Publications

    Ktena SI, Schirmer MD, Etherton MR, Giese A-K, Tuozzo C, Mills BB, Rueckert D, Wu O, Rost NS. Brain Connectivity Measures Improve Modeling of Functional Outcome After Acute Ischemic Stroke. Stroke 2019;50(10):2761-2767.Abstract
    Background and Purpose- The ability to model long-term functional outcomes after acute ischemic stroke represents a major clinical challenge. One approach to potentially improve prediction modeling involves the analysis of connectomics. The field of connectomics represents the brain's connectivity as a graph, whose topological properties have helped uncover underlying mechanisms of brain function in health and disease. Specifically, we assessed the impact of stroke lesions on rich club organization, a high capacity backbone system of brain function. Methods- In a hospital-based cohort of 41 acute ischemic stroke patients, we investigated the effect of acute infarcts on the brain's prestroke rich club backbone and poststroke functional connectomes with respect to poststroke outcome. Functional connectomes were created using 3 anatomic atlases, and characteristic path-length () was calculated for each connectome. The number of rich club regions affected were manually determined using each patient's diffusion weighted image. We investigated differences in with respect to outcome (modified Rankin Scale score; 90 days) and the National Institutes of Health Stroke Scale (NIHSS; early: 2-5 days; late: 90-day follow-up). Furthermore, we assessed the effect of including number of rich club regions and in outcome models, using linear regression and assessing the explained variance (R). Results- Of 41 patients (mean age [range]: 70 [45-89] years), 61% were male. Lower was generally associated with better outcome. Including number of rich club regions in the backward selection models of outcome, R increased between 1.3- and 2.6-fold beyond that of traditional markers (age and acute lesion volume) for NIHSS and modified Rankin Scale score. Conclusions- In this proof-of-concept study, we showed that information on network topology can be leveraged to improve modeling of poststroke functional outcome. Future studies are warranted to validate this approach in larger prospective studies of outcome prediction in stroke.
    Schirmer MD, Ktena SI, Nardin MJ, Donahue KL, Giese A-K, Etherton MR, Wu O, Rost NS. Rich-Club Organization: An Important Determinant of Functional Outcome After Acute Ischemic Stroke. Front Neurol 2019;10:956.Abstract
    To determine whether the rich-club organization, essential for information transport in the human connectome, is an important biomarker of functional outcome after acute ischemic stroke (AIS). Consecutive AIS patients ( = 344) with acute brain magnetic resonance imaging (MRI) (<48 h) were eligible for this study. Each patient underwent a clinical MRI protocol, which included diffusion weighted imaging (DWI). All DWIs were registered to a template on which rich-club regions have been defined. Using manual outlines of stroke lesions, we automatically counted the number of affected rich-club regions and assessed its effect on the National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS; obtained at 90 days post-stroke) scores through ordinal regression. Of 344 patients (median age 65, inter-quartile range 54-76 years) with a median DWI lesion volume (DWIv) of 3cc, 64% were male. We established that an increase in number of rich-club regions affected by a stroke increases the odds of poor stroke outcome, measured by NIHSS (OR: 1.77, 95%CI 1.41-2.21) and mRS (OR: 1.38, 95%CI 1.11-1.73). Additionally, we demonstrated that the OR exceeds traditional markers, such as DWIv (OR 1.08, 95%CI 1.06-1.11; OR 1.05, 95%CI 1.03-1.07) and age (OR 1.03, 95%CI 1.01-1.05; OR 1.05, 95%CI 1.03-1.07). In this proof-of-concept study, the number of rich-club nodes affected by a stroke lesion presents a translational biomarker of stroke outcome, which can be readily assessed using standard clinical AIS imaging protocols and considered in functional outcome prediction models beyond traditional factors.
    Winzeck S, Mocking SJT, Bezerra R, Bouts MJRJ, McIntosh EC, Diwan I, Garg P, Chutinet A, Kimberly WT, Copen WA, Schaefer PW, Ay H, Singhal AB, Kamnitsas K, Glocker B, Sorensen AG, Wu O. Ensemble of Convolutional Neural Networks Improves Automated Segmentation of Acute Ischemic Lesions Using Multiparametric Diffusion-Weighted MRI. AJNR Am J Neuroradiol 2019;40(6):938-945.Abstract
    BACKGROUND AND PURPOSE: Accurate automated infarct segmentation is needed for acute ischemic stroke studies relying on infarct volumes as an imaging phenotype or biomarker that require large numbers of subjects. This study investigated whether an ensemble of convolutional neural networks trained on multiparametric DWI maps outperforms single networks trained on solo DWI parametric maps. MATERIALS AND METHODS: Convolutional neural networks were trained on combinations of DWI, ADC, and low b-value-weighted images from 116 subjects. The performances of the networks (measured by the Dice score, sensitivity, and precision) were compared with one another and with ensembles of 5 networks. To assess the generalizability of the approach, we applied the best-performing model to an independent Evaluation Cohort of 151 subjects. Agreement between manual and automated segmentations for identifying patients with large lesion volumes was calculated across multiple thresholds (21, 31, 51, and 70 cm). RESULTS: An ensemble of convolutional neural networks trained on DWI, ADC, and low b-value-weighted images produced the most accurate acute infarct segmentation over individual networks ( < .001). Automated volumes correlated with manually measured volumes (Spearman ρ = 0.91, < .001) for the independent cohort. For the task of identifying patients with large lesion volumes, agreement between manual outlines and automated outlines was high (Cohen κ, 0.86-0.90; < .001). CONCLUSIONS: Acute infarcts are more accurately segmented using ensembles of convolutional neural networks trained with multiparametric maps than by using a single model trained with a solo map. Automated lesion segmentation has high agreement with manual techniques for identifying patients with large lesion volumes.
    Lorenzano S, Rost NS, Khan M, Li H, Batista LM, Chutinet A, Green RE, Thankachan TK, Thornell B, Muzikansky A, Arai K, Som AT, Pham L-DD, Wu O, Harris GJ, Lo EH, Blumberg JB, Milbury PE, Feske SK, Furie KL. Early molecular oxidative stress biomarkers of ischemic penumbra in acute stroke. Neurology 2019;93(13):e1288-e1298.Abstract
    OBJECTIVES: To assess whether plasma biomarkers of oxidative stress predict diffusion-perfusion mismatch in patients with acute ischemic stroke (AIS). METHODS: We measured plasma levels of oxidative stress biomarkers such as F2-isoprostanes (F2-isoPs), total and perchloric acid Oxygen Radical Absorbance Capacity (ORAC and ORAC), urinary levels of 8-oxo-7,8-dihydro-2'-deoxyguoanosine, and inflammatory and tissue-damage biomarkers (high-sensitivity C-reactive protein, matrix metalloproteinase-2 and -9) in a prospective study of patients with AIS presenting within 9 hours of symptom onset. Diffusion-weighted (DWI) and perfusion-weighted (PWI) MRI sequences were analyzed with a semiautomated volumetric method. Mismatch was defined as baseline mean transit time volume minus DWI volume. A percent mismatch cutoff of >20% was considered clinically significant. A stricter definition of mismatch was also used. Mismatch salvage was the region free of overlap by final infarction. RESULTS: Mismatch >20% was present in 153 of 216 (70.8%) patients (mean [±SD] age 69.2 ± 14.3 years, 41.2% women). Patients with mismatch >20% were more likely to have higher baseline plasma levels of ORAC ( = 0.020) and F2-isoPs ( = 0.145). Multivariate binary logistic regression demonstrated that lnF2-isoP (odds ratio [OR] 2.44, 95% confidence interval [CI] 1.19-4.98, = 0.014) and lnORAC (OR 4.18, 95% CI 1.41-12.41, = 0.010) were independent predictors of >20% PWI-DWI mismatch and the stricter mismatch definition, respectively. lnORAC significantly predicted mismatch salvage volume (>20% mismatch = 0.010, stricter mismatch definition = 0.003). CONCLUSIONS: Elevated hyperacute plasma levels of F2-isoP and ORAC are associated with radiographic evidence of mismatch and mismatch salvage in patients with AIS. If validated, these findings may add to our understanding of the role of oxidative stress in cerebral tissue fate during acute ischemia.
    Mazwi NL, Izzy S, Tan CO, Martinez S, Glenn MB, Giacino JT, Wu O, Zafonte R, Edlow BL. Traumatic Microbleeds in the Hippocampus and Corpus Callosum Predict Duration of Posttraumatic Amnesia. J Head Trauma Rehabil 2019;34(6):E10-E18.Abstract
    OBJECTIVE: Radiologic predictors of posttraumatic amnesia (PTA) duration are lacking. We hypothesized that the number and distribution of traumatic microbleeds (TMBs) detected by gradient recalled echo (GRE) magnetic resonance imaging (MRI) predicts PTA duration. SETTING: Academic, tertiary medical center. PARTICIPANTS: Adults with traumatic brain injury (TBI). DESIGN: We identified 65 TBI patients with acute GRE MRI. PTA duration was determined with the Galveston Orientation and Amnesia Test, Orientation Log, or chart review. TMBs were identified within memory regions (hippocampus, corpus callosum, fornix, thalamus, and temporal lobe) and control regions (internal capsule and global). Regression tree analysis was performed to identify radiologic predictors of PTA duration, controlling for clinical PTA predictors. MAIN MEASURES: TMB distribution, PTA duration. RESULTS: Sixteen patients (25%) had complicated mild, 4 (6%) had moderate, and 45 (69%) had severe TBI. Median PTA duration was 43 days (range, 0-240 days). In univariate analysis, PTA duration correlated with TMBs in the corpus callosum (R = 0.29, P = .02) and admission Glasgow Coma Scale (GCS) score (R = -0.34, P = .01). In multivariate regression analysis, admission GCS score was the only significant contributor to PTA duration. However, in regression tree analysis, hippocampal TMBs, callosal TMBs, age, and admission GCS score explained 26% of PTA duration variance and distinguished a subgroup with prolonged PTA. CONCLUSIONS: Hippocampal and callosal TMBs are potential radiologic predictors of PTA duration.
    Snider SB, Bodien YG, Bianciardi M, Brown EN, Wu O, Edlow BL. Disruption of the ascending arousal network in acute traumatic disorders of consciousness. Neurology 2019;93(13):e1281-e1287.Abstract
    OBJECTIVE: To determine whether ascending arousal network (AAn) connectivity is reduced in patients presenting with traumatic coma. METHODS: We performed high-angular-resolution diffusion imaging in 16 patients with acute severe traumatic brain injury who were comatose on admission and in 16 matched controls. We used probabilistic tractography to measure the connectivity probability (CP) of AAn axonal pathways linking the brainstem tegmentum to the hypothalamus, thalamus, and basal forebrain. To assess the spatial specificity of CP differences between patients and controls, we also measured CP within 4 subcortical pathways outside the AAn. RESULTS: Compared to controls, patients showed a reduction in AAn pathways connecting the brainstem tegmentum to a region of interest encompassing the hypothalamus, thalamus, and basal forebrain. When each pathway was examined individually, brainstem-hypothalamus and brainstem-thalamus CPs, but not brainstem-forebrain CP, were significantly reduced in patients. Only 1 subcortical pathway outside the AAn showed reduced CP in patients. CONCLUSIONS: We provide initial evidence for the reduced integrity of axonal pathways linking the brainstem tegmentum to the hypothalamus and thalamus in patients presenting with traumatic coma. Our findings support current conceptual models of coma as being caused by subcortical AAn injury. AAn connectivity mapping provides an opportunity to advance the study of human coma and consciousness.
    Wu O, Winzeck S, Giese A-K, Hancock BL, Etherton MR, Bouts MJRJ, Donahue K, Schirmer MD, Irie RE, Mocking SJT, McIntosh EC, Bezerra R, Kamnitsas K, Frid P, Wasselius J, Cole JW, Xu H, Holmegaard L, Jiménez-Conde J, Lemmens R, Lorentzen E, McArdle PF, Meschia JF, Roquer J, Rundek T, Sacco RL, Schmidt R, Sharma P, Slowik A, Stanne TM, Thijs V, Vagal A, Woo D, Bevan S, Kittner SJ, Mitchell BD, Rosand J, Worrall BB, Jern C, Lindgren AG, Maguire J, Rost NS. Big Data Approaches to Phenotyping Acute Ischemic Stroke Using Automated Lesion Segmentation of Multi-Center Magnetic Resonance Imaging Data. Stroke 2019;50(7):1734-1741.Abstract
    Background and Purpose- We evaluated deep learning algorithms' segmentation of acute ischemic lesions on heterogeneous multi-center clinical diffusion-weighted magnetic resonance imaging (MRI) data sets and explored the potential role of this tool for phenotyping acute ischemic stroke. Methods- Ischemic stroke data sets from the MRI-GENIE (MRI-Genetics Interface Exploration) repository consisting of 12 international genetic research centers were retrospectively analyzed using an automated deep learning segmentation algorithm consisting of an ensemble of 3-dimensional convolutional neural networks. Three ensembles were trained using data from the following: (1) 267 patients from an independent single-center cohort, (2) 267 patients from MRI-GENIE, and (3) mixture of (1) and (2). The algorithms' performances were compared against manual outlines from a separate 383 patient subset from MRI-GENIE. Univariable and multivariable logistic regression with respect to demographics, stroke subtypes, and vascular risk factors were performed to identify phenotypes associated with large acute diffusion-weighted MRI volumes and greater stroke severity in 2770 MRI-GENIE patients. Stroke topography was investigated. Results- The ensemble consisting of a mixture of MRI-GENIE and single-center convolutional neural networks performed best. Subset analysis comparing automated and manual lesion volumes in 383 patients found excellent correlation (ρ=0.92; P<0.0001). Median (interquartile range) diffusion-weighted MRI lesion volumes from 2770 patients were 3.7 cm (0.9-16.6 cm). Patients with small artery occlusion stroke subtype had smaller lesion volumes ( P<0.0001) and different topography compared with other stroke subtypes. Conclusions- Automated accurate clinical diffusion-weighted MRI lesion segmentation using deep learning algorithms trained with multi-center and diverse data is feasible. Both lesion volume and topography can provide insight into stroke subtypes with sufficient sample size from big heterogeneous multi-center clinical imaging phenotype data sets.
    Schirmer MD, Etherton Md PhD MR, Dalca PhD AV, Giese Md A-K, Cloonan MSc L, Wu PhD O, Golland PhD P, Rost Md Mph Faan NS. Effective Reserve: A Latent Variable to Improve Outcome Prediction in Stroke. J Stroke Cerebrovasc Dis 2019;28(1):63-69.Abstract
    Prediction of functional outcome after stroke based on initial presentation remains an open challenge, suggesting that an important aspect is missing from these prediction models. There exists the notion of a protective mechanism called brain reserve, which may be utilized to understand variations in disease outcome. In this work, we expand the concept of brain reserve (effective reserve) to improve prediction models of functional outcome after acute ischemic stroke (AIS). Consecutive AIS patients with acute brain magnetic resonance imaging (<48 hours) were eligible for this study. White matter hyperintensity and acute infarct volume were determined on T2 fluid attenuated inversion recovery and diffusion weighted images, respectively. Modified Rankin Scale scores were obtained at 90days poststroke. Effective reserve was defined as a latent variable using structural equation modeling by including age, systolic blood pressure, and intracranial volume measurements. Of 453 AIS patients (mean age 66.6 ± 14.7 years), 36% were male and 311 hypertensive. There was inverse association between effective reserve and 90-day modified Rankin Scale scores (path coefficient -0.18 ± 0.01, P < .01). Compared to a model without effective reserve, correlation between predicted and observed modified Rankin Scale scores improved in the effective-reserve-based model (Spearman's ρ 0.29 ± 0.18 versus 0.15 ± 0.17, P < .001). Furthermore, hypertensive patients exhibited lower effective reserve (P < 10). Using effective reserve in prediction models of stroke outcome is feasible and leads to better model performance. Furthermore, higher effective reserve is associated with more favorable functional poststoke outcome and might correspond to an overall better vascular health.
    Etherton MR, Wu O, Giese A-K, Lauer A, Boulouis G, Mills B, Cloonan L, Donahue KL, Copen W, Schaefer P, Rost NS. White Matter Integrity and Early Outcomes After Acute Ischemic Stroke. Transl Stroke Res 2019;10(6):630-638.Abstract
    Chronic white matter structural injury is a risk factor for poor long-term outcomes after acute ischemic stroke (AIS). However, it is unclear how white matter structural injury predisposes to poor outcomes after AIS. To explore this question, in 42 AIS patients with moderate to severe white matter hyperintensity (WMH) burden, we characterized WMH and normal-appearing white matter (NAWM) diffusivity anisotropy metrics in the hemisphere contralateral to acute ischemia in relation to ischemic tissue and early functional outcomes. All patients underwent brain MRI with dynamic susceptibility contrast perfusion and diffusion tensor imaging within 12 h and at day 3-5 post stroke. Early neurological outcomes were measured as the change in NIH Stroke Scale score from admission to day 3-5 post stroke. Target mismatch profile, percent mismatch lost, infarct growth, and rates of good perfusion were measured to assess ischemic tissue outcomes. NAWM mean diffusivity was significantly lower in the group with early neurological improvement (ENI, 0.79 vs. 0.82 × 10, mm/s; P = 0.02). In multivariable logistic regression, NAWM mean diffusivity was an independent radiographic predictor of ENI (β = - 17.6, P = 0.037). Median infarct growth was 118% (IQR 26.8-221.9%) despite good reperfusion being observed in 65.6% of the cohort. NAWM and WMH diffusivity metrics were not associated with target mismatch profile, percent mismatch lost, or infarct growth. Our results suggest that, in AIS patients, white matter structural integrity is associated with poor early neurological outcomes independent of ischemic tissue outcomes.
    Schirmer MD, Giese A-K, Fotiadis P, Etherton MR, Cloonan L, Viswanathan A, Greenberg SM, Wu O, Rost NS. Spatial Signature of White Matter Hyperintensities in Stroke Patients. Front Neurol 2019;10:208.Abstract
    White matter hyperintensity (WMH) is a common phenotype across a variety of neurological diseases, particularly prevalent in stroke patients; however, vascular territory dependent variation in WMH burden has not yet been identified. Here, we sought to investigate the spatial specificity of WMH burden in patients with acute ischemic stroke (AIS). We created a novel age-appropriate high-resolution brain template and anatomically delineated the cerebral vascular territories. We used WMH masks derived from the clinical T2 Fluid Attenuated Inverse Recovery (FLAIR) MRI scans and spatial normalization of the template to discriminate between WMH volume within each subject's anterior cerebral artery (ACA), middle cerebral artery (MCA), and posterior cerebral artery (PCA) territories. Linear regression modeling including age, sex, common vascular risk factors, and TOAST stroke subtypes was used to assess for spatial specificity of WMH volume (WMHv) in a cohort of 882 AIS patients. Mean age of this cohort was 65.23 ± 14.79 years, 61.7% were male, 63.6% were hypertensive, 35.8% never smoked. Mean WMHv was 11.58c ± 13.49 cc. There were significant differences in territory-specific, relative to global, WMH burden. In contrast to PCA territory, age (0.018 ± 0.002, < 0.001) and small-vessel stroke subtype (0.212 ± 0.098, < 0.001) were associated with relative increase of WMH burden within the anterior (ACA and MCA) territories, whereas male sex (-0.275 ± 0.067, < 0.001) was associated with a relative decrease in WMHv. Our data establish the spatial specificity of WMH distribution in relation to vascular territory and risk factor exposure in AIS patients and offer new insights into the underlying pathology.
    Schirmer MD, Dalca AV, Sridharan R, Giese A-K, Donahue KL, Nardin MJ, Mocking SJT, McIntosh EC, Frid P, Wasselius J, Cole JW, Holmegaard L, Jern C, Jimenez-Conde J, Lemmens R, Lindgren AG, Meschia JF, Roquer J, Rundek T, Sacco RL, Schmidt R, Sharma P, Slowik A, Thijs V, Woo D, Vagal A, Xu H, Kittner SJ, McArdle PF, Mitchell BD, Rosand J, Worrall BB, Wu O, Golland P, Rost NS. White matter hyperintensity quantification in large-scale clinical acute ischemic stroke cohorts - The MRI-GENIE study. Neuroimage Clin 2019;23:101884.Abstract
    White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery. In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94-0.95; p < 0.01) and Pearson correlation of total brain volume (r = 0.90). Subsequently, we apply it to the large-scale clinical multi-site MRI-GENIE study (N = 2783) and identify a decrease in total brain volume of -2.4 cc/year. Additionally, we show that the resulting total brain volumes can successfully be used for quality control of image preprocessing. Finally, we obtain WMH volumes by building on an existing automatic WMH segmentation algorithm that delineates and distinguishes between different cerebrovascular pathologies. The learning method mimics expert knowledge of the spatial distribution of the WMH burden using a convolutional auto-encoder. This enables successful computation of WMH volumes of 2533 clinical AIS patients. We utilize these results to demonstrate the increase of WMH burden with age (0.950 cc/year) and show that single site estimates can be biased by the number of subjects recruited.
    Rocha EA, Ji R, Ay H, Li Z, Arsava EM, Silva GS, Sorensen AG, Wu O, Singhal AB. Reduced Ischemic Lesion Growth with Heparin in Acute Ischemic Stroke. J Stroke Cerebrovasc Dis 2019;28(6):1500-1508.Abstract
    OBJECTIVE: The role of heparin in acute ischemic stroke is controversial. We investigated the effect of heparin on ischemic lesion growth. METHODS: Data were analyzed on nonthrombolyzed ischemic stroke patients in whom diffusion-weighted imaging (DWI)/perfusion-weighted imaging (PWI) MRI was performed less than 12 hours of last known well and showed a PWI-DWI lesion mismatch, and who underwent follow-up neuroimaging at least 4 days after admission. Lesion growth was assessed by (1) absolute lesion growth and (2) percentage mismatch lost (PML). Univariate and multivariate regression analysis, and propensity score matching, were used to determine the effects of heparin on ischemic lesion growth. RESULTS: Of the 113 patients meeting study criteria, 59 received heparin within 24 hours. Heparin use was associated with ∼5-fold reductions in PML (3.5% versus 19.2%, P = .002) and absolute lesion growth (4.7 versus 20.5 mL, P = .009). In multivariate regression models, heparin independently predicted reduced PML (P = .04) and absolute lesion growth (P = .04) in the entire cohort, and in multiple subgroups (patients with and without proximal artery occlusion; DWI volume greater than 5 mL; cardio-embolic mechanism; DEFUSE-3 target mismatch). In propensity score matching analysis where patients were matched by admission NIHSS, DWI volume and proximal artery occlusion, heparin remained an independent predictor of PML (P = .048) and tended to predict absolute lesion growth (P = .06). Heparin treatment did not predict functional outcome at discharge or 90 days. CONCLUSION: Early heparin treatment in acute ischemic stroke patients with PWI-DWI mismatch attenuates ischemic lesion growth. Clinical trials with careful patient selection are warranted to investigate the potential ischemic protective effects of heparin.
    Joutsa J, Shih LC, Horn A, Reich MM, Wu O, Rost NS, Fox MD. Identifying therapeutic targets from spontaneous beneficial brain lesions. Ann Neurol 2018;84(1):153-157.Abstract
    Brain damage can occasionally result in paradoxical functional benefit, which could help identify therapeutic targets for neuromodulation. However, these beneficial lesions are rare and lesions in multiple different brain locations can improve the same symptom. Using a technique called lesion network mapping, we show that heterogeneous lesion locations resulting in tremor relief are all connected to common nodes in the cerebellum and thalamus, the latter of which is a proven deep brain stimulation target for tremor. These results suggest that lesion network mapping can identify the common substrate underlying therapeutic lesions and effective therapeutic targets. Ann Neurol 2018;83:153-157.
    Schwamm LH, Wu O, Song SS, Latour LL, Ford AL, Hsia AW, Muzikansky A, Betensky RA, Yoo AJ, Lev MH, Boulouis G, Lauer A, Cougo P, Copen WA, Harris GJ, Warach S. Intravenous thrombolysis in unwitnessed stroke onset: MR WITNESS trial results. Ann Neurol 2018;83(5):980-993.Abstract
    OBJECTIVE: Most acute ischemic stroke (AIS) patients with unwitnessed symptom onset are ineligible for intravenous thrombolysis due to timing alone. Lesion evolution on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) correlates with stroke duration, and quantitative mismatch of diffusion-weighted MRI with FLAIR (qDFM) might indicate stroke duration within guideline-recommended thrombolysis. We tested whether intravenous thrombolysis ≤4.5 hours from the time of symptom discovery is safe in patients with qDFM in an open-label, phase 2a, prospective study (NCT01282242). METHODS: Patients aged 18 to 85 years with AIS of unwitnessed onset at 4.5 to 24 hours since they were last known to be well, treatable within 4.5 hours of symptom discovery with intravenous alteplase (0.9mg/kg), and presenting with qDFM were screened across 14 hospitals. The primary outcome was the risk of symptomatic intracranial hemorrhage (sICH) with preplanned stopping rules. Secondary outcomes included symptomatic brain edema risk, and functional outcomes of 90-day modified Rankin Scale (mRS). RESULTS: Eighty subjects were enrolled between January 31, 2011 and October 4, 2015 and treated with alteplase at median 11.2 hours (IQR = 9.5-13.3) from when they were last known to be well. There was 1 sICH (1.3%) and 3 cases of symptomatic edema (3.8%). At 90 days, 39% of subjects achieved mRS = 0-1, as did 48% of subjects who had vessel imaging and were without large vessel occlusions. INTERPRETATION: Intravenous thrombolysis within 4.5 hours of symptom discovery in patients with unwitnessed stroke selected by qDFM, who are beyond the recommended time windows, is safe. A randomized trial testing efficacy using qDFM appears feasible and is warranted in patients without large vessel occlusions. Ann Neurol 2018;83:980-993.
    Threlkeld ZD, Bodien YG, Rosenthal ES, Giacino JT, Nieto-Castanon A, Wu O, Whitfield-Gabrieli S, Edlow BL. Functional networks reemerge during recovery of consciousness after acute severe traumatic brain injury. Cortex 2018;106:299-308.Abstract
    Integrity of the default mode network (DMN) is believed to be essential for human consciousness. However, the effects of acute severe traumatic brain injury (TBI) on DMN functional connectivity are poorly understood. Furthermore, the temporal dynamics of DMN reemergence during recovery of consciousness have not been studied longitudinally in patients with acute severe TBI. We performed resting-state functional magnetic resonance imaging (rs-fMRI) to measure DMN connectivity in 17 patients admitted to the intensive care unit (ICU) with acute severe TBI and in 16 healthy control subjects. Eight patients returned for follow-up rs-fMRI and behavioral assessment six months post-injury. At each time point, we analyzed DMN connectivity by measuring intra-network correlations (i.e. positive correlations between DMN nodes) and inter-network anticorrelations (i.e. negative correlations between the DMN and other resting-state networks). All patients were comatose upon arrival to the ICU and had a disorder of consciousness (DoC) at the time of acute rs-fMRI (9.2 ± 4.6 days post-injury): 2 coma, 4 unresponsive wakefulness syndrome, 7 minimally conscious state, and 4 post-traumatic confusional state. We found that, while DMN anticorrelations were absent in patients with acute DoC, patients who recovered from coma to a minimally conscious or confusional state while in the ICU showed partially preserved DMN correlations. Patients who remained in coma or unresponsive wakefulness syndrome in the ICU showed no DMN correlations. All eight patients assessed longitudinally recovered beyond the confusional state by 6 months post-injury and showed normal DMN correlations and anticorrelations, indistinguishable from those of healthy subjects. Collectively, these findings suggest that recovery of consciousness after acute severe TBI is associated with partial preservation of DMN correlations in the ICU, followed by long-term normalization of DMN correlations and anticorrelations. Both intra-network DMN correlations and inter-network DMN anticorrelations may be necessary for full recovery of consciousness after acute severe TBI.
    Schröder J, Cheng B, Malherbe C, Ebinger M, Köhrmann M, Wu O, Kang D-W, Liebeskind DS, Tourdias T, Singer OC, Campbell B, Luby M, Warach S, Fiehler J, Kemmling A, Fiebach JB, Gerloff C, Thomalla G. Impact of Lesion Load Thresholds on Alberta Stroke Program Early Computed Tomographic Score in Diffusion-Weighted Imaging. Front Neurol 2018;9:273.Abstract
    Background and aims: Assessment of ischemic lesions on computed tomography or MRI diffusion-weighted imaging (DWI) using the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is widely used to guide acute stroke treatment. However, it has never been defined how many voxels need to be affected to label a DWI-ASPECTS region ischemic. We aimed to assess the effect of various lesion load thresholds on DWI-ASPECTS and compare this automated analysis with visual rating. Materials and methods: We analyzed overlap of individual DWI lesions of 315 patients from the previously published predictive value of fluid-attenuated inversion recovery study with a probabilistic ASPECTS template derived from 221 CT images. We applied multiple lesion load thresholds per DWI-ASPECTS region (>0, >1, >10, and >20% in each DWI-ASPECTS region) to compute DWI-ASPECTS for each patient and compared the results to visual reading by an experienced stroke neurologist. Results: By visual rating, median ASPECTS was 9, 84 patients had a DWI-ASPECTS score ≤7. Mean DWI lesion volume was 22.1 (±35) ml. In contrast, by use of >0, >1-, >10-, and >20%-thresholds, median DWI-ASPECTS was 1, 5, 8, and 10; 97.1% (306), 72.7% (229), 41% (129), and 25.7% (81) had DWI-ASPECTS ≤7, respectively. Overall agreement between automated assessment and visual rating was low for every threshold used (>0%: κ = 0.020 1%: κ = 0.151; 10%: κ = 0.386; 20% κ = 0.381). Agreement for dichotomized DWI-ASPECTS ranged from fair to substantial (≤7: >10% κ = 0.48; >20% κ = 0.45; ≤5: >10% κ = 0.528; and >20% κ = 0.695). Conclusion: Overall agreement between automated and the standard used visual scoring is low regardless of the lesion load threshold used. However, dichotomized scoring achieved more comparable results. Varying lesion load thresholds had a critical impact on patient selection by ASPECTS. Of note, the relatively low lesion volume and lack of patients with large artery occlusion in our cohort may limit generalizability of these findings.
    Etherton MR, Barreto AD, Schwamm LH, Wu O. Neuroimaging Paradigms to Identify Patients for Reperfusion Therapy in Stroke of Unknown Onset. Front Neurol 2018;9:327.Abstract
    Despite the proven efficacy of intravenous alteplase or endovascular thrombectomy for the treatment of patients with acute ischemic stroke, only a minority receive these treatments. This low treatment rate is due in large part to delay in hospital arrival or uncertainty as to the exact time of onset of ischemic stroke, which renders patients outside the current guideline-recommended window of eligibility for receiving these therapeutics. However, recent pivotal clinical trials of late-window thrombectomy now force us to rethink the value of a simplistic chronological formulation that "time is brain." We must recognize a more nuanced concept that the rate of tissue death as a function of time is not invariant, that still salvageable tissue at risk of infarction may be present up to 24 h after last-known well, and that those patients may strongly benefit from reperfusion. Multiple studies have sought to address this clinical dilemma using neuroimaging methods to identify a radiographic time-stamp of stroke onset or evidence of salvageable ischemic tissue and thereby increase the number of patients eligible for reperfusion therapies. In this review, we provide a critical analysis of the current state of neuroimaging techniques to select patients with unwitnessed stroke for revascularization therapies and speculate on the future direction of this clinically relevant area of stroke research.
    Lorenzano S, Rost NS, Khan M, Li H, Lima FO, Maas MB, Green RE, Thankachan TK, Dipietro AJ, Arai K, Som AT, Pham L-DD, Wu O, Harris GJ, Lo EH, Blumberg JB, Milbury PE, Feske SK, Furie KL. Oxidative Stress Biomarkers of Brain Damage: Hyperacute Plasma F2-Isoprostane Predicts Infarct Growth in Stroke. Stroke 2018;Abstract
    BACKGROUND AND PURPOSE: Oxidative stress is an early response to cerebral ischemia and is likely to play an important role in the pathogenesis of cerebral ischemic injury. We sought to evaluate whether hyperacute plasma concentrations of biomarkers of oxidative stress, inflammation, and tissue damage predict infarct growth (IG). METHODS: We prospectively measured plasma F2-isoprostane (F2-isoP), urinary 8-oxo-7,8-dihydro-2'-deoxyguoanosine, plasma oxygen radical absorbance capacity assay, high sensitivity C reactive protein, and matrix metalloproteinase 2 and 9 in consecutive patients with acute ischemic stroke presenting within 9 hours of symptom onset. Patients with baseline diffusion-weighted magnetic resonance imaging and follow-up diffusion-weighted imaging or computed tomographic scan were included to evaluate the final infarct volume. Baseline diffusion-weighted imaging volume and final infarct volume were analyzed using semiautomated volumetric method. IG volume was defined as the difference between final infarct volume and baseline diffusion-weighted imaging volume. RESULTS: A total of 220 acute ischemic stroke subjects were included in the final analysis. One hundred seventy of these had IG. Baseline F2-isoP significantly correlated with IG volume (Spearman ρ=0.20; P=0.005) and final infarct volume (Spearman ρ=0.19; P=0.009). In a multivariate binary logistic regression model, baseline F2-isoP emerged as an independent predictor of the occurrence of IG (odds ratio, 2.57; 95% confidence interval, 1.37-4.83; P=0.007). In a multivariate linear regression model, baseline F2-isoP was independently associated with IG volume (B, 0.38; 95% confidence interval, 0.04-0.72; P=0.03). CONCLUSIONS: Elevated hyperacute plasma F2-isoP concentrations independently predict the occurrence of IG and IG volume in patients with acute ischemic stroke. If validated in future studies, measuring plasma F2-isoP might be helpful in the acute setting to stratify patients with acute ischemic stroke for relative severity of ischemic injury and expected progression.
    Donahue MJ, Achten E, Cogswell PM, De Leeuw F-E, Derdeyn CP, Dijkhuizen RM, Fan AP, Ghaznawi R, Heit JJ, Ikram AM, Jezzard P, Jordan LC, Jouvent E, Knutsson L, Leigh R, Liebeskind DS, Lin W, Okell TW, Qureshi AI, Stagg CJ, van Osch MJ, van Zijl PC, Watchmaker JM, Wintermark M, Wu O, Zaharchuk G, Zhou J, Hendrikse J. Consensus statement on current and emerging methods for the diagnosis and evaluation of cerebrovascular disease. J Cereb Blood Flow Metab 2018;38(9):1391-1417.Abstract
    Cerebrovascular disease (CVD) remains a leading cause of death and the leading cause of adult disability in most developed countries. This work summarizes state-of-the-art, and possible future, diagnostic and evaluation approaches in multiple stages of CVD, including (i) visualization of sub-clinical disease processes, (ii) acute stroke theranostics, and (iii) characterization of post-stroke recovery mechanisms. Underlying pathophysiology as it relates to large vessel steno-occlusive disease and the impact of this macrovascular disease on tissue-level viability, hemodynamics (cerebral blood flow, cerebral blood volume, and mean transit time), and metabolism (cerebral metabolic rate of oxygen consumption and pH) are also discussed in the context of emerging neuroimaging protocols with sensitivity to these factors. The overall purpose is to highlight advancements in stroke care and diagnostics and to provide a general overview of emerging research topics that have potential for reducing morbidity in multiple areas of CVD.

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