(Stroke. 1997;28:2045-2052.)
© 1997 American Heart Association, Inc.
Articles |
Early Detection of Irreversibly Damaged Ischemic Tissue by Flumazenil Positron Emission Tomography in Cats
From the Max-Planck-Institut für neurologische Forschung, Köln, Germany.
Correspondence to W.-D. Heiss, MD, Max-Planck-Institut für neurologische Forschung, Gleueler Str 50, D-50931 Köln, Germany.
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Abstract |
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Background and Purpose Ligands for cerebral benzodiazepine receptors were used in the past to indicate the intactness of cortical neurons in subacute to chronic states after stroke and thus to differentiate among brain regions with complete or incomplete infarction and with functional deactivation. For planning acute interventional therapy, however, a marker of irreversible damage in early ischemia is needed. We studied the applicability of [11C]flumazenil (FMZ) for differentiation between tissue with and without potential of recovery in the first hours after focal experimental ischemia.
Methods In 11 cats, cerebral blood flow, cerebral
metabolic rate for oxygen, oxygen extraction fraction, and
FMZ binding were studied repeatedly by positron emission tomography
before, during, and up to 12 hours after transient middle cerebral
artery occlusion (MCAO) (30 minutes in 2, 60 minutes in 7, and 120
minutes in 2 cats, respectively). Development of the defects in energy
metabolism were compared with the defects in FMZ binding (2
to 3 hours and 8 to 9 hours after MCAO), with the pattern of disturbed
glucose metabolism (determined 12 hours after MCAO), and
with the size of the infarcts (determined 
15 hours after MCAO).
Results Irrespective of the level of reperfusion, defects in FMZ binding (2 to 3 hours after MCAO) were closely related to areas with severely depressed oxygen consumption and predicted the size of the final infarcts, whereas preserved FMZ binding indicated intact cortex. Depression of glucose metabolism was in all animals larger than the defects in FMZ binding and the infarcts, indicating functional deactivation of brain areas beyond the permanent morphological damage. In addition, FMZ distribution within 2 minutes after injection was significantly correlated to flow and yielded reliable perfusion images.
Conclusions The reduction of FMZ binding early after focal ischemia reflects irreversible neuronal damage that otherwise only can be detected by multitracer studies. Our experimental data and first clinical applications suggest that FMZ has potential as an indicator of developing infarction. Since FMZ distribution additionally images perfusion, this tracer might be useful for the selection of patients who would benefit from acute therapeutic intervention.
Key Words: cerebral blood flow • cerebral ischemia, focal • flumazenil • neuronal damage • positron emission tomography • receptors, benzodiazepine • cats
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Therapeutic interventions in patients with acute ischemic stroke can only be successful if they are initiated as long as viable tissue exists within the territory affected by the flow disturbance. Functionally impaired but morphologically intact tissue—the so-called penumbra1 —is a common finding in animal models of acute focal ischemia2 but is difficult to define in patients with acute stroke in the usual clinical setting. In contrast to irreversibly damaged tissue in which flow and energy metabolism are severely depressed,3 4 ischemically compromised but still viable tissue shows "misery perfusion,"5 which is characterized by severely reduced blood flow but oxygen consumption preserved at a higher level and consequently an increase in OEF. However, the fate of this tissue is undetermined: while most of misery-perfused tissue turns into necrosis, in some instances this critical condition is reversible, and
the tissue preserves morphology and regains function.6 7 This important information on the condition of the tissue—permanent morphological destruction or viable penumbra with a potential of recovery and that is eventually amenable to therapy—can only be obtained by complex multitracer studies requiring determinations of flow and oxygen consumption at one session. Therefore, a single marker selectively distinguishing necrotic from penumbral tissue would be helpful. Central BZR ligands were suggested by Sette et al8 for that purpose, since they mark intact cortical neurons and therefore can detect early neuronal damage. In the past, labeled BZR ligands were successfully used, eg, as PET tracers ([11C]flumazenil) for focal brain damage responsible for partial seizures9 10 11 12 and as SPECT tracers ([123I]iomazenil) for the separation between infarcted and deactivated tissue after stroke.13 14 However, a study relating early changes in flow and energy metabolism to deficits in the uptake of BZR ligands and histologically verified infarcts is still lacking. Since repeated multitracer studies under reproducible conditions are not feasible in patients, such a study was executed in the cat MCAO model. To follow changes in flow, energy metabolism, and [11C]flumazenil uptake from the preocclusion control state over the ischemic period to the final infarct after reperfusion, transient MCAO for 30 to 120 minutes was chosen because the outcome is variable in this model, ranging from large space-occupying infarcts to small lesions in the basal ganglia, sparing the cortex.15
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Materials and Methods |
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Eleven adult cats of either sex weighing 3.8 to 4.7 kg were used. Anesthesia was induced with 25 mg/kg IM ketamine hydrochloride. After catheterization of the left femoral artery and vein, the cats were tracheostomized, immobilized with 0.2 mg/kg IV pancuronium bromide, and artificially ventilated. Anesthesia was continued with 0.8% to 1.5% halothane in a 70%/30% N2O/O2 gas mixture. An intravenous infusion of 2 mL/kg per hour Ringer's solution containing 5 mg/kg per hour gallamine triethiodide for muscle relaxation was maintained throughout the experiment. Physiological variables were kept in the normal range known for awake cats16 (Table 1
). Deep body temperature was kept at
37°C by means of a controlled heating blanket. The left MCA was
exposed transorbitally, and an occluding device was implanted as
described elsewhere.17 This device permitted occlusion and
reopening of the MCA with a microdrive after the orbita was sealed. By
this procedure, leakage of cerebrospinal fluid was avoided and
intracranial pressure was maintained. In 2 cats the MCA was reopened
after 30 minutes, in 7 cats after 60 minutes, and in 2 cats after 120
minutes of occlusion. Reopening of the vessel led in all animals to
immediate reperfusion to the territory of the MCA. The procedures were
in accordance with the German laws for animal protection and were
approved by the local Animal Care Committee and the
Regierungspräsident of Cologne.
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Multiple consecutive PET studies were performed in each cat before and
up to 12 hours after MCAO. Using a head holder and a crosshair laser
beam system, we positioned the animals in the scanner gantry such that
coronal brain sections corresponding to a stereotaxic cat
brain atlas18 were obtained. The animals were kept in the
scanner throughout the experiment. Correction of photon attenuation was
performed in each cat with the use of a transmission scan performed
with rotating 68Ge rod sources. For the assessment of
CMRO2, CBF, and CMRglc, bolus applications were
used.19 20 21 For CMRO2 determination, 10 mCi
15O2 was administered in a single breath by the
respirator followed by a 30-second breathhold; a blood volume of 6
mL/100 g was assumed.22 CBF was determined after
intravenous bolus injection of 20 mCi
15O-labeled water. CMRglc was measured after
injection of 5 mCi FDG with the use of regionally estimated rate
constants23 and a lumped constant of 0.42. Experimental
background and limitations of these methods for measurement of cerebral
hemodynamics and energy metabolism were
discussed previously.24 BZR density was estimated from the
distribution of [11C]flumazenil 30 to 60 minutes after
bolus injection of 10 mCi.25 Additionally, the initial
tracer distribution reached within 2 minutes after injection served as
an indicator of the perfusion pattern in comparison to the flow values
determined by H215O.
Serial PET scanning was performed with a 24-ring, high-resolution
camera (Siemens/CTI ECAT EXACT HR) with an axial field of view of 15
cm, an in-plane spatial resolution of 3.6 mm full width at half
maximum, and an axial resolution of 4.0 mm full width at half
maximum.26 For CMRO2 and CBF studies, a total
of 6x106 counts and 107 counts, respectively,
were collected for 2 minutes. For CMRglc studies, a total
of 2x108 counts were collected for 40 minutes starting at
20 minutes after injection, thus permitting the reconstruction of
transaxial slices from 107 counts per slice. During
H215O and 15O2 scans,
activity in arterial blood was measured continuously in an
arteriovenous shunt with the use of an automatic, calibrated blood
sampling system.27 Additionally, three
arterial blood samples were taken during
15O2 scans for determination of blood gases and
for whole-blood and plasma radioactivity measurements in a sample
changer cross-calibrated to the camera; mean values were used for
parametric image generation. During the FDG studies, eight
blood samples were taken starting at tracer injection, and plasma
radioactivity was used for CMRglc calculations according to
the model equation.21 Additionally, plasma glucose content
was determined. At the end of the experiment, usually 15 hours after
MCAO, animals were perfusion-fixed with formalin (4%), and the brains
were removed. Serial 7-µm sections (stained with hematoxylin-eosin or
Luxol Fast Blue) were obtained in parallel with the PET planes
according to a stereotaxic cat brain atlas.18
Corresponding to the PET slice thickness, serial sections were matched
to PET slices and were analyzed at a section-to-section
distance of 3 mm for histological verification
of infarcts. Areas of ischemic damage in cortex were determined
on an image analyzer (Gesotec) under microscopic control and
expressed in percentage of cortical areas in the
histological sections. Correction for brain swelling
was performed.
PET images of CBF, CMRO2, and OEF were obtained before and
up to five times after MCAO and reperfusion, with each multitracer
study taking 20 minutes. BZR density ([11C]flumazenil
distribution, 60 minutes) was obtained before and up to three times
after MCAO. CMRglc (60 minutes) was determined at 12
hours after MCAO. Data analyses were based on the
parametric images of 16 transaxial brain slices. The obtained
images permitted the identification of the main anatomic structures of
the cat's brain and a distinction of gray and white matter with the
best resolution obtained in the CMRglc images. Quantitative
data analysis was accomplished by stepwise definition of
thresholds in control CMRglc and ischemic CBF
images, as described before.15 In a first step,
hemispheres were defined by including all intracerebral
voxels with control CMRglc >75% of the mean of the
planes. In these images, cortical areas were marked using a threshold
of control CMRglc >100% of the mean over both
hemispheres, combined with rough anatomic definition. Within these
depicted cortical areas, regions showing FMZ deficits were defined
using a threshold of <75% of the mean FMZ activity over corresponding
contralateral cortical areas. Thereafter, the ischemic CBF
image was used to mark the ischemic territory using a threshold
of CBF <50% of the mean over the contralateral hemisphere. Circular
regions (diameter 3 mm) were located in intersecting areas of
cortical and ischemic regions. Means of these regions of
interest in percentage of individual preischemic controls
were used for quantification in sequential multiparametric
studies.
The experimental protocol included control studies of BZR density 12
hours and CBF and CMRO2 0.5 hour before
arterial occlusion. During ischemia, measurements
of CBF and CMRO2 were started 5 minutes after occlusion.
During reperfusion, the first CBF and CMRO2 measurements
were started 5 minutes after reopening of the MCA, followed by
measurements at 3.0, 4.5, 6.5, and 8.0 hours after reopening of the
MCA. BZR density measurements were started at 2.0, 5.5, and 8.5
hours after reopening of the MCA. Subsequently, CMRglc was
measured. This study concentrated on early changes in FMZ uptake in
relation to alterations in flow and energy metabolism and
to the final infarct. The effect of the dynamic relationship between
flow and energy metabolism during ischemia and
reperfusion on tissue damage was analyzed in a previous
article.15
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Results |
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In preocclusion controls, distribution of tracers representing flow, oxygen consumption, and receptor density was symmetrical—with a few variations as a consequence of surgery—and imaged the anatomic details of the cat's brain. Because of the spacial distribution of BZR and their low concentration in basal ganglia, FMZ was mainly accumulated in the cortex. During MCAO the severity of ischemia was reflected in the decrease of regional CBF, but CMRO2 was usually preserved, leading to increased OEF as an indicator of misery perfusion and viable tissue (Fig 1
, Table 2). With
reopening of the MCA, the MCA territory was reperfused immediately, but
decreases in CMRO2 and in OEF early indicated developing
infarcts.
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Stable FMZ distribution approximately 3 hours after MCAO was closely
related to the pattern of CMRO2 indicating neuronal damage.
In cats with significant decreases of CMRO2 in large
cortical areas, FMZ uptake as well as CMRglc was reduced
(Fig 1
), and infarcts found in histology corresponded to regions with
FMZ uptake deficiency (Fig 3). In some of these animals, reperfusion
reached flow values far above the normal range and persisted for
extended periods (>6 hours). In animals with shorter lasting (30
minutes) or less severe ischemia (1 animal with 60 minutes of
MCAO), reperfusion efficiently normalized oxygen consumption, and OEF
returned to the normal range within a short period. In these cats
cortical FMZ uptake 3 hours after MCAO was symmetrical and indicated
neuronal integrity. The moderately decreased CMRglc in
these animals suggests cortical deactivation due to small lesions in
white matter and basal ganglia. The differences in the distribution of
decreased cortical FMZ uptake and reduced CMRglc may be
seen in a series of transaxial slices through the cat's brain 8 to 9
hours after MCAO: The extension of decreased FMZ uptake as a marker of
neuronal loss is smaller than the area of decreased glucose
metabolism as an indicator of deactivation (Fig 2). Infarct size, determined 15 hours
after MCAO, correlated significantly with the extent of the defect in
FMZ uptake 2 to 3 hours after reperfusion following 1-hour MCAO (Fig 3). However, FMZ defects slightly
underestimated the final infarcted area, since ischemic damage
may increase due to delayed neuronal loss occurring during the
reperfusion period.
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The applicability of FMZ as a tracer for perfusion was tested in 5 cats
in which the regional FMZ uptake within 2 minutes after bolus injection
was compared with flow values (milliliters per 100 g per minute)
measured after H215O bolus injection. In these
5 animals, data sets from the preischemic control and at 2
to 3 hours after reperfusion following 1-hour MCAO were available. The
pattern of flow obtained by the two tracers was in excellent agreement.
A correlation analysis of the regional values from the data
sets in 5 cats demonstrates the significant correspondence
(r=.93) between the procedures (Fig 4). Therefore, early FMZ distribution can
be used as a perfusion tracer.
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Discussion |
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Central BZR ligands such as [11C]flumazenil and [133I]iomazenil binding specifically to the postsynaptic GABAergic complex, which is highly concentrated in the cortical synapse-rich neuropil as a reflection of the abundant GABAergic inhibitoring system,28 29 30 were favored as ideal markers of peri-infarct tissue and incomplete brain infarcts8 13 14 in which selective or partial neuronal necrosis had occurred during an ischemic episode without loss of glial cells and hence without gross tissue destruction on CT.31 32 This recommendation is based on observations in the baboon MCAO model,8 in which FMZ uptake was reduced 2 days and continued to decrease up to 54 days after the vascular attack, and in the gerbil brain after transient ischemia,33 in which preserved BZR binding predicted survival and depleted binding sites indicated damage of brain tissue in the chronic phase. Clinical SPECT studies with [133I]iomazenil, which exerts a higher affinity to BZR than FMZ34 in patients with chronic cerebrovascular disease35 and in subacute to chronic states after ischemic stroke,13 14 supported these results and permitted distinction between peri-infarct tissue with neuronal loss and tissue with deactivation due to functional deafferentation (diaschisis).
In accordance with the decreases of [I]iomazenil uptake shown by
SPECT in the acute phase after ischemia, which were equal
to36 or less pronounced than flow changes,37
we observed a significant reduction in FMZ binding sites 2 to 3 hours
after 1-hour MCAO in those regions that were found to be infarcted in
histological examination of brain fixed 15 hours after
the ischemic period. The decrease in FMZ uptake was related to
severity and extent of ischemia, as documented by
disturbance of regional flow and energy metabolism,
but not affected by hyperreperfusion. By a comparison of
CMRglc and FMZ uptake, morphologically damaged cortex could
be clearly distinguished from deactivated cortex without
neuronal destruction: whereas the latter condition—also observed in
cerebellar diaschisis38 —is characterized by symmetrical
cortical FMZ uptake but moderately decreased glucose
metabolism (Fig 2), in the developing infarction FMZ uptake
as well as CMRglc is significantly reduced (Fig 1).
Between the histological changes determined after ischemia and the reduced FMZ binding observed in the early course, some discrepancy exists. Histological studies have demonstrated that up to 1 day after focal ischemia the neuronal somata are maintained to some extent,39 40 41 and neurons bearing their receptor population could still be in situ.42 Considerable synaptic disruption was observed early after ischemia in ultrastructural studies, and 5-hydroxytryptamine receptors were reduced in frontal cortex of gerbils as early as 3 hours after bilateral carotid occlusion.43 Additionally, contrary to the glutamate receptors that are resistant to ischemia,44 45 the functioning of GABA receptors is disturbed early in ischemia.46 The decreased FMZ uptake therefore may reflect irreversible synaptic dismantlement and indicate neuronal damage very early in the course of ischemia.
Flumazenil is therefore an early marker of neuronal destruction in the core of ischemia and corresponds to the findings in CBF and CMRO2 determinations, by which viable, misery-perfused tissue can be separated from already necrotic areas. Combined quantitation of CBF and CMRO2, which is necessary for defining the state of the tissue, requires arterial blood sampling, which is precluded in many patients, eg, those undergoing thrombolytic therapy. The discrimination between viable and not viable tissue in early ischemia is of essential importance for planning therapeutic strategies since only areas with preserved neuronal integrity can benefit from thrombolytic or neuroprotective therapies. The ischemic core with severe early metabolic disturbance turns into macroscopic infarction, and that condition can be predicted by BZR binding studies early after the insult. Selective neuronal loss in moderately ischemic areas occurs later than necrosis in the ischemic core, and neuronal loss progresses over extended periods of time, extending the area of final infarction. Therefore, such regions could not be observed in the present study of acute focal ischemia but are described in studies of chronic vascular occlusion in the baboon,8 47 in which changes in flow and energy metabolism are less profound and more protracted than in the cat.15 22 Therefore, significant reductions of FMZ uptake were not observed up to 2 days after MCAO in the baboon model.
Another advantage of FMZ is its application as a tracer of perfusion
when the distribution within the first 2 minutes after bolus injection
is recorded. The regional tracer concentration reached within this
short period closely correlates to absolute flow values and can be used
in a manner similar to SPECT procedures for the semiquantitative
assessment of regional perfusion. Early FMZ distribution images low and
high perfusion values and also reflects postischemic
hyperperfusion comparable to traditional quantitative flow tracers (Fig 4). However, even marked hyperperfusion does not change the stable
uptake of FMZ at steady state, since the distribution volume of FMZ is
not affected by an alteration in delivery.48 As a
consequence, only one tracer—and one study—is necessary for the
dynamic determination of regional perfusion and BZR distribution.
The advantages of FMZ as a tracer for perfusion and neuronal integrity in early ischemia are confronted with certain disadvantages of this compound, the most important being the low density of BZR in basal ganglia, white matter, and brain stem.49 50 51 52 Therefore, the sensitivity of FMZ to assess neuronal damage in these regions is very low. The quantitative determination of BZR density requires repeated injections of tracer with different specific activity,25 50 53 which is impractical in acute experiments as well as in the clinical setting. For fast decision making about acute therapeutic intervention, eg, the initiation of thrombolytic therapy, the complete study might take too much time since a steady state must be reached for determination of BZR distribution. The particular problem in this case might be overcome by executing the perfusion study (2 minutes) before initiation of thrombolysis, to demonstrate the extent of the perfusional defect, and by completing the assessment of BZR distribution during the infusion of the thrombolytic agent, which takes time to recanalize occluded vessels. The initial phase would then be used in decision making, and the latter phase would yield information on irreversibly damaged tissue not amenable to treatment. Whereas the value of FMZ in this acute application is thereby limited, FMZ could also yield valuable information for pharmaceutical research to determine the efficacy of a therapeutic strategy.
In conclusion, FMZ is a tracer for regional perfusion and a marker of
cortical neuronal integrity in early ischemia. FMZ therefore
has a potential for studies in patients with acute ischemic
stroke, (Fig 5) in whom it can detect
regions of early infarction and thereby help in the selection of
patients who might benefit from thrombolysis and/or
neuroprotective therapy.
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Selected Abbreviations and Acronyms |
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-aminobutyric acid
Received March 31, 1997; revision received July 1, 1997; accepted July 7, 1997.
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