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ABSTRACT: Early postischemic hyperperfusion (EPIH) has long been documented in animal stroke models and is the hallmark of efficient recanalization of the occluded artery with subsequent reperfusion of the tissue (although occasionally it may be seen in areas bordering the hypoperfused area during arterial occlusion). In experimental stroke, early reperfusion has been reported to both prevent infarct growth and aggravate edema formation and hemorrhage, depending on the severity and duration of prior ischemia and the efficiency of reperfusion, whereas neuronal damage with or without enlarged infarction also may result from reperfusion (so-called "reperfusion injury"). In humans, focal hyperperfusion in the subacute stage (i.e., more than 48 hours after onset) has been associated with tissue necrosis in most instances, but regarding the acute stage, its occurrence, its relations with tissue metabolism and viability, and its clinical prognostic value were poorly understood before the advent of positron emission tomography (PET), in part because of methodologic issues. By measuring both CBF and metabolism, PET is an ideal imaging modality to study the pathophysiologic mechanism of EPIH. Although only a few PET studies have been performed in the acute stage that have systematically assessed tissue and clinical outcome in relation to EPIH, they have provided important insights. In one study, about one third of the patients with first-ever middle cerebral artery (MCA) territory stroke studied within 5 to 18 hours after symptom onset exhibited EPIH. In most cases, EPIH affected large parts of the cortical MCA territory in a patchy fashion, together with abnormal vasodilation (increased cerebral blood volume), "luxury perfusion" (decreased oxygen extraction fraction), and mildly increased CMRO2, which was interpreted as postischemic rebound of cellular metabolism in structurally preserved tissue. In that study, the spontaneous outcome of the tissue exhibiting EPIH was good, with late structural imaging not showing infarction. This observation was supported by another PET study, which showed, in a few patients, that previously hypoperfused tissue that later exhibited hyperperfusion after thrombolysis did not undergo frank infarction at follow-up. In both studies, clinical outcome was excellent in all patients showing EPIH except one, but in this case the hyperperfused area coexisted with an extensive area of severe hypoperfusion and hypometabolism. These findings from human studies therefore suggest that EPIH is not detrimental for the tissue, which contradicts the experimental concept of "reperfusion injury" but is consistent with the apparent clinical benefit from thrombolysis. However, PET studies performed in the cat have shown that although hyperperfusion was associated with prolonged survival and lack of histologic infarction when following brief (30-minute) MCA occlusion, it often was associated with poor outcome and extensive infarction when associated with longer (60-minute) MCA occlusion. It is unclear whether this discrepancy with human studies reflects a shorter window for tissue survival after stroke in cats, points to the cat being more prone to reperfusion injury, or indicates that EPIH tends not to develop in humans after severe or prolonged ischemia because of a greater tendency for the no-reflow phenomenon, for example. Nevertheless, the fact that the degree of hyperperfusion in these cat studies was related to the severity of prior flow reduction suggests that hyperperfusion is not detrimental per se. Preliminary observations in temporary MCA occlusion in baboons suggest that hyperperfusion developing even after 6 hours of occlusion is mainly cortical and associated with no frank infarction, as in humans. Overall, therefore, PET studies in both humans and the experimental animal, including the baboon, suggest that hyperperfusion is not a key factor in the development of tissue infarction and that it may be a harmless phenomenon
Journal of Cerebral Blood Flow & Metabolism 06/1999; 19(5):467-82. · 5.01 Impact Factor
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ABSTRACT: Local cerebral perfusion pressure (CPP), a crucial parameter that should allow a better assessment of the haemodynamic compromise in cerebrovascular diseases, is not currently measurable by non-invasive means. Experimental and clinical studies have suggested that the regional ratio of cerebral blood flow to cerebral blood volume (CBF:CBV), as measured by PET, represents an index of local CPP in focal ischaemia. The present study was designed to evaluate further the reliability of the CBF:CBV ratio during manipulations of CPP by deliberately varying mean arterial pressure (MAP) in the anaesthetized baboon. Cortical CBF, CBV, cerebral metabolic rate for oxygen (CMRO2) and oxygen extraction fraction were measured by PET using the (15)O steady-state technique in 10 anaesthetized baboons. Five baboons (Group A) underwent four PET examinations at different levels of MAP: base line (101 +/- 6 mmHg) followed by moderate hypotension (58 +/- 3 mmHg) and, in a separate experiment, minor hypotension (72 +/- 3 mmHg) followed by profound hypotension (34 +/- 5 mmHg). Trimetaphan was used to lower MAP to minor and moderate levels while profound hypotension was achieved by the combined effects of trimetaphan and lower-body negative pressure. Five other baboons (Group B) were subjected to hypertension (121 +/- 2 mmHg) induced by metaraminol and were compared with their base line state (81 +/- 10 mmHg). While CBF displayed significant changes with varying MAP, i.e. decrease and increase with hypotension and hypertension, respectively (-11% from base line to moderate hypotension compared with -20%, from minor to profound hypotension and +31% from base line to hypertension), CBV was more variable and did not significantly change, except with profound hypotension when the increase was significant (+13%). The CBF:CBV ratio decreased significantly at all stages of hypotension (-21 and -31%) and was significantly increased during hypertension (+30%). Importantly, the CBF:CBV ratio demonstrated a significant correlation with MAP (rho = 0.78, Spearman's rank correlation coefficient, P < 0.01). No major changes in CMRO2 were noted during either hypotension or hypertension. Our results demonstrate that, under physiological conditions, cortical CBF:CBV is significantly correlated with CPP, itself a function of MAP. In the investigated range of MAP, the relationships between CBF:CBV and MAP appear to be linear. These findings further argue for the reliability of CBF:CBV as an index of CPP in situations where increases or decreases of MAP without superimposed changes in cerebrovascular tone are encountered, and they confirm the potential usefulness of this regional ratio for clinical investigations and management in cerebrovascular diseases.
Brain 07/1998; 121 ( Pt 7):1369-79. · 9.46 Impact Factor
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L Besret,
F Dauphin,
S Guillouet,
M Dhilly,
F Gourand,
X Blaizot, A R Young,
M C Petit-Taboué,
P Mickala,
A Barbelivien,
S Rault,
L Barré,
J C Baron
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ABSTRACT: We recently labeled with carbon-11, a high affinity, selective, 5-HT3 receptor (5-HT3R) ligand, S21007, for potential positron emission tomography (PET) applications. To evaluate the in vivo binding properties of [11C]S21007, its brain regional distribution, tissue and plasma pharmacokinetics and plasma metabolisation were characterized. To circumvent the problem of highly discrete brain localization of the 5-HT3R (area postrema, hippocampus), we designed an original approach combining high-resolution imaging techniques (ex vivo phosphor plate autoradiography and MRI-guided coronal PET in the rat and baboon, respectively). After i.v. injection of trace amounts of [11C]S21007 to rats, phosphorimager autoradiography failed to reveal in vivo specific binding to, nor selectivity for 5-HT3R-rich areas. PET studies in the baboon showed consistent results, i.e., there was no selective accumulation of [11C]S21007 in the area postrema or hippocampus, and neither displacement nor presaturation with cold S21007 resulted in significant changes in tissue distribution or kinetics of [11C]S21007.
Life Sciences 02/1998; 62(2):115-29. · 2.53 Impact Factor
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ABSTRACT: A better understanding of the temporospatial evolution of ischaemic brain tissue towards necrosis would be of crucial value to establish and validate therapeutic strategies for stroke in man. By means of sequential positron emission tomographic (PET) studies performed through the acute to the chronic stages of infarction, we addressed the question of the effect of 6 h temporary occlusion of the middle cerebral artery (MCAO) on the evolution of the volume of severely hypometabolic tissue in anaesthetized baboons and compared it to that reported previously in permanently occluded baboons. Thirteen anaesthetized baboons underwent serial PET (15O steady-state technique) examinations before and 1, 4, 7, 24-48 h and 15-62 days following transorbital MCAO. Reperfusion, at 6 h post-occlusion, was assessed by Doppler sonography and cerebral blood flow (CBF) values after clip removal. In each baboon, the infarct volume was calculated by standard histological procedures 20-91 days after MCAO. The severely hypometabolic tissue volume, as defined by a threshold of oxidative metabolism, showed a progressive increase for up to 24-48 h in a not dissimilar manner to that found in baboons with permanent occlusion. However, these hypometabolic volumes regressed in the chronic stage (p < 0.05). Permanent and temporary occluded baboons, when taken together, showed a highly significant relationship between histological and chronic hypometabolic volumes (r = 0.84; p < 0.001). Moreover, the final hypometabolic volume where cerebral metabolic rate of oxygen (CMRO2) was below 40% of contralateral metabolism corresponded well to that of histological infarction volume. We conclude that, in anaesthetized baboons, restoration of blood flow will reverse (even if not immediately) the progressive derangement of metabolism after MCAO and markedly limit the final volume of consolidated infarction.)
Brain Research 08/1997; 767(1):17-25. · 2.73 Impact Factor
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ABSTRACT: Because in humans the clinical benefits of reperfusion remain controversial, it is important to determine whether reperfusion per se reduces infarct volume. In the nonhuman primate, mostly semiquantitative assessments of infarction have been performed. When ischemic volumes have been calculated, it has been for the acute or subacute stages of experimental stroke and may thus not adequately reflect the total volume of consolidated infarction.
Anesthetized baboons were subjected to 6 hours of either reversible or permanent middle cerebral artery occlusion (MCAO). Approximately 4 weeks later, the brains were processed for neuropathological examination to allow assessment of the final infarct volume determined by the difference of healthy tissue between occluded and nonoccluded hemispheres.
Reversible MCAO resulted in a small essentially subcortical infarction (mean+/-SD, 0.58+/-0.31 cm3) in 6 of 10 baboons: the infarct (pannecrosis) was restricted to the head of the caudate nucleus, internal capsule, and putamen; 4 of 10 baboons showed no evidence of macroscopic infarction. Permanent MCAO produced a larger subcortical infarct in all 7 baboons studied (2.37+/-1.32 cm3; P=.0006 by Wilcoxon-Mann-Whitney test); the lesion was more extensive and encompassed the external capsule and, in 2 baboons, the adjacent insular cortex.
We conclude that under optimal experimental conditions, an ischemic episode of 6 hours in duration is well tolerated in the anesthetized adolescent baboon, with 4 animals showing no signs of macroscopic brain damage. Thus, early reestablishment of cerebral blood flow after a focal ischemic insult is not detrimental but indeed is beneficial in terms of the final infarct volume (both at the subcortical and cortical levels) produced by occlusion of a major cerebral artery. The data further suggest a feasible time window in which to initiate and continue therapeutic interventions.
Stroke 04/1997; 28(3):632-7; discussion 637-8. · 5.73 Impact Factor
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ABSTRACT: The aim of this study was to clarify the controversy about the effects of indomethacin on the coupling of cerebral blood flow (CBF) to cerebral oxygen metabolism (CMRO2). CBF, blood volume (CBV), oxygen extraction fraction (OEF) and CMRO2 were measured by positron emission tomography (PET) in five anaesthetized baboons before and during an i.v. administration of indomethacin (bolus 20 mg/kg followed by perfusion 10 mg/kg.h). Administration of indomethacin resulted in a marked and homogenous decrease of CBF in every region analysed (-28% to -40%) and a moderate reduction in CBV (-8% to -16%). In contrast, CMRO2 displayed a small increase in thalamus and pons (+10% and +13%, respectively). OEF increased greatly in all structures studied (+59% to +96%). These findings show that the potent cerebrovascular effects of indomethacin are not related to a decrease in CMRO2 as measured through the use of PET.
Neuroscience Letters 01/1997; 220(2):137-41. · 2.11 Impact Factor
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ABSTRACT: Studies in humans suggest that regions that show maximal increases in brain oxygen extraction fraction (OEF) in the hours following an ischemic episode are those most vulnerable for infarction and are often, although not always, associated with the final site of infarction. To clarify this issue, we followed the hemodynamic and metabolic characteristics of regions with an initially maximally increased OEF and compared them with the ultimately infarcted region in an experimental stroke model. Positron emission tomography (PET) was used to obtain functional images of the brain prior to and following reversible unilateral middle cerebral artery occlusion (MCAO) in 11 anesthetized baboons. To model early reperfusion, the clips were removed 6 h after occlusion. Successive measurements of regional CBF (rCBF), regional CMRO2 (rCMRO2), regional cerebral blood volume, and regional OEF (rOEF) were performed during the acute (up to 2 days) and chronic (> 15 days) stage. Late magnetic resonance imaging (MRI) scans (co-registered with PET) were obtained to identify infarction. Reversible MCAO produced an MRI-measurable infarction in 6 of 11 baboons; the others had no evidence of ischemic damage. Histological analysis confirmed the results of the MRI investigation but failed to show any evidence of cortical ischemic damage. The lesion was restricted to the head of the caudate nucleus, internal capsule, and putamen. The infarct volume obtained was 0.58 +/- 0.31 cm3. The infarcts were situated in the deep MCA territory, while the area of initially maximally increased OEF was within the cortical mantle. The mean absolute rCBF value in the infarct region of interest (ROI) was not significantly lower than in the highest-OEF ROI until 1-2 days post-MCAO. Cerebral metabolism in the deep MCA territory was always significantly lower than that of the cortical mantle; decreases in CMRO2 in the former region were evident as early as 1 h post-MCAO. In the cortical mantle, the rOEF was initially significantly higher than in the infarct-to-be zone. Subsequently, the OEF declined in both regions. The differences in the time course of changes in CMRO2 and OEF between these two regions, with the eventually infarcted area showing earlier metabolic degradation and in turn decline in OEF, presumably underlie their different final outcomes. In conclusion, following MCAO, the region that shows an early maximal increase in the OEF is both topographically and physiologically distinct from the region with final consolidated infarction if reperfusion is allowed at 6 h. This high OEF, although indicative of a threatened condition, is not an indicator of inescapable consolidated infarction and is thus a situation in which therapy could be envisaged. Whether or not it is at risk of infarction and thus constitutes one target for therapy remains to be seen.
Journal of Cerebral Blood Flow & Metabolism 11/1996; 16(6):1176-88. · 5.01 Impact Factor
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ABSTRACT: In the positron emission tomography literature, markedly hypometabolic brain tissue (oxygen metabolism < 1.3 to 1.7 mL.100 g-1.min-1) has often been equated with irreversible damage in the human brain. By serial positron emission tomography measurements, we investigated the temporal evolution of the volume of severely hypometabolic brain tissue after permanent middle cerebral artery occlusion in anesthetized baboons with, as a perspective, the development of rational therapeutic strategies.
Seven anesthetized and ventilated baboons underwent sequential positron emission tomography examinations with the 15O steady-state technique before and 1, 4, 7, and 24 hours and 14 to 29 days after occlusion. In each baboon the infarct volume was calculated by quantitative histological procedures after 19 to 41 days of occlusion.
The sequential measurement of regional oxygen metabolism demonstrated an extension (for > or = 24 hours) of the volume of severely hypometabolic tissue as defined by both absolute and relative metabolic thresholds, and this profile of evolutivity is observed no matter the threshold used. Mean (+/- SEM) infarction volume of 2.4 +/- 0.6 cm3 was comparable to a tissue volume with oxygen consumption < 40% of contralateral metabolism. The volume of hypometabolic tissue was essentially stable at the 1-, 4-, and 7-hour postocclusion studies, increased markedly at the 24-hour study point, and increased even further in the chronic-stage study (on average, 17 days after occlusion). The tissue that eventually displayed a severely hypometabolic state at the final measurement showed a significant decrease of oxygen metabolism and cerebral blood flow at each time analyzed. In that tissue, the oxygen extraction fraction increased significantly at 1 hour (although not thereafter).
The extension of severely hypometabolic volume after middle cerebral artery occlusion reinforces the concept of a dynamic penumbra and suggests the existence of a relatively large window of therapeutic opportunity in which it may be possible to develop neuroprotective strategies. Our study suggests that maximum infarct volume is determined at some time between 24 hours and 17 days after permanent middle cerebral artery occlusion in anesthetized baboons.
Stroke 11/1995; 26(11):2112-9. · 5.73 Impact Factor
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ABSTRACT: Recent reports have shown an increase in specific binding (in vitro) of [3H]PK 11195 to peripheral-type benzodiazepine receptors in both experimental animals and humans, reflecting a glial/macrophagic reaction within and around focal ischemic insults. We have evaluated by positron emission tomography the time course of changes in brain uptake in vivo of 11C-labeled PK 11195 and flumazenil (an antagonist of central benzodiazepine receptors) as indirect and direct markers of neuronal loss, respectively, after focal cerebral ischemia.
Ten anesthetized baboons were submitted to sequential positron emission tomography studies between day 1 and day 91 after unilateral middle cerebral artery occlusion. The studies consisted of successive assessments, in the same positron emission tomography session, of [11C]PK 11195, [11C]flumazenil, cerebral blood flow, and oxygen consumption; late computed tomographic scans were obtained to map the approximate contours of infarction and to define a concentric peri-infarct area.
We found a significant time-dependent increase in [11C]PK 11195 uptake in the peri-infarcted area, maximum at 20 to 40 days after occlusion. In contrast, there was a time- and perfusion-independent significant decrease in [11C]flumazenil uptake in the infarcted area, stable from day 2 onward, and already present in one baboon at day 1. Challenge studies with saturating doses of cold ligands confirmed that these changes represented alterations in specific binding. [11C]Flumazenil uptake was not affected in hypometabolic (but apparently noninfarcted, ie, deafferented) cortical areas.
The delayed and apparently transient increases in [11C]PK 11195 specific uptake in vivo presumably represent glial/macrophage reaction; the marked depression in [11C]flumazenil specific binding, which appears selective for synaptic damage, is both precocious and sustained and thus may be better suited for the early assessment of ischemic damage in humans.
Stroke 01/1994; 24(12):2046-57; discussion 2057-8. · 5.73 Impact Factor
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ABSTRACT: We have determined the rate constants (ki*) of 18F-fluorodeoxyglucose (FDG) in the unlesioned baboon brain, for use in positron emission tomography (PET) measurements of glucose utilization. In contrast to earlier reports, we used a radiosynthesis which guarantees production of FDG essentially uncontaminated by fluorodeoxymannose, and an improved determination of ki* by (1) direct measurement of the time-shift between bolus arrival in femoral arterial plasma and brain, (2) rapid initial PET frames, and (3) extended data acquisition (up to 180 min). Young adult baboons were studied under anesthesia with either phencyclidine or etomidate. The FDG time-activity curves obtained from temporal grey matter showed a consistent decline after about 80 min, indicating true product loss. Three-compartment modelling was performed for increasing fitting intervals (20-120 min) with both a 5-parameter (K1*-k4*, and vascular volume (Vo)) and a 4-parameter (K1*-k3*,Vo) model. With the latter, both the calculated FDG net clearance ((K* = K1*.k3*/(k2* + k3*)) and the fitted kinetic constants were dependent on fitting interval, i.e., they showed sustained unstability. With the former, the constant k4*, which presumably represents dephosphorylation, was overestimated and unstable for short fitting times (presumably due to heterogeneous brain compartments in the sample tissue), but stabilized at approximately 0.01 min-1 for fitting times > or = 80 min; K1*-k3* and K* were also stable after this time. These findings were identical for both anesthetic regimen. Thus, in the anesthetized baboon, the FDG ki* values can be reliably determined based on an adequate PET acquisition paradigm and with a model that incorporates k4* and > or = 80 min time-activity data.
Journal of Neuroscience Methods 12/1993; 50(3):263-72. · 1.98 Impact Factor
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ABSTRACT: We have determined the rate constants of 18F-fluorodeoxyglucose (FDG) in the unlesioned baboon brain, for use in positron emission tomography (PET) measurements of glucose utilization. In contrast to earlier reports, we used a radiosynthesis which garantees production of FDG essentially uncontaminated by fluorodeoxymannose, and an improved determination of by (1) direct measurement of the time-shift between bolus arrival in femoral arterial plasma and brain, (2) rapid initial PET frames, and (3) extended data acquisition (up to 180 min). Young adult baboons were studied under anesthesia with either phencyclidine or etomidate. The FDG time-activity curves obtained from temporal grey matter showed a consistent decline after about 80 min, indicating true product loss. Three-compartment modelling was performed for increasing fitting intervals (20–120 min) with both a 5-parameter (, and vascular volume (Vo)) and a 4-parameter () model. With the latter, both the calculated FDG net clearance and the fitted kinetic constants were dependent on fitting interval, i.e., they showed sustained unstability. With the former, the constant , which presumably represents dephosphorylation, was overestimated and unstable for short fitting times (presumably due to heterogeneous brain compartments in the sample tissue), but stabilized at − 0.01 min−1 for fitting times ≥80 min; and K∗ were also stable after this time. These findings were identical for both anesthetic regimen. Thus, in the anesthetized baboon, the FDG values can be reliably determined based on an adequate PET acquisition paradigm and with a model that incorporates and ≥80 min time-activity data.
Journal of Neuroscience Methods.
