Jean-Claude Baron

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.

Prolonged Persistence of Substantial Volumes of Potentially Viable Brain Tissue After Stroke A Correlative PET-CT Study With Voxel-Based Data Analysis

BACKGROUND AND PURPOSEnThe existence in humans of brain tissue at risk for infarction but potentially viable (eg, the penumbra) remains unproven. One retrospective operational definition of such tissue includes its final infarction despite a relatively preserved or even normal cerebral metabolic rate of oxygen (CMRO2) in the early hours after stroke onset. Although previous positron emission tomography (PET) studies identified tissue whose CMRO2 declined from the acute to the subacute stage, in principle compatible with deteriorating penumbra, they all lacked a coregistered CT scan mapping of final infarct and an objective three-dimensional PET data analysis, while many patients were studied in the subacute (up to 48 hours) phase. We have evaluated whether tissue with CMRO2 ranging above a threshold for presumably irreversible damage in the first 18 hours of middle cerebral artery territory stroke, but below it in the chronic stage, could be retrospectively identified within the final infarct volume.nnnMETHODSnOur data bank comprises 30 consecutive patients with first-ever middle cerebral artery territory stroke prospectively studied with PET within the first 18 hours after clinical onset; the 15O equilibrium method was used to measure cerebral blood flow and CMRO2. All survivors with the following criteria were eligible for the present study: (1) technically adequate chronic-stage PET performed in the same stereotaxic conditions, (2) coregistered CT scan also performed in the chronic stage, and (3) an infarct of sufficient dimension (>16mm diameter) on late CT. Corresponding CT scan cuts and PET slices were exactly realigned, and the outlines of CT hypodensities were superimposed on the corresponding CMRO2 matrix. Infarcted voxels with CMRO2 values less than or greater than 1.40 mL/100 mL per minute (ie, the generally accepted threshold for irreversible damage) were automatically identified and projected on matrices of all other PET parameters and for both PET studies.nnnRESULTSnEight patients (mean age, 78 Years) were eligible for the present study. The acute-stage PET study was performed 7 to 17 hours after stroke onset and the chronic-stage PET 13 to 41 days later. Within the final infarct, mean CMRO2 fell significantly from the acute- to the chronic-stage PET study (P<.001). Eventually infarcted voxels with acute-stage CMRO2 values above the threshold were found in each of these eight patients; they were most often situated near the infarct borders and constituted 10% to 52% (mean, 32%) of the final infarct volume. The acute-stage CMRO2 in these voxels ranged up to 4.13 mL/100 mL per minute but fell below 1.40 mL/100 mL per minute in 93% of them at the chronic-stage PET. in 7 of 8 patients the acute-stage mean cerebral blood flow ranged from 10 to 22 mL/100 mL per minute, and the mean oxygen extraction fraction was markedly increased (>0.70) in these voxels, consistent with a penumbral state.nnnCONCLUSIONnIn 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.

Perfusion Thresholds in Human Cerebral Ischemia: Historical Perspective and Therapeutic Implications

After middle cerebral artery occlusion (MCAO) in the laboratory animal, the ischemic penumbra has been documented as a severely hypoperfused, functionally impaired, but still viable cortex which can regain its function and escape infarction if it is reperfused before a certain time has elapsed. The penumbra surrounds the ischemic core of already irreversibly damaged tissue, and is progressively recruited into the core with increasing MCAO duration. In the animal, the threshold of cerebral blood flow (CBF) below which neuronal function is impaired and the tissue is at risk of infarction is around 22 ml/100 g/min (∼40% of normal) in the awake or lightly anesthetized monkey, and around 30–35 ml/100 g/min in the cat and the rat. The threshold of CBF below which the tissue becomes irreversibly damaged and will progress to infarction depends on the duration of ischemia, and is around 10 ml/100 g/min for 1–2 h (∼20% of normal) and around 18 ml/100 g/min for permanent ischemia in the monkey. Mildly reduced CBF down to the 40% threshold (termed ‘oligemia’) is normally well tolerated, and the affected tissue is not at risk of infarction under uncomplicated conditions (in the animal, however, selective neuronal death may occur even with only mildly reduced CBF values, but this sequela of stroke seems an exceptional encounter in man). Classic studies with carotid artery clamping in man have provided estimates for the penumbra threshold at around 20 ml/ 100 g/min for the whole brain, but only recently have imaging studies allowed to document the existence of the penumbra in acute stroke and given estimates of local CBF thresholds. With PET, the penumbra is characterized by a reduced CBF, an increased oxygen extraction fraction, and a relatively preserved oxygen consumption (CMRO2). In a series of PET studies performed 5–18 h after stroke onset, we have determined the threshold for penumbra to be around 20 ml/100 g/min, and documented that the extent of neurological recovery is proportional to the volume of penumbra that eventually escaped infarction. Within this time interval, the thresholds for irreversible damage were around 8 ml/ 100 g/min for CBF and around 0.9 ml/100 g/min for CMRO2. Recent studies with diffusion-weighted and perfusion MR have reported similar relative thresholds for CBF of about 50 and 18% for penumbra and core, respectively. Although it is likely that the threshold for irreversibility will be lower with shorter duration since clinical onset, this has not been documented thus far. Because saving the penumbra will improve clinical outcome, it should constitute the main target of acute stroke therapy. We found evidence of penumbra in about one third of the cases studied between 5 and 18 h after onset, and as late as 16 h after symptom onset in occasional patients, suggesting the therapeutic window may be protracted in at least a fraction of the cases; similar experience has recently accrued from diffusion-weighted MR and perfusion MR. In the remaining patients, there was evidence of early extensive damage or early spontaneous reperfusion, which would make them inappropriate candidates for neuroprotective therapy. Recent evidence from PET studies of relative perfusion performed within 3 h of onset suggests that early thrombolysis indeed saves the tissue with CBF below a critical threshold of 12 ml/ 100 g/min, with a correlation between the volume of such tissue escaping infarction and subsequent neurological recovery. Thus, mapping the penumbra in the individual patient with physiologic imaging should allow to formulate a pathophysiological diagnosis, and in turn to design a rational management of the stroke patient and to increase the sensitivity of drug trials by appropriate patient selection.

The Functional Neuroanatomy of Episodic Memory: The Role of the Frontal Lobes, the Hippocampal Formation, and Other Areas

Because it allows direct mapping of synaptic activity during behavior in the normal subject, functional neuroimaging with the activation paradigm, especially positron emission tomography, has recently provided insight into our understanding of the functional neuroanatomy of episodic memory over and above established knowledge from lesional neuropsychology. The most striking application relates to the ability to distinguish the structures implicated in the encoding and the retrieval of episodic information, as these processes are extremely difficult to differentiate with behavioral tasks, either in healthy subjects or in brain-damaged patients. Regarding encoding and retrieval, the results from most studies converge on the involvement of the prefrontal cortex in these processes, with a hemispheric encoding/retrieval asymmetry (HERA) such that the left side is preferentially involved in encoding, and the right in retrieval. However, there are still some questions, for instance, about bilateral activation during retrieval and a possible specialization within the prefrontal cortex. More expected from human and monkey lesional data, the hippocampal formation appears to play a role in both the encoding and the retrieval of episodic information, but the exact conditions which determine hippocampal activation and its fine-grained functional neuroanatomy have yet to be fully elucidated. Other structures are activated during episodic memory tasks, with asymmetric activation that fits the HERA model, such as preferentially left-sided activation of the association temporal and posterior cingulate areas in encoding tasks and preferentially right-sided activation of the association parietal cortex, cerebellum, and posterior cingulate in retrieval tasks. However, this hemispheric asymmetry appears to depend to some extent on the material used. These new data enhance our capacity to comprehend episodic memory deficits in neuropsychology, as well as the neural mechanisms underlying the age-related changes in episodic memory performances.

Effects of Healthy Aging on the Regional Cerebral Metabolic Rate of Glucose Assessed with Statistical Parametric Mapping

The aging process is thought to result in changes in synaptic activity reflecting both functional and structural cell derangement. However, previous PET reports on age-related changes in resting brain glucose utilization (CMRglc) have been discrepant, presumably because of methodological as well as subject screening differences. In contrast to other studies, which used a region of interest approach, the objective of the present work was to determine, by means of the SPM software, the changes in regional CMRglc as a function of age in 24 optimally healthy, unmedicated volunteers of ages from 20 to 67 years. Global CMRglc showed a significant decline with age (approximately 6% per decade, P < 0.05), which concerned all the voxels studied save for most of the occipital cortex and part of the cerebellum. The most significant effects (P < 0.001) concerned the association neocortex in perisylvian temporoparietal and anterior temporal areas, the insula, the inferior and posterior-lateral frontal regions, the anterior cingulate cortex, the head of caudate nucleus, and the anterior thalamus, in a bilateral and essentially symmetrical fashion. The high posterior parietal cortex was not sampled in this study. This distribution of changes in CMRglc with age may differ from that seen in Alzheimer disease, where the earliest metabolic reduction has been shown to affect the posterior cingulate cortex.

Early Postischemic Hyperperfusion: Pathophysiologic Insights from Positron Emission Tomography

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 when it occurs in the acute setting. However, an important issue that needs to be resolved by future studies with respect to EPIH relates to the possible occurrence of selective neuronal loss, as opposed to pan-necrosis, in the previously hyperperfused tissue.

In vivo mapping of brain benzodiazepine receptor changes by positron emission tomography after focal ischemia in the anesthetized baboon.

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 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. 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 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. Results 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 perrasion-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. Conclusions 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.

Sequential Studies of Severely Hypometabolic Tissue Volumes After Permanent Middle Cerebral Artery Occlusion A Positron Emission Tomographic Investigation in Anesthetized Baboons

BACKGROUND AND PURPOSEnIn 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.nnnMETHODSnSeven 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.nnnRESULTSnThe 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).nnnCONCLUSIONSnThe 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.

Central benzodiazepine receptors in human brain: estimation of regional Bmax and KD values with positron emission tomography

Studies of central benzodiazepine receptors in the human brain in vivo are now possible using positron emission tomography (PET) and [11C]flumazenil. With the aim of measuring Bmax and Kd in brain regions, we used a two-injection [11C]flumazenil (at high and low specific radioactivity, respectively) pseudo-equilibrium paradigm to evaluate, in seven unmedicated healthy volunteers, the relative merits of three reference structures (pons, hemispheric white matter and corpus callosum) in which the free radioligand concentration in brain tissue was estimated 15-40 min after i.v. injection of the radioligand. By means of high-resolution PET, the Bmax and Kd were calculated for each subject in 18 gray matter structures, based on a two-point Scatchard plot. We found that the use of the corpus callosum as reference often resulted in spurious Bmax and Kd values. The pons was the best reference structure because it provided satisfactory Bmax values (closest to in vitro data) and most consistent Kd values, and was the region easiest to sample on PET images. The pattern of regional Bmax was consistent with that expected from in vitro studies, with values highest in the cerebral cortex, intermediate in the cerebellum, and lowest in the striatum and the thalamus. The Kd values were uniform among regions and were consistent with earlier in vitro and in vivo data. This work documents the feasibility of estimating Bmax and Kd of central benzodiazepine receptors in multiple brain regions for clinical research.

Brain kinetics and specific binding of [11C]PK 11195 to ω3 sites in baboons: positron emission tomography study

We characterized, in vivo, using positron emission tomography in baboons, the kinetics and specific binding of i.v. injected [11C]PK 11195 to omega 3 sites in the brain. Following immediate access to brain tissue, the brain kinetics of [11C] K 11195 showed a slow elimination for the 60 min of study. Both coinjection and pulse-chase (at t = 8 min) with saturating amounts of cold PK 11195 immediately enhanced the availability of radiotracer to brain tissue, but also markedly increased the rate of washout. These effects presumably reflect displacement or inhibition of specifically bound [11C]PK 11195 to both peripheral and central omega 3 sites, respectively. These results indicate that [11C]PK 11195 has easy access and binds with moderate specificity to the normal primate brain in vivo.