Cerebrovascular and brain metabolism reviews最新文献

The preventive and acute treatment of cardioembolic stroke is based upon its pathogenesis and location. Typically, cardioembolic cerebral infarction is multiple, bilateral, and often large and wedge shaped. Less frequently, smaller infarcts are produced, but the incidence of lacunar infarction or small cortico-medullary junction infarction due to cardioembolism is uncertain. Microembolism has been detected by Doppler sonography and may be constant, but the factors leading to symptomatic embolism are poorly understood. The natural lytic properties of endothelium play a role in thrombus formation in the heart and embolus lysis intracranially. In addition, site-specific tissue factors may be important in the production of complications occurring in the wake of embolic infarction: hemorrhagic transformation and edema. The treatment of cardioembolic stroke may involve prevention of both red (fibrin-based) and white (platelet-predominant) clot formation as well as a combination of clot lysis and the use of agents to prevent damage due to the final ischemic cascade after embolism has occurred. This review attempts to clarify the arterial topography, mechanism, and presentation of cardioembolic stroke.

Current evidence does not preclude the possibility that breach of the blood-brain barrier (BBB) is causally involved in the pathogenesis of Alzheimer disease (AD). There is abundant evidence, however, indicating morphological and biochemical abnormalities in the cerebral microvasculature that implicate breakdown of the BBB in AD. These abnormalities include profound irregularities in the course of vessels and the vascular basement membrane, changes in specific proteins and receptors associated with the cerebral endothelium, and increases in perivascular infiltrates. While noninvasive imaging and permeability studies provide no clear functional evidence to support the prevailing morphological evidence, focal and transient loss of integrity of the BBB in AD is probable. Thus, neuronal populations in circumscribed areas could become vulnerable. Cerebral amyloid angiopathy (CAA) is one of the pathological features highly associated with AD that may exacerbate the degenerative process. CAA may develop as a consequence of vascular changes at predisposed sites and precede at least some of the parenchymal amyloid deposits. It is not unlikely that many of these vascular changes contribute to the development of chronic hypoperfusion (or cerebrovascular insufficiency) that may lead to the progressive decline of cerebral functions in concert with aging.

A close relationship exists between the local capillary density in different brain structures and their local blood flow and metabolism. Capillary density appears to have developed depending on local functional demands. Investigation of single capillary perfusion has shown that all capillaries are perfused with plasma in the brain at any time point. Theories of capillary cycling and capillary recruitment have been based on experimental artifacts. Indirect evidence exists for a heterogeneity of perfusion under normal conditions, especially with respect to erythrocyte flow. The capillary diffusion capacity depends on, among other things, the available capillary surface area, which would increase with recruitment of capillaries. In the case of capillary perfusion heterogeneity, the capillary diffusion capacity may also be increased by homogenization of the perfusion rate (slowly perfused capillaries becoming faster perfused). This could give a physiological impression of an "apparent" increase in the capillary surface area. It is recommended that the terms "capillary cycling" and "recruitment" should be used in conjunction with more specific explanations, like "recruitment of erythrocytes" and "recruitment of previously nonperfused capillaries".

Multiple neuroreceptor changes are present in Alzheimer disease. These observations are based upon analysis from autopsy brain tissue or more seldom from neurosurgical biopsies. The drawback of information from autopsy material is that the receptor changes represent the final stage of the dementia disorder. It might therefore be somewhat misleading to base therapeutic strategies on these findings. Hopefully, new imaging techniques such as positron emission tomography (PET) and single photon emission tomography (SPECT) will provide valuable new in vivo data from the earlier course of the disease. Among the transmitter systems changed in Alzheimer disease, the cholinergic system shows the most consistent deficits. Cholinergic muscarinic receptors seem to be preserved in Alzheimer brains while nicotinic receptors show losses. The number of serotonin (both 5-HT1 and 5-HT2) and glutamate receptors are also reduced. Interestingly, kainate receptors increase in number while NMDA receptors are reduced in cortical Alzheimer tissue. Common for all receptor changes in Alzheimer disease is that the changes in number of binding sites are seen while the affinity constant remains unchanged. alpha- and beta-receptors and dopamine receptors are relatively preserved in Alzheimer brains. Among the neuropeptides, losses in receptor sites have been reported for somatostatin and neuropeptide Y (NPY). Interestingly, the number of CRF receptors are increased in cortical areas of Alzheimer brains. Thus, the muscarinic (M1), kainate, and CRF receptors show receptor compensatory reactions probably due to degenerative reactions in Alzheimer disease. Few attempts have been made to visualize neuroreceptors in vivo in Alzheimer patients. The field, however, is in dynamic progress. Reduced numbers of nicotinic receptors have been visualized in the brain of Alzheimer patients by PET and [11C]-nicotine and confirm earlier observations in post-mortem brain tissues. A lower uptake of (R)(+)[11C]nicotine compared to (S)(-)[11C]nicotine in patients with a mild form of dementia might be a possible diagnostic marker. SPECT studies indicate preserved muscarinic receptors in Alzheimer brains. Analysis of neuroreceptor changes in peripheral nonneural tissues have shown a reduction in nicotinic and muscarinic receptors in peripheral lymphocytes obtained from Alzheimer patients.

Hypothermia was first applied therapeutically as a local anesthetic and later was used to achieve organ protection during procedures necessitating circulatory interruption. Profound whole-body hypothermia, typically carried out in conjunction with extracorporeal bypass, has long been employed during cardiac and neurosurgical operative procedures. More recently, studies in small-animal experimental models of cerebral ischemia have provided persuasive evidence that even small decreases in brain temperature confer striking protection against ischemic neuronal injury. By contrast, small elevations of brain temperature during ischemia accelerate and extend pathologic changes in the brain and promote early disruption of the blood-brain barrier. Hypothermia retards the rate of high-energy phosphate depletion during ischemia and promotes postischemic metabolic recovery. More importantly, mild intraischemic hypothermia markedly attenuates the release of glutamate into the brain's extracellular space and significantly diminishes the release of dopamine. Similarly, the inhibition of calcium-calmodulin-dependent protein kinase II triggered by normothermic ischemia is prevented by hypothermia, as is the ischemia-induced translocation and inhibition of the key regulatory enzyme protein kinase C. Hypothermia also appears to facilitate the resynthesis of ubiquitin following ischemia. Studies of potential clinical importance have shown that moderate hypothermia is capable of attenuating ischemic damage even if instituted early in the postischemic period. In the setting of focal cerebral ischemia, moderate brain hypothermia reduces the infarct size (particularly in the setting of reversible middle cerebral artery occlusion); conversely, hyperthermia markedly increases the infarct volume. These studies underscore the importance of monitoring and regulating the brain temperature during experimental studies of cerebral ischemia to insure a consistent pathologic outcome and to avoid the false attribution of "pharmacoprotection" to drugs that reduce the body temperature. The measurement of brain temperature is now practicable in neurosurgical patients requiring invasive monitoring, and human studies have shown that cortical and cerebroventricular temperatures may exceed systemic temperatures. Mild to moderate decreases in brain temperature are neuroprotective in cerebral ischemia, while mild elevations of brain temperature are markedly deleterious in the setting of ischemia or injury. It is anticipated that controlled clinical trials of therapeutic brain temperature modulation will be undertaken over the next several years.

To date, positron emission tomography (PET) has been the only technology for the quantitative imaging of the changes of regional cerebral glucose (rCMRGl) or oxygen metabolism and blood flow (rCBF) associated with psychophysical stimulation and with the performance of mental tasks. So far, the majority of studies performed in healthy subjects demonstrated activation patterns involving not only certain limbic structures, most of all hippocampus, amygdala, parahippocampus, and cingulate, but also temporal, parietal, and occipital association cortex, depending on the applied paradigm. Indeed, the closest correlation between regional metabolism and memory test scores was found in mesiotemporal structures during the performance of memory tasks. Metabolic or CBF studies also seem to indicate that memorizing strategies may differ among individuals. PET was repeatedly used to investigate metabolic and/or blood flow abnormalities in patients with various amnestic syndromes. In cases with uni- or bilateral lesions of mesiotemporal structures, caused by surgery, herpes simplex encephalitis, or permanent ischemic, anoxic, or toxic damage, disturbances of metabolism and blood flow typically extended far beyond the morphological defects detected by computed tomography or magnetic resonance. In acute transient global amnesia, CBF and metabolism were decreased bilaterally in the mesiotemporal lobes, where hypometabolism persisted for some time, while higher values were observed in thalamus and some cortical areas. Diencephalic lesions causing Korsakoff's syndrome were associated with decreased rCMRGl in the hippocampal formation, upper brainstem, cingulate, and thalamus. Discrete thalamic infarcts caused amnesia and metabolic depression in the morphologically intact ipsilateral thalamus and in various projection areas of the infarcted nuclei. In ischemic forebrain lesions, amnestic deficits could be related to involvement of the anterior cingulate and of basal cholinergic nuclei. A large number of pathologies are diffusely spread out in the brain and affect partially or predominantly structures in memory processing. This holds true especially in the various dementias where memory disturbances are a consistent and often leading feature. Notably, Alzheimer's disease can be distinguished from other dementias by its characteristic pattern of metabolic dysfunction, with the most prominent changes occurring in parietotemporal and frontal association cortex whose residual metabolism is related to the severity of the disease. Therefore, activation studies using paradigms involving memory functions enhance that typical pattern. Only in the activated state is metabolism of mesiotemporal structures significantly correlated with the performance in memory tests. Other dementias also affect some of the distributed memory networks, with Huntington's disease suggesting a role of the striatum in memory processing.(ABSTRACT TRUNCATED AT 400 WORDS)

Over the past 20 years, tritiated radioligand receptor binding has been used to study the relationship between dopamine receptor binding and various movement disorders, in particular Parkinson disease. More recently, in vivo imaging techniques like positron emission tomography and single photon emission computed tomography have been used to study the dopaminergic system in these disorders. This review describes the data that have been obtained using in vivo and in vitro measurements of the dopaminergic system in movement disorders, and examines the relationship between them. The contribution of these techniques to clinical management is described.

Synthesis of the polyamines putrescine, spermidine, and spermine is controlled by the activity of the key enzymes ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC). Beside their function in cellular growth processes, polyamines and particularly putrescine play a role in calcium-related events at the cell membrane, coupling an extracellular stimulus to an intracellular response (second messenger-like reactions), modulate the calcium-buffering capacity of mitochondria (spermine), and, if present in the extracellular compartment, modulate the activity of the N-methyl-D-aspartate receptor (spermidine and spermine). Reversible cerebral ischemia triggers pathological disturbances in polyamine metabolism that are characterized by a sharp increase in ODC synthesis, even in the most vulnerable hippocampal CA1 subfield in which overall protein synthesis is severely depressed at the same time, and a marked suppression of SAMDC synthesis in parallel with the inhibition of overall protein synthesis. ODC immunohistochemistry has revealed that the observed changes are neuronal responses to reversible ischemia. These changes in enzyme activities result in an overshoot in the formation of putrescine, the product of ODC activity. Spermine levels are significantly reduced in vulnerable brain structures after prolonged recirculation. In addition, evidence is accumulating that polyamines may be released from the cell during ischemia and after prolonged recirculation at a time when cell necrosis is apparent. This review will summarize the major features of ischemia-induced disturbances in polyamine metabolism and the possible consequences for the cells involved, taking into account that the underlying changes may be indicative of either the activation of a recovery process of neurons from the metabolic stress produced by reversible ischemia or pathological disturbances resulting in the manifestation of neuronal necrosis. Elucidating the mechanisms responsible for the postischemic disturbances in polyamine metabolism may lead to a better understanding of the molecular mechanisms involved in the development of neuronal necrosis after different pathological stimuli.