Rapid MR imaging of a vascular challenge to focal ischemia in cat brain

Deoxygenated blood was effectively used as a magnetic resonance (MR) susceptibility contrast agent to distinguish perfused and nonperfused (ischemic) regions in a focal ischemia model in cat brain at 2 T. Modulation of cerebral blood oxygenation levels in response to apnea was followed in real time with T2*-weighted (gradient-recalled) echo-planar MR imaging. Signal loss in the T2*-weighted images occurred only in perfused tissues as blood became globally deoxygenated. These data complemented information from diffusion-weighted and contrast agent bolus–-tracking images. In addition, observation of the signal recovery behavior on reventilation in both normal and ischemic brain offered potentially useful information about the state of the cerebral autoregulatory mechanism.     

Dynamic changes of ADC, perfusion, and NMR relaxation parameters in transient focal ischemia of rat brain.

The potential of multiparametric MRI parameters for differentiating between reversibly and irreversibly damaged brain tissue was investigated in an experimental model of focal brain ischemia in the rat. The middle cerebral artery (MCA) was occluded by intraluminal suture insertion for 60 or 90 min, followed by 4.5 h of reperfusion. The apparent diffusion coefficient (ADC) of brain water, T(1) and T(2) relaxation times, and CBF(i), an MR-derived index of cerebral perfusion, were repeatedly measured and correlated with the outcome from the ischemic impact. A novel user-independent approach for segmentation of ADC maps into classes of increasing injury was introduced to define regions of interest (ROIs) in which these parameters were evaluated. MCA occlusion led to a graded decline of ADC, which corresponded with both the severity of flow reduction and an increase in T(1) and T(2) relaxation times. Removal of the suture led to a triphasic restitution of blood flow consisting of a fast initial rise, a secondary decline, and final normalization. Postischemic reperfusion led to a rise of ADC irrespective of the duration of ischemia. However, the quality of recovery declined with increasing severity of the ischemic impact. Throughout the observation time, T(1) and T(2) showed a continuous increase, the intensity of which correlated with the severity of ADC decline during ischemia. Particularly with longer ischemia time, elevated T(2) in combination with reduced ADC yielded a lower probability of recovery during recirculation, while intraischemic perfusion information contributed less to the prediction of outcome. In conclusion, the combination of MR parameters at the end of ischemia correlated with the probability of tissue recovery but did not permit reliable differentiation between reversibly and irreversibly damaged tissue.     

Changes in metabolites and tissue water status after focal ischemia in cat brain assessed with localized proton MR spectroscopy

Localized proton spectroscopy was used to monitor changes in metabolism and the biophysical status of tissue water in cat brain induced by occlusion of the middle cerebral artery. Changes in the intensity of N-acetyl-aspartate (NAA), total creatine (tCr), and lactate (Lac) signals in localized volumes of interest in the ischemic hemisphere were quantified relative to the preischemic signal. Changes in the apparent diffusion coefficient (ADC), T₁- and T₂-relaxation times of water in those volumes were also quantified. Lactate was shown to increase rapidly in the first 0.5?2.0 h of ischemia and stabilized afterwards. The ADC of water started to decrease from 0.64 × 10^?9 m2/s to 0.54 × 10^?9 m2/s in the first minutes following occlusion, as was shown in two cases where ADC was measured with high temporal resolution, and stabilized after approximately 3 h at 0.38 × 10^?9 m2/s (n = 6). NAA and tCr decreased by 35% (P< 0.0001) and 30% (P< 0.005), respectively, in the first 8 h of ischemia in comparison with the preischemic control levels. T₁ and T₂ gradually increased with 0.3 s (P< 0.0001) and 5.2 ms (P< 0.0001), respectively, during the same time span.     

Neuroprotective effects of an immunosuppressant agent on diffusion/perfusion mismatch in transient focal ischemia.

The immunosuppressant FK506 (tacrolimus) exerts potent neuroprotection following focal ischemia in animals; however, the separate effects of FK506 on the ischemic core and penumbra have not been reported. The ischemic penumbra is clinically defined as the difference between a large abnormal area on perfusion-weighted imaging (PWI) and a smaller lesion on diffusion-weighted imaging (DWI). The goal of this study was to determine the effect of FK506 on DWI/PWI match and mismatch areas in transient focal ischemia in rats. Twelve rats were subjected to 1 hr of transient middle cerebral artery (MCA) occlusion, and given an intravenous injection of a placebo (N = 6) or 1 mg/kg FK506 (N = 6) immediately before reperfusion. Magnetic resonance imaging (MRI) was performed during MCA occlusion, and 0.5, 1, and 24 hr after reperfusion. FK506 significantly protected the ischemic brain only in the mismatch cortex where the initial apparent diffusion coefficient (ADC) was normal and there was a mild reduction of cerebral blood flow (CBF). This is the first report to describe the protective effects of FK506 on ischemic penumbra, as measured by DWI/PWI mismatch. The findings provide direct evidence for the utility of DWI/PWI mismatch as a guideline for therapeutic intervention with FK506.     

Serial triple quantum sodium MRI during non-human primate focal brain ischemia.

Triple quantum (TQ) sodium MRI techniques with clinically acceptable 18-min data acquisition times were demonstrated in vivo in a nonhuman primate model of focal brain ischemia. Focal brain ischemia was induced in four animals using embolization coils to occlude the posterior cerebral artery, and a balloon catheter to occlude the middle cerebral artery. A statistically significant increase (P < 0.001) in the TQ sodium MRI signal intensity in the ischemic hemisphere relative to the contralateral hemisphere was seen at all time points in all four animals. This increased TQ sodium MRI signal intensity was demonstrated as early as 0.6 hr after the onset of ischemia. The TQ sodium MRI hyperintensity corresponded to the anatomical location of the ischemic cortex, as indicated by the registration of the TQ imaging data with anatomical proton MRI data. The results demonstrate that early after the onset of ischemia, there was an increase in the TQ signal intensity in the ischemic hemisphere, and a negligible change in the single quantum (SQ) signal intensity.     

Interleukin-1 exacerbates focal cerebral ischemia and reduces ischemic brain temperature in the rat.

The proinflammatory cytokine interleukin-1 (IL-1) is a key mediator of inflammation in cerebral ischemia, but its precise mechanisms of action remain elusive. Temperature is critical to outcome in brain injury and given the importance of IL-1 in pyrogenesis this has clear mechanistic implications. IL-1 exacerbates ischemia independently of core (rectal) temperature. However, it is temperature in the ischemic brain that influences outcome and rectal temperature is likely to be a poor surrogate marker. This study tested the hypothesis that IL-1 exacerbates cerebral ischemia by increasing ischemic brain temperature. Wistar rats undergoing transient middle cerebral artery occlusion received either 4 microg/kg IL-1 (n=9) or vehicle (n=10) intraperitoneally. NMR-generated maps of brain temperature, tissue perfusion, and the trace of the diffusion tensor were collected during occlusion, early reperfusion, and at 24 hr. IL-1 significantly increased ischemic damage at 24 hr by 35% but rectal temperature did not vary significantly between groups. However, ischemic brain was 1.7 degrees C cooler on reperfusion in IL-1-treated animals (vs. vehicle) and a corresponding reduction in cerebral blood flow was identified in the ischemic striatum. Contrary to the stated hypothesis, IL-1 reduced ischemic brain temperature during reperfusion and this may be due to a reduction in tissue perfusion.     

Radiologic manifestations of focal cerebral hyperemia in acute stroke

In 16 acute stroke patients with focal cerebral hyperemia angiography and regional cerebral blood flow (rCBF) were studied 1 to 4 days post stroke. CT was performed twice with and without contrast enhancement 3 +/- 1 days and 16 +/- 4 days post stroke. Angiographic evidence of focal cerebral hyperemia was seen in 8 patients in the form of early filling veins. In 5 of these the hyperemic areas were located within infarcted areas and in 3 patients in areas which appeared normal on CT. In the remaining 8 patients the hyperemias were located perifocally around ischemic infarcts. Early filling veins were not seen in this type of hyperemia. The blood flow was higher and the transit time of the contrast medium was faster in the former type of hyperemia probably because of arteriovenous shunting. Contrast enhancement was not observed on the early CT but was typically seen in the infarcts on the late CT at a time when the hyperemic state is known to have vanished. It is concluded that focal cerebral hyperemia is not responsible for contrast enhancement on CT.     

短暂性脑缺血发作患者SPECT脑显像的研究

目的:探讨SPECT脑血流灌注显像评估短暂性脑缺血发作(TIA)进展为脑梗死的临床应用价值。方法:对97例颈内动脉系统TIA患者发病72h内进行SPECT脑血流灌注显像及磁共振检查。对感兴趣区放射性计数进行半定量分析,按如下公式计算脑血流的不对称指数(AI):〔(正常区域放射性计数-感兴趣区放射性计数)/正常区域放射性计数〕×100。入组患者根据不对称指数分为轻度(AI≤5)、中度(510)组。发病6个月后对各组患者进行临床评估,分析低灌注程度与是否进展为脑梗死、发作持续时间、发作次数及卒中史之间的关系。结果:97例TIA患者,根据低灌注程度分为轻、中、重三组,三组间在是否进展为脑梗死、发作次数、发作持续时间、卒中史具有显著的统计学差异。进展为脑梗死患者在低灌注程度、发作次数、发作持续时间、卒中史上与未进展为脑梗死患者比较,差异有统计学意义。结论:SPECT脑血流灌注显像检查能观察TIA患者脑血流情况,可评估TIA预后。对于低灌注程度严重的患者,进展为脑梗死风险更大,应积极防治。     

Effects of blood sugar level on rat transient focal brain ischemia consecutively observed by diffusion-weighted EPI and (1)H echo planar spectroscopic imaging.

The effects of blood sugar level on transient focal brain ischemia were examined by consecutive diffusion-weighted EPI and (1)H echo planar spectroscopic imaging. A remote-controlled rat intraluminal suture middle cerebral artery occlusion (MCAO) model was prepared. Animals were divided into three experimental groups: control, 1 g/kg, and 2 g/kg glucose groups (n = 6 for each). Saline or glucose was infused intraperitoneally 30 min prior to MCAO. The glucose-loaded groups showed increased lactate accumulation and marked decreases in average diffusion coefficient in the ischemic region during 40-min MCAO. These changes were correlated with blood sugar levels at the onset of MCAO. After reperfusion, all rats in the control and 1 g/kg groups recovered from the ischemic changes, but three rats with marked hyperglycemia in the 2 g/kg group showed irreversible changes. The adverse effects of hyperglycemia on transient focal brain ischemia were clearly demonstrated by sequential 2D images. Magn Reson Med 42:895-902, 1999.     

Quantitation and localization of blood-to-brain influx by magnetic resonance imaging and quantitative autoradiography in a model of transient focal ischemia.

The ability of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) enhanced MRI to localize and quantitate blood-brain barrier (BBB) opening was evaluated against quantitative autoradiographic (QAR) imaging of (14)C-alpha-aminoisobutyric acid (AIB) distribution. The blood-to-brain transfer constant (K(i)) for Gd-DTPA was determined by MRI in rats after 3 h of focal cerebral ischemia plus 2.5 h of reperfusion (n = 9), and that of AIB was determined by QAR shortly thereafter. Tissue regions of interest (ROIs) for Gd-DTPA leakage were identified by ISODATA segmentation of pre- and post-Gd-DTPA Look-Locker (L-L) T(1) maps. Patlak plots were constructed using time course of blood and tissue T(1) changes induced by Gd for estimating K(i). Among the nine rats, 14 sizable regions of AIB uptake were found; 13 were also identified by ISODATA segmentation. Although the 13 MRI-ROIs spatially approximated those of AIB uptake, the segmentation sometimes missed small areas of lesser AIB uptake that did not extend through more than 60% of the 2.0-mm-thick slice. Mean K(i)'s of AIB were highly correlated with those of Gd-DTPA across the 13 regions; the group means (+/-SD) were similar for the two tracers (7.1 +/- 3.3 x 10(-3) and 6.8 +/- 3.5 x 10(-3) ml.g(-1) . min(-1), respectively). In most instances, Gd-DTPA MRI accurately localized areas of BBB opening.     

携带人肝细胞生长因子基因的重组腺病毒对大鼠局灶性脑缺血治疗的实验研究

目的 :观察携带人肝细胞生长因子基因的重组腺病毒 (Ad_HGF)对大鼠局灶性脑缺血的治疗作用。方法 :建立大鼠局灶性脑缺血动物模型。携带人肝细胞生长因子基因的穿梭质粒与携带复制缺陷的人血清 5型腺病毒基因组的质粒在 2 93细胞进行同源重组 ,构建Ad_HGF。携带绿色荧光蛋白基因的重组腺病毒 (Ad_GFP)载体注射到局灶性缺血大鼠的缺血侧侧脑室 ,观察其在脑内的表达部位和持续时间。动物给药治疗后 3d ,取大脑 ,平均切成 4片 ,用TTC染色评价Ad_HGF对缺血的治疗效果。结果 :Ad_GFP仅在大鼠双侧侧脑室壁及脑室内的脉络膜细胞表达 ,表达持续两周左右 ;Ad_HGF治疗组动物大脑缺血区明显小于非治疗组动物 (P <0 .0 5 )。结论 :Ad_HGF能显著缩小大鼠局灶性脑缺血区。     

Human focal cerebral ischemia: evaluation of brain pH and energy metabolism with P-31 NMR spectroscopy.

The authors investigated early human focal ischemia with phosphorus-31 nuclear magnetic resonance spectroscopy at 1.89 T to characterize the temporal evolution and relationship of brain pH and phosphate energy metabolism. Data from 65 symptomatic patients were prospectively studied; none of the patients had had ischemic stroke in the internal carotid artery territory before. Twenty-eight neurologically normal individuals served as control subjects. Serial ischemic brain pH levels indicated a progression from early acidosis to subacute alkalosis. When acidosis was present there was a significant elevation in the relative signal intensity of inorganic phosphate (Pi) and significant reductions in signal intensities of alpha-adenosine triphosphate (ATP) and gamma-ATP compared with those of control subjects. Ischemic brain pH values directly correlated with the relative signal intensity of phosphocreatine (PCr) and the PCr index and inversely correlated with the signal intensity of Pi. There was a general lack of correlation between either ischemic brain pH or phosphate energy metabolism and the initial clinical stroke severity. The data suggest a link between high-energy phosphate metabolism and brain pH, especially during the period of ischemic brain acidosis, and the authors propose that effective acute stroke therapy should be instituted during this period.     

Rapid monitoring of changes in water diffusion coefficients during reversible ischemia in cat and rat brain

Changes in the diffusion constant of water during reversible brain ischemia and cardiac arrest were monitored with a 10-s time resolution. Results (five cats, three rats) indicate that these changes are reversible and that the bulk of the changes are not caused by temperature or motion related to brain pulsations and blood flow. The rapid time course of the changes corresponds to the known time course for changes in energy state, signal transduction, and ionic homeostasis.     

Demonstration of focal hyperemia in acute cerebral infarction with iodine-123 iodoamphetamine

Focal hyperemia is known to occur in regions of acute cerebral infarction. Presented here are two cases in which SPECT images with 125I-labeled iodoamphetamine demonstrated focal areas of increased tracer concentration associated with cerebral infarction. These results may have important implications regarding the physiology of iodoamphetamine in cerebral infarction and, in particular, whether the distribution of this tracer is related to regional blood flow in this setting. In addition, interpretation of iodoamphetamine images in cerebral infarction should include consideration of this finding.     

Separating changes in the intra- and extracellular water apparent diffusion coefficient following focal cerebral ischemia in the rat brain.

Selective intracellular (IC) and extracellular (EC) brain water apparent diffusion coefficient (ADC) values were measured in normal and ischemic rat brain. Selective T(1)-relaxation enhancement of the EC water, using intracerebroventricular (ICV) infusion of an NMR contrast reagent (CR), was used to separate the IC and EC signal contributions. In the CR-infused, normal brain (n = 4), T(1) = 235 +/- 10 ms and T(2) = 46 +/- 2 ms for IC water (85%) and T(1) = 48 +/- 8 ms and T(2) = 6 +/- 2 ms for EC water (15%). Volume-localized ADC(z) (z-gradient axis) values were 0.90 +/- 0.02 (EC+IC), 0.81 +/- 0.05 (IC), 0.51 +/- 0.02 (EC+IC), and 0.53 +/- 0.07 (IC), for normal, CR-infused, ischemic, and ischemic/CR-infused groups, respectively (ADC values are x10(-3) mm(2)/s; n = 5 for each group). Imaging ADC(z) values were 0.81 +/- 0.03 (EC+IC), 0.75 +/- 0.05 (IC), 0.51 +/- 0.04 (EC+IC), and 0.52 +/- 0.05 (IC), respectively, for the same groups. Imaging ADC(av) (average diffusivity) values for the same groups were 0.70 +/- 0.05 (EC+IC), 0.69 +/- 0.06 (IC), 0.45 +/- 0.06 (EC+IC), and 0.44 +/- 0.06 (IC), respectively. These results suggest that the IC water ADC determines the overall water ADC value in normal and ischemic rat brain.     

Proton T2 relaxation of cerebral metabolites during transient global ischemia in rat brain

Putative changes of metabolite T₂ relaxation times were investigated before and after a 20-min period of global ischemia in rat brain in vivo (n= 10) using localized proton MRS at different echo times (2.35 T). Neither absolute T₂ relaxation times (TE = 20-270 ms) nor time courses of T₂-weighted metabolite signals (TE = 135 ms) revealed statistically significant changes during the occlusion or early reperfusion relative to pre-ischemic baseline. These findings are in line with reports of relaxation changes at much later stages and further demonstrate that altered T₂ relaxation is not a confounding factor in diffusion-weighted long-TE proton MRS during early ischemic events.     

Quantitative regional brain water measurement with magnetic resonance imaging in a focal ischemia model

Therapeutic approaches to cerebral edema require an understanding of both the magnitude and location of changes in brain water content. It is desirable to have a sensitive, accurate means of measuring brain water noninvasively so that effective therapies for cerebral edema in stroke, head trauma, and other conditions can be investigated. In this work, a three-dimensional magnetic resonance imaging technique that is able to provide both spin density and T₁ simultaneously is described. This method was used to quantitate regional changes in brain water content in a rat model of focal cerebral ischemia. Brain water contents estimated from both relative spin density and relative T₁ measurements made in vivo were compared with ex vivo measurements of relative tissue water content based on the wet-dry technique. Correlation coefficients of 0.95 and 0.98 were obtained between the wet-dry measurements and magnetic resonance measurements of T₁ and spin density, respectively. Notably, the slope of the relationship between T₁ and tissue water content changed dramatically after the injection of a paramagnetic contrast agent while precontrast and postcontrast spin density measurements remained essentially invariant. In addition, a plot of absolute spin density (obtained by normalizing spin density from agar gelatin phantoms of different water contents to the spin density of a sample of 100% water) was linearly related to wet-dry measurements with a slope of 0.99 (R² = 0.99).     

Neurotolerability of gadobenate dimeglumine in a rat model of focal brain ischemia: EEG evaluation

RATIONALE AND OBJECTIVES: The neurologic pathologies for which contrast-enhanced MRI is indicated are often accompanied by a disruption of the blood-brain barrier (BBB), which allows the contrast agent to come into contact with the nervous tissue. Thus, assessment of the neurologic safety for a new contrast agent is of crucial importance. The objective of this study was to assess the neurotolerability of the new MRI contrast agent gadobenate dimeglumine using EEG in the presence of focal lesions of the BBB. METHODS: Lesions of the BBB were obtained inducing a photochemical ischemia in rats. Gadobenate dimeglumine was intravenously administered at 4.0 mmol/kg. An EEG was recorded during sleep/awake behavior and was analyzed for pathologic tracing and for changes in spectral content in terms of total power and frequency index. The presence of the BBB lesions was verified using high-performance liquid chromatography measurement of the gadobenate ion content in the brain. RESULTS: Gadobenate dimeglumine did not have any epileptogenic effect in ischemic rats. However, it caused a transitory shift of the EEG power spectrum toward the 0.5 to 9 Hz frequency bands of the lesioned hemisphere during quiet wake. In the lesioned cortex, higher levels of gadobenate ion were found until 3 hours after administration. CONCLUSIONS: In experimental conditions of focal brain ischemia associated with BBB lesions, gadobenate dimeglumine was well tolerated up to doses even 10 times higher than the maximum clinical dose (0.3 mmol/kg) intended for brain imaging procedures.