In a strictly homogeneous sample of prospectively studied patients, we have identified, up to 17 hours after stroke onset, substantial volumes of tissue with CMRO2 well above the assumed threshold for viability that nevertheless spontaneously evolved toward necrosis. This tissue exhibited penumbral ranges of both cerebral blood flow and oxygen extraction fraction and thus could represent the part of penumbra that might be saved with appropriate therapy.
Background and Purpose: 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 "C-labeled PK 11195 and flumazenil (an antagonist of central benzodiazepine receptors) as indirect and direct markers of neuronal loss, respectively, after focal cerebral ischemia.Methods: 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
Objective mapping of irreversible tissue damage in the acute stage of ischaemic stroke would be useful for prognosis and in assessing the efficacy of therapeutic manoeuvres in impeding extension of infarction. From our database of 30 patients studied with 15O-PET within 5-18 h after onset of first-ever middle cerebral artery territory stroke, we extracted a subgroup of 19 survivors (age 74.6 +/- 8.5 years) in whom late CT coregistered with PET was available to determine final infarct topography. By means of a voxel-based analysis of the PET data, we determined putative thresholds for irreversible tissue damage as the lower limit of the 95% confidence interval calculated from all voxels within the ultimately non-infarcted brain parenchyma ipsilateral to the insult. The following values were found: 8.43 ml/100 ml/min, 0.87 ml/100 ml/min, 1.64 ml/100 ml, 0.27 and 2.21/min, for cerebral blood flow (CBF), oxygen consumption (CMRO2), blood volume (CBV), oxygen extraction fraction and the ratio CBF : CBV, respectively. Voxels below these thresholds occurred significantly more frequently in the final infarct region than in the non-infarcted parenchyma for CBF and CMRO2 (P = 0.016 and P = 0.0045, respectively, Wilcoxon test), but not for the other PET variables. Furthermore, with both CBF and CMRO2, the percentage of irreversible tissue damage voxels in the affected hemisphere relative to the opposite hemisphere was significantly positively correlated to both the volume of final infarct and the neurological outcome at 2 months (all P < 0.005, Spearman ranked test). These findings validate our voxel-based CBF and CMRO2 thresholds for probabilistic mapping of irreversible tissue damage within the 5-18 h interval after stroke onset; however, whether they would be applicable to earlier intervals remains to be determined. Transfer of our procedure for determination of irreversible tissue damage thresholds to other imaging modalities such as single proton emission computed tomography and diffusion-weighted MRI should be straightforward.
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.
Several studies have shown that the prognosis of oligodendrogliomas is dependent on their histological grade. In order to identify a non-invasive method for the primary diagnosis and follow-up of these tumours, we investigated the relationship between their in vivo metabolism, assessed by positron emission tomography (PET), and their histological grade assessed at the same time. Forty-seven patients with histologically confirmed oligodendrogliomas were investigated. Conventional neuroradiological assessment by computed tomography and magnetic resonance imaging (MRI) was performed in all the patients. All the histology slices were reviewed by the same pathologist after referral from various pathology laboratories. The PET investigation included a carbon-1 methionine (11C-MET) uptake study and, in the majority of cases, a fluorine-18 fluorodeoxyglucose (18F-FDG) uptake study, in order to investigate at the same time both amino acid metabolism and glycolysis. The sampled tumour region of interest (ROI) was defined from the T1-weighted 3D MR scan matched with the PET scan. Tracer concentration in each voxel of the tumour ROI was divided by the mean concentration in an ROI of the same size located in the healthy brain tissue. For each tumour and each tracer, we characterized the metabolic pattern on the basis of the mean and the maximum tumour to healthy tissue concentration ratio, and also the standard deviation and range of the ratios, which indicate the degree of metabolic heterogeneity of the tumour. The histological criteria for differentiating between high- and low-grade tumours were those of the WHO and, partially, of the Sainte-Anne-Daumas-Duport classification. Highly significant differences between high- and low-grade oligodendrogliomas (Mann-Whitney test: P<0.0001) were observed for all the assessed parameters of 11C-MET uptake. On the other hand, the pattern of 18F-FDG uptake showed only moderate differences between the two tumour groups.
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.
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