Cerebrovascular and brain metabolism reviews最新文献

Approximately 10 in 100,000 persons suffer rupture of a saccular intracranial aneurysm annually, and roughly 60% of these will survive the initial catastrophe in reasonable neurological condition. Of the many ensuing complications of aneurysmal subarachnoid hemorrhage, the most frustrating continues to be a form of delayed-onset cerebral arterial narrowing known as vasospasm. Because it is caused by thick subarachnoid blood clots coating the adventitial surface of cerebral arteries, the distribution and severity of vasospasm correlates closely with location and volume of subarachnoid hematoma as visualized on computed tomography (CT). Critical vasospasm causes cerebral ischemia and infarction: the "second stroke." It is now know that vasospasm represents sustained arterial contraction rather than structural thickening of the vessel wall with lumen encroachment. A large body of evidence points to oxyhemoglobin, released from lysing erythrocytes, as the principal component of blood clot responsible for this contraction. The precise mechanism by which oxyhemoglobin causes prolonged vascular smooth muscle cell constriction has not yet been established, but possibilities include secondary generation of vasoactive free radicals, lipid peroxides, eicosanoids, bilirubin, and endothelin. Vasospasm treatments are directed at preventing or reversing arterial narrowing, or at preventing or reversing cerebral ischemia. Several treatments from the latter category, namely, hypertensive, hypervolemic hemodilutional therapy and the calcium channel blocker nimodipine, have proven moderately effective and are in widespread clinical use. It has also been possible to mechanically dilate vasospastic vessels with transluminal angioplasty improving cerebral blood flow to ischemic brain. However we are still in need of an effective agent to prevent arterial narrowing, and several hopeful candidates in this category of treatment are clot lytic agent tissue plasminogen activator (rt-PA) and an inhibitor of iron-dependent peroxidation, 21-aminosteroid U74006F (tirilazad mesylate).

In vitro studies have shown that monosialoganglioside GM1 reduces excitatory amino acid-related neurotoxicity by limiting the downstream consequences of abusive excitatory amino acid receptor stimulation, while enhancing neuronotrophic factor action in a variety of neuronal cell types. Systemic administration of GM1 appears to be efficacious in reducing acute nerve cell damage and in facilitating medium- and long-term functional recovery after brain injury. Although the mechanism of action remains unclear, it appears likely that GM1 protective effects in the acute injury phase are at least in part due to the attenuation of excitotoxicity, while the long-term functional recovery might reflect GM1 potentiation of neuronotrophic factors. The potential therapeutic efficacy of GM1 administration in different conditions in humans, as suggested by pioneer clinical studies, is reviewed. Further larger, randomized, double-blind clinical studies are necessary to define the therapeutic efficacy.

The distribution of brain cell injury following transient ischemia is remarkable because only certain neurons in distinct brain regions are destroyed (selective neuronal death). Because excitatory neurotransmitters (glutamate and aspartate) cause a similar pattern of selective neuronal death, it seemed only natural to associate these effects with the trauma of ischemia. This led to the formulation of the excitotoxin hypothesis, which explains selective neuronal death as a result of excessive interstitial concentration increases of excitatory amino acids during ischemia, resulting in the opening of receptor-coupled ionophores, of which calcium channels are of particular interest. A large influx of calcium associated with impaired intracellular calcium sequestration mechanisms due to energy failure activates a host of catabolic enzymes that ultimately will cause neuronal death. The purpose of this work was (a) to measure extracellular glutamate concentration increases during ischemia in a selective vulnerable brain region (rat CA1 hippocampus), (b) to evaluate the toxicity of such a concentration increase, and (c) to investigate the relationship between ischemia-induced glutamate accumulation and changes of calcium homeostasis. The execution of these experiments required a method that was able to sample excitatory amino acids in the brain extracellular space for subsequent analysis by high performance liquid chromatography (HPLC). The choice of the microdialysis technique proved most satisfactory and further mathematical analysis made it possible to transform dialysate glutamate concentrations to extracellular concentrations. The study demonstrated that extracellular glutamate in CA1 reached toxic concentrations during ischemia. There appeared to be a clear correlation between ischemia-induced glutamate accumulation and the decrease in extracellular calcium since both changes were prevented in the denervated CA1 (the destruction of glutamatergic innervation from CA3 protects CA1 pyramidal neurons from ischemic damage). By contrast, blockade of N-methyl-D-aspartate (NMDA) receptors with the glutamate antagonist APV was only partially effective in preventing the ischemia-induced calcium changes in CA1. Taken together, these results support the excitotoxin hypothesis but question the rational of treating neuronal injury caused by transient global ischemia exclusively with NMDA antagonists.

The pathogenesis of atherosclerosis has been extensively studied and the cellular aspects increasingly characterized. This review will focus on the basic pathology, presumed cellular events, cellular interactions, cell-lipid relationships, and potential therapies of atherosclerosis. Fatty streaks, fibrous plaques, and complicated plaques are the pathologic hallmarks of atherosclerosis. These lesions insidiously progress, and symptoms appear to develop when the plaque luminal surface destabilizes. The major cellular contributors to plaque development are monocytes/macrophages, endothelial cells, smooth muscle cells, and, to a lesser degree, lymphocytes and platelets. They interact in a complicated fashion. Growth factors and cytokines produced by these cells are also of great importance for cell-cell interaction. Hemodynamic factors contribute to atherogenesis at preferential sites within the arterial vasculature, presumably by effects on the cellular mechanisms. Hyperlipidemia, especially elevations of total and LDL-cholesterol, has been well characterized as an atherosclerotic risk factor. Cellular modification of LDL-cholesterol, primarily by oxidation, leads to more rapid uptake by macrophage-derived foam cells, enhancing plaque growth by this and other mechanisms. These observations may unify the cellular and lipid contributors to atherogenesis. Therapies directed at the cellular contributors to atherosclerosis are being assessed. Dietary n-3 fatty acid supplementation reduces the extent of experimental atherosclerosis, and human studies are in progress. Many potential cellular effects of n-3 fatty acids have been demonstrated. Other potential therapies for atherosclerosis that probably work at the cellular level include calcium channel blockers, antioxidants, and heparinoids. An exciting new era of atherosclerosis research and, hopefully, therapy has dawned, as knowledge about its cellular basis accrues.

Thrombolytic therapy has recently been shown to be beneficial in the setting of acute myocardial infarction, and thrombolysis resulting in vascular recanalization has been achieved in several other human disease states, including stroke. Advances in the understanding of the fibrinolytic system have led to the development of several new and distinctive thrombolytic strategies. Animal studies of stroke have been encouraging with regard to arterial recanalization and safety. Clinically, the availability of brain computed tomography has allowed pilot studies to proceed by providing rapid identification of patients with nonhemorrhagic stroke. Arterial recanalization has been demonstrated in patients with ischemic stroke following the administration of any one of several thrombolytic drugs. Placebo-controlled trials have not been completed, and so clinical benefit has not been established. Even though the development of brain hemorrhage has been an infrequent complication, the very high morbidity and mortality have been worrisome. Ironically, thrombolytic therapy holds promise for treatment of subarachnoid hemorrhage and perhaps also for spontaneous intracerebral hemorrhage. Human studies have been limited, but complications have been modest, and clinical outcomes have been encouraging.

PET studies of brain metabolism and blood flow in Alzheimer's disease (AD) patients lead to the following conclusions: (a) Reductions in "resting state" regional brain metabolism are roughly proportional to dementia severity. (b) These reductions are greater in association than in primary sensory and motor neocortical regions, and correlate with the distribution of neuropathology and cell loss postmortem. (c) Demented but not nondemented Down syndrome adults also have worse metabolic reductions in the association than primary neocortices, suggesting an equivalent pathological process in demented Down syndrome and AD patients. (d) Brain metabolic patterns in AD patients are heterogeneous, belonging to at least four distinct metabolic groups that correspond to different patterns of cognitive and behavioral abnormalities; the metabolic patterns have not been shown to be related to disease etiology. (e) Abnormal right-left metabolic asymmetries in mildly demented AD patients can retain their initial directions for as long as 48 months; these asymmetries precede and predict the cognitive "discrepancies" that later appear, such that moderately demented patients with disproportionate visuospatial compared with language deficits, or disproportionate visual recall compared with verbal recall, have a greater metabolic reduction in the right than left hemisphere, and vice versa. (f) Parietal association/frontal association metabolic ratios also retain their direction over time; in moderately demented patients, relative hypometabolism in the prefrontal association cortex is related to deficits in verbal fluency and attention to simple sets, whereas relative hypometabolism in the parietal association cortex correlates with failure in arithmetic, verbal comprehension, drawing, and immediate memory for visuospatial location. (g) Although metabolically spared compared with the association cortices, the primary sensory cortices, basal ganglia, thalamus, and cerebellar hemispheres show metabolic declines in AD using high-resolution PET scanners, possibly due to their connections with more pathologically affected regions. (h) Early metabolic deficits in AD are hypothesized to arise from synaptic failure in association cortical areas; such failure in the occipitotemporal visual cortex can be reversed in mildly to moderately demented AD patients who are capable of performing a face-matching task.

It is well known that various systemic parameters can modulate the deleterious effects of cerebral ischemia. We have reviewed the experimental data concerning the relationship between blood glucose concentration and brain ischemic morphological damage. Whereas the influence of hyperglycemia has been extensively investigated, the effect of a decrease in blood glucose concentration is not well documented. In models of transient ischemia, the cytologic damage is increased if the insult is induced in glucose-infused fed or fasted animals and decreased if it is induced in fasted animals. A more recent finding is the modulation of the extent of the cellular ischemic injury by manipulation of postischemic blood glucose concentration. In models of focal ischemia, conflicting results (a deleterious, a protective, or no effect) have been reported on the influence of elevated blood glucose concentration. Differences between the models of focal ischemia with respect to the possibility of collateral blood flow to enter the infarcted region may be an important factor for the explanation of the discrepant results. Because glycemia differences may explain some of the divergences on the susceptibility of the brain to ischemia, it becomes obvious (a) that the monitoring of glycemia before, during, and following the ischemic period is a prerequisite for the validation and the comparison of histological results, and (b) that every situation known to interfere with glycemia, such as food intake, anesthesia, or stress, have to be strictly controlled.

Techniques of monitoring surface blood flow in the brain allow observation of dynamic "real-time" changes in cortical blood flow (CoBF). These techniques have evolved from pial window observations that have not been quantitative and frequently are unreliable. Surface monitoring does not require the development of a clearance curve so changes in flow are seen immediately. On the other hand, the local vascular geometry may affect these techniques; therefore, large surface vessels must be avoided and the probe must be of large enough size so that some averaging effect of the cortical capillary bed will be obtained. At the present time, the two techniques available for surface monitoring are thermal diffusion flowmetry (TDF) and laser-Doppler flowmetry (LDF). Thermal methods have been available longer and more experience has been obtained in experimental, operative, and postoperative monitoring of CoBF with these techniques. LDF was used in retina, gastric mucosa, and skin, and has only recently been applied to the cerebral cortex. In the operating theater, both techniques have demonstrated increased CoBF in normal brain after arteriovenous malformation resection and have demonstrated reduced CoBF in normal brain around brain tumors. Acute changes in CoBF with vascular manipulation during aneurysm surgery have been demonstrated with TDF. Postoperative monitoring of aneurysm patients has demonstrated the development of cerebral vasospasm with TDF as well as increased flow preceding the development of malignant cerebral edema in trauma patients. Artifacts occur in TDF with irrigation, loss of surface contact, and contact with large surface vessels. LDF has artifactual changes with movement, light, if large surface vessels come in view of the probe, and changes in hematocrit. Surface monitoring shows a great deal of promise in continuous evaluation of CoBF intraoperatively and postoperatively.

There are different approaches to the assessment of acute stroke. Its causes, its severity, and/or its final prognosis may be investigated. The traditional approach is anatomoclinical. It is basically limited to finding out if the lesion is a hemorrhage or an ischemia, and its location. This approach is derived from and supported by the fact that acute stroke is still without a valid therapy. In our opinion, not stroke but individual patients presenting with stroke should be treated. The pathophysiology of the individual stroke should be investigated by means of new techniques: magnetic resonance, emission tomography, and transcranial Doppler. These new techniques will be important in the future, making it possible to create effective therapeutic strategies, designed for treating a particular subgroup of patients, as in the case of fibrinolytic agents. The main aspects of these new techniques for evaluating acute ischemic stroke have been reviewed in this article.

A review of the current literature regarding sleep-induced changes in cerebral blood flow (CBF) and cerebral metabolic rate (CMR) is presented. Early investigations have led to the notion that dreamless sleep was characterized by global values of CBF and CMR practically at the level of wakefulness, while rapid eye movement (REM) sleep (dream sleep) was a state characterized by a dramatically increased level of CBF and possibly also of CMR. However, recent investigations firmly contradict this notion. Investigations on CBF and CMR performed during non-REM sleep, taking the effect of different levels of sleep into consideration, show that light sleep (stage II) is characterized by global levels of CBF and CMR only slightly reduced by 3-10% below the level associated with wakefulness, whereas CBF and CMR during deep sleep (stage III-IV) is dramatically reduced by 25-44%. Furthermore, recent data indicate that global levels of CBF and CMR are about the same during REM sleep as in wakefulness. On the regional level, deep sleep seems to be associated with a uniform decrease in regional CBF and CMR. Investigations concerning regional CBF and CMR during REM sleep are few but data from recent investigations seem to identify site-specific changes in regional CBF and CMR during REM sleep. CBF and CMR are reflections of cerebral synaptic activity and the magnitude of reduction in these variables associated with deep sleep indicates that overall cerebral synaptic activity is reduced to approximately one-half the level associated with wakefulness, while cerebral synaptic activity levels during REM sleep are similar to wakefulness. However, even though the new understanding of CBF and CMR during sleep provides significant and important information of the brain's mode of working during sleep, it does not at its current state identify the physiological processes involved in sleep or the physiological role of sleep.