Publications

    Etherton MR, Wu O, Cougo P, Giese A-K, Cloonan L, Fitzpatrick KM, Kanakis AS, Boulouis G, Karadeli HH, Lauer A, Rosand J, Furie KL, Rost NS. Integrity of normal-appearing white matter and functional outcomes after acute ischemic stroke. Neurology 2017;88(18):1701-1708.Abstract
    OBJECTIVE: To characterize the effect of white matter microstructural integrity on cerebral tissue and long-term functional outcomes after acute ischemic stroke (AIS). METHODS: Consecutive AIS patients with brain MRI acquired within 48 hours of symptom onset and 90-day modified Rankin Scale (mRS) score were included. Acute infarct volume on diffusion-weighted imaging (DWIv) and white matter hyperintensity volume (WMHv) on T2 fluid-attenuated inversion recovery MRI were measured. Median fractional anisotropy (FA), mean diffusivity, radial diffusivity, and axial diffusivity values were calculated within normal-appearing white matter (NAWM) in the hemisphere contralateral to the acute lesion. Regression models were used to assess the association between diffusivity metrics and acute cerebral tissue and long-term functional outcomes in AIS. Level of significance was set at p < 0.05 for all analyses. RESULTS: Among 305 AIS patients with DWIv and mRS score, mean age was 64.4 ± 15.9 years, and 183 participants (60%) were male. Median NIH Stroke Scale (NIHSS) score was 3 (interquartile range [IQR] 1-8), and median normalized WMHv was 6.19 cm3 (IQR 3.0-12.6 cm3). Admission stroke severity (β = 0.16, p < 0.0001) and small vessel stroke subtype (β = -1.53, p < 0.0001), but not diffusivity metrics, were independently associated with DWIv. However, median FA in contralesional NAWM was independently associated with mRS score (β = -9.74, p = 0.02), along with age, female sex, NIHSS score, and DWIv. CONCLUSIONS: FA decrease in NAWM contralateral to the acute infarct is associated with worse mRS category at 90 days after stroke. These data suggest that white matter integrity may contribute to functional recovery after stroke.
    Copen WA, Yoo AJ, Rost NS, Morais LT, Schaefer PW, González GR, Wu O. In patients with suspected acute stroke, CT perfusion-based cerebral blood flow maps cannot substitute for DWI in measuring the ischemic core. PLoS One 2017;12(11):e0188891.Abstract
    BACKGROUND: Neuroimaging may guide acute stroke treatment by measuring the volume of brain tissue in the irreversibly injured "ischemic core." The most widely accepted core volume measurement technique is diffusion-weighted MRI (DWI). However, some claim that measuring regional cerebral blood flow (CBF) with CT perfusion imaging (CTP), and labeling tissue below some threshold as the core, provides equivalent estimates. We tested whether any threshold allows reliable substitution of CBF for DWI. METHODS: 58 patients with suspected stroke underwent DWI and CTP within six hours of symptom onset. A neuroradiologist outlined DWI lesions. In CBF maps, core pixels were defined by thresholds ranging from 0%-100% of normal, in 1% increments. Replicating prior studies, we used receiver operating characteristic (ROC) curves to select thresholds that optimized sensitivity and specificity in predicting DWI-positive pixels, first using only pixels on the side of the brain where infarction was clinically suspected ("unilateral" method), then including both sides ("bilateral"). We quantified each method and threshold's accuracy in estimating DWI volumes, using sums of squared errors (SSE). For the 23 patients with follow-up studies, we assessed whether CBF-derived volumes inaccurately exceeded follow-up infarct volumes. RESULTS: The areas under the ROC curves were 0.89 (unilateral) and 0.90 (bilateral). Various metrics selected optimum CBF thresholds ranging from 29%-32%, with sensitivities of 0.79-0.81, and specificities of 0.83-0.85. However, for the unilateral and bilateral methods respectively, volume estimates derived from all CBF thresholds above 28% and 22% were less accurate than disregarding imaging and presuming every patient's core volume to be zero. The unilateral method with a 30% threshold, which recent clinical trials have employed, produced a mean core overestimation of 65 mL (range: -82-191), and exceeded follow-up volumes for 83% of patients, by up to 191 mL. CONCLUSION: CTP-derived CBF maps cannot substitute for DWI in measuring the ischemic core.
    Edlow BL, Chatelle C, Spencer CA, Chu CJ, Bodien YG, O'Connor KL, Hirschberg RE, Hochberg LR, Giacino JT, Rosenthal ES, Wu O. Early detection of consciousness in patients with acute severe traumatic brain injury. Brain 2017;140(9):2399-2414.Abstract
    See Schiff (doi:10.1093/awx209) for a scientific commentary on this article. Patients with acute severe traumatic brain injury may recover consciousness before self-expression. Without behavioural evidence of consciousness at the bedside, clinicians may render an inaccurate prognosis, increasing the likelihood of withholding life-sustaining therapies or denying rehabilitative services. Task-based functional magnetic resonance imaging and electroencephalography techniques have revealed covert consciousness in the chronic setting, but these techniques have not been tested in the intensive care unit. We prospectively enrolled 16 patients admitted to the intensive care unit for acute severe traumatic brain injury to test two hypotheses: (i) in patients who lack behavioural evidence of language expression and comprehension, functional magnetic resonance imaging and electroencephalography detect command-following during a motor imagery task (i.e. cognitive motor dissociation) and association cortex responses during language and music stimuli (i.e. higher-order cortex motor dissociation); and (ii) early responses to these paradigms are associated with better 6-month outcomes on the Glasgow Outcome Scale-Extended. Patients underwent functional magnetic resonance imaging on post-injury Day 9.2 ± 5.0 and electroencephalography on Day 9.8 ± 4.6. At the time of imaging, behavioural evaluation with the Coma Recovery Scale-Revised indicated coma (n = 2), vegetative state (n = 3), minimally conscious state without language (n = 3), minimally conscious state with language (n = 4) or post-traumatic confusional state (n = 4). Cognitive motor dissociation was identified in four patients, including three whose behavioural diagnosis suggested a vegetative state. Higher-order cortex motor dissociation was identified in two additional patients. Complete absence of responses to language, music and motor imagery was only observed in coma patients. In patients with behavioural evidence of language function, responses to language and music were more frequently observed than responses to motor imagery (62.5-80% versus 33.3-42.9%). Similarly, in 16 matched healthy subjects, responses to language and music were more frequently observed than responses to motor imagery (87.5-100% versus 68.8-75.0%). Except for one patient who died in the intensive care unit, all patients with cognitive motor dissociation and higher-order cortex motor dissociation recovered beyond a confusional state by 6 months. However, 6-month outcomes were not associated with early functional magnetic resonance imaging and electroencephalography responses for the entire cohort. These observations suggest that functional magnetic resonance imaging and electroencephalography can detect command-following and higher-order cortical function in patients with acute severe traumatic brain injury. Early detection of covert consciousness and cortical responses in the intensive care unit could alter time-sensitive decisions about withholding life-sustaining therapies.
    Rannikmäe K, Sivakumaran V, Millar H, Malik R, Anderson CD, Chong M, Dave T, Falcone GJ, Fernandez-Cadenas I, Jimenez-Conde J, Lindgren A, Montaner J, O'Donnell M, Paré G, Radmanesh F, Rost NS, Slowik A, Söderholm M, Traylor M, Pulit SL, Seshadri S, Worrall BB, Woo D, Markus HS, Mitchell BD, Dichgans M, Rosand J, Sudlow CLM. COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls. Neurology 2017;89(17):1829-1839.Abstract
    OBJECTIVE: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD. METHODS: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing. RESULTS: A locus in COL4A2 was associated (significance threshold p < 3.5 × 10-4) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11-1.24, p = 6.62 × 10-8) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13-1.44, p = 5.76 × 10-5). A SNP in HTRA1 was associated (significance threshold p < 5.5 × 10-4) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10-1.37, p = 1.90 × 10-4) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype. CONCLUSIONS: These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.
    Kimberly TW, Battey TWK, Wu O, Singhal AB, Campbell BCV, Davis SM, Donnan GA, Sheth KN. Novel Imaging Markers of Ischemic Cerebral Edema and Its Association with Neurological Outcome. Acta Neurochir Suppl 2016;121:223-6.Abstract
    Ischemic cerebral edema (ICE) is a recognized cause of secondary neurological deterioration after large hemispheric stroke, but little is known about the scope of its impact. To study edema in less severe stroke, our group has developed several markers of cerebral edema using brain magnetic resonance imaging (MRI). These tools, which are based on categorical and volumetric measurements in serial diffusion-weighted imaging (DWI), are applicable to a wide variety of stroke volumes. Further, these metrics provide distinct volumetric measurements attributable to ICE, infarct growth, and hemorrhagic transformation. We previously reported that ICE independently predicted neurological outcome after adjustment for known risk factors. We found that an ICE volume of 11 mL or greater was associated with worse neurological outcome.
    Warach SJ, Luby M, Albers GW, Bammer R, Bivard A, Campbell BCV, Derdeyn C, Heit JJ, Khatri P, Lansberg MG, Liebeskind DS, Majoie CBLM, Marks MP, Menon BK, Muir KW, Parsons MW, Vagal A, Yoo AJ, Alexandrov AV, Baron J-C, Fiorella DJ, Furlan AJ, Puig J, Schellinger PD, Wintermark M. Acute Stroke Imaging Research Roadmap III Imaging Selection and Outcomes in Acute Stroke Reperfusion Clinical Trials: Consensus Recommendations and Further Research Priorities. Stroke 2016;47(5):1389-98.Abstract
    BACKGROUND AND PURPOSE: The Stroke Imaging Research (STIR) group, the Imaging Working Group of StrokeNet, the American Society of Neuroradiology, and the Foundation of the American Society of Neuroradiology sponsored an imaging session and workshop during the Stroke Treatment Academy Industry Roundtable (STAIR) IX on October 5 to 6, 2015 in Washington, DC. The purpose of this roadmap was to focus on the role of imaging in future research and clinical trials. METHODS: This forum brought together stroke neurologists, neuroradiologists, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke (NINDS), industry representatives, and members of the US Food and Drug Administration to discuss STIR priorities in the light of an unprecedented series of positive acute stroke endovascular therapy clinical trials. RESULTS: The imaging session summarized and compared the imaging components of the recent positive endovascular trials and proposed opportunities for pooled analyses. The imaging workshop developed consensus recommendations for optimal imaging methods for the acquisition and analysis of core, mismatch, and collaterals across multiple modalities, and also a standardized approach for measuring the final infarct volume in prospective clinical trials. CONCLUSIONS: Recent positive acute stroke endovascular clinical trials have demonstrated the added value of neurovascular imaging. The optimal imaging profile for endovascular treatment includes large vessel occlusion, smaller core, good collaterals, and large penumbra. However, equivalent definitions for the imaging profile parameters across modalities are needed, and a standardization effort is warranted, potentially leveraging the pooled data resulting from the recent positive endovascular trials.
    Nelson S, Edlow BL, Wu O, Rosenthal ES, Westover BM, Rordorf G. Default Mode Network Perfusion in Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 2016;25(2):237-42.Abstract
    BACKGROUND: The etiology of altered consciousness in patients with high-grade aneurysmal subarachnoid hemorrhage (SAH) is not thoroughly understood. We hypothesized that decreased cerebral blood flow (CBF) in brain regions critical to consciousness may contribute. METHODS: We retrospectively evaluated arterial-spin labeled (ASL) perfusion magnetic resonance imaging (MRI) measurements of CBF in 12 patients with aneurysmal SAH admitted to our neurocritical care unit. CBF values were analyzed within gray matter nodes of the default mode network (DMN), whose functional integrity has been shown to be necessary for consciousness. DMN nodes studied were the bilateral medial prefrontal cortices, thalami, and posterior cingulate cortices. Correlations between nodal CBF and admission Glasgow Coma Scale (GCS) score, admission Hunt and Hess (HH) class, and GCS score at the time of MRI (MRI GCS) were tested. RESULTS: Spearman's correlation coefficients were not significant when comparing admission GCS, admission HH, and MRI GCS versus nodal CBF (p > 0.05). However, inter-rater reliability for nodal CBF was high (r = 0.71, p = 0.01). CONCLUSIONS: In this retrospective pilot study, we did not identify significant correlations between CBF and admission GCS, admission HH class, or MRI GCS for any DMN node. Potential explanations for these findings include small sample size, ASL data acquisition at variable times after SAH onset, and CBF analysis in DMN nodes that may not reflect the functional integrity of the entire network. High inter-rater reliability suggests ASL measurements of CBF within DMN nodes are reproducible. Larger prospective studies are needed to elucidate whether decreased cerebral perfusion contributes to altered consciousness in SAH.
    Edlow BL, Copen WA, Izzy S, van der Kouwe A, Glenn MB, Greenberg SM, Greer DM, Wu O. Longitudinal Diffusion Tensor Imaging Detects Recovery of Fractional Anisotropy Within Traumatic Axonal Injury Lesions. Neurocrit Care 2016;24(3):342-52.Abstract
    BACKGROUND: Traumatic axonal injury (TAI) may be reversible, yet there are currently no clinical imaging tools to detect axonal recovery in patients with traumatic brain injury (TBI). We used diffusion tensor imaging (DTI) to characterize serial changes in fractional anisotropy (FA) within TAI lesions of the corpus callosum (CC). We hypothesized that recovery of FA within a TAI lesion correlates with better functional outcome. METHODS: Patients who underwent both an acute DTI scan (≤day 7) and a subacute DTI scan (day 14 to inpatient rehabilitation discharge) at a single institution were retrospectively analyzed. TAI lesions were manually traced on the acute diffusion-weighted images. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), and radial diffusivity (RD) were measured within the TAI lesions at each time point. FA recovery was defined by a longitudinal increase in CC FA that exceeded the coefficient of variation for FA based on values from healthy controls. Acute FA, ADC, AD, and RD were compared in lesions with and without FA recovery, and correlations were tested between lesional FA recovery and functional recovery, as determined by disability rating scale score at discharge from inpatient rehabilitation. RESULTS: Eleven TAI lesions were identified in 7 patients. DTI detected FA recovery within 2 of 11 TAI lesions. Acute FA, ADC, AD, and RD did not differ between lesions with and without FA recovery. Lesional FA recovery did not correlate with disability rating scale scores. CONCLUSIONS: In this retrospective longitudinal study, we provide initial evidence that FA can recover within TAI lesions. However, FA recovery did not correlate with improved functional outcomes. Prospective histopathological and clinical studies are needed to further elucidate whether lesional FA recovery indicates axonal healing and has prognostic significance.
    Edlow BL, Copen WA, Izzy S, Bakhadirov K, van der Kouwe A, Glenn MB, Greenberg SM, Greer DM, Wu O. Diffusion tensor imaging in acute-to-subacute traumatic brain injury: a longitudinal analysis. BMC Neurol 2016;16:2.Abstract
    BACKGROUND: Diffusion tensor imaging (DTI) may have prognostic utility in patients with traumatic brain injury (TBI), but the optimal timing of DTI data acquisition is unknown because of dynamic changes in white matter water diffusion during the acute and subacute stages of TBI. We aimed to characterize the direction and magnitude of early longitudinal changes in white matter fractional anisotropy (FA) and to determine whether acute or subacute FA values correlate more reliably with functional outcomes after TBI. METHODS: From a prospective TBI outcomes database, 11 patients who underwent acute (≤7 days) and subacute (8 days to rehabilitation discharge) DTI were retrospectively analyzed. Longitudinal changes in FA were measured in 11 white matter regions susceptible to traumatic axonal injury. Correlations were assessed between acute FA, subacute FA and the disability rating scale (DRS) score, which was ascertained at discharge from inpatient rehabilitation. RESULTS: FA declined from the acute-to-subacute period in the genu of the corpus callosum (0.70 ± 0.02 vs. 0.55 ± 0.11, p < 0.05) and inferior longitudinal fasciculus (0.54+/-0.07 vs. 0.49+/-0.07, p < 0.01). Acute correlations between FA and DRS score were variable: higher FA in the body (R = -0.78, p = 0.02) and splenium (R = -0.83, p = 0.003) of the corpus callosum was associated with better outcomes (i.e. lower DRS scores), whereas higher FA in the genu of the corpus callosum (R = 0.83, p = 0.02) corresponded with worse outcomes (i.e. higher DRS scores). In contrast, in the subacute period higher FA in the splenium correlated with better outcomes (R = -0.63, p < 0.05) and no inverse correlations were observed. CONCLUSIONS: White matter FA declined during the acute-to-subacute stages of TBI. Variability in acute FA correlations with outcome suggests that the optimal timing of DTI for TBI prognostication may be in the subacute period.
    Hirsch KG, Mlynash M, Eyngorn I, Pirsaheli R, Okada A, Komshian S, Chen C, Mayer SA, Meschia JF, Bernstein RA, Wu O, Greer DM, Wijman CA, Albers GW. Multi-Center Study of Diffusion-Weighted Imaging in Coma After Cardiac Arrest. Neurocrit Care 2016;24(1):82-9.Abstract
    BACKGROUND: The ability to predict outcomes in acutely comatose cardiac arrest survivors is limited. Brain diffusion-weighted magnetic resonance imaging (DWI MRI) has been shown in initial studies to be a simple and effective prognostic tool. This study aimed to determine the predictive value of previously defined DWI MRI thresholds in a multi-center cohort. METHODS: DWI MRIs of comatose post-cardiac arrest patients were analyzed in this multi-center retrospective observational study. Poor outcome was defined as failure to regain consciousness within 14 days and/or death during the hospitalization. The apparent diffusion coefficient (ADC) value of each brain voxel was determined. ADC thresholds and brain volumes below each threshold were analyzed for their correlation with outcome. RESULTS: 125 patients were included in the analysis. 33 patients (26%) had a good outcome. An ADC value of less than 650 × 10(-6) mm(2)/s in ≥10% of brain volume was highly specific [91% (95% CI 75-98)] and had a good sensitivity [72% (95% CI 61-80)] for predicting poor outcome. This threshold remained an independent predictor of poor outcome in multivariable analysis (p = 0.002). An ADC value of less than 650 × 10(-6) mm(2)/s in >22% of brain volume was needed to achieve 100% specificity for poor outcome. CONCLUSIONS: In patients who remain comatose after cardiac arrest, quantitative DWI MRI findings correlate with early recovery of consciousness. A DWI MRI threshold of 650 × 10(-6) mm(2)/s in ≥10% of brain volume can differentiate patients with good versus poor outcome, though in this patient population the threshold was not 100% specific for poor outcome.
    Etherton MR, Wu O, Rost NS. Recent Advances in Leukoaraiosis: White Matter Structural Integrity and Functional Outcomes after Acute Ischemic Stroke. Curr Cardiol Rep 2016;18(12):123.Abstract
    Leukoaraiosis, a radiographic marker of cerebral small vessel disease detected on T2-weighted brain magnetic resonance imaging (MRI) as white matter hyperintensity (WMH), is a key contributor to the risk and severity of acute cerebral ischemia. Prior investigations have emphasized the pathophysiology of WMH development and progression; however, more recently, an association between WMH burden and functional outcomes after stroke has emerged. There is growing evidence that WMH represents macroscopic injury to the white matter and that the extent of WMH burden on MRI influences functional recovery in multiple domains following acute ischemic stroke (AIS). In this review, we discuss the current understanding of WMH pathogenesis and its impact on AIS and functional recovery.
    Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study. Lancet Neurol 2016;15(2):174-184.Abstract
    BACKGROUND: The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes. METHODS: To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis. FINDINGS: We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50 × 10-8; joint OR 1·19, 1·12-1·26, p=1·30 × 10-9). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26 × 10-19; joint OR 1·37, 1·30-1·45, p=2·79 × 10-32) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93 × 10-7; joint OR 1·17, 1·11-1·23, p=2·29 × 10-10) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50 × 10-8; joint OR 1·24, 1·15-1·33, p=4·52 × 10-9) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82 × 10-8; joint OR 1·17, 1·11-1·23, p=2·92 × 10-9). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed. INTERPRETATION: Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke. FUNDING: US National Institute of Neurological Disorders and Stroke, National Institutes of Health.
    Bouts MJRJ, Westmoreland SV, de Crespigny AJ, Liu Y, Vangel M, Dijkhuizen RM, Wu O, D'Arceuil HE. Magnetic resonance imaging-based cerebral tissue classification reveals distinct spatiotemporal patterns of changes after stroke in non-human primates. BMC Neurosci 2015;16:91.Abstract
    BACKGROUND: Spatial and temporal changes in brain tissue after acute ischemic stroke are still poorly understood. Aims of this study were three-fold: (1) to determine unique temporal magnetic resonance imaging (MRI) patterns at the acute, subacute and chronic stages after stroke in macaques by combining quantitative T2 and diffusion MRI indices into MRI 'tissue signatures', (2) to evaluate temporal differences in these signatures between transient (n = 2) and permanent (n = 2) middle cerebral artery occlusion, and (3) to correlate histopathology findings in the chronic stroke period to the acute and subacute MRI derived tissue signatures. RESULTS: An improved iterative self-organizing data analysis algorithm was used to combine T2, apparent diffusion coefficient (ADC), and fractional anisotropy (FA) maps across seven successive timepoints (1, 2, 3, 24, 72, 144, 240 h) which revealed five temporal MRI signatures, that were different from the normal tissue pattern (P < 0.001). The distribution of signatures between brains with permanent and transient occlusions varied significantly between groups (P < 0.001). Qualitative comparisons with histopathology revealed that these signatures represented regions with different histopathology. Two signatures identified areas of progressive injury marked by severe necrosis and the presence of gitter cells. Another signature identified less severe but pronounced neuronal and axonal degeneration, while the other signatures depicted tissue remodeling with vascular proliferation and astrogliosis. CONCLUSION: These exploratory results demonstrate the potential of temporally and spatially combined voxel-based methods to generate tissue signatures that may correlate with distinct histopathological features. The identification of distinct ischemic MRI signatures associated with specific tissue fates may further aid in assessing and monitoring the efficacy of novel pharmaceutical treatments for stroke in a pre-clinical and clinical setting.
    Wu O, Cloonan L, Mocking SJT, Bouts MJRJ, Copen WA, Cougo-Pinto PT, Fitzpatrick K, Kanakis A, Schaefer PW, Rosand J, Furie KL, Rost NS. Role of Acute Lesion Topography in Initial Ischemic Stroke Severity and Long-Term Functional Outcomes. Stroke 2015;46(9):2438-44.Abstract
    BACKGROUND AND PURPOSE: Acute infarct volume, often proposed as a biomarker for evaluating novel interventions for acute ischemic stroke, correlates only moderately with traditional clinical end points, such as the modified Rankin Scale. We hypothesized that the topography of acute stroke lesions on diffusion-weighted magnetic resonance imaging may provide further information with regard to presenting stroke severity and long-term functional outcomes. METHODS: Data from a prospective stroke repository were limited to acute ischemic stroke subjects with magnetic resonance imaging completed within 48 hours from last known well, admission NIH Stroke Scale (NIHSS), and 3-to-6 months modified Rankin Scale scores. Using voxel-based lesion symptom mapping techniques, including age, sex, and diffusion-weighted magnetic resonance imaging lesion volume as covariates, statistical maps were calculated to determine the significance of lesion location for clinical outcome and admission stroke severity. RESULTS: Four hundred ninety subjects were analyzed. Acute stroke lesions in the left hemisphere were associated with more severe NIHSS at admission and poor modified Rankin Scale at 3 to 6 months. Specifically, injury to white matter (corona radiata, internal and external capsules, superior longitudinal fasciculus, and uncinate fasciculus), postcentral gyrus, putamen, and operculum were implicated in poor modified Rankin Scale. More severe NIHSS involved these regions, as well as the amygdala, caudate, pallidum, inferior frontal gyrus, insula, and precentral gyrus. CONCLUSIONS: Acute lesion topography provides important insights into anatomic correlates of admission stroke severity and poststroke outcomes. Future models that account for infarct location in addition to diffusion-weighted magnetic resonance imaging volume may improve stroke outcome prediction and identify patients likely to benefit from aggressive acute intervention and personalized rehabilitation strategies.
    Copen WA, Deipolyi AR, Schaefer PW, Schwamm LH, González RG, Wu O. Exposing hidden truncation-related errors in acute stroke perfusion imaging. AJNR Am J Neuroradiol 2015;36(4):638-45.Abstract
    BACKGROUND AND PURPOSE: The durations of acute ischemic stroke patients' CT or MR perfusion scans may be too short to fully sample the passage of the injected contrast agent through the brain. We tested the potential magnitude of hidden errors related to the truncation of data by short perfusion scans. MATERIALS AND METHODS: Fifty-seven patients with acute ischemic stroke underwent perfusion MR imaging within 12 hours of symptom onset, using a relatively long scan duration (110 seconds). Shorter scan durations (39.5-108.5 seconds) were simulated by progressively deleting the last-acquired images. CBV, CBF, MTT, and time to response function maximum (Tmax) were measured within DWI-identified acute infarcts, with commonly used postprocessing algorithms. All measurements except Tmax were normalized by dividing by the contralateral hemisphere values. The effects of the scan duration on these hemodynamic measurements and on the volumes of lesions with Tmax of >6 seconds were tested using regression. RESULTS: Decreasing scan duration from 110 seconds to 40 seconds falsely reduced perfusion estimates by 47.6%-64.2% of normal for CBV, 1.96%-4.10% for CBF, 133%-205% for MTT, and 6.2-8.0 seconds for Tmax, depending on the postprocessing method. This truncation falsely reduced estimated Tmax lesion volume by 71.5 or 93.8 mL, depending on the deconvolution method. "Lesion reversal" (ie, change from above-normal to apparently normal, or from >6 seconds to ≤6 seconds for the time to response function maximum) with increasing truncation occurred in 37%-46% of lesions for CBV, 2%-4% for CBF, 28%-54% for MTT, and 42%-44% for Tmax, depending on the postprocessing method. CONCLUSIONS: Hidden truncation-related errors in perfusion images may be large enough to alter patient management or affect outcomes of clinical trials.
    Chu CJ, Tanaka N, Diaz J, Edlow BL, Wu O, Hämäläinen M, Stufflebeam S, Cash SS, Kramer MA. EEG functional connectivity is partially predicted by underlying white matter connectivity. Neuroimage 2015;108:23-33.Abstract
    Over the past decade, networks have become a leading model to illustrate both the anatomical relationships (structural networks) and the coupling of dynamic physiology (functional networks) linking separate brain regions. The relationship between these two levels of description remains incompletely understood and an area of intense research interest. In particular, it is unclear how cortical currents relate to underlying brain structural architecture. In addition, although theory suggests that brain communication is highly frequency dependent, how structural connections influence overlying functional connectivity in different frequency bands has not been previously explored. Here we relate functional networks inferred from statistical associations between source imaging of EEG activity and underlying cortico-cortical structural brain connectivity determined by probabilistic white matter tractography. We evaluate spontaneous fluctuating cortical brain activity over a long time scale (minutes) and relate inferred functional networks to underlying structural connectivity for broadband signals, as well as in seven distinct frequency bands. We find that cortical networks derived from source EEG estimates partially reflect both direct and indirect underlying white matter connectivity in all frequency bands evaluated. In addition, we find that when structural support is absent, functional connectivity is significantly reduced for high frequency bands compared to low frequency bands. The association between cortical currents and underlying white matter connectivity highlights the obligatory interdependence of functional and structural networks in the human brain. The increased dependence on structural support for the coupling of higher frequency brain rhythms provides new evidence for how underlying anatomy directly shapes emergent brain dynamics at fast time scales.
    Jafari-Khouzani K, Emblem KE, Kalpathy-Cramer J, Bjørnerud A, Vangel MG, Gerstner ER, Schmainda KM, Paynabar K, Wu O, Wen PY, Batchelor T, Rosen B, Stufflebeam SM. Repeatability of Cerebral Perfusion Using Dynamic Susceptibility Contrast MRI in Glioblastoma Patients. Transl Oncol 2015;8(3):137-46.Abstract
    OBJECTIVES: This study evaluates the repeatability of brain perfusion using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) with a variety of post-processing methods. METHODS: Thirty-two patients with newly diagnosed glioblastoma were recruited. On a 3-T MRI using a dual-echo, gradient-echo spin-echo DSC-MRI protocol, the patients were scanned twice 1 to 5 days apart. Perfusion maps including cerebral blood volume (CBV) and cerebral blood flow (CBF) were generated using two contrast agent leakage correction methods, along with testing normalization to reference tissue, and application of arterial input function (AIF). Repeatability of CBV and CBF within tumor regions and healthy tissues, identified by structural images, was assessed with intra-class correlation coefficients (ICCs) and repeatability coefficients (RCs). Coefficients of variation (CVs) were reported for selected methods. RESULTS: CBV and CBF were highly repeatable within tumor with ICC values up to 0.97. However, both CBV and CBF showed lower ICCs for healthy cortical tissues (up to 0.83), healthy gray matter (up to 0.95), and healthy white matter (WM; up to 0.93). The values of CV ranged from 6% to 10% in tumor and 3% to 11% in healthy tissues. The values of RC relative to the mean value of measurement within healthy WM ranged from 22% to 42% in tumor and 7% to 43% in healthy tissues. These percentages show how much variation in perfusion parameter, relative to that in healthy WM, we expect to observe to consider it statistically significant. We also found that normalization improved repeatability, but AIF deconvolution did not. CONCLUSIONS: DSC-MRI is highly repeatable in high-grade glioma patients.
    Wintermark M, Luby M, Bornstein NM, Demchuk A, Fiehler J, Kudo K, Lees KR, Liebeskind DS, Michel P, Nogueira RG, Parsons MW, Sasaki M, Wardlaw JM, Wu O, Zhang W, Zhu G, Warach SJ. International survey of acute stroke imaging used to make revascularization treatment decisions. Int J Stroke 2015;10(5):759-62.Abstract
    BACKGROUND: To assess the differences across continental regions in terms of stroke imaging obtained for making acute revascularization therapy decisions, and to identify obstacles to participating in randomized trials involving multimodal imaging. METHODS: STroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA)-Imaging circulated an online survey through its website, through the websites of national professional societies from multiple countries as well as through email distribution lists from STIR and the above mentioned societies. RESULTS: We received responses from 223 centers (2 from Africa, 38 from Asia, 10 from Australia, 101 from Europe, 4 from Middle East, 55 from North America, 13 from South America). In combination, the sites surveyed administered acute revascularization therapy to a total of 25,326 acute stroke patients in 2012. Seventy-three percent of these patients received intravenous (i.v.) tissue plasminogen activator (tPA), and 27%, endovascular therapy. Vascular imaging was routinely obtained in 79% (152/193) of sites for endovascular therapy decisions, and also as part of standard IV tPA treatment decisions at 46% (92/198) of sites. Modality, availability and use of acute vascular and perfusion imaging before revascularization varied substantially between geographical areas. The main obstacles to participate in randomized trials involving multimodal imaging included: mainly insufficient research support and staff (50%, 79/158) and infrequent use of multimodal imaging (27%, 43/158) . CONCLUSION: There were significant variations among sites and geographical areas in terms of stroke imaging work-up used tomake decisions both for intravenous and endovascular revascularization. Clinical trials using advanced imaging as a selection tool for acute revascularization therapy should address the need for additional resources and technical support, and take into consideration the lack of routine use of such techniques in trial planning.
    Copen WA, Morais LT, Wu O, Schwamm LH, Schaefer PW, González GR, Yoo AJ. In Acute Stroke, Can CT Perfusion-Derived Cerebral Blood Volume Maps Substitute for Diffusion-Weighted Imaging in Identifying the Ischemic Core?. PLoS One 2015;10(7):e0133566.Abstract
    BACKGROUND AND PURPOSE: In the treatment of patients with suspected acute ischemic stroke, increasing evidence suggests the importance of measuring the volume of the irreversibly injured "ischemic core." The gold standard method for doing this in the clinical setting is diffusion-weighted magnetic resonance imaging (DWI), but many authors suggest that maps of regional cerebral blood volume (CBV) derived from computed tomography perfusion imaging (CTP) can substitute for DWI. We sought to determine whether DWI and CTP-derived CBV maps are equivalent in measuring core volume. METHODS: 58 patients with suspected stroke underwent CTP and DWI within 6 hours of symptom onset. We measured low-CBV lesion volumes using three methods: "objective absolute," i.e. the volume of tissue with CBV below each of six published absolute thresholds (0.9-2.5 mL/100 g), "objective relative," whose six thresholds (51%-60%) were fractions of mean contralateral CBV, and "subjective," in which two radiologists (R1, R2) outlined lesions subjectively. We assessed the sensitivity and specificity of each method, threshold, and radiologist in detecting infarction, and the degree to which each over- or underestimated the DWI core volume. Additionally, in the subset of 32 patients for whom follow-up CT or MRI was available, we measured the proportion of CBV- or DWI-defined core lesions that exceeded the follow-up infarct volume, and the maximum amount by which this occurred. RESULTS: DWI was positive in 72% (42/58) of patients. CBV maps' sensitivity/specificity in identifying DWI-positive patients were 100%/0% for both objective methods with all thresholds, 43%/94% for R1, and 83%/44% for R2. Mean core overestimation was 156-699 mL for objective absolute thresholds, and 127-200 mL for objective relative thresholds. For R1 and R2, respectively, mean±SD subjective overestimation were -11±26 mL and -11±23 mL, but subjective volumes differed from DWI volumes by up to 117 and 124 mL in individual patients. Inter-rater agreement regarding the presence of infarction on CBV maps was poor (kappa = 0.21). Core lesions defined by the six objective absolute CBV thresholds exceeded follow-up infarct volumes for 81%-100% of patients, by up to 430-1002 mL. Core estimates produced by objective relative thresholds exceeded follow-up volumes in 91% of patients, by up to 210-280 mL. Subjective lesions defined by R1 and R2 exceeded follow-up volumes in 18% and 26% of cases, by up to 71 and 15 mL, respectively. Only 1 of 23 DWI lesions (4%) exceeded final infarct volume, by 3 mL. CONCLUSION: CTP-derived CBV maps cannot reliably substitute for DWI in measuring core volume, or even establish which patients have DWI lesions.
    Schaefer PW, Pulli B, Copen WA, Hirsch JA, Leslie-Mazwi T, Schwamm LH, Wu O, González RG, Yoo AJ. Combining MRI with NIHSS thresholds to predict outcome in acute ischemic stroke: value for patient selection. AJNR Am J Neuroradiol 2015;36(2):259-64.Abstract
    BACKGROUND AND PURPOSE: Selecting acute ischemic stroke patients for reperfusion therapy on the basis of a diffusion-perfusion mismatch has not been uniformly proved to predict a beneficial treatment response. In a prior study, we have shown that combining clinical with MR imaging thresholds can predict clinical outcome with high positive predictive value. In this study, we sought to validate this predictive model in a larger patient cohort and evaluate the effects of reperfusion therapy and stroke side. MATERIALS AND METHODS: One hundred twenty-three consecutive patients with anterior circulation acute ischemic stroke underwent MR imaging within 6 hours of stroke onset. DWI and PWI volumes were measured. Lesion volume and NIHSS score thresholds were used in models predicting good 3-month clinical outcome (mRS 0-2). Patients were stratified by treatment and stroke side. RESULTS: Receiver operating characteristic analysis demonstrated 95.6% and 100% specificity for DWI > 70 mL and NIHSS score > 20 to predict poor outcome, and 92.7% and 91.3% specificity for PWI (mean transit time) < 50 mL and NIHSS score < 8 to predict good outcome. Combining clinical and imaging thresholds led to an 88.8% (71/80) positive predictive value with a 65.0% (80/123) prognostic yield. One hundred percent specific thresholds for DWI (103 versus 31 mL) and NIHSS score (20 versus 17) to predict poor outcome were significantly higher in treated (intravenous and/or intra-arterial) versus untreated patients. Prognostic yield was lower in right- versus left-sided strokes for all thresholds (10.4%-20.7% versus 16.9%-40.0%). Patients with right-sided strokes had higher 100% specific DWI (103.1 versus 74.8 mL) thresholds for poor outcome, and the positive predictive value was lower. CONCLUSIONS: Our predictive model is validated in a much larger patient cohort. Outcome may be predicted in up to two-thirds of patients, and thresholds are affected by stroke side and reperfusion therapy.

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