(Stroke. 1997;28:124-132.)
© 1997 American Heart Association, Inc.
Articles |
Incomplete Brain Infarction of Reperfused Cortex May Be Quantitated With Iomazenil
the Department of Neurosurgery and Nuclear Medicine, Nakamura Memorial Hospital, Sapporo, Japan (J.N.), and the Department of Clinical Physiology/Nuclear Medicine, Bispebjerg Hospital, Copenhagen, Denmark (B.S., N.A.L.).
Correspondence to Jyoji Nakagawara, MD, Department of Neurosurgery and Nuclear Medicine, Nakamura Memorial Hospital, South-1, West-14, Chuo-ku, Sapporo, 060, Japan. E-mail george@med.nmh.or.jp.
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Abstract |
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Background and Purpose [123I]Iomazenil is a specific radioligand for the central benzodiazepine receptor that may be useful as an indicator of the intactness of cortical neurons after focal cerebral ischemia. We evaluated the binding of this receptor in reperfused cortex among patients with ischemic stroke to detect viable neurons in cortex that appeared structurally intact on conventional neuroimaging studies.
Methods Fourteen patients were selected by (1) angiography within 24 hours of onset showing embolic occlusion of an intracranial artery, (2) cerebral blood flow showing ischemia of moderate severity in 12 cases and spontaneous reflow in 2 cases, and (3) thrombolysis with reperfusion within 24 hours in most cases. Thirty reperfused cortical areas that remained structurally intact, 7 infarcted cortical areas, and 6 contralateral cerebellar areas with reduced blood flow were selected as regions of interest to estimate receptor binding 5 days to 23 months after the stroke. A two-compartment model was used to compute the distribution volume (Vd) of iomazenil in relative units, with Vd proportional to benzodiazepine receptor concentration. The side-to-side asymmetry ratio of Vd was calculated.
Results The mean asymmetry ratio was 0.89±0.11 (range, 0.64 to 1.05), 0.50±0.15 (range, 0.23 to 0.67), and 0.97±0.05 (range, 0.90 to 1.04) in reperfused cortex, infarcted cortex, and contralateral cerebellum, respectively. Compared with unity, both reperfused cortex and infarcted cortex showed significant decrease of Vd (P<.00l). Contralateral cerebellum showing diaschisis had no reduction of Vd. On MRI, obtained 3 or 6 months after the stroke, mild cortical atrophy was observed in two reperfused areas where the asymmetry ratio was moderately reduced (0.64 and 0.80).
Conclusions The reduction of benzodiazepine receptor concentration in reperfused cortex that remained structurally intact is likely to be the result of injury involving only a limited number of neurons (ie, incomplete infarction). Our data suggest that the degree of viability of ischemic cortex apparently salvaged by early reperfusion can be quantified by iomazenil.
Key Words: cerebral blood flow • cerebral ischemia • reperfusion • tomography, emission-computed
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Introduction |
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Early thrombolysis is often followed by rapid recovery of some or all neurological symptoms in patients with ischemic stroke.1 This suggests that early reperfusion may restore neuronal function in parts of the originally ischemic region. CT or MRI often reveals cerebral lesions in parts of the involved territory, while other parts appear to survive without developing visible lesions. In this study, we used IMZ (Ro 16-0154)2 to determine the integrity of reperfused cortical regions that appear structurally intact on CT and MRI. IMZ is a specific radioligand of the central BZ receptor. This receptor is a part of the postsynaptic GABA receptor complex,3 which is present in high concentration on all cortical neurons because the numerous inhibitory intracortical neurons are all GABA-ergic and communicate with all neurons.
The in vivo measurement of BZ receptor binding by IMZ is performed by SPECT with the use of well-established mathematical models for evaluating the SPECT images.4 5 6 Our study is an extension of observations made on baboons by Sette et al,7 who used FMZ, a BZ receptor ligand with properties similar to those of IMZ, and PET to study the effects of MCA occlusion of either 3 or 6 hours' duration. In our clinical studies, we concentrated on cortical areas exposed to moderately severe ischemia and with reperfusion within a few hours either spontaneously or after thrombolytic therapy. In several such areas we, just as Sette et al,7 found a somewhat reduced BZ receptor binding in reperfused cortical areas that remained structurally intact, suggesting that loss of a limited number of neurons (ie, incomplete infarction8 ) had occurred.
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Subjects and Methods |
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Patients and Selection Criteria
We studied 14 patients with embolic stroke (12 men and 2 women; mean age, 62 years; range, 54 to 78 years). Table 1
summarizes the clinical data for each patient regarding site of occlusion demonstrated by cerebral angiography, CBF on admission, timing of thrombolytic therapy, degree and time of reperfusion documented by repeated angiography or CBF SPECT, area of the ischemic lesion demonstrated on CT or MRI in the subacute or chronic stage, and neurological deficits at the time of the IMZ study. The patients were selected with the aim of defining moderately ischemic cortical areas that appeared to have been salvaged from pannecrosis by early reperfusion. At the time of the IMZ study, 9 patients had no residual neurological deficits, and 5 patients still showed focal neurological deficits. Fig 1 shows the initial distribution of CBF demonstrated by 133Xe or 99mTc-HMPAO with SPECT on admission and the areas of infarction seen on CT or MRI after several weeks. Written informed consent was given by all patients or their family before the study. The selection criteria of patients are discussed below.
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Criterion 1: Evidence of Major Cerebral Artery Embolism
In each of the 14 patients, cerebral angiography in the acute stage showed embolic occlusion of one or several intracranial cerebral arteries and fairly efficient collateral blood flow. The embolic origin of the occlusion was evidenced by the nontapering shape of the occluding material and by clinical evidence pointing to a cardiac origin in 11 patients and evidence suggesting artery-to-artery embolism in the remaining 3 patients (patients 7, 9, and 12). The patients were admitted to our stroke care unit within 30 minutes to 15 hours (mean, 4 hours) after the acute onset of symptoms, and angiography, CT, and CBF SPECT were performed within 2 hours of admission.
Criterion 2: Moderate Severity of Ischemia
We set a lower limit of residual CBF of 15 mL·100 g-1·min-1 using 133Xe SPECT and of 50% of the contralateral symmetrical region using 99mTc-HMPAO SPECT. Twelve of the 14 patients had residual CBF at or above the limits mentioned. The remaining 2 patients (patients 1 and 8) showed spontaneous reflow hyperemia by 133Xe SPECT at 24 hours and 4 hours from onset. Thus, in these 2 patients we could not assess the adequacy of residual CBF during the ischemic period. Nevertheless, these patients were included because we interpreted the early reflow hyperemia as evidence of an ischemic event of short duration.
Criterion 3: Early Reopening of the Occluded Arteries
Evidence of arterial reopening was obtained in all 14 patients. In most cases, repeated angiography and CBF SPECT showed partial or complete reopening and reperfusion. The term "partial reopening" refers to opening of the occluded site with filling of some but not all of the distal branches. In 11 patients, partial or complete reopening occurred within 24 hours; in the remaining 3, the confirmation was obtained no later than day 8 (with day 0 being the day of onset) (Table 1
). On the basis of this evidence, we refer to "early reperfusion" as a characteristic of the material as a whole.
CT and MRI Scans
The initial CT scan (Somatom, Siemens) was performed on admission, and it was negative in all cases. Repeated CT scans obtained on day 7, day 14, and 1 month after onset showed in most cases areas of infarction (Fig 1). MRI scans (Magnetom Impact 1.0 T, Siemens) were obtained in all cases within the first 2 weeks and repeated at 3 and 6 months in 7 cases. In patient 7, in whom no lesion was seen on either CT or MRI 2 weeks after onset, gadolinium-enhanced MRI was performed. The CT and MRI scans were imaged in axial slices parallel to the orbitomeatal plane, as were the SPECT scans. No attempt was made at strict alignment or coregistration by processing these images. We simply identified the approximate same sections and compared each region visually, since all regions were fairly large.
CBF SPECT on Admission
In 12 patients, 133Xe SPECT was obtained with the use of a ring-type scanner (Headtome Set 031, Shimadzu Co). 133Xe gas (370 MBq/L) was inhaled for 1 minute, and dynamic images were acquired every 1 minute for 10 minutes with a high-sensitivity collimator. Data were recorded on a 32x32 matrix; the in-plane and axial spatial resolutions of the scanner were 18 and 24 mm with full width at half maximum, respectively. Quantitative CBF maps were calculated by the algorithm of Kanno and Lassen9 as modified by Celsis et al.10 Two patients (patients 3 and 5) underwent a perfusion study in which 99mTc-HMPAO was used on admission, with the same scanner but a high-resolution collimator 10 minutes after intravenous injection of 740 MBq of 99mTc-HMPAO. Data were recorded on a 64x64 matrix; the in-plane and axial resolutions were 9.6 and 16 mm with full width at half maximum, respectively.
Procedures for IMZ SPECT
The IMZ study was performed 5 days to 23 months after the stroke. Patients received 167 to 222 MBq of IMZ by intravenous bolus injection. For imaging brain uptake of IMZ, a SPECT system equipped with three gamma cameras (GCA 9300-A/HG, Toshiba Co) was used to collect the projection data over 14 to 20 minutes. These data were reconstructed in a 128x128 matrix with a Butterworth filter and back projection. The in-plane spatial resolution was 9 to 10 mm with full width at half maximum in a slice thickness of 1.7 mm to obtain a total of approximately 40 transaxial slices. Image sets were collected at a mid-scan of 15 minutes (range, 8 to 22 minutes) and at 3 hours (range, 170 to 190 minutes) after bolus injection.
Using a two-compartment, two-parameter model, we calculated the Vd of IMZ in relative units, with Vd (almost) proportional to BZ receptor concentration (Bmax), using both early (15 minutes) and delayed (3 hours) images (see "Appendix"). In this analysis, two constants, K1 (influx constant or "clearance") and k2 (efflux constant), are calculated for a 64x64 matrix, and Vd=Kl/k2 is thus obtained on a pixel-by-pixel basis. Blood sampling was not performed because a standardized input function reported by Abi-Dargham et al11 was used for obtaining Vd in relative units (for details, see "Appendix").
Evaluation of BZ Receptor Binding
In all 14 patients, the size of the infarct as seen on CT or MRI was considerably smaller than the originally ischemic area (Fig 1). Therefore, in every case one or more areas of reperfused cortex that remained structurally intact could be identified. Because of the heterogeneity of BZ receptor binding in these regions, we arbitrarily selected within them a total of 30 reperfused cortical areas, each appearing fairly homogeneous, as ROIs (one to three such areas per patient) (Table 2). BZ receptor binding was also estimated for 7 ROIs overlying well-defined cortical infarcts in 6 patients and 6 ROIs of contralateral cerebellum showing moderately reduced CBF due to CCD12 (Table 2). Among the 7 infarcted cortical ROIs defined in these 6 patients, reperfusion on CBF SPECT was noted in 5. In the remaining 8 of the 14 patients, the infarcts either were localized subcortically (patients 4, 7, 11, and 12) or involved cortical areas too small to be analyzed with BZ receptor binding (patients 2, 3, 5, and 8) (Fig 1).
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The Vd-IMZ maps were evaluated by calculating the side-to-side AR, ie, the Vd value of an ROI divided by that of the opposite symmetrical region. For the aforementioned three ROI categories, the statistical significance of the difference between mean AR of Vd-IMZ and unity was estimated by one-sample paired t test. The values of AR of Vd-IMZ in the 30 reperfused cortical areas and in the 7 infarcted cortical areas were plotted as a function of time from stroke onset to estimate chronological changes of BZ receptor binding. In 7 patients with moderately reduced AR of Vd-IMZ in reperfused cortex, the possible development of cortical atrophy was evaluated by MRI 3 and 6 months after the stroke.
Evaluation of CBF SPECT After Early Reperfusion
We estimated CBF changes after early reperfusion using IMP and SPECT. Approximately 222 MBq of IMP was administered per study. To compare the IMZ study with the IMP-CBF study, the same planes of SPECT image were obtained with a SPECT system with three gamma cameras equipped with a low-energy, high-resolution collimator. SPECT imaging was started 10 minutes after injection with a data acquisition time of 20 minutes. The first CBF-IMP study (I) was performed within a 15-day interval from the IMZ study in all 14 patients. In three of these patients (patients 2, 5, and 6), the first (and only) IMP study (I) was performed so late that it coincided with the second IMP study (II) in the other 10 patients. Therefore, for patients 2, 5, and 6 the results of IMP (I) were also evaluated as an IMP (II) study (see arrows in Table 2).
The CBF maps were evaluated by the side-to-side AR in the ROIs defined from the IMZ study. For the three categories of ROIs defined for the IMZ study, the statistical significance of the difference between mean AR of CBF and unity was examined by one-sample paired t test. The difference between mean AR of Vd-IMZ and mean AR of CBF was analyzed by two-sample t test with Welch's correction.
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AR of Vd-IMZ and CBF
Fig 2
shows the distributions of the AR of Vd-IMZ and those of CBF using IMP in the three categories of ROI. The mean AR of Vd-IMZ was 0.89±0.11 (range, 0.64 to 1.05), 0.50±0.15 (range, 0.23 to 0.67), and 0.97±0.05 (range, 0.90 to 1.04) in reperfused cortex, infarcted cortex, and contralateral cerebellum, respectively. The reperfused cortex and infarcted cortex showed significant decrease of mean AR of Vd-IMZ compared with unity (P<.00l), while contralateral cerebellum had no reduction of mean AR of Vd-IMZ (Table 3 and Fig 2).
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), AR of CBF using IMP (
) at the time of the IMZ study (CBF I), and AR of CBF using IMP (
) in the chronic stage (CBF II). Bars indicate mean±SD of each column.
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The mean AR of CBF-IMP (I) was 0.90±0.18 (range, 0.61 to 1.31), 0.74±0.25 (range, 0.31 to 1.14), and 0.83±0.07 (range, 0.73 to 0.92) in reperfused cortex, infarcted cortex, and contralateral cerebellum, respectively. Not only reperfused cortex and infarcted cortex but also contralateral cerebellum demonstrated a significant decrease of mean AR of CBF compared with unity (Table 3 and Fig 2). CBF-IMP (I) study at the time of the IMZ study showed either reflow hyperemia or mild hypoperfusion in the acute/subacute stage (ie, within 1 month) in 23 reperfused cortical and 6 infarcted cortical ROIs. Therefore, in many cases AR of CBF-IMP (I) in both reperfused cortex and infarcted cortex showed relatively high values in comparison with AR of Vd-IMZ in the same ROIs (Table 2 and Fig 2).
The mean AR of CBF-IMP (II) in the chronic stage was 0.80±0.12 (range, 0.55 to 0.95), 0.46±0.07 (range, 0.31 to 0.54), and 0.87±0.03 (range, 0.82 to 0.90) in reperfused cortex, infarcted cortex, and contralateral cerebellum, respectively. A significant decrease of mean AR of CBF-IMP (II) compared with unity was observed in reperfused cortex and in infarcted cortex (Table 3). A statistical difference was found between Vd-IMZ and CBF-IMP (II) in both reperfused cortex and contralateral cerebellum (Table 3). In the reperfused cortex, the decrease of Vd-IMZ was of a milder degree than the decrease of CBF in the chronic stage. Decreased CBF of contralateral cerebellum persisted into the chronic stage.
Variations of Vd-IMZ, Cortical Dysfunctions, and Cortical Atrophy
The AR of Vd-IMZ in reperfused cortex (30 ROIs) showed either normal value or moderately reduced value, from 1.05 to 0.64. Several patients had ROIs with different degrees of Vd reduction in reperfused cortex. This was seen in particular in the patients with small perisylvian cortical or subcortical infarction due to MCA occlusion (patients 2, 3, and 12), in whom ROIs of cortex near the infarct had lower Vd-IMZ than that of more distant cortical areas. On the other hand, there was no difference between Vd-IMZ of infarcts with reperfusion and those of infarcts without reperfusion. This was well illustrated in patient 13 (Table 2).
Clinical signs of cortical dysfunction at the time of the IMZ study were observed in 5 patients (Table 1). Four of these patients (patients 1, 6, 10, and 13) had well-defined cortical infarction and moderately decreased AR of Vd-IMZ (range, 0.67 to 0.82) in reperfused cortex. The remaining patient (patient 2) had global aphasia and showed markedly decreased AR of Vd-IMZ in the reperfused perisylvian cortex (0.64), while infarction involved only small areas of frontal cortex and subcortical regions. In contrast, 2 patients with smaller, well-defined cortical infarcts (patients 9 and 14) had no signs of cortical dysfunction and only mildly reduced AR of Vd-IMZ in reperfused cortex.
In 7 patients (patients 1, 2, 3, 6, 9, 10, and 13) with moderately reduced AR of Vd-IMZ (<0.82) in reperfused cortex, follow-up MRI at 3 or 6 months showed mild cortical atrophy in 2 patients (patients 2 and 10). In patient 2, MRI at 6 months showed progression of the atrophy of the left perisylvian cortex where AR of Vd-IMZ was measured 0.64 on day 36 (Fig 3). In patient 10, MRI on day 94 demonstrated slight atrophy in the right anterior parietal cortex with AR of Vd-IMZ of 0.80 on day 11.
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In 6 patients (patients 3, 7, 10, 11, 12, and 14) with normal levels of Vd-IMZ in reperfused cortex, CBF in the chronic stage (ie, after approximately 6 weeks) was evaluated. In a total of 11 such ROIs, the mean AR of CBF was 0.89±0.04, which was mildly reduced below unity (P<.00l, one-sample paired t test). This is suggestive evidence of local intrahemispheric diaschisis (see "Discussion").
Time-Dependent Changes of BZ Receptor Binding
In Fig 4, individual AR values of Vd-IMZ in reperfused cortex and infarcted cortex are plotted as a function of time after stroke onset. The values of AR of Vd-IMZ in two reperfused cortical ROIs where cortical atrophy subsequently developed were in the low range compared with other such ROIs. We noted a tendency of a time-dependent reduction of AR of Vd-IMZ for both reperfused cortex and infarcted cortex within the first 1 month after stroke onset. In the chronic stage, low Vd-IMZ values were observed not only in the infarcted cortex but also in reperfused cortex without cortical atrophy (patient 6, Fig 5).
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ROI with cortical atrophy on MRI at 3 months (patient 10); 
ROI with hemorrhagic transformation; §ROI without reperfusion at the time of the IMZ study.
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Discussion |
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IMZ has a high affinity for the central BZ receptors. This receptor, part of the GABA-ergic complex, is widely distributed in high concentration in the cerebral cortex as a reflection of the numerous GABA-ergic inhibitory synapses that exist there. Therefore, measuring the binding potential of BZ receptor radioligands could correspond to an approximate measure of the number of synapses and hence be taken as an indicator of the intactness of the cortical neurons.3 13 14
To assess the binding potential of IMZ to the BZ receptor, we obtained Vd maps of IMZ in relative units using a two-compartment model.5 6 15 Since the non–receptor-bound fraction of this tracer is approximately 1% to 2% of the receptor-bound fraction in normal cortex,4 Vd of IMZ is practically proportional to the binding potential, which in turn is proportional to the BZ receptor concentration as the affinity of receptor to tracer probably remains constant, since there is no reason to suspect changes of the dissociation constant.
In conventional two-compartment analysis, the two kinetic parameters, the influx constant (K1) and the efflux constant (k2), are calculated by a least-square, nonlinear iterative procedure filling pixel by pixel. This demands several image sets and is very time consuming. Instead of this approach, we used a table look-up procedure. This approach, described in the "Appendix," allows fast calculation of parameters pixel by pixel with the input function and only two SPECT image sets. As a further simplification, the standardized input function calculated from six normal subjects by Abi-Dargham et al11 was used for obtaining Vd-IMZ in relative units. We found this simplification justified, since only the relative Vd-IMZ values were needed to calculate the side-to-side AR accurately.
The main methodological difficulty is related to systematic errors in SPECT imaging. These errors lead to a considerable overestimation of Vd-IMZ in ROIs with very low BZ receptor binding because of Compton scatter, reconstruction artifacts, and partial volume effects due to limited spatial resolution. This explains why Vd-IMZ in the infarcts averaged 50% that of the opposite side and not 0% as expected with all synapses being destroyed. Therefore, the Vd-IMZ images are not linear with respect to distribution of the BZ receptor binding.
Changes of BZ receptor binding capacity resulting from transient ischemia have been studied on tissue slices of gerbils with [3H]flunitrazepam autoradiography.16 Diminished binding was observed in areas showing ischemic necrosis, not in histologically intact tissue. Since gerbils are known to have poor collateral blood flow, the ischemic insult is likely to have been dense, with no extensive border zone of moderate ischemia as in our patients. This may explain why decreased [3H]flunitrazepam uptake was not seen outside the infarcted area.
The recent study of permanent or transient ischemia (lasting 3 to 6 hours) in baboons by Sette et al7 has a more direct relevance to our studies. They occluded the MCA stem mesially and found that infarcts mainly involved the basal ganglia on CT. Using FMZ and PET, they observed a decrease of BZ receptor binding not only in the infarcted area but also, albeit to a lesser degree, in the CT-intact opercular cortex overlying the hypodense area. In this cortical area, circulation was sustained at a moderately ischemic level by collateral blood flow as measured by the 15O technique. The authors suggested that the 17% decrease of FMZ uptake in the CT-intact opercular cortex was caused by selective neuronal loss. In our study, areas of reperfused cortex that remained intact on CT showed an IMZ uptake ranging from normal levels to clearly reduced values (lowest 36% below that of the opposite side). Histological evidence of neuronal loss outside the area of frank infarction is not available from our study because all patients survived. However, histological evaluation of brain tissue slices from the baboons of Sette et al7 showed selective neuronal necrosis and gliosis in the insular cortex in some of the animals.8 Loss of selected neurons with gross preservation of tissue structure has been termed "incomplete infarction."8 This type of lesion is usually seen in human autopsy specimens only in a very narrow rim (<1 mm) surrounding areas of large cavitary lesions.17 However, occasionally extensive areas are involved, as first described by Spatz.18 Two stroke cases of this type have been reported by Lassen et al,19 both showing extensive areas of incomplete infarction with a greater than 50% loss of neurons in otherwise intact cortex at autopsy.
Selective neuronal necrosis with sparing of glia and microvessels is seen after transient occlusion of the MCA in macaque monkey20 and rats.21 The extent of neuronal loss in those experiments depends on both duration and intensity of ischemia.21 22 23 24 In a recent study by Garcia et al,25 up to 60 minutes of MCA occlusion followed by 7 days of survival in rats resulted in neuronal necrosis that involved isolated groups of cortical neurons (ie, incomplete infarction), while no cases of cortical infarction were found. A close correlation existed between the number of necrotic neurons and the severity of the neurological deficits. More importantly, these authors documented that areas of incomplete infarction do not evolve into a complete infarct. Many other experimental studies in animals have shown similar evidence of incomplete infarction after transient ischemia of moderate intensity. A review of the literature has recently been published by Garcia et al,8 presenting evidence that selective neuronal loss involves both ischemic necrosis and apoptosis, the so-called programmed cell death.
Of relevance for discussing our data is also the study of Weiller et al26 concerning a selected group of stroke patients with only subcortical infarcts after MCA occlusion. The lack of infarction of the cortex lateral to the subcortical infarct was thought to be due to a fairly efficient collateral blood flow. However, in many of their patients (in 26 of the 57 cases studied) symptoms of cortical damage were noted since these patients, in addition to hemiparesis, had aphasia or hemineglect. In our study, one patient (patient 2) with left MCA occlusion and treated with thrombolytic agents showed permanent global aphasia even though only very small infarcts involving the frontal cortex and certain subcortical structures were seen after successful reperfusion. In this case the clinical evidence suggested lesions of structurally intact cortex areas, and this suggestion was supported by the reduced IMZ uptake observed.
Focal atrophy seems to develop after some months in cortex with incomplete infarction. This was suggested by the study of Weiller et al26 by follow-up MRI studies approximately 1 year after the insult, showing atrophy of the opercular cortex overlying the subcortical infarct. We found similar evidence in two of our patients. Moreover, as shown in Fig 4, our observations suggested that perhaps neuronal loss progresses over months, as reported in some experimental studies.27 28 Serial studies of IMZ binding in individual cases should clarify this point.
The six contralateral cerebellar areas with reduced CBF had symmetrical Vd for IMZ. Axonal disconnection of the corticopontocerebellar tract reduces both neuronal activity and local CBF in contralateral cerebellum (ie, CCD12 ). In agreement with our results, no change of BZ receptor binding was observed in CCD in a study by Minoshima et al,29 who used FMZ and PET. Therefore, intrahemispheric diaschisis is unlikely to be the cause of the observed reductions of Vd-IMZ in reperfused cortex. However, diaschisis may very well also affect these cortical areas, because in our study a significant reduction of CBF in 11 cases of reperfused cortex without reduction of Vd-IMZ was observed in the chronic stage. The mildly reduced CBF in these areas may be explained by intrahemispheric diaschisis.
Early thrombolysis for patients with ischemic stroke is currently being tested as a therapeutic modality.30 In our study, despite successful thrombolysis, some degree of loss of BZ receptor binding was observed in wider cortical areas along with smaller infarcts. In other words, thrombolytic therapy would appear to have resulted in partial salvage of brain tissue in many of our patients. The good clinical recovery associated with early reperfusion in most cases strongly suggests that the large number of salvaged neurons is important for functional recovery. Selecting patients within the therapeutic window defined by the combination of duration and intensity of ischemia31 seems to be the most promising approach for tissue salvage. The present study suggests that the degree of viability of ischemic cortex that may have been salvaged completely or partially by thrombolysis and/or neuroprotection can be quantified by SPECT with the use of IMZ.
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Appendix |
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BZ Receptor Quantitation by IMZ
The Vd of IMZ is the equilibrium ratio of the brain and plasma concentrations (Cb and Cp). In a bolus injection study, the complete time integrals must be used instead6 :
 | (E1) |
As shown by Koeppe et al,5 a simple two-compartment model suffices to describe the brain uptake of FMZ. If we assume that this is also true for IMZ, the tissue concentration in a given small region (in a homogeneous region) is the convolution integral of the input and the monoexponential impulse response function.
 | (E2) |
A kinetic analysis shows that the following relation relates the receptor parameters to the observed data6 :
 | (E3) |
is the nonspecific distribution volume of IMZ in the brain. Since is approximately 1 mL/mL and Vd typically has values of 50 to 80 mL/mL, it follows that can be neglected. Therefore, since Kd is the same for all cortical regions, Vd is proportional to Bmax. Thus, a map of Vd in relative units can be taken as a map of the BZ receptor concentration in the same relative units.
The method is based on using Equation 2 to determine K1 and k2 pixel by pixel. Since the aim is only to determine Vd=K1/k2 in relative units, it is not necessary to know Cp(t) in absolute units. We therefore used a standard plasma IMZ concentration curve obtained by Abi-Dargham et al11 in six normal subjects. This curve is corrected for labeled metabolites and can be represented by the sum of three monoexponential curves:
 | (E4) |
The experimental data consist of two SPECT images in a 64x64 matrix: one early (from 8 to 20 minutes) and one delayed (from 170 to 190 minutes).
One may obtain the simulated data by solving the double integral resulting from Equation 2 when considering the time interval of recording. For pixel i in one image (early or delayed),
 | (E5) |
 | (E6) |
The table look-up procedure described here is derived from the theoretical study of Kanno and Lassen.9 Essentially the same approach as ours was independently developed by Iida et al32 for the calculation of K1 and Vd of IMP. Their primary aim was to isolate K1, which for IMP (as for IMZ) can be taken as a measure of CBF.
Correspondence for details regarding the algorithms used should be addressed to Niels A. Lassen, MD, and Anders Lassen, MSc, Department of Clinical Physiology and Nuclear Medicine, Bispebjerg Hospital, GK-2400 Copenhagen NV, Denmark.
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Selected Abbreviations and Acronyms |
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-aminobutyric acid
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Acknowledgments |
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This study was supported by a grant from the Alfred Benzon Foundation, Copenhagen, Denmark. The authors wish to acknowledge the valuable advice given by Julio H. Garcia, Department of Pathology, Henry Ford Hospital, Detroit, Mich, and Cornelius Weiller, Neurologishe Klinik der Friedrich-Schiller Universitat, Jena, Germany. We are also grateful for the technical support of Masaaki Takahashi and Katsuyasu Satoh, Department of Nuclear Medicine, and the secretarial support of Masabumi Nakamura, Nakamura Memorial Hospital, Sapporo, Japan. We thank Nihon Medi-physics, Hyogo, Japan, for providing the IMZ.
Received June 24, 1996; revision received September 3, 1996; accepted September 3, 1996.
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References |
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