Evaluation of Cerebral Infarction with Iodine 123-Iomazenil SPECT

Jun Hatazawa, Takao Satoh, Eku Shimosegawa,Toshio Okudera, Atsushi Inugami, Toshihide Ogawa, Hideaki Fujita, Kyo Noguchi, Iwao Kanno, Shuhichi Miura, Matsutaroh Murakami, Hidehiro lida, Yuhko Miura and Kazuo Uemura

Department of Radiology and Nuclear Medicine, Akita Research Institute of Brain and Blood Vessels, Senshuh-Kubota Mach4 Akita, Japan

predicted the clinical outcome (4). By measuring perfusion This study evaluatesischemicdamageto centralbenzodiaz and metabolism, the balance of the supply and demand of epine(BZD)receptorbindingin the brainwith r23oiom&enil substrates (i.e., misery or luxury perfusion) was evaluated SPECTin relationto CT hypodenselesionsand blood flow (5). Nevertheless, these imaging modalities are unable to abnormalities.Methods:Ninepatientswithmiddlecerebralar provide direct information on neuron-specific damage after teryterritoryinfarctionwerestudied.lomazenilimagesobtained ischemic insult. 180 mm postinjectionwere analyzedfor BZD receptor binding. Recently, Sette et al. performed in vivo mapping in the Thecorticalinfarction,visualizedasCThypodenseareaon CT, baboon of the central benzodiazepine (BZD) receptor after the peti-infarctarea,visualizedas normodensttysurroundingthe focal ischemia with PET and 11C-flumazenil (6). The cen infarctionon CT, the intrahemisphencremote areaand the car ebellum ware analyzedby taking the ratio of the lesionto con tral BZD receptor exists with variable density in the mem tralateral mirror region (tiC ratio). CT during the chronic stage brane of neurons. Carbon-i 1-flumazenil is a ligand which and perfusion images obtained during the smallest time differ binds specifically to the central BZD receptor. The study encebetweenthetwo studieswareusedforcomparativeanal demonstrated decreased binding of ‘1C-flumazenilto the ysis.Results:ThemeanLJCratioof iomazeniluptakewas0.53 central BZD receptor in the infarct and pen-infarct lesions. ±0.08, 0.79 ±0.07, 0.98 ±0.03 and 1 .00 ±0.04 in the infarct, It was suggested that the decrease in central BZD receptor pen-infarct and remote areas and the cerebellum,respectively. binding may reflect damage to synapses and may therefore The infarct and pen-infarct areas showed significant decrease be sensitive to neuronal injury due to ischemia. comparedwith unity.The correspondingmeanL/C ratiofor Iodine-123-Ro16-0154(ethyl-5,6-dihydro-7-iodo-5-methyl blood flow was 0.52 ±0.08, 0.73 ±0.07, 0.83 ±0.09,and 0.80 6-oxo-4H-imidaw[i,5-a}[i,4]-benzodiazepine-3-carboxylate; ± 0.07, respectively. In all areas, the ratios were signfficantly iomazenil) is a SPECT tracer developed for central BZD decreased compared with unity. There was significant differ encebetweenthe L/Cratiofor bloodflowandiomazenilinthe receptor imaging (7—10).The ligand is highly selective, with remoteareaandthecerebellum.Conclusion:Iodine-i23-ioma an affinity tenfold greater than that of 11C-flumazenil. Do zenilSPECTimagingmayprovidenewinformationonischemic simetry estimates for [123I]iomazenil, based on human bio damage to the brain, particulatlyto neurons. distribution data, were found to be within the dose range acceptable in clinical studies (11 ). With this ligand, it is now Key Words: single-photon emission computed tomography; possible to study central BZD receptor binding in patients benzodiazepine receptors; iodine-i23-iomazenil; cerebral in farction with cerebral infarction with SPECIE'. The purpose of this study was: (a) to visualize the changes in central BZD J NucI Med 1995; 36-2154-2161 receptor binding in the infarct, pen-infarct and nonisch emic remote areas, (b) to compare the abnormality in central BZD receptor binding with the CT lesion and blood flow abnormality and (c) to assess lesion localization with number of imaging techniques have been used to iomazenil SPED.' imaging in aphasic patients. visualize ischemic damage to the brain. Of these, CT and MRI are sensitive to edematous change in the early stage of MATERIALS AND METhODS brain ischemia and localize ischemic necrosis at the chronic Patients stage (1,2). Perfusion imaging revealed the severity and Nine patients (6 men, 3 women, aged 51—63yr, mean 58.8 ±3.7 extent of disturbedblood flow at a very early stage(3) and yr)withcerebralinfarctioninthemiddlecerebralartery(MCA) territory were examined. Seven patients had cortical infarction resulting from a trunk or branch occlusion of the MCA. Two ReCeiVedOct.19,1994;revisionacceptedFeb.14,1995. patients (nos. 7 and 8) had CT hypodensity only in the subcortical ForcorrespondenceorrepintscontactJunHatazawa,MD,PhD,Department of RadiciOgyand NuclearMedk@tne,AkitaResearchInstituteof Brainand Blood white matter, with normal appearance of the adjacent cortex. One Vessels,6-10Senshu-KubotaMachi,AkitaCity,Akita,Japan 010. patient (no. 5) had both cortical and subcortical white matter

2154 The Journal of Nuclear Medicine •Vol. 36 •No. i2 •December i995 TABLE I ClinicalData

Timeofstudyafteronset

Patient(days)163FCortical,no.AgeSexInfarction locationCortical signsduringlomazenilstudySPECT (days)Blood flow(days)PET aphasia4144261MCortical, I.pailetalGlobal paiietalAprada8n.a.n.a361MCortical,r. temporalHemianopsia916n.a.451FCortical,r. temporalNone104n.a.561MCortical,r. aphasia19n.ana.659MCortical,I.frontal Subcortlcal,I.temporalMotor aphasia3538n.a.761MSubcortlcal,I.temporalSensory aphasia4640n.a.854FSUbcOrtiCaI,I.frontalGlobal frontalNone49n.a.82958MCortical,r. temporalNone196n.a167n.a. r.

= notavailable.

infarction in different brain regions. These lesions were analyzed attenuation coefficient of 0.125 cm ‘.In-plane and axial spatial separately. resolution of the scanner were 14and 22 mm FWHM, respectively. For Patient 1, the iomazenil SPECT studywas performeddur To evaluate initial tracer uptake to the brain, a dynamicSPECT ing the acute stage 4 days after onset (= Day 0). In four patients, study, seven scans with 3 mm of data acquisition followed by seven studies were performed during the subacute phase from 2 to 3 wk scans with 6 mm of data acquisition, was initiated with iomazenil after onset. The other four patients were examined during the administration.Final SPECT imagingwas started 180 mm postin chronic phase, from 35 days to 196 days after onset. Clinical data jection, with 12 mm of data acquisition.The plane of the CT and are summarized in Table 1. None of the patients had experienced iomazenilimagingwas set parallelto the OM line. All image data cerebrovascular disease before the present attack. Seven of nine were transferredto a conventional UNIX workstation. patients (nos. 1, 2, 4, 5, 6, 8, and 9) suffered from hemiparesis of the contralateralside of theirbrainlesion duringthe SPECTstudy. Evaluation of Central BZD Receptor Binding of Patient 3 showed sensory disturbanceof the left side. No patient Io@ne-I23-Iomazenil was treated with a BZD receptor agonist such as diazepam before Iodine-123-iomazenil SPECT images obtained 180 mm postin the iomazenil study. Written informed consent was received from jection were used to analyze central BZD receptor distribution. all patients prior to study initiation. The areaof corticalinfarctionwas identifiedas the CT hypodense lesion (n = 7). The pen-infarct area was defined as the CT Radioligand normodense area surrounding the cortical infarction or the cortex Patients received approximately 165 MBq [‘@IJiomazenilby adjacentto the subcorticalwhitematterinfarctionwithinthe MCA intravenous bolus injection of 1.5ml of solution into a cubital vein. territory. In Patient 3, CT hypodensity extended over the whole Specfficactivitywas approximately 222 MBq/@gat administration, MCAterritoryanda pen-infarctareacouldnot be identified.A resulting in an injected dose of 0.75 @g.Prior to the study, patients total of nine lesions served as the pen-infarct area. orallyreceived potassiumchloride to avoid thyroidcontamination The superiorfrontal gyrus,a territoryof the anteriorcerebral from the administeredradioactivity. artery,was defined as the remote area of the infarction(n = 9). Morphological Evaluation of Infarction The cerebellum also served as a remote area. No patient had CT All patients underwent repeat serial CF over the clinical course. evidence of a local morphological abnormality in the superior Ten axial images with 10-mm slice thickness and 10-mm center frontal gyri and cerebellum bilaterally. Image counts of the in to-center spacing were obtained parallel to the orbitomeatal (OM) farcted and the pen-infarct areas, the superior frontal gyrus, as line. To compare iomazenil binding, the CT scan taken during the well as their mirrorregions, were read using a 16-mm diameter circularregionof interest(ROI). The CT andSPECTimageswere chronic stage was selected as a reference to designate the fmal topography of the infarction. CF images were transferredto a not fused in this analysis.Instead, the ROI's position was deter conventional UNIX workstation system (TITAN 750, Kubota minedmanuallyas follows:The CT imagewhichmost depictedthe ComputerCorp., Tokyo, Japan) for comparisonwith the SPECF infarction was first displayed on the left half field of the monitor of data. a workstation.Then, the early SPECT images obtained 15 mm postinjection were displayed on the right half of the monitor. SPECT Because the early images depicted the landmark structures of the A ring-type single-photon emission computed tomograph cerebrum, such as the basal ganglia and thalamus, they were used (Headtome SET-080, Shimadzu Co., Kyoto) was used to measure to match the iomazenil image with the correspondingCT image. radioactivity distribution in the brain. The scanner simultaneously ROIs for the infarcted area, pen-infarct area, superior frontal produces 31 tomographic axial slices. A low-energy, all-purpose gyms, cerebellum and their mirror regions were defined on the collimator was used for data acquisition. Data were recorded on a early iomazenil image by visual comparison with the CT image. 64x 64matrix.A Butterworthfilter,cutoff0.45Nyquistandorder The ROIs were fmally superimposedon the SPECT images ob 3, and a ramp filter were used for image reconstruction. Recon tained 180mm afteradministration.The count ratioof the lesion structed images were corrected for tissue absorption using an to-contralateral mirror region was defmed as the L/C ratio. For the

Iodine-123-lomazenilSPECTin Cerebral Infarction•Hatazawaat al. 2155 cerebellum, an irregular ROl encompassing the cerebellar hemi sphere was drawn manually. The contralateral-to-ipsilateral count ratio was calculated to give the L/C ratio. Statistical significance was determined by a paired t-test and the one-sample Wilcoxon test. The LjC ratio was analyzed in relation to the age of the infarction for the seven cortical and nine pen-infarct areas to determine time-dependent changes in ischemic lesions. Evaluation of Blood Flow Blood flow imaging was performed using [‘231]IMP(Patients 1, FIGURE 1. Patient6. ReferenceCT Qeft),[1@OIMP(center)and 4, 6, 7), 99mTcHMpAO (Patient 3) or ‘50-water(Patients8, 9). [1231]iomazenil(right)images40 mm aboveand parallelto the OM From 111to 167MBq [1231]IMPor 740 MBq @mTc@HMPAOwere line. Cortical gray matter in the left temporal lobe was primarily affectedasevidencedbyCThypodensity.Bloodflow reductionwas administered per injection. SPECT perfusion images were ob severein the left MCA and was mild in the left anteriorcerebral tamed with the same scanner used in the iomazenil study along artery. Reduced iomazenil uptake extended beyond the CT hypo with a low-energy, all-purpose collimator for the [‘231]IMPstudy densityto the MCA. No right-leftasymmetryof iomazeniluptake and a low-energy, high-resolution collimator for the @mTc@HM@was found in the frontallobe. PAO study.The ‘50-waterPET studyis describedas follows:The imaging plane was adjusted until parallel to the OM line. All IMP studies were performed according to the autoradiographic method decrease in iomazenil uptake in the infarction and pen (12) to quantifycerebralbloodflow. For the 99mTc@HMPAOinfarct area was detected. The area of reduced iomazenil images, linearization correction (13) was applied. Two patients uptake was larger than the CT hypodense area in five of (nos. 1 and 4) were studied during the acute stage. One patient seven lesions of cortical infarction. Two patients were stud (no. 3) was studied during the subacute stage. In the other four ied 8 (Patient 2) and 9 (Patient 3) days after onset. In these patients, iomazenil uptake and blood flow were measured during the chronic stage (35 to 196days after onset). The IJC ratios of the patients, the lesion was partly associated with elevated blood flow images were calculated for the infarction, pen-infarct iomazenil uptake during the early phase after administra and intrahemisphenic remote areas and the cerebellum cone tion compared to the mirror region. Such lesions showed sponding to the iomazenil image. normal iomazenil uptake in the iomazenil image obtained 180 mm after administration. Three lesions of subcortical PET Imaging of Cerebral Blood Flow and Oxygen infarction showed decreased iomazenil uptake in the adja Metabolism cent cortex. Regional cerebral blood flow (rCBF), regional extraction frac tion for oxygen (rOEF), regional metabolic rate for oxygen LJC Ratios for lomazenil Uptake and Blood Flow (rCMRO2)andregionalcerebralblood volume (rCBV)were mea Figure 3 shows the L/C ratio of blood flow and iomazenil sured in Patients 1, 8 and 9 during the chronic stage. By adminis uptake for the infarct, pen-infarct and intrahemisphenic tering ‘5O-waterand following the autoradiographic method remote areas and the cerebellum. Mean L/C ratio of the (14,15), rCBFwas estimated.Inhalationof ‘50-labeledcarbon infarction was 0.52 ±0.08 for blood flow and 0.53 ±0.08 monoxide was performed to estimate rCBV. By inhaling 150 for iomazenil uptake. Both were significantly reduced corn labeled molecular oxygen, rOEF and rCMRO2 were obtained after blood volume correction (16). The details of the procedure pared with unity (p < 0.001). In the pen-infarct area, the are described elsewhere (15). The values of rCBF, nCMRO2 and ratio was 0.73 ±0.07 for blood flow and 0.79 ±0.07 for rOEFwere estimatedfor the infarct,pen-infarctandremote areas iomazenil uptake. Both values were significantly reduced (superior frontal gyrus), as well as the mirror regions in the when compared with unity (p < 0.001) and were increased contralateral hemisphere using 16-mm diameter circular ROIs. when compared with those of the infarction (p < 0.01). No statistical difference was found between blood flow and Aphasia and lomazenil Uptake Patients 1, 5, 6 and 7 were aphasic. The aphasia was not transient. Patients I and 5 showed symptoms continuously throughout the chronic stage. Patients 1 and 7 showed global aphasia, Patient 5 motor aphasia and Patient 6 sensory aphasia. The Broca area of the inferior frontal gyrus for the global and motor aphasia (n = 3 patients) and the Wernicke area of the supramarginal gyrus for the global and sensory aphasias (n = 3 patients) were analyzed by examining the reference CT images and the IJC ratio for the SPECT images.

FiGURE 2. Reference CT image Qeft),[123l]IMPimage (center) RESULTS and [1231]iomazenilimages (right)of the patient with subcortical lodine-123-lomazenil Distribution infarction (no. 7). CT scan shows hypodensity in the frontal deep The reference CT image, blood flow image and iomaze white matterwith no involvementof the corticalarea.Blood flow wasreducedinthefrontalandtemporalcorticesandinthebasal nil uptake of the cortical infarction (Fig. 1, Patient 6) and gangliaand the thalamus.lomazenilimagedemonstratesreduced the subcortical white matter infarction (Fig. 2, Patient 7) uptakeinthe Brocaareaandmoremildreductioninthefrontaland are illustrated. In most cases of cortical infarction, a focal temporallobesthat werenormalon the CT images.

2156 The Journal of Nuclear Medicine •Vol. 36 •No. 12 •December 1995 0 I .4 1.0 @ 1.2 0 0 @ S Is @8@, 0 0@ 1.0 .:: 0.8 Is S I- @ 0.8 Is . 00 C Is 0 S U 0.6 @I ::@ @ii@. . 0

Infarct pert-infarct remote cerebellum

FiGURE3. MeanL/Cratioofbloodflowandiomazeniluptakein 0 50 100 150 200 250 the infarct,pen-infarctand remoteareasand the cerebellum.(A) Significantreductioncomparedwithunity(p< 0.001).(B)@gnfficant day after onset (day) differencebetweenCBFand iomazenil-BZDreceptorbinding(p < 0.001). FIGURE5. L/Cratiofortheinfarct(•)andpen-infarctedareas(0) plotted against the age after onset. LJCratio was consistently below unity,irrespectiveof infarctionage. iornazenil uptake L/C ratios in either the infarct or pen infarct areas. In the remote area, the ratio was 0.83 ±0.09 for blood flow and 0.98 ±0.03 for iomazenil uptake. Blood iomazenil uptake, rCBF, rOEF and rCMRO2 for Patient 8. flow was significantly reduced compared with unity (p < The right middle and inferior frontal gyri adjacent to the 0.001) while iomazenil uptake was not. There was also a frontal deep white matter infarction showed CT normo significant difference between the L/C ratio for blood flow density where decreased iomazenil uptake, rCBF and and iomazenil uptake (p < 0.001). In the cerebellum, the rCMRO2wereevident.The rOEF wasnot focallychanged. contralateral-to-ipsilateral ratio was 0.80 ±0.07 for blood Table 2 summarizes the mean values for the infarct, pen flow and 1.00 ±0.04 for iomazenil uptake. The LIC ratio infarct and remote areas as well as the mirror regions. for blood flow was significantly reduced compared with Mean rOEF was not significantlydifferent in the infarct, unity (p < 0.001). The blood flow ratio was also signifi pen-infarct and remote areas. cantly lower than that for iomazenil uptake (p < 0.001). Aphasia and lomazenil Imaging Figure 4 shows the cerebellar images of blood flow and In the Broca area, the CT scan revealed faint hypoden iomazenil uptake obtained in Patient 7. sity in one patient with motor aphasia (Patient 5) and Age of Infarction and lomazenil Uptake nonmodensity in two patients with global aphasia (Patients In Figure 5, the L/C ratios for iornazenil uptake in the 1 and 7). The mean [IC ratio of the Broca area in these infarct and the pen-infarct areas are plotted against infarc @ ------.--@ —-- :@ _j_@@@

‘I S

a 0

FiGURE4. Iodine-123-IMPQeft)andr@k@enil (right)images (bottomcenter)and rCMRO2(bottornnght)in Patient8. Bloodflow of the cerebellumin Patient7, who hada lefttemporallesion.Inthe and oxygen consumption are decreased in the right frontal lobe, but right cerebellarhemisphere,blood flow was decreasedby 20%, iomazeniluptakeismaintainedintheterritoryofthe anteriorcerebral whileiomazeniluptakewasunchanged. artery. No focal increase in extraction fraction was observed.

lodine-123-lomazenilSPECTin Cerebral Infarction•Hatazawaet al. 2157 TABLE 2 Cerebral Blood Flow, Oxygen Extraction Fraction and Cerebral Oxygen Metabolic Rate for the Infarct, Pail-infarct and Remote Areas and the Mirror Region of the COntralateral Hemisphere regionCBF AffectedsideContralateral mirror CMRO2CBFOEFCMRO2Infarction OEF 25.8±7.1* 0.39±0.05 1.59±O.29@ ±1.9 ±0.02 ±0.46 Pen-infarct 34.7±43* 0.43±0.05 2.40±0.46 50.0 ±5.7 0.46±0.05 3.44±0.50 0.17*signffi@fltRemotearea 39.2 ±2.2 0.46 ±0.06 2.88 ±0.3249.6 47.1 ±5.60.46 0.45±0.033.66 3.35±

difference(p< 0.05)comparedwiththemirrorregion. tSigflifr@t difference(p < 0.01)comparedwiththemirrorregion. CBF = cerebralbloodflow;OEF = oxygenextractionfraction;CMRO2= cerebraloxygenmetabolicrate. patients was 0.68 ±0.10 for blood flow and 0.63 ±0.08 for emia predicted the survival of brain tissue in the chronic iomazenil uptake. These values were significantly de phase. Middle cerebral artery occlusion in the rat yielded a creased compared with unity (p < 0.001). The Wernicke more profoundreductionin [‘@I]iomazeniluptake than in area showed CF hypodensity in Patients 1 and 6 and sub bloodflowmeasuredby99mTcHMpAO3 to 4 wkafter the cortical hypodensity in Patient 7. The mean [.IC ratio was ictus (29). More recently, central BZD receptor change decreased to 0.5i ±0.08 for blood flow and 0.56 ±0.iO for after focal ischemia was evaluated in vivo in baboon with iomazenil uptake, with statistical significance compared serial PET studies and ‘1C-flumazenil(6). A reduction in with unity (p < 0.OOi). 11C-flumazenil uptake in the infarcted area, produced by a unilateral middle cerebral artery occlusion, was found 2 DISCUSSION days after onset and uptake continued to decrease up to 54 Central BZD Receptor Imaging days. Similar findings were also observed for the pen The central BZD receptor is a postsynaptic membrane infarct area. A saturation study demonstrated that radioac receptor ionophore complex which contains a gamma tivity in the infarction was less displaceable than that in amino butyric acid (GABA) receptor (17). The GABA intact brain, indicating that diminished 11C-flumazenil up receptor mediates inhibitory signals in the regulation of take resulted from reduced necepton-ligand binding. cerebral function. The BZD/GABA receptor complex in In the present study,iomazeniluptake was significantly the human brain was first measured in vivo with PET and decreased in the infarction identified as the CT hypodense 11C-flumazenil (18—20).The observed distribution of BZD area. In the pen-infarct CT normodense area, the reduction receptors in the brain was similar to that obtained in post was less severe than in the infarction. Both the experimen mortem studies (21). Decreased BZD receptor densitywas tal (6) and human infarction indicated that ischemic dam associated with a reduction in neuron density in a his age extends beyond the CF hypodense lesion into the sun topathological study of traumatic brain injury (22). Carbon rounding @Tnormodensearea. The reductionin iomazenil li-flumazenil (23) and [‘@I]iomazenil (24) radioactivity uptake in the infarct and pen-infarct areas were associated were displaced by pharmacological doses of these ligands. with a decrease in CBF. In the ipsilateralsuperior frontal These studies indicate that central BZD receptor binding is gyrus, however, a i7% reduction in the LIC ratio of CBF a specific marker of the BZD/GABA mediating synapses of resulted in only a 2% decrease than that of iomazenil neurons. Imagingof the BZD receptor has been applied to uptake. In the contralateral cerebellum, 20% reduction in several diseases. BZD receptor density was reduced in the 1./C ratio of CBF resulted in no decrease in that of epileptogenic foci without any morphological abnormality iomazenil uptake. The discrepancy between iomazenil up in CT and MRI (25). Canbon-il-flumazenil binding was take and CBF in these areas, in addition to the preclinical more sensitive and accurate for localization of epileptic foci study (6), indicated that the alteration in iomazenil uptake than [‘8F]FDG(26). A preliminary study indicated dimin is not due to altered delivery but may predominantly reflect ished iomazenil accumulation in patients with Alzheimer's a receptor-mediated phenomenon. disease (27). Selective Neuronal Necrosis Brain lschemia and Central BZD Receptor Binding Several neurohistological studies revealed that occlusion Changes in BZD receptor binding resulting from tran of the cerebral artery produces an infarction,total tissue sient brain ischemia were studied in the gerbil brain with necrosis, in the center of the ischemia, and neuron-specific 3H-flunitrazepam autoradiography. In relation to his alteration in the surroundingarea. Mies et a!. observeda topathologic changes, diminished binding of 3H-flunitraz decreased number of cortical neurons in the area surround epam was specifically observed in ischemic necrosis (28). ing experimentally produced chronic infarction in cat brain BZD receptor binding was sensitive to ischemic damage, (30). and preservation of BZD receptor binding soon after isch In a transient MCA occlusion model using the macaque

2158 The Journal of Nuclear Medicine •Vol. 36 •No. 12 •December 1995 monkey, DeGirolami et al. (31 ) observed selective necrosis minished iomazenil uptake in the CT-negative Broca and characterized by the disappearance of neuron cell bodies Wernicke areas (Fig. 2). Another globally aphasic patient with preserved tissue framework, spared myelinated fibers (no. 1) had reduced iomazenil uptake in the CT-negative and no evidence of vascular or intravascular abnormality in Broca area and in the CT hypodenseWennickearea. Our the area adjacent to or tapering away from the total tissue study indicated that not only the disconnection resulting necrosis. Since neurons are more vulnerable to reduction of from the CT lesion, but also CT-negative structural damage blood flow and oxygen deficiency than either glial cells or to the speech center, may be responsiblefor aphasia in blood vessels (32,33), there may be a dividing ischemic these two patients. threshold above which only neurons are specifically dam Cerebral Perfusion, Metabolism and lomazenil Uptake aged. Although such neuron loss has not been confirmed in Measurement of cerebral perfusion and metabolism in human autopsied brain (34), the reduction in iomazenil patients with infarction revealed a reduction in both param binding in the pen-infarct area may correspond to a selec eters which spread far beyond the CT lesion (44,45). Al tive neuronal necrosis. Lassen et al. observed neuronal loss though the number of patients was limited, we observed the in the CT normodense area in autopsied brain (35). They same phenomenon. Regional CBF decreased by 48% in the emphasized the importance of CT-negative irreversible infarction, 31% in the pen-infarcted area and 17% in the ischemic damage, referred to as incomplete infarction, sun remote area. Although iomazenil uptake in the infarct and rounding the ischemic center (36). Raynaud et al. also pen-infarct areas were reduced by the same magnitude as speculated that the mild reduction in CBF observed in the nCBF and rCMRO2, normal iomazenil uptake was ob pen-infarct area of chronic infarction is due to selective served in the intrahemispheric remote area. These results neuronal necrosis, although deaffenentiation cannot be are consistent with a previous study using “C-flumazenilin ruled out completely (37). The present study supports this the baboon. Since no increase in oxygen extraction fraction view and provides more direct evidence of neuronal dam was found, the hypoperfusion of the pen-infarct and re age in the pen-infarct area. mote areas was not a miseryperfusion (5). In the pen A reduction in iomazenil binding was found in the pa infarct area, hypoperfusion and hypometabolism may be tient studied at 4 days after onset. In the baboon study, this due not to deaffenentiation, but rather to an adaptation to reduction was not evident on Day 1, but was revealed on Day 2 (6). The time course of the acute stage reduction neuron damage. In the ipsilateral superior frontal gyrus, reduced blood flowassociatedwith normal iomazenilup remains unknown for human infarction. Within a 6-mo take might be an intrahemisphenicremote effect of the period, however, all patients showed consistent reduction infarction. The [‘23I]iomazenilstudy may distinguish the and no increase was found. This may indicate that damage extension of synaptic impairment from functionally macti observed by iomazenil binding is irreversible. vated and therefore hypoperfused lesions in the CT-non modense area outside the infarction. Aphasia and lomazenil Imaging CT has been used to depict the lesion responsible for Umitations clinical symptoms. In aphasia, there is good correlation There are several methodological limitations in this between aphasia type and lesion localization (38). Various study. Although quantitative evaluation of BZD receptor types of aphasia sometimes appear in patients without in density and affinity was developed recently (24,46), we did volving the classical language center of Broca and Wernicke not perform such analysis. Instead, we evaluated BZD re on CT images (39—41). These studies assumed that lesions ceptor binding by taking the LIC ratio in the mirror region are confined to CT hypodensity. In such cases, the discon in the iomazenil image obtained 180 mm postinjection. As nection of specific neural pathways connecting the language indicated in the displacement trial in normal volunteers, center was considered. Metabolic measurement by PET more than 85%of corticalradioactivity6 hr after injection (42) revealed that purely subcortical infarcts were accom was associated with specific binding to BZD receptors (24). panied by temporopanietal hypometabolism in patients with Iomazenil images analyzed in this study may predominantly sensory aphasia, which supports the view that functional reflect specific binding. This does not, however, hold true changes in undamaged cortical areas may underlie aphasia. under certain conditions after brain ischemia. Weiller et al. (43 ) studied 57 patients with strictly subcor It is difficultto evaluatequantitativelythe relativecon tical infarcts. Of these, patients with aphasia or neglect had tnibution of impaired delivery and reduced receptor density a significantly longer duration of MCA occlusion and in the ischemic region by the LIC ratio analysis. For exam mostly poor leptomeningeal collaterals. The rCBF was sig ple, in luxury perfusion, nonspecific binding may corre nificantly decreased in the cortical MCA territory in the spondingly increase with increased delivery of the ligand, so patients with aphasia on neglect only. They speculated that that the fraction of nonspecific binding is higher than that aphasia on neglect after subcortical infarcts are most likely in the reference region. Two patients studied at 8 and 9 due to selective neunonal loss of the cerebral cortex due to days after onset had CT hypodensity associated, in part, prolonged MCA occlusion. with normal iomazenil uptake. These patients demon In the present study, one patient (no. 7) with global strated a 20%—30%increase in the LIC ratio in iomazenil aphasia had purely subcortical lesions and significantly di images obtained 15 mm after injection, most likely as a lodine-123-IomazenilSPECTin CerebralInfarction•Hatazawaat al. 2159 result of luxury perfusion. In such a case, the IJC ratio injection of the benzodiazepine receptor ligand [1@I]iomazenil in healthy overestimates specific binding when images are taken be human subjects. Psych Res 1992;45:67—77. 9. Johnson EW, Woods SW, Zoghbi 5, McBride BJ, Baldwin RM, Innis RB. fore sufficient time has passed for nonspecific binding Receptor binding characterization of the benzodiazepine radioligand washout. Holthoff et al. separately estimated distribution [WIJRo 16-0154: potential probe for SPECT brain imaging. Life Sci 1990; volume, a measure corresponding to ligand-receptor bind 47:1535—1546. 10. Innis R, Zoghbi 5, Johnson E, et al. SPED' imaging of the benzodiazepine ing potential, and the transport rate of ‘‘C-flumazenilby receptor in nonhuman primate brain with [‘23I1Ro16-0154.EurfPharmacol applying a two-compartment, two-parameter model (47). 1993;193:249—252. They demonstrated that the distribution volume is stable 11. Dey HM, Seibyl JP, Stubbs JB, et al. Human Biodistribution and dosimetry of the SPED' benzodiazepine receptor radioligand iodine-123-iomazenil. J @ even if the delivery of ‘C-flumazenil is altered. Because of Nuci Med 1994;35:399—404. unstable and unexpected flow changes during the acute and 12. lida H, Itoh H, Nakazawa M, et al. Quantitative mapping of regional subacute stages of cerebral infarction, such quantitative cerebral blood flow using [‘231]N-isopropyl-p-iodoamphetamineand single photon emission tomography. J Nuci Med 1994;35:2019—2030. measurement should be carried out to avoid the uncertainty 13. Lassen NA, Andersen AR, Neininckx RD. Ell PJ, Costa DC. Validation of resulting from the flow dependency of the L/C ratio. Ceretec. In: Eli JP, Costa DC, Cullum ID, Jarritt PH, Lui D, eds. rCBF Another methodological limitation is that iomazenil is atlas—theclinical application of TCBFimaging by SPECT. High wycombe: Brier Press; 1987:14—18. not sensitive to infarction in the central gray matter, sub 14. Raichle ME, Martin WRW, Herscovitch P, Mintun MA, Markham J. Brain cortical white matter and brainstem as a result of the lower blood flow measured with intravenous H2150. II. Implementation and vat BZD receptor densityin these areas (17,24). idation. I NucI Med 1983;24:790—798. 15. Kanno I, lida H, Miura 5, et at. A system for cerebral blood flow measure ment using H2'50 autoradiographic method and positron emission tomog CONCLUSION raphy. I Cereb Blood Flow Metab 1987;7:143—153. Iodine-123-iomazenil uptake is decreased in cerebral in 16. Mintun MA, Raichle ME, Martin wRw, Herscovitch P. Brain oxygen utilization measured with 0-15 radiotracers and positron emission tomog farction. This reduction extends to the surrounding CT raphy. J Nucl Med 1984;25:177—187. normodense area. Reduced [‘231]iomazeniluptake in the 17. Olsen RW. The GABA postsynaptic membrane receptor-ionophore com pen-infarct area may be due to a selective neunonal necro plex. Mol Cell Biochem 1981;39:261—279. 18. Samson Y, Hantraye P, Baron JC, Soussaline F, Comar D, Maziere M. @ sis not previously revealed by other imaging modalities. In Kineticsand displacementof ‘C-Ro15-1788,a benzodiazepineantagonist, the remote area and contralatenal cerebellum, hypoperfu studied in human brain in vivo by positron emission tomography. Eur J sion was associated with normal [‘231]iomazeniluptake, Pharmacol1985;l10:247—251. 19. Persson A, Ehnin E, Eriksson L, et at. Imaging of [‘‘C]-labeledRO 15-1788 indicating that neurons in these areas have normal synapses binding to benzodiazepine receptors in the human brain by positron emis but are functionally deafferentiated. Therefore, [‘23I]ioma sion tomography. I Psychiat Res 1985;19:609—622. zenil SPECT provides new information on ischemic dam 20. Shinotoh H, Yamasaki 1, Inoue 0, et at. Visualization of specific binding sites of benzodiazepine in human brain. J NucI Med 1986;27:1593—1599. age to the brain. Quantitative measurement of receptor 21. Richards JG, Mohter H. Benzodiazepine receptors. Neuropharmacology density would further improve its accuracy. 1984;23:233—242. 22. Benavides J, Serrano A, Duvat D, Bourdiol F, Toulmond S, Scatton B. ACKNOWLEDGMENTS Autoradiographic detection and quantitation of traumatic brain lesions in the rat brain by using site radiotigands. In: Kriegstein J, Oberpichter H, eds. We thank Dr. Niels A. Lassen, Department of Clinical Physi Pharmacology of cerebral ischemia. Stuttgart: wissenschafttiche Verlagsge ology and Nuclear Medicine, Bispebjerg Hospital, Copenhagen, settschaft mbH; 1989:39—45. for his generous comments and valuable discussions about this 23. Persson A, Ehrin E, Eriksson L, et at. Imaging of [‘1CJ-tabeted RO-15-1788 binding to benzodiazepine receptors in the human brain by positron emis study. We are grateful to the technical staff of the Department of sion tomography. I Psychiat Res 1985;19:609—622. Radiology and Nuclear Medicine. We also thank Y. Aizawa, T. 24. Abi-Dargham A, Lauruelle M, Seibyt J, et at. SPEC!' measurement of Hachiya and Y. Shohji for preparing the photographs and Nihon benzodiazepine receptors in human brain with iodine-123-iomazenit: kinetic Medi-Physics, Hyogo, Japan, for providing the [‘@IJiomazenil. and equilibrium paradigms. J Nucl Med 1994;35:228—238. 25. Savic I, Rotand P, Sedvati 0, Persson A, Pautis 5, Widen L. 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Scatter (Continuedfrom page 3A) “Wellofcourse we want to be consistent with JAMA.― “AsI suspected. Not very original, are you? You should be more original in your standards. Try something innovative!― “Whatdo you mean?― “Inoticed that all ofyour articlescontain many references.Why don't you eliminatethem?― “You'resupposed to reference the ideas ofothens. That avoids accusations of plagiarism.― “Well,you can't have it both ways. You want your articlesto be original,but you won't let the authorsclaim their ideas are ‘new'on ‘thefirst observation', and then you make them reference everything. How can you do that and claim that everything you publish is original? Anyway, your reviewers criticize everything new. They usually don't believe something that hasn't been observed before.― “I'mnot finding you very helpful. I had hoped that I could rely on the integrity and competence of the authors, reviewers and editorial board members, including me. What's wrong with that?― “Howlonghaveyoubeenlostinthesewoods?―

Stanley J. Goldsmith, MD Editor-in-Chief The Journal ofNuclear Medicine December 1995

lodine-123-lomazenilSPECTin Cerebral Infarction•Hatazawaat al. 2161