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Background and Purpose: We aimed to investigate fluid-attenuated inversion recovery changes in the penumbra., Methods: We determined core and perfusion lesions in subjects from the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) and AXIS 2 trial (Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke) with perfusion- and diffusion-weighted imaging at baseline. Only subjects with a mismatch volume >15 mL and ratio >1.2 were included. We created voxel-based relative fluid-attenuated inversion recovery signal intensity (rFLAIR SI) maps at baseline and follow-up. We studied rFLAIR SI in 2 regions of interest: baseline penumbra (baseline perfusion lesion−[core lesion+voxels with apparent diffusion coefficient <620 10−6 mm2/s]) and noninfarcted penumbra (baseline perfusion lesion−follow-up fluid-attenuated inversion recovery lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). We analyzed the association between rFLAIR SI and severity of hypoperfusion, defined as time to maximum of the residue function., Results: In the baseline penumbra, rFLAIR SI was elevated (ratio, 1.04; P=1.7×10−13; n=126) and correlated with severity of hypoperfusion (Pearson r, 0.03; P<1.0×10−4; n=126). In WAKE-UP, imaging at 24 hours revealed a further increase of rFLAIR SI in the noninfarcted penumbra (ratio, 1.05 at 24 hours versus 1.03 at baseline; P=7.1×10−3; n=43). In AXIS 2, imaging at 30 days identified reversibility of the rFLAIR SI (ratio, 1.02 at 30 days versus 1.04 at baseline; P=1.5×10−3; n=26) since it was no longer different from 1 (ratio, 1.01 at 30 days; P=0.099; n=26)., Conclusions: Penumbral rFLAIR SI increases appear early after stroke onset, correlate with severity of hypoperfusion, further increase at 24 hours, and are reversible by 30 days., Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://clinicaltrials.gov; Unique identifier: NCT00927836.

Background and Purpose: It is unclear if sex differences explain some of the variability in the outcomes of stroke patients who undergo endovascular treatment (EVT). In this study we assess the effect of sex on radiological and functional outcomes in EVT-treated acute stroke patients and determine if differences in baseline perfusion status between men and women might account for differences in outcomes., Methods: We included patients from the CRISP (Computed tomographic perfusion to Predict Response to Recanalization in ischemic stroke) study, a prospective cohort study of acute stroke patients who underwent EVT up to 18 hours after last seen well. We designed ordinal regression and univariable and multivariable regression models to examine the association between sex and infarct growth, final infarct volume and 90-day mRS score., Results: We included 198 patients. At baseline, women had smaller perfusion lesions, more often had a target mismatch perfusion profile, and had better collateral perfusion. Women experienced less ischemic core growth (median 15 mL vs. 29 mL, p < 0.01) and had smaller final infarct volumes (median 26 mL vs. 50 mL, p < 0.01). Female sex was associated with a favorable shift on the modified Rankin Scale (adjusted cOR 1.79 [1.04 - 3.08; p = 0.04]) and lower odds of severe disability or death (adjusted OR 0.29 [0.10 - 0.81]; p = 0.02)., Conclusions: The results suggest that women have better collaterals and, therefore, more often exhibit a favorable imaging profile on baseline imaging, experience less lesion growth, and have better clinical outcomes following endovascular therapy., Competing Interests: Declaration of Competing Interest Sören Christensen and Gregory Albers have equity interest in and are consultants for iSchemaView. Gregory Albers is a consultant for Medtronic. RL reports institutional fees from Bayer, Boehringer-Ingelheim, Genentech, Ischemaview, Medtronic and Occlutec., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is widely used to quantify early ischemic changes in the anterior circulation but has limited inter-rater reliability., Aims: We investigated whether application of 3-dimensional boundaries outlining the ASPECTS regions improves inter-rater reliability and accuracy., Methods: We included all patients from our DEFUSE 2 database who had a pretreatment noncontrast computed tomography scan (NCCT) of acceptable quality. Six raters (2 neuroradiologists, 2 vascular neurologists, and 2 neurology residents) scored ASPECTS of each NCCT without ("CT-native") and with the superimposed boundary template ("CT-template"). Gold-standard ASPECTS were generated by the 2 neuroradiologists through joint adjudication. Inter-rater reliability and accuracy were assessed using the intraclass correlation coefficient (ICC) for full-scale agreements and Gwet's AC1 for dichotomized (ASPECTS 0-6 vs 7-10) agreements., Results: Eighty-two patients were included. Inter-rater reliability improved with higher training level for both CT-native (ICC = .15, .31, .54 for residents, neurologists, and radiologists, respectively) and CT-template (ICC = .18, .33, .56). Use of the boundary template improved correlation with the gold-standard for one resident on full-scale agreement (ICC increased from .01 to .31, P = .01) and another resident on dichotomized agreement (AC1 increased from .36 to .64, P = .01), but resulted in no difference for other raters. The template did not improve ICC between raters of the same training level., Conclusions: Inter-rater reliability of ASPECTS improves with physician training level. Standardized display of ASPECTS region boundaries on NCCT does not improve inter-rater reliability but may improve accuracy for some less experienced raters., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Malignant profile computed tomography perfusion (CTP) lesions are associated with poor outcomes after administration of intravenous tissue-plasminogen activator (IV-tPA) for ischemic stroke., Aims: To determine whether published CTP-based lesion thresholds predictive of poor outcomes in a predominantly 8 cm of CTP anatomic coverage cohort would predict poor outcomes in an independent 4 cm of CTP anatomic coverage cohort and to generate optimized 4 cm CTP thresholds., Methods: Ischemic stroke patients with baseline CTP imaging with 4 cm of anatomic coverage before receiving IV-tPA at a single institution were retrospectively studied. Perfusion lesion time to maximum of tissue residue function (Tmax) and cerebral blood flow (CBF) volumes were determined using RAPID automated software. Fisher's exact tests assessed associations between lesion thresholds and outcomes. Receiver operating characteristic (ROC) curves generated optimized thresholds for 4 cm of CTP coverage., Results: Sixty-three patients were included. Poor outcomes were associated with published thresholds of Tmax >6 s > 103 mL, Tmax > 8 s > 86 mL, and Tmax > 10 s > 78 mL but not CBF core >53 mL. Thresholds optimized for 4 cm of CTP coverage and associated with poor outcomes were Tmax > 6 s > 100 mL, Tmax > 8 s > 65 mL, Tmax >10 s > 46 mL, and CBF core >39 mL., Conclusions: We validated the ability of published CTP Tmax lesion volume thresholds to predict poor outcomes despite IV-tPA in an independent cohort using only 4 cm of CTP anatomical coverage. A CBF > 39 mL threshold, rather than the predominantly 8 cm CTP coverage derived CBF threshold of >53 mL, was associated with poor outcomes in this 4 cm CTP coverage cohort.

Background and Purpose- Imaging is frequently used to select acute stroke patients for intra-arterial therapy. Quantitative cerebral blood flow can be measured noninvasively with arterial spin labeling magnetic resonance imaging. Cerebral blood flow levels in the contralateral (unaffected) hemisphere may affect capacity for collateral flow and patient outcome. The goal of this study was to determine whether higher contralateral cerebral blood flow (cCBF) in acute stroke identifies patients with better 90-day functional outcome. Methods- Patients were part of the prospective, multicenter iCAS study (Imaging Collaterals in Acute Stroke) between 2013 and 2017. Consecutive patients were enrolled after being diagnosed with anterior circulation acute ischemic stroke. Inclusion criteria were ischemic anterior circulation stroke, baseline National Institutes of Health Stroke Scale score ≥1, prestroke modified Rankin Scale score ≤2, onset-to-imaging time <24 hours, with imaging including diffusion-weighted imaging and arterial spin labeling. Patients were dichotomized into high and low cCBF groups based on median cCBF. Outcomes were assessed by day-1 and day-5 National Institutes of Health Stroke Scale; and day-30 and day-90 modified Rankin Scale. Multivariable logistic regression was used to test whether cCBF predicted good neurological outcome (modified Rankin Scale score, 0-2) at 90 days. Results- Seventy-seven patients (41 women) met the inclusion criteria with median (interquartile range) age of 66 (55-76) yrs, onset-to-imaging time of 4.8 (3.6-7.7) hours, and baseline National Institutes of Health Stroke Scale score of 13 (9-20). Median cCBF was 38.9 (31.2-44.5) mL per 100 g/min. Higher cCBF predicted good outcome at day 90 (odds ratio, 4.6 [95% CI, 1.4-14.7]; P =0.01), after controlling for baseline National Institutes of Health Stroke Scale, diffusion-weighted imaging lesion volume, and intra-arterial therapy. Conclusions- Higher quantitative cCBF at baseline is a significant predictor of good neurological outcome at day 90. cCBF levels may inform decisions regarding stroke triage, treatment of acute stroke, and general outcome prognosis. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02225730.

Objective: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), caused by dominant mutations in the NOTCH3 receptor, is the most aggressive small vessel disease of the brain. A key feature of its pathogenesis is accumulation of the extracellular domain of NOTCH3 receptor (Notch3 ECD ) in small vessels, with formation of characteristic extracellular deposits termed granular osmiophilic material (GOM). Here, we investigated the therapeutic potential of a mouse monoclonal antibody (5E1) that specifically recognizes Notch3 ECD ., Methods: The binding affinity of 5E1 toward purified NOTCH3 was assessed using Octet analysis. The ability of 5E1 to bind Notch3 ECD deposits in brain vessels and its effects on disease-related phenotypes were evaluated in the CADASIL mouse model, which overexpresses a mutant rat NOTCH3. Notch3 ECD and GOM deposition, white matter lesions, and cerebral blood flow deficits were assessed at treatment initiation (10 weeks) and study completion (30 weeks) using quantitative immunohistochemistry, electron microscopy, and laser-Doppler flowmetry., Results: 5E1 antibody bound recombinant rat NOTCH3 with an average affinity of 317nM. A single peripheral injection of 5E1 robustly decorated Notch3 ECD deposits in the brain vasculature. Chronic administration of 5E1 did not attenuate Notch3 ECD or GOM deposition and was not associated with perivascular microglial activation. It also failed to halt the development of white matter lesions. Despite this, 5E1 treatment markedly protected against impaired cerebral blood flow responses to neural activity and topical application of vasodilators and normalized myogenic responses of cerebral arteries., Interpretation: This study establishes immunotherapy targeting Notch3 ECD as a new avenue for disease-modifying treatment in CADASIL that warrants further development. Ann Neurol 2018;84:246-259., (© 2018 American Neurological Association.)

Introduction: The goal of this study was to assess the changes in arterial spin labeling (ASL) cerebral blood flow (CBF) and arterial transit time (ATT), and in apparent diffusion coefficient (ADC), before and after an acetazolamide challenge in moyamoya patients, as function of arterial stenosis severity., Methods: Pre-operative patients diagnosed with moyamoya disease who could undergo MRI at 3.0T were recruited for this study. A multi-delay pseudo-continuous ASL and a diffusion-weighted sequence were acquired before and 15 min after acetazolamide injection. The severity of anterior, middle, and posterior cerebral artery pathology was graded on time-of-flight MR angiographic images. CBF, ATT, and ADC were measured on standardized regions of interest as function of the vessel stenosis severity., Results: Thirty patients were included. Fifty-four percent of all vessels were normal, 28% mildly/moderately stenosed, and 18% severely stenosed/occluded. Post-acetazolamide, a significantly larger CBF (ml/100 g/min) increase was observed in territories of normal (+19.6 ± 14.9) compared to mildly/moderately stenosed (+14.2 ± 27.2, p = 0.007), and severely stenosed/occluded arteries (+9.9 ± 24.2, p < 0.0001). ATT was longer in territories of vessel anomalies compared with normal regions at baseline. ATT decreases were observed in all territories post-acetazolamide. ADC did not decrease after acetazolamide in any regions, and no correlation was found between ADC changes and baseline ATT, change in ATT, or CVR., Conclusion: The hemodynamic response in moyamoya disease, as measured with ASL CBF, is impaired mostly in territories with severe arterial stenosis/occlusion, while ATT was prolonged in all non-normal regions. No significant changes in ADC were observed after acetazolamide.

Background and Purpose: The minimal scan duration needed to obtain reliable lesion volumes with computed tomographic perfusion (CTP) has not been well established in the literature., Methods: We retrospectively assessed the impact of gradual truncation of the scan duration on acute ischemic lesion volume measurements. For each scan, we identified its optimal scan time, defined as the shortest scan duration that yields measurements of the ischemic lesion volumes similar to those obtained with longer scanning, and the relative height of the fitted venous output function at its optimal scan time., Results: We analyzed 70 computed tomographic perfusion scans of acute stroke patients. An optimal scan time could not be determined in 11 scans (16%). For the other 59 scans, the median optimal scan time was 32.7 seconds (90th percentile 52.6 seconds; 100th percentile 68.9 seconds), and the median relative height of the fitted venous output function at the optimal scan times was 0.39 (90th percentile 0.02; 100th percentile 0.00). On the basis of a linear model, the optimal scan time was T 0 plus 1.6 times the width of the venous output function (P<0.001; R 2 =0.49)., Conclusions: This study shows how the optimal duration of a computed tomographic perfusion scan relates to the arrival time and width of the contrast bolus. This knowledge can be used to optimize computed tomographic perfusion scan protocols and to determine whether a scan is of sufficient duration. Provided a baseline (T 0 ) of 10 seconds, a total scan duration of 60 to 70 seconds, which includes the entire downslope of the venous output function in most patients, is recommended., Competing Interests: DISCLOSURES/CONFLICT OF INTEREST G. Albers has received consulting fees and expenses from Lundbeck for Steering Committee work and consulting fees from Concentric for serving on a Data Safely and Monitory Board. G Albers and R Bammer are equity shareholders in iSchemaView and perform consulting work for iSchemaView. Soren Christensen performs consulting work for iSchemaView. All other authors report no conflicts of interest., (© 2016 American Heart Association, Inc.)

Purpose: There is currently controversy regarding the benefits of deconvolution-based parameters in stroke imaging, with studies suggesting a similar infarct prediction using summary parameters. We investigate here the performance of deconvolution-based parameters and summary parameters for dynamic-susceptibility contrast (DSC) MRI analysis, with particular emphasis on precision., Methods: Numerical simulations were used to assess the contribution of noise and arterial input function (AIF) variability to measurement precision. A realistic AIF range was defined based on in vivo data from an acute stroke clinical study. The simulated tissue curves were analyzed using two popular singular value decomposition (SVD) based algorithms, as well as using summary parameters., Results: SVD-based deconvolution methods were found to considerably reduce the AIF-dependency, but a residual AIF bias remained on the calculated parameters. Summary parameters, in turn, show a lower sensitivity to noise. The residual AIF-dependency for deconvolution methods and the large AIF-sensitivity of summary parameters was greatly reduced when normalizing them relative to normal tissue., Conclusion: Consistent with recent studies suggesting high performance of summary parameters in infarct prediction, our results suggest that DSC-MRI analysis using properly normalized summary parameters may have advantages in terms of lower noise and AIF-sensitivity as compared to commonly used deconvolution methods. Magn Reson Med 76:1282-1290, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Objective: To evaluate whether time to treatment modifies the effect of endovascular reperfusion in stroke patients with evidence of salvageable tissue on MRI., Methods: Patients from the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution 2 (DEFUSE 2) cohort study with a perfusion-diffusion target mismatch were included. Reperfusion was defined as a decrease in the perfusion lesion volume of at least 50% between baseline and early follow-up. Good functional outcome was defined as a modified Rankin Scale score ≤2 at day 90. Lesion growth was defined as the difference between the baseline and the early follow-up diffusion-weighted imaging lesion volumes., Results: Among 78 patients with the target mismatch profile (mean age 66 ± 16 years, 54% women), reperfusion was associated with increased odds of good functional outcome (adjusted odds ratio 3.7, 95% confidence interval 1.2-12, p = 0.03) and attenuation of lesion growth (p = 0.02). Time to treatment did not modify these effects (p value for the time × reperfusion interaction is 0.6 for good functional outcome and 0.3 for lesion growth). Similarly, in the subgroup of patients with reperfusion (n = 46), time to treatment was not associated with good functional outcome (p = 0.2)., Conclusion: The association between endovascular reperfusion and improved functional and radiologic outcomes is not time-dependent in patients with a perfusion-diffusion mismatch. Proof that patients with mismatch benefit from endovascular therapy in the late time window should come from a randomized placebo-controlled trial., (© 2015 American Academy of Neurology.)

Background and Purpose: Ischemic stroke patients with regional very low cerebral blood volume (VLCBV) on baseline imaging have increased risk of parenchymal hemorrhage (PH) after intravenous alteplase-induced reperfusion. We developed a method for automated detection of VLCBV and examined whether patients with reperfused-VLCBV are at increased risk of PH after endovascular reperfusion therapy., Methods: Receiver operating characteristic analysis was performed to optimize a relative CBV threshold associated with PH in patients from the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution 2 (DEFUSE 2) study. Regional reperfused-VLCBV was defined as regions with low relative CBV on baseline imaging that demonstrated normal perfusion (Tmax <6 s) on coregistered early follow-up magnetic resonance imaging. The association between VLCBV, regional reperfused-VLCBV and PH was assessed in univariate and multivariate analyses., Results: In 91 patients, the greatest area under the curve for predicting PH occurred at an relative CBV threshold of <0.42 (area under the curve, 0.77). At this threshold, VLCBV lesion volume ≥3.55 mL optimally predicted PH with 94% sensitivity and 63% specificity. Reperfused-VLCBV lesion volume was more specific (0.74) and equally sensitive (0.94). In total, 18 patients developed PH, of whom 17 presented with VLCBV (39% versus 2%; P=0.001), all of them had regional reperfusion (47% versus 0%; P=0.01), and 71% received intravenous alteplase. VLCBV lesion (odds ratio, 33) and bridging with intravenous alteplase (odds ratio, 3.8) were independently associated with PH. In a separate model, reperfused-VLCBV remained the single independent predictor of PH (odds ratio, 53)., Conclusions: These results suggest that VLCBV can be used for risk stratification of patients scheduled to undergo endovascular therapy in trials and routine clinical practice., (© 2015 American Heart Association, Inc.)

Background and Purpose: The aim of this study was to assess the frequency and extent of early diffusion-weighted imaging (DWI) lesion reversal after endovascular therapy and to determine whether early reversal is sustained or transient., Methods: MRI with DWI perfusion imaging was performed before (DWI 1) and within 12 hours after (DWI 2) endovascular treatment; follow-up MRI was obtained on day 5. Both DWIs were coregistered to follow-up MRI. Early DWI reversal was defined as the volume of the DWI 1 lesion that was not superimposed on the DWI 2 lesion. Permanent reversal was the volume of the DWI 1 lesion not superimposed on the day 5 infarct volume. Associations between early DWI reversal and clinical outcomes in patients with and without reperfusion were assessed., Results: A total of 110 patients had technically adequate DWI before endovascular therapy (performed median [interquartile range], 4.5 [2.8-6.2] hours after onset); 60 were eligible for this study. Thirty-two percent had early DWI reversal >10 mL; 17% had sustained reversal. The median volume of permanent reversal at 5 days was 3 mL (interquartile range, 1.7-7.0). Only 2 patients (3%) had a final infarct volume that was smaller than their baseline DWI lesion. Early DWI reversal was not an independent predictor of clinical outcome and was not associated with early reperfusion., Conclusions: Early DWI reversal occurred in about one third of patients after endovascular therapy; however, reversal was often transient and was not associated with a significant volume of tissue salvage or favorable clinical outcome.

Introduction: A new deconvolution algorithm, the Bayesian estimation algorithm, was reported to improve the precision of parametric maps created using perfusion computed tomography. However, it remains unclear whether quantitative values generated by this method are more accurate than those generated using optimized deconvolution algorithms of other software packages. Hence, we compared the accuracy of the Bayesian and deconvolution algorithms by using a digital phantom., Methods: The digital phantom data, in which concentration-time curves reflecting various known values for cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and tracer delays were embedded, were analyzed using the Bayesian estimation algorithm as well as delay-insensitive singular value decomposition (SVD) algorithms of two software packages that were the best benchmarks in a previous cross-validation study. Correlation and agreement of quantitative values of these algorithms with true values were examined., Results: CBF, CBV, and MTT values estimated by all the algorithms showed strong correlations with the true values (r = 0.91-0.92, 0.97-0.99, and 0.91-0.96, respectively). In addition, the values generated by the Bayesian estimation algorithm for all of these parameters showed good agreement with the true values [intraclass correlation coefficient (ICC) = 0.90, 0.99, and 0.96, respectively], while MTT values from the SVD algorithms were suboptimal (ICC = 0.81-0.82)., Conclusions: Quantitative analysis using a digital phantom revealed that the Bayesian estimation algorithm yielded CBF, CBV, and MTT maps strongly correlated with the true values and MTT maps with better agreement than those produced by delay-insensitive SVD algorithms.

Purpose: To design a digital phantom data set for computed tomography (CT) perfusion and perfusion-weighted imaging on the basis of the widely accepted tracer kinetic theory in which the true values of cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and tracer arrival delay are known and to evaluate the accuracy and reliability of postprocessing programs using this digital phantom., Materials and Methods: A phantom data set was created by generating concentration-time curves reflecting true values for CBF (2.5-87.5 mL/100 g per minute), CBV (1.0-5.0 mL/100 g), MTT (3.4-24 seconds), and tracer delays (0-3.0 seconds). These curves were embedded in human brain images. The data were analyzed by using 13 algorithms each for CT and magnetic resonance (MR), including five commercial vendors and five academic programs. Accuracy was assessed by using the Pearson correlation coefficient (r) for true values. Delay-, MTT-, or CBV-dependent errors and correlations between time to maximum of residue function (Tmax) were also evaluated., Results: In CT, CBV was generally well reproduced (r > 0.9 in 12 algorithms), but not CBF and MTT (r > 0.9 in seven and four algorithms, respectively). In MR, good correlation (r > 0.9) was observed in one-half of commercial programs, while all academic algorithms showed good correlations for all parameters. Most algorithms had delay-dependent errors, especially for commercial software, as well as CBV dependency for CBF or MTT calculation and MTT dependency for CBV calculation. Correlation was good in Tmax except for one algorithm., Conclusion: The digital phantom readily evaluated the accuracy and characteristics of the CT and MR perfusion analysis software. All commercial programs had delay-induced errors and/or insufficient correlations with true values, while academic programs for MR showed good correlations with true values., Supplemental Material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12112618/-/DC1., (RSNA, 2012)

In acute stroke magnetic resonance imaging, a 'mismatch' between visibility of an ischemic lesion on diffusion-weighted imaging (DWI) and missing corresponding parenchymal hyperintensities on fluid-attenuated inversion recovery (FLAIR) data sets was shown to identify patients with time from symptom onset ≤4.5 hours with high specificity. However, moderate sensitivity and suboptimal interpreter agreement are limitations of a visual rating of FLAIR lesion visibility. We tested refined image analysis methods in patients included in the previously published PREFLAIR study using refined visual analysis and quantitative measurements of relative FLAIR signal intensity (rSI) from a three-dimensional, segmented stroke lesion volume. A total of 399 patients were included. The rSI of FLAIR lesions showed a moderate correlation with time from symptom onset (r=0.382, P<0.001). A FLAIR rSI threshold of <1.0721 predicted symptom onset ≤4.5 hours with slightly increased specificity (0.85 versus 0.78) but also slightly decreased sensitivity (0.47 versus 0.58) as compared with visual analysis. Refined visual analysis differentiating between 'subtle' and 'obvious' FLAIR hyperintensities and classification and regression tree algorithms combining information from visual and quantitative analysis also did not improve diagnostic accuracy. Our results raise doubts whether the prediction of stroke onset time by visual image judgment can be improved by quantitative rSI measurements.

Introduction: Computed tomography perfusion (CTP) and magnetic resonance perfusion (MRP) are expected to be usable for ancillary tests of brain death by detection of complete absence of cerebral perfusion; however, the detection limit of hypoperfusion has not been determined. Hence, we examined whether commercial software can visualize very low cerebral blood flow (CBF) and cerebral blood volume (CBV) by creating and using digital phantoms., Methods: Digital phantoms simulating 0-4% of normal CBF (60 mL/100 g/min) and CBV (4 mL/100 g/min) were analyzed by ten software packages of CT and MRI manufacturers. Region-of-interest measurements were performed to determine whether there was a significant difference between areas of 0% and areas of 1-4% of normal flow., Results: The CTP software detected hypoperfusion down to 2-3% in CBF and 2% in CBV, while the MRP software detected that of 1-3% in CBF and 1-4% in CBV, although the lower limits varied among software packages., Conclusion: CTP and MRP can detect the difference between profound hypoperfusion of <5% from that of 0% in digital phantoms, suggesting their potential efficacy for assessing brain death.

Background and Purpose: CT perfusion (CTP) is widely and rapidly accessible for imaging acute ischemic stroke but has limited validation. Cerebral blood volume (CBV) has been proposed as the best predictor of infarct core. We tested CBV against other common CTP parameters using contemporaneous diffusion MRI., Methods: Patients with acute ischemic stroke<6 hours after onset had CTP and diffusion MRI<1 hour apart, before any reperfusion therapies. CTP maps of time to peak (TTP), absolute and relative CBV, cerebral blood flow (CBF), mean transit time (MTT), and time to peak of the deconvolved tissue residue function (Tmax) were generated. The diffusion lesion was manually outlined to its maximal visual extent. Receiver operating characteristic (ROC) analysis area under the curve (AUC) was used to quantify the correspondence of each perfusion parameter to the coregistered diffusion-weighted imaging lesion. Optimal thresholds were determined (Youden index)., Results: In analysis of 98 CTP slabs (54 patients, median onset to CT 190 minutes, median CT to MR 30 minutes), relative CBF performed best (AUC, 0.79; 95% CI, 0.77-81), significantly better than absolute CBV (AUC, 0.74; 95% CI, 0.73-0.76). The optimal threshold was <31% of mean contralateral CBF. Specificity was reduced by low CBF/CBV in noninfarcted white matter in cases with reduced contrast bolus intensity and leukoaraiosis., Conclusions: In contrast to previous reports, CBF corresponded with the acute diffusion-weighted imaging lesion better than CBV, although no single threshold avoids detection of false-positive regions in unaffected white matter. This relates to low signal-to-noise ratio in CTP maps and emphasizes the need for optimized acquisition and postprocessing.

In bolus-tracking perfusion magnetic resonance imaging (MRI), temporal dispersion of the contrast bolus due to stenosis or collateral supply presents a significant problem for accurate perfusion quantification in stroke. One means to reduce the associated perfusion errors is to deconvolve the bolus concentration time-course data with local Arterial Input Functions (AIFs) measured close to the capillary bed and downstream of the arterial abnormalities causing dispersion. Because the MRI voxel resolution precludes direct local AIF measurements, they must be extrapolated from the surrounding data. To date, there have been no published studies directly validating these local AIFs. We assess the effectiveness of local AIFs in reducing dispersion-induced perfusion error by measuring the residual dispersion remaining in the local AIF deconvolved perfusion maps. Two approaches to locating the local AIF voxels are assessed and compared with a global AIF deconvolution across 19 bolus-tracking data sets from patients with stroke. The local AIF methods reduced dispersion in the majority of data sets, suggesting more accurate perfusion quantification. Importantly, the validation inherently identifies potential areas for perfusion underestimation. This is valuable information for the identification of at-risk tissue and management of stroke patients.

The time-to-maximum of the tissue residue function (T(max)) perfusion index has proven very predictive of infarct growth in large clinical trials, yet its dependency on simple tracer delays remains unknown. Here, we determine the dependency of computed tomography (CT) perfusion (CTP) T(max) estimates on tracer delay using a range of deconvolution techniques and digital phantoms. Digital phantom data sets simulating the tracer delay were created from CTP data of six healthy individuals, in which time frames of the left cerebral hemisphere were shifted forward and backward by up to ±5 seconds. These phantoms were postprocessed with three common singular value decomposition (SVD) deconvolution algorithms-standard SVD (sSVD), block-circulant SVD (bSVD), and delay-corrected SVD (dSVD)-with an arterial input function (AIF) obtained from the right middle cerebral artery (MCA). The T(max) values of the left hemisphere were compared among different tracer delays and algorithms by a region of interest-based analysis. The T(max) values by sSVD were positively correlated with 'positive shifts' but unchanged with 'negative shifts,' those by bSVD had an excellent positive linear correlation with both positive and negative shifts, and those by dSVD were relatively constant, although slightly increased with the positive shifts. The T(max) is a parameter highly dependent on tracer delays and deconvolution algorithm.

Background and Purpose: Many perfusion-related MRI parameters are used to investigate the penumbra in stroke. Although time-to-maximum (Tmax) of the residue function has been suggested as a very promising parameter, its physiological meaning and sensitivity to experimental conditions are not well-understood., Methods: We used simulations to further our understanding of the practical meaning of Tmax and to provide recommendations for its use in clinical investigations. We interpret in vivo examples guided by the simulation findings., Results: Whereas Tmax has several attractive properties for clinical use, it is shown that its physiological interpretation is complex and affected by experimental conditions. Tmax is found to reflect a combination of delay, dispersion, and, to a lesser degree, mean transit time. It should therefore mainly be considered a measure of macrovascular characteristics. Furthermore, based on the simulations, use of temporal-interpolation is highly recommended, as is correction for slice-acquisition timing differences., Conclusions: Special care should be taken when setting-up Tmax thresholds for data acquired with different protocols (eg, multicenter studies) because various factors can influence the measured Tmax. Because of its complementary information, used in conjunction with delay-insensitive cerebral blood-flow, cerebral blood volume, and mean transit time maps, Tmax should provide important additional information on brain hemodynamic status.

Background and Purpose: Currently, diffusion-weighted imaging (DWI) lesion volume is the most useful magnetic resonance imaging predictor of hemorrhagic transformation (HT). Preliminary studies have suggested that very low cerebral blood volume (VLCBV) predicts HT. We compared HT prediction by VLCBV and DWI using data from the EPITHET study., Methods: Normal-percentile CBV values were calculated from the nonstroke hemisphere. Whole-brain masks with CBV thresholds of the <0, 2.5, 5, and 10th percentiles were created. The volume of tissue with VLCBV was calculated within the acute DWI ischemic lesion. HT was graded as per ECASS criteria., Results: HT occurred in 44 of 91 patients. Parenchymal hematoma (PH) occurred in 13 (4 symptomatic) and asymptomatic hemorrhagic infarction (HI) in 31. The median volume of VLCBV was significantly higher in cases with PH. VLCBV predicted HT better than DWI lesion volume and thresholded apparent diffusion coefficient lesion volume in receiver operating characteristic analysis and logistic regression. A cutpoint at 2 mL VLCBV with the <2.5th percentile had 100% sensitivity for PH and, in patients treated with tissue plasminogen activator, defined a population with a 43% risk of PH (95% CI, 23% to 66%, likelihood ratio=16). VLCBV remained an independent predictor of PH in multivariate analysis with traditional clinical risk factors for HT., Conclusions: VLCBV predicted HT after thrombolysis better than did DWI or apparent diffusion coefficient volume in this large patient cohort. The advantage was greatest in patients with smaller DWI volumes. Prediction was better in patients who recanalized. If validated in an independent cohort, the addition of VLCBV to prethrombolysis decision making may reduce the incidence of HT.

Background: For MR perfusion-diffusion mismatch to be clinically useful as a means of selecting patients for thrombolysis, it needs to occur in real time at the MRI console. Visual mismatch assessment has been used clinically and in trials but has not been systematically validated. We compared the accuracy of visually rating console-generated images with offline volumetric measurements using data from the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET)., Methods: Perfusion time-to-peak (TTP) and diffusion-weighted images (DWI) (as generated by commercial MRI console software) and T(max) perfusion maps (which required offline calculation) were visually rated. Perfusion-diffusion mismatch, defined as a ratio of perfusion:diffusion lesion volume of >1.2, was independently scored by 1 expert and 2 inexperienced raters blinded to calculated volumes and clinical information. Visual mismatch was compared with region-of-interest-based volumetric calculation, which was used as the gold standard., Results: Volumetric calculation demonstrated perfusion-diffusion mismatch in 85/99 patients. Visual TTP-DWI mismatch was correctly classified by the experienced rater in 82% of the cases (sensitivity: 0.86; specificity: 0.54) compared to 73% for the inexperienced raters (sensitivity: 0.75; specificity: 0.57). The interrater reliability for TTP-DWI mismatch was moderate (kappa = 0.50). Visual T(max)-DWI mismatch performed better (agreement - 93 and 87%, sensitivity - 95 and 88%, specificity - 77 and 82% for the experienced and inexperienced raters, respectively)., Conclusions: The assessment of visual TTP-DWI mismatch at the MRI console is insufficiently reliable for use in clinical trials. Differences in perfusion analysis technique and visual inaccuracies combine to make visual TTP-DWI mismatch substantially different to volumetric T(max)-DWI mismatch. Automated software that applies perfusion thresholds may improve the reproducibility of real-time mismatch assessment., (Copyright 2010 S. Karger AG, Basel.)

Background and Purpose: Perfusion-weighted imaging can predict infarct growth in acute stroke and potentially be used to select patients with tissue at risk for reperfusion therapies. However, the lack of consensus and evidence on how to best create PWI maps that reflect tissue at risk challenges comparisons of results and acute decision-making in trials. Deconvolution using an arterial input function has been hypothesized to generate maps of a more quantitative nature and with better prognostic value than simpler summary measures such as time-to-peak or the first moment of the concentration time curve. We sought to compare 10 different perfusion parameters by their ability to predict tissue infarction in acute ischemic stroke., Methods: In a retrospective analysis of 97 patients with acute stroke studied within 6 hours from symptom onset, we used receiver operating characteristics in a voxel-based analysis to compare 10 perfusion parameters: time-to-peak, first moment, cerebral blood volume and flow, and 6 variants of time to peak of the residue function and mean transit time maps. Subanalysis assessed the effect of reperfusion on outcome prediction., Results: The most predictive maps were the summary measures first moment and time-to-peak. First moment was significantly more predictive than time to peak of the residue function and local arterial input function-based methods (P<0.05), but not significantly better than conventional mean transit time maps., Conclusions: Results indicated that if a single map type was to be used to predict infarction, first moment maps performed at least as well as deconvolved measures. Deconvolution decouples delay from tissue perfusion; we speculate this negatively impacts infarct prediction.

Purpose: To investigate the potential of novel postprocessing and visualization techniques to distinguish presence of collateral flow using Bolus Tracking MRI. Collateral blood supply is believed to be of paramount importance in acute stroke, yet clinical evaluation is challenging as the gold standard digital subtraction angiography is often not feasible in the acute scenario., Materials and Methods: In principle, bolus arrival delay data contains information about the route of blood supply into tissue and hereby presence of collateral flow patterns. We first examined the potential of current clinical bolus tracking protocols to accurately characterize bolus arrival delay. Using the simulation results, we analyzed bolus tracking data from one normal volunteer and one acute stroke patient., Results: The bolus arrival patterns in the volunteer and in the normal hemisphere of the patient were found to be qualitatively similar and in good agreement with physiology. The bolus was seen to spread from the larger arteries toward the periphery. The stroke hemisphere in the patient indicated a retrograde direction of flow on the cortical mantle consistent with leptomeningeal vessels., Conclusion: Bolus tracking MRI can likely be used to distinguish collateral flow patterns from normal flow patterns., (2008 Wiley-Liss, Inc)

Background and Purpose: Perfusion magnetic resonance imaging (pMR) is increasingly used in acute stroke, but its physiologic significance is still debated. A reasonably good correlation between pMR and positron emission tomography (PET) has been reported in normal subjects and chronic cerebrovascular disease, but corresponding validation in acute stroke is still lacking., Methods: We compared the cerebral blood flow (CBF), cerebral blood volume, and mean transit time (MTT) maps generated by pMR (deconvolution method) and PET ((15)O steady-state method) in 5 patients studied back-to-back with the 2 modalities at a mean of 16 hours (range, 7 to 21 hours) after stroke onset. We also determined the penumbra thresholds for pMR-derived MTT, time to peak (TTP), and Tmax against the previously validated probabilistic PET penumbra thresholds., Results: In all patients, the PET and pMR relative distribution images were remarkably similar, especially for CBF and MTT. Within-patient correlations between pMR and PET were strong for absolute CBF (average r(2)=0.45) and good for MTT (r(2)=0.35) but less robust for cerebral blood volume (r(2)=0.24). However, pMR overestimated absolute CBF and underestimated MTT, with substantial variability in individual slopes. Removing individual differences by normalization to the mean resulted in much stronger between-patient correlations. Penumbra thresholds of approximately 6, 4.8, and 5.5 seconds were obtained for MTT delay, TTP delay, and Tmax, respectively., Conclusions: Although derived from a small sample studied relatively late after stroke onset, our data show that pMR tends to overestimate absolute CBF and underestimate MTT, but the relative distribution of the perfusion variables was remarkably similar between pMR and PET. pMR appears sufficiently reliable for clinical purposes and affords reliable detection of the penumbra from normalized time-based thresholds.

Quantification of cerebral blood flow (CBF) using dynamic susceptibility contrast MRI requires determination of the arterial input function (AIF) representing the delivery of intravascular tracer to tissue. This is typically accomplished manually by inspection of concentration time curves (CTCs) in regions containing the ICA, VA, and MCA. This is, however, a time consuming and operator dependent procedure. We suggest a completely automatic procedure for establishing the AIF based on a cluster analysis algorithm. In 20 normal subjects CBF maps calculated in 2 slices by the automatic procedure were compared to maps obtained with AIFs selected individually by 7 experienced operators. The average manual to automatic CBF ratio was 1.03+/-0.15 in the lower slice and 1.05+/-0.12 in the upper slice, demonstrating excellent agreement between the manual and automatic method. The algorithm provides means for objectively assessing AIF candidates in local AIF search algorithms designed to reduce bias due to delay and dispersion. Given the reproducibility and speed (10 s) of the automatic method, we speculate that it will greatly improve the accuracy of perfusion images and facilitate their use in clinical diagnosis and decision-making, particularly in acute stroke but also in cerebrovascular disease in general., (Magn Reson Med, 2006. (c) 2006 Wiley-Liss, Inc.)

Purpose: To evaluate the feasibility of using the rapid principles of echo shifting with a train of observations (PRESTO) sequence for measurements of cerebral hemodynamic parameters based on first pass of a contrast agent., Materials and Methods: Simulations were performed to investigate potential resolution loss due to relaxation effects. Experimental evaluation was conducted in healthy monkey brains using PRESTO and echo-planar imaging (EPI)., Results: For short echo trains, an insignificant contribution of the longitudinal and transversal relaxation rates to the signal amplitude in white matter and gray matter was found, whereas a contribution as large as 40% was found in large vessels. Simulations of the point spread function demonstrated that PRESTO, despite its shorter readout trains, only has a small advantage in terms of maintenance of image resolution during bolus passage compared to EPI as long as the EPI echo train can be kept similar to the T2* value at the top of the bolus. Experimental studies revealed that the PRESTO and EPI gray matter to white matter ratio were similar with respect to cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT)., Conclusion: The study showed that PRESTO and EPI led to comparable quantitative perfusion parameters., (2004 Wiley-Liss, Inc.)

Administration of indomethacin may aid treatment of intracranial hypertension, and the present study was conducted to determine the optimal dose. In healthy volunteers, cerebral blood flow (CBF) has been shown to decrease considerably after a bolus dose of indomethacin, 0.4 mg/kg, followed by continuous infusion, 0.4 mg/kg/h. This decrease was sustained for 6 h without any evidence of adaptation. In a randomized study in healthy volunteers, indomethacin, 0.1, 0.2 and 0.3 mg/kg, was given as bolus, followed by continuous infusion of 0.1, 0.2 and 0.3 mg/kg/h. CBF decreased from normal levels (52-74 ml/100 mg/min) to 38-51 ml/100 g/min. There were no differences among the three groups in CBF reduction, and the reduction was sustained during the 6-h infusion period. Rectal application of 100 mg indomethacin was found to reduce CBF from normal levels (54-74 ml/100 mg/min) to 33-48 ml/100 mg/min. These low levels were only sustained for 2 h, and values returned to normal over the next 6 h. We observed no rebound phenomenon 2 h after stopping the infusion and no rebound after 100 mg of rectally applied indomethacin. Since a dose as low as 0.1 mg/kg/h is effective, it is possible to treat most patient in a 24-h schedule without going over maximum recommended doses.

Cerebral blood flow (CBF) and cardiac output (CO) were measured during cardiopulmonary resuscitation in patients who were unsuccessfully resuscitated by use of C14-iodoantipyrine injected into the left ventricle. CO varied between 1.3 and 2.2 l/min with mean 1.8 +/- 0.6 l/min (+/- SD) (28 ml/kg/min). The cortical CBF was found between 14 and 211 ml 100 g-1.min-1 with mean 42 ml 100 g-1.min-1 and mean white matter CBF equal to 27 ml 100 g-1.min-1. It is suggested that the external cardiac massage in humans may be of poor efficacy in terms of brain revival. Cortical CBF after long-lasting cardiopulmonary resuscitation showed signs of maldistribution suggestive of a patchy and incomplete perfusion.