Delayed rt-PA treatment in a rat embolic stroke model: diagnosis and prognosis of ischemic injury and hemorrhagic transformation with magnetic resonance imaging.

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.     

Monteplase reduces infarct volume and hemorrhagic transformation in rat model of embolic stroke

Monteplase, a modified recombinant tissue plasminogen activator (rt-PA), has a long half-life and reduces binding to plasminogen activator inhibitor. In this study we investigated whether its systemic administration reduces infarct volume without increasing the risk of intra-cerebral hemorrhage. The effect of the drug was tested on an embolic stroke rat model that uses white clots. Thirty minutes after clot embolization, rats were infused with 2.2 mg kg(-1) of monteplase or the same amount of saline, over 60 min. Relative regional cerebral blood flow had recovered 60 min after monteplase administration and infarct volume was significantly smaller 24 h after clot embolization in the monteplase-treated rats (47.0 mm3) than in the saline-treated rats (130.4 mm3). Also, the hemorrhagic transformation area was significantly smaller in monteplase-treated rats (0.8 mm2 vs. 18.0 mm2, respectively). These results indicate monteplase can be a promising thrombolytic agent for treatment of the acute stage of cerebral ischemia.     

Magnetic resonance imaging and neurosphere therapy of stroke in rat

We intracisternally transplanted subventricular zone (SVZ) cells labeled by ferromagnetic particles into stroked rats. Migration of transplanted cells was non-invasively tracked using magnetic resonance imaging (MRI). We found that transplanted cells selectively migrated towards the ischemic parenchyma at a mean speed of 65 +/- 14.6 microm/hr in living rats. Migration of transplanted cells in the brain was also measured histopathologically. Rats transplanted with SVZ cells exhibited significant improvement of neurological function. Our data suggest that intracisternal transplantation of SVZ cells provides an avenue for cell therapy of stroke and that MRI can be used to track grafted cells in the brain.     

Magnetic resonance imaging indexes of therapeutic efficacy of recombinant tissue plasminogen activator treatment of rat at 1 and 4 hours after embolic stroke.

With use of magnetic resonance imaging (MRI), the effects of early and delayed treatment of embolic stroke in rat with recombinant tissue plasminogen activator (rt-PA) were investigated. Rats with embolic stroke were treated with rt-PA at 1 (n = 9) or 4 (n = 7) hours after stroke onset or were untreated (n = 15). Diffusion-weighted imaging, perfusion-weighted imaging, and T2-weighted imaging were performed before and after embolization from 1 hour to 7 days. No significant differences were detected in the relative areas with low cerebral blood flow (CBF), apparent diffusion coefficient of water (ADCw), and T2 between the 4-hour treated group and the untreated group. Significant decreases in the average relative areas with low CBF were detected in the 1-hour treated group from 4 to 48 hours after embolization as compared with the untreated group. The increase in T2 in the 1-hour treated group was significantly lower than in the untreated and 4-hour treated groups. A significant increase in ADCw was detected in the 1-hour treated group at 3 and 24 hours after embolization as compared with the untreated and 4-hour treated groups. Secondary embolization was detected by both MRI and laser scanning confocal microscopy. The data suggest that MRI can detect the efficacy of rt-PA treatment and secondary ischemic damage.     

Prediction of hemorrhagic transformation following acute stroke: role of diffusion- and perfusion-weighted magnetic resonance imaging

BACKGROUND: Acute diffusion-weighted (DWI) and perfusion-weighted (PWI) magnetic resonance imaging (MRI) findings may correlate with secondary hemorrhagic transformation (HT) risk in patients with stroke. This information could be of value, particularly in individuals being considered for thrombolytic therapy. OBJECTIVE: To determine the relationship between DWI and PWI findings and the risk of secondary HT in patients with acute stroke. DESIGN: Retrospective case series. SETTING: Academic medical center. PATIENTS: Twenty-seven patients with acute stroke capable of being evaluated with DWI/PWI 8 hours or less after symptom onset. MAIN OUTCOME MEASURES: Apparent diffusion coefficient values, perfusion delay measurements, and subsequent MRI or computed tomographic scans detected HT. RESULTS: The mean +/- SD apparent diffusion coefficient of ischemic regions that experienced HT was significantly lower than the overall mean +/- SD apparent diffusion coefficient of all ischemic areas analyzed (0.510 +/- 0.140 x 10(-3) mm(2)/s vs 623 +/- 0.113 x 10(-3) mm(2)/s; P =.004). This difference remained significant when comparing the HT-destined ischemic areas with the non-HT-destined areas within the same ischemic lesion (P =.02). Patients receiving recombinant tissue-type plasminogen activator (rt-PA) experienced HT significantly earlier than patients not receiving rt-PA (P =.002). Moreover, a persistent perfusion deficit in the area of subsequent hemorrhage at 3 to 6 hours after the initial MRI scan was identified in significantly more patients who experienced HT than in those who did not (83% vs 30%; P =.03). CONCLUSION: Both DWI and PWI scans detect abnormalities that are associated with HT. These findings support a role for MRI in identifying patients who are at increased risk for secondary HT following acute ischemic stroke.     

Cerebral tissue repair and atrophy after embolic stroke in rat: A magnetic resonance imaging study of erythropoietin therapy

Using magnetic resonance imaging (MRI) protocols of T₂‐, T₂*‐, diffusion‐ and susceptibility‐weighted imaging (T2WI, T2*WI, DWI, and SWI, respectively) with a 7T system, we tested the hypothesis that treatment of embolic stroke with erythropoietin (EPO) initiated at 24 hr and administered daily for 7 days after stroke onset has benefit in repairing ischemic cerebral tissue. Adult Wistar rats were subjected to embolic stroke by means of middle cerebral artery occlusion (MCAO) and were randomly assigned to a treatment (n = 11) or a control (n = 11) group. The treated group was given EPO intraperitoneally at a dose of 5,000 IU/kg daily for 7 days starting 24 hr after MCAO. Controls were given an equal volume of saline. MRI was performed at 24 hr and then weekly for 6 weeks. MRI and histological measurements were compared between groups. Serial T2WI demonstrated that expansion of the ipsilateral ventricle was significantly reduced in the EPO‐treated rats. The volume ratio of ipsilateral parenchymal tissue relative to the contralateral hemisphere was significantly increased after EPO treatment compared with control animals, indicating that EPO significantly reduces atrophy of the ipsilateral hemisphere, although no significant differences in ischemic lesion volume were observed between the two groups. Angiogenesis and white matter remodeling were significantly increased and occurred earlier in EPO‐treated animals than in the controls, as evident from T2*WI and diffusion anisotropy maps, respectively. These data indicate that EPO treatment initiated 24 hr poststroke promotes angiogenesis and axonal remodeling in the ischemic boundary, which may potentially reduce atrophy of the ipsilateral hemisphere. © 2010 Wiley‐Liss, Inc.     

Magnetic resonance imaging correlates of depression after ischemic stroke

BACKGROUND: Depression affects up to 40% of patients with ischemic stroke. The relationship between site and size of brain infarcts and poststroke depression is still not well characterized. Further possible contribution and interaction of white matter lesions and brain atrophy has not been studied previously. We conducted a magnetic resonance image-based study of the radiologic correlates of depression in a large, well-defined series of patients with ischemic stroke. METHODS: Modified DSM-III-R and DSM-IV criteria were used to diagnose depressive disorders during a comprehensive psychiatric evaluation in 275 of 486 consecutive patients aged 55 to 85 years 3 to 4 months after ischemic stroke. A standardized magnetic resonance imaging protocol detailed side, site, type, and extent of brain infarcts and extent of white matter lesions and brain atrophy. RESULTS: Depressive disorders were diagnosed in 109 patients (40%). Patients with depression had a higher number and larger volume of infarcts affecting the prefrontosubcortical circuits, especially the caudate, pallidum, and genu of internal capsule, with left-sided predominance. Extent of white matter lesions and atrophy did not differ in patients with and without depression. Independent correlates of poststroke depression in a logistic regression model were mean frequency of infarcts in the genu of internal capsule on the left side (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.0-10.1), mean frequency of infarcts in the pallidum of any side (OR, 1.6; 95% CI, 1.1-2.3), and mean volume of infarcts in the right occipital lobe (OR, 0.98; 95% CI, 0.96-0.99). CONCLUSION: Lesions affecting the prefrontosubcortical circuits, especially on the left side, are correlates of depression after ischemic stroke.     

Magnetic resonance imaging white matter hyperintensities and mechanism of ischemic stroke.

BACKGROUND AND PURPOSE: We sought to determine the relations between infarct subtype and white matter hyperintensities (WMHIs) on MRI. MATERIALS AND METHODS: We studied 395 ischemic stroke patients with 1. 0-T MRI. The number of lacunar, border-zone, and cortical infarcts was registered. WMHIs were analyzed in 6 areas. Univariate and multivariate statistical analyses were used to find the risk factors for different infarct subtypes and to study the connections between WMHIs and brain infarcts. RESULTS: Lacunar infarcts were associated with hypertension (odds ratio [OR], 1.79; 95% CI, 1.17 to 2.73), alcohol consumption (OR, 1.96; 95% CI, 1.17 to 3.28), and age (OR, 1. 03; 95% CI, 1.00 to 1.06). Border-zone infarcts were associated with carotid atherosclerosis (OR, 2.20; 95% CI, 1.15 to 4.19). Atrial fibrillation (OR, 3.02; 95% CI, 1.66 to 5.50) and carotid atherosclerosis (OR, 1.94; 95% CI, 1.12 to 3.36) were independent positive predictors, and history of hyperlipidemia (OR, 0.44; 95% CI, 0.26 to 0.75) and migraine (OR, 0.48; 95% CI, 0.25 to 0.93) were negative predictors for cortical infarcts. Patients with lacunar infarcts had more severe WMHIs than patients with nonlacunar infarcts in all WM areas (P相似文献   

Magnetic resonance imaging in parkinsonism.

MRI is a relatively simple, safe, in vivo technique that has proved to be of great value in differentiating patients with Parkinson's disease from those with atypical parkinsonism, and it is the first laboratory marker to be able to do so. By permitting the in vivo detection of increased iron in the nigra and striatum of patients with parkinsonism, MRI may also have provided a clue into the mechanism of cell death in neurodegenerative disorders. Finally it is conceivable that MRI scanning may serve as a screening tool that permits the early recognition of pathologic iron accumulation before the development of clinical symptoms. This is reasonable to anticipate for patients with atypical parkinsonism in whom large quantities of iron appear to accumulate in the putamen early in the disease. It is possible that with some refinement, abnormalities in the nigra may be detected on MRI with a higher level of certainty. In an era in which we may be able to provide neuroprotective therapy, MRI might be an important technique for defining a population of patients at risk for the development of Parkinson's disease who might benefit from presymptomatic therapy.     

Patency of cerebral microvessels after focal embolic stroke in the rat.

In patients with thrombotic stroke, the occluded artery often reopens over time. This results through a natural dissolution of the occluding material, and fragments of the material may move downstream to obstruct distal arteries. The current study was undertaken to investigate the patency of brain microvessels at varying time intervals after injection of a preformed clot into the right internal carotid artery of rats. Cerebral microvessels in brain sections were visualized using immunohistochemistry for fibronectin (detecting existing microvessels) and Evans blue (visualizing perfused microvessels). The percentage of patent microvessels was calculated as the number of Evans blue-positive microvessels divided by the number of fibronectin-positive microvessels. In normal control animals, results showed that 98% +/- 3% (mean +/- SD) of microvessels in the cortex and 94% +/- 14% in the striatum were patent. In the ischemic animals, immediately after clot injection, microvessels in the cortex and striatum were occluded, mainly in the territory irrigated by the middle cerebral artery. One hour after clot injection, microvessels had reopened in most of the cortex but remained occluded in some portions of the striatum, possibly as a result of downstream movement of fragments formed from the original clot. By 3 hours after clot injection, microvessels in the cortex were patent in all animals, whereas in the striatum microvessels were patent in 50% of the animals. In the other 50%, small striatal perfusion deficits persisted. At 24 hours after clot injection, microvessels were patent in both the cortex and striatum of all animals except one. These findings suggest that intracerebral clots dissolve spontaneously in a relatively short period of time, but that fragments formed from the clot may obstruct more distal blood vessels. It is likely that clot fragments lodge in arteries with lower blood flow and poor collateral perfusion, where they continue to cause ischemia for a longer duration. These results may in part explain the resistance of the striatum to neuroprotective strategies used for the treatment of focal cerebral ischemia.     

Use of diffusion weighted MRI to predict the occurrence and severity of hemorrhagic transformation in a rabbit model of embolic stroke

Alpha-synuclein is a brain presynaptic protein that is linked to familiar early onset Parkinson's disease and it is also a major component of Lewy bodies in sporadic Parkinson's disease and other neurodegenerative disorders. Alpha-synuclein expression increases in substantia nigra of both MPTP-treated rodents and non-human primates, used as animal models of parkinsonism. Here we describe an increase in alpha-synuclein expression in a human neuroblastoma cell line, SH-SY5Y, caused by 5-100 microM MPP+, the active metabolite of MPTP, which induces apoptosis in SH-SY5Y cells after a 4-day treatment. We also analysed the activation of the MAPK family, which is involved in several cellular responses to toxins and stressing conditions. Parallel to the increase in alpha-synuclein expression we observed activation of MEK1,2 and ERK/MAPK but not of SAPK/JNK or p38 kinase. The inhibition of the ERK/MAPK pathway with U0126, however, did not affect the increase in alpha-synuclein. The highest increase in alpha-synuclein (more than threefold) in 4-day cultures was found in adherent cells treated with low concentrations of MPP+ (5 microM). Inhibition of ERK/MAPK reduced the damage caused by MPP+. We suggest that alpha-synuclein increase and ERK/MAPK activation have a prominent role in the cell mechanisms of rescue and damage, respectively, after MPP+ -treatment.     

Magnetic resonance imaging after seizures in patients with an ischemic stroke

BACKGROUND: Seizures related to ischemic strokes are harmful. Their pathogenesis is not very well understood. The present study investigates whether diffusion-weighted imaging (DWI) can detect if those seizures are due to recurrent infarction or responsible for secondary ischemic changes. PATIENTS AND METHODS: DWI was obtained within 8 days in 60 patients with seizures (7 early and 53 late onset) related to an ischemic stroke. RESULTS: In 30 patients, positive DWI with decreased apparent diffusion coefficient was found. In 11 patients with late-onset seizures, the DWI showed a positive rim, surrounding the old infarct, while in 12 patients a large positive zone corresponding to a new infarct was observed. All 7 patients with early-onset seizures had positive DWI corresponding to the establishing infarct. A large positive zone on DWI was mainly observed in cardioembolic stroke. CONCLUSIONS: The positive rim around the old infarct can be considered as cytotoxic edema. Recurrent acute infarction, mainly of cardioembolic origin, seems to be a significant cause of so-called late-onset seizures, making the subdivision into early- and late-onset seizures arbitrary.     

Magnetic resonance imaging of transplanted oligodendrocyte precursors in the rat brain

The lack of any markers for oligodendrocyte precursors that can be visualized within the intact CNS is a significant barrier to trials of transplantation of these cells which aim to enhance remyelination in multiple sclerosis. We have therefore asked whether dextran-coated superparamagnetic iron oxide (SPIO) can be used to label cells prior to transplantation and then visualized within the brain using MRI. We have shown that an oligodendrocyte precursor cell line CG-4 will take up dextran-coated SPIO particles in vitro. The label remains within the cells after transplantation into adult rat brain, as assessed by electron microscopy, and is visible by MRI as a reduction in signal intensity at the transplant site at both 1 and 7 days after surgery. We conclude that MRI detection of SPIO-labelled cells represents a promising and novel approach to the analysis of oligodendroglial cell behaviour following transplantation that has very significant advantages over currently available methods.