Characterizing the diffusion/perfusion mismatch in experimental focal cerebral ischemia

Diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) can rapidly detect lesions in acute ischemic stroke patients. The PWI volume is typically substantially larger than the DWI volume shortly after onset, that is, a diffusion/ perfusion mismatch. The aims of this study were to follow the evolution of the diffusion/ perfusion mismatch in permanent and 60- minute temporary focal experimental ischemia models in Sprague-Dawley rats using the intraluminal middle cerebral artery occlusion (MCAO) method. DWI and arterial spin-labeled PWI were performed at 30, 60, 90, 120, and 180 minutes after occlusion and lesion volumes (mm(3)) calculated At 24 hours after MCAO, and infarct volume was determined using triphenyltetrazolium chloride staining. In the permanent MCAO group, the lesion volume on the ADC maps was significantly smaller than that on the cerebral blood flow maps through the first 60 minutes after MCAO; but not after 90 minutes of occlusion. With 60 minutes of transient ischemia, the diffusion/perfusion mismatch was similar, but after reperfusion, the lesion volumes on ADC and cerebral blood flow maps became much smaller. There was a significant difference in 24- hour infarct volumes between the permanent and temporary occlusion groups.     

Magnetic resonance imaging and clinical patterns of patients with 'spectacular shrinking deficit' after acute middle cerebral artery stroke

BACKGROUND: Rapid resolution of neurological deficits after severe middle cerebral artery (MCA) stroke has been coined spectacular shrinking deficit (SSD). We studied clinical and MRI patterns in patients with SSD. METHODS: Patients with acute MCA stroke <6 h were examined by stroke MRI (perfusion- and diffusion-weighted imaging (PWI, DWI), MR angiography (MRA)) at admission, day 1 and day 7. SSD was defined as a > or =8-point-reduction of neurological deficit in the National Institute of Health Stroke Scale (NIHSS) to a score of < or =4 within 24 h. PWI and DWI lesion volumes were measured on ADC (ADC < 80%) and time to peak maps (TTP > +4 s). Recanalization was assessed by MRA after 24 h. Final infarct volumes were defined on T2 weighted images at day seven. Outcome was assessed after 90 days using modified Rankin Scale (mRS) and Barthel Index (BI). RESULTS: SSD was present in 14 of 104 patients. Initial DWI and PWI lesion volumes were smaller in SSD patients - ADC < 80%: 8.9 (4.3-20.5) vs. 30 (0-266.7) ml; TTP > +4 s: 91.6 (29.7-205.8) vs. 131.5 (0-311.5) ml. Early recanalization was associated with SSD resulted in smaller final infarct volumes (11.9 (2.4-25.9) vs. 47.7 (1.2-288.5)). All SSD patients were independent at day 90 (mRS 0 (0-2); BI 100). CONCLUSION: The clinical syndrome of SSD is reflected by a typical MRI pattern with small initial DWI and PWI lesion volumes, timely recanalization and small final infarct volumes.     

Effects of normobaric hyperoxia in a rat model of focal cerebral ischemia-reperfusion.

Recent studies suggest that normobaric hyperoxia can be beneficial, if administered during transient stroke. However, increased oxygenation theoretically may increase oxygen free-radical injury, particularly during reperfusion. In the present study, the authors assessed the benefit and risks of hyperoxia during focal cerebral ischemia and reperfusion. Rats were subjected to hyperoxia (Fio2 100%) or normoxia (Fio2 30%) during 2-hour filament occlusion and 1-hour reperfusion of the middle cerebral artery. At 24 hours, the hyperoxia group showed 70% (total) and 92% (cortical) reduction in infarct volumes as compared to the normoxia group. Levels of oxidative stress were evaluated using three indirect methods. First, since oxygen free radicals increase blood-brain barrier (BBB) damage, Evan's blue dye extravasation was quantified to assess BBB damage. Second, the expression of heme oxygenase-1 (HO-1), a heat shock protein inducible by oxidative stress, was assessed using Western blot techniques. Third, an immunoblot technique ("OxyBlot") was used to assess levels of protein carbonyl formation as a marker of oxidative stress-induced protein denaturation. At 24 hours, Evan's blue dye extravasation per average lesion volume was similar between groups. There were no significant differences in HO-1 induction and protein carbonyl formation between groups, in the ipsilateral or contralateral hemispheres, at 6 hours and at 24 hours. These results indicate that hyperoxia treatment during focal cerebral ischemia-reperfusion is neuroprotective, and does not increase oxidative stress.     

Neuroprotective effect of hyperbaric oxygen therapy monitored by MR-imaging after embolic stroke in rats

The potential neuroprotective effects of hyperbaric oxygen (HBO) were tested in an embolic model of focal cerebral ischemia with partially spontaneous reperfusion. Rats (n = 10) were subjected to embolic middle cerebral artery occlusion (MCAO) and diffusion weighted MRI (DWI) was performed at baseline, 1, 3, and 6 h after MCAO to determine the ADC viability threshold yielding the lesion volumes that best approximated the 2,3,5-triphenyltetrazolium chloride (TTC) infarct volumes at 24 h (experiment 1). For assessment of neuroprotective effects, rats were treated with 100% oxygen at 2.5 atmospheres absolute (ATA, n = 15) or normobaric room air (n = 15) for 60 min beginning 180 min after MCAO (experiment 2). DWI-, perfusion (PWI)- and T2-weighted MRI (T2WI) started within 0.5 h after MCAO and was continued 5 h, 24 h (PWI and T2WI only), and 168 h (T2WI only). Infarct volume was calculated based on TTC-staining at 24 h (experiment 1) or 168 h (experiment 2) post-MCAO. ADC-lesion evolution was maximal between 3 and 6 h. In experiment 2, the relative regional cerebral blood volume (rCBV) of both groups showed similar incomplete spontaneous reperfusion in the ischemic core. HBO reduced infarct volume to 145.3 +/- 39.6 mm3 vs. 202.5 +/- 58.3 mm3 (control, P = 0.029). As shown by MRI and TTC, HBO treatment demonstrated significant neuroprotection at 5 h after embolic focal cerebral ischemia that lasted for 168 h.     

Normobaric hyperoxia delays perfusion/diffusion mismatch evolution, reduces infarct volume, and differentially affects neuronal cell death pathways after suture middle cerebral artery occlusion in rats.

Normobaric hyperoxia (NBO) has been shown to extend the reperfusion window after focal cerebral ischemia. Employing diffusion (DWI)- and perfusion (PWI)-weighted magnetic resonance imaging (MRI), the effect of NBO (100% started at 30 mins after middle cerebral artery occlusion (MCAO)) on the spatiotemporal evolution of ischemia during and after permanent (pMCAO) and transient suture middle cerebral artery occlusion (tMCAO) was investigated (experiment 3). In two additional experiments, time window (experiment 1) and cell death pathways (experiment 2) were investigated in the pMCAO model. In experiment 1, NBO treatment reduced infarct volume at 24 h after pMCAO by 10% when administered for 3 h (P>0.05) and by 44% when administered for 6 h (P<0.05). In experiment 2, NBO acutely (390 mins, P<0.05) reduced in situ end labeling (ISEL) positivity in the ipsilesional penumbra but increased contralesional necrotic as well as caspase-3-mediated apoptotic cell death. In experiment 3, CBF characteristics and CBF-derived lesion volumes did not differ between treated and untreated animals, whereas the apparent diffusion coefficient (ADC)-derived lesion volume essentially stopped progressing during NBO treatment, resulting in a persistent PWI/DWI mismatch that could be salvaged by delayed (3 h) reperfusion. In conclusion, NBO (1) acutely preserved the perfusion/diffusion mismatch without altering CBF, (2) significantly extended the time window for reperfusion, (3) induced lasting neuroprotection in permanent ischemia, and (4) although capable of reducing cell death in hypoperfused tissue it also induced cell death in otherwise unaffected areas. Our data suggest that NBO may represent a promising strategy for acute stroke treatment.     

Secondary decline in apparent diffusion coefficient and neurological outcomes after a short period of focal brain ischemia in rats

This study was designed to characterize the initial and secondary changes of the apparent diffusion coefficient (ADC) of water with high temporal resolution measurements of ADC values and to correlate ADC changes with functional outcomes. Fourteen rats underwent 30 minutes of temporary middle cerebral artery occlusion (MCAO). Diffusion-, perfusion-, and T2-weighted imaging was performed during MCAO and every 30 minutes for a total of 12 hours after reperfusion (n = 6). Neurological outcomes were evaluated during MCAO, every 30 minutes for a total of 6 hours and at 24 hours after reperfusion (n = 8). The decreased cerebral blood flow during MCAO returned to normal after reperfusion and remained unchanged thereafter. The decreased ADC values during occlusion completely recovered at 1 hour after reperfusion. The renormalized ADC values started to decrease secondarily at 2.5 hours, accompanied by a delayed increase in T2 values. The ADC-defined secondary lesion grew over time and was 52% of the ADC-defined initial lesion at 12 hours. Histological evaluation demonstrated neuronal damage in the regions of secondary ADC decline. Complete resolution of neurological deficits was seen in 1 rat at 1 hour and in 6 rats between 2.5 and 6 hours after reperfusion; no secondary neurological deficits were observed at 24 hours. These data suggest that (1) a secondary ADC reduction occurs as early as 2.5 hours after reperfusion, evolves in a slow fashion, and is associated with neuronal injury; and (2) renormalization and secondary decline in ADC are not associated with neurological recovery and worsening, respectively.     

Evaluation of early reperfusion and i.v. tPA therapy using diffusion- and perfusion-weighted MRI.

OBJECTIVE: To characterize the effects of recombinant tissue plasminogen activator (rt-PA) therapy and early reperfusion on diffusion-weighted (DWI) and perfusion-weighted imaging (PWI) changes observed following acute ischemic injury. METHODS: Twelve patients were evaluated prospectively using echo planar DWI and bolus tracking PWI. Six patients received i.v. rt-PA 0.9 mg/kg and were compared with six patients who did not. Patients receiving rt-PA were initially imaged (T1) 3 to 5 hours postictus (mean, 4 hours 20 minutes) whereas those not treated with tissue plasminogen activator (tPA) were imaged 4 to 7 hours postictus (mean, 5 hours, 25 minutes). Follow-up imaging was performed 3 to 6 hours (T2), 24 to 36 hours (T3), 5 to 7 days (T4), and 30 days (T5) after the first scan in all patients. Lesion volumes were measured on both DWI and time-to-peak maps constructed from PW images. RESULTS: PWI was performed successfully at T1 and T3 in 11 of 12 patients. In the group that received i.v. tPA, initial PWI volumes were less than DWI volumes in five of six patients (83%), whereas only one of five patients (20%) not receiving tPA had PWI < DWI volume (p = 0.08). PWI normalized by 24 to 36 hours (T3) in 6 of 11 patients (early reperfusers), with 5 of 6 of these early reperfusers having received tPA. The aggregate apparent diffusion coefficient (ADC) values for the early reperfusers were consistently higher at T2 (p = 0.04), T3 (p = 0.002), and T4 (p = 0.0005). Five of six patients with early reperfusion demonstrated regions of elevated ADC within the ischemic zone (mean ipsilateral ADC/contralateral ADC, 1.46 +/- 0.19) by 24 to 36 hours, whereas none of the nonearly reperfusers showed these regions of elevated ADC (p = 0.015). CONCLUSION: Early reperfusion is seen more frequently with i.v. tPA therapy. In addition, the study showed that ADC may undergo early increases that are tied closely to reperfusion, and marked ADC heterogeneity may exist within the same lesion. Early reperfusion is seen more frequently with i.v. tPA therapy.     

Penumbra detection using PWI/DWI mismatch MRI in a rat stroke model with and without comorbidity: comparison of methods

Perfusion-diffusion (perfusion-weighted imaging (PWI)/diffusion-weighted imaging (DWI)) mismatch is used to identify penumbra in acute stroke. However, limitations in penumbra detection with mismatch are recognized, with a lack of consensus on thresholds, quantification and validation of mismatch. We determined perfusion and diffusion thresholds from final infarct in the clinically relevant spontaneously hypertensive stroke-prone (SHRSP) rat and its normotensive control strain, Wistar-Kyoto (WKY) and compared three methods for penumbra calculation. After permanent middle cerebral artery occlusion (MCAO) (WKY n=12, SHRSP n=15), diffusion-weighted (DWI) and perfusion-weighted (PWI) images were obtained for 4 hours post stroke and final infarct determined at 24 hours on T₂ scans. The PWI/DWI mismatch was calculated from volumetric assessment (perfusion deficit volume minus apparent diffusion coefficient (ADC)-defined lesion volume) or spatial assessment of mismatch area on each coronal slice. The ADC-derived lesion growth provided the third, retrospective measure of penumbra. At 1 hour after MCAO, volumetric mismatch detected smaller volumes of penumbra in both strains (SHRSP: 31±50 mm³, WKY: 22±59 mm³, mean±s.d.) compared with spatial assessment (SHRSP: 36±15 mm³, WKY: 43±43 mm³) and ADC lesion expansion (SHRSP: 41±45 mm³, WKY: 65±41 mm³), although these differences were not statistically significant. Spatial assessment appears most informative, using both diffusion and perfusion data, eliminating the influence of negative mismatch and allowing the anatomical location of penumbra to be assessed at given time points after stroke.     

Deleterious effect of hyperoxia at birth on white matter damage in the newborn rat

White matter damage (WMD) remains the leading cause of cerebral palsy in children born prematurely. The release of an excessive amount of reactive oxygen species is recognized as a risk factor for WMD. We hypothesize that free radical injury during reoxygenation at birth may be harmful to the immature white matter and may underlie, at least in part, the pathogenesis of WMD. We tested this hypothesis in rat pups delivered from normoxic pregnant rats, and by investigating an animal model based on protracted antenatal hypoxia in the pregnant rat and mimicking the main features of human WMD in rat pups. From embryonic day (E)5 to E21, the pregnant rats were placed in a chamber supplied with a gas mixture that either induced hypoxia (FiO(2) = 10%) or maintained normoxia (FiO(2) = 21%). On E21, the dams were removed from the chamber and housed under either normoxia (FiO(2) = 21%), hyperoxia (FiO(2) = 60%) or slowly reoxygenated (FiO(2) from 15% at E21 to 21% at postnatal day 7). Postnatal hyperoxia was associated with a significantly increased density of activated microglial cells (+105%) and TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling)-positive cells (+85%) within the developing white matter. Myelin content (-31%) and mature oligodendrocyte density (-37%) in the normal developing white matter were significantly decreased by postnatal hyperoxia. Postnatal hyperoxia significantly potentiated the myelination delay and oligodendroglial dysmaturation induced by antenatal hypoxia. In contrast, progressive reoxygenation at birth did not induce any change in white matter inflammation, myelination and cell death as compared with normoxic controls, and prevented most of the WMD observed following antenatal hypoxia. This study demonstrates a deleterious effect of hyperoxia at birth on the developing white matter in normal rat pups. Postnatal hyperoxia worsened the WMD induced by antenatal hypoxia. Hyperoxia at birth should be avoided in preterm infants at risk of WMD.     

Clinical and radiological correlates of reduced cerebral blood flow measured using magnetic resonance imaging

BACKGROUND: Methods for determining cerebral blood flow (CBF) using bolus-tracking magnetic resonance imaging (MRI) have recently become available. Reduced apparent diffusion coefficient (ADC) values of brain tissue are associated with reductions in regional CBF in animal stroke models. OBJECTIVES: To determine the clinical and radiological features of patients with severe reductions in CBF on MRI and to analyze the relationship between reduced CBF and ADCs in acute ischemic stroke. DESIGN: Case series. SETTING: Referral center. METHODS: We studied 17 patients with nonlacunar acute ischemic stroke in whom perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) were performed within 7 hours of symptom onset. A PWI-DWI mismatch of more than 20% was required. We compared patients with ischemic lesions that had CBF of less than 50% relative to the contralateral hemisphere with patients with lesions that had relative CBF greater than 50%. Characteristics analyzed included age, time to MRI, baseline National Institutes of Health Stroke Scale score, mean ADC, DWI and PWI lesion volumes, and 1-month Barthel Index score. RESULTS: Patients with low CBF (n = 5) had lower ADC values (median, 430 x 10 (-6) mm(2)/s vs. 506 x 10 (-6) mm(2)/s; P =.04), larger DWI volumes (median, 41.8 cm(3) vs. 14.5 cm(3); P =.001) and larger PWI lesions as defined by the mean transit time volume (median, 194.6 cm(3) vs. 69.3 cm(3); P =.01), and more severe baseline National Institutes of Health Stroke Scale scores (median, 15 vs. 9; P =.02). CONCLUSION: Ischemic lesions with severe CBF reductions, measured using bolus-tracking MRI, are associated with lower mean ADCs, larger DWI and PWI volumes, and higher National Institutes of Health Stroke Scale scores.     

Effects of intravenous dimethyl sulfoxide on ischemia evolution in a rat permanent occlusion model.

Dimethyl sulfoxide (DMSO) has a variety of biological actions that suggest efficacy as a neuroprotectant. We (1) tested the neuroprotective potential of DMSO at different time windows on infarct size using 2,3,5-triphenyltetrazolium staining and (2) investigated the effects of DMSO on ischemia evolution using quantitative diffusion and perfusion imaging in a permanent middle cerebral artery occlusion (MCAO) model in rats. In experiment 1, DMSO treatment (1.5 g/kg intravenously over 3 h) reduced infarct volume 24 h after MCAO by 65% (P<0.00001) when initiated 20 h before MCAO, by 44% (P=0.0006) when initiated 1 h after MCAO, and by 17% (P=0.11) when started 2 h after MCAO. Significant infarct reduction was also observed after a 3-day survival in animals treated 1 h after MCAO (P=0.005). In experiment 2, treatment was initiated 1 h after MCAO and maps for cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) were acquired before treatment and then every 30 mins up to 4 h. Cerebral blood flow characteristics and CBF-derived lesion volumes did not differ between treated and untreated animals, whereas the ADC-derived lesion volume essentially stopped progressing during DMSO treatment, resulting in a persistent diffusion/perfusion mismatch. This effect was mainly observed in the cortex. Our data suggest that DMSO represents an interesting candidate for acute stroke treatment.     

Clinical and imaging predictors of intracerebral haemorrhage in stroke patients treated with intravenous tissue plasminogen activator

OBJECTIVE: To evaluate clinical, biological, and pretreatment imaging variables for predictors of tissue plasminogen activator (tPA) related intracerebral haemorrhage (ICH) in stroke patients. METHODS: 48 consecutive patients with hemispheric stroke were given intravenous tPA within seven hours of symptom onset, after computed tomography (CT) and magnetic resonance imaging (MRI) of the brain. Baseline diffusion weighted (DWI) and perfusion weighted (PWI) imaging volumes, time to peak, mean transit time, regional cerebral blood flow index, and regional cerebral blood volume were evaluated. The distribution of apparent diffusion coefficient (ADC) values was determined within each DWI lesion. RESULTS: The symptomatic ICH rate was 8.3% (four of 48); the rate for any ICH was 43.8% (21 of 48). Univariate analysis showed that age, weight, history of hyperlipidaemia, baseline NIHSS score, glucose level, red blood cell count, and lacunar state on MRI were associated with ICH. However, mean 24 hour systolic blood pressure and a hyperdense artery sign on pretreatment CT were the only independent predictors of ICH. Patients with a hyperdense artery sign had larger pretreatment PWI and DWI lesion volumes and a higher NIHSS score. Analysis of the distribution of ADC values within DWI lesions showed that a greater percentage of pixels had lower ADCs (< 400 x 10(-6) mm(2)/s) in patients who experienced ICH than in those who did not. CONCLUSION: Key clinical and biological variables, pretreatment CT signs, and MRI indices are associated with tPA related intracerebral haemorrhage.     

Normobaric hyperoxia retards the evolution of ischemic brain tissue toward infarction in a rat model of transient focal cerebral ischemia

Objectives: Oxygen therapy has been long considered a logical therapy for ischemic stroke. Our previous studies showed that normobaric hyperoxia (normobaric hyperoxia (NBO), 95% O₂ with 5% CO₂) treatment during ischemia reduced ischemic neuronal death and cerebromicrovascular injury in animal stroke models. In this study, we studied the effects of NBO on the evolution of ischemic brain tissue to infarction in a rat model of transient focal cerebral ischemia.

Methods: Male Sprague-Dawley rats were given NBO (95% O₂) or normoxia (21% O₂) during 90-min filament occlusion of the middle cerebral artery (MCAO), followed by 3 or 22.5 h of reperfusion. 2,3,5-triphenyltetrazolium chloride (TTC) staining was used to evaluate the longitudinal evolution of tissue infarction.

Results： In normoxic rats, MCA-supplied cortical and striatal tissue was infarcted after 90-min MCAO with 22.5 h of reperfusion. NBO-treated rats showed a 61.4% reduction in infarct size and tissue infarction mainly occurred in the ischemic striatum. When infarction was assessed at an earlier time point, i.e. at 3 h of reperfusion, normoxic rats showed significantly smaller but mature infarction (no TTC staining, white color), with the infarction mainly occurring in the striatum. Unexpectedly, NBO-treated rats only showed immature lesion (partially stained by TTC, light white color) in the ischemic striatum, indicating that NBO treatment also retarded the process of neuronal death in the ischemic core. Of note, NBO-preserved striatal tissue underwent infarction after prolonged reperfusion.

Conclusions： Our results demonstrate that NBO treatment given during cerebral ischemia retards the evolution of ischemic brain tissue toward infarction and NBO-preserved cortical tissue survives better than NBO-preserved striatal tissue during the phase of reperfusion.     

表观弥散系数对确定急性缺血性卒中缺血半暗带的潜在价值

目的 探讨表观弥散系数（apparent diffusion coefficient,ADC）对确定急性缺血性卒中缺血半暗带的潜在价值。 方法 选择发病9 h内完成多模式磁共振成像（magnetic resonance imaging,MRI）检查的前循环急性缺血性卒中患者49例。应用自制软件进行灌注加权像（perfusion-weighted imaging,PWI）和弥散加权像（diffusion-weighted imaging,DWI）异常区域的体积测量。缺血半暗带以PWI/DWI错配表示。同时采用全自动图像分析系统,以DWI图像计算得到的ADC图作为输入数据,来判断缺血半暗带的存在（以下简称为ADC方法）,然后比较这两种方法在判断缺血半暗带方面的差异。 结果 入选的49例患者中,存在PWI/DWI错配者为43例,符合ADC方法判断缺血半暗带标准者有41例。这两种方法在判断是否存在缺血半暗带的结果中有41例相符,对判断缺血半暗带的差异无统计学意义（P>0.05）。ADC方法判断缺血半暗带的敏感度为88.4%、特异度为50.0%。 结论 由于不需做PWI检查,ADC方法对确定缺血半暗带具有潜在的临床实用价值,有可能成为一种简便易行的确定缺血半暗带的方法。     

Spectacular shrinking deficit: insights from multimodal magnetic resonance imaging after embolic middle cerebral artery occlusion in Sprague-Dawley rats.

Almost no data is available on the serial changes in the brain after spectacular shrinking deficit (SSD) that may help understand this relatively rare clinical phenomenon. Quantitative diffusion-(DWI), perfusion-(PWI), T(1)-(T1WI), T(2)-weighted (T2WI), and functional magnetic resonance imaging (fMRI) were performed before, during, and up to 7 days after embolic middle cerebral artery occlusion (eMCAO) in male Sprague-Dawley rats (n=9). Region of interest (ROI) analysis was used to evaluate structural and functional MR signal changes within three ROIs defined by the apparent diffusion coefficient (ADC), cerebral blood flow (CBF) signatures, and final tissue viability. DWI, PWI, and T2WI lesion volumes were calculated using previously established viability thresholds and final infarct volumes ascertained with 2,3,5-triphenyltetrazolium chloride (TTC) staining. Serial MRI demonstrated spontaneous reperfusion of initially hypoperfused MCA regions accompanied by substantial reduction of initial ADC and CBF lesions and gradual recovery of neurological outcome. Recovery rates of CBF/ADC abnormalities differed among ROIs. Functional magnetic resonance imaging showed persistent tissue dysfunction after the recovery of the CBF/ADC lesions. This study may facilitate our understanding of the pathophysiological mechanisms by which early, spontaneous reperfusion affects tissue fate and neurological function.     

Progesterone administration during reperfusion, but not preischemia alone, reduces injury in ovariectomized rats.

Although progesterone is neuroprotective in traumatic brain injury, its efficacy in stroke is unclear. The authors determined whether there are infarction differences after middle cerebral artery occlusion (MCAO) in ovariectomized rats treated acutely with progesterone before MCAO or both pre- and postischemia. Rats received vehicle, 5 (P5), 10 (P10), or 20 (P20) mg/kg progesterone intraperitoneally 30 minutes before MCAO. In another cohort, animals received vehicle or 5 (P5R) mg/kg progesterone intraperitoneally 30 minutes before MCAO, at reperfusion initiation, and at 6-hour reperfusion. Animals underwent 2-hour MCAO by the intraluminal filament technique, followed by 22-hour reperfusion. Cortical (CTX) and caudate-putamen (CP) infarctions were determined by 2,3,5-triphenyltetrazolium chloride staining and digital image analysis. End-ischemic and early reperfusion regional cerebral blood flow (CBF) was measured by [ C]-iodoantipyrine quantitative autoradiography in vehicle- or progesterone (5 mg/kg)-treated rats. Cortical infarction (% contralateral CTX) was 31 +/- 30% (vehicle), 39 +/- 23% (P5), 41 +/- 14% (P10), and 28 +/- 20% (P20). Caudate-putamen infarction (% contralateral CP) was 45 +/- 37% (vehicle), 62 +/- 34% (P5), 75 +/- 17% (P10), and 52 +/- 30% (P20). In vehicle and P5R groups, CTX infarction was 37 +/- 20% and *20 +/- 17%, respectively (* < 0.05 from vehicle). In vehicle and P5R groups, CP infarction was 63 +/- 26% and 43 +/- 29%, respectively. End-ischemic regional CBF and CBF recovery during initial reperfusion was unaffected by progesterone treatment. These data suggest that progesterone administration both before MCAO and during reperfusion decreases ischemic brain injury.     

Diffusion- and perfusion-weighted MRI. The DWI/PWI mismatch region in acute stroke.

BACKGROUND AND PURPOSE: Diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) are relatively new MR techniques increasingly used in acute stroke. During the first hours of stroke evolution, the regions with abnormal perfusion are typically larger than the DWI lesions, and this mismatch region has been suggested to be "tissue at risk." The aim of this study was to evaluate the PWI/DWI mismatch region in acute stroke patients and find parameters indicative of both infarct progression and functional impairment. METHODS: Twenty patients with nonlacunar ischemic stroke were imaged with DWI, PWI, and conventional MRI within 24 hours of symptom onset and after 1 week; in addition, the European Stroke Scale (ESS) score was recorded. With PWI, the volumes of regions with "time-to-peak" (TTP) delays of >/=2, 4, 6, 8, and 10 seconds were measured; these volumes were compared with the acute DWI lesion volumes, final infarct size, and ESS score. RESULTS: In 80% of patients the acute DWI lesion was surrounded by regions with abnormal TTP delays (PWI>DWI lesion). A TTP delay of >/=6 s in the mismatch region was found to be associated with lesion enlargement between the initial and follow-up MRI scans. Lesions increased in 9 of 12 patients (75%) in whom the area with TTP delay >/=6 s was larger than the DWI lesion, but they increased in only 1 of 8 (12.5%) of the remaining patients, in whom the area with a TTP delay >/=6 s was smaller than the DWI lesion. The volume of the regions with TTP delays of >/=4 s correlated better with ESS (r=-0.88, P<0.001) than other PWI (or DWI) volumes, which indicated that a TTP delay of approximately 4 s might be the threshold for functional impairment of brain tissue. CONCLUSIONS: Only patients with severe perfusion deficits in the PWI/DWI mismatch (TTP delays of >/=6 s) are at high risk of lesion enlargement. Functionally, more moderate perfusion deficits (TTP delays >/=4 and <6 s) appear to also contribute to the acute clinical deficit.     

Longitudinal magnetic resonance imaging study of perfusion and diffusion in stroke: evolution of lesion volume and correlation with clinical outcome.

A prospective longitudinal diffusion-weighted and perfusion-weighted magnetic resonance imaging (DWI/PWI) study of stroke patients (n = 21) at five distinct time points was performed to evaluate lesion evolution and to assess whether DWI and PWI can accurately and objectively demonstrate the degree of ischemia-induced deficits within hours after stroke onset. Patients were scanned first within 7 hours of symptom onset and then subsequently at 3 to 6 hours, 24 to 36 hours, 5 to 7 days, and 30 days after the initial scan. Lesion evolution was dynamic during the first month after stroke. Most patients (18 of 19, 95%) showed increased lesion volume over the first week and then decreased at 1 month relative to 1 week (12 of 14, 86%). Overall, lesion growth appeared to depend on the degree of mismatch between diffusion and perfusion at the initial scan. Abnormal volumes on the acute DWI and PWI (<7 hours) correlated well with initial National Institutes of Health (NIH) stroke scale scores, outcome NIH stroke scale scores, and final lesion volume. DWI and PWI can provide an early measure of metabolic and hemodynamic insufficiency, and thus can improve our understanding of the evolution and outcome after acute ischemic stroke.     

Effects of combined estrogen and progesterone on brain infarction in reproductively senescent female rats.

Recent data from the Women's Health Initiative have highlighted many fundamental issues about the utility and safety of long-term estrogen use in women. Current hormone replacement therapy for postmenopausal women incorporates progestin with estrogen, but it is uncertain if combined therapy provides major cerebrovascular risks or benefits to these women. No experimental animal stroke studies have examined combined hormone administration. The authors tested the hypothesis that combined hormone treatment reduces ischemic injury in middle-aged female rat brain. Reproductively senescent female rats underwent 2-hour middle cerebral artery occlusion (MCAO) followed by 22 hours reperfusion. Estrogen implants were placed subcutaneously at least 7 days before MCAO, and progesterone intraperitoneal injections were given 30 minutes before MCAO, at initiation, and at 6 hours of reperfusion. Rats received no hormone, a 25-microg estrogen implant, a 25-microg estrogen implant plus 5 mg/kg intraperitoneal progesterone, or 5 mg/kg intraperitoneal progesterone. Cortical, caudoputamen, and total infarct volumes were assessed by 2,3,5-triphenyltetrazolium chloride staining and digital image analysis at 22 hours reperfusion. Cortical and total infarct volumes, except in the acute progesterone-treated group, were significantly attenuated in all estrogen-alone and combined hormone-treated groups. There were no significant differences in caudoputamen infarct volumes in all hormone-treated groups as compared with untreated rats. These data have potential clinical implications relative to stroke for postmenopausal women taking combined hormone replacement therapy.     

Assessing the outcome of stroke: a comparison between MRI and clinical stroke scales

OBJECTIVES: To assess the correlation of diffusion-weighted (DWI) and perfusion-weighted imaging (PWI) findings with the severity of acute neurologic deficit and their ability to predict short and long-term clinical outcomes of stroke. The ability of DWI and PWI to predict the outcome was compared with the ability of clinical stroke scales to predict the outcome. METHODS: Forty-eight patients with acute stroke underwent diffusion DWI and PWI on the first and eighth day after the ictus. Clinical and functional scales were carried out before each scan and 3 months after the stroke. RESULTS: The volumes of both the DWI and the PWI lesions correlated well with the acute neurologic deficit and the final outcome. The first day PWI (r = 0.64) and the National Institutes of Health Stroke Scale (NIHSS) scores (r = 0.70) correlated well with the final outcome. However, in logistic regression analysis, only the NIHSS score at the acute stage was the only independent predictor of the long-term clinical outcome. CONCLUSION: While the PWI and DWI lesion volumes correlated well with the outcome of the stroke, the imaging measurements did not improve the prognostic power over plain clinical stroke scale scores.