Cerebrovascular and brain metabolism reviews最新文献

Since the late 1800s, when Alzheimer and Binswanger proposed the concept of "arteriosclerotic brain degeneration," there has been an evolution in thinking regarding cerebrovascular disease (CVD) as a basis for dementia. While later work recognized the importance of specific infarct characteristics including volume, multiplicity, and location, recent studies have found that many factors may work in combination with those characteristics to produce dementia, including white matter disease; vascular risk factors such as diabetes; comorbid illnesses, particularly those that might produce cerebral ischemia or hypoxia; genetic factors; and host characteristics such as older age and fewer years of education. Studies of the prevalence of vascular dementia (VaD) have suggested that CVD is second only to Alzheimer's disease as a basis for dementia in Western countries and the most common basis in certain Asian countries, but those studies may have underestimated the frequency of dementia associated with CVD due to a failure to perform brain imaging and decreased survival among patients with CVD. Few studies of the incidence of VaD have been performed, but they have also consistently demonstrated an elevated risk associated with CVD. While certain methodologic issues have contributed to the debate regarding the importance of CVD as a basis for dementia, including variability in the techniques that have been used to characterize brain lesions, assess cognitive function, and diagnose dementia; difficulties inherent in the determination of a causal role for CVD in dementia; and the potential confounding effects of aphasia and depression in patients with stroke, it is clear that VaD remains an important public health problem.

Brain damage due to an episode of cerebral hypoxia/ischemia remains a major problem in the human infant, providing impetus for the testing of potential neuroprotective agents in animal models. Although these animal models do not mirror the human pathology exactly (e.g., with respect to regions vulnerable to damage), they usually have the histological characteristics of gray matter hypoxic/ischemic injury in the human. An important factor in comparing models directly is the stage of development of the brain at birth, which varies widely between species. Approaches to prevent or treat cerebral hypoxic/ischemic damage in neonates have paralleled those in adults. However, most of these results should be interpreted cautiously, since neonatal rat models with little concurrent physiological monitoring are often used. As in adults, moderate hypothermia during the insult or a preconditioning stress prior to the insult has prevented hypoxic/ ischemic brain damage. Different from adults is the demonstration that pretreatment with moderate doses of glucocorticoids or hyperglycemia during the hypoxic/ ischemic insult protects the brain against infarction. Partial protection, primarily in neonatal rats, has also been produced by pretreatment with voltage-sensitive calcium channel antagonists, free radical scavengers, growth factors, gangliosides, anticonvulsants, antiinflammatory agents, and nitric oxide synthase inhibitors. Posttreatment has been effective with a few agents. The most consistent has been the protective effect observed with glutamate receptor antagonists administered before but also up to 4 h after the insult. The effects of most of these therapies on blood glucose, body temperature, and/or the systemic circulation should be measured and the protective effects confirmed in larger species prior to considering clinical applications.

This article contains an overview of selected clinical techniques employed for neurointensive care monitoring and testing of cerebral autoregulation of patients following severe head injury. Multiple modalities are used for monitoring of cerebral haemodynamic reserve, including intracranial pressure, cerebral perfusion pressure (CPP), blood flow velocity (FV) in the middle cerebral artery (MCA), jugular bulb oxygen saturation, laser-Doppler cortical flowmetry, near infrared spectroscopy of cerebral cortex, tissue oxygenation, and microdialysis. Large volumes of information demand specialised computer support for sensible interpretation and filtration of artifacts. Methods of testing of cerebral autoregulatory reserve based on transcranial Doppler ultrasonography are reviewed. Repetitive or continuous assessment is important in practice as autoregulatory reserve may fluctuate in time. Static and dynamic rates of autoregulation show sensitivity to carbon dioxide-induced vasodilatation, but fail to correlate with outcome following head injury. The carotid artery compression test, useful for assessment of patients after subarachnoid haemorrhage, has yet to prove its usefulness in head injury. Continuous waveform analysis of MCA FV and CPP correlates with coma score after resuscitation and outcome and hence may be considered as a robust method for the assessment of autoregulation in ventilated head trauma patients.

Cerebral blood flow (CBF) is vital for the perfusion of brain tissue. It is frequently deranged in acute neurosurgical disorders, particularly subarachnoid haemorrhage and head injury. Despite its importance, in clinical practice the routine measurement of CBF is uncommon, as changes in CBF can occur abruptly. However, a method of CBF monitoring may be potentially useful, particularly if warning could be obtained of impending ischaemia before neurological deterioration. Measurement of tissue thermal clearance has been used as an estimate of local tissue blood flow since 1933. Its history is full of controversy, mostly centred around quantification. The ability of perfused tissues to clear heat is, as a first approximation, the sum of two components: a fixed component related to the constituents of the tissue, primarily the water content, and a variable convective component, related to the local blood flow. The mathematical relationship between flow and the observed increment in thermal clearance is still debatable. Here, the history of thermal clearance is reviewed, and the results of our work with a relatively simple device are described. It consisted of an implantable probe, designed to measure the thermal clearance of the cortical surface in arbitrary clearance units (CU), ranging from 27 CU (cadaveric) to 69 CU (well perfused brain). Pre- and postoperative studies showed that the system was capable of following changes in blood flow rapidly. The cortical thermal clearance (CTC) was monitored postoperatively in 24 patients after aneurysm surgery. Most remained clinically stable and had thermal clearances over 50 CU. In others, however, it was seen that a low-or falling-thermal clearance was associated with development of a neurological deficit. Analysis using receiver operating characteristics curves established that the method had a sensitivity of 0.86 and a specificity of 0.82 in the detection of a contralateral ischaemic motor deficit. No patient in whom the CTC remained above 50 CU ever developed a new neurological deficit, whereas all patients with a CTC below 35 did. The evidence-historical, mathematical, practical, and theoretical-that CTC is closely related to local blood flow is discussed. Changes in thermal clearance have been observed prior to the development of ischaemic neurological deterioration. Detection of imminent ischaemia may become increasingly important as means of improving cortical blood flow become more widely available. Whether such early detection- and subsequent treatment-of ischaemia will result in better patient outcome remains to be established. I believe it will.

Changes in gene expression in the brain in response to adverse conditions, such as ischemia or excitotoxin exposure, may be part of the injury process or represent an adaptive response which may be protective during subsequent stressful events. In this review we have considered the regulation, functions and potential relationships to the pathophysiology of ischemia of several major groups of stress-induced genes, including those of the M(r) 27,000, 32,000 (heme oxygenase), 70,000 and 90,000 heat shock protein families, the glucose-regulated proteins, glucose transporters and ubiquitin. Patterns of gene expression in several injury models, including focal and global ischemia, excitotoxin/ seizure-related injury and hyperthermia are reviewed. In vitro expression studies and the phenomenon of ischemic tolerance are also discussed. It is concluded that stress gene expression provides a useful marker of cellular injury, and that disjunction of mRNA and protein expression may be indicative of imminent death in cells which survive the initial insult. Though other stress proteins may play a role, it seems unlikely that neuronal hsp70 expression is a major contributor to ischemic tolerance.

Recent advances in the clinical and neuroimaging features of vascular dementia (VAD) versus Alzheimer type dementia (DAT) are described. The lacunar type of VAD, which is often accompanied by silent strokes and a progressive course, is easily confused with DAT. Measurements of cerebral blood flow (CBF) and metabolism (CMR) displayed as brain maps, identify VAD from DAT because of the multifocal and often subcortical nature of the infarcts in VAD, which are strikingly different from the diffuse cortical reductions of CBF and CMR in DAT. Thus, neuroimaging is important for establishing the diagnosis in these two most common forms of dementia in the elderly. A dramatic method for separating VAD from DAT is by utilizing the noninvasive acetazolamide test and xenon contrast CT scanning for measuring the cerebral vasomotor capacitance. In DAT the vasodilator reserve is increased due to the law of initial values. In VAD it is absent or severely blunted so that the differences between the two underlying causes of the dementias become readily apparent.

In the last two decades, a tremendous amount of knowledge has been accumulated in various fields of biomedical research that discloses mechanisms of platelet/leukocyte/endothelium interactions. Occupying a strategically important location between circulating blood and underlying tissues, the endothelium effectively modulates both the functional state of the blood cells and the tone of vascular smooth muscle by generating or metabolizing a host of humoral substances. Under normal conditions, the endothelium releases agents with predominantly vasodilator and antiaggregant/anticoagulant activity that prevent thrombotic and angiospastic disorders. However, a variety of pathophysiological stimuli may trigger endothelial reorganization with the expression of different prothrombotic factors and activation of platelets and leukocytes that, combined, leads to blood cell adhesion to the endothelial monolayer, aggregation as thrombi, and the formation of numerous spasmogenic substances. Activation of the blood cells in the vicinity of the endothelium may induce endothelial dysfunction/injury, resulting in impairment of normal endothelial antispasmodic control. Within the microcirculatory bed, intravascular activation of the blood cells leads to scattered microvessel plugging, increased vascular permeability, edema formation, and cytotoxic actions of blood cell-released agents on the underlying tissue. A growing body of evidence suggests that these processes may be involved in pathophysiological cerebrovascular reactions including symptomatic angiospasm following subarachnoid hemorrhage, segmental occlusive constriction in atherosclerotic cerebral arteries, and constrictive vasomotion in microvessels. A perturbation in the delicate equilibrium between blood cells and endothelium in the microcirculation seems to be a factor aggravating ischemic brain damage or even primarily causing focal cerebral ischemia and scattered microinfarctions. Increased predisposition to these pathophysiologic events might influence unfavorably the effects of risk factors such as hypercholesterolemia, hypertension, and diabetes on cerebrovascular morbidity and mortality. Although the importance of blood cell/endothelium imbalance appears to be clear, its pharmacologic regulation is not sufficiently established. Some drugs have been demonstrated to limit platelet and/or leukocyte activity and protect the endothelial defense mechanisms, but the optimal therapeutic strategy has yet to be elaborated.

In the surroundings of focal ischemic lesions, repetitive spreading depression (SD)-like depolarizations occur. These depolarizations are triggered by the anoxic release of potassium and excitatory amino acids from the infarct core, and they are propagated over the whole hemisphere at a speed of approximately 3 mm/min. The associated fluid shifts can be detected by diffusion-weighted magnetic resonance imaging (MRI) and correlate with an aggravation of the metabolic disturbance. In the peripheral, normally perfused brain regions of the infarcted hemisphere, the metabolic workload of SD is coupled to a parallel increase of blood flow, ensuring undisturbed oxygen supply. In the periinfarct penumbra, in contrast, the reduced hemodynamic capacity of the collateral system prevents adequate oxygenation and results in episodes of tissue hypoxia. Periinfarct SDs induce expression of immediate early genes in all brain regions except the ischemic core, i.e, in the penumbra and the surrounding normal brain tissue. In the penumbra, the hypoxic episodes evoked by SDs produce an additional stress response that is reflected by the expression of stress proteins and the suppression of global protein synthesis. In the most severely ischemic parts of the penumbra, periinfarct depolarizations may turn into terminal depolarization, resulting in a stepwise expansion of the infarct core. Postischemic application of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor antagonists suppresses periinfarct depolarizations, reverses the penumbral suppression of protein synthesis, and reduces infarct size. These observations demonstrate that periinfarct depolarizations aggravate focal ischemic injury and suggest that therapeutic suppression of these depolarizations minimizes infarct size.

In this article we review recent developments in the field of "first-" and "second-generation" perfluorochemical (PFC) oxygen carriers. Particular emphasis is placed on the latest research and its implications regarding the clinical and experimental neurosciences. These compounds are ideally suited to the transportation of O2 within the vascular system. Two properties that facilitate their use in this respect are their very high solubility coefficients for O2 and CO2 and their biological inertness. Unfortunately, their widespread use has been limited by logistical difficulties associated particularly with their molecular behavior in vivo. However, advances in PFC technology have led to renewed interest. A potential role for second-generation PFCs in cerebral protection is exciting. Other possible significant applications are slowly becoming established in clinical practice. Currently under investigation are potential uses in the management of severe head injuries, radiotherapy or chemotherapy of malignant brain tumors, protection against air embolism, preservation of organs for transplantation, and as a tool in microsurgery of the retina or other parts of the CNS. Diagnostic neuroimaging applications could include the employment of PFCs as adjuncts in ultrasound, Doppler, computed tomography (CT), and magnetic resonance (MR) to achieve enhanced imaging and precise staging of inflammatory, neoplastic, and vascular disease processes. Research applications could include their use in magnetic resonance imaging and spectroscopy in assessing cerebral blood flow, local oxygen tension, and brain metabolism, in molecule-specific imaging, and as physiological markers of O2, ions, and pH.

Endogenous opioid peptides are present in cerebral perivascular nerves and in the CSF, and their concentrations are changing in response to stimuli that activate regulatory mechanisms of the cerebral circulation (e.g., alterations of the perfusion pressure or changes of the arterial O2 tension). Opiate receptors are expressed in the cells of the CNS and the cerebrovascular bed, and their activation modulates the function of other vasoregulatory mechanisms (i.e., the autonomic nervous system, nitric oxide, prostanoids, vasopressin) that are involved in the control of the cerebrovascular tone. The direct vasomotor effects of opioid peptides and opiates on the cerebral arteries under in vitro or in situ conditions appear to be weak or absent in several species. However, Met- and Leu-enkephalin induce pial arterial vasodilation in the newborn pig. In this species, beta-endorphin acts as a constrictor, whereas dynorphin may induce either dilation or constriction depending on the experimental conditions. The influence of exogenously applied natural and synthetic opioids on the cerebral blood flow (CBF) is determined mainly by their metabolic, neuronal, and respiratory effects. Hypothalamic and pituitary circulations are especially sensitive to opioids. Under resting conditions, endogenous opioid peptides do not participate in the regulation of the cerebrovascular tone and CBF. On the other hand, mu and delta opiate receptor stimulation by endogenous opioid peptides, interacting with other vasoactive factors, obviously contributes to the hypoxia- and hypercapnia-induced cerebral vasodilation. Furthermore, endogenous opioid mechanisms are involved in the autoregulation of the hypothalamic blood flow. Thus, the endogenous opioid system may well represent a latent regulatory mechanism, which is of limited importance under basal conditions, but becomes more important under conditions of stress. Synthetic exogenous opioids do not appear to influence the hypoxic or hypercapnic CBF responses or the cerebral autoregulatory process.