ro-16-0154 and Cerebral-Infarction

Neuronal cells are susceptible to cerebral ischaemia. As gamma-aminobutyric acid(A) (GABA(A)) receptors are specific for neurones, functional receptor imaging using I-iomazenil (IMZ), a ligand to the GABA benzodiazepine receptor, has been proposed as an imaging modality for the assessment of neuronal integrity. However, there is only limited experience with IMZ in patients with acute cerebral infarction. Therefore, the aim of this study was to evaluate IMZ single photon emission computed tomography (SPECT) in patients with acute cerebral ischaemia. IMZ SPECT was performed in 21 patients with acute cerebral infarction 7-10 days after stroke onset. Eleven patients underwent systemic thrombolysis within 6 h after symptom onset (group 1), whereas 10 patients were treated conservatively (group 2). IMZ (150-200 MBq) was injected intravenously and imaging was performed using a dedicated four-head SPECT camera at 5 min (perfusion) and 90 min (receptor distribution) post-injection, with an acquisition time of 50 min each. Images were analysed by visual inspection. Four patients showed normal IMZ distribution, and 17 patients showed abnormalities of IMZ uptake on both early and late images. In six patients with regional uptake deficits, a crossed cerebellar diaschisis was observed on early images. Cerebellar inhomogeneity of tracer uptake was absent at the time of late images in all six patients. In eight patients, areas of hypoperfusion corresponded exactly to the regions of receptor deficiency (match). In five patients, preserved neuronal integrity was present in hypoperfused areas (mismatch). In four patients, normally or even hyperperfused areas exhibited regional receptor deficiency (inverse mismatch). In conclusion, IMZ SPECT demonstrated differences between regional perfusion and receptor distribution in about one-half of patients 7-10 days after acute cerebral ischaemia. Interesting patterns between the early phase (perfusion) and the late phase (receptor distribution) were found. These patterns are indicative of the heterogeneous development of cerebral ischaemia where, even days after stroke onset, areas of hypoperfusion but preserved neuronal integrity may be present. However, the evaluation of the potential clinical and therapeutic impact of individual IMZ distribution patterns requires further investigation.

Topics: Adult; Aged; Aged, 80 and over; Cerebral Infarction; Data Interpretation, Statistical; Female; Flumazenil; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Radiopharmaceuticals; Receptors, GABA-A; Sterilization, Reproductive; Stroke; Thrombolytic Therapy; Tomography, Emission-Computed, Single-Photon

The mismatch of hypoperfused tissue on perfusion imaging and ischemic tissue on diffusion-weighted imaging is used as a surrogate marker for thrombolytic therapy in the extended time window. Mismatch tissue may recover completely, progress toward infarction, or proceed toward incomplete infarction with selective loss of cortical neurons. We used [(123)I]iomazenil-single-photon emission computed tomography (IMZ-SPECT) to characterize the neuronal integrity of reperfused "tissue at risk of infarction" that appeared morphologically intact on follow-up magnetic resonance imaging (MRI).. Twelve patients with acute stroke with striatocapsular (SC) infarctions were examined with multimodal MRI at days 0, 1, and 7; IMZ-SPECT was performed at days 5 to 15. The PI at day 0, fluid-attenuated inversion recovery (FLAIR) image at day 7, and IMZ-SPECT were coregistered and stereotactically normalized. The mismatch volume of interest (VOI) was defined as the initial PI lesion subtracted by the FLAIR lesion at day 7. An asymmetry ratio (AR) was computed by dividing the mean IMZ uptake of the mismatch VOI by the unaffected mirror VOI. The same AR was computed for signal intensity on FLAIR images at day 7. Three patients with cortical infarctions were included for calibration of the AR. In this group, the VOI consisted of the FLAIR lesion at day 7.. All patients with SC infarctions had a large mismatch of initially hypoperfused (112+/-31 mL; mean+/-SD) and finally infarcted tissue (19+/-14 mL). Mean AR of cortical IMZ uptake was 0.85+/-0.01 in cortical infarctions and 0.95+/-0.03 in SC infarctions; thereby AR showed a continuous distribution from clearly reduced (0.89) to normal (1.01) in SC infarctions. Mean AR for FLAIR signal intensity was 1.84+/-0.14 for cortical infarctions and normal (1.01+0.03) for SC infarctions.. IMZ-SPECT detected a selective loss of cortical neurons in patients with SC infarctions in transient hypoperfused tissue, which was morphologically intact on MRI.

Topics: Adult; Aged; Cell Count; Cerebral Infarction; Female; Flumazenil; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neurons; Stroke; Tomography, Emission-Computed, Single-Photon

We report two patients with occlusive cerebrovascular disease who were examined by means of benzodiazepine receptor SPECT(BZR-SPECT) with 123I-iomazenil (IMZ) before extracranial-intracranial bypass surgery (EC/IC bypass). Preoperative low perfusion areas detected by cerebral blood flow SPECT (CBF-SPECT) were divided into two parts on BZR-SPECT images. In the low perfusion areas where the BZR were preserved, regional cerebral blood flow (rCBF) increased on postoperative CBF-SPECT, but where the BZR were not preserved, rCBF did not increase on postoperative CBF-SPECT. On visual inspection, the SPECT images of postoperative CBF-SPECT appeared similar to those of preoperative BZR-SPECT. For evaluation of the ischemic brain condition itself, instead of the cerebral metabolism, the distribution and activity of cerebral neurons indicated by BZR-SPECT with IMZ might be utilized.

Topics: Aged; Arterial Occlusive Diseases; Brain; Carotid Artery, Internal; Carotid Stenosis; Cerebral Arterial Diseases; Cerebral Infarction; Cerebral Revascularization; Flumazenil; Humans; Iodine Radioisotopes; Male; Middle Aged; Middle Cerebral Artery; Radiopharmaceuticals; Receptors, GABA-A; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Treatment Outcome

We report a case of 61-year old man who was suffering from cerebrovascular disease with right hemiparesis and received I-123 iomazenil (IMZ) SPECT prior to carotid endoarterectomy. Severe stenosis of the right internal carotid artery and occlusion of the left middle cerebral artery (MCA) were revealed by cerebral angiography, and a hypoperfused area in left MCA territory and crossed cerebellar diaschisis (CCD) on I-123 IMP SPECT was demonstrated. In contrast, IMZ SPECT showed symmetric normal distribution. After the carotid endoarterectomy, the hypoperfused area in left MCA territory on IMP SPECT and hemiparesis had improved. It is thought that IMZ SPECT can be a useful tool for the prediction of improvement of cerebral perfusion and the clinical outcome.

Topics: Arterial Occlusive Diseases; Brain; Carotid Artery, Internal; Carotid Stenosis; Cerebral Arterial Diseases; Cerebral Infarction; Cerebrovascular Circulation; Endarterectomy, Carotid; Female; Flumazenil; Functional Laterality; Humans; Iodine Radioisotopes; Male; Middle Aged; Paresis; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

Two patients with subacute cerebral infarction underwent benzodiazepine receptor imaging using I-123-iomazenil and cerebral perfusion imaging with Tc-99m HMPAO and Tc-99m ECD. Iomazenil early images resembled HMPAO images, which demonstrated increased uptake in a part of the infarcted site. Iomazenil delayed images and ECD images showed reduced accumulation in the same area. Crossed cerebellar diaschisis was observed in HMPAO, ECD, and iomazenil early images, but it was not remarkable in iomazenil delayed images. These cases suggest that sequential iomazenil images visualized increased uptake with relatively impaired viability in the infarcted site and hypoperfusion with preserved viability in the contralateral cerebellar hemisphere, which could not be recognized without using both HMPAO and ECD in the subacute phase of cerebral infarction.

Topics: Adult; Brain; Cerebellum; Cerebral Infarction; Cerebrovascular Circulation; Cysteine; Female; Flumazenil; Humans; Iodine Radioisotopes; Male; Middle Aged; Organotechnetium Compounds; Radiopharmaceuticals; Receptors, GABA-A; Technetium Tc 99m Exametazime; Temporal Lobe; Tissue Survival; Tomography, Emission-Computed, Single-Photon

[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.. 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.. 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 < .001). 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).. 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.

Topics: Aged; Cerebellum; Cerebral Cortex; Cerebral Infarction; Cerebrovascular Circulation; Female; Flumazenil; Humans; Intracranial Embolism and Thrombosis; Iodine Radioisotopes; Magnetic Resonance Imaging; Male; Middle Aged; Models, Theoretical; Organotechnetium Compounds; Oximes; Receptors, GABA-A; Reperfusion; Technetium Tc 99m Exametazime; Time Factors; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Xenon Radioisotopes

Single photon emission computed tomography (SPECT) using [123I]iomazenil (radioligand of central-type benzodiazepine receptors) was employed to examine two patients with striatocapsular infarction. Patient 1 was a 61-year-old female with motor aphasia and hemiplegia on the right side. Magnetic resonance imaging (MRI) showed a lesion in the anterior limb of internal capsule and putamen on the left side. SPECT using 99mTc-HMPAO revealed a reduction of cerebral blood flow (CBF) in the frontoparietal region on the left side, but the delayed images in SPECT using [123I]iomazenil showed only a mild decrease of accumulation in the frontal lobe. Patient 2 was a 55-year-old male with hemiplegia on the left side. MRI showed a lesion localized in the basal ganglia and posterior limb of the internal capsule on the right side. SPECT using 99mTc-HMPAO revealed a reduction of CBF in the frontoparietal region on the right side and in the cerebellar hemisphere on the left side, but the delayed images in SPECT using [123I]iomazenil showed little decrease of accumulation in parietal lobe. The discrepancy between CBF and receptor images suggested that cortical hypoperfusion on striatocapsular infarction might reflect hypometabolism due to disconnection of the neuronal network between subcortical structure and cortex.

Topics: Aphasia; Basal Ganglia; Cerebral Cortex; Cerebral Infarction; Cerebrovascular Circulation; Female; Flumazenil; Hemiplegia; Humans; Iodine Radioisotopes; Magnetic Resonance Imaging; Male; Middle Aged; Neostriatum; Radionuclide Imaging; Technetium Tc 99m Exametazime; Tomography, Emission-Computed, Single-Photon

The brain benzodiazepine (BZD) receptor distribution in patients with chronic cerebrovascular disease was assessed with 123I-iomazenil (IMZ) SPECT, and the findings were compared with the data for the cerebral blood flow (CBF) and cerebral metabolism.. We examined nine patients with chronic cerebrovascular diseases, six patients with cerebral infarction and three with moyamoya disease. Iodine-123-IMZ SPECT images were obtained for 15 min, 3 hr after the administration of 167 or 222 MBq 123I-IMZ. In seven patients, the CBF and oxygen metabolism were measured by the 50 steady-state method. In two patients, the CBF and glucose metabolism were measured by 99mTc-HMPAO SPECT and 18F-fluoro-2-deoxy-D-glucose-PET, respectively. The brain was initially classified into 18 regions, and abnormalities in the BZD receptor distribution, CBF and cerebral metabolism were visually evaluated. The count ratio of lesion-to-contralateral normal region (L-to-C ratio) was then used for comparison.. In the core of the infarct, the 123I-IMZ uptake decreased (L-to-C ratios of the blood flow 0.42 +/- 0.26; metabolism 0.45 +/- 0.24; and 123I-IMZ uptake 0.46 +/- 0.14). In the peri-infarct region, the 123I-IMZ uptake slightly decreased (L-to-C ratios of 0.81, 0.82 and 0.89, respectively). In the region of misery perfusion, the 123I-IMZ uptake was preserved (L-to-C ratios of 0.73, 1.07 and 1.02, respectively). In the remote deafferentiated areas in the ipsilateral cerebrum, the 123I-IMZ uptake was preserved (L-to-C ratios of 0.76 +/- 0.10, 0.75 +/- 0.04 and 0.98 +/- 0.05, respectively). In the remote areas in the contralateral cerebellum, the 123I-IMZ uptake was preserved (L-to-C ratios of 0.84 +/- 0.08, 0.85 +/- 0.04 and 0.94 +/- 0.05, respectively).. The BZD receptor distribution, as measured by 123I-IMZ SPECT, is not considered to reflect neuronal function, but it may reflect neuronal cell viability. Iodine-123-IMZ SPECT may, therefore, hold promise as a potential probe for neuronal damage.

Topics: Brain; Cerebral Infarction; Cerebrovascular Circulation; Female; Flumazenil; Humans; Iodine Radioisotopes; Male; Middle Aged; Moyamoya Disease; Radiopharmaceuticals; Receptors, GABA-A; Technetium Tc 99m Exametazime; Tomography, Emission-Computed, Single-Photon

"Delayed" single-photon emission tomograpic (SPET) images after an intravenous bolus injection of iodine-123 iomazenil have been used as a relative map of benzodiazepine receptor binding. We determined the optimal scan time for obtaining such a map and assessed the errors of the map. SPET and blood data from six healthy volunteers and five patients were used. A three-compartment kinetic model was employed in simulation studies and analyses of actual data. The simulation studies suggested that, in the normal brain, the scan time at which a single SPET image best represented the relative receptor binding was 3.0-3.5 h post-injection. This finding was supported by actual data from the volunteers. The simulation studies also suggested that the optimal scan time was not greatly changed by the variability of the input functions, and that the error in the SPET image contrast in the vicinity of the optimal scan time was not increased by changes in the tracer kinetics in the entire brain. The SPET image contrast in the patients at 3.0 h post-injection agreed well with the reference receptor binding estimated by kinetic analysis, with a mean error of 3.6%. These findings support the use of a single SPET image after bolus injection of [123I]iomazenil as a relative map of benzodiazepine receptor binding. For this purpose, a SPET scan time of 3.0-3.5 h post-injection is recommended.

Topics: Alzheimer Disease; Brain; Case-Control Studies; Cerebral Infarction; Computer Simulation; Dementia, Vascular; Flumazenil; Humans; Iodine Radioisotopes; Male; Parkinson Disease; Receptors, GABA-A; Time Factors; Tomography, Emission-Computed, Single-Photon

In the treatment and therapy of patients suffering a stroke, it is very important to predict whether viable neurones, even those of poor function, remain intact in the lesions of the brain. To determine whether viable neurones of low functional activity are represented in in vivo neuroreceptor imaging, we undertook experiments in gerbils with cerebral infarction, in which we examined histological changes and the results of dual-tracer in vivo autoradiography of glucose utilization with 14C-labelled deoxyglucose and benzodiazepine receptor binding with 123I-labelled Ro 16-0154. The unrelated findings of cerebral glucose metabolism and benzodiazepine receptor binding were observed in the primary infarct lesion and in remote areas, including the ipsilateral striatum and thalamus. Our experiments showed that when viable neurones with low functional activity remain intact, normal in vivo binding to benzodiazepine receptors is demonstrated as hypometabolism of glucose utilization. This functional, contrast-enhanced technique with 123I-labelled Ro 16-0154 may have an important role to play in the prediction of neuronal cell viability after recent brain infarction in experimental animals and humans using single photon emission tomography (SPET).

Topics: Animals; Autoradiography; Brain; Carbon Radioisotopes; Cell Survival; Cerebral Infarction; Cerebrovascular Disorders; Deoxyglucose; Flumazenil; Gerbillinae; Humans; Iodine Radioisotopes; Neurons; Predictive Value of Tests; Receptors, GABA-A; Tomography, Emission-Computed

This study evaluates ischemic damage to central benzodiazepine (BZD) receptor binding in the brain with [123]iomazenil SPECT in relation to CT hypodense lesions and blood flow abnormalities.. Nine patients with middle cerebral artery territory infarction were studied. Iomazenil images obtained 180 min postinjection were analyzed for BZD receptor binding. The cortical infraction, visualized as CT hypodense area on CT, the peri-infarct area, visualized as normodensity surrounding the infarction on CT, the intrahemispheric remote area and the cerebellum were analyzed by taking the ratio of the lesion to contralateral mirror region (L/C ratio). CT during the chronic stage and perfusion images obtained during the smallest time difference between the two studies were used for comparative analysis.. The mean L/C ratio of iomazenil uptake was 0.53 +/_ 0.08, 0.79 +/- 0.07, 0.98 +/- 0.03 and 1.00 +/- 0.04 in the infarct, peri-infarct and remote areas and the cerebellum, respectively. The infarct and peri-infarct areas showed significant decrease compared with unity. The corresponding mean L/C ratio for blood flow was 0.52 +/- 0.08, 0.73 +/- 0.07, 0.83 +/- 0.09, and 0.80 +/- 0.07, respectively. In all areas, the ratios were significantly decreased compared with unity. There was significant difference between the L/C ratio for blood flow and iomazenil in the remote area and the cerebellum.. Iodine-123-iomazenil SPECT imaging may provide new information on ischemic damage to the brain, particularly neurons.

Topics: Aphasia, Broca; Aphasia, Wernicke; Brain; Cerebral Infarction; Cerebrovascular Circulation; Female; Flumazenil; Humans; Iodine Radioisotopes; Male; Middle Aged; Oxygen Consumption; Receptors, GABA-A; Tomography, Emission-Computed, Single-Photon

Double tracer autoradiography was performed to measure regional cerebral blood flow (rCBF) and the binding of central type benzodiazepine receptors (BZR) in infarction by means of permanent occlusion of the unilateral middle cerebral arteries (MCA) in rat. Iodine-125 Iomazenil and 99mTc-HMPAO was used to label BZR and rCBF respectively. In the chronic phase of infarction 21 to 28 days after occlusion (5 rats), rCBF in the left MCA territory was decreased to 62% of the sham control (4 rats), while BZR was more decreased to 45% of the control. In remote areas from the MCA lesion, the ipsilateral thalamus showed 28% decrease of BZR as compared to the control, though the decrease of rCBF was not significant. Iomazenil distribution may represent neuron density or BZR density on a neuron, since central type BZR is reported to be located on neurons. These results suggest that central type BZR imaging is more useful tool for the evaluation of brain tissue viability and transneuronal degeneration than rCBF imaging in brain infarction.

Topics: Animals; Autoradiography; Brain; Cerebral Infarction; Cerebrovascular Circulation; Chronic Disease; Flumazenil; Iodine Radioisotopes; Male; Organotechnetium Compounds; Oximes; Radionuclide Imaging; Rats; Rats, Inbred Strains; Receptors, GABA-A; Technetium Tc 99m Exametazime