Greer DM, Yang J, Scripko PD, Sims JR, Cash S, Kilbride R, Wu O, Hafler JP, Schoenfeld DA, Furie KL. Clinical examination for outcome prediction in nontraumatic coma. Crit Care Med 2012;40(4):1150-6.Abstract
    OBJECTIVES: Determine the utility of the neurologic examination in comatose patients from nontraumatic causes in the modern era. DESIGN: Prospective observational study. SETTING: Single academic medical center. PATIENTS: Data from 500 patients in nontraumatic coma collected sequentially from 2000 to 2007 in the emergency department and neuroscience, medical, and cardiac intensive care units. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical data were collected on days 0, 1, 3, and 7. Outcome was assessed at 6 months; good outcome was determined at two levels by modified Rankin Scale, ≤3 as independence and ≤4 as moderate but not severe disability. A classification and regression tree analysis was performed to determine prognostic variables, creating predictive algorithms of good vs. poor outcome for each day. Patients with coma attributable to subarachnoid hemorrhage (4/80; 5%) or global hypoxic-ischemic injury (20/202, 10%) were more likely to achieve good outcomes. The pupillary reflex was an important determinant, regardless of day or modified Rankin Scale cut point (mean odds ratio 12.51, range [6.01, 22.56] for modified Rankin Scale ≤3; mean odds ratio 19.26, range [5.38, 42.26] for modified Rankin Scale ≤4). A less robust effect was seen for oculocephalic reflexes (mean odds ratio 62.61, range [2.24, 177] for modified Rankin Scale ≤3; mean odds ratio 34.13, range [4.95, 89.93] for modified Rankin Scale ≤4). The motor response was selected as a predictor of outcome only on day 0 (odds ratio 2.35, 95% confidence interval 0.64-5.74 for modified Rankin Scale ≤3; odds ratio 2.1, 95% confidence interval 0.81-4.24 for modified Rankin Scale score ≤4). Age was not associated with outcome. CONCLUSIONS: The clinical neurologic examination remains central to determining prognosis in nontraumatic coma. Additional clinical and diagnostic variables may also aid in outcome prediction for specific disease states.
    Edlow BL, Takahashi E, Wu O, Benner T, Dai G, Bu L, Grant PE, Greer DM, Greenberg SM, Kinney HC, Folkerth RD. Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders. J Neuropathol Exp Neurol 2012;71(6):531-46.Abstract
    The ascending reticular activating system (ARAS) mediates arousal, an essential component of human consciousness. Lesions of the ARAS cause coma, the most severe disorder of consciousness. Because of current methodological limitations, including of postmortem tissue analysis, the neuroanatomic connectivity of the human ARAS is poorly understood. We applied the advanced imaging technique of high angular resolution diffusion imaging (HARDI) to elucidate the structural connectivity of the ARAS in 3 adult human brains, 2 of which were imaged postmortem. High angular resolution diffusion imaging tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, the hypothalamus, and the basal forebrain. Each pathway contained different distributions of fiber tracts from known neurotransmitter-specific ARAS nuclei in the brainstem. The histologically guided tractography findings reported here provide initial evidence for human-specific pathways of the ARAS. The unique composition of neurotransmitter-specific fiber tracts within each ARAS pathway suggests structural specializations that subserve the different functional characteristics of human arousal. This ARAS connectivity analysis provides proof of principle that HARDI tractography may affect the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state.
    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.
    Edlow BL, Wu O. Advanced neuroimaging in traumatic brain injury. Semin Neurol 2012;32(4):374-400.Abstract
    Advances in structural and functional neuroimaging have occurred at a rapid pace over the past two decades. Novel techniques for measuring cerebral blood flow, metabolism, white matter connectivity, and neural network activation have great potential to improve the accuracy of diagnosis and prognosis for patients with traumatic brain injury (TBI), while also providing biomarkers to guide the development of new therapies. Several of these advanced imaging modalities are currently being implemented into clinical practice, whereas others require further development and validation. Ultimately, for advanced neuroimaging techniques to reach their full potential and improve clinical care for the many civilians and military personnel affected by TBI, it is critical for clinicians to understand the applications and methodological limitations of each technique. In this review, we examine recent advances in structural and functional neuroimaging and the potential applications of these techniques to the clinical care of patients with TBI. We also discuss pitfalls and confounders that should be considered when interpreting data from each technique. Finally, given the vast amounts of advanced imaging data that will soon be available to clinicians, we discuss strategies for optimizing data integration, visualization, and interpretation.
    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.
    Arkink EB, Bleeker EJW, Schmitz N, Schoonman GG, Wu O, Ferrari MD, van Buchem MA, van Osch MJ, Kruit MC. Cerebral perfusion changes in migraineurs: a voxelwise comparison of interictal dynamic susceptibility contrast MRI measurements. Cephalalgia 2012;32(4):279-88.Abstract
    INTRODUCTION: The increased risk of cerebro- and cardiovascular disease in migraineurs may be the consequence of a systemic condition affecting whole body vasculature. At cerebrovascular level, this may be reflected by interictal global or regional cerebral perfusion abnormalities. Whether focal perfusion changes occur during interictal migraine has not been convincingly demonstrated. METHODS: We measured brain perfusion with dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) in 29 interictal female migraineurs (12 migraine with aura (MA), 17 migraine without aura (MO)), and 16 female controls. Perfusion maps were compared between these groups with a voxelwise (p < 0.001, uncorrected, minimum cluster size 20 voxels) and a region-of-interest approach. RESULTS: In whole brain voxelwise analyses interictal hyperperfusion was observed in the left medial frontal gyrus in migraineurs and in the inferior and middle temporal gyrus in MO patients, in comparison with controls. Hypoperfusion was seen in the postcentral gyrus and in the inferior temporal gyrus in MA patients and in the inferior frontal gyrus in MO patients. Additional focal sites of hyperperfusion were noted in subgroups based on attack frequency and disease history. Region-of-interest analyses of the pons, hypothalamus, occipital lobe, and cerebellum did not show interictal perfusion differences between migraineurs and controls. CONCLUSIONS: We conclude that interictal migraine is characterized by discrete areas of hyper- and hypoperfusion unspecific for migraine pathophysiology and not explaining the increased vulnerability of particular brain regions for cerebrovascular damage.
    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

    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.


    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.


    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.


    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.

    Wu O, Batista LM, Lima FO, Vangel MG, Furie KL, Greer DM. Predicting clinical outcome in comatose cardiac arrest patients using early noncontrast computed tomography. Stroke 2011;42(4):985-92.Abstract
    BACKGROUND AND PURPOSE: Early assessment of the likelihood of neurological recovery in comatose cardiac arrest survivors remains challenging. We hypothesize that quantitative noncontrast computed tomography (NCCT) combined with neurological assessments, are predictive of outcome. METHODS: We analyzed data sets acquired from comatose cardiac arrest patients who underwent CT within 72 hours of arrest. Images were semiautomatically segmented into anatomic regions. Median Hounsfield units (HU) were measured regionally and in the whole brain (WB). Outcome was based on the 6-month modified Rankin Scale (mRS) score. Logistic regression was used to combine Glasgow Coma Scale (GCS) score measured on Day 3 post arrest (GCS_Day3) with imaging to predict poor outcome (mRS>4). RESULTS: WB HU (P=0.02) and the ratio of HU in the putamen to the posterior limb of the internal capsule (PLIC) (P=0.004) from 175 datasets from 151 patients were univariate predictors of poor outcome. Thirty-three patients underwent hypothermia treatment. Multivariate analysis showed that combining median HU in the putamen (P=0.0006) and PLIC (P=0.007) was predictive of poor outcome. Combining WB HU and GCS_Day3 resulted in 72% [61% to 80%] sensitivity and 100% [73% to 100%] specificity for predicting poor outcome in 86 patients with measurable GCS_Day3. This was an improvement over prognostic performance based on GCS_Day3≤8 (98% sensitive but 71% specific). DISCUSSION: Combining density changes on CT with GCS_Day3 may be useful for predicting poor outcome in comatose cardiac arrest patients who are neither rapidly improving nor deteriorating. Improved prognostication with CT compared with neurological assessments can be achieved in patients treated with hypothermia.
    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.
    Kwong KK, Wu O, Chan S-T, Nelissen K, Kholodov M, Chesler DA. Early time points perfusion imaging: relative time of arrival, maximum derivatives and fractional derivatives. Neuroimage 2011;57(3):979-90.Abstract
    Time of arrival (TOA) of a bolus of contrast agent to the tissue voxel is a reference time point critical for the Early Time Points Perfusion Imaging Method (ET) to make relative cerebral blood flow (rCBF) maps. Due to the low contrast to noise (CNR) condition at TOA, other useful reference time points known as relative time of arrival data points (rTOA) are investigated. Candidate rTOA's include the time to reach the maximum derivative, the maximum second derivative, and the maximum fractional derivative. Each rTOA retains the same relative time distance from TOA for all tissue flow levels provided that ET's basic assumption is met, namely, no contrast agent has a chance to leave the tissue before the time of rTOA. The ET's framework insures that rCBF estimates by different orders of the derivative are theoretically equivalent to each other and monkey perfusion imaging results supported the theory. In rCBF estimation, maximum values of higher order fractional derivatives may be used to replace the maximum derivative which runs a higher risk of violating ET's assumption. Using the maximum values of the derivative of orders ranging from 1 to 1.5 to 2, estimated rCBF results were found to demonstrate a gray-white matter ratio of approximately 3, a number consistent with flow ratio reported in the literature.
    Kwong KK, Reese TG, Nelissen K, Wu O, Chan S-T, Benner T, Mandeville JB, Foley M, Vanduffel W, Chesler DA. Early time points perfusion imaging. Neuroimage 2011;54(2):1070-82.Abstract
    The aim was to investigate the feasibility of making relative cerebral blood flow (rCBF) maps from MR images acquired with short TR by measuring the initial arrival amount of Gd-DTPA evaluated within a time window before any contrast agent has a chance to leave the tissue. We named this rCBF measurement technique utilizing the early data points of the Gd-DTPA bolus the "early time points" method (ET), based on the hypothesis that early time point signals were proportional to rCBF. Simulation data were used successfully to examine the ideal behavior of ET while monkey's MRI results offered encouraging support to the utility of ET for rCBF calculation. A better brain coverage for ET could be obtained by applying the Simultaneous Echo Refocusing (SER) EPI technique. A recipe to run ET was presented, with attention paid to the noise problem around the time of arrival (TOA) of the contrast agent.
    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, 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.
    Wu O, Dijkhuizen RM, Sorensen AG. Multiparametric magnetic resonance imaging of brain disorders. Top Magn Reson Imaging 2010;21(2):129-38.Abstract
    Magnetic resonance imaging (MRI) has been shown to improve the diagnosis and management of patients with brain disorders. Multiparametric MRI offers the possibility of noninvasively assessing multiple facets of pathophysiological processes that exist simultaneously, thereby further assisting in patient treatment management. Voxel-based analysis approaches, such as tissue theme mapping, have the benefit over volumetric approaches in being able to identify spatially heterogeneous colocalized changes on multiple parametric MR images that are not readily discernible. Tissue theme maps seem to be a promising tool for integrating the plethora of novel imaging contrasts that are being developed for the noninvasive investigation of the different stages of disease progression into easily interpretable maps of brain injury. We describe here various implementations for combining multiparametric imaging and their merits in the evaluation of brain diseases.
    Emmer BJ, van Osch MJ, Wu O, Steup-Beekman GM, Steens SC, Huizinga TW, van Buchem MA, van der Grond J. Perfusion MRI in neuro-psychiatric systemic lupus erthemathosus. J Magn Reson Imaging 2010;32(2):283-8.Abstract
    PURPOSE: To use perfusion weighted MR to quantify any perfusion abnormalities and to determine their contribution to neuropsychiatric (NP) involvement in systemic lupus erythematosus (SLE). MATERIALS AND METHODS: We applied dynamic susceptibility contrast (DSC) perfusion MRI in 15 active NPSLE, 26 inactive NPSLE patients, and 11 control subjects. Cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) maps were reconstructed and regions of interest were compared between groups. In addition, the effect of SLE criteria, NPSLE syndromes, immunological coagulation disorder, and medication on CBF, CBV, and MTT was investigated. RESULTS: No significant differences were found between the groups in CBF, CBV, and MTT. No significant influence of SLE criteria or NPSLE syndromes on CBF, CBV, or MTT was found. No significant influence of anti-cardiolipin antibodies, lupus anti-coagulant, the presence of anti-phospholipid syndrome (APS), or medication on CBF, CBV, or MTT was found. CONCLUSION: Our findings suggest CBF, CBV, and MTT in the white and the gray matter in SLE patients is not significantly different from healthy controls or between patients with and without specific symptoms or with and without immunological disorder involving coagulation.
    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.