Cerebrovascular and brain metabolism reviews最新文献

Experimental models of focal ischemia have provided an unparalleled insight into the dynamic events that surround ischemic brain injury. The dichotomous capacity of existing rodent models of focal ischemia to provide a controlled environment to examine the pathogenesis of focal ischemia and to allow assessment of the efficacy of potential therapeutic intervention is reviewed. The established rodent model of permanent middle cerebral artery occlusion (electrocoagulation) is critically examined and set against the distinctive features of novel methods that have been developed to reduce invasive surgery and to examine the pathological consequences of reperfusing a previously ischemic area. Emphasis has been placed on the technical requirements of each model that affect outcome and reproducibility.

Amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease are major human neurodegenerative disorders, the etiologies for which remain unknown. Although a unique subset of neurons is particularly affected in each of the three diseases, they have several intriguing overlapping similarities. Evidence is reviewed supporting the hypothesis that these diseases result from an inability to protect against accumulated damage by free radicals due to oxidative stress. If oxidative stress underlies or exacerbates the etiology of these diseases, then agents that effectively attenuate brain tissue lipid peroxidation or otherwise limit free radical damage may hold promise for the treatment of these neurodegenerative diseases. Although antioxidant chemical supplementation may provide effective therapy, the most effective therapy for neurodegenerative diseases may be treatment with specific neurotrophic, survival-promoting proteins. For example, brain-derived neurotrophic factor promotes survival of spinal motor neurons and mesencephalic dopaminergic neurons. One mechanism through which these proteins may exert their protection may be by stimulating endogenous defenses against oxidative stress and damage by free radicals. This hypothesis is being tested in several laboratories and provides exciting direction both for basic neurobiological research and therapeutic drug discovery.

The vascular territories of the major cerebral arteries supplying the cerebral cortex, subcortical structures, cerebellum, and brainstem in humans are relatively uniform. Because of their anatomical distribution, and the specialized neurologic functions located within these territories, infraction due to arterial occlusion gives rise to distinct clinical syndromes. Thus, the physical findings on neurologic examination permit a reliable topographic diagnosis. With extensive infraction involving all or major portions of a particular vascular territory, the resultant clinical syndromes tend to be severe, reflecting the large area of involvement. More typically, however, infarcts do not involve a vascular territory in its entirety but are limited to the distribution of secondary branches by various mechanisms of arterial occlusion. Depending on their location, these smaller infarcts produce syndromes that may vary in severity and manifestations. Our understanding of the clinical approach of clinicoanatomical correlations in these forms of cerebral infarction has been facilitated by the widespread use of brain CT and MRI scans, that have virtually replaced the classical approach of clinicopathological correlations in autopsy material. In this review we have divided the manifestations of occlusive cerebrovascular disease according to the vascular territories affected. The distinct clinical syndromes which thus arise and their common mechanisms are described. Correlation is made with the typical CT and MRI images.

New developments in instrumentation, radiochemistry, and data analysis, particularly the introduction of 99M TC-labeled brain-retained tracers for perfusion studies, have opened up a new era of single photon emission computed tomography (SPECT). In this review critical methodological issues relating to the SPECT instrument, the radioactive tracers, the scanning procedure, the data analysis and interpretation of data, and subject selection are discussed together with the changes in regional cerebral blood flow (rCBF) observed in normal aging. An overview is given of the topography and the pathophysiological and diagnostic significance of focal rCBF deficits in Alzheimer's disease and in other dementia disorders, in which SPECT is capable of early or preclinical disease detection. In Alzheimer's disease, the diagnostic sensitivity and specificity of focal rCBF deficits measured with SPECT and brain-retained tracers are very high, in particular when combined with medial temporal lobe atrophy on CT. Together with neuropsychological testing, SPECT serves to map the topography of brain dysfunction. Thus, in the clinical setting, SPECT provides information that is supplemental to that obtained in other studies. Future applications include neuroreceptor studies and treatment studies, in which SPECT may serve as a diagnostic aid in the selection of patients and as a potential mean for monitoring treatment effects. Although positron emission tomography is the best characterized tool for addressing some of these clinical and research issues in dementia, only the less expensive and technically simpler SPECT technique will have the potential of being available as a screening diagnostic instrument in the clinical setting. It is concluded that, properly approached, functional brain imaging with SPECT represents an important tool in the diagnosis, management, and research of dementia disorders.

The coupling of brain cell function to the vascular system is the basis for a number of functional neuroimaging methods relevant for human studies. These include methods as diverse as functional magnetic resonance imaging, positron emission tomography, single photon emission tomography, optimal intrinsic signals, as well as near infrared spectroscopy, a method that may have imaging capabilities in the near future. These methods map a specific localized brain activation through a vascular response, such as an increase in cerebral blood flow or a change in blood oxygenation. To understand these direct maps to obtain high resolution maps of localized functional brain activity, a precise knowledge of the specific underlying physiological mechanisms and methodological properties and restrictions is essential. In this article, these fundamental physiological and methodological aspects will be discussed. After reviewing how the techniques cited obtain maps of functional activity, we will discuss our current knowledge of the physiology of coupling with particular reference to the functional imaging techniques. Specifically, we will consider the function, the mediators, and the hemodynamic mechanisms of coupling and point out potential interference by diet, and neurological disease.

Over the last few years, diffusion and perfusion magnetic resonance (MR) imaging methods have found increasing user for monitoring the effects of cerebral ischemia under clinical and experimental conditions. Blood perfusion can be visualized by studying the patency of the cerebrovascular bed (MR angiography), by recording exchange of diffusible tracers between blood and brain ([2H]water or [19F]trifluoromethane clearance), or by measuring the volume and transit time of the circulating blood (bolus track or spin-tagging imaging). In addition, changes in blood oxygenation level can be visualized by taking advantage of the susceptibility changes of the magnetic field homogeneity (functional or blood-oxygenation-level-dependent imaging). Diffusion imaging is based on the modulation of signal intensity by brain water diffusion. Recording a series of diffusion-weighted images allows calculation of the apparent diffusion coefficient (ADC) and the reconstruction of quantitative ADC images. Brain ADC changes are a function of intra-extracellular water homeostasis and therefore are a sensitive marker of ionic equilibrium. Since disturbances of ion and water homeostasis are among the first pathological alterations induced by brain ischemia, diffusion imaging is able to detect the incipient injury within minutes. Conversely, the reversal of these alterations is able to detect the incipient injury within minutes. Conversely, the reversal of these alterations is an early and reliable predictor of postischemic recovery. Applications of perfusion and diffusion imaging are reviewed in relation to the pathophysiology, the pathobiochemistry, and the therapy of evolving brain infarct after focal ischemia and the manifestation and reversal of ischemic injury during and after global ischemia.

The discovery that blockade of N-methyl-D-aspartate (NMDA) receptors protects brain tissue against ischaemic damage has triggered enormous interest; and with the advance of intracerebral microdialysis, hundreds of studies have investigated changes in the extracellular levels of glutamate and other neurotransmitters during and after cerebral ischaemia. This work has made it apparent that the current concept of ischaemia-induced excitotoxicity, centred on excessive efflux of glutamate from nerve terminals, fails to correspond with reality since it conflicts with a number of key findings: (a) Excessive effluxes during ischaemia are not specific to excitatory amino acids--inhibitory transmitters are released to a similar extent; (b) neuronal death can occur several hours after a short ischaemic episode, whereas glutamate and aspartate accumulation in the neuronal microenvironment is cleared within minutes of reperfusion; (c) the penumbra is most receptive to cerebroprotection with glutamate receptor antagonists, but extracellular glutamate levels may not reach critical levels in this region; and (d) postischaemic treatment with glutamate receptor antagonists were neuroprotective in a number of studies. It has also become evident that most of the glutamate released in ischaemia is of metabolic origin, which questions the validity of therapeutic strategies aimed at preventing or reducing excessive release of neurotransmitter glutamate in ischaemia. However, the possibility that glutamate changes at the synaptic level may be small but pathologically important cannot be totally refuted. Apart from increased extracellular glutamate, the exceptional complexity of glutamate-operated ion channels can give rise to many potentially damaging mechanisms. Of particular interest are the possibilities of recurrent spreading depression in focal ischaemia, widespread and persistent strengthening of glutamatergic transmission, and abnormal modulation of the NMDA receptor-ionophore complex. There is also considerable evidence that, in certain brain regions, monoamines or their metabolic by-products may become neurotoxic either directly or from interplay with glutamatergic systems. All these processes deserve further examination to identify the most damaging and to indicate possible methods of intervention.