Publications

    Sridharan R, Dalca AV, Fitzpatrick KM, Cloonan L, Kanakis A, Wu O, Furie KL, Rosand J, Rost NS, Golland P. Quantification and Analysis of Large Multimodal Clinical Image Studies: Application to Stroke. Multimodal Brain Image Anal (2013) 2013;8159:18-30.Abstract
    We present an analysis framework for large studies of multimodal clinical quality brain image collections. Processing and analysis of such datasets is challenging due to low resolution, poor contrast, mis-aligned images, and restricted field of view. We adapt existing registration and segmentation methods and build a computational pipeline for spatial normalization and feature extraction. The resulting aligned dataset enables clinically meaningful analysis of spatial distributions of relevant anatomical features and of their evolution with age and disease progression. We demonstrate the approach on a neuroimaging study of stroke with more than 800 patients. We show that by combining data from several modalities, we can automatically segment important biomarkers such as white matter hyperintensity and characterize pathology evolution in this heterogeneous cohort. Specifically, we examine two sub-populations with different dynamics of white matter hyperintensity changes as a function of patients' age. Pipeline and analysis code is available at http://groups.csail.mit.edu/vision/medical-vision/stroke/.
    Cheng B, Brinkmann M, Forkert ND, Treszl A, Ebinger M, Köhrmann M, Wu O, Kang D-W, Liebeskind DS, Tourdias T, Singer OC, Christensen S, Luby M, Warach S, Fiehler J, Fiebach JB, Gerloff C, Thomalla G. Quantitative measurements of relative fluid-attenuated inversion recovery (FLAIR) signal intensities in acute stroke for the prediction of time from symptom onset. J Cereb Blood Flow Metab 2013;33(1):76-84.Abstract
    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.
    Wintermark M, Albers GW, Broderick JP, Demchuk AM, Fiebach JB, Fiehler J, Grotta JC, Houser G, Jovin TG, Lees KR, Lev MH, Liebeskind DS, Luby M, Muir KW, Parsons MW, von Kummer R, Wardlaw JM, Wu O, Yoo AJ, Alexandrov AV, Alger JR, Aviv RI, Bammer R, Baron J-C, Calamante F, Campbell BCV, Carpenter TC, Christensen S, Copen WA, Derdeyn CP, Haley CE, Khatri P, Kudo K, Lansberg MG, Latour LL, Lee T-Y, Leigh R, Lin W, Lyden P, Mair G, Menon BK, Michel P, Mikulik R, Nogueira RG, Ostergaard L, Pedraza S, Riedel CH, Rowley HA, Sanelli PC, Sasaki M, Saver JL, Schaefer PW, Schellinger PD, Tsivgoulis G, Wechsler LR, White PM, Zaharchuk G, Zaidat OO, Davis SM, Donnan GA, Furlan AJ, Hacke W, Kang D-W, Kidwell C, Thijs VN, Thomalla G, Warach SJ. Acute Stroke Imaging Research Roadmap II. Stroke 2013;44(9):2628-39.
    Meschia JF, Arnett DK, Ay H, Brown RD, Benavente OR, Cole JW, de Bakker PIW, Dichgans M, Doheny KF, Fornage M, Grewal RP, Gwinn K, Jern C, Conde JJ, Johnson JA, Jood K, Laurie CC, Lee J-M, Lindgren A, Markus HS, McArdle PF, McClure LA, Mitchell BD, Schmidt R, Rexrode KM, Rich SS, Rosand J, Rothwell PM, Rundek T, Sacco RL, Sharma P, Shuldiner AR, Slowik A, Wassertheil-Smoller S, Sudlow C, Thijs VNS, Woo D, Worrall BB, Wu O, Kittner SJ. Stroke Genetics Network (SiGN) study: design and rationale for a genome-wide association study of ischemic stroke subtypes. Stroke 2013;44(10):2694-702.Abstract
    BACKGROUND AND PURPOSE: Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke. METHODS: The National Institute of Neurological Disorders and Stroke SiGN includes ischemic stroke cases from 24 genetic research centers: 13 from the United States and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the Web-based causative classification of stroke system, with data entered by trained and certified adjudicators at participating genetic research centers. Through the Center for Inherited Diseases Research, the Network plans to genotype 10,296 carefully phenotyped stroke cases using genome-wide single nucleotide polymorphism arrays and adds to these another 4253 previously genotyped cases, for a total of 14,549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. Center for Inherited Diseases Research-generated genotypes and corresponding phenotypes will be shared with the scientific community through the US National Center for Biotechnology Information database of Genotypes and Phenotypes, and brain MRI studies will be centrally archived. CONCLUSIONS: The Stroke Genetics Network, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.
    Saver JL, Jovin TG, Smith WS, Albers GW, Baron J-C, Boltze J, Broderick JP, Davis LA, Demchuk AM, DeSena S, Fiehler J, Gorelick PB, Hacke W, Holt B, Jahan R, Jing H, Khatri P, Kidwell CS, Lees KR, Lev MH, Liebeskind DS, Luby M, Lyden P, Megerian TJ, Mocco J, Muir KW, Rowley HA, Ruedy RM, Savitz SI, Sipelis VJ, Shimp SK, Wechsler LR, Wintermark M, Wu O, Yavagal DR, Yoo AJ. Stroke treatment academic industry roundtable: research priorities in the assessment of neurothrombectomy devices. Stroke 2013;44(12):3596-601.Abstract
    BACKGROUND AND PURPOSE: The goal of the Stroke Treatment Academic Industry Roundtable (STAIR) meetings is to advance the development of stroke therapies. At STAIR VIII, consensus recommendations were developed for clinical trial strategies to demonstrate the benefit of endovascular reperfusion therapies for acute ischemic stroke. SUMMARY OF REVIEW: Prospects for success with forthcoming endovascular trials are robust, because new neurothrombectomy devices have superior reperfusion efficacy compared with earlier-generation interventions. Specific recommendations are provided for trial designs in 3 populations: (1) patients undergoing intravenous fibrinolysis, (2) early patients ineligible for or having failed intravenous fibrinolysis, and (3) wake-up and other late-presenting patients. Among intravenous fibrinolysis-eligible patients, key principles are that CT or MRI confirmation of target arterial occlusions should precede randomization; endovascular intervention should be pursued with the greatest rapidity possible; and combined intravenous and neurothrombectomy therapy is more promising than neurothrombectomy alone. Among patients ineligible for or having failed intravenous fibrinolysis, scientific equipoise was affirmed and the need to randomize all eligible patients emphasized. Vessel imaging to confirm occlusion is mandatory, and infarct core and penumbral imaging is desirable in later time windows. Additional STAIR VIII recommendations include approaches to test multiple devices in a single trial, utility weighting of disability end points, and adaptive designs to delineate time and tissue injury thresholds at which benefits from intervention no longer accrue. CONCLUSIONS: Endovascular research priorities in acute ischemic stroke are to perform trials testing new, highly effective neuro thrombectomy devices rapidly deployed in patients confirmed to have target vessel occlusions.
    Bouts MJRJ, Tiebosch IA, van der Toorn A, Viergever MA, Wu O, Dijkhuizen RM. Early identification of potentially salvageable tissue with MRI-based predictive algorithms after experimental ischemic stroke. J Cereb Blood Flow Metab 2013;33(7):1075-82.Abstract
    Individualized stroke treatment decisions can be improved by accurate identification of the extent of salvageable tissue. Magnetic resonance imaging (MRI)-based approaches, including measurement of a 'perfusion-diffusion mismatch' and calculation of infarction probability, allow assessment of tissue-at-risk; however, the ability to explicitly depict potentially salvageable tissue remains uncertain. In this study, five predictive algorithms (generalized linear model (GLM), generalized additive model, support vector machine, adaptive boosting, and random forest) were tested in their potency to depict acute cerebral ischemic tissue that can recover after reperfusion. Acute T2-, diffusion-, and perfusion-weighted MRI, and follow-up T2 maps were collected from rats subjected to right-sided middle cerebral artery occlusion without subsequent reperfusion, for training of algorithms (Group I), and with spontaneous (Group II) or thrombolysis-induced reperfusion (Group III), to determine infarction probability-based viability thresholds and prediction accuracies. The infarction probability difference between irreversible-i.e., infarcted after reperfusion-and salvageable tissue injury-i.e., noninfarcted after reperfusion-was largest for GLM (20±7%) with highest accuracy of risk-based identification of acutely ischemic tissue that could recover on subsequent reperfusion (Dice's similarity index=0.79±0.14). Our study shows that assessment of the heterogeneity of infarction probability with MRI-based algorithms enables estimation of the extent of potentially salvageable tissue after acute ischemic stroke.
    Wu O, Benner T, Roccatagliata L, Zhu M, Schaefer PW, Sorensen AG, Singhal AB. Evaluating effects of normobaric oxygen therapy in acute stroke with MRI-based predictive models. Med Gas Res 2012;2(1):5.Abstract
    BACKGROUND: Voxel-based algorithms using acute multiparametric-MRI data have been shown to accurately predict tissue outcome after stroke. We explored the potential of MRI-based predictive algorithms to objectively assess the effects of normobaric oxygen therapy (NBO), an investigational stroke treatment, using data from a pilot study of NBO in acute stroke. METHODS: The pilot study of NBO enrolled 11 patients randomized to NBO administered for 8 hours, and 8 Control patients who received room-air. Serial MRIs were obtained at admission, during gas therapy, post-therapy, and pre-discharge. Diffusion/perfusion MRI data acquired at admission (pre-therapy) was used in generalized linear models to predict the risk of lesion growth at subsequent time points for both treatment scenarios: NBO or Control. RESULTS: Lesion volume sizes 'during NBO therapy' predicted by Control-models were significantly larger (P = 0.007) than those predicted by NBO models, suggesting that ischemic lesion growth is attenuated during NBO treatment. No significant difference was found between the predicted lesion volumes at later time-points. NBO-treated patients, despite showing larger lesion volumes on Control-models than NBO-models, tended to have reduced lesion growth. CONCLUSIONS: This study shows that NBO has therapeutic potential in acute ischemic stroke, and demonstrates the feasibility of using MRI-based algorithms to evaluate novel treatments in early-phase clinical trials.
    Song SS, Latour LL, Ritter CH, Wu O, Tighiouart M, Hernandez DA, Ku KD, Luby M, Warach S. A pragmatic approach using magnetic resonance imaging to treat ischemic strokes of unknown onset time in a thrombolytic trial. Stroke 2012;43(9):2331-5.Abstract
    BACKGROUND AND PURPOSE: Toward the goal of designing a clinical trial using imaging parameters to treat stroke patients with unknown onset time, we investigated the timing of changes on MRI in patients with well-defined stroke onset. METHODS: Hypothesis-generating (n=85) and confirmatory (n=111) samples were scored by blinded readers for fluid-attenuated inversion recovery (FLAIR) hyperintensity in diffusion-positive regions. Reader-measured signal intensity ratio (SIR) of the lesion to contralateral tissue was compared with SIR measured by coregistration. RESULTS: Lesion conspicuity increased with time on FLAIR (P=0.006). Qualitative assessment of FLAIR-negative vs FLAIR hyperintensity (k=0.7091; 95% CI, 0.61-0.81) showed good interrater agreement. Subtle hyperintensity was less reliably categorized (k=0.59; 95% CI, 0.47-0.71). Reader-measured SIR <1.15 can identify patients within the treatable time window of 4.5 hours (positive predictive value=0.90). The SIR was greater for right hemisphere lesions (P=0.04) for a given reported time from stroke symptom onset. CONCLUSIONS: The SIR on FLAIR provides a quantitative tool to identify early ischemic strokes. In developing SIR thresholds, right hemisphere lesions may confound the accurate estimate of stroke onset time. Image coregistration for thrombolytic trial enrollment is not necessary. A SIR <1.15 on FLAIR yields a practical estimate of stroke onset within 4.5 hours.
    Cheng B, Ebinger M, Kufner A, Köhrmann M, Wu O, Kang D-W, Liebeskind D, Tourdias T, Singer OC, Christensen S, Warach S, Luby M, Fiebach JB, Fiehler J, Gerloff C, Thomalla G. Hyperintense vessels on acute stroke fluid-attenuated inversion recovery imaging: associations with clinical and other MRI findings. Stroke 2012;43(11):2957-61.Abstract
    BACKGROUND AND PURPOSE: Hyperintense vessels (HVs) have been observed in fluid-attenuated inversion recovery imaging of patients with acute ischemic stroke and been linked to slow flow in collateral arterial circulation. Given the potential importance of HV, we used a large, multicenter data set of patients with stroke to clarify which clinical and imaging factors play a role in HV. METHODS: We analyzed data of 516 patients from the previously published PRE-FLAIR study (PREdictive value of FLAIR and DWI for the identification of acute ischemic stroke patients≤3 and ≤4.5 hours of symptom onset-a multicenter study) study. Patients were studied by MRI within 12 hours of symptom onset. HV were defined as hyperintensities in fluid-attenuated inversion recovery corresponding to the typical course of a blood vessel that was not considered the proximal, occluded main artery ipsilateral to the diffusion restriction. Presence of HV was rated by 2 observers and related to clinical and imaging findings. RESULTS: Presence of HV was identified in 240 of all 516 patients (47%). Patients with HV showed larger initial ischemic lesion volumes (median, 12.3 versus 4.9 mL; P<0.001) and a more severe clinical impairment (median National Institutes of Health Stroke Scale 10.5 versus 6; P<0.001). In 198 patients with MR angiography, HVs were found in 80% of patients with vessel occlusion and in 17% without vessel occlusion. In a multivariable logistic regression model, vessel occlusion was associated with HV (OR, 21.7%; 95% CI, 9.6-49.9; P<0.001). HV detected vessel occlusion with a specificity of 0.86 (95% CI, 0.80-0.90) and sensitivity of 0.76 (95% CI, 0.69-0.83). CONCLUSIONS: HVs are a common finding associated with proximal arterial occlusions and more severe strokes. HVs predict arterial occlusion with high diagnostic accuracy.
    Deipolyi AR, Wu O, Macklin EA, Schaefer PW, Schwamm LH, Gilberto Gonzalez R, Copen WA. Reliability of cerebral blood volume maps as a substitute for diffusion-weighted imaging in acute ischemic stroke. J Magn Reson Imaging 2012;36(5):1083-7.Abstract
    PURPOSE: To assess the reliability of cerebral blood volume (CBV) maps as a substitute for diffusion-weighted MRI (DWI) in acute ischemic stroke. In acute stroke, DWI is often used to identify irreversibly injured "core" tissue. Some propose using perfusion imaging, specifically CBV maps, in place of DWI. We examined whether CBV maps can reliably subsitute for DWI, and assessed the effect of scan duration on calculated CBV. MATERIALS AND METHODS: We retrospectively identified 58 patients who underwent DWI and MR perfusion imaging within 12 h of stroke onset. CBV in each DWI lesion's center was divided by CBV in the normal-appearing contralateral hemisphere to yield relative regional CBV (rrCBV). The proportion of lesions with decreased rrCBV was calculated. After using the full scan duration (110 s after contrast injection), rrCBV was recalculated using simulated shorter scans. The effect of scan duration on rrCBV was tested with linear regression. RESULTS: Using the full scan duration (110 s), rrCBV was increased in most DWI lesions (62%; 95% confidence interval, 48-74%). rrCBV increased with increasing scan duration (P < 0.001). Even with the shortest duration (39.5 s) rrCBV was increased in 33% of lesions. CONCLUSION: Because DWI lesions may have elevated or decreased CBV, CBV maps cannot reliably substitute for DWI in identifying the infarct core.
    Wu O, Lu J, Mandeville JB, Murata Y, Egi Y, Dai G, Marota JJ, Diwan I, Dijkhuizen RM, Kwong KK, Lo EH, Singhal AB. Dynamic functional cerebral blood volume responses to normobaric hyperoxia in acute ischemic stroke. J Cereb Blood Flow Metab 2012;32(9):1800-9.Abstract
    Studies suggest that neuroprotective effects of normobaric oxygen (NBO) therapy in acute stroke are partly mediated by hemodynamic alterations. We investigated cerebral hemodynamic effects of repeated NBO exposures. Serial magnetic resonance imaging (MRI) was performed in Wistar rats subjected to focal ischemic stroke. Normobaric oxygen-induced functional cerebral blood volume (fCBV) responses were analyzed. All rats had diffusion-weighted MRI (DWI) lesions within larger perfusion deficits, with DWI lesion expansion after 3 hours. Functional cerebral blood volume responses to NBO were spatially and temporally heterogeneous. Contralateral healthy tissue responded consistently with vasoconstriction that increased with time. No significant responses were evident in the acute DWI lesion. In hypoperfused regions surrounding the acute DWI lesion, tissue that remained viable until the end of the experiment showed relative preservation of mean fCBV at early time points, with some rats showing increased fCBV (vasodilation); however, these regions later exhibited significantly decreased fCBV (vasoconstriction). Tissue that became DWI abnormal by study-end initially showed marginal fCBV changes that later became moderate fCBV reductions. Our results suggest that a reverse-steal hemodynamic effect may occur in peripheral ischemic zones during NBO treatment of focal stroke. In addition, CBV responses to NBO challenge may have potential as an imaging marker to distinguish ischemic core from salvageable tissues.
    Gökçay F, Arsava EM, Baykaner T, Vangel M, Garg P, Wu O, Singhal AB, Furie KL, Sorensen AG, Ay H. Age-dependent susceptibility to infarct growth in women. Stroke 2011;42(4):947-51.Abstract
    BACKGROUND AND PURPOSE:

    It is not known if there is a relationship between gender and tissue outcome in human ischemic stroke. We sought to identify whether the proportion of initially ischemic to eventually infarcted tissue was different between men and women with ischemic stroke.

    METHODS:

    We studied 141 consecutive patients with acute ischemic stroke who had a baseline MRI obtained within 12 hours of symptom onset, a follow-up imaging on Day 4 or later, and diffusion-weighted imaging/mean transmit time mismatch on initial MRI. Lesion growth was calculated as percentage of mismatch tissue that underwent infarction on follow-up (percentage mismatch lost). Multivariable analyses explored the effect of gender and other predictors of tissue outcome on percentage mismatch lost.

    RESULTS:

    There was no difference in median percentage mismatch lost between men (19%) and women (11%; P=0.720). There was, however, an interaction between gender and age; median percentage mismatch lost was 7% (0% to 12%) in women and 18% (1% to 35%) in men younger than the population median (71 years, P=0.061). The percentage mismatch lost was not different between men and women ≥71 years old (25% in both groups). The linear regression model revealed gender (P=0.027) and the interaction between age and gender (P=0.023) as independent predictors of percentage mismatch lost.

    CONCLUSIONS:

    There is an age-by-gender interaction in tissue outcome after ischemic stroke; brain infarcts in women <70 years grow approximately 50% less than infarcts in their male counterparts. These findings extend the well-known concept that there is a differential age-by-gender effect on stroke incidence, mortality, and functional outcome to the tissue level.

    Copen WA, Schaefer PW, Wu O. MR perfusion imaging in acute ischemic stroke. Neuroimaging Clin N Am 2011;21(2):259-83, x.Abstract
    Magnetic resonance (MR) perfusion imaging offers the potential for measuring brain perfusion in acute stroke patients, at a time when treatment decisions based on these measurements may affect outcomes dramatically. Rapid advancements in both acute stroke therapy and perfusion imaging techniques have resulted in continuing redefinition of the role that perfusion imaging should play in patient management. This review discusses the basic pathophysiology of acute stroke, the utility of different kinds of perfusion images, and research on the continually evolving role of MR perfusion imaging in acute stroke care.
    Thomalla G, Cheng B, Ebinger M, Hao Q, Tourdias T, Wu O, Kim JS, Breuer L, Singer OC, Warach S, Christensen S, Treszl A, Forkert ND, Galinovic I, Rosenkranz M, Engelhorn T, Köhrmann M, Endres M, Kang D-W, Dousset V, Sorensen GA, Liebeskind DS, Fiebach JB, Fiehler J, Gerloff C. DWI-FLAIR mismatch for the identification of patients with acute ischaemic stroke within 4·5 h of symptom onset (PRE-FLAIR): a multicentre observational study. Lancet Neurol 2011;10(11):978-86.Abstract
    BACKGROUND: Many patients with stroke are precluded from thrombolysis treatment because the time from onset of their symptoms is unknown. We aimed to test whether a mismatch in visibility of an acute ischaemic lesion between diffusion-weighted MRI (DWI) and fluid-attenuated inversion recovery (FLAIR) MRI (DWI-FLAIR mismatch) can be used to detect patients within the recommended time window for thrombolysis. METHODS: In this multicentre observational study, we analysed clinical and MRI data from patients presenting between Jan 1, 2001, and May 31, 2009, with acute stroke for whom DWI and FLAIR were done within 12 h of observed symptom onset. Two neurologists masked to clinical data judged the visibility of acute ischaemic lesions on DWI and FLAIR imaging, and DWI-FLAIR mismatch was diagnosed by consensus. We calculated predictive values of DWI-FLAIR mismatch for the identification of patients with symptom onset within 4·5 h and within 6 h and did multivariate regression analysis to identify potential confounding covariates. This study is registered with ClinicalTrials.gov, number NCT01021319. FINDINGS: The final analysis included 543 patients. Mean age was 66·0 years (95% CI 64·7-67·3) and median National Institutes of Health Stroke Scale score was 8 (IQR 4-15). Acute ischaemic lesions were identified on DWI in 516 patients (95%) and on FLAIR in 271 patients (50%). Interobserver agreement for acute ischaemic lesion visibility on FLAIR imaging was moderate (κ=0·569, 95% CI 0·504-0·634). DWI-FLAIR mismatch identified patients within 4·5 h of symptom onset with 62% (95% CI 57-67) sensitivity, 78% (72-84) specificity, 83% (79-88) positive predictive value, and 54% (48-60) negative predictive value. Multivariate regression analysis identified a longer time to MRI (p<0·0001), a lower age (p=0·0009), and a larger DWI lesion volume (p=0·0226) as independent predictors of lesion visibility on FLAIR imaging. INTERPRETATION: Patients with an acute ischaemic lesion detected with DWI but not with FLAIR imaging are likely to be within a time window for which thrombolysis is safe and effective. These findings lend support to the use of DWI-FLAIR mismatch for selection of patients in a future randomised trial of thrombolysis in patients with unknown time of symptom onset. FUNDING: Else Kröner-Fresenius-Stiftung, National Institutes of Health.
    Wu O, Schwamm LH, Sorensen GA. Imaging stroke patients with unclear onset times. Neuroimaging Clin N Am 2011;21(2):327-44, xi.Abstract
    Stroke is a leading cause of death and adult morbidity worldwide. By defining stroke symptom onset by the time the patient was last known to be well, many patients whose onsets are unwitnessed are automatically ineligible for thrombolytic therapy. Advanced brain imaging may serve as a substitute witness to estimate stroke onset and duration in those patients who do not have a human witness. This article reviews and compares some of these imaging-based approaches to thrombolysis eligibility, which can potentially expand the use of thrombolytic therapy to a broader population of acute stroke patients.
    Kimberly TW, Wu O, Arsava ME, Garg P, Ji R, Vangel M, Singhal AB, Ay H, Sorensen GA. Lower hemoglobin correlates with larger stroke volumes in acute ischemic stroke. Cerebrovasc Dis Extra 2011;1(1):44-53.Abstract
    BACKGROUND: Hemoglobin tetramers are the major oxygen-carrying molecules within the blood. We hypothesized that a lower hemoglobin level and its reduced oxygen-carrying capacity would associate with larger infarction in acute ischemic stroke patients. METHODS: We studied 135 consecutive patients with acute ischemic stroke and perfusion brain MRI. We explored the association of admission hemoglobin with initial infarct volumes on acute images and the volume of infarct expansion on follow-up images. Multivariable linear regression was performed to analyze the independent effect of hemoglobin on imaging outcomes. RESULTS: Bivariate analyses showed a significant inverse correlation between hemoglobin and initial volume in diffusion-weighted imaging (r = -0.20, p = 0.02) and absolute infarct growth (r = -0.20, p = 0.02). Multivariable linear regression modeling revealed that hemoglobin remained independently predictive of larger infarct volumes acutely (p < 0.005) and with greater infarct expansion (p < 0.01) after adjusting for known covariates. CONCLUSIONS: Hemoglobin level at the time of acute ischemic stroke associates with larger infarcts and increased infarct growth. Clarification of the mechanism of this effect may yield novel insights for therapy.
    Christensen S, Mouridsen K, Wu O, Hjort N, Karstoft H, Thomalla G, Röther J, Fiehler J, Kucinski T, Østergaard L. Comparison of 10 perfusion MRI parameters in 97 sub-6-hour stroke patients using voxel-based receiver operating characteristics analysis. Stroke 2009;40(6):2055-61.Abstract
    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.
    Fujiwara N, Murata Y, Arai K, Egi Y, Lu J, Wu O, Singhal AB, Lo EH. Combination therapy with normobaric oxygen (NBO) plus thrombolysis in experimental ischemic stroke. BMC Neurosci 2009;10:79.Abstract
    BACKGROUND: The widespread use of tissue plasminogen activator (tPA), the only FDA-approved acute stroke treatment, remains limited by its narrow therapeutic time window and related risks of brain hemorrhage. Normobaric oxygen therapy (NBO) may be a useful physiological strategy that slows down the process of cerebral infarction, thus potentially allowing for delayed or more effective thrombolysis. In this study we investigated the effects of NBO started simultaneously with intravenous tPA, in spontaneously hypertensive rats subjected to embolic middle cerebral artery (MCA) stroke. After homologous clot injection, animals were randomized into different treatment groups: saline injected at 1 hour; tPA at 1 hour; saline at 1 hour plus NBO; tPA at 1 hour plus NBO. NBO was maintained for 3 hours. Infarct volume, brain swelling and hemorrhagic transformation were quantified at 24 hours. Outcome assessments were blinded to therapy. RESULTS: Upon clot injection, cerebral perfusion in the MCA territory dropped below 20% of pre-ischemic baselines. Both tPA-treated groups showed effective thrombolysis (perfusion restored to nearly 100%) and smaller infarct volumes (379 +/- 57 mm3 saline controls; 309 +/- 58 mm3 NBO; 201 +/- 78 mm3 tPA; 138 +/- 30 mm3 tPA plus NBO), showing that tPA-induced reperfusion salvages ischemic tissue and that NBO does not significantly alter this neuroprotective effect. NBO had no significant effect on hemorrhagic conversion, brain swelling, or mortality. CONCLUSION: NBO can be safely co-administered with tPA. The efficacy of tPA thrombolysis is not affected and there is no induction of brain hemorrhage or edema. These experimental results require clinical confirmation.
    Copen WA, Rezai Gharai L, Barak ER, Schwamm LH, Wu O, Kamalian S, Gonzalez GR, Schaefer PW. Existence of the diffusion-perfusion mismatch within 24 hours after onset of acute stroke: dependence on proximal arterial occlusion. Radiology 2009;250(3):878-86.Abstract
    PURPOSE: To assess the existence of a mismatch between lesions on diffusion-weighted (DW) and perfusion-weighted (PW) magnetic resonance (MR) images obtained within 24 hours after onset of acute stroke and to use mismatch data and angiographic evidence of proximal arterial occlusion (PAO) to investigate whether the existence of the mismatch depends on the existence of PAO. MATERIALS AND METHODS: In this institutional review board-approved, HIPAA-compliant study, 109 retrospectively identified patients had undergone DW and PW imaging within 24 hours of stroke onset. Relative mismatch was computed as the difference between lesion volumes on mean transit time maps and DW images, divided by DW lesion volume. Computed tomographic (CT) angiography or MR angiography distinguished patients with PAO (n = 68) from those with no PAO (NPAO; n = 41). Eligibility for hypothetical thrombolysis was assessed with two different criteria: (a) one derived from the successful Desmoteplase in Acute Ischemic Stroke Trial (DIAS) and Dose Escalation of Desmoteplase for Acute Ischemic Stroke Trial (DEDAS), and (b) another requiring 160% mismatch. RESULTS: Of the 109 patients, 77 (71%) satisfied the DIAS-DEDAS eligibility criteria, and 61 (56%) satisfied the 160% criterion. The NPAO patients demonstrated decreasing eligibility with increasing time after onset by using DIAS-DEDAS criteria (P = .015) and showed a similar trend with the 160% criterion (P = .078). The NPAO patients were less likely to be eligible after 9 hours than before 9 hours (17% for >9 hours vs 72% for <9 hours with DIAS-DEDAS criteria, P = .002; and 8% for >9 hours vs 45% for <9 hours with 160% criterion, P = .033). However, PAO patients demonstrated a trend toward increasing eligibility with the DIAS-DEDAS criteria (P = .099) and no significant difference for after 9 hours versus before 9 hours (84% for >9 hours vs 78% for <9 hours with DIAS-DEDAS criteria, P = .742; and 68% for >9 hours vs 69% for <9 hours with 160% criterion, P > .999). CONCLUSION: Persistence of mismatch after 9 hours is common and occurs most often in patients with PAO.
    Hjort N, Wu O, Ashkanian M, Sølling C, Mouridsen K, Christensen S, Gyldensted C, Andersen G, Østergaard L. MRI detection of early blood-brain barrier disruption: parenchymal enhancement predicts focal hemorrhagic transformation after thrombolysis. Stroke 2008;39(3):1025-8.Abstract
    BACKGROUND AND PURPOSE: Blood-brain barrier disruption may be a predictor of hemorrhagic transformation (HT) in ischemic stroke. We hypothesize that parenchymal enhancement (PE) on postcontrast T1-weighted MRI predicts and localizes subsequent HT. METHODS: In a prospective study, 33 tPA-treated stroke patients were imaged by perfusion-weighted imaging, T1 and FLAIR before thrombolytic therapy and after 2 and 24 hours. RESULTS: Postcontrast T1 PE was found in 5 of 32 patients (16%) 2 hours post-thrombolysis. All 5 patients subsequently showed HT compared to 11 of 26 patients without PE (P=0.043, specificity 100%, sensitivity 31%), with exact anatomic colocation of PE and HT. Enhancement of cerebrospinal fluid on FLAIR was found in 4 other patients, 1 of which developed HT. Local reperfusion was found in 4 of 5 patients with PE, whereas reperfusion was found in all cases of cerebrospinal fluid hyperintensity. CONCLUSIONS: PE detected 2 hours after thrombolytic therapy predicts HT with high specificity. Contrast-enhanced MRI may provide a tool for studying HT and targeting future therapies to reduce risk of hemorrhagic complications.

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