Selection of thrombolytic therapy beyond 3 h using magnetic resonance imaging

PURPOSE OF REVIEW: Use of intravenous thrombolytic therapy in ischaemic stroke is restricted to a 3-h time window because of the proof of this time window in pivotal clinical trials. Thrombolysis is aimed at recanalization of occluded arteries and reperfusion of the ischaemic penumbra, a region of critically hypoperfused, functionally impaired, but potentially viable brain. There are a number of current prospective trials that are testing the hypothesis that the presence of the penumbra will predict thrombolytic responders beyond 3 h. RECENT FINDINGS: Using magnetic resonance imaging, a mismatch between a larger perfusion-weighted imaging lesion and smaller diffusion-weighted imaging lesion is considered to represent the ischaemic penumbra. Perfusion-weighted imaging provides semiquantitative cerebral blood flow imaging and diffusion-weighted imaging is an index of the largely irreversible ischaemic core. This definition has been modified with the recognition that the perfusion-weighted imaging lesion includes benign oligaemia and that a portion of the diffusion-weighted imaging core is potentially salvageable with rapid reperfusion. Most acute stroke patients have a magnetic resonance imaging-penumbral signature within 6 h of stroke onset. The penumbra is commonly, but not invariably, associated with proximal arterial occlusion and is time-dependent. Preliminary studies have shown benefit from thrombolytic therapy beyond the established 3-h window. SUMMARY: Penumbral imaging using magnetic resonance imaging with perfusion over diffusion weighted imaging mismatch can provide a physiological 'tissue clock' in individual patients. Based on this hypothesis, a number of prospective trials are being performed. These include EPITHET, DEFUSE, DIAS, MR RESCUE and ROSIE.     

表观弥散系数对确定急性缺血性卒中缺血半暗带的潜在价值

目的 探讨表观弥散系数（apparent diffusion coefficient,ADC）对确定急性缺血性卒中缺血半暗带的潜在价值。 方法 选择发病9 h内完成多模式磁共振成像（magnetic resonance imaging,MRI）检查的前循环急性缺血性卒中患者49例。应用自制软件进行灌注加权像（perfusion-weighted imaging,PWI）和弥散加权像（diffusion-weighted imaging,DWI）异常区域的体积测量。缺血半暗带以PWI/DWI错配表示。同时采用全自动图像分析系统,以DWI图像计算得到的ADC图作为输入数据,来判断缺血半暗带的存在（以下简称为ADC方法）,然后比较这两种方法在判断缺血半暗带方面的差异。 结果 入选的49例患者中,存在PWI/DWI错配者为43例,符合ADC方法判断缺血半暗带标准者有41例。这两种方法在判断是否存在缺血半暗带的结果中有41例相符,对判断缺血半暗带的差异无统计学意义（P>0.05）。ADC方法判断缺血半暗带的敏感度为88.4%、特异度为50.0%。 结论 由于不需做PWI检查,ADC方法对确定缺血半暗带具有潜在的临床实用价值,有可能成为一种简便易行的确定缺血半暗带的方法。     

Expanding the window for thrombolytic therapy in acute stroke. The potential role of acute MRI for patient selection.

BACKGROUND: Effective therapy was not available for treatment of acute stroke until 1995, when tissue plasminogen activator (tPA) was shown to improve neurological and functional outcome in stroke patients who were treated within 3 hours of symptom onset. SUMMARY OF REVIEW: Currently, many patients do not qualify for tPA therapy because they present for evaluation beyond 3 hours after stroke onset. Attempts to expand the treatment window to 6 hours, using CT to select patients, have failed. Use of early MR imaging may provide significant advantages over CT for identification of patients who are likely to benefit from thrombolytic therapy because (1) the early perfusion-weighted imaging (PWI) lesion estimates the region of acute dysfunctional brain tissue, whereas the acute diffusion-weighted imaging (DWI) lesion appears to correspond to the core of the early infarction; (2) the mismatch between the acute PWI lesion and the smaller DWI lesion represents potentially salvageable brain tissue (an estimate of the ischemic penumbra); and (3) in patients with a PWI/DWI mismatch, early reperfusion is often associated with substantial clinical improvement and reversal or reduction of DWI lesion growth. CONCLUSIONS: Clinical trials that use new MRI techniques to screen patients may be able to identify a subset of acute stroke patients who are ideal candidates for thrombolytic therapy even beyond 3 hours after stroke onset.     

Automated core–penumbra quantification in neonatal ischemic brain injury

Neonatal hypoxic-ischemic brain injury (HII) and arterial ischemic stroke (AIS) result in irreversibly injured (core) and salvageable (penumbral) tissue regions. Identification and reliable quantification of salvageable tissue is pivotal to any effective and safe intervention. Magnetic resonance imaging (MRI) is the current standard to distinguish core from penumbra using diffusion-perfusion mismatch (DPM). However, subtle MR signal variations between core–penumbral regions make their visual delineation difficult. We hypothesized that computational analysis of MRI data provides a more accurate assessment of core and penumbral tissue evolution in HII/AIS. We used two neonatal rat-pup models of HII/AIS (unilateral and global hypoxic-ischemia) and clinical data sets from neonates with AIS to test our noninvasive, automated computational approach, Hierarchical Region Splitting (HRS), to detect and quantify ischemic core–penumbra using only a single MRI modality (T2- or diffusion-weighted imaging, T2WI/DWI). We also validated our approach by comparing core–penumbral images (from HRS) to DPM with immunohistochemical validation of HII tissues. Our translational and clinical data results showed that HRS could accurately and reliably distinguish the ischemic core from penumbra and their spatiotemporal evolution, which may aid in the vetting and execution of effective therapeutic interventions as well as patient selection.     

Combined diffusion and perfusion MRI with correlation to single-photon emission CT in acute ischemic stroke. Ischemic penumbra predicts infarct growth.

BACKGROUND AND PURPOSE: More effective imaging methods are needed to overcome the limitations of CT in the investigation of treatments for acute ischemic stroke. Diffusion-weighted MRI (DWI) is sensitive in detecting infarcted brain tissue, whereas perfusion-weighted MRI (PWI) can detect brain perfusion in the same imaging session. Combining these methods may help in identifying the ischemic penumbra, which is an important concept in the hemodynamics of acute stroke. The purpose of this study was to determine whether combined DWI and PWI in acute (<24 hours) ischemic stroke can predict infarct growth and final size. METHODS: Forty-six patients with acute ischemic stroke underwent DWI and PWI on days 1, 2, and 8. No patient received thrombolysis. Twenty-three patients underwent single-photon emission CT in the acute phase. Lesion volumes were measured from DWI, SPECT, and maps of relative cerebral blood flow calculated from PWI. RESULTS: The mean volume of infarcted tissue detected by DWI increased from 46.1 to 75.6 cm(3) between days 1 and 2 (P<0.001; n=46) and to 78.5 cm(3) after 1 week (P<0.001; n=42). The perfusion-diffusion mismatch correlated with infarct growth (r=0. 699, P<0.001). The volume of hypoperfusion on the initial PWI correlated with final infarct size (r=0.827, P<0.001). The hypoperfusion volumes detected by PWI and SPECT correlated significantly (r=0.824, P<0.001). CONCLUSIONS: Combined DWI and PWI can predict infarct enlargement in acute stroke. PWI can detect hypoperfused brain tissue in good agreement with SPECT in acute stroke.     

Etiology of Perfusion-Diffusion Magnetic Resonance Imaging Mismatch Patterns

BACKGROUND AND PURPOSE: Diffusion-and perfusion-weighted magnetic resonance imaging (DWI and PWI) are useful tools for the assessment of brain ischemia. Discrepancies between the extent of DWI and PWI abnormalities are thought to depend pre dominantly on time from symptom onset to magnetic resonance imaging (MRI) examination. However, underlying ischemic stroke etiology can also be important. A mismatch may indicate the presence of tissue at risk for infarction, whereas the relevance of other DWI/PWI patterns is uncertain. The authors therefore investigated the etiology of brain ischemia in patients with different DWI/PWI patterns. METHODS: Retrospective study of 130 patients with acute brain ischemia and detailed stroke workup, including MRI within a week after symptom onset (40 +/- 39 hours). Patients were divided into the following groups: mis-match (PWI > DWI), reverse mismatch (DWI > PWI), and match (<25% difference between PWI and DWI). RESULTS: Mismatch occurred in 49% of patients, whereas 22% had reverse mis-match and 29% matched lesions. Time from symptom onset to MRI examination was similar between the 3 groups. Largeartery atherosclerosis increased by almost 4-fold the odds of mismatch (odds ratio: 3.89, 95% confidence interval: 1.72-8.78; P < .001), whereas patients with reverse mismatch were likely to have cryptogenic stroke. Patients with matched lesions were similarly distributed among different stroke subtypes. CONCLUSIONS: Ischemic stroke etiology appears to influence the development of specific DWI/PWI patterns. Prospective studies are needed to confirm these observations.     

Cerebrovascular diseases

Conventional neuroradiological techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), make a fundamental contribution in both the acute and chronic phases of stroke. Recent years have witnessed the development of new imaging modalities, which include diffusion-weighted imaging (DWI), perfusion-weighted imaging (PWI), CT-angiography (CTA), MR-angiography (MRA), magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI) and functional MRI (fMRI). While CTA, MRA, DWI and PWI are commonly used for clinical purposes, DTI, MRS and fMRI are becoming increasingly important in the field of experimental research of cerebrovascular diseases, but are still far from becoming of primary usefulness in the everyday clinical setting.     

Detection of the ischemic penumbra using pH-weighted MRI.

The classic definition of the ischemic penumbra is a hypoperfused region in which metabolism is impaired, but still sufficient to maintain cellular polarization. Perfusion- and diffusion-weighted MRI (PWI, DWI) can identify regions of reduced perfusion and cellular depolarization, respectively, but it often remains unclear whether a PWI-DWI mismatch corresponds to benign oligemia or a true penumbra. We hypothesized that pH-weighted MRI (pHWI) can subdivide the PWI-DWI mismatch into these regions. Twenty-one rats underwent permanent middle cerebral artery occlusion and ischemic evolution over the first 3.5 h post-occlusion was studied using multiparametric MRI. End point was the stroke area defined by T(2)-hyperintensity at 24 h. In the acute phase, areas of reduced pH were always larger than or equal to DWI deficits and smaller than or equal to PWI deficits. Group analysis showed that pHWI deficits during this phase coincided with the resulting infarct area at endpoint. Final infarcts were smaller than PWI deficits (range 65% to 90%, depending on the severity of the occlusion) and much larger than acute DWI deficits. These data suggest that the outer boundary of the hypoperfused area showing a decrease in pH without DWI abnormality may correspond to the outer boundary of the ischemic penumbra, while the hypoperfused region at normal pH may correspond to benign oligemia. These first results show that pHWI can provide information complementary to PWI and DWI in the delineation of ischemic tissue.     

Absent middle cerebral artery flow predicts the presence and evolution of the ischemic penumbra

OBJECTIVES: In acute ischemic stroke the pattern of a perfusion-imaging (PI) lesion larger than the diffusion-weighted imaging (DWI) lesion may be a marker of the ischemic penumbra. We hypothesized that acute middle cerebral artery (MCA) occlusion would predict the presence of presumed "penumbral" patterns (PI > DWI), ischemic core evolution, and stroke outcome. METHODS: Echoplanar PI, DWI, and magnetic resonance angiography (MRA) were performed in 26 patients with MCA territory stroke. Imaging and clinical studies (Canadian Neurological Scale, Barthel Index, and Rankin Scale) were performed within 24 hours of onset and repeated at days 4 and 90. RESULTS: MCA flow was absent in 9 of 26 patients. This was associated with larger acute PI and DWI lesions, greater PI/DWI mismatch, early DWI lesion expansion, larger final infarct size, worse clinical outcome (p < 0.01) and provided independent prognostic information (multiple linear regression analysis, p < 0.05). Acute penumbral patterns were present in 14 of 26 patients. Most of these patients (9 of 14) had no MCA flow, whereas all nonpenumbral patients (PI < or = DWI lesion) had MCA flow (p < 0.001). Penumbral-pattern patients with absent MCA flow had greater DWI lesion expansion (p < 0.05) and worse clinical outcome (Rankin Scale score, p < 0.05). CONCLUSIONS: Absent MCA flow on MRA predicts the presence of a presumed penumbral pattern on acute PI and DWI and worse stroke outcome. Combined MRA, PI, and DWI can identify individual patients at risk of ischemic core progression and the potential to respond to thrombolytic therapy beyond 3 hours.     

Role of diffusion and perfusion MRI in selecting patients for reperfusion therapies

After onset of ischemic stroke, potentially viable tissue at risk (ischemic penumbra) may be salvageable. Currently, intravenous alteplase is approved for up to 4.5 hours after symptom onset of acute ischemic stroke. Increasing this time window may allow many more patients to be treated. The ability to use MRI to help define the irreversibly damaged brain (infarct core) and the reversible ischemic penumbra shows great promise for stroke treatment. Recent advances in penumbral imaging technology may enable a phase III trial of an intravenous thrombolytic to be performed beyond 4.5 hours using techniques to select patients with penumbral tissue.     

3-Tesla versus 1.5-Tesla magnetic resonance diffusion and perfusion imaging in hyperacute ischemic stroke

BACKGROUND: Clinical 3-tesla magnetic resonance imaging systems are becoming widespread. No studies have examined differences between 1.5-tesla and 3-tesla imaging for the assessment of hyperacute ischemic stroke (<6 h from symptom onset). Our objective was to compare 1.5-tesla and 3-tesla diffusion and perfusion imaging for hyperacute stroke using optimized protocols. METHODS: Three patients or their surrogate provided informed consent. Diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) was performed sequentially at 1.5 T and 3 T. DWI, apparent diffusion coefficient (ADC) maps and relative time-to-peak (TTP) maps were registered and assessed. DWI contrast-to-noise ratio (CNR) and ADC contrast were measured and compared. The infarct lesion volume (ILV) and thresholded ischemic volume (TIV) were estimated on the ADC and TTP maps, respectively, with the penumbral volume being defined as the difference between these volumes. RESULTS: Qualitatively, the 3-tesla TTP images exhibited greater feature detail. Quantitatively, the DWI CNR and ILV were similar at both field strengths, the ADC contrast was greater at 3 T and the TIV and penumbral volumes were much smaller at 3 T. CONCLUSIONS: Overall, the 3-tesla diffusion and perfusion images were at least as good and in some ways superior to the 1.5-tesla images for assessing hyperacute stroke. The TTP maps showed greater feature detail at 3 T. The ischemic and penumbra volumes were much greater at 1.5 T, indicating a potential difference in the diagnostic utility of the PWI-DWI mismatch between field strengths.     

Advanced imaging to extend the therapeutic time window of acute ischemic stroke

Reperfusion therapy for acute stroke has evolved from the initial use of intravenous tissue plasminogen activator (tPA) within 3 hours of symptom onset to more recent guideline‐recommended use up to 4.5 hours. In addition, endovascular therapy is increasingly utilized for stroke treatment and is typically initiated up to 8 hours after onset. Recent studies demonstrate that imaging of the ischemic penumbra with diffusion/perfusion magnetic resonance imaging (MRI) can identify subgroups of patients who are likely to improve following successful reperfusion (Target Mismatch profile) and others who are at increased risk for hemorrhage and poor clinical outcomes (Malignant profile). New data indicate that stent retriever devices provide better recanalization efficacy and clinical outcomes than the previously available mechanical thrombectomy devices. Going forward, we believe that the use of penumbral imaging with validated MRI techniques, as well as the currently less well‐validated computed tomography (CT) perfusion approach, will maximize benefit and reduce the risk of adverse events and poor outcomes when used both early after stroke onset and at later time points. New trials that feature diffusion/perfusion MRI or CT perfusion‐based patient selection for treatment with intravenous tPA and or endovascular therapies versus nonreperfused control groups are planned or in progress. We predict that these trials will confirm the hypothesis that penumbral imaging can enhance patient selection and extend the therapeutic time window for acute ischemic stroke. ANN NEUROL 2013.     

Influence of pretreatment MRI parameters on clinical outcome, recanalization and infarct size in 49 stroke patients treated by intravenous tissue plasminogen activator

We hypothesized that pretreatment magnetic resonance imaging (MRI) parameters might predict clinical outcome, recanalization and final infarct size in acute ischemic stroke patients treated by intravenous recombinant tissue plasminogen activator (rt-PA). MRI was performed prior to thrombolysis and at day 1 with the following sequences: magnetic resonance angiography (MRA), T2*-gradient echo (GE) imaging, diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI). Final infarct size was assessed at day 60 by T2-weighted imaging (T2-WI). The National Institutes of Health Stroke Scale (NIHSS) score was assessed prior to rt-PA therapy and the modified Rankin Scale (m-RS) score was assessed at day 60. A poor outcome was defined as a day 60 m-RS score >2. Univariate and multivariate logistic regression analyses were used to identify the predictors of clinical outcome, recanalization and infarct size. Forty-nine patients fulfilled the inclusion criteria. Baseline NIHSS score was the best independent indicator of clinical outcome (p=0.002). A worse clinical outcome was observed in patients with tandem internal carotid artery (ICA)+middle cerebral artery (MCA) occlusion versus other sites of arterial occlusion (p=0.009), and in patients with larger pretreatment PWI (p=0.001) and DWI (p=0.01) lesion volumes. Two factors predict a low rate of recanalization: a proximal site of arterial occlusion (p=0.02) and a delayed time to peak (TTP) on pretreatment PWI (p=0.05). The final infarct size was correlated with pretreatment DWI lesion volume (p=0.025). Recanalization was associated with a lower final infarct size (p=0.003). In conclusion, a severe baseline NIHSS score, a critical level of pretreatment DWI/PWI parameters and a proximal site of occlusion are predictive of a worse outcome after IV rt-PA for acute ischemic stroke.     

Perfusion and diffusion magnetic resonance imaging in human cerebral venous thrombosis

Background Diagnosis of cerebral venous thrombosis (CVT) is usually achieved by digital subtraction angiography or magnetic resonance angiography, while structural brain tissue damage can be assessed by computed tomography or magnetic resonance imaging (MRI). Using perfusion and diffusion weighted imaging (PWI, DWI) we aimed in this study to identify pathophysiological patterns corresponding to only functional and hence reversible tissue involvement. Methods PWI, DWI, and conventional MRI were performed in six CVT patients acutely and after 16–26 days when their clinical condition had improved. All patients were treated with partial thromboplastin time-effective intravenous heparin. After intravenous administration of a paramagnetic contrast agent, bolus track PWI allows pixel based determination of mean transit time (MTT) and cerebral blood volume (CBV). DWI was performed with two different b values (0, 1000 s/mm²) for calculation of apparent diffusion coefficient (ADC) maps. Results In five of six cases increased MTT values were observed initially, whereas the CBV was normal, indicating a reduction of cerebral blood flow. ADC values were normal. On follow up after clinical recovery MTT prolongations had resolved. Areas with prolonged MTT did not evolve into structural lesions. Conclusion In patients with CVT, prolongations of MTT in the absence of changes in CBV and ADC seem to indicate reversible involvement of brain tissue, a situation corresponding to the ischaemic penumbra. Received: 20 June 2000 / Received in revised form: 27 November 2000 / Accepted: 19 January 2001     

Imaging the ischaemic penumbra

PURPOSE OF REVIEW: Imaging the penumbra is essential, not only to identify patients who might benefit from thrombolysis, but also to further understanding of the ischaemic process, thereby potentially revealing new opportunities for therapeutic intervention. Here we review recent imaging studies of the acute stroke process. RECENT FINDINGS: Perfusion-computed tomography and computed tomography angiography enable assessment of the haemodynamic status and site of occlusion, leading to their promising use in guiding thrombolysis. The magnetic resonance concept of the diffusion-perfusion 'mismatch' being representative of penumbra appears to be an oversimplification. The mapping of simple variables such as time-to-peak might not directly reveal true penumbral perfusion levels. Also, lesions seen with diffusion-weighted imaging may be reversible as a result of early reperfusion. This reversal with subsequent normalization may represent selective neuronal damage. Late secondary injury, as indicated by the reappearance of the diffusion-weighted imaging lesion, has recently been documented; the mechanisms are unknown but form potential targets for future therapies. Despite these caveats, diffusion-weighted imaging-perfusion-weighted imaging remains the most useful approach to map the pathophysiology of stroke in the clinical setting. Acute/subacute flumazenil positron emission tomography studies are being used as markers of neuronal integrity to help shed further light on infarction thresholds, and potentially document selective neuronal loss. F-labelled fluoromisonidazole positron emission tomography imaging of brain hypoxia documents the temporal and spatial progression of the penumbra. SUMMARY: The goal of understanding the complex process that is acute ischaemia in stroke, and subsequently the development of therapeutic strategies, continues to be advanced by imaging the penumbra in novel ways.     

Diffusion weighted image negative transient ischaemic attack and reversible ischaemic neurological deficit. A report of 10 patients with complete recovery.

Diffusion-weighted magnetic resonance imaging (DWI MRI)-negative transient ischaemic attack (TIA) in hyperacute stroke is a well-known clinical entity. However, no precise analysis of this phenomenon has been reported. We identified 10 patients with TIA or reversible ischaemic neurological deficits (RIND) with no focal hyperintensity on DWI MRI among 108 consecutive acute stroke patients who underwent DWI MRI. In these patients, we analysed the apparent diffusion coefficient (ADC) and determined the ipsilateral/contralateral ratio (IC ratio) to elucidate factors that may contribute to this phenomenon. Each patient also underwent simultaneous magnetic resonance angiography (MRA). The mean IC ratio in our study population was 0.976. Of the 10 patients, 7 had a proximal vascular stenosis on MRA. We discuss the pathophysiology underlying negative DWI MRI results in patients with TIA or RIND.     

The ischaemic penumbra

The concept of an ischaemic penumbra, surrounding a focal cerebral lesion, is now widely accepted, although no universal definition of the 'penumbra' exists. In the present review, we consider the penumbra as that volume of brain tissue at the periphery of a focal, irreversibly damaged area that is threatened by recruitment into necrosis. Implicit to such a definition are several secondary concepts. First, the penumbra is both spatial, in that it surrounds the densely ischaemic core, but it is also temporal, in that its evolution toward infarction is a relatively progressive phenomenon. The pertinent literature is summarized. Second, penumbral tissue is potentially salvageable; the most recent animal studies are reviewed. Third, because electrically silent and pathologically damaged tissues have identical functional characteristics, it is evident that most clinical rating scales, be they neurological, behavioural, or psychological, are poorly adapted to address the problem of the penumbra. Finally, the penumbral tissue is remarkably and intensively 'active': multiple processes of cell death and repair occur and involve molecular mechanisms, electrophysiology and the vasculature.     

Diffusion-weighted and perfusion-weighted magnetic resonance imaging to monitor acute intra-arterial thrombolysis

Diffusion-weighted and perfusion-weighted magnetic resonance imaging (DWI, PWI) are useful in detecting early cerebral ischemic lesions. Intra-arterial thrombolysis is an effective treatment for some patients with acute thromboembolic occlusion. We evaluated the efficacy of acute thrombolytic therapy by using DWI and PWI in 3 patients who presented with internal carotid artery or middle cerebral artery occlusion. On the initial magnetic resonance imaging scans, the abnormal areas shown by PWI were bigger than those shown by DWI. All patients received thrombolytic therapy within 6 hours after stroke onset. In 1 patient, the hyperintensity area detected by initial DWI scanning diminished after thrombolysis. DWI and PWI may be useful to monitor the effectiveness of intra-arterial thrombolysis.     

SB 234551 selective ET(A) receptor antagonism: perfusion/diffusion MRI used to define treatable stroke model, time to treatment and mechanism of protection

Mismatches between tissue perfusion-weighted imaging (PWI; an index of blood flow deficit) and cellular diffusion-weighted imaging (DWI; an index of tissue injury) provide information on potentially salvageable penumbra tissue in focal stroke and can identify “treatable” stroke patients. The present pre-clinical studies were conducted to: a.) Determine PWI (using perfusion delay) and DWI measurements in two experimental stroke models, b.) Utilize these measurements to characterize selective ET_A receptor antagonism (i.e., determine efficacy, time-to-treatment and susceptibility to treatment in the different stroke models), and c.) Determine if increasing the reduced blood flow following a stroke is a mechanism of protection. Permanent middle cerebral artery occlusion (MCAO) or sham surgeries were produced in Sprague Dawley rats (SD; proximal MCAO; hypothesized to be a model of slowly evolving brain injury with a significant penumbra) and in spontaneously hypertensive rats (SHR; distal MCAO; hypothesized to be a model of rapidly evolving brain injury with little penumbra). Infusions of vehicle or SB 234551 (3, 10, or 30 µg/kg/min) were initiated at 0, 75, and/or 180 min post-surgery and maintained for the remainder of 24 h post-surgery. Hyper-intense areas of perfusion delay (PWI) in the forebrain were measured using Gadolinium (Gd) bolus contrast. DWI hyper-intense areas were also measured, and the degree of forebrain DWI-PWI mismatch was determined. Region specific analyses (ROI) were also conducted in the core ischemic and low perfusion/penumbra areas to provide indices of perfusion and changes in the degree of tissue perfusion due to SB 234551 treatment. At 24 h post-surgery, final infarct volume was measured by DWI and by staining forebrain slices. Following SD proximal MCAO, there was a significant mismatch in the ischemic forebrain PWI compared to DWI (PWI > DWI) at 60 min which was maintained up to 150 min (all p < 0.05). By 24 h post-stroke, infarct volume was identical to the area of early perfusion deficit/PWI, suggesting a slow progression of infarct development that expanded into the significant, earlier cortical penumbra (i.e., model with salvageable tissue with potential for intervention). When SB 234551 was administered within the period of peak mismatch (i.e., at 75 min post-stroke), SB 234551 provided significant dose-related reductions in cortical (penumbral) progression to infarction (p < 0.05). Cortical protection was related to an increased/normalization of the stroke-induced decrease in tissue perfusion in cortical penumbra areas (p < 0.05). No SB 234551-induced changes in reduced tissue perfusion were observed in the striatum core ischemic area. Also, when SB-234551 was administered beyond the time of mismatch, no effect on cortical penumbra progression to infarct was observed. In comparison and strikingly different, following SHR distal MCAO there was no mismatch between PWI and DWI (PWI = DWI) as early as 60 min post-stroke, with this early change in SHR DWI being identical to the final infarct volume at 24 h, suggesting a rapidly occurring brain injury with little cortical penumbra (i.e., model with little salvageable tissue or potential for intervention). In distal MCAO, SB 234551 administered immediately at the time of stroke did not have any effect on infarct volume in SHR. These data demonstrate that selective blockade of ET_A receptors is protective following proximal MCAO in SD (i.e. a model similar to “treatable” clinical patients). The protective mechanism appears to be due to enhanced collateral blood flow and salvage of penumbra. Therefore, the use of PWI-DWI mismatch signatures can identify treatable stroke models characterized by a salvageable penumbra and can define appropriate time to treatment protocols. In addition, tissue perfusion information obtained under these conditions might clarify mechanism of protection in the evaluation of protective compounds for focal stroke.     

CT and MRI in the diagnosis of acute stroke and their role in thrombolysis

Thrombolysis is an effective but potential deleterious therapy and should therefore be limited to patients with acute intracerebral vessel occlusion and salvageable tissue. MRI currently develops towards the new diagnostic standard for the selection of stroke patients eligible for acute thrombolytic treatment and acute stroke studies. Diffusion- and perfusion-weighed MRI provides diagnostic information not available from the neurological assessments or from CCT and conventional spin-echo MRI. As high-speed DWI and PWI protocols become standardized, a 15-minute integrated stroke protocol of employing echo-planar imaging (EPI) can be outinely performed in the setting of acute clinical stroke. The combination of these MR techniques is suitable to define tissue at risk of infarction that is potentially salvageable brain tissue (an estimate of the ischemic penumbra) and may respond to early recanalization even beyond 3 hours after stroke onset. The extension of the therapeutic window for thrombolytic therapy towards 6 hours in a subpopulation of acute stroke patients might open the way for the successful reperfusion therapy in more stroke patients.