(Stroke. 1997;28:1776-1782.)
© 1997 American Heart Association, Inc.
Articles |
Assessment of Benzodiazepine Receptors Using Iodine-123–Labeled Iomazenil Single-Photon Emission Computed Tomography in Patients With Ischemic Cerebrovascular Disease
A Comparison With PET Study
From the Departments of Brain Pathophysiology (Y.D., H.F., H.S.) and Neurology (H.Y.), Faculty of Medicine, Kyoto University; Department of Neurology, Shiga Medical Center for Adult Disease (H.N.), Moriyama, Shiga; and Biomedical Center, Fukui Medical School (Y.Y.), Fukui, Japan.
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Abstract |
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Background and Purpose [123I]Iomazenil (IMZ) is a tracer used for single-photon emission computed tomography (SPECT) that has the characteristics of selectively binding to central benzodiazepine receptors (BZR) in the neuron membrane. To determine whether IMZ SPECT provides new information on assessing neuronal damage after ischemic insult to the brain, we compared IMZ SPECT images with the cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and cerebral metabolic rate of glucose (CMRGlc) studied by positron emission tomography in the chronic stage of ischemic stroke.
Methods Five patients (male; mean age, 63.2±6.0 years) with ischemic cerebrovascular disease and 6 age- and sex-matched normal control subjects were studied. IMZ images obtained 180 minutes after injection were analyzed for BZR binding, and these images were compared with the CBF, CMRO2, and CMRGlc obtained by positron emission tomography in the same perfusion areas both visually and quantitatively.
Results In the visual analysis of data obtained from 4 patients with subcortical infarction, decreased IMZ accumulation was observed locally in the overlying normal-appearing cortices of the affected hemisphere, where extensive hypoperfusion and hypometabolism were seen on the images of CBF, CMRO2, and CMRGlc. The regional relative IMZ uptake (regional to cerebellar ratio) for all 5 patients was significantly correlated with the corresponding regional CMRO2 values (r=.45, P<.05). However, no significant correlation was found of the IMZ uptake with either the regional CBF or the regional CMRGlc.
Conclusions The use of IMZ SPECT provides new information on the neuronal alteration induced by chronic ischemic cerebrovascular disease.
Key Words: cerebral blood flow • cerebral oxygen metabolism • receptors, benzodiazepine • tomography, emission
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Introduction |
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Benzodiazepine receptors are known to be coupled with
-aminobutyric acid receptors
and chloride channel proteins, and central BZR are present at
variable density in neuronal membranes.1 2 Alterations
of central BZR have been reported in degenerative diseases such as
Huntington's disease and Alzheimer's
disease.3 4 Recently, imaging of the central type BZR has been performed in humans with the use of PET or SPECT.5 6 7 8 Sette et al9 performed in vivo mapping of the central BZR in baboons using [11C]flumazenil PET. Their study demonstrated decreased binding of [11C]flumazenil to the central BZR in infarct and peri-infarct cerebral regions. It was suggested that this decreased binding in central BZR might reflect neuronal damage due to ischemia. CMRO2 represents the aerobic oxygen metabolism of neurons in mitochondria. Irreversible mitochondrial damage causes derangement of oxidative metabolism, which leads to cell death, and this disturbance is reflected as CMRO2 hypometabolism. Thus, it is expected to be a correlation between BZR binding and regional oxygen metabolism. Until now, there has not been a good SPECT tracer to visualize the metabolic state of neurons.
Iomazenil, an analogue of flumazenil, is a reversible radiotracer with high affinity to the central BZR (10-fold greater than that of flumazenil). Preliminary studies with IMZ in human and nonhuman primates have suggested that this radioligand is a useful SPECT tracer of the BZR in the central nervous system.10 11 The clinical feasibility of IMZ for the assessment of BZR has been demonstrated in the previous SPECT studies in living human brain.12 13 14 A recent evaluation of MCA territory infarction with IMZ SPECT revealed a significant reduction of iomazenil uptake in the acute cerebral infarcted regions.15 With this radioligand it is possible to study the central BZR binding alteration with the use of SPECT in patients with chronic cerebral ischemic disorders.
In the present study we visualized the changes in central BZR binding with IMZ SPECT in patients with chronic ischemic cerebrovascular disease and compared the IMZ SPECT image with the CBF, oxygen metabolism, and glucose utilization that were studied by PET in the same subjects. The purpose of this study was to elucidate the relationships among these measurements and to determine whether IMZ can provide new information on assessing neuronal loss and/or damage after ischemic insult to the brain compared with CBF tracers.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects
Five male patients suffering from ischemic cerebrovascular disease (mean age, 63.2±6.0 years) were studied by PET and IMZ SPECT (Table 1
). Three patients
(patients 3, 4, and 5) had ICA occlusion or stenosis, and 2
others (patients 1 and 2) had MCA occlusion that was confirmed by
conventional angiography. In 4 of them, T2-weighted MRI revealed
punctate or small patchy high-intensity areas in the subcortical white
matter on the side of arterial occlusion or
stenosis. The other patient (patient 5) presented with
only aphasia of acute onset followed by gradual recovery, and no lesion
was found on MRI. No patient had any history of taking drugs that would
affect BZR. The IMZ SPECT and PET studies were performed at least 2
months after ischemic attack. For the PET measurements, we also
studied 6 age-matched, normal male subjects (mean age, 61.3±5.8 years)
as the control. Another 6 age-matched, normal male subjects (mean age,
60.8±2.2 years) were studied for IMZ SPECT study. All of these normal
subjects underwent a routine neurological examination. None of them
showed any cerebral symptoms, abnormal neurological findings, or
specific neurological disease. No abnormalities were found on
T2-weighted MRI in any of the control subjects.
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PET Scan
The subjects were scanned with a PCT-3600 W system (Hitachi
Medical). The characteristics of the PET scanner have been reported
elsewhere.16 17 The maximum spatial resolution at FWHM was
6.5 mm in the center of the scan field on the cross plane. The
slice thickness at the center was 7 mm with 15 slices. Before the
PET scanning, 68Ge/68Ga transmission scanning
was performed for 20 minutes for attenuation correction. The CBF was
measured while the subject continuously inhaled 300 MBq
[15O]CO2 per minute through a mask, and the
measurement of CMRO2 and OEF was performed during
continuous inhalation of 500 GBq [15O]O2 per
minute. Data were collected for 5 minutes after steady state
radioactivity was achieved in the brain, with blood sampling at 0, 2,
and 4 minutes after the start of data acquisition. Inhalation of 1.00
to 1.20 GBq of [15O]CO was used to measure the cerebral
blood volume. During PET scanning, physiological
parameters such as blood gas and pH values were examined.
After the gas study, 185 MBq of 18F-deoxyglucose was
administered intravenously. Arterial blood
samples were drawn just before the injection and at 15, 30, 45, 60, 75,
and 90 seconds and at 2, 2.5, 3, 4, 5, 6, 8, 10, 15, 20, 30, 45, and 60
minutes after the injection. Scan data collection started at 40 minutes
after injection and lasted for 20 minutes. Plasma glucose level was
checked before the injection and at 20 and 60 minutes after injection,
and the averaged value was adopted as the plasma glucose concentration.
CBF, CMRO2, and OEF were calculated according to the steady
state method.18 Cerebral blood volume was used to correct
the vascular space for CMRO2 and OEF.19 CMRGlc
was calculated by Phelps' method using
18F-deoxyglucose.20 The metabolic
rate constants were as follows: k1*=0.102,
k2*=0.130, k3*=0.062, and
k4*=0.0068; the lumped constant used was
0.52.21 Functional images were reconstructed as 128x128
pixels in 15 slices, with each voxel representing
2.0x2.0x7.0 mm in actual size. All subjects were examined by PET
under the same protocol within 2 months after IMZ SPECT
examination.
IMZ SPECT
Each patient received 222 MBq IMZ by intravenous
bolus injection of 1.5 mL solution. A triple-head rotating gamma camera
(GCA9300A, Toshiba) was used for SPECT imaging. The spatial resolution
was 12 mm FWHM in the center of the field of view, and the axial
resolution was 23.5 mm FWHM. Data acquisition was started at 5
minutes and 165 minutes after injection and was continued for 30
minutes (early and late IMZ images, respectively). The image was
reconstructed as a 128x128 matrix with 16 slices, with each voxel
being 2x2x6.8 mm in actual size. Another 6 normal age-matched
control subjects were examined under a similar protocol.
Data Analysis
For the analysis of PET and SPECT images under the same
conditions, PET and SPECT data were reconstructed into
three-dimensional images parallel to the orbitomeatal line, and each
image consisted of 64 planes with 2-mm cubic voxels. IMZ SPECT images
were coregistered to the CBF image with use of the realignment program
of the Statistical Parametric Mapping 95, in which we realigned
the early IMZ image, which was similar to the CBF image, onto the PET
CBF image; we also realigned the late IMZ image to fit on the PET image
using the same parameter.22 This allowed a
direct regional comparison between the PET and SPECT images. For the
quantitative comparison of IMZ SPECT and PET images, three slices of
PET and SPECT images parallel to the orbitomeatal line (corresponding
to the levels of the basal ganglia, body of the lateral ventricle, and
centrum semiovale, respectively) were analyzed. ROIs
were placed on the CBF images, and each image was examined by setting
36 to 40 circular ROIs, each containing 32 pixels, over the cortical
ribbons (Fig 1).23 According
to the atlas by Kretschmann and Weinrich,24 the ROIs on
the three slices were determined in the territories of the ACA, MCA,
and PCA and in the anterior watershed area (area between ACA and MCA)
and the posterior watershed area (area between MCA and PCA). The
hemispheric value was calculated as the average of the values at the
anterior watershed area, the MCA territory, and the posterior watershed
area weighted by pixel size. The same ROIs were transferred to each of
the CMRO2, CMRGlc, and IMZ SPECT images. ROIs were also
drawn in the bilateral cerebellar hemispheres. In the calculation of
relative regional distribution of central BZR, the cerebellum was used
as a reference area, and the relative IMZ uptake ratio for each region
was calculated as the ratio between the IMZ count in each ROI divided
by the cerebellar IMZ count. The individual affected and patent
hemispheric CBF, CMRO2, and OEF values for each of the 5
patients were compared with the bilaterally averaged hemispheric value
obtained from 6 normal control subjects with the use of ANOVA; the
affected and patent hemispheric relative IMZ uptake ratios were also
compared with the bilaterally averaged hemispheric values of 6 normal
control subjects by ANOVA. Pearson's correlation coefficient was
calculated to analyze the correlations between regional
relative IMZ uptake and PET parameters based on the
vascular territory data. A value of P<.05 was considered
statistically significant.
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Results |
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The 4 patients showed subcortical white matter infarction but no evidence of cortical lesion on MRI. Visual inspection of the IMZ SPECT images revealed focal decrease of IMZ uptake in the overlying cortices of the affected hemisphere. The location of IMZ reduction was found in the parietal cortex of the affected hemisphere in 2 patients (patients 1 and 2). Patient 3 showed local IMZ reduction in the right frontotemporal cortex. In patient 4, decreased IMZ uptake was detected in the right temporoparietal cortex. In patient 5, in whom no lesion was found on MRI, the IMZ uptake showed no focal abnormalities. Comparison between IMZ SPECT and PET images in the first 4 patients revealed that the cortical areas of hypoperfusion and hypometabolism detected in the hemisphere on the side of the subcortical infarction were more extensive than those of decreased IMZ uptake. Fig 2
illustrates MRI, IMZ
SPECT, CBF, CMRO2, OEF, and CMRGlc images obtained in
patient 2.
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Table 2 summarizes the hemispheric values
of IMZ, CBF, CMRO2, and OEF for the 5 patients and the 6
normal control subjects. In 4 patients the CBF was reduced on the
occluded side, and 1 of them (patient 3) showed bilateral hemispheric
CBF reduction. Three patients showed bilateral OEF elevation, but all
patients had normal CMRO2. IMZ uptake ratio in the cerebral
cortex revealed no hemispheric changes in all patients compared with
the normal control subjects.
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No cerebellar asymmetry was found on the IMZ SPECT image. The ratio of
the IMZ uptake between the two cerebellar hemispheres (contralateral to
ipsilateral) for the patients (1.01±0.01) disclosed no asymmetry (Fig 3). The corresponding ratio in the
cerebellum was 0.87±0.04 for CBF, 0.92±0.04 for CMRO2,
and 0.87±0.04 for CMRGlc. All of them were significantly reduced
compared with unity (Wilcoxon signed rank test,
P<.05).
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In all perfusion vascular territories of the 5 patients, the regional
relative IMZ uptake was significantly correlated with the corresponding
regional CMRO2 (P<.05; Fig 4). However, no significant correlation
was found of the IMZ uptake with the regional CBF (Fig 5) or with the regional CMRGlc (Fig 6) or the regional OEF.
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Discussion |
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In the present study the BZR binding in the cerebral cortex was evaluated by calculating the ratio to that in the cerebellum on the IMZ SPECT image obtained 180 minutes after injection. After intravenous administration of IMZ in humans, the tracer accumulates slowly in the brain, reaches a peak at approximately 30 minutes, and then is washed out of the brain at approximately 10% to 15% per hour.25 In an experiment on the human brain, more than 85% of the cortical radioactivity was associated with specific binding to BZR 6 hours after injection.26 A preliminary study of IMZ in normal volunteers suggested that the regional tracer distribution soon after injection was a reflection of the CBF and that the distribution at 3 hours after injection represented the distribution of BZR.27 Therefore, the late IMZ image (3 hours after injection) analyzed in the present study most likely reflects specific binding to BZR in the brain.
The cerebellar accumulation of IMZ was symmetrical in the present patients, although CBF, CMRO2, and CMRGlc showed asymmetrical values as a result of crossed cerebellar hypoperfusion or hypometabolism.28 From this finding, we can also confirm that the IMZ SPECT images reflect the BZR receptors on the neuronal membrane and are not influenced by the perfusional or metabolic conditions of the brain.
Changes of BZR binding are sensitive to ischemic damage, and the preservation of the BZR binding after ischemia is predictive of the survival of brain tissue in the chronic phase.9 15 29 Neuronal damage after ischemia varies depending on the degree and duration of ischemia.30 Histological studies have revealed that irreversible neuronal loss occurs in the infarct region, whereas in the areas affected by transient ischemia or in the areas remote from the infarct, selective neuronal damage occurs only in the neurons that are vulnerable to ischemia.31 32 33 The pyramidal cells of cortical layers 3 and 5 are known to be especially vulnerable to ischemia.34 Chronic progressive neuronal loss may result from mild but prolonged CBF decrease with increased OEF.35 Comparison between IMZ SPECT findings and PET parameters in the present study revealed the mild and limited decrease of BZR binding within the cortical areas, where extensive hypoperfusion and hypometabolism, including the cortical and subcortical regions, were detected in the PET studies. In the present 4 patients there was subcortical infarction, but we could find no signal changes in the cortical regions on MRI. Hemodynamic and metabolic impairments in morphologically normal brain areas distant from the subcortical lesion have been observed,28 36 which sometimes persist months or even years after the onset of stroke. Selective neuronal loss due to ischemic damage not visible on CT scan or MRI might occur in such regions. Thus, the present findings support the concept that selective neuronal loss results from prolonged cerebral ischemia.
We could find no differences on IMZ uptake and CMRO2 among
normal control subjects and ischemic patients in hemispheric
values (Table 2
). To clarify the characteristics of IMZ accumulation in
the cerebral cortex in conditions of chronic ischemia, we
analyzed the relationship of IMZ uptake to each of the regional
CBF, CMRO2, OEF, and CMRGlc values in five perfusion areas,
and a significant correlation was found only with the regional
CMRO2. This finding suggests that in conditions of chronic
ischemia, BZR binding is related to the neuronal oxidative
metabolism. CMRO2 is an index of the aerobic
oxygen metabolism of neurons that occurs chiefly in
mitochondria. Neuronal damage with irreversible mitochondrial change,
whether due to ischemic necrosis or apoptosis, causes
cessation of oxidative metabolism, and this
disturbance is reflected as hypometabolism on the
CMRO2 image. Thus, it is not unexpected to find a
correlation between BZR binding and regional oxygen
metabolism. On the other hand, we could find no
relationship between CBF and IMZ uptake. This fact indicates that
ischemia itself does not affect the -aminobutyric acid
receptor numbers or affinities on the cell body. We cannot predict the
viability of neurons solely on the basis of the CBF value, and we must
therefore seek other imaging methodologies to indicate the viability of
neurons. Our present results suggest that IMZ might be a
diagnostic aid useful for detecting damaged cells early in
the development of neuronal loss. In some clinical situations we need
to estimate neuronal viability to determine the choice of therapy in
patients with chronic occlusive disorders, such as intravascular
surgery, vascular reconstruction surgery, or antiplatelet therapy.
The present results suggest that we will be able to predict the
viable neurons of the hypoperfusion area by IMZ SPECT in such
circumstances and obtain sufficient evidence to determine effective
strategies to prevent further neuronal damage.
In another study, cerebral glucose utilization and BZR binding were examined with the use of in vivo autoradiography in gerbils with chronic cerebral infarction, and the results were compared with histological changes.37 In that experiment, cerebral glucose metabolism and BZR binding were observed to be unrelated in both the primary infarct region and remote areas. The IMZ accumulation was consistent with the distribution of neurons detected by histological examination, but the neurons with low functional activity and normal BZR binding were found to be in a glucose hypometabolic state. These experimental data are consistent with our findings of a lack of correlation between IMZ uptake and regional glucose metabolism in the present study.
In conclusion, in the chronic stage of ischemic cerebrovascular disease IMZ uptake is decreased in cortical regions on the side of subcortical small infarctions, although there are no abnormal high-intensity signals in the same cortical regions on T2-weighted MRI. This reduction may be due to selective neuronal loss that may not be revealed by other SPECT imaging tracers. Comparison with PET parameters disclosed a significant correlation between IMZ uptake and regional cerebral oxygen consumption. IMZ SPECT has the potential to be useful in the clinical evaluation of patients with chronic cerebrovascular disorders. Subsequent studies with large numbers are certainly needed.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by grants-in-aid for scientific research ([A]06404031 and [A]088558083 and priority area 08279106) from the Japan Ministry of Education, Science, Sports and Culture; by a research grant for nervous and mental disorders (Functional Imaging); and by a general research grant for aging and health from the Japan Ministry of Health and Welfare.
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Footnotes |
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Reprint requests to H. Fukuyama, MD, Department of Brain Pathophysiology, Faculty of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606, Japan.
Received December 12, 1996; revision received May 13, 1997; accepted June 4, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
1. Olsen RW. The GABA postsynaptic membrane receptor-ionophore complex. Mol Cell Biochem. 1981;39:261-279.[Medline] [Order article via Infotrieve]
2. Hunkeler W, Mohler H, Pieri L, Polc P, Bonetti EP, Cumin R, Schaffner R, Haefely W. Selective antagonists of benzodiazepines. Nature. 1981;290:514-516.[Medline] [Order article via Infotrieve]
3. Reisine TD, Wastek GJ, Speth RC, Bird ED, Yamamura HI. Alterations in the benzodiazepine receptor of Huntington's diseased human brain. Brain Res. 1979;165:183-187.[Medline] [Order article via Infotrieve]
4. Owen F, Poulter M, Waddington JL, Mashal RD, Crow TJ. [3H]R05-4864 and [3H]flunitrazepam binding in kainate-lesioned rat striatum and in temporal cortex of brains from patients with senile dementia of the Alzheimer type. Brain Res. 1983;278:373-375.[Medline] [Order article via Infotrieve]
5.
Shinotoh H, Yamasaki T, Inoue O, Itoh T, Suzuki K,
Hashimoto K, Tateno Y, Ikehira H. Visualization of specific
binding sites of benzodiazepine in human brain. J
Nucl Med. 1986;27:1593-1599.
6. Holl K, Deisenhammer E, Dauth J, Carmann H, Schubiger PA. Imaging benzodiazepine receptors in the human brain by single photon emission computed tomography (SPECT). Int J Radiat Appl Instrum B. 1989;16:759-763.
7. Samson Y, Hantraye P, Baron JC, Soussaline F, Comar D, Maziere M. Kinetics and displacement of [11C]RO 15-1788, a benzodiazepine antagonist, studied in human brain in vivo by positron tomography. Eur J Pharmacol. 1985;110:247-251.[Medline] [Order article via Infotrieve]
8. Persson A, Ehrin E, Eriksson L, Farde L, Hedstrom CG, Litton JE, Mindus P, Sedvall G. Imaging of [11C]-labelled Ro 15-1788 binding to benzodiazepine receptors in the human brain by positron emission tomography. J Psychiatr Res. 1985;19:609-622.[Medline] [Order article via Infotrieve]
9.
Sette G, Baron JC, Young AR, Miyazawa H, Tillet I,
Barre L, Travere JM, Derlon JM, MacKenzie ET. In vivo mapping of
brain benzodiazepine receptor changes by positron emission tomography
after focal ischemia in the anesthetized
baboon. Stroke. 1993;24:2046-2058.
10.
Beer HF, Blauenstein PA, Hasler PH, Delaloye B,
Riccabona G, Bangerl I, Hunkeler W, Bonetti EP, Pieri L, Richards JG,
Schubiger PA. In vitro and in vivo evaluation of iodine-123-Ro
16-0154: a new imaging agent for SPECT investigations of benzodiazepine
receptors. J Nucl Med. 1990;31:1007-1014.
11. Johnson EW, Woods SW, Zoghbi S, McBride BJ, Baldwin RM, Innis RB. Receptor binding characterization of the benzodiazepine radioligand 125I-Ro16-0154: potential probe for SPECT brain imaging. Life Sci. 1990;47:1535-1546.[Medline] [Order article via Infotrieve]
12. Cordes M, Henkes H, Ferstl F, Schmitz B, Hierholzer J, Schmidt D, Felix R. Evaluation of focal epilepsy: a SPECT scanning comparison of 123-I-iomazenil versus HM-PAO. AJNR Am J Neuroradiol. 1992;13:249-253.[Abstract]
13. Bartenstein P, Ludolph A, Schober O, Lottes G, Scheidhauer K, Sciuk J, Beer HF. Benzodiazepine receptors and cerebral blood flow in partial epilepsy. Eur J Nucl Med. 1991;18:111-118.[Medline] [Order article via Infotrieve]
14. van Huffelen AC, van Isselt JW, van Veelen CWM, van Rijk PP, van Bentum AME, Dive D, Maquet P, Franck G, Velis DN, van Emde Boas W, Debets RMC. Identification of the side of epileptic focus with 123I-iomazenil SPECT: a comparison with 18FDG-PET and ictal EEG findings in patients with medically intractable complex partial seizures. Acta Neurochir Suppl Wien. 1990;50:95-99.[Medline] [Order article via Infotrieve]
15.
Hatazawa J, Satoh T, Shimosegawa E, Okudera T, Inugami
I, Ogawa T, Fugita H, Noguchi K, Kanno I, Miura S, Murakami M, Iida H,
Miura Y, Uemura K. Evaluation of cerebral infarction with
iodine-123-iomazenil SPECT. J Nucl Med. 1995;36:2154-2161.
16. Mukai T, Senda M, Yonekura Y, Tamaki N, Yamamoto K, Nishizawa S, Saji H, Fujita T, Konishi J, Torizaka K, Inoue S, Ohgushi A, Kumamoto M. System, design and performance of a newly developed high resolution PET scanner using double wobbling mode. J Nucl Med.. 1988;29:877. Abstract.
17. Endo M, Fukuda H, Suhara T, Matsumoto T, Iimura T, Yamasaki T, Tateno Y, Nohara N, Ohgushi A, Kumamoto M, Inoue S. Design and performance of PCT-3600W (15 slice type): a whole-body positron emission tomography. J Nucl Med. 1991;32(suppl):1061.
18. Frackowiak RSJ, Lenzi GL, Jones T, Heather JD. Quantitative measurement of regional cerebral blood flow and oxygen metabolism in man using 15O and positron emission tomography: theory, procedure, and normal values. J Comput Assist Tomogr. 1980;4:727-736.[Medline] [Order article via Infotrieve]
19. Lammertsma AA, Jones T. Correction for the presence of intravascular oxygen-15 in the steady-state technique for measuring regional oxygen extraction ratio in the brain, I: description of the method. J Cereb Blood Flow Metab. 1983;3:416-424.[Medline] [Order article via Infotrieve]
20. Phelps ME, Huang SC, Hoffman EJ, Selin C, Sokoloff L, Kuhl DE. Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: validation of method. Ann Neurol. 1979;6:371-388.[Medline] [Order article via Infotrieve]
21. Reivich M, Alavi A, Wolf A, Fowler J, Russell J, Arnett C, MacGregor RR, Shiue CY, Atkins H, Anand A, Dann R, Greenberg JH. Glucose metabolic rate kinetic model parameter determination in humans: the lumped constants and rate constants for [18F]fluorodeoxyglucose and [11C]deoxyglucose. J Cereb Blood Flow Metab. 1985;5:179-192.[Medline] [Order article via Infotrieve]
22. Friston KJ, Ashburner J, Frith CD, Poline JB, Heather JD, Frackowiak RSJ. Spatial registration and normalization of images. Hum Brain Mapping. 1995;2:165-189.
23.
Yamauchi H, Fukuyama H, Kimura J, Konishi J, Kameyama
M. Hemodynamics in internal carotid artery
occlusion examined by positron emission tomography.
Stroke. 1990;21:1400-1406.
24. Krestchmann HJ, Weinrich W. Neuroanatomy and Cranial Computed Tomography. New York, NY: Thiem Medical Publishers, Inc; 1986:70-74.
25.
Innis RB, Al-Tikriti MS, Zoghbi SS, Baldwin RM,
Sybirska EH, Laruelle MA, Malison RT, Seibyl JP, Zimmermann RC, Johnson
EW, Smith EO, Charney DS, Heninger GR, Woods SW, Hoffer PB.
SPECT imaging of the benzodiazepine receptor: feasibility of in vivo
potency measurements from stepwise displacement curves.
J Nucl Med. 1991;32:1754-1761.
26.
Abi Dargham A, Laruelle M, Seibyl J, Rattner Z, Baldwin
RM, Zoghbi SS, Zea Ponce Y, Bremner JD, Hyde TM, Charney DS, Hoffer PB,
Innis RB. SPECT measurement of benzodiazepine receptors in human
brain with iodine-123-iomazenil: kinetic and equilibrium
paradigms. J Nucl Med. 1994;35:228-238.
27. Yonekura Y, Nishizawa S, Tanaka F, Ishizu K, Okazawa H, Fujita T, Konishi J, Torizuka K. Phase 1 clinical study of 123I-iomazenil: a new probe to evaluate central-type benzodiazepine receptor with SPECT. Kaku Igaku. 1995;32:87-97.[Medline] [Order article via Infotrieve]
28.
Feeney DM, Baron JC. Diaschisis.
Stroke. 1986;17:817-830.
29. Onodera H, Sato G, Kogure K. GABA and benzodiazepine receptors in the gerbil brain after transient ischemia: demonstration by quantitative receptor autoradiography. J Cereb Blood Flow Metab. 1987;7:82-88.[Medline] [Order article via Infotrieve]
30. Jones TH, Morawetz RB, Crowell RM, Marcoux FW, FitzGibbon SJ, DeGirolami U, Ojemann RG. Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg. 1981;54:773-782.[Medline] [Order article via Infotrieve]
31. Graham DI. Hypoxia and vascular disorders. In: Adams JH, Duchen LW, eds. Greenfield's Neuropathology. London, England: Edward Arnold; 1992: 153-268.
32. Kogure K, Kato H. Neurochemistry of stroke. In: Barnett HJM, Mohr JP, Stein BM, Yatsu FM, eds. Stroke: Pathophysiology, Diagnosis, and Management. New York, NY: Churchill Livingstone, Inc; 1992:69-95.
33. Kirino T. Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res. 1982;239:57-69.[Medline] [Order article via Infotrieve]
34. Pulsinelli WA, Brierley JB, Plum F. Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol. 1982;11:491-498.[Medline] [Order article via Infotrieve]
35.
Yamauchi H, Pagani M, Fukuyama H, Ouchi Y, Nagahama Y,
Matsuzaki S, Kimura J, Yonekura Y, Konishi J. Progression of
atrophy of the corpus callosum with deterioration of cerebral cortical
oxygen metabolism after carotid artery occlusion: a follow
up study with MRI and PET. J Neurol Neurosurg
Psychiatry. 1995;59:420-426.
36. Baron JC. Positron tomography in cerebral ischemia: a review. Neuroradiology. 1985;27:509-516.[Medline] [Order article via Infotrieve]
37. Odano I, Miyashita K, Minoshima S, Nakajima T, Fujita M, Takahashi N, Ikuta F. A potential use of a 123-I-labeled benzodiazepine receptor antagonist as a predictor of neuronal cell viability: comparisons with 14C-labeled 2-deoxyglucose autoradiography and histopathological examination. Nucl Med Commun. 1995;16:443-446.[Medline] [Order article via Infotrieve]
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  J. V. Guadagno, P. S. Jones, F. I. Aigbirhio, D. Wang, T. D. Fryer, D. J. Day, N. Antoun, I. Nimmo-Smith, E. A. Warburton, and J. C. Baron Selective neuronal loss in rescued penumbra relates to initial hypoperfusion Brain, October 1, 2008; 131(10): 2666 - 2678. [Abstract] [Full Text] [PDF]
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 C. Giffard, B. Landeau, N. Kerrouche, A. R. Young, L. Barre, and J.-C. Baron Decreased Chronic-Stage Cortical 11C-Flumazenil Binding After Focal Ischemia-Reperfusion in Baboons: A Marker of Selective Neuronal Loss? Stroke, March 1, 2008; 39(3): 991 - 999. [Abstract] [Full Text] [PDF]
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D. Saur, R. Buchert, R. Knab, C. Weiller, and J. Rother Iomazenil-Single-Photon Emission Computed Tomography Reveals Selective Neuronal Loss in Magnetic Resonance-Defined Mismatch Areas Stroke, November 1, 2006; 37(11): 2713 - 2719. [Abstract] [Full Text] [PDF]
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 H. Yamauchi, T. Kudoh, Y. Kishibe, J. Iwasaki, and S. Kagawa Selective Neuronal Damage and Borderzone Infarction in Carotid Artery Occlusive Disease: A 11C-Flumazenil PET Study J. Nucl. Med., December 1, 2005; 46(12): 1973 - 1979. [Abstract] [Full Text] [PDF]
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 H. Yamauchi, H. Okazawa, K. Sugimoto, Y. Kishibe, and M. Takahashi The Effect of Deafferentation on Cerebral Blood Flow Response to Acetazolamide AJNR Am. J. Neuroradiol., January 1, 2004; 25(1): 92 - 96. [Abstract] [Full Text] [PDF]
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J. Fiehler, M. Foth, T. Kucinski, R. Knab, M. von Bezold, C. Weiller, H. Zeumer, and J. Rother Severe ADC Decreases Do Not Predict Irreversible Tissue Damage In Humans Stroke, January 1, 2002; 33(1): 79 - 86. [Abstract] [Full Text] [PDF]
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E. E. Camargo Brain SPECT in Neurology and Psychiatry J. Nucl. Med., April 1, 2001; 42(4): 611 - 623. [Abstract] [Full Text]
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 H Yamauchi, H Fukuyama, Y Dong, H Nabatame, Y Nagahama, S Nishizawa, J Konishi, and H Shio Atrophy of the corpus callosum associated with a decrease in cortical benzodiazepine receptor in large cerebral arterial occlusive diseases J. Neurol. Neurosurg. Psychiatry, March 1, 2000; 68(3): 317 - 322. [Abstract] [Full Text] [PDF]
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