Infarcted Brain Tissue Research Articles

Theoretic Basis and Technical Implementations of CT Perfusion in Acute Ischemic Stroke, Part 2: Technical Implementations

CT perfusion (CTP) is a functional imaging technique that provides important information about capillary-level hemodynamics of the brain parenchyma and is a natural complement to the strengths of unenhanced CT and CT angiography in the evaluation of acute stroke, vasospasm, and other neurovascular disorders. CTP is critical in determining the extent of irreversibly infarcted brain tissue (infarct "core") and the severely ischemic but potentially salvageable tissue ("penumbra"). This is achieved by generating parametric maps of cerebral blood flow, cerebral blood volume, and mean transit time.

Theoretic Basis and Technical Implementations of CT Perfusion in Acute Ischemic Stroke, Part 1: Theoretic Basis

CT perfusion (CTP) is a functional imaging technique that provides important information about capillary-level hemodynamics of the brain parenchyma and is a natural complement to the strengths of unenhanced CT and CT angiography in the evaluation of acute stroke, vasospasm, and other neurovascular disorders. CTP is critical in determining the extent of irreversibly infarcted brain tissue (infarct "core") and the severely ischemic but potentially salvageable tissue ("penumbra"). This is achieved by generating parametric maps of cerebral blood flow, cerebral blood volume, and mean transit time.

Decompressive Hemicraniectomy and Durotomy for Malignant Middle Cerebral Artery Infarction

The high early case fatality among patients with massive hemispheric strokes calls for effective treatments. Release of the restriction created by the dura mater and bony skull to allow the infarcted brain tissue to swell has been successfully adopted by some while considered controversial by others. A recent pooled analysis provides estimates for the efficacy of decompressive surgery. Further analyses of current trial data suggest that in particular patient age and timing of surgery determine outcome. Nonetheless, in order to guide the management of individual patients, carefully adjusted medical care, ongoing futility analysis, and simultaneous caregiver meetings should be conducted to reach a joint decision addressing any ethical concerns. In conclusion, decompressive surgery increases the probability of survival but produces patients with moderate or moderately severe disability (albeit not severe disability). Currently, the decision to perform decompressive surgery should remain an individual one in each and every patient.

Symptomatic intracranial haemorrhage after intra-arterial thrombolysis in acute ischaemic stroke: assessment of 294 patients treated with urokinase

Background: The PROACT II trial showed that intra-arterial thrombolysis (IAT) is effective for treatment of acute ischaemic stroke attributable to M1 and M2 segment occlusions. Incidence of symptomatic intracranial haemorrhage...

Role of oxidative stress on pathogenesis of hypertensive cerebrovascular lesions

The hypertensive rat brain exhibited softening, severe edema and intracerebral hemorrhage. The NO(2) (-) + NO(3) (-) (NOx) level in the hypertensive rat brain was higher than in the normotensive rat brain. Light microscopy demonstrated severe arterial and arteriolar lesions with fibrinoid deposits and medial lesion. After injecting hypertensive rats with nitroblue tetrazolium (NBT), formazan deposits, which are the reaction product of reduction of NBT by superoxide, were observed in the microvessels and nervous tissue around the microvessels of injured brain. Immunohistochemistry showed that copper zinc superoxide dismutase and manganese superoxide dismutase expression of the endothelial cells of hypertensive rats were also upregulated in comparison with normotensive rat endothelial cells. Inducible nitric oxide synthase and endothelial nitric oxide synthase expression in endothelial cells of normotensive rats were strongly positive, whereas the expression in hypertensive rat endothelial cells was weaker. Nitrotyrosine, a biomarker of peroxynitrite, which is a powerful oxidant formed by the reaction of nitric oxide (NO) with superoxide, was found in the microvessels, injured arteries and arterioles and infarcted brain tissue. Deposition of a major aldehydic product of lipid peroxidation, that is, 4-hydroxy-2-nonenal (4-HNE) was found in microvessels, perivascular tissue, and edematous and infarcted brain. Hypertensive cerebrovascular disease is the result of hypertension-induced oxidative stress.

Accumulated Mannitol and Aggravated Cerebral Edema in a Rat Model of Middle Cerebral Artery Infarction

Repeated administration of mannitol in the setting of large hemispheric infarction is a controversial and poorly defined therapeutic intervention. This study was performed to examine the effects of multiple-dose mannitol on a brain edema after large hemispheric infarction. A middle cerebral artery was occluded with the rat suture model for 6 hours and reperfused in 22 rats. The rats were randomly assigned to either control (n=10) or the mannitol-treated group (n=12) in which intravenous mannitol infusions (0.8 g/kg) were performed six times every four hours. After staining a brain slice with 2,3,5-triphenyltetrazolium chloride, the weight of hemispheres, infarcted (IH) and contralateral (CH), and the IH/CH weight ratio were examined, and then hemispheric accumulation of mannitol was photometrically evaluated based on formation of NADH catalyzed by mannitol dehydrogenase. Mannitol administration produced changes in body weight of -7.6+/-1.1%, increased plasma osmolality to 312+/-8 mOsm/L. It remarkably increased weight of IH (0.77+/-0.06 gm versus 0.68+/-0.03 gm : p<0.01) and the IH/CH weight ratio (1.23+/-0.07 versus 1.12+/-0.05 : p<0.01). The photometric absorption at 340 nm of the cerebral tissue in the mannitol-treated group was increased to 0.375+/-0.071 and 0.239+/-0.051 in the IH and CH, respectively from 0.167+/-0.082 and 0.162+/-0.091 in the IH and CH of the control group (p<0.01). Multiple-dose mannitol is likely to aggravate cerebral edema due to parenchymal accumulation of mannitol in the infarcted brain tissue.

Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats

Stroke represents one of the leading causes of death and disability in Western countries, but despite intense research, only few options exist for the treatment of stroke-related infarction of brain tissue. In experimental stroke, cell therapy can partly reverse some behavioural deficits. However, the underlying mechanisms have remained unknown as most studies revealed only little, if any, evidence for neuronal replacement and the observed behavioural improvements appeared to be related rather to a graft-derived induction of a positive response in the remaining host tissue than to cell replacement by the graft itself. The present study was performed to test a murine embryonic stem cell (ESC)-based approach in rats subjected to endothelin-induced middle cerebral artery occlusion. Efficacy of cell therapy regarding graft survival, neuronal yield and diversity, and electrophysiological features of the grafted cells were tested after transplanting ESC-derived neural precursors into the infarct core and periphery of adult rats. Here, we show that grafted cells can survive, albeit not entirely, most probably as a consequence of an ongoing immune response, within the infarct core for up to 12 weeks after transplantation and that they differentiate with high yield into immunohistochemically mature glial cells and neurons of diverse neurotransmitter-subtypes. Most importantly, transplanted cells demonstrate characteristics of electrophysiologically functional neurons with voltage-gated sodium currents that enable these cells to fire action potentials. Additionally, during the first 7 weeks after transplantation we observed spontaneous excitatory post-synaptic currents in graft-derived cells indicating synaptic input. Thus, our observations show that ESC-based regenerative approaches may be successful in an acutely necrotic cellular environment.

The neuroprotective effect of glial cell line-derived neurotrophic factor in fibrin glue against chronic focal cerebral ischemia in conscious rats

Glial cell line-derived neurotrophic factor (GDNF) is a transforming growth factor-β which has shown beneficial effects in rats after acute focal cerebral ischemia (FCI). To study the effects of GDNF on chronic FCI injury in conscious rats, we used fibrin glue (GDNF-fibrin glue) and fibrin glue free (GDNF-only)-GDNF topically applied to the ischemic brain after right middle cerebral artery (MCA) ligation. Infarct brain volume and functional motor deficits were measured before and after FCI injury. After FCI injury induced by right MCA ligation, rats were randomly assigned to one of four treatment groups: (a) sham, (b) control, (c) topically applied GDNF (1 μg)-only, and (d) topically applied GDNF (1 μg)-fibrin glue. The degree of ischemic brain injury was estimated by infarct volume of right MCA territory at 4 weeks after occlusion. The functional motor deficits were quantified with rotarod test and grasping power test once a week. Topically applied GDNF-fibrin glue at infarct brain tissue after 4 weeks FCI injury significantly reduced the total infarct volume by 44.3% and 36%, respectively, compared to that of control group and GDNF-only group. The mean latencies for rats to stay on the rotarod were 55.0%, 50.3%, and 92.2% ( P < 0.05 vs. control group and GDNF-only group) of baseline, respectively, in the control, GDNF-only, and GDNF-fibrin glue groups at the end of the 1st week after FCI injury but 75.3%, 67.3%, and 106.6% ( P < 0.05 vs. control group and GDNF-only group) of baseline at the end of the 4th week after FCI injury. The mean values of grasping power were 78.7%, 71.7%, and 101.2% ( P < 0.05 vs. control group and GDNF-only group) of baseline, respectively, in the control, GDNF-only, and GDNF-fibrin glue groups at the end of 1st week after FCI injury but 89.6%, 97.6%, and 120.7% ( P < 0.05 vs. control group) of baseline at the end of 4th week after FCI injury. These results indicate that GDNF-fibrin glue not only reduced the total infarct volume after FCI injury but can also improve motor deficits after FCI injury. We concluded GDNF-fibrin glue could facilitate delivery of GDNF to the damaged brain tissue with subsequent reduction of ischemic brain injury accompanied by enhancing functional recovery in rats with chronic FCI injury.

MRI for the management of neonatal cerebral infarctions: importance of timing

Focal ischemic stroke in neonates is a rare occurrence. Diagnosis with most imaging modalities is difficult, but necessary for initiating an anticoagulatory treatment. The purpose of this study was to evaluate the sensitivity of MRI sequences within the first 14 days of birth. Four patients with neonatal stroke presenting as seizures were examined using a standard MRI protocol including diffusion-weighted images (DWI) and magnetic resonance angiography (MRA) within 72 h of birth. The time between the onset of symptoms and MRI ranged from 6 h to 48 h. Follow-up examinations were performed on days 5 ( n=1), 7 ( n=2), and 14 ( n=1) for the control of a treatment with low-molecular heparin. Eight infarctions were detected in the four patients, 5 in the middle cerebral artery (MCA), three in the posterior cerebral artery (PCA) territory. All lesions were visible using DWI, four on T2-weighted images. Whereas in two patients small lesions contralateral to a large stroke were missed on T2-weighted images, the diagnosis would have been missed altogether without DWI in one patient. On follow-up, the visibility of the infarctions had declined using DWI after 5 days and the lesions were invisible after 1 week. Fourteen days after the stroke, an increased diffusion was detected in the infarcted brain tissue. By this time, all lesions were visible on T2-weighted images. In neonates, infarcted brain tissue can be detected using DWI with high sensitivity during the first 2 days after stroke and before other sequences are diagnostic. However, the diffusion restriction does not persist beyond 1 week. After 5 days, diagnosis has to rest mainly on T2-weighted images.

Beyond mismatch: evolving paradigms in imaging the ischemic penumbra with multimodal magnetic resonance imaging.

The ability to quickly and efficiently identify the ischemic penumbra in the acute stroke clinical setting is an important goal for stroke researchers and clinicians. Early and accurate identification of potentially salvageable versus irreversibly infarcted brain tissue may enable selection of the most appropriate candidates for early stroke therapies and identify patients who may still benefit from late recanalization or neuroprotective treatment. Recent advances in magnetic resonance imaging of the ischemic penumbra have been driven by serial MRI studies characterizing the natural evolution of cerebral infarction as well as the brain's response to reperfusion. Based on these studies, various models for imaging the penumbra with MRI have been proposed, including the pioneering diffusion-perfusion mismatch model and later multivariate approaches. Each model has its own unique advantages and disadvantages. There now are sufficient data to support paradigm shifts in a variety of central tenets regarding MRI and the ischemic penumbra. These include the insights that diffusion-perfusion mismatch does not optimally define the penumbra; that early diffusion lesions are in part reversible and often include both irreversibly infarcted tissue and penumbra; that the visible zone of perfusion abnormality overestimates the penumbra by including regions of benign oligemia; that MRI is a very practical method for acute stroke imaging; and that therapeutic salvage of the ischemic penumbra has been demonstrated in humans using diffusion-perfusion MRI.

Design of future acute-stroke treatment trials

Very few trials of acute stroke treatments show efficacy of a tested agent on the prespecified primary outcome. We can learn many lessons from the studies that achieve only neutral results. Preclinical studies have been flawed by use of models of transient not permanent brain ischaemia, treatments that aim to protect cerebral grey matter independently of white matter, delivery of the study drug within too short a time window after ischaemic insult, use of surrogate outcome measures in the short term instead of function in the long-term, and small sample sizes. Clinical trials have been hampered by heterogeneity in causes of stroke and inability to classify subtypes of cause; the short time available to rescue ischaemic brain tissue; the haemorrhagic transformation that can cause severe functional consequences seen frequently in infarcted brain tissue; the lack of valid, reliable, sensitive, and simple tools for assessment of functional outcome; and, above all, small treatment effects that are difficult to detect or refute. In this review, we look at the designs and results of all controlled trials of treatments for ischaemic stroke, and try to identify opportunities to improve future treatment assessment.

Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia.

Oxidative stress generated during stroke is a critical event leading to blood-brain barrier (BBB) disruption with secondary vasogenic edema and hemorrhagic transformation of infarcted brain tissue, restricting the benefit of thrombolytic reperfusion. In this study, the authors demonstrate that ischemia-reperfusion-induced BBB disruption in mice deficient in copper/zinc-superoxide dismutase (SOD1) was reduced by 88% ( P < 0.0001) and 73% ( P < 0.01), respectively, after 3 and 7 hours of reperfusion occurring after 1 hour of ischemia by the inhibition of matrix metalloproteinases. Accordingly, the authors show that local metalloproteinase-generated proteolytic imbalance is more intense in ischemic regions of SOD1 mice than in wild-type litter mates. Moreover, active in situ proteolysis is, for the first time, demonstrated in ischemic leaking capillaries that produce reactive oxygen species. By showing that oxidative stress mediates BBB disruption through metalloproteinase activation in experimental ischemic stroke, this study provides a new target for future therapeutic strategies to prevent BBB disruption and potentially reperfusion-triggered intracerebral hemorrhage.

Expression of P-selectin and intercellular adhesion molecule-1 in human brain after focal infarction or cardiac arrest.

Data from experimental studies indicate that acute inflammation contributes to ischaemic brain damage. Tethering of neutrophils to brain endothelium is mediated by selectins, and subsequent adhesion and migration by endothelial intercellular adhesion molecule-1 (ICAM-1) and neutrophil CD18. In experimental studies of ischaemia-reperfusion injury, brain damage has been ameliorated by administration of antibodies to these adhesion molecules. We studied the expression of P-selectin and ICAM-1 in sections of brain from patients who had experienced cardiac arrest or focal brain infarction, and who died 3.5 h to 9 days later. Endothelial immunopositivity for both adhesion molecules was maximal at about 2-3 days then declined. Between 1 day and 3 days, P-selectin was also detected on platelets in blood vessels within infarcted tissue. Within infarcts, but not sections of brain from cardiac arrest patients, P-selectin and ICAM-1 were again detectable at 1 week, when hyperplastic endothelial cells were labelled in capillaries in and immediately adjacent to the infarcted tissue. The finding that P-selectin and ICAM-1 are upregulated within focally infarcted brain tissue supports the concept that blocking neutrophil adhesion may be of benefit in treating atherothrombotic strokes in man.

Postvaricella angiopathy: report of a case with pathologic correlation

Varicella is a common childhood illness, and central nervous system complications occur frequently. Delayed angiopathy has been described, although there are few reports of clinicopathologic correlation. A previously well 4-year-old male is presented. He suffered varicella 2 months before presentation with extensive right middle cerebral artery (MCA) territory infarction. Cerebral angiography demonstrated an isolated 89% stenosis of the right proximal MCA. He developed cerebral edema refractory to medical treatment and progressed to transtentorial herniation. Right frontal temporoparietal craniotomies were performed with evacuation of infarcted brain tissue. Pathologic studies revealed small vessel vasculitis with lymphocytic infiltration of the vessel wall. Areas of demyelination were present within the white matter. Polymerase chain reaction for varicella was negative on brain tissue. Postvaricella angiopathy, although an uncommon complication, may affect both small and large blood vessels, with catastrophic results.

S100B as a predictor of size and outcome of stroke after cardiac surgery

Background. Stroke after cardiac surgery is a clinical problem with often fatal or disabling outcome. To assess severity and probable outcome in affected patients only from clinical and radiological examinations is difficult. The glial-derived protein S100B has been suggested to be a marker of cerebral ischemia, and increased blood concentrations of S100B have been shown to correlate with size of lesion and prognosis after stroke. We studied the validity of S100B as a predictor of size of brain lesion and median term outcome in a consecutive group of patients suffering from stroke after cardiac surgery.Methods. During a period of 17 months, 20 patients with clinical signs of postoperative stroke were investigated with S100B measurement, sampled at 5, 15 and 48 hours after surgery. All patients were examined with computed tomography or magnetic resonance imaging to confirm the diagnosis, and the size of cerebral infarction was estimated from the radiological examinations. The patients were followed up for survival 24 to 39 months after surgery.Results. S100B concentration in blood 48 hours after surgery correlated with the size of infarcted brain tissue (r = 0.68, p < 0.001). Nine patients had S100B levels exceeding 0.5 μg/L and a 2-year mortality of 78%, whereas the 11 patients with S100B below 0.5 μg/L had a mortality of 18%.Conclusions. Increased S100B in patients with a stroke following cardiac surgery correlate with the size of infarcted brain tissue. High S100B levels 48 hours after surgery have a negative predictive value for median term survival.

Design, synthesis, SAR, and biological evaluation of highly potent benzimidazole-spaced phosphono-alpha-amino acid competitive NMDA antagonists of the AP-6 type.

A series of 2-amino-(phosphonoalkyl)-1H-benzimidazole-2-alkanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H]CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Several compounds of the AP-6 type demonstrated potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular, [R(-)]-2-amino-3-(5-chloro-1-phosphonomethyl-1H-benzoimidazol-2-yl)-propionic acid (1) displayed an IC(50) value of 7.1 nM in the [3H]CPP binding assay and an ED(50) value of 0.13 mg/kg (ip) in the NMDA lethality model. Compound 1, when administered intravenously as a single bolus dose of 3 mg/kg following permanent occlusion of the middle cerebral artery in the rat, reduced the volume of infarcted brain tissue by 45%. These results support a promising therapeutic potential for compound 1 as a neuroprotective agent.

Long‐term protection of brain tissue from cerebral ischemia by peripherally administered peptidomimetic caspase inhibitors

AbstractApoptotic cell death occurs in the injured and diseased central nervous system. It is mediated by a family of caspases, which are activated by the lethal stimulus and cleave multiple protein substrates that are critical for cell viability. Previous studies demonstrated that caspase‐mediated apoptotic cell death contributes to the loss of brain tissue after experimental cerebral ischemia and that peptidic caspase inhibitors can be efficacious in reducing infarct size after icv administration. Here we present the novel small molecule peptidomimetic caspase inhibitor IDN5370/CGP82630, which belongs to the structural class of oxoazepinoindoline caspase inhibitors. It is 10–100‐fold more potent than current peptidic inhibitors in inhibiting multiple caspases in vitro and promoting neuronal survival. IDN5370 and a derivative, IDN7866, were tested for their ability to reduce infarct size after permanent and transient cerebral ischemia. When administered icv to rats subjected to permanent middle cerebral artery occlusion (MCAO), IDN5370 significantly reduced cortical infarct as measured by magnetic resonance imaging at 2 days after artery occlusion. Protection of brain tissue persisted for 28 days after artery occlusion. To determine whether compounds of this structural class could reduce infarct size after peripheral administration, IDN7866, which penetrates the blood–brain barrier and inhibits caspase 3 in situ in the hippocampus after kainate‐induced seizures, was administered iv in both permanent and transient MCAO models. Infarct size was reduced significantly in both models 24 h after artery occlusion. These results demonstrate that peripherally administered peptidomimetic caspase inhibitors can attenuate brain injury after cerebral ischemia and confer a long‐lasting protective effect on the infarcted brain tissue. Drug Dev. Res. 52:579–586, 2001. © 2001 Wiley‐Liss, Inc.

Magnetic Resonance Perfusion Imaging: A new method for localizing regions of brain dysfunction associated with specific lexical impairments?

We investigated correlations between lexical impairments and regional infarction versus hypoperfusion in hyperacute stroke (within 24 hours of onset). Seven patients with hyperacute dominant hemisphere stroke underwent a battery of lexical tasks, and investigational MRI techniques of Diffusion-Weighted Imaging (DWI) and Magnetic Resonance Perfusion Imaging (MRPI). Lexical performance was a function of regional hypoperfusion (on MRPI) rather than region of (probably) completed infarct (on DWI). Strong correlations were found between: accuracy in auditory word comprehension and volume of left temporal and parietal hypoperfusion, and accuracy of naming and left parietal hypoperfusion. Frequent errors in repetition were associated with left temporal and/or left frontal hypoperfusion, but the volume of infarct in these areas was not significantly correlated with the rate of repetition errors. Results of this preliminary study indicate that MRPI is a promising tool for investigating the regions of hypoperfused (dysfunctional, but not infarcted) brain tissue associated with specific language impairments in hyperacute stroke.

Vascular endothelial growth factor in Alzheimer's disease and experimental cerebral ischemia

Several growth factors have been implicated in the pathogenesis of Alzheimer's disease (AD). We considered whether the vascular endothelial growth factor (VEGF) is involved in the vascular pathology associated with most cases of AD. We observed enhanced VEGF immunoreactivity in clusters of reactive astrocytes in the neocortex of subjects with AD compared to elderly controls. VEGF reactivity was also noted in walls of many large intraparenchymal vessels and diffuse perivascular deposits. In addition, we established that astrocytic and perivascular VEGF reactivity was enhanced in cerebral cortex of rats subjected to cerebral ischemia and to chronic hypoxia; experimental conditions known to be associated with astrogliosis and angiogenesis. We suggest the increased VEGF reactivity, also observed in infarcted human brain tissue, implicates compensatory mechanisms to counter insufficient vascularity or reduced perfusion (oligemia) apparent in AD.

Heparin Treatment in Acute Cerebral Sinus Venous Thrombosis: A Retrospective Clinical and MR Analysis of 42 Cases

The only randomized data on heparin treatment in acute cerebral sinus venous thrombosis (CSVT) are derived from a small number of patients. The rate of intracranial hemorrhages as a complication of high-dose heparin treatment is still unknown. This retrospective study evaluates the clinical features, neuroimaging monitoring and outcome of 42 patients with proven CSVT. Diagnosis was established by DSA, CT, MR tomography and MR angiography. All patients received heparin intravenously guided by doubling the aPTT value for 3 weeks, followed by oral anticoagulation. Partial or complete recanalization was found in 36 cases. 40 patients improved clinically, in 26 of them complete recovery was observed. One patient deteriorated and developed an apallic syndrome, one further patient died of septic multiorgan failure. Only in one patient was hemorrhagic transformation of infarcted brain tissue observed but without clinical deterioration.