Flumazenil is a specific antagonist of the central benzodiazepine receptor (CBZR). Labelled with 11C, this compound is the reference radioligand for positron emission tomography (PET) study of the CBZR in humans and primates. The time-course of [11C]-flumazenil radioactivity and its main acid metabolite [11C] Ro 15-3890 were reconstructed from the time-course of total radioactivity in plasma after administration with high or low SRA in primates and humans, applying an extraction procedure validated by TLC. The measured pharmacokinetics of [11C]-flumazenil (T1/2 beta = 45.1 +/- 12.3 min, T1/2 alpha = 1.5 +/- 1.5 min; K = 0.14 +/- 0.14 min-1; Vd area = 44.0 +/- 17.0 l; Clp = 40.0 +/- 8.5 l/h) exhibited a very rapid distribution phase followed by fast elimination, with a large volume of distribution; these results were confirmed by HPLC determinations and agree with previously published data on unlabelled flumazenil. Pharmacokinetics of [11C] Ro 15-3890 acid metabolite show that high drug concentrations in the blood are promptly achieved (kf = 0.13 +/- 0.004 min-1), with a very rapid elimination half-life (T1/2m = 4.47 +/- 1.31 min) comparable to that of [11C]-flumazenil. The percentage metabolization of parent compound to the acid [11C] Ro 15-3890 was constant from the 15th minute and was significantly higher in man compared to the monkey. This percentage was increased by prior eating. The other putative metabolites, i.e. labelled [11C] Ro 15-4965 and unlabelled Ro 15-5528, were never observed at detectable concentrations with TLC and HPLC in rabbit, baboon and human blood samples. This pharmacokinetic study of plasma flumazenil may be useful to implement a dynamic method of CBZR quantification using PET and for analysis of pharmacokinetics in brain tissue.

Adult↗

PubMedDate not supplied

Mapping the ischaemic penumbra with PET: implications for acute stroke treatment.

The ischaemic penumbra has been documented in the laboratory animal as a severely hypoperfused, non-functional, but still viable cortex surrounding the irreversibly damaged ischaemic core; with elapsing time, more penumbra gets recruited into the core, while tissue reperfusion is able to stop this deleterious process until a certain point in time. As saving the penumbra should improve clinical outcome, it should constitute the main target of acute stroke therapy. In a series of PET studies performed 5-18 h after stroke onset, we were able to (i) document, for the first time in man, the existence of tissue fulfilling operational criteria for penumbra in about one third of the cases; (ii) show that long-term neurological recovery is proportional to the volume of penumbra that eventually escapes infarction, and (iii) detect penumbral tissue as late as 16 h after symptom onset in occasional patients, suggesting the therapeutic window may be protracted in such cases. Mapping the penumbra in the individual patient with neuroimaging procedures should allow to formulate a pathophysiological diagnosis, and thus to design a rational management of the stroke patient and to improve the selection of candidates for therapeutic trials.

Acute Disease↗

PubMedDate not supplied

Predictive value of (99m)Tc-HMPAO-SPECT for neurological Outcome/Recovery at the acute stage of stroke.

BACKGROUND AND PURPOSE: Combined perfusion and oxygen metabolism PET imaging is highly predictive of spontaneous outcome after middle cerebral artery (MCA) stroke, independent of clinical scores, but whether the assessment of perfusion alone by SPECT provides similar information remains unclear. We have assessed the prognostic value of (99m)Tc-HMPAO-SPECT at the acute stage of stroke. METHODS: Twenty-seven first-ever nonhemorrhagic MCA territory stroke patients were prospectively studied 4-20 h (mean: 12 h) after onset with (99m)Tc-HMPAO-SPECT. None was part of a therapeutic trial or received thrombolysis. Neurological deficits were quantified at admission and 2 months later with Orgogozo's MCA scale. SPECT images were visually classified by 3 independent observers into one of three patterns, as follows: pattern I = marked and extensive tracer hypofixation; pattern II = moderate and/or focal hypofixation with or without combined hyperfixation, and pattern III = normal or increased uptake without hypofixation. In addition to this visual analysis, we also calculated a voxel-based 'hypoperfusion score', an index of severity x extent of hypofixation according to Mountz's method. RESULTS: There was a good intra- and interobserver agreement. After consensus, 9, 14 and 4 patients were classified in patterns I, II and III, respectively. These patterns had a significant predictive value for raw outcome but not for percentage recovery (p = 0.008 and p = 0.127, respectively). Thus, all patients in pattern III had a good outcome, while most (but not all) patients in pattern I had a poor or intermediate outcome; pattern II patients were more evenly distributed among outcomes. Hypoperfusion scores were highly significantly positively correlated with both 2-month outcomes and percentage recoveries, even after controlling the predictive value of day 0 MCA scores by partial correlations. COMMENTS: We found that SPECT had a significant added predictive value even when compared to admission neurological scores. Although less accurate than PET, (99m)Tc-HMPAO-SPECT may help to predict spontaneous individual neurological evolution, especially whenever perfusion images are normal or show an increased tracer uptake without associated hypofixation.

Acute Disease↗

PubMedDate not supplied

Early (99m)Tc-ethylcysteinate dimer brain SPECT patterns in the acute phase of stroke as predictors of neurological recovery.

OBJECTIVES: Accurate prediction of outcome in acute stroke would help in identifying subgroups of patients for therapeutic trials and intravenous thrombolysis. The purpose of this study was to prospectively test the hypothesis that brain SPECT, with (99m)Tc-L, L-ethylcysteinate dimer (ECD), a tracer sensitive to cell function, performed in the first hours after stroke onset, adds predictive power to concomitant neurological evaluation. METHODS: Twenty-four patients with a first-ever middle cerebral artery stroke were prospectively studied with ECD-SPECT within 12 h after stroke onset. Neurological evaluation was performed using Orgogozo's scale at admission and 3 months later in order to calculate the percent Martinez-Vila evolution indices (EI%). Semiquantitative visual analysis of SPECT images was performed in 6 cortical regions relevant for carotid artery territory. Both the extent and the intensity of cortical reduced ECD uptake were calculated, leading to an 'ischemia' score, corresponding to the sum of regions of interest (ROI) where ECD uptake was between 40 and 80% of the contralateral healthy hemisphere, and an 'irreversibly damaged tissue' (IDT) score, corresponding to an uptake below 40%, and a total score (ischemia + IDT). Each patient was assigned to one of three patterns: (1) pattern I with severe ECD cortical uptake reduction defined by at least one ROI with uptake under 40%, (2) pattern II with moderate ECD cortical uptake reduction (40-80%) only and (3) pattern III with normal ECD uptake. RESULTS: There were 11 patients (46%) with pattern I ECD-SPECT. This group had almost invariably (10/11 patients) a poor outcome. The 12 patients (50%) classified in pattern II had a variable clinical outcome, ranging from improvement to deterioration. The single patient with a normal SPECT (pattern III) had a full clinical recovery. Both total score and IDT score were strongly significantly correlated with neurological recovery EI% (respectively p = 0.006 and 0.004). Their predictive value was significantly higher than, and independent of, day 0 neurological evaluation. No patient had an increased ECD uptake. CONCLUSION: Our results show that the degree of ECD cortical uptake reduction, measured on early brain SPECT, is a strong predictor of neurological recovery. ECD-SPECT data have a higher predictive value than day 0 neurological evaluation. The apparently better predictive value of ECD over hexamethylpropyleneamine oxime may reflect this tracer's brain retention mechanisms which are weighted more towards cell function than towards perfusion. ECD-SPECT is easily obtainable and may help in selecting out from therapy those patients who are likely to have either very good or very poor spontaneous outcome, and thus improve the assessment of acute stroke and the choice of therapeutic strategy.

Acute Disease↗

PubMedDate not supplied

Delayed intrahemispheric remote hypometabolism. Correlations with early recovery after stroke.

Although 'intrahemispheric diaschisis' (i.e. a hypometabolism affecting the cerebral hemisphere ipsilateral to but remote from the infarct) may classically exacerbate acute-stage neurological deficit and influence early recovery, it has been studied only rarely. Out of a series of 30 patients with first-ever middle cerebral artery (MCA) territory stroke, we analyzed the data from 19 survivors investigated by (15)O positron emission tomography (PET) both in the acute (within 5-18 h of clinical onset) and subacute (approximately 3 weeks later) stage, and for whom chronic-stage CT coregistered with PET was available to assess infarct topography and size. Orgogozo's MCA scale was used to assess neurological deficits at the time of, and recovery between, the PET studies. Oxygen consumption was obtained for both PET sessions for the whole ipsilateral hemisphere (excluding ventricles and infarct), as well as for the thalamus and the occipital and mesial-prefrontal cortex (i.e. potentially deafferented tissue outside the MCA territory). In all regions except the occipital cortex, the oxygen consumption significantly decreased between the first and the second session, without significant correlation with the concomitant changes in MCA scores. However, acute-stage mesial-prefrontal metabolism was significantly correlated with neurological recovery. Also, both the hemisphere and the mesial-prefrontal metabolism at the second session were significantly correlated with both infarct size and concomitant MCA scores, but the latter relationship became insignificant when infarct size was taken into account. This study reveals no evidence of acute intrahemispheric diaschisis after MCA territory stroke in man. However, it documents for the first time a phenomenon of delayed intrahemispheric remote hypometabolism developing while the patients clinically recover. Because the degree of this secondary phenomenon is a function of infarct size, a mechanism of degeneration of the damaged neuron terminals is likely. Finally, contrary to other reports, neurological recovery was not a function of thalamic hypometabolism, but appeared to be influenced by acute-stage mesial-frontal metabolism, perhaps because this region is part of a network that has an important compensatory role in motor recovery.

Acute Disease↗

PubMedDate not supplied

Migrainous cerebral infarction: a tomographic study of cerebral blood flow and oxygen extraction fraction with the oxygen-15 inhalation technique.

A patient with migraine who had a permanent visual field defect was studied by angiography and CT scan. He also had a tomographic study of cerebral blood flow (CBF) and oxygen extraction fraction (EO2) using the non-invasive continuous oxygen-15 (15O) inhalation technique. Angiography was normal. CT scan revealed an area of decreased density with contrast enhancement suggestive of a recent infarct in the left occipital lobe. The 15O inhalation technique showed a decrease in CBF and EO2, typical of recent infarcts, in the corresponding area, an increase in CBF with normal EO2 in the left temporal lobe, and a decrease in CBF with increased EO2 in the right occipital cortex. These findings illustrate the unusual nature and extent of the ischemic process underlying migrainous cerebral infarction.

Cerebral Angiography↗

PubMedDate not supplied

Reversal of focal "misery-perfusion syndrome" by extra-intracranial arterial bypass in hemodynamic cerebral ischemia. A case study with 15O positron emission tomography.

Tomographic images of cerebral blood flow (CBF) and oxygen extraction fraction (OEF) using the 15O continuous inhalation technique, and positron emission tomography, were obtained from a patient with cerebral ischemia distal to an occluded left internal carotid artery. There was a focal mismatch between CBF and oxygen metabolism in the brain supplied by the middle cerebral artery where CBF was decreased and OEF increased ("misery-perfusion syndrome" as opposed to "luxury-perfusion syndrome"). These abnormalities were most marked in the parieto-occipital watershed area. After left superficial temporal to middle cerebral artery anastomosis, the clinical attacks ceased and a repeat study did not demonstrate the previous CBF and OEF abnormalities. This suggests that this pattern of abnormalities indicates potential viable tissue. The concept of "misery-perfusion" may be of some importance in the pathophysiological mechanisms of hemodynamic cerebral ischemia and serve as a rational basis for revascularization procedures.

Aged↗

PubMedDate not supplied

Regional cerebral blood flow and oxygen consumption in human aging.

The oxygen-15 continuous inhalation technique and PET were used to study the age-related changes in regional CBF and CMRO2. Twenty-seven patients, aged 19 to 76 years, free of any history of cerebral disease and vascular risk factors were examined in "resting state." CBF, CMRO2 and oxygen extraction fraction (OEF) values were calculated in seven different brain structures as well as in mean gray matter. Left-right ratios were also computed for all symmetrical structures analyzed. Mean gray CBF, but not mean gray CMRO2, decreased linearly with age (p less than 0.02). However, when younger subjects (less than or equal to 50 yrs) were compared to older subjects (greater than 50 yrs), an age-related matched decrease in CBF and CMRO2 was observed in mean gray matter (18% and 17%, p less than 0.05) and in all gray matter regions analyzed, particularly in frontal, temporo-sylvian and parieto-occipital cortex. White matter CBF and CMRO2 remained remarkably stable with advancing age. Although the possibility of methodological artifacts was considered, we favor progressive loss of cortical neurones and/or diminished activity of those remaining to explain our findings. In addition, age-related changes in cognitive activities might also be involved.

Adult↗

PubMedDate not supplied

Effects of extra-intracranial arterial bypass on cerebral blood flow and oxygen metabolism in humans.

Twelve patients, eleven with a carotid obstruction and one with an occlusion of the middle cerebral artery, were studied before and after a successful unilateral extra-intracranial arterial by-pass, (EIAB) using PET and the 15-0 steady-state technique to measure regional cerebral blood flow (CBF), oxygen extraction fraction and oxygen metabolic rate (CMRO2). In the whole group of patients, both CBF and CMRO2 increased significantly on both cerebral hemispheres after EIAB, returning toward control levels defined in age-matched subjects. Mean oxygen extraction fraction, on the other hand, was not affected. Individually, three different effects of EIAB emerged: 1) Alleviation of a state of long standing unilateral "misery-perfusion", as reported earlier; 2) parallel increase of CBF and CMRO2 bilaterally, which appeared due to improvement of a hemodynamic depression of metabolism, the precise mechanism of which remains obscure; 3) Complex, unexpected changes in the CBF-CMRO2 couple again resulting in increases in CMRO2. This metabolic improvement afforded by EIAB in our patients has not been reported before; it suggests that long-standing hemodynamic failure may induce a metabolic depression that is still potentially reversible by surgical revascularization.

Adult↗

PubMedDate not supplied

Stroke, migraine and intracranial aneurysm: a case report.

A man had since childhood recurrent attacks typical of ophthalmic migraine. After an otherwise unremarkable attack, he was left with a permanent quadrantanopsia due to a right occipital infarct. The remarkable pattern of progression, which characterized the visual phenomenon of subsequent attacks, favours a primary neuronal phenomenon. The first angiography revealed an occlusion of the posterior cerebral artery (PCA) but the second one, performed two years later, disclosed a PCA aneurysm. Such a finding emphasizes the need of thorough and repeated evaluations of patients with so-called "migrainous infarcts."

Adult↗

PubMedDate not supplied

Diaschisis.

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Animals↗