Stroke

Ostergaard L, Sorensen AG, Chesler DA, Weisskoff RM, Koroshetz WJ, Wu O, Gyldensted C, Rosen BR. Combined diffusion-weighted and perfusion-weighted flow heterogeneity magnetic resonance imaging in acute stroke. Stroke 2000;31(5):1097-103.Abstract
BACKGROUND AND PURPOSE: The heterogeneity of microvascular flows is known to be an important determinant of the efficacy of oxygen delivery to tissue. Studies in animals have demonstrated decreased flow heterogeneity (FH) in states of decreased perfusion pressure. The purpose of the present study was to assess microvascular FH changes in acute stroke with use of a novel perfusion-weighted MRI technique and to evaluate the ability of combined diffusion-weighted MRI and FH measurements to predict final infarct size. METHODS: Cerebral blood flow, FH, and plasma mean transit time (MTT) were measured in 11 patients who presented with acute (<12 hours after symptom onset) stroke. Final infarct size was determined with follow-up MRI or CT scanning. RESULTS: In normal brain tissue, the distribution of relative flows was markedly skewed toward high capillary flow velocities. Within regions of decreased cerebral blood flow, plasma MTT was prolonged. Furthermore, subregions were identified with significant loss of the high-flow component of the flow distribution, thereby causing increased homogeneity of flow velocities. In parametric maps that quantify the acute deviation of FH from that of normal tissue, areas of extreme homogenization of capillary flows predicted final infarct size on follow-up scans of 10 of 11 patients. CONCLUSIONS: Flow heterogeneity and MTT can be rapidly assessed as part of a routine clinical MR examination and may provide a tool for planning of individual stroke treatment, as well as in targeting and evaluation of emerging therapeutic strategies.
Ay H, Buonanno FS, Rordorf G, Schaefer PW, Schwamm LH, Wu O, Gonzalez RG, Yamada K, Sorensen GA, Koroshetz WJ. Normal diffusion-weighted MRI during stroke-like deficits. Neurology 1999;52(9):1784-92.Abstract
BACKGROUND: Diffusion-weighted MRI (DWI) represents a major advance in the early diagnosis of acute ischemic stroke. When abnormal in patients with stroke-like deficit, DWI usually establishes the presence and location of ischemic brain injury. However, this is not always the case. OBJECTIVE: To investigate patients with stroke-like deficits occurring without DWI abnormalities in brain regions clinically suspected to be responsible. METHODS: We identified 27 of 782 consecutive patients scanned when stroke-like neurologic deficits were still present and who had normal DWI in the brain region(s) clinically implicated. Based on all the clinical and radiologic data, we attempted to arrive at a pathophysiologic diagnosis in each. RESULTS: Best final diagnosis was a stroke mimic in 37% and a cerebral ischemic event in 63%. Stroke mimics (10 patients) included migraine, seizures, functional disorder, transient global amnesia, and brain tumor. The remaining patients were considered to have had cerebral ischemic events: lacunar syndrome (7 patients; 3 with infarcts demonstrated subsequently) and hemispheric cortical syndrome (10 patients; 5 with TIA, 2 with prolonged reversible deficits, 3 with infarction on follow-up imaging). In each of the latter three patients, the regions destined to infarct showed decreased perfusion on the initial hemodynamically weighted MRI (HWI). CONCLUSIONS: Normal DWI in patients with stroke-like deficits should stimulate a search for nonischemic cause of symptoms. However, more than one-half of such patients have an ischemic cause as the best clinical diagnosis. Small brainstem lacunar infarctions may escape detection. Concomitant HWI can identify some patients with brain ischemia that is symptomatic but not yet to the stage of causing DWI abnormality.
Wu O, Østergaard L, Koroshetz WJ, Schwamm LH, O'Donnell J, Schaefer PW, Rosen BR, Weisskoff RM, Sorensen GA. Effects of tracer arrival time on flow estimates in MR perfusion-weighted imaging. Magn Reson Med 2003;50(4):856-64.Abstract
A common technique for calculating cerebral blood flow (CBF) and mean transit time (MTT) is to track a bolus of contrast agent using perfusion-weighted MRI (PWI) and to deconvolve the change in concentration with an arterial input function (AIF) using singular value decomposition (SVD). This method has been shown to often overestimate the volume of tissue that infarcts and in cases of severe vasculopathy to produce CBF maps that are inconsistent with clinical presentation. This study examines the effects of tracer arrival time differences between tissue and a user-selected global AIF on flow estimates. CBF and MTT were calculated in both numerically simulated and clinically acquired PWI data where the AIF and tissue signals were shifted backward and forward in time with respect to one another. Results show that when the AIF leads the tissue, CBF is underestimated independent of extent of delay, but dependent on MTT. When the AIF lags the tissue, flow may be over- or underestimated depending on MTT and extent of timing differences. These conditions may occur in practice due to the application of a user-selected AIF that is not the "true AIF" and therefore caution must be taken in interpreting CBF and MTT estimates.
Dijkhuizen RM, Asahi M, Wu O, Rosen BR, Lo EH. Rapid breakdown of microvascular barriers and subsequent hemorrhagic transformation after delayed recombinant tissue plasminogen activator treatment in a rat embolic stroke model. Stroke 2002;33(8):2100-4.Abstract
BACKGROUND AND PURPOSE: Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) after stroke increases risk of hemorrhagic transformation, particularly in areas with blood-brain barrier leakage. Our aim was to characterize acute effects of rtPA administration on the integrity of microvascular barriers. METHODS: Stroke was induced in spontaneously hypertensive rats by unilateral embolic middle cerebral artery occlusion. Six hours after stroke, rtPA was intravenously administered (n=10). Controls received saline (n=4). Extravasation of the large-diameter contrast agent monocrystalline iron oxide nanocolloid (MION) was assessed with susceptibility contrast-enhanced MRI during rtPA injection. In addition, we performed perfusion MRI and diffusion-weighted MRI. After MRI, 2 hours after rtPA treatment, intracerebral hemorrhage was quantified with a spectrophotometric hemoglobin assay. RESULTS: Late rtPA treatment resulted in increased hemorrhage volume (8.4+/-1.7 versus 2.9+/-0.9 micro L in controls; P<0.05). In MION-injected animals, during rtPA administration, transverse relaxation rate change (DeltaR2*) increased from 12.4+/-6.0 to 31.6+/-19.2 s(-1) (P<0.05) in areas with subsequent hemorrhage. Significant DeltaR2* changes were absent in nonhemorrhagic areas, in animals without injected MION, and in saline-treated animals. Thrombolytic therapy did not improve perfusion in regions with hemorrhagic transformation (cerebral blood flow index was 22.8+/-19.7% [of contralateral] at 0.5 hours before and 22.4+/-18.0% at 1 hour after rtPA administration). CONCLUSIONS: The DeltaR2* changes during rtPA delivery in MION-injected animals indicate extravasation of MION, which reflects increased permeability of the blood-brain barrier. This implies that late rtPA treatment rapidly aggravates early ischemia-induced damage to microvascular barriers, thereby enhancing hemorrhagic transformation.
Ay H, Koroshetz WJ, Benner T, Vangel MG, Wu O, Schwamm LH, Sorensen GA. Transient ischemic attack with infarction: a unique syndrome?. Ann Neurol 2005;57(5):679-86.Abstract
It is debated whether transient symptoms associated with infarction (TSI) are best considered a minor ischemic stroke, a subtype of transient ischemic attack (TIA), or a separate ischemic brain syndrome. We studied clinical and imaging features to establish similarities and differences among ischemic stroke, TIA without infarction, and TSI. Eighty-seven consecutive patients with TIA and 74 patients with ischemic stroke were studied. All underwent diffusion-weighted imaging on admission. Symptom duration and infarct volume were determined in each group. Thirty-six patients (41.3%) with TIA had acute infarct(s). Although TIA-related infarcts were smaller than those associated with ischemic stroke (mean, 0.7 vs 27.3 ml; p < 0.001), there was no lesion size threshold that distinguished ischemic stroke from TSI. In contrast, the symptom duration probability density curve was not broad, but instead peaked early with only a few patients having symptoms for longer than 200 minutes. The probability density function for symptom duration was similar between TIA with or without infarction. The in-hospital recurrent ischemic stroke and TIA rate was 19.4% in patients with TSI and 1.3% in those with ischemic stroke. TIA with infarction appears to have unique features separate from TIA without infarction and ischemic stroke. We propose identifying TSI as a separate clinical syndrome with distinct prognostic features.
Dijkhuizen RM, Ren J, Mandeville JB, Wu O, Ozdag FM, Moskowitz MA, Rosen BR, Finklestein SP. Functional magnetic resonance imaging of reorganization in rat brain after stroke. Proc Natl Acad Sci U S A 2001;98(22):12766-71.Abstract
Functional recovery after stroke has been associated with brain plasticity; however, the exact relationship is unknown. We performed behavioral tests, functional MRI, and histology in a rat stroke model to assess the correlation between temporal changes in sensorimotor function, brain activation patterns, cerebral ischemic damage, and cerebrovascular reactivity. Unilateral stroke induced a large ipsilateral infarct and acute dysfunction of the contralateral forelimb, which significantly recovered at later stages. Forelimb impairment was accompanied by loss of stimulus-induced activation in the ipsilesional sensorimotor cortex; however, local tissue and perfusion were only moderately affected and cerebrovascular reactivity was preserved in this area. At 3 days after stroke, extensive activation-induced responses were detected in the contralesional hemisphere. After 14 days, we found reduced involvement of the contralesional hemisphere, and significant responses in the infarction periphery. Our data suggest that limb dysfunction is related to loss of brain activation in the ipsilesional sensorimotor cortex and that restoration of function is associated with biphasic recruitment of peri- and contralesional functional fields in the brain.
Ozsunar Y, Grant EP, Huisman TAGM, Schaefer PW, Wu O, Sorensen GA, Koroshetz WJ, Gonzalez GR. Evolution of water diffusion and anisotropy in hyperacute stroke: significant correlation between fractional anisotropy and T2. AJNR Am J Neuroradiol 2004;25(5):699-705.Abstract
BACKGROUND AND PURPOSE: We hypothesized that, in acute cerebral ischemic stroke, anisotropic diffusion increases if T2 signal intensity is not substantially elevated and decreases once T2 hyperintensity becomes apparent. Our purpose was to correlate fractional anisotropy (FA) measurements with the clinical time of stroke onset, apparent diffusion coefficients (ADC), and T2 signal intensity. METHODS: Tensor diffusion-weighted images (DWIs) of 25 patients were obtained within 12 hours of symptom onset. Trace DWIs, ADCs, FAs, and echo-planar T2-weighted images (T2WI) were generated. Stroke and contralateral normal volumes of interest (VOIs) were outlined on DWIs and projected onto the inherently coregistered ADC map, FA map, and echo-planar T2WI. Mean signal intensity of the ischemic and contralateral normal VOIs were compared for relatives change in ADC, FA, and signal intensity on T2WIs. RESULTS: A significant negative correlation was observed between FA and T2 signal-intensity change (r = -0.61, P =.00009). A trend of correlation between FA signal intensity and time of onset were found (r = -0.438, P =.025). No significant correlation was found between ADC and FA values (r = -0.302, P =.134). The mean ADC reduction in the ipsilateral ischemic volume was 31% +/- 11 compared with the contralateral normal side. CONCLUSION: Change in FA is inversely correlated with T2 signal intensity and, to a lesser extent, the time of onset, but it is not well correlated with ADC values in the acute stage.
Dijkhuizen RM, Singhal AB, Mandeville JB, Wu O, Halpern EF, Finklestein SP, Rosen BR, Lo EH. Correlation between brain reorganization, ischemic damage, and neurologic status after transient focal cerebral ischemia in rats: a functional magnetic resonance imaging study. J Neurosci 2003;23(2):510-7.Abstract
The pattern and role of brain plasticity in stroke recovery has been incompletely characterized. Both ipsilesional and contralesional changes have been described, but it remains unclear how these relate to functional recovery. Our goal was to correlate brain activation patterns with tissue damage, hemodynamics, and neurologic status after temporary stroke, using functional magnetic resonance imaging (fMRI). Transverse relaxation time (T2)-weighted, diffusion-weighted, and perfusion MRI were performed at days 1 (n = 7), 3 (n = 7), and 14 (n = 7) after 2 hr unilateral middle cerebral artery occlusion in rats. Functional activation and cerebrovascular reactivity maps were generated from contrast-enhanced fMRI during forelimb stimulation and hypercapnia, respectively. Before MRI, rats were examined neurologically. We detected loss of activation responses in the ipsilesional sensorimotor cortex, which was related to T2 lesion size (r = -0.858 on day 3, r = -0.979 on day 14; p < 0.05). Significant activation responses in the contralesional hemisphere were detected at days 1 and 3. The degree of shift in balance of activation between the ipsilesional and contralesional hemispheres, characterized by the laterality index, was linked to the T2 and apparent diffusion coefficient in the ipsilesional contralesional forelimb region of the primary somatosensory cortex and primary motor cortex at day 1 (r = -0.807 and 0.782, respectively; p < 0.05) and day 14 (r = -0.898 and -0.970, respectively; p < 0.05). There was no correlation between activation parameters and perfusion status or cerebrovascular reactivity. Finally, we found that the laterality index and neurologic status changed in parallel over time after stroke, so that when all time points were grouped together, neurologic status was inversely correlated with the laterality index (r = -0.571; p = 0.016). This study suggests that the degree of shift of activation balance toward the contralesional hemisphere early after stroke increases with the extent of tissue injury and that functional recovery is associated mainly with preservation or restoration of activation in the ipsilesional hemisphere.
Hjort N, Christensen S, Sølling C, Ashkanian M, Wu O, Røhl L, Gyldensted C, Andersen G, Østergaard L. Ischemic injury detected by diffusion imaging 11 minutes after stroke. Ann Neurol 2005;58(3):462-5.Abstract
A 78-year-old woman suffered a stroke inside a magnetic resonance scanner while being imaged because of a brief transient ischemic attack 2 hours earlier. Diffusion-weighted images obtained 11 minutes after stroke showed tissue injury not found on initial images. The data show early, abrupt diffusion changes in hypoperfused tissue, adding to our understanding of the progression of microstructural abnormalities in the hyperacute phase of stroke.
Yamada K, Wu O, Gonzalez GR, Bakker D, Østergaard L, Copen WA, Weisskoff RM, Rosen BR, Yagi K, Nishimura T, Sorensen GA. Magnetic resonance perfusion-weighted imaging of acute cerebral infarction: effect of the calculation methods and underlying vasculopathy. Stroke 2002;33(1):87-94.Abstract
BACKGROUND AND PURPOSE: Various calculation methods are available to estimate the transit-time on MR perfusion-weighted imaging (PWI). Each method may affect the results of PWI. Steno-occlusive disease in the parent vessels is another factor that may affect the results of the PWI. The purpose of this study was to elucidate the effect of the calculation methods and underlying vasculopathy on PWI. METHODS: From a pool of 113 patients who had undergone PWI during the study period, a total of 12 patients with nonlacunar ischemic strokes who were scanned within 24 hours after onset of symptom were selected for the study. The patient population consisted of 6 patients who had extracranial internal carotid artery stenosis (>70%) and 6 individuals without stenosis. Seven different postprocessing methods were evaluated: first moment, ratio of area to peak, time to peak (TTP), relative TTP, arrival time, full-width at half-maximum, and deconvolution methods. Follow-up MR or CT images were used to determine the areas that evolved into infarcts, which served as the gold standard. Sensitivity and specificity of each transit time technique were calculated. RESULTS: Calculation methods with high sensitivity were the first moment (sensitivity, 74%), TTP (sensitivity, 77%), and deconvolution methods (sensitivity, 81% to 94%). Between the 2 groups with and without internal carotid artery stenosis, the specificity of most of the techniques was lower in the internal carotid artery stenosis group. The first moment and deconvolution methods maintained relatively high specificity even in the stenosis group. CONCLUSIONS: The calculation technique and presence of underlying vasculopathy have a direct impact on the results of PWI. The methods with high sensitivity even in the presence of steno-occlusive disease were the first moment and deconvolution methods with arterial input function derived from the peri-infarct arteries; the deconvolution method was the superior choice because of higher lesion conspicuity.
Gottrup C, Thomsen K, Locht P, Wu O, Sorensen GA, Koroshetz WJ, Østergaard L. Applying instance-based techniques to prediction of final outcome in acute stroke. Artif Intell Med 2005;33(3):223-36.Abstract
OBJECTIVE: Acute cerebral stroke is a frequent cause of death and the major cause of adult neurological disability in the western world. Thrombolysis is the only established treatment of ischemic stroke; however, its use carries a substantial risk of symptomatic intracerebral hemorrhage. A clinical tool to guide the use of thrombolysis would be very valuable. One of the major goals of such a tool would be the identification of potentially salvageable tissue. This requires an accurate prediction of the extent of infarction if untreated. In this study, we investigate the applicability of highly flexible instance-based (IB) methods for such predictions. METHODS AND MATERIALS: Based on information obtained from magnetic resonance imaging of 14 patients with acute stroke, we explored three different implementations of the IB method: k-NN, Gaussian weighted, and constant radius search classification. Receiver operating characteristics analysis, in particular area under the curve (AUC), was used as performance measure. RESULTS: We found no significant difference (P = 0.48) in performance for the optimal k-NN (k = 164, AUC = 0.814 +/- 0.001) and Gaussian weight (sigma = 0.17, AUC = 0.813 +/- 0.001) implementations, while they were both significantly better (P < 1 x 10(-6) for both) than the constant radius implementation (R = 0.28, AUC = 0.809 +/- 0.001). Qualitative analyses of the distribution of instances in the feature space indicated that non-infarcted instances tends to cluster together while infarcted instances are more dispersed, and that there may not exist a stringent boundary separating infarcted from non-infarcted instances. CONCLUSIONS: This study shows that IB methods can be used, and may be advantageous, for predicting final infarct in patients with acute stroke, but further work must be done to make them clinically applicable.
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.
Cheng B, Brinkmann M, Forkert ND, Treszl A, Ebinger M, Köhrmann M, Wu O, Kang D-W, Liebeskind DS, Tourdias T, Singer OC, Christensen S, Luby M, Warach S, Fiehler J, Fiebach JB, Gerloff C, Thomalla G. Quantitative measurements of relative fluid-attenuated inversion recovery (FLAIR) signal intensities in acute stroke for the prediction of time from symptom onset. J Cereb Blood Flow Metab 2013;33(1):76-84.Abstract
In acute stroke magnetic resonance imaging, a 'mismatch' between visibility of an ischemic lesion on diffusion-weighted imaging (DWI) and missing corresponding parenchymal hyperintensities on fluid-attenuated inversion recovery (FLAIR) data sets was shown to identify patients with time from symptom onset ≤4.5 hours with high specificity. However, moderate sensitivity and suboptimal interpreter agreement are limitations of a visual rating of FLAIR lesion visibility. We tested refined image analysis methods in patients included in the previously published PREFLAIR study using refined visual analysis and quantitative measurements of relative FLAIR signal intensity (rSI) from a three-dimensional, segmented stroke lesion volume. A total of 399 patients were included. The rSI of FLAIR lesions showed a moderate correlation with time from symptom onset (r=0.382, P<0.001). A FLAIR rSI threshold of <1.0721 predicted symptom onset ≤4.5 hours with slightly increased specificity (0.85 versus 0.78) but also slightly decreased sensitivity (0.47 versus 0.58) as compared with visual analysis. Refined visual analysis differentiating between 'subtle' and 'obvious' FLAIR hyperintensities and classification and regression tree algorithms combining information from visual and quantitative analysis also did not improve diagnostic accuracy. Our results raise doubts whether the prediction of stroke onset time by visual image judgment can be improved by quantitative rSI measurements.

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