the initially reduced values to pseudonormalization and further elevation above normal levels, DWI is especially useful in estimating the lesion age and differentiating acute ischemic lesions from chronic ones. 37 Typically, an untreated ischemic infarct increases in size during the first week after an insult. 38, 39 Further, the increase in the volume of the lesion is more pronounced between the first two days of the developing infarct than between the second day and a week. 38, 40 The acute DWI volume has been shown to correlate with the final volume, but not, however, to predict volumetric progression of the infarct. 41 Whereas the lesion visible on the acute DWI generally predicts the irreversibly damaged ischemic core, this is not always the case; reversal of the DWI lesion back to normal without any intervention has been reported. 42 Based on animal studies, this does not mean that the ischemic tissue would have fully recovered. 43 The results of previous studies, therefore, indicate that tissue with elevated signal intensity on DWI is not necessarily infarcted, and early normalization of high signal intensity lesions does not mean that the tissue will eventually survive. Hypoperfusion lesions Generally, the relative sizes of the hypoperfusion volumes in the acute phase can be shown by the following relation: MTT > CBF > CBV. At one week there is no significant difference between the volumes (Figure 3). Different perfusion parameters give very different information concerning the degree of the perfusion abnormality, and a combination of information from all perfusion parameters provides a more precise view of the probable evolution of the infarct. 44 MTT overestimates the risk of infarct growth, since it includes many different levels of ischemia and oligemia, even areas that may not progress to infarction. 45 The size of the CBV defect is the best predictor of the final infarct size. Assessment of the risk for stroke progression The site of arterial occlusion determines progression to infarction. 46 The absence of flow in proximal middle cerebral artery is significantly associated with unfavorable clinical outcome. 45 Even when vessel occlusion persists, hypoperfused tissue on MR imaging does not necessarily progress toward infarction. 46 The main purpose of an imaging study for an acute stroke patient is to assess the risks associated with the temporal evolution of the ischemia to aid the clinical decision making about the treatment strategy of the patient. There are several approaches to interpreting clinical and image information, but typically all utilize information from both DWI and PWI. These techniques are especially important because combining the information from ADC and PWI can possibly distinguish the surviving and nonsurviving subregions of ischemic brain tissue in the acute phase of stroke. 47 The assessment of the risk of infarction is obtained with higher specificity and sensitivity with algorithms that combine acute DWI and PWI than with algorithms that use DWI or PWI individually. 48 This underlines the importance of utilizing both methods in the acute stroke imaging protocol. Volumes of diffusion and hypoperfusion lesions Identifying and characterizing the volume of an ischemic stroke lesion is important for determining initial treatment and following subsequent changes related to treatment or progression of the initial ischemic event. Combined diffusion and PWI has been shown to be able to detect hemodynamically different subregions inside the initial perfusion abnormality. These subregions may have different levels of survival which can be predicted with DWI/PWI. 49 Measurement of ADC combined with perfusion MRI may help distinguish different subregions in acutely hypoperfused brain. 47 Absolute estimates of perfusion parameters have been used to assess the infarct evolution. Both increases in MTT and decreases in CBF have been found to predict infarction. 50 Moreover, a CBF value of 12 ml/100 g/min in a tissue volume of at least 50 ml predicts further lesion growth in hyperacute stroke patients. 42 The lower baseline ADC precedes delayed perfusion normalization, suggesting that worse cell swelling impedes reperfusion. 51 While both PWI and DWI lesion volumes have 276 EUROPA MEDICOPHYSICA June 2007

7 DIFFUSION AND PERFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING TECHNIQUES IN STROKE RECOVERY ARONEN Figure 4. Right hemiparesis and aphasia in a 71-year-old woman at the time of the initial MR imaging examination. This is an example where there is significant perfusion diffusion mismatch in the initial imaging and significant growth of the infarcted tissue during the follow-up. A hyperintense lesion (arrow in A) representing infarct in the left hemisphere is depicted on transverse trace DW images obtained 7 h (A), 28 h (B), and 1 week (C) after the onset of symptoms. On the 1 st day, the transverse CBF (E) and MTT (F) maps depict larger hypoperfused tissue areas (arrows in F) than the CBV (D) map does. As shown by the follow-up trace DW images (B, C), the infarct (arrow in C) in this patient grows posteriorly outside the visually abnormal initial CBV lesion. D-F were obrained at the same time point and section position as in A. (From Karonen JO et al. Combined perfusion- and diffusion-weighted MR imaging in acute ischemic stroke during the 1st week: a longitudinal study. Radiology 2000;217: ; with permission). 40 been shown to correlate with the outcome of the stroke, the NIHSS score at the acute stage has been shown to be the only independent predictor of the long-term clinical outcome. 52 In addition, it has been shown that particular DWI lesion patterns are a stronger and more consistent outcome predictor of stroke than DWI lesion volume. 53 Mismatch between diffusion and perfusion in ischemic lesions Typically in acute ischemic stroke, a perfusion abnormality exceeds the volume of a diffusion abnormality. This is usually seen as the DSC-based image exceeding the DWI-based ischemic lesion. 38, 39, The difference in size between the perfusion abnormality and the DWI-based lesion is referred to as diffusion-perfusion mismatch and is considered to be an estimate of the ischemic penumbra, tissue where the neurons are functionally silent but structurally intact and thereby potentially salvageable with recanalization. 38, 39, 44 The sizes of CBV-DWI, CBF-DWI, and MTT-DWI perfusion-diffusion mismatches all correlate significantly with the infarct growth and the initial CBV lesion is the closest estimate to the final infarct size. The sizes of the initial perfusion-diffusion mismatches correlate significantly with the extent of the infarct growth; in case of a large mismatch the infarct growth is more significant than in case of a small or no mismatch 38, 40 (Figures 4, 5). A substantial mismatch (>50%) between initial CBF- DWI mismatch (obtained within 24 h of symptom onset) is associated with substantial (>50%) infarct growth during the first week after stroke. 58 Also, a less significant PWI-DWI mismatch (PWI lesion 10 ml and 120% of the DWI lesion) is strongly associat- Vol No. 2 EUROPA MEDICOPHYSICA 277

8 ARONEN DIFFUSION AND PERFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING TECHNIQUES IN STROKE RECOVERY Figure 5. Aphasia and mild hemiparesis on the right side in a 67-year-old man at the time of the initial MR imaging examination. This is an example where there is practically no significant perfusion diffusion mismatch in the initial imaging and no significant growth of the infarcted tissue during the follow-up. The transverse trace DW images were obtained 11 h (A), 28 h (B), and 1 week (C) after the onset of symptoms and demonstrate a hyperintense lesion (arrow in A) in the left hemisphere, which represents infarct. The bottom row shows transverse CBV (D), rcbf (E), and MTT (F) maps at the same time point and section position as in A. No mismatch area can be seen between the infarct in A and hypoperfusion areas (arrows in F) in D-F, and no infarct growth is seen on the follow-up trace images in B and C. (From Karonen JO et al. Combined perfusion- and diffusion-weighted MR imaging in acute ischemic stroke during the 1st week: a longitudinal study. Radiology 2000;217: ; with permission). 40 ed with early reperfusion and favorable clinical outcome. 59 However, infarct growth may still occur in the absence of mismatch. 60 Also the detection of T1 contrast enhancement has been shown to assist in determining the age of infarct. 61 Additionally, a genetic bias has been found in carriers with an apolipoprotein polymorphism epsilon 4 that shows enhanced infarct growth during the first week supporting the increased general vulnerability of the brain in epsilon 4 carriers. 62, 63 While the PWI-DWI mismatch is considered one of the most accurate methods of identifying areas of hypoperfusion tissue, it is still a method under development. It has been shown that not all tissue in the mismatch area has the same risk of damage. 64 This means that, although a mismatch may be identified, accurate prediction of salvageable tissue may not be possible. In addition, the PWI parameter used in the mismatch definition is far less important than the threshold chosen to represent significant oligemia. 65 Moreover, absolute PWI thresholds for infarction are not plausible because they are time dependent. Thus, it appears that there is no single threshold and, therefore, no mismatch definition that can predict tissue fate for all patients. 65 Moreover, the ischemic penumbra includes not only the region of diffusion/perfusion mismatch, but also portions of the region of initial diffusion abnormality. 66 In addition to DWI-PWI mismatch, clinical-diffusion mismatch (CDM), defined as NIHSS 8 and DWI 278 EUROPA MEDICOPHYSICA June 2007

9 DIFFUSION AND PERFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING TECHNIQUES IN STROKE RECOVERY ARONEN 25 ml, has been suggested to indicate infarct growth 67 and neurological deterioration. 68 Although, the CDM correlates with DWI-PWI mismatch with high specificity, 67 there is little agreement between the two mismatch models 69 suggesting that the two models identify two very different groups of patients. Finally, tissue oxygen utilization detected by BOLD imaging adds additional information concerning the metabolic state of the threatened brain tissue and provides a better estimation of the real penumbra than PWI. 46 While current stroke evaluation relies on PWI-DWI MRI that does not distinguish gray and white matter, compelling evidence shows that this may overlook some important diagnostic and therapeutic differences between the two types of tissue. Gray matter has higher blood flow requirements than white matter in normal brain 70 and blood flow thresholds for ischemia are different in gray and white matter 71 indicating the need for rather tissue-specific than whole-brain thresholds as more precise measures of predicting the likelihood of infarction. 72 Also, the ischemic penumbra evolves more slowly in white matter than in gray matter 73 indicating that gray and white matter may require different therapeutic strategies. 74 Current research is focused on identifying imaging markers that may identify patients most likely to benefit from treatment. Predictive models of functional and ischemic tissue recovery Improving the ability to predict patient outcome after acute ischemic stroke may require statistical modeling of several imaging parameters rather than relying on a single imaging measurement alone. As such, multivariable statistical models have been acknowledged and developed to predict the outcome of stroke after treatment, with varying results. 75, 76 Previously, a multiparametric MRI model has been developed 77, 78 as an Iterative Self-Organizing Data Analysis Technique (ISO- DATA) for the purpose of identifying ischemic tissue in clinical stroke. It was found that the results of this technique were significantly correlated with the NIHSS scale compared with just acute DWI volumes. In addition to using maps of ADC, T2 and the same self-organizing data analysis (ISODATA) technique, another group 79 has shown that the ability to predict final infarct size increased when subacute MRI parameters were included along with acute DWI, DWI-ISODATA mismatch and acute T2W image lesion size. Atlas methodology, in which the anatomical location of the lesion is accounted for, is a novel, feasible way of integrating infarct size and location to predict stroke severity and can estimate stroke severity better than volume alone. 80 Whereas the actual predictive value of DWI and DSC MRI of stroke evolution remains at the group level, these techniques already are a vital part of clinical decision making and are actively being developed to allow forming risk profiles on an individual basis. Generalized linear models (GLM) have also been used 81 to predict infarction risk in acute ischemic stroke and may be a more sensitive means for monitoring therapeutic effects on a voxel-wise basis. Similarly, GLMs have been used to help predict tissue outcome by finding the most optimal AIF for estimating CBF. 82 Another group used a fully Bayesian approach 83 to obtain more accurate estimates of CBF, compared with the standard singular value decomposition method. Other methods have used a parametric normal classifier algorithm 84 incorporating CBF, CBV and MTT to predict infarct. It has also been shown 85 that a combination of clinical variables and MR DWI variables in a statistical model allow more reliable early prediction of stroke recovery than any factor alone. Cluster analysis has also been used 86 to explore the spatial characteristics of infarcted and noninfarcted tissue and has found that noninfarcted instances tends to cluster together while infarcted instances are more dispersed, suggesting that there may not exist a stringent boundary separating infarcted from noninfarcted instances. While these predictive models give new information about ischemic tissue, they are still being developed in the hopes of better characterizing and predicting the initial and final outcome of stroke. Treatment of ischemic stroke For minimizing the neuronal damage, currently, the only FDA approved drug for the treatment of stroke, recombinant tissue plasminogen activator (rt- PA), should to be administered within 3 to 6 h after the onset of symptoms of stroke, i.e. during the hyperacute phase. Thus, it is of the utmost importance to utilize methods for the reliable detection and localization of hemodynamic disturbances already in the hyperacute phase of human ischemic stroke. For instance, DWI and PWI could be helpful for the selection of Vol No. 2 EUROPA MEDICOPHYSICA 279

10 ARONEN DIFFUSION AND PERFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING TECHNIQUES IN STROKE RECOVERY patients for tpa therapy 87 and it has been shown that DWI signatures of early tissue ischemic injury can be reversed in humans by prompt thrombolytic vessel recanalization. 66 Thromboylysis/reperfusion of ischemic tissue tpa therapy has been shown to have a beneficial effect on vessel recanalization and functional outcome, appearing to be safe and effective beyond a 3- h time window. 87 However, the sooner that rt-pa is given to stroke patients, the greater the benefit, especially if started within 90 min. 88 Even after thrombolysis has begun, imaging is still an important part of treatment and follow-up. For instance, PWI can be used to indicate the clinical benefit of thrombolytic therapy only hours after the tpa 89 and the main factors influencing clinical outcome after rtpa has been found to be the acute DWI volume and recanalization. 90 Differences in MTT have been found to predict salvage in more severely hypoperfused tissue after reperfusion, suggesting that it is the most clinically useful quantitative perfusion measure. 50 However, while PWI-DWI imaging is considered essential to stroke characterization and management, the definition of diffusion-perfusion mismatch is not standardized and there is still not enough data available to determine the role of mismatch in guiding thrombolysis in routine practice. 60 Cerebral reperfusion injury can be defined as a deterioration of ischemic but salvageable brain tissue after reperfusion. Therefore, it would be highly beneficial to patient survival if reperfusion injury could be assessed accurately. An increase of DWI signal intensity after tpa is likely to indicate cerebral reperfusion injury and the risk of intracerebral hemorrhage after thrombolysis is best predicted by lowered ADC. 91 Also, the reduction in the volume of hypoperfused brain on PWI is a marker of response to treatment and improved function in ischemic stroke patients. Experimental treatments for acute ischemic stroke While tpa is the standard treatment for acute ischemic stroke, other thrombolytic agents are being investigated to improve the mobidity and mortality associated with stroke. Platelet inhibitors have been used in combination with thrombolytics and have shown an improved recanalization rate of 90% compared with thrombolytic alone. 92 Combinations with direct thrombin inhibitors have also been studied with promising, preliminary results. 93 In addition, it has been shown that there is a potential benefit for intravenous thrombolysis to as long as 4-5 h after onset 94 and even up to 9 h after stroke onset. 95 Newer thrombolytic agents, such as desmoteplase, tenecteplase, ancrod and batroxobin, have shown a 10% relative-risk reduction for death and disability in treated patients. 94 Furthermore, the combination of ultrasound with thrombolytic agents may enhance their potential benefit by means of enzyme-mediated thrombolysis increasing tpa-mediated thrombolysis, while enhancing the recanalization rate. 96 In addition to newer thrombolytic agents, alternative methods of stroke treatment are being investigated, as well. Induced hypertension has been considered as a potential option to augment cerebral perfusion, particularly in patients with large-vessel disease and infarcts thought to be due to hemodynamic compromise. 94, 97 A number of neuroprotective agents are undergoing trials to assess their effectiveness of reducing brain injury during acute stroke, generally through actions on the brain itself rather than by directly improving blood flow and perfusion through occluded cerebral vessels. 94 These neuroprotective agents include albumin, caffeinol, transdermal glycerl trinitrate, piclozotan, magnesium, citicolin and lovastatin. Diffusion and perfusion weighted magnetic resonance imaging vs alternative techniques for imaging ischemic stroke Currently, noncontrast computed tomography (CT) scan is the established imaging procedure for the initial evaluation of stroke patients. 98 However, DWI is highly sensitive and specific for detecting acute cerebral ischemia 35, 99 and is more sensitive than CT and T2-weighted MRI 99, 101 DWI also depicts well acute and chronic intracerebral hemorrhage. 98, 100, 102, 103 In addition, the odds of a favorable clinical outcome have been reported to be 1/3 higher for acute stroke patients who received diffusion-perfusion MRI to determine the appropriateness of tpa thrombolysis than patients assessed with conventional noncontrast CT. 104 Single photon emission computed tomography (SPECT) has also been used in stroke evaluation. A large perfusion-diffusion mismatch measured with MRI or SPECT at the acute phase of the infarct can successfully predict infarct growth. There is good agree- 280 EUROPA MEDICOPHYSICA June 2007

11 DIFFUSION AND PERFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING TECHNIQUES IN STROKE RECOVERY ARONEN ment between volumes of decreased CBF measured by SPECT and PWI. Lesions that are apparently small on SPECT are somewhat larger on PWI, probably because of the difference in resolution of these techniques. 38 Combining PET and MRI in acute stroke imaging, recent research suggests that the ADC lesion may not only describe the ischemic core but can also include a considerable portion of penumbral tissue. 105 Measurements of oxygen metabolism by PET have indicated that, although the DWI lesion does indicate cell injury, there is heterogeneity in actual tissue metabolic disruption in the DWI lesion. 106 Phase-contrast MR angiography characterizes the blood flow in the macroscopic arteries providing complementary information to that with diffusion- and PWI in predicting the outcome of patients with acute stroke. 45 It is important to include angiography in the imaging protocol (Figure 6). Stroke and stroke recovery can be followed by many imaging modalities. Primarily, the diagnostics in the acute or hyperacute phase are made with CT to exclude hemorrhage. It is important to note that diffusion and perfusion-weighted MRI studies are very fast to perform and provide significantly more information than CT alone, which potentially may lead to more accurate and effective therapeutic interventions. 104 Not only do they provide information about the characteristics and extent of the ischemic lesion itself, but also about the hypoperfused area around the lesion even at both micro and macrovascular levels. Although, the optimal characterization of stroke recovery is a combination of different techniques, even neurophysiological measurements playing an important role, 107 diffusion and perfusionweighted MRI should be included in the diagnostic armament for following stroke recovery to get the whole picture. Conclusions The imaging value of PWI and DWI is primarily in the acute and hyperacute phases of stroke. However, these techniques may also be used to characterize subacute and chronic phases of stroke. After the initial decrease, the ADC rises above normal levels in the chronic phase 33, 34 making it possible to some extent estimate the age of the infarct. 37 The volumes of perfusion deficits typically decrease after the acute phase 30 returning to either normal levels or proceeding to infarction in the chronic phase. In patients with chronic cerebral Figure 6. Images in a 73-year-old woman with left hemiparesis. This is an example where there is practically significant perfusion diffusion mismatch in the initial imaging and occlusion in the right internal carotid artery. There is significant growth of the infarcted tissue during the follow-up. Initial transverse maps of CBV (A), CBF (B), and MTT (C) and 2D phase-contrast MR angiogram (D) (115/9, 12 flip angle, one signal acquired, 45-cm/s velocity encoding) and transeverse trace diffusion- (E) and T2-wekghted (F) (3,250/90, one signal acquired) images obtained 6.25 h after onset of symptoms. D shows right internal carotid artery occlusion without collateral flow to the middle cerebral artery territory. Significant CBF-diffusion and MTT-diffusion mismatches are detected. (G) Follow-up 2D phase-contrast MR angiogram obtained on 8 th day after stroke shows no recanalization or collateral M1 flow. Transverse trace diffusion-(h) and T2- weighted (I) images obtained 1 week after stroke demonstrate substantial infarct growth in the right basal ganglia and frontal and temporal lobes. (From Liu Y et al. Acute ischemic stroke: predictive value of 2D phase-contrast MR angiography Serial study with combined diffusion and perfusion MR imaging. Radiology 2004;231: ; with permission). 45 ischemia the blood volume has been shown to remain normal, despite the depression of cerebral perfusion. 108 Stroke and stroke recovery can be followed by many imaging modalities. Primarily, the diagnostics in the acute or hyperacute phase are made with CT to exclude hemorrhage. While this is an essential part of every stroke work-up, it is important to note Vol No. 2 EUROPA MEDICOPHYSICA 281

12 ARONEN DIFFUSION AND PERFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING TECHNIQUES IN STROKE RECOVERY that diffusion and perfusion-weighted MRI studies are very fast to perform and provide significantly more information than CT alone, which potentially may lead to more accurate and effective therapeutic interventions. 104 Not only do they provide information about the features and extent of the ischemic lesion itself, but they also help characterize the hypoperfused area around the lesion at both the micro and macrovascular levels. Although, the optimal characterization of stroke recovery utilizes a combination of different techniques, neurophysiological measurements are increasingly playing an important role. 107 To get a complete picture of acute stroke, diffusion and perfusion weighted MRI should be included in the diagnostic armament for following stroke recovery. References 1. Schellinger PD, Kaste M, Hacke W. An update on thrombolytic therapy for acute stroke. 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