Minimal ischaemic neuronal damage and HSP70 expression in MF1 strain mice following bilateral common carotid artery occlusion

Investigation into the influence of specific genes and gene products upon the pathophysiology of cerebral ischaemia has been greatly enhanced by the use of genetically modified mice. A simple model of global cerebral ischaemia in mouse is bilateral common carotid artery occlusion (BCCAo) and the neuropathological impact of BCCAo has been investigated in several mouse strains. Bilateral carotid occlusion produces extensive neuronal damage in C57Bl/6J strain mice and this damage is linked to posterior communicating artery (PcomA) hypoplasticity in the circle of Willis. In the present study, we investigated the effect of BCCAo in MF1 strain mice and compared them with C57Bl/6J mice. The neuropathological consequences of BCCAo were assessed using standard histochemical staining and heat shock protein 70 (HSP70) immunohistochemical staining (to demarcate cells that had been ischaemically stressed). The effect of BCCAo on mean arterial blood pressure (MABP) was also measured. The plasticity of the circle of Willis was recorded using carbon black perfusion. MF1 mice displayed significantly less ischaemic neuronal damage and HSP70 immunoreactivity compared to C57Bl/6J mice following 10-20 min BCCAo. Moreover, ischaemic neuronal damage and HSP70 immunoreactivity in MF1 mice subjected to extended BCCAo (25-45 min) was never as extensive or widespread as that observed in C57Bl/6J mice after 20 min BCCAo. MABP in MF1 mice (102+/-5 mmHg) was significantly higher than in C57Bl/6J mice (87+/-5) during 20 min BCCAo. MABP in MF1 mice during 20 and 40 min (103+/-12 mmHg) BCCAo remained above pre-occlusion values for the entire occlusion period. MF1 mice had significantly greater circle of Willis plasticity (more PcomAs) than C57Bl/6J mice did. These data indicate that MF1 mice are less susceptible to BCCAo than C57Bl/6J mice and that this could be due to maintained increases in MABP during BCCAo and the lower prevalence of abnormalities of the circle of Willis in MF1 mice.     

Nimodipine prevents hyperglycemia-induced cerebral acidosis in middle cerebral artery occluded rats

The effects of acute moderate hyperglycemia on local cerebral pH (LCpH) and local cerebral blood flow (LCBF) were studied in rats infused with glucose before middle cerebral artery (MCA) occlusion, and compared with findings in MCA occlusion alone. The effects of nimodipine infusion on LCBF and LCpH in MCA-occluded hyperglycemic rats were also studied. LCpH and LCBF were determined simultaneously by a double-label autoradiographic technique. Hyperglycemia was induced by an intraperitoneal injection of 2 g/kg D-glucose before MCA occlusion. Nimodipine-treated rats received the drug as an intravenous infusion of 0.5 micrograms/kg/min starting 15 min after occlusion, and ending at decapitation 4 h postocclusion. Cortical LCpH of five structures in the MCA territory of hyperglycemic rats varied between 6.64 +/- 0.04 and 6.72 +/- 0.02 (mean +/- SEM). These values were significantly lower than LCpH in the same ischemic structures in the control rats, which varied between 6.76 +/- 0.04 and 6.82 +/- 0.03 (p less than 0.05 for four of five structures). Cortical LCpH of hyperglycemic nimodipine-treated rats ranged between 6.94 +/- 0.02 and 7.05 +/- 0.02, indicating significant elevations in LCpH (p less than 0.001) compared with the untreated ischemic hyperglycemic animals. LCBF in the ischemic structures was not modified by hyperglycemia or nimodipine treatment. This suggests that nimodipine, by mechanisms other than improvement in blood flow, can prevent the enhanced cerebral tissue acidosis produced by hyperglycemia before incomplete focal ischemia.     

Quantitative measurement of cerebral blood flow and cerebral blood volume after cerebral ischaemia

CBF obtained by the hydrogen clearance technique and cerebral blood volume (CBV) calculated from the [14C]dextran space were measured in three groups of rats subjected to temporary four-vessel occlusion to produce 15 min of ischaemia, followed by 60 min of reperfusion. In the control animals, mean CBF was 93 +/- 6 ml 100 g-1 min-1, which fell to 5.5 +/- 0.5 ml 100 g-1 min-1 during ischaemia. There was a marked early postischaemic hyperaemia (262 +/- 18 ml 100 g-1 min-1), but 1 h after the onset of ischaemia, there was a significant hypoperfusion (51 +/- 3 ml 100 g-1 min-1). Mean cortical dextran space was 1.58 +/- 0.09 ml 100 g-1 prior to ischaemia. Early in reperfusion there was a significant increase in CBV (1.85 +/- 0.24 ml 100 g-1) with a decrease during the period of hypoperfusion (1.33 +/- 0.03 ml 100 g-1). Therefore, following a period of temporary ischaemia, there are commensurate changes in CBF and CBV, and alterations in the permeability-surface area product at this time may be due to variations in surface area and not necessarily permeability.     

Reperfusion after cerebral ischemia: influence of duration of ischemia

The influence of the duration of ischemia on the pattern of cerebral blood flow in recirculation was studied in anesthetised rats. Severe incomplete cerebral ischemia (mean ischemic flow = 5.8 +/- 0.4 ml/100 g/min) was produced by four-vessel occlusion and recirculation permitted after 15, 30 or 60 minutes ischemia. All three groups showed an immediate hyperemia followed by hypoperfusion. Hyperemia was maximal following 15 minutes ischemia and least pronounced following 60 minutes ischemia (p = 0.0249). Hypoperfusion started most quickly following 15 minutes ischemia and was delayed following 60 minutes ischemia (p less than 0.001). In established hypoperfusion there was no difference in flow between the three groups. The possible mechanisms of these changes in flow are discussed.     

Effect of Fluosol-DA and hetastarch on local cerebral blood flow, cortical O2 availability and computerized EEG data during cerebral ischaemia.

This study was designed to assess the effects of volume expansion with Fluosol-DA and hetastarch on local cerebral blood flow (CBF), cortical O2 availability (O2a) and computerized EEG power data during cerebral ischaemia in a primate stroke model. Focal cerebral ischaemia was produced in 20 anaesthetized Macaca monkeys by right unilateral middle cerebral artery (MCA) occlusion by the transorbital technique. Following occlusion of the right MCA, monkeys were randomized into one of the following treatment groups: Group A--Fluosol-DA 15 ml kg-1 i.v. + 40% O2; Group B--Fluosol-DA 15 ml kg-1 i.v. + 100% O2; Group C--hetastarch 30 ml kg-1 i.v. + 40% O2; Group D--hetastarch 30 ml kg-1 i.v. + 100% O2. In Group A, local CBF increased and EEG power data improved while O2a showed no change in the right MCA territory. In Group B, local CBF increased from 84% (P less than 0.001), O2a improved significantly, and EEG power data showed significant improvement in the right hemisphere. Cardiac output did not change during the Fluosol-DA infusions. In Groups C and D, local CBF increased significantly, O2a did not change, and EEG power data improved significantly in the right hemisphere. Cardiac output also increased significantly during the hetastarch infusions. These results show that Fluosol-DA and hetastarch improve local CBF and EEG power data in ischaemic brain. Only the Fluosol-DA + 100% O2 increased the O2a in the ischaemic brain. We conclude that the benefits with Fluosol-DA are due to its ability to increase O2 delivery to ischaemic brain.     

Role of a hydrostatic pressure gradient in the formation of early ischemic brain edema

We studied whether a hydrostatic pressure gradient between arterial blood and brain tissue plays a role in the formation of early ischemic cerebral edema after middle cerebral artery (MCA) occlusion in cats. Tissue pressure, regional CBF, and water content were measured from the cortex in the core and the peripheral zone of brain normally perfused by the MCA. Intraluminal arterial pressure was altered at intervals by inflation of an aortic balloon to vary the blood-tissue pressure gradient in the ischemic zone. Brain water content in the ischemic core, where flow fell to 5.5 ml/100 g/min, increased within 1 h of occlusion. After occlusion tissue pressure rose from 7.95 +/- 0.72 mm Hg at 1 h to 13.16 +/- 1.13 mm Hg at 3 h. When intraluminal pressure was increased, water content increased further, but only at 1 h after occlusion. In the periphery where flow was 18.9 ml/100 g/min during normotension, neither water content nor tissue pressure rose within 3 h of occlusion. Increased intraluminal pressure was accompanied by increased water content only at 3 h. This study indicates that a hydrostatic pressure gradient is an important element in the development of ischemic brain edema, exerting its major effect during the initial phase of the edema process.     

Transient focal ischemia in subhuman primates. Neuronal injury as a function of local cerebral blood flow

Unilateral, transient (30, 60, and 120 minutes (min)) middle-cerebral-artery (MCA) occlusion was induced via transorbital craniotomy in 11 waking subhuman primates. Local cerebral blood flow (LCBF) was calculated from hydrogen clearance curves obtained through the use of intracerebral platinum microelectrodes. Unilateral MCA occlusion decreased LCBF in the territory of the ipsilateral MCA. Within minutes of the arterial occlusion all monkeys developed contralateral neurologic deficits that began disappearing three hours (h) after reopening the MCA. Regional ischemia, followed by 24 h of reperfusion, produced varying degrees of tissue vacuolation which correlated (r = 0.60, p less than 0.01, n = 49) with the percent reduction in LCBF multiplied by the occlusion time. Neurons were classified according to the structural features of their perikaryon. A plot of neuron types versus percent vacuolation suggested that normal neurons become increasingly scalloped under increasingly severe ischemic conditions. The number of scalloped neurons decreased precipitously in areas of marked sponginess coincident with the appearance of irreversibly damaged neurons. Local tissue edema values exceeding 30% correlated with irreversible injury to all neurons in the same area. Regional cerebral ischemia of increasing severity was acompanied by increasing numbers of lethally injured neurons.     

Effect of the NMDA antagonist MK-801 on local cerebral blood flow in focal cerebral ischaemia in the rat

The effects of MK-801 upon local CBF after permanent middle cerebral artery (MCA) occlusion have been examined using [14C]iodoantipyrine autoradiography in halothane-anaesthetised rats. MK-801 (0.5 mg kg-1 i.v.) or saline was administered 30 min before MCA occlusion and CBF measured approximately 40 min after occlusion. In the hemisphere contralateral to the occluded MCA, MK-801 significantly reduced local CBF in 19 of the 22 regions examined from the levels in saline-treated rats. In the contralateral hemisphere, after treatment with MK-801, blood flow was reduced by an average of 37% with little variation in the magnitude of the reductions in different regions. In the hemisphere ipsilateral to MCA occlusion, MK-801 reduced CBF in almost every region located outside the territory of the occluded MCA. Within the territory of the occluded MCA, blood flow in the MK-801-treated rat did not significantly differ from values in vehicle-treated rats in any of the five cortical areas examined, although in the caudate nucleus there was a tendency for CBF to be lower in rats pretreated with MK-801. MK-801 had no effect on the amount of hypoperfused cerebral tissue (CBF less than 30 ml 100 g-1 min-1) in the ipsilateral hemisphere at any coronal plane examined; e.g., at coronal plane anterior 7.2 mm, 51 +/- 5% of the hemisphere displayed CBF of less than 30 ml 100 g-1 min-1 in saline-treated rats with MCA occlusion compared with 52 +/- 8% of the hemisphere in rats treated with MK-801 prior to MCA occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic trigeminal ganglionectomy or topical capsaicin application to pial vessels attenuates postocclusive cortical hyperemia but does not influence postischemic hypoperfusion.

Marked hyperemia accompanies reperfusion after ischemia in the brain, and may account for the propensity of cerebral hemorrhage to follow embolic stroke or carotid endarterectomy, and for the morbidity that follows head injury or the ligation of large arteriovenous malformations. To evaluate the contribution of trigeminal sensory fibers to the hyperemic response, CBF was determined in 12 symmetrical brain regions, using microspheres with up to five different isotopic labels, in four groups of cats. Measurements were made at 15-min intervals for up to 2 h of reperfusion after global cerebral ischemia induced by four-vessel occlusion combined with systemic hypotension of either 10- or 20-min duration. In normal animals, hyperemia in cortical gray matter 30 min after reperfusion was significantly greater after 20 min (n = 10) than after 10 min (n = 7) of ischemia (312 ml/100 g/min versus 245 ml/100 g/min; p less than 0.01). CBF returned to preischemic levels approximately 45 min after reperfusion and was reduced to approximately 65% of basal CBF for the remaining 75 min. In cats subjected to chronic trigeminal ganglionectomy (n = 15), postocclusive hyperemia in cortical gray matter was attenuated by up to 48% on the denervated side (249 versus 150 ml/100 g/min; p less than 0.01) after 10 min of ischemia. This effect was maximal in the middle cerebral artery (MCA) territory, and was confined to regions known to receive a trigeminal innervation. In these animals, substance P (SP) levels in the MCA were reduced by 64% (p less than 0.01), and the density of nerve fibers containing calcitonin gene-related peptide (but not vasoactive intestinal polypeptide or neuropeptide Y) was decreased markedly on the lesioned side. Topical application of capsaicin (100 nM; 50 microliters) to the middle or posterior temporal branch of the MCA 10-14 days before ischemia decreased SP levels by 36%. Postocclusive hyperemia in cortical gray matter was attenuated throughout the ipsilateral hemisphere by up to 58%, but the cerebral vascular response to hypercapnia (PaCO2 = 60 mm Hg) was unimpaired. The duration of hyperemia and the severity of the delayed hypoperfusion were not influenced by trigeminalectomy, capsaicin application, or the intravenous administration of ATP. These data demonstrate the importance of neurogenic mechanisms in the development of postischemic hyperperfusion, and suggest the potential utility of strategies aimed at blocking axon reflex-like mechanisms to reduce severe cortical hyperemia.     

Changes in regional cortical tissue oxygen tension and cerebral blood flow during temporary middle cerebral artery occlusion in baboons.

Cortical tissue oxygen measured by a platinum cathode, and cerebral blood flow recorded by a hydrogen clearance technique, were measured in 13 baboons before, during and after temporary occlusion of the middle cerebral artery. Mean control pO2 was 23.8 +/- 14 mm Hg and mean flow 51.3 +/- 12 ml/100g/min. During the occlusion, there was a gradation in pO2 from values in the opercular area of 3.6 +/- 5.9 mm Hg, to values in the high parietal area of 11.9 +/- 11.7, these being statistically different (P less than 0.05) from each other. The corresponding flow values were 5.5 +/- 7.5 (opercular) and 22.3 +/- 21.7 ml/100 g/min parietal (P less than 0.01). Following removal of the MCA clip, between 20% and 30% of the electrodes registered an early hyperoxia and hyperaemia, which lasted up to 5 min. A late and prolonged hyperoxia, with less evidence of hyperaemia, was also noted in about 20%. The mean tissue pO2, however, at 5-min intervals up to 40 min following the removal of the clip only reached 60-80% of control values in the most ischaemic areas. Only the parietal region showed a mean pO2 above control levels. The mean flow data were uniformly reduced in all regions to about 80% of control values. During and after a second occlusion in 6 animals, similar changes were noted but with even fewer instances of hyperoxia. The mean oxygen and flow results were lower than with the first occlusion, but the reduction was not significant. There was no overall effect of hypercapnia on cortical tissue pO2 during the control period, but there was a significant (P less than 0.05) reduction during the same procedure after the period of ischaemia. An increase in pO2 during hypercapnia could be observed if there were arousal responses of blood pressure "spikes".     

Occlusion of the MCA by an intraluminal filament may cause disturbances in the hippocampal blood flow due to anomalies of circle of Willis and filament thickness

We examined blood flow changes and histology in the hippocampus induced by occlusion of the middle cerebral artery (MCA) by a filament in Swiss albino and SV-129 mice (n=67) and in Wistar rats (n=64). Filling cerebral arteries with carbon black revealed that one or both posterior communicating arteries were hypoplastic in 50% of Swiss mice. Ischemic changes were detected in the ipsilateral hippocampus with 2,3,5-triphenyl tetrazolium chloride or hematoxylin and eosin staining when these mice were subjected to 2-h MCA occlusion and 22-h reperfusion. No such abnormalities were found in SV-129 mice and Wistar rats (except one). The hippocampal blood flow dropped to 60+/-2.3% of the baseline in mice with a normal circle of Willis but to 37+/-4.2% in those with an incomplete circle when the MCA was occluded with a 6/0 nylon filament. When an 8/0 filament was used, no flow change in mice with a normal circle but a decrease to 60+/-2% in those with an incomplete circle was observed. A flow drop to 63+/-4% was also seen in Wistar rats when a 3/0 filament used. These data demonstrate that occlusion of the MCA by a thick filament may cause flow reduction in the hippocampus, which may be severe enough to lead to infarction if the circle of Willis is anomalous.     

Evaluation of cerebral hemodynamics with perfusion CT]

We report on the evaluation of cerebral ischemic lesions with perfusion CT. Cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) of 52 patients mostly with ischemic cerebrovascular disease were analysed using the box-modulation transfer function method with 30 ml of contrast medium intravenously injected at 5 ml/sec. CBF, CBV and MTT of the middle cerebral artery (MCA) territory were 43.5 +/- 4.6 ml/100 g/min, 1.9 +/- 0.2 ml/100 g and 2.9 +/- 0.6 seconds at the unaffected side, and 37.7 +/- 7.3 ml/100 g/min, 2.1 +/- 0.3 ml/100 g, 3.7 +/- 0.9 seconds at the lesion side with stenosis or occlusion in the main MCA trunks or internal carotid artery, respectively. A statistically significant difference was shown in CBF and MTT values. Furthermore, there was a close correlation in CBF values of MCA territories between Xe-CT and perfusion CT (r = 0.645, n = 76, p < 0.0001). MTT showed a positive correlation with CBV in those subjects when MTT was below 4.1 seconds (r = 0.526, p < 0.0001, n = 83). MTT also showed a negative correlation with CBF in those patients when MTT indicated more than 4.1 seconds (r = 0.818, p < 0.001, n = 21). These results suggest that the progression of cerebral ischemia may be classified in 4 stages using perfusion CT. The stages are as follows: stage 0; normal CBF without prolonged MTT and increased CBV, stage 1; relatively increased CBV, stage 2; significantly prolonged MTT, and stage 3; significantly decreased CBF with prolonged MTT.     

Interleukin-10 modulates neuronal threshold of vulnerability to ischaemic damage

Interleukin-10 (IL-10) is a powerful suppressor of cellular immune responses, with a postulated role in brain inflammation. First, we have evaluated the role of this cytokine in ischaemic brain damage using IL-10 knockout (IL-10-/-) mice. The middle cerebral artery (MCA) was occluded in either IL-10-/- or wild-type animals of corresponding strain (C57Bl/6) and age. Infarct volume was assessed 24 h later in serial brain sections. Brain infarct produced by MCA occlusion was 30% larger in the IL-10-/- than in wild-type mice (21. 8 +/- 1.2 vs. 16.9 +/- 1.0 mm3, respectively; P < 0.01; Student's t-test). To further characterize these findings, studies were extended to in vitro models. Primary neuronal cortical cultures derived from IL-10-/- animals were more susceptible to both excitotoxicity and combined oxygen-glucose deprivation compared with cell cultures from wild-type mice. Moreover, when added to the culture medium, recombinant murine IL-10 (0.1-100 ng/mL) exerted a concentration-dependent prevention of neuronal damage induced by excitotoxicity in both cortical and cerebellar granule cell cultures taken from either strain. The accordance of in vivo and in vitro data allows us to suggest a potential neuroprotective role of IL-10 against cerebral ischaemia when administered exogenously or made available from endogenous sources.     

The effects of disturbance of cerebral venous drainage on focal cerebral blood flow and ischemic cerebral edema

The effect of disturbance of cerebral venous drainage on acute ischemic cerebral edema and cerebral circulation were studied by measuring local cerebral blood flow (LCBF) and local changes in brain water content using a middle cerebral artery (MCA) occlusion model. Rats were anesthetized with halothane and the stem of the left MCA was occluded. Disturbance of cerebral venous drainage was induced by bilateral occlusion of the external jugular veins, i.e., the right external jugular vein was cannulated and the left one was occluded by a clip. LCBF was measured by the 14C-iodoantipyrine (14C-IAP) autoradiographic method at 2 hours after MCA occlusion. Local changes in brain water content were studied 2 hours after MCA occlusion by measuring the specific gravity of cerebral tissue in the gradient column with bromobenzene and kerosene. The control rats which underwent the same anesthesia and surgical procedure including the MCA occlusion and cannulation into the right external jugular veins, but which did not undergo occlusion of the left external jugular veins, were prepared and studied at the same time after MCA occlusion. In the rats with bilateral occlusion of the external jugular veins, the external jugular venous pressure was evaluated up to about 8 mmHg (100 mmH2O) (control: 1.3 mmHg). At 2 hours after MCA occlusion, LCBF in the ischemic core was decreased. The ischemic area was more extensive in the rats with bilateral occlusion of the external jugular veins compared with the controls. Furthermore, specific gravity of the brain was decreased in the entire left MCA territory in the rats with bilateral occlusion of the external jugular veins.(ABSTRACT TRUNCATED AT 250 WORDS)     

The novel dihydronaphthyridine Ca2+ channel blocker CI-951 improves CBF, brain pHi, and EEG recovery in focal cerebral ischemia

The effects of the novel dihydronaphthyridine Ca2+ antagonist CI-951 on focal cerebral ischemia were assessed during MCA occlusion in 30 white New Zealand rabbits under 1.0% halothane anesthesia. In vivo brain pHi and focal CBF were measured with umbelliferone fluorescence. Baseline normocapnic brain pHi and CBF were 7.02 +/- 0.02 and 48.4 +/- 2.9 ml/100 g/min, respectively. In the severe ischemic regions, 15 min postocclusion brain pHi and CBF were 6.62 +/- 0.04 and 14.4 +/- 0.7 ml/100 g/min in controls vs. 6.60 +/- 0.02 and 12.9 +/- 2.3 ml/100 g/min, respectively, in animals destined to receive CI-951. Twenty minutes after MCA occlusion, CI-951 was administered at 0.5 microgram/kg/min and brain pHi and CBF were determined in both regions of severe and moderate ischemia for 4 h postocclusion. Control severe ischemic sites demonstrated no significant improvement in brain pHi and only mild increases in CBF over the next 4 h. CI-951 caused significant improvement in both of these parameters. Postocclusion 4 h brain pHi and CBF measured 6.69 +/- 0.04 and 18.5 +/- 3.2 ml/100 g/min in controls vs. 7.01 +/- 0.04 and 41.7 +/- 5.3 ml/100 g/min, respectively, in CI-951 animals (p less than 0.001). Similar improvements were observed in moderate ischemic sites. In animals that demonstrated postocclusion EEG attenuation, 75% of CI-951 animals had EEG recovery as compared to 18% in controls. CI-951 may be a useful therapeutic agent for focal cerebral ischemia if histological and outcome studies verify these data.     

Autoradiographic evaluation of forskolin and D1 dopamine receptor binding in a rat model of focal cerebral ischaemia.

Post-ischaemic changes in forskolin and D1 dopamine receptor (labelled with SCH23390) binding sites were evaluated in a rat unilateral middle cerebral artery occlusion (MCA) model. The changes in binding were assessed acutely (2 h post-MCA occlusion) in relation to local cerebral blood flow (lCBF) and chronically (24 h post-MCA occlusion) in relation to histopathological alterations. Two hours following occlusion lCBF was significantly reduced throughout the territory of the MCA. Despite the widespread hypoperfusion, significant reductions in binding were only observed in the dorsolateral caudate nucleus--the region with the most profound reduction in blood flow (6% of the control contralateral lCBF value). Forskolin binding sites were reduced to 40% of the contralateral value while D1 binding sites were reduced to 80% of the contralateral value. Analysis of the relationship between forskolin binding and CBF in the caudate nucleus revealed that the ischaemic threshold for alteration in forskolin binding sites 2 h after MCA occlusion was approximately 34 ml/100 g/min. Twenty-four h post-occlusion forskolin binding sites were further reduced in the dorsolateral caudate nucleus (to 6% of contralateral) while D1 binding showed minimal reduction from that observed at 2 h. The areas of reduced binding corresponded to the area of histopathological change in the caudate nucleus and rostral neocortex. In conclusion, reduction in forskolin binding progresses further than reduction in D1 binding within the first 24 h following focal cerebral ischaemia. For both forskolin and D1 binding sites, the areas of reduced binding 24 h post-MCA occlusion predicted the area of histopathological change.     

CBF and transcranial Doppler sonography during vasodilatory stress tests in patients with common carotid artery occlusion.

Cerebral blood flow (CBF) and the cerebral vasoreactivity was measured in patients with cerebrovascular disease and longstanding occlusion of the common carotid artery (CCA). In addition, regional CBF was correlated with transcranial doppler (TCD) measurements at baseline and during 6% CO2 inhalation and after intravenous administration of 1 g of acetazolamide. Twelve patients with a mean age of 62 years (range 45 to 71 years) were included, and the data compared to age-matched healthy controls. CBF was measured by intravenous injection of xenon-133 and SPECT (Tomomatic 564). TCD of the middle cerebral artery (MCA) was done by EME TC-64B. A very low global CBF value of 28 +/- 5 (SD) ml 100 g-1 min-1 was found at baseline as compared to 55 +/- 5 ml 100 g-1 min-1 in the normal controls. During 6% CO2-inhalation and after acetazolamide administration, CBF increased by 58 +/- 24% and 51 +/- 21%, respectively, indicating substantial collateral supply. Correlative analysis of CBF in the MCA territory and TCD in the MCA showed statistical significance only for the pooled data, i.e. compiling the data obtained during baseline and the two vasodilatory tests, and then only for the mean and peak TCD velocity (e.g. r = 0.59, p less than 0.002, n = 35, mean velocity, right side). We conclude that TCD measurements do not predict regional CBF in patients with CCA occlusion. The study emphasizes that these two methods yield supplementary information, with TCD measurements providing information of the circle of Willis and CBF studies of the flow distribution.     

Superficial temporal artery duplex ultrasonography for improved cerebral hemodynamics after extracranial-intracranial bypass surgery

BACKGROUND: To investigate the utility of superficial temporal artery (STA) duplex ultrasonography (STDU) for evaluating the improvement of the cerebral hemodynamics after extracranial-intracranial (EC-IC) bypass. METHODS: This study included 40 consecutive patients who underwent EC-IC bypass for occlusive disease of cerebral arteries. STDU was performed to measure the flow velocity, pulsatility index, and diameter of the operated STA before and 14 days after EC-IC bypass. Regional cerebral blood flow (rCBF) and acetazolamide (ACZ) reactivity of the ipsilateral middle cerebral artery (MCA) territory were evaluated by quantitative single-photon emission computed tomography with the ACZ challenge test. We investigated the correlation between STA flow velocity/diameter and rCBF/ACZ reactivity in the ipsilateral MCA territory. RESULTS: Mean flow velocity (MFV; 26.3 +/- 8.8 to 55.3 +/- 16.3 cm/s, p < 0.0001) and diameter (1.57 +/- 0.24 to 2.26 +/- 0.29 mm, p < 0.0001) of the STA, and rCBF (29.1 +/- 3.1 to 35.0 +/- 6.4 ml/100 g/min, p < 0.0001) and ACZ reactivity (-0.02 +/- 0.10 to 0.28 +/- 0.21, p < 0.0001) of the MCA territory increased after EC-IC bypass compared with the baseline values. STA MFV was significantly correlated with the rCBF 14 days after EC-IC bypass (R = 0.70, p < 0.0001). A cutoff value of postsurgical STA MFV greater than 48.5 cm/s yielded the highest diagnostic accuracy (sensitivity 86%; specificity, 82%) for rCBF > or = 32 ml/100 g/min after EC-IC bypass. CONCLUSIONS: STDU was available for evaluating postsurgical patency of the bypass flow and the rCBF of the ipsilateral MCA territory. The mean blood flow velocity of the operated STA is a highly sensitive parameter for predicting rCBF in the ipsilateral MCA territory after EC-IC bypass.     

Pial arterial pressure contribution to early ischemic brain edema

The effect of pial arterial pressure (PAP) on brain edema was examined in cats with middle cerebral artery (MCA) occlusion. Measurements of PAP and regional CBF (rCBF) were collected in the central core and the peripheral margin of the MCA territory over 180 min post MCA occlusion. Brain water content in each region was determined at the end of the experiment. MCA occlusion resulted in decreased PAP and rCBF in both the core (PAP = 13 mm Hg, rCBF = 9 ml/100 g/min) and the peripheral region (PAP = 15 mm Hg, rCBF = 18 ml/100 g/min). Brain edema developed in both the core and the peripheral region. Brain water content was correlated inversely with PAP in the core region and positively in the peripheral region. The results indicate that decreased blood flow contributes to cytotoxic edema in the core, and a hydrostatic pressure gradient preferentially enhances edema formation in the peripheral region. Maintenance of high perfusion pressure early after ischemia onset may suppress brain edema in the core region.     

Oedema and glial cell involvement in the aged mouse brain after permanent focal ischaemia

This study examines the effect of age on oedema and brain swelling, and associated glial cell involvement on the size of the lesion in two models of permanent, focal cerebral ischaemia. Ischaemia was induced in male C57BL/Icrfat mice (4-6 and 26-31-month-old) by middle cerebral artery (MCA) occlusion using either electrocoagulation after craniotomy (MCA/craniotomy), or by an intraluminal filament through the carotid artery (MCA/icf). Twenty-four hours after inducing ischaemia, brain swelling and lesion size were measured in young and aged mice, and cerebral oedema by wet/dry brain weights. Histopathology and immunocytochemistry were performed on a separate set of perfusion fixed brains. The MCA/icf technique produced a significantly larger lesion than MCA/craniotomy in both age groups. The percentage of water taken into the brain was significantly greater after MCA/icf, with aged mice showing the greatest increase. When lesion size was corrected for brain swelling there was no age-related increase in the size of the lesion. The numbers of microglia and astroglia increased significantly in the parietal cortex of aged control animals, and there were qualitative differences in the glial response between the two stroke models. This study emphasizes the importance of age in models of permanent focal ischaemia, with oedema clearly being a significant factor. Differ-ences in the responsiveness of the glial cell population with age may be of fundamental importance in the progress of ischaemic brain damage.