PET脑血流量测量方法和临床应用进展

脑血流量测量对于脑血管疾病、脑肿瘤诊断和疗效评估具有重要的临床价值。PET是基于正电子示剂技术无创性、精确测量脑血流量的方法,正日益广泛地应用于临床。按照PET测量脑血流量的方法和使用的正电子示踪剂不同,其测量方法分为平衡法、放射自显影法和动力学方法三种。18O-H2O示踪剂PET测量脑血流量被认为测量脑血流方法的"金标准"。随着PET设备分辨率提高、新的图像重建方法使用和PET与MRI图像融合技术不断成熟,18F-FDG首次通过、采用图像衍生动脉输入函数(imagederived arterial input function,IDAIF)替代动脉抽血样精确测量脑血量方法受到广泛重视,有可能逐步取代高成本的18O-H2O测量脑血流量。PET无创、方便和精确测量脑血流量的方法在临床应使用有助于脑血管性疾病、脑肿瘤和脑退行性病变早期诊断、鉴别诊断和个性化医疗。本文介绍PET脑血流量测量原理、方法和临床应用进展。     

Targeting Therapeutics Across the Blood Brain Barrier (BBB), Prerequisite Towards Thrombolytic Therapy for Cerebrovascular Disorders—an Overview and Advancements

Cerebral tissues possess highly selective and dynamic protection known as blood brain barrier (BBB) that regulates brain homeostasis and provides protection against invading pathogens and various chemicals including drug molecules. Such natural protection strictly monitors entry of drug molecules often required for the management of several diseases and disorders including cerebral vascular and neurological disorders. However, in recent times, the ischemic cerebrovascular disease and clinical manifestation of acute arterial thrombosis are the most common causes of mortality and morbidity worldwide. The management of cerebral Ischemia requires immediate infusion of external thrombolytic into systemic circulation and must cross the blood brain barrier. The major challenge with available thrombolytic is their poor affinity towards the blood brain barrier and cerebral tissue subsequently. In the clinical practice, a high dose of thrombolytic often prescribed to deliver drugs across the blood brain barrier which results in drug dependent toxicity leading to damage of neuronal tissues. In recent times, more emphasis was given to utilize blood brain barrier transport mechanism to deliver drugs in neuronal tissue. The blood brain barrier expresses a series of receptor on membrane became an ideal target for selective drug delivery. In this review, the author has given more emphasis molecular biology of receptor on blood brain barrier and their potential as a carrier for drug molecules to cerebral tissues. Further, the use of nanoscale design and real-time monitoring for developed therapeutic to encounter drug dependent toxicity has been reviewed in this study.KEY WORDS: blood brain barrier (BBB), cerebral ischemic disorders, drug delivery, earthworm protease, neurodegenerative disorder, thrombolytic     

Influence of an extract of Ginkgo biloba on cerebral blood flow and metabolism

The purpose of the present investigation was to examine the effects of an extract of Ginkgo biloba (EGB) on blood glucose levels, on local cerebral blood flow as well as on cerebral glucose concentration and consumption. The local cerebral blood flow (LCBF) was measured in conscious rats by means of the 14C-iodoantipyrine technique and local cerebral glucose utilization (LCGU) by 14C-2-deoxy-glucose autoradiography. EGB increased the LCBF in 39 analyzed, anatomically defined brain structures by 50 to 100 per cent. No influence of EGB on LCGU was demonstrable. However, EGB enhanced the blood glucose level dose-dependently. Substrates and metabolites of energy metabolism were measured in the cortex of the isolated rat brain perfused at constant rate and with 7 mmol/l glucose added to the perfusion medium. In these experiments EGB decreased the cortical glucose concentration without other substrate levels being changed. These results suggest that glucose uptake may be inhibited by EGB. It is argued that the effects of EGB on brain glucose concentration and blood flow may contribute to its protection of brain tissue against ischemic or hypoxic damage.     

Effect of intravenous eicosapentaenoic acid on cerebral blood flow, edema and brain prostaglandins in ischemic gerbils

Eicosapentaenoic acid is converted by cyclo-oxygenase to the prostacyclin, PGI3. Consequently eicosapentaenoic acid might protect the brain from the impairment in cerebral blood flow that follows temporary cerebral arterial occlusion. We studied the effect of 90% pure eicosapentaenoic acid, given intravenously, on cerebral blood flow, brain water and prostaglandins after ischemia in gerbils. Ischemia was produced by bilateral carotid occlusion for 15 min followed by reperfusion for 2 h. In experimental gerbils, 0.833 mg or 0.167 mg of eicosapentaenoic acid (Na salt) was given intravenously followed by a continuous infusion of 1 mg h-1. Control gerbils were given 0.167 mg of linoleic acid (Na salt) intravenously followed by a continuous infusion of 1 mg h-1 or a saline infusion. Regional cerebral blood flow was measured by the hydrogen clearance method and brain water by the specific gravity technique. Brain diene prostaglandins were measured by radioimmunoassay. In control gerbils cerebral blood flow decreased significantly during reperfusion and remained depressed after 2 h of reperfusion. In eicosapentaenoic acid treated gerbils blood flow decreased initially but after 2 h of reperfusion blood flow was significantly higher than in control gerbils. Brain edema and brain diene prostaglandins were not significantly different between control and experimental groups. Our study indicates that eicosapentaenoic acid, given intravenously, improves cerebral blood flow after ischemia and reperfusion. We speculate that this effect may be due to the formation of the prostacyclin, PGI3.     

Regional Cerebral Glucose Metabolism and Blood Flow During the Silent Phase of Methylmercury Neurotoxicity in Rats

Methylmercuric chloride was given to rats in a neurotoxic dose regimen (six daily doses of 8 mg kg-1 p.o.). During the silent (asymptomatic) phase of intoxication, the rates of cerebral glucose influx and cerebral glucose phosphorylation were measured simultaneously using 2-deoxyglucose. Regional cerebral blood flow was also measured using iodoantipyrine. The unidirectional flux of glucose into brain was not affected by methylmercury, and differences in the rates of glucose phosphorylation from region to region remained coupled to the regional cerebral blood flow. However, the blood flow was reduced throughout the brain, an observation suggesting that the operational level of metabolically regulated blood flow had been reset. Thus, in spite of a generalised reduction in blood flow, there was no indication of impaired cerebral glucose supply or utilization during the silent phase of methylmercury intoxication.     

Effect of Selective Brain Hypothermia on Regional Cerebral Blood Flow and Tissue Metabolism Using Brain Thermo-Regulator in Spontaneously Hypertensive Rats

To investigate the effect of selective hypothermia of the brain (brain cooling) on regional cerebral blood flow and tissue metabolism, we have developed a brain thermo-regulator. Brain temperature was modulated by a water-cooled metallic plate placed on the surface of the rats' scalp to get the appropriate brain temperature precisely with ease. Regional cerebral blood flow and brain temperature were measured simultaneously using a Teflon-coated platinum electrode and thermocouple probe inserted stereotaxically into the parietal cortex and thalamus in spontaneously hypertensive rats. Experimental forebrain ischemia was induced by the occlusion of bilateral common carotid artery under normo- and hypothermic brain condition, and the supratentorial brain tissue metabolites were measured enzymatically after 60 min of forebrain ischemia. When cortical temperature was set to hypothermia, cortical blood flow was significantly lowered by 40% at 30°C and 20% at 33°C as compared with that at 36°C (p < 0.0001 and p < 0.05, respectively). Thalamic blood flow was also significantly reduced by 20% when cortical temperature was set to 30°C as compared with 36°C (p < 0.05). There were no significant differences in arterial blood pressure and gas parameters throughout these experiments. In the rats with selective brain hypothermia (30°C) immediately after the induction of cerebral ischemia, the level of brain ATP concentration after 60 min of ischemia was significantly higher than that in normothermia rats (36°C) (p < 0.05). Our findings indicate that: 1) the metallic plate brain thermo-regulator is useful in small animal experiments; 2) regional brain temperature regulates regional cerebral blood flow; and 3) selective brain hypothermia, even started after the forebrain ischemia, ameliorates the derangement of brain metabolism, suggesting its effectiveness as a cytoprotective strategy.     

Effect of intravenous eicosapentaenoic acid on cerebral blood flow, edema and brain prostaglandins in ischemic gerbils

Eicosapentaenoic acid is converted by cyclo-oxygenase to the prostacyclin, PGI₃. Consequently eicosapentaenoic acid might protect the brain from the impairment in cerebral blood flow that follows temporary cerebral artirial occlusion. We studied the effect of 90% pure eicosapentaenoic acid, given intravenously, on cerebral blood flow, brain water and prostaglandins after ischemia in gerbils. Ischemia was produced by bilateral carotid occlusion for 15 min followed by reperfusion for 2 h. In experimental gerbils, 0.833 mg or 0.167 mg of eicosapentaenoic acid (Na salt) was given intravenously followed by a continuous infusion of 1 mg h⁻¹. Control gerbils were given 0.167 mg of linoleic acid (Na salt) intravenously followed by a continuous infusion of 1 mg h⁻¹ or a saline infusion. Regional cerebral blood flow was measured by the hydrogen clearance method and brain water by the specific gravity technique. Brain diene prostaglandins were measured by radioimmunoassay. In control gerbils cerebral blood flow decreased significantly during reperfusion and remained depressed after 2 h of reperfusion. In eicosapentaenoic acid treated gerbils blood flow decreased initially but after 2 h of reperfusion blood flow was significantly higher than in control gerbils. Brain edema and brain diene prostaglandins were not significantly different between control and experimental groups.Our study indicates that eicosapentaenoic acid, given intravenously, improves cerebral blood flow after ischemia and reperfusion. We speculate that this effect may be due to the formation of the prostacyclin, PGI₃.     

Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging

Pericytes play a key role in the development of cerebral microcirculation. The exact role of pericytes in the neurovascular unit in the adult brain and during brain aging remains, however, elusive. Using adult viable pericyte-deficient mice, we show that pericyte loss leads to brain vascular damage by two parallel pathways: (1) reduction in brain microcirculation causing diminished brain capillary perfusion, cerebral blood flow, and cerebral blood flow responses to brain activation that ultimately mediates chronic perfusion stress and hypoxia, and (2) blood-brain barrier breakdown associated with brain accumulation of serum proteins and several vasculotoxic and/or neurotoxic macromolecules ultimately leading to secondary neuronal degenerative changes. We show that age-dependent vascular damage in pericyte-deficient mice precedes neuronal degenerative changes, learning and memory impairment, and the neuroinflammatory response. Thus, pericytes control key neurovascular functions that are necessary for proper neuronal structure and function, and pericyte loss results in a progressive age-dependent vascular-mediated neurodegeneration.     

Simultaneous Measurement of Cerebral Blood Flow and Unidirectional Movement of Substances Across the Blood-Brain Barrier: Theory, Method, and Application to Leucine

Abstract: The uptake of compounds by the brain depends upon cerebral blood flow. To determine the normal blood flow-cerebral extraction relationship, a method for rapid, simultaneous measurement of cerebral blood flow and brain extraction was developed and applied to blood-brain leucine transfer. Awake rats were injected intravenously with a mixture of n-[¹⁴C]butanol and [³H]leucine. The quantities of indicators accumulated over the following 5–12 s in brain and in a sample of arterial blood withdrawn at a known rate were used to determine the flux of butanol and leucine into brain. Butanol extraction was assessed independently by measuring arterial and cerebral venous concentrations of the indicator after a bolus injection. Cerebral blood flow was equal to the ratio of butanol flux into brain to butanol extraction by brain; leucine extraction was then calculated as the ratio of leucine influx to cerebral blood flow. Leucine extraction by brain and cerebral blood flow were shown to be related exponentially. The maximum velocity of active leucine transport was virtually the same at flows of 150 and 400 ml/100 g/min. The present method is theoretically applicable to the measurement of the extraction of any compound from blood by brain. By measuring the noimal blood flow-extraction relationship, one can differentiate changes in extraction secondary to altered flow from changes intrinsic to pathologic conditions with inconstant cerebral blood flow.     

Immunohistochemistry of Atrial Natriuretic Peptide in Brain Infarction

Atrial natriuretic peptide (ANP) was originally isolated from cardiac atria, and has potent natriuretic, diuretic, and vasorelaxant properties. It has been localized in neurons and astrocytes in the cerebral cortex and the white matter. We hypothesize that glial ANP may contribute to the regulation of cerebral blood flow in brain infarction. In order to elucidate this possible role, the immunohistochemistry of ANP was studied in cases of brain infarction and in other cases of brain trauma for comparison. A statistically significant increase in the number of ANP-immunoreactive glial cells (mainly astrocytes) was observed in the white matter surrounding the brain infarction compared with the intact area. No statistically significant increase in ANP-immunoreactive glial cell number was observed in the cerebral white matter from brain haemorrhage, contusion and control cases. Our results indicate that glial ANP may increase in number in brain infarction, and that it may be involved in the regulation of the cerebral blood flow in the infarcted area.     

Local and global cerebral blood flow and glucose utilization in the α-galactosidase A knockout mouse model of Fabry disease

Fabry disease is an X-linked lysosomal disorder characterized by deficient alpha-galactosidase A activity and intracellular accumulations of glycosphingolipids, mainly globotriaosylceramide (Gb3). Clinically, patients occasionally present CNS dysfunction. To examine the pathophysiology underlying brain dysfunction, we examined glucose utilization (CMR(glc)) and cerebral blood flow (CBF) globally and locally in 18 brain structures in the alpha-galactosidase A gene knockout mouse. Global CMR(glc) was statistically significantly reduced by 22% in Fabry mice (p < 0.01). All 18 structures showed decreases in local CMR(glc) ranging from 14% to 33%. The decreases in all structures of the diencephalon, caudate-putamen, brain stem, and cerebellar cortex were statistically significant (p < 0.05). Global cerebral blood flow (CBF) and local CBF measured in the same 18 structures were lower in Fabry mice than in control mice, but none statistically significantly. Histological examination of brain revealed no cerebral infarcts but abundant Gb3 deposits in the walls of the cerebral vessels with neuronal deposits localized to the medulla oblongata. These results indicate an impairment in cerebral energy metabolism in the Fabry mice, but one not necessarily due to circulatory insufficiency.     

Hypertension and cerebrovascular dysfunction

Essential hypertension has devastating effects on the brain, being the major cause of stroke and a leading cause of dementia. Hypertension alters the structure of cerebral blood vessels and disrupts intricate vasoregulatory mechanisms that assure an adequate blood supply to the brain. These alterations threaten the cerebral blood supply and increase the susceptibility of the brain to ischemic injury as well as Alzheimer's disease. This review focuses on the mechanisms by which hypertension disrupts cerebral blood vessels, highlighting recent advances and outstanding issues.     

Regional cerebral blood flow changes during hypothermia

1. 1. When brain temperature was decreased from 38 to 22 °C using selective hypothermia, tissue blood flow decreased significantly in cerebral cortex, cerebellum, and thalamus, but did not significantly change in hypothalamic or brain stem tissue.

2. 2. A further decrease in brain temperature to 8 °C produced an increase in blood flow in all tissues except cerebral cortex compared to tissue blood flow measured at 22 °C. Compared to normothermic values, blood flow remained significantly decreased at 8 °C in cerebral and cerebellar cortex and was increased in brain stem.

3. 3. After rewarming, tissue blood flow returned to original baseline values in all tissues except cerebral cortex where blood flow was slightly but significantly decreased and brain stem, where blood flow was increased.

4. 4. These results indicate that the cerebrovascular effects of selective brain cooling are regionally specific. These changes appear to be due to both direct and indirect effects of cerebral hypothermia since brain tissue blood flow changes are apparent, compared to control values, after rewarming of the brain.

     

Electroacupuncture increased cerebral blood flow and reduced ischemic brain injury: dependence on stimulation intensity and frequency

Stroke causes ischemic brain injury and is a leading cause of neurological disability and death. There is, however, no promising therapy to protect the brain from ischemic stress to date. Here we show an exciting finding that optimal electroacupuncture (EA) effectively protects the brain from ischemic injury. The experiments were performed on rats subjected to middle cerebral artery occlusion (MCAO) with continuous monitoring of cerebral blood flow. EA was delivered to acupoints of "Shuigou" (Du 26) and "Baihui" (Du 20) with different intensities and frequencies to optimize the stimulation parameters. The results showed that 1) EA at 1.0-1.2 mA and 5-20 Hz remarkably reduced ischemic infarction, neurological deficit, and death rate; 2) the EA treatment increased the blood flow by >100%, which appeared immediately after the initiation of EA and disappeared after the cessation of EA; 3) the EA treatment promoted the recovery of the blood flow after MCAO; 4) "nonoptimal" parameters of EA (e.g., <0.6 mA or >40 Hz) could not improve the blood flow or reduce ischemic injury; and 5) the same EA treatment with optimal parameters could not increase the blood flow in naive brains. These novel observations suggest that appropriate EA treatment protects the brain from cerebral ischemia by increasing blood flow to the ischemic brain region via a rapid regulation. Our findings have far-reaching impacts on the prevention and treatment of ischemic encephalopathy, and the optimized EA parameters may potentially be a useful clue for the clinical application of EA.     

Ex vivo analysis of lactate and glucose metabolism in the rat brain under different states of depressed activity

Brain metabolism of glucose and lactate was analyzed by ex vivo NMR spectroscopy in rats presenting different cerebral activities induced after the administration of pentobarbital, alpha-chloralose, or morphine. The animals were infused with a solution of either [1-(13)C]glucose plus lactate or glucose plus [3-(13)C]lactate for 20 min. Brain metabolite contents and enrichments were determined from analyses of brain tissue perchloric acid extracts according to their post-mortem evolution kinetics. When amino acid enrichments were compared, both the brain metabolic activity and the contribution of blood glucose relative to that of blood lactate to brain metabolism were linked with cerebral activity. The data also indicated the production in the brain of lactate from glycolysis in a compartment other than the neurons, presumably the astrocytes, and its subsequent oxidative metabolism in neurons. Therefore, a brain electrical activity-dependent increase in the relative contribution of blood glucose to brain metabolism occurred via the increase in the metabolism of lactate generated from brain glycolysis at the expense of that of blood lactate. This result strengthens the hypothesis that brain lactate is involved in the coupling between neuronal activation and metabolism.     

Acute effects of three isoflavone class phytoestrogens and a mycoestrogen on cerebral microcirculation

Phytoestrogens and mycoestrogens are naturally occurring plant and fungus secondary metabolites with estrogen-like structure and/or actions. We aimed to check the hypothesis that phytoestrogens and mycoestrogens, due to their ability to elicit cerebral vasodilation, can induce acute increases in brain blood perfusion. For this purpose, we continuously recorded cerebrocortical perfusion by laser-Doppler flowmetry in anesthetized rats receiving intracarotid infusions (1 mg/kg) of one of the following estrogenic compounds: biochanin A, daidzein, genistein or zearalanone. We have shown the ability of two isoflavone class phytoestrogens (daidzein and biochanin A) and the mycoestrogen zearalanone to induce acute increases in brain blood flow when locally infused into the cerebral circulation of anesthetized rats. The isoflavone genistein failed to induce a significant increase in brain perfusion. No concomitant changes in blood pressure were recorded during the cerebral effects of the estrogenic compounds. Therefore, these microcirculatory effects were due to direct actions of the estrogenic compounds on the cerebrovascular bed.     

Inflammation in utero exacerbates ventilation-induced brain injury in preterm lambs

Cerebral blood flow disturbance is a major contributor to brain injury in the preterm infant. The initiation of ventilation may be a critical time for cerebral hemodynamic disturbance leading to brain injury in preterm infants, particularly if they are exposed to inflammation in utero. We aimed to determine whether exposure to inflammation in utero alters cardiopulmonary hemodynamics, resulting in cerebral hemodynamic disturbance and related brain injury during the initiation of ventilation. Furthermore, we aimed to determine whether inflammation in utero alters the cerebral hemodynamic response to challenge induced by high mean airway pressures. Pregnant ewes received intra-amniotic lipopolysaccharide (LPS) or saline either 2 or 4-days before preterm delivery (at 128 ± 1 days of gestation). Lambs were surgically instrumented for assessment of pulmonary and cerebral hemodynamics before delivery and positive pressure ventilation. After 30 min, lambs were challenged hemodynamically by incrementing and decrementing positive end-expiratory pressure. Blood gases, arterial pressures, and blood flows were recorded. The brain was collected for biochemical and histological assessment of inflammation, brain damage, vascular extravasation, hemorrhage, and oxidative injury. Carotid arterial pressure was higher and carotid blood flow was more variable in 2-day LPS lambs than in controls during the initial 15 min of ventilation. All lambs responded similarly to the hemodynamic challenge. Both 2- and 4-day LPS lambs had increased brain interleukin (IL)-1β, IL-6, and IL-8 mRNA expression; increased number of inflammatory cells in the white matter; increased incidence and severity of brain damage; and vascular extravasation relative to controls. Microvascular hemorrhage was increased in 2-day LPS lambs compared with controls. Cerebral oxidative injury was not different between groups. Antenatal inflammation causes adverse cerebral hemodynamics and increases the incidence and severity of brain injury in ventilated preterm lambs.     

Exercise induces the release of heat shock protein 72 from the human brain in vivo

The present study tested the hypothesis that in response to physical stress the human brain has the capacity to release heat shock protein 72 (Hsp72) in vivo. Therefore, 6 humans (males) cycled for 180 minutes at 60% of their maximal oxygen uptake, and the cerebral Hsp72 response was determined on the basis of the internal jugular venous to arterial difference and global cerebral blood flow. At rest, there was a net balance of Hsp72 across the brain, but after 180 minutes of exercise, we were able to detect the release of Hsp72 from the brain (335 +/- 182 ng/min). However, large individual differences were observed as 3 of the 6 subjects had a marked increase in the release of Hsp72, whereas exercise had little effect on the cerebral Hsp72 balance in the remaining 3 subjects. Given that cerebral blood flow was unchanged during exercise compared with values obtained at rest, it is unlikely that the cerebral Hsp72 release relates to necrosis of specific cells within the brain. These data demonstrate that the human brain is able to release Hsp72 in vivo in response to a physical stressor such as exercise. Further study is required to determine the biological significance of these observations.     

Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease.

The brain is critically dependent on a continuous supply of blood to function. Therefore, the cerebral vasculature is endowed with neurovascular control mechanisms that assure that the blood supply of the brain is commensurate to the energy needs of its cellular constituents. The regulation of cerebral blood flow (CBF) during brain activity involves the coordinated interaction of neurons, glia, and vascular cells. Thus, whereas neurons and glia generate the signals initiating the vasodilation, endothelial cells, pericytes, and smooth muscle cells act in concert to transduce these signals into carefully orchestrated vascular changes that lead to CBF increases focused to the activated area and temporally linked to the period of activation. Neurovascular coupling is disrupted in pathological conditions, such as hypertension, Alzheimer disease, and ischemic stroke. Consequently, CBF is no longer matched to the metabolic requirements of the tissue. This cerebrovascular dysregulation is mediated in large part by the deleterious action of reactive oxygen species on cerebral blood vessels. A major source of cerebral vascular radicals in models of hypertension and Alzheimer disease is the enzyme NADPH oxidase. These findings, collectively, highlight the importance of neurovascular coupling to the health of the normal brain and suggest a therapeutic target for improving brain function in pathologies associated with cerebrovascular dysfunction.     

Effect of angiotensin II and peptide YY on cerebral and circumventricular blood flow

Angiotensin II and peptide YY (PYY) are putative neuro/humoral agents acting at several circumventricular regions. These peptides also constrict cerebral vessels. We examined the effect of acute intravenous infusion of saline, angiotensin II and peptide YY on local cerebral blood flow (14C-iodoantipyrine autoradiography) in the circumventricular and non-circumventricular brain regions of 17 conscious rats. No reductions in brain blood flow (28 regions) were observed although angiotensin II and PYY infusion elevated arterial blood pressure 15-25% without influencing heart rate, suggesting an increase in peripheral resistance. However, local blood flow was dependent on the peptide infused. During PYY infusion, blood flow was rather constant in the 20 non-circumventricular regions examined whereas an increase in blood flow and a slight decrease in cerebrovascular resistance occurred in the circumventricular regions. The area postrema exhibited the most pronounced changes--an elevation in blood flow of 44 +/- 11% and a reduction in resistance of 20 +/- 5% in comparison to that in control animals. During angiotensin II infusion, local cerebral blood flow was similar to that in controls and local cerebrovascular resistance was elevated. Thus, the local cerebral circulatory response to peptide administration was dependent on the location of the region examined (circumventricular or non-circumventricular) and on the vasoactive peptide infused.