Publications

    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    Yoshiura T, Wu O, Zaheer A, Reese TG, Sorensen AG. Highly diffusion-sensitized MRI of brain: dissociation of gray and white matter. Magn Reson Med 2001;45(5):734-40.Abstract
    The brains of six healthy volunteers were scanned with a full tensor diffusion MRI technique to study the effect of a high b value on diffusion-weighted images (DWIs). The b values ranged from 500 to 5000 s/mm(2). Isotropic DWIs, trace apparent diffusion coefficient (ADC) maps, and fractional anisotropy (FA) maps were created for each b value. As the b value increased, ADC decreased in both the gray and white matter. Furthermore, ADC of the white matter became lower than that of the gray matter, and, as a result, the white matter became brighter than the gray matter in the isotropic DWIs. Quantitative analysis showed that these changes were due to nonmonoexponential diffusion signal decay of the brain tissue, which was more prominent in white matter than in gray matter. There was no significant change in relation to the b value in the FA maps. High b value appears to have a dissociating effect on gray and white matter in DWIs.
    Hadjikhani N, Sanchez Del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, Kwong KK, Cutrer FM, Rosen BR, Tootell RB, Sorensen AG, Moskowitz MA. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A 2001;98(8):4687-92.Abstract
    Cortical spreading depression (CSD) has been suggested to underlie migraine visual aura. However, it has been challenging to test this hypothesis in human cerebral cortex. Using high-field functional MRI with near-continuous recording during visual aura in three subjects, we observed blood oxygenation level-dependent (BOLD) signal changes that demonstrated at least eight characteristics of CSD, time-locked to percept/onset of the aura. Initially, a focal increase in BOLD signal (possibly reflecting vasodilation), developed within extrastriate cortex (area V3A). This BOLD change progressed contiguously and slowly (3.5 +/- 1.1 mm/min) over occipital cortex, congruent with the retinotopy of the visual percept. Following the same retinotopic progression, the BOLD signal then diminished (possibly reflecting vasoconstriction after the initial vasodilation), as did the BOLD response to visual activation. During periods with no visual stimulation, but while the subject was experiencing scintillations, BOLD signal followed the retinotopic progression of the visual percept. These data strongly suggest that an electrophysiological event such as CSD generates the aura in human visual cortex.
    Copen WA, Schwamm LH, González RG, Wu O, Harmath CB, Schaefer PW, Koroshetz WJ, Sorensen AG. Ischemic stroke: effects of etiology and patient age on the time course of the core apparent diffusion coefficient. Radiology 2001;221(1):27-34.Abstract
    PURPOSE: To determine whether the evolution of the core apparent diffusion coefficient (ADC) of water in ischemic stroke varies with patient age or infarct etiology. MATERIALS AND METHODS: One hundred forty-seven patients with stroke underwent 236 diffusion-weighted magnetic resonance imaging examinations. Etiologies of lesions were classified according to predefined criteria; in 224 images, the diagnosis of lacune could be firmly established or excluded. ADC was measured in the center of each lesion and in contralateral normal-appearing brain. A model was used to describe the time course of relative ADC (rADC), which is calculated by dividing the lesion ADC by the contralateral ADC, and to test for age- or etiology-related differences in this time course. RESULTS: Transition from decreasing to increasing rADC was estimated at 18.5 hours after stroke onset. In subgroup analysis, transition was earlier in nonlacunes than in lacunes (P =.02). There was a trend toward earlier transition in patients older than the median age of 66.0 years, compared with younger patients (P =.06). Pseudonormalization was estimated at 216 hours. Among nonlacunes, the rate of subsequent rADC increase was more rapid in younger patients than in older patients (P =.001). Within the smaller sample of lacunes, however, no significant age-related difference in this rate was found. CONCLUSION: Differences in ADC depending on the patient's age and infarct etiology suggest differing rates of ADC progression.
    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.
    Wu O, Koroshetz WJ, Ostergaard L, Buonanno FS, Copen WA, Gonzalez RG, Rordorf G, Rosen BR, Schwamm LH, Weisskoff RM, Sorensen AG. Predicting tissue outcome in acute human cerebral ischemia using combined diffusion- and perfusion-weighted MR imaging. Stroke 2001;32(4):933-42.Abstract
    BACKGROUND AND PURPOSE: Tissue signatures from acute MR imaging of the brain may be able to categorize physiological status and thereby assist clinical decision making. We designed and analyzed statistical algorithms to evaluate the risk of infarction for each voxel of tissue using acute human functional MRI. METHODS: Diffusion-weighted MR images (DWI) and perfusion-weighted MR images (PWI) from acute stroke patients scanned within 12 hours of symptom onset were retrospectively studied and used to develop thresholding and generalized linear model (GLM) algorithms predicting tissue outcome as determined by follow-up MRI. The performances of the algorithms were evaluated for each patient by using receiver operating characteristic curves. RESULTS: At their optimal operating points, thresholding algorithms combining DWI and PWI provided 66% sensitivity and 83% specificity, and GLM algorithms combining DWI and PWI predicted with 66% sensitivity and 84% specificity voxels that proceeded to infarct. Thresholding algorithms that combined DWI and PWI provided significant improvement to algorithms that utilized DWI alone (P=0.02) but no significant improvement over algorithms utilizing PWI alone (P=0.21). GLM algorithms that combined DWI and PWI showed significant improvement over algorithms that used only DWI (P=0.02) or PWI (P=0.04). The performances of thresholding and GLM algorithms were comparable (P>0.2). CONCLUSIONS: Algorithms that combine acute DWI and PWI can assess the risk of infarction with higher specificity and sensitivity than algorithms that use DWI or PWI individually. Methods for quantitatively assessing the risk of infarction on a voxel-by-voxel basis show promise as techniques for investigating the natural spatial evolution of ischemic damage in humans.
    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.
    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.
    Yoshiura T, Wu O, Sorensen AG. Advanced MR techniques: diffusion MR imaging, perfusion MR imaging, and spectroscopy. Neuroimaging Clin N Am 1999;9(3):439-53.Abstract
    Recent technical advances in MR imaging have enabled the authors to investigate early physiological changes in acute ischemic stroke lesion. Diffusion and perfusion MR imaging can provide clinically useful information not only for early detection of ischemia, but also for prediction of tissue outcome. MR spectroscopy is a potentially powerful tool to study acute stroke, but its clinical value has been limited due to long examination time and low spatial resolution.

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