Publications

2007
Makris N, Papadimitriou GM, van der Kouwe A, Kennedy DN, Hodge SM, Dale AM, Benner T, Wald LL, Wu O, Tuch DS, Caviness VS, Moore TL, Killiany RJ, Moss MB, Rosene DL. Frontal connections and cognitive changes in normal aging rhesus monkeys: a DTI study. Neurobiol Aging 2007;28(10):1556-67.Abstract
Recent anatomical studies have found that cortical neurons are mainly preserved during the aging process while myelin damage and even axonal loss is prominent throughout the forebrain. We used diffusion tensor imaging (DT-MRI) to evaluate the hypothesis that during the process of normal aging, white matter changes preferentially affect the integrity of long corticocortical association fiber tracts, specifically the superior longitudinal fasciculus II and the cingulum bundle. This would disrupt communication between the frontal lobes and other forebrain regions leading to cognitive impairments. We analyzed DT-MRI datasets from seven young and seven elderly behaviorally characterized rhesus monkeys, creating fractional anisotropy (FA) maps of the brain. Significant age-related reductions in mean FA values were found for the superior longitudinal fasciculus II and the cingulum bundle, as well as the anterior corpus callosum. Comparison of these FA reductions with behavioral measures demonstrated a statistically significant linear relationship between regional FA and performance on a test of executive function. These findings support the hypothesis that alterations to the integrity of these long association pathways connecting the frontal lobe with other forebrain regions contribute to cognitive impairments in normal aging. To our knowledge this is the first investigation reporting such alterations in the aging monkey.
Wu O, Sumii T, Asahi M, Sasamata M, Ostergaard L, Rosen BR, Lo EH, Dijkhuizen RM. Infarct prediction and treatment assessment with MRI-based algorithms in experimental stroke models. J Cereb Blood Flow Metab 2007;27(1):196-204.Abstract
There is increasing interest in using algorithms combining multiple magnetic resonance imaging (MRI) modalities to predict tissue infarction in acute human stroke. We developed and tested a voxel-based generalized linear model (GLM) algorithm to predict tissue infarction in an animal stroke model in order to directly compare predicted outcome with the tissue's histologic outcome, and to evaluate the potential for assessing therapeutic efficacy using these multiparametric algorithms. With acute MRI acquired after unilateral embolic stroke in rats (n=8), a GLM was developed and used to predict infarction on a voxel-wise basis for saline (n=6) and recombinant tissue plasminogen activator (rt-PA) treatment (n=7) arms of a trial of delayed thrombolytic therapy in rats. Pretreatment predicted outcome compared with post-treatment histology was highly accurate in saline-treated rats (0.92+/-0.05). Accuracy was significantly reduced (P=0.04) in rt-PA-treated animals (0.86+/-0.08), although no significant difference was detected when comparing histologic lesion volumes. Animals that reperfused had significantly lower (P<0.01) GLM-predicted infarction risk (0.73+/-0.03) than nonreperfused animals (0.81+/-0.05), possibly reflecting less severe initial ischemic injury and therefore tissue likely more amenable to therapy. Our results show that acute MRI-based algorithms can predict tissue infarction with high accuracy in animals not receiving thrombolytic therapy. Furthermore, alterations in disease progression due to treatment were more sensitively monitored with our voxel-based analysis techniques than with volumetric approaches. Our study shows that predictive algorithms are promising metrics for diagnosis, prognosis and therapeutic evaluation after acute stroke that can translate readily from preclinical to clinical settings.
2006
Wu O, Christensen S, Hjort N, Dijkhuizen RM, Kucinski T, Fiehler J, Thomalla G, Röther J, Østergaard L. Characterizing physiological heterogeneity of infarction risk in acute human ischaemic stroke using MRI. Brain 2006;129(Pt 9):2384-93.Abstract
Viable tissues at risk of infarction in acute stroke patients have been hypothesized to be detectable as volumetric mismatches between lesions on perfusion-weighted (PWI) and diffusion-weighted magnetic resonance imaging (DWI). Because tissue response to ischaemic injury and to therapeutic intervention is tissue- and patient-dependent, changes in infarct progression due to treatment may be better detected with voxel-based methods than with volumetric mismatches. Acute DWI and PWI were combined using a generalized linear model (GLM) to predict infarction risk on a voxel-wise basis for patients treated either with non-thrombolytic (Group 1; n = 11) or with thrombolytic therapy (Group 2; n = 27). Predicted infarction risk for both groups was evaluated in four ipsilateral regions of interest: tissue acutely abnormal on DWI (Core), tissue acutely abnormal on PWI but normal on DWI that either infarcts (Recruited) or does not (Salvaged), and tissue normal on both DWI and PWI that does not infarct (Normal) by follow-up imaging > or = 5 days. The performance of the models was significantly reduced for the thrombolysed group compared with the group receiving standard treatment, suggesting an alteration in natural progression of the ischaemic cascade. Average GLM-predicted infarction risk values in the four regions were different from one another for both groups. GLM-predicted infarction risk in Salvaged tissue was significantly higher (P = 0.02) for thrombolysed patients than for non-thrombolysed patients, suggesting that thrombolysis rescued tissue with higher infarction risk than typically measured in tissue that spontaneously recovered. The observed spatial heterogeneity of GLM-predicted infarction risk values probably reflects the varying degrees of tissue injury and salvageability that exist after stroke. MRI-based algorithms may therefore provide a more sensitive means for monitoring therapeutic effects on a voxel-wise basis.
2005
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.
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.
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.
Wu O, Ostergaard L, Sorensen GA. Technical aspects of perfusion-weighted imaging. Neuroimaging Clin N Am 2005;15(3):623-37, xi.Abstract
There is increasing interest in using diffusion-weighted (DWI) MR imaging and perfusion-weighted MR imaging (PWI) to assist clinical decision-making in the management of acute stroke patients. Larger PWI than DWI lesions have been speculated to represent potentially salvageable tissue that is at risk of infarction unless nutritive flow is restored and presence of these mismatches have been proposed as inclusion criteria for identifying patients most likely to benefit from therapeutic intervention. Understanding the technical aspects of PWI may improve comprehension of the capabilities and limitations of this technique.
2004
Huisman TAGM, Schwamm LH, Schaefer PW, Koroshetz WJ, Shetty-Alva N, Ozsunar Y, Wu O, Sorensen GA. Diffusion tensor imaging as potential biomarker of white matter injury in diffuse axonal injury. AJNR Am J Neuroradiol 2004;25(3):370-6.Abstract
BACKGROUND AND PURPOSE: Multiple biomarkers are used to quantify the severity of traumatic brain injury (TBI) and to predict outcome. Few are satisfactory. CT and conventional MR imaging underestimate injury and correlate poorly with outcome. New MR imaging techniques, including diffusion tensor imaging (DTI), can provide information about brain ultrastructure by quantifying isotropic and anisotropic water diffusion. Our objective was to determine if changes in anisotropic diffusion in TBI correlate with acute Glasgow coma scale (GCS) and/or Rankin scores at discharge. METHODS: Twenty patients (15 male, five Female; mean age, 31 years) were evaluated. Apparent diffusion coefficients (ADCs) and fractional anisotropy (FA) values were measured at multiple locations and correlated with clinical scores. Results were compared with those of 15 healthy control subjects. RESULTS: ADC values were significantly reduced within the splenium (Delta18%, P =.001). FA values were significantly reduced in the internal capsule (Delta14%; P <.001) and splenium (Delta16%; P =.002). FA values were significantly correlated with GCS (r = 0.65-0.74; P <.001) and Rankin (r = 0.68-0.71; P <.001) scores for the internal capsule and splenium. The correlation between FA and clinical markers was better than for the corresponding ADC values. No correlation was found between ADC of the internal capsule and GCS/Rankin scores. CONCLUSION: DTI reveals changes in the white matter that are correlated with both acute GCS and Rankin scores at discharge. DTI may be a valuable biomarker for the severity of tissue injury and a predictor for outcome.
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.
van Eijsden P, Notenboom RGE, Wu O, de Graan PNE, van Nieuwenhuizen O, Nicolay K, Braun KPJ. In vivo 1H magnetic resonance spectroscopy, T2-weighted and diffusion-weighted MRI during lithium-pilocarpine-induced status epilepticus in the rat. Brain Res 2004;1030(1):11-8.Abstract
Temporal lobe epilepsy (TLE) is associated with febrile convulsions and childhood status epilepticus (SE). Since the initial precipitating injury, triggering epileptogenesis, occurs during this SE, we aimed to examine the metabolic and morphological cerebral changes during the acute phase of experimental SE noninvasively. In the rat lithium-pilocarpine model of SE, we performed quantified T(2)- and isotropic-diffusion-weighted (DW) magnetic resonance imaging (MRI) at 3 and 5 h of SE and acquired single-voxel (1)H MR spectra at 2, 4 and 6 h of SE. T(2) was globally decreased, most pronounced in the amygdala (Am) and piriformic cortex (Pi), in which also a significant decrease in apparent diffusion coefficient (ADC) was found. In contrast, ADC values increased transiently in the hippocampus (HC) and thalamus (Th). MR spectra showed a decrease in N-acetylaspartate (NAA) and choline (Cho) and an increase of lactate in a hippocampal voxel. The T(2) decrease, attributed to raised deoxyhemoglobin, and the presence of lactate both indicate a mismatch between oxygen demand and delivery. The ADC decrease, indicative of excitotoxicity, confirms that the amygdala and piriformic cortex are particularly vulnerable to lithium-pilocarpine-induced seizures. The transient ADC increase in the thalamus may reflect the breakdown of the blood-brain barrier (BBB), which is shown to occur in this region at these time points. Neuronal damage and failure of energy-dependent formation of NAA are likely causes of an observed decrease in NAA, while the decrease in Cho is possibly due to depletion of the cholinergic system. This study illustrates that relative hypoxia, excitotoxicity and concomitant neuronal damage associated with SE can be probed noninvasively with MR. These pathological phenomena are the first to contribute to the pathophysiology of spontaneous recurrent seizures in a later stage in this animal model.
2003
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.
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.
van Osch MJ, Vonken E-JPA, Wu O, Viergever MA, van der Grond J, Bakker CJG. Model of the human vasculature for studying the influence of contrast injection speed on cerebral perfusion MRI. Magn Reson Med 2003;50(3):614-22.Abstract
Simulations of dynamic susceptibility contrast (DSC) MRI are frequently performed by assuming a certain shape for the input function and the microvascular response function. However, to investigate the influence of parameters that will affect the shape of the input function, a more complex model of the human vasculature is required. In this study, a model of the human vasculature is proposed that consists of a network of vascular operators based on physiological data typical of a 35-year-old male subject. The simulated contrast passage curves were found to be within the range of observed contrast passage curves in a population of patients without vascular disease. The model was used to predict the effect of different injection speeds of the contrast agent on the accuracy of the perfusion experiment. It was found that injection speeds of <3 ml/s lead to an underestimation of the observed cerebral blood flow (CBF). Additionally, it was determined that decreasing the temporal resolution of the acquisition results in an underestimation of the CBF values, and an increase of the standard deviation (SD) of CBF measurements.
Wu O, Østergaard L, Weisskoff RM, Benner T, Rosen BR, Sorensen GA. Tracer arrival timing-insensitive technique for estimating flow in MR perfusion-weighted imaging using singular value decomposition with a block-circulant deconvolution matrix. Magn Reson Med 2003;50(1):164-74.Abstract
Relative cerebral blood flow (CBF) and tissue mean transit time (MTT) estimates from bolus-tracking MR perfusion-weighted imaging (PWI) have been shown to be sensitive to delay and dispersion when using singular value decomposition (SVD) with a single measured arterial input function. This study proposes a technique that is made time-shift insensitive by the use of a block-circulant matrix for deconvolution with (oSVD) and without (cSVD) minimization of oscillation of the derived residue function. The performances of these methods are compared with standard SVD (sSVD) in both numerical simulations and in clinically acquired data. An additional index of disturbed hemodynamics (oDelay) is proposed that represents the tracer arrival time difference between the AIF and tissue signal. Results show that PWI estimates from sSVD are weighted by tracer arrival time differences, while those from oSVD and cSVD are not. oSVD also provides estimates that are less sensitive to blood volume compared to cSVD. Using PWI data that can be routinely collected clinically, oSVD shows promise in providing tracer arrival timing-insensitive flow estimates and hence a more specific indicator of ischemic injury. Shift maps can continue to provide a sensitive reflection of disturbed hemodynamics.
2002
Schaefer PW, Romero JM, Grant EP, Wu O, Sorensen GA, Koroshetz W, González GR. Diffusion magnetic resonance imaging of acute ischemic stroke. Semin Roentgenol 2002;37(3):219-29.
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.
Schaefer PW, Romero JM, Grant EP, Wu O, Sorensen GA, Koroshetz W, González GR. Perfusion magnetic resonance imaging of acute ischemic stroke. Semin Roentgenol 2002;37(3):230-6.
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.
2001
Dijkhuizen RM, Asahi M, Wu O, Rosen BR, Lo EH. Delayed rt-PA treatment in a rat embolic stroke model: diagnosis and prognosis of ischemic injury and hemorrhagic transformation with magnetic resonance imaging. J Cereb Blood Flow Metab 2001;21(8):964-71.Abstract
The authors characterized effects of late recombinant tissue plasminogen activator (rt-PA) administration in a rat embolic stroke model with magnetic resonance imaging (MRI), to assess potential MRI correlates, or predictors, or both, of rt-PA-induced hemorrhage. Diffusion-, perfusion-, and postcontrast T1-weighted MRI were performed between 4 and 9 hours and at 24 hours after embolic stroke in spontaneously hypertensive rats. Treatment with either rt-PA or saline was started 6 hours after stroke. A spectrophotometric hemoglobin assay quantified hemorrhage severity. Before treatment, relative cerebral blood flow index (rCBFi) and apparent diffusion coefficient (ADC) in the ischemic territory were 30% +/- 23% and 60% +/- 5% (of contralateral), respectively, which increased to 45% +/- 39% and 68% +/- 4% 2 hours after rt-PA. After 24 hours, rCBFi and ADC were 27% +/- 27% and 59 +/- 5%. Hemorrhage volume after 24 hours was significantly greater in rt-PA-treated animals than in controls (8.7 +/- 3.7 microL vs. 5.1 +/- 2.4 microL, P < 0.05). Before rt-PA administration, clear postcontrast T1-weighted signal intensity enhancement was evident in areas of subsequent bleeding. These areas had lower rCBFi levels than regions without hemorrhage (23% +/- 22% vs. 36% +/- 29%, P < 0.05). In conclusion, late thrombolytic therapy does not necessarily lead to successful reperfusion. Hemorrhage emerged in areas with relatively low perfusion levels and early blood-brain barrier damage. Magnetic resonance imaging may be useful for quantifying effects of thrombolytic therapy and predicting risks of hemorrhagic transformation.
Grant PE, He J, Halpern EF, Wu O, Schaefer PW, Schwamm LH, Budzik RF, Sorensen AG, Koroshetz WJ, Gonzalez RG. Frequency and clinical context of decreased apparent diffusion coefficient reversal in the human brain. Radiology 2001;221(1):43-50.Abstract
PURPOSE: To determine the probability that regions of decreased apparent diffusion coefficient (ADC) return to normal without persistent symptoms or T2 change and the settings in which these ADC reversals occur. MATERIALS AND METHODS: Three hundred magnetic resonance (MR) imaging studies were selected at random from a database of 7,147 examinations to determine the probability of a pathologically decreased ADC. In cases with decreased ADC, the clinical history was recorded and, if available, follow-up MR imaging findings were evaluated. Five cases of ADC reversal became known during the same period and were evaluated to determine the initial ADC decrease, clinical outcome, and findings at follow-up imaging. RESULTS: Findings in 116 of 300 MR imaging studies revealed regions of decreased ADC. In 49 of 116 studies, follow-up MR imaging examinations were performed at least 4 weeks after the onset of symptoms; ADC did not reverse. Five cases of ADC reversal were identified in the same period, giving an estimated 0.2%-0.4% probability of ADC reversal. Clinical settings were venous sinus thrombosis and seizure (n = 3), hemiplegic migraine (n = 1), and hyperacute arterial infarction (n = 1). Both white matter (n = 3) and gray matter (n = 3) regions were involved. CONCLUSION: Reversal of ADC lesions is rare, occurs in complicated clinical settings, and can involve white or gray matter.

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