ro-16-0154 and Cerebrovascular-Disorders

Pathophysiology of cerebrovascular disease has been studied by measuring cerebral blood flow and energy metabolism using single photon emission computed tomography (SPECT) and positron emission tomography (PET). These parameters are measures for brain tissue consisting of heterogeneous components such as neurons, glial cells, and blood vessels. It is still difficult to evaluate brain damages specifically involving either neurons or other components. Several trials were recently conducted to visualize neuron-specific injury in cerebrovascular disease by means of 11C flumazenil for PET and 123I-iomazenil for SPECT. These tracers selectively bind to central benzodiazepine receptor which is purely neuronal. A reduced accumulation of these ligands was found in the area surrounding the complete infarction and in the cortex remote from putaminal hemorrhage, indicating the existence of neuron specific injury not visualized by CT and MR. Neurological deficits were well correlated with the loss of cortical accumulation of these ligands. These preliminary studies indicated a potential of neurochemical imaging in cerebrovascular disease. Vulnerability to ischemia which may differ among brain tissue components, among subpopulations of neurons, and among pre-synaptic and post-synaptic functions can be more precisely examined. Neurochemical imaging can be also applied to reveal releases and re-organization of each neurotransmitter-acceptor system after stroke.

Topics: Brain; Carbon Radioisotopes; Cerebrovascular Disorders; Flumazenil; Humans; Receptors, GABA-A; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon

Adoption of standard input function (SIF) has been proposed for kinetic analysis of receptor binding potential (BP), instead of invasive frequent arterial samplings. The purpose of this study was to assess the SIF method in quantitative analysis of [123I]iomazenil (IMZ), a central benzodiazepine antagonist, for SPECT. SPECT studies were performed on 10 patients with cerebrovascular disease or Alzheimer disease. Intermittent dynamic SPECT scans were performed from 0 to 201 min after IMZ-injection. BPs calculated from SIFs obtained from normal volunteers (BPs) were compared with those of individual arterial samplings (BPo). Good correlations were shown between BP(o)s and BP(s)s in the 9 subjects, but maximum BP(s)s were four times larger than the corresponding BP(o)s in one case. There were no abnormal laboratory data in this patient, but the relative arterial input count in the late period was higher than the SIF. Simulation studies with modified input functions revealed that height in the late period can produce significant errors in estimated BPs. These results suggested that the simplified method with one-point arterial sampling and SIF can not be applied clinically. One additional arterial sampling in the late period may be useful.

Topics: Adolescent; Adult; Aged; Algorithms; Alzheimer Disease; Brain; Cerebrovascular Disorders; Epilepsy; Female; Flumazenil; Humans; Image Interpretation, Computer-Assisted; Male; Middle Aged; Radioisotope Dilution Technique; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Tomography, Emission-Computed, Single-Photon

Single photon emission computed tomography (SPECT) using 123I-Iomanzenil (IMZ), a tracer which binds specifically to central-type benzodiazepine receptors, was performed in patients with cerebrovascular diseases (CVD) to determine the clinical signicigance of IMZ SPECT studies in evaluating the pathophysiology of CVD. IMZ SPECT images obtained three hours after administration of the tracer were compared with the images of cerebral blood flow (CBF) studies in 206 cases. In regions with decreased CBF, the uptake of IMZ was relatively preserved in patients with cerebral thrombosis in comparison with cerebral embolism, and in those with perforator branch infarction in comparison with cortical infarction. The uptake of IMZ decreased as a function of both the severity of the decrease in the CBF and the duration of illness in regions with a significantly decreased perfusion reserve. These results suggest that decreased IMZ binding in ischemic stroke reflects the neuronal damage caused by the cerebral ischemia. On the other hand, in patients with intracerebral hemorrhage, the cortical uptake of IMZ was relatively well-preserved in regions with decreased CBF, and the decrease in the uptake of IMZ was more profound as a function of the decrease in the CBF, especially in cases of putaminal hemorrhage. These results also suggest that the decreased cortical CBF is a remote effect caused by a neuronal disconnection, and neuronal damage may occur in regions with severely impaired CBF.

Topics: Brain; Cerebrovascular Disorders; Flumazenil; GABA-A Receptor Agonists; Humans; Iodine Radioisotopes; Japan; Male; Middle Aged; Predictive Value of Tests; Tomography, Emission-Computed, Single-Photon

Clinical evaluation of 123I-iomazenil, a new imaging agent for central-type benzodiazepine receptors with SPECT, was performed in patients with ischemic cerebrovascular disease. We investigated 15 patients with angiographically-proven severe occlusive lesions (occlusion or > 70% stenosis) in the unilateral carotid system. 123I-iomazenil SPECT images were compared with cerebral blood flow (CBF) images and the cerebral perfusion reserve, which were measured using the "split dose 123I-IMP SPECT method" before and after the intravenous injection of 1 g of acetazolamide. For the detection of ischemic lesions, CBF images were superior to 123I-iomazenil images based on visual analysis. Regarding the count ratio of the affected MCA territory to the non-affected (L/N), 123I-IMP was lower than 123I-iomazenil in most of the cases. In five patients showing "crossed cerebellar diaschisis" by 123I-IMP, asymmetry of the cerebellar accumulation was observed in only one patient with 123I-iomazenil, which was less prominent than with 123I-IMP. There was no significant correlation between the L/N ratio with 123I-iomazenil and the cerebral perfusion reserve in the affected MCA territory. However, in some cases showing a decreased L/N ratio (< 90%) with 123I-iomazenil, a decreased CBF with normal perfusion reserve and cerebral hemi-atrophy were observed with 123I-IMP and MRI, which suggested the influence of neuronal loss due to chronic ischemia. These results indicate that 123I-iomazenil SPECT, which provides new information regarding neuronal loss due to ischemic damage to the brain, is useful for the evaluation of ischemic cerebrovascular disease.

Topics: Adult; Aged; Amphetamines; Brain; Cerebrovascular Disorders; Female; Flumazenil; Humans; Iodine Radioisotopes; Iofetamine; Male; Middle Aged; Nerve Degeneration; Neurons; Radionuclide Imaging; Regional Blood Flow

Although cerebral hyperperfusion after carotid endarterectomy (CEA) often impairs cognitive function, MRI does not always demonstrate structural brain damage associated with postoperative cognitive impairment. The purpose of the present study was to determine whether postoperative cortical neural loss, which can be detected by (123)I-iomazenil single-photon emission CT, is associated with cerebral hyperperfusion after CEA and whether it correlates with postoperative cognitive impairment.. In 60 patients undergoing CEA for ipsilateral internal carotid artery stenosis (>70%), cerebral blood flow was measured using N-isopropyl-p-[(123)I]-iodoamphetamine single-photon emission CT before and immediately after CEA and on the third postoperative day. The distribution of benzodiazepine receptor binding potential in the cerebral cortex was assessed using (123)I-iomazenil single-photon emission CT before and 1 month after surgery and was analyzed using 3-dimensional stereotactic surface projection. Neuropsychological testing was also performed preoperatively and at the first postoperative month.. Post-CEA hyperperfusion and postoperative cognitive impairment were observed in 9 patients (15%) and 8 patients (13%), respectively. Post-CEA hyperperfusion was significantly associated with postoperative hemispheric reduction of benzodiazepine receptor binding potential (95% CIs, 2.765 to 148.804; P=0.0031). Post-CEA hyperperfusion (95% CIs, 1.183 to 229.447; P=0.0370) and postoperative hemispheric reduction of benzodiazepine receptor binding potential (95% CIs, 1.003 to 77.381; P=0.0496) were also significantly associated with postoperative cognitive impairment.. Cerebral hyperperfusion after CEA results in postoperative cortical neural loss that correlates with postoperative cognitive impairment.

Topics: Adult; Aged; Analysis of Variance; Carotid Stenosis; Cerebral Cortex; Cerebrovascular Circulation; Cerebrovascular Disorders; Cognition Disorders; Endarterectomy, Carotid; Female; Flumazenil; Humans; Iofetamine; Male; Middle Aged; Neurons; Neuropsychological Tests; Postoperative Complications; Radiopharmaceuticals; Stereotaxic Techniques; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

Iodine-123-iomazenil (IMZ) is a SPECT ligand for central-type benzodiazepine receptors, which are located only on neurons. We evaluated the feasibility of using IMZ SPECT for identifying neuronal damage in patients with the chronic phase of thrombotic cerebral ischemia.. We studied 15 patients with angiographically-confirmed unilateral severe occlusive lesions (occlusion or > 70% stenosis) in the carotid system. IMZ SPECT images obtained 180 min after injection of 167-222 MBq IMZ were analyzed. The regional cerebral blood flow and perfusion reserve were evaluated for comparison with IMZ SPECT findings, using the split-dose 123I-iodoamphetamine (IMP) SPECT method, coupled with intravenous injection of 1 g acetazolamide. On both SPECT images, the count ratio of the affected to the nonaffected whole MCA territory (A/NA ratio) and of the contralateral to the ipsilateral cerebellar cortex (C/I ratio) were determined.. The A/NA ratio with IMZ was significantly higher than that with IMP (94.5% +/- 6.2% versus 91.4% +/- 6.6%, p < 0.005), although a significantly positive correlation was found between these two ratios (r = 0.854, p < 0.0001). The C/I ratio with IMP was decreased significantly in 5 patients compared with that in normal subjects, whereas the C/I ratio with IMZ was decreased in only 1 patient. There was no significant correlation between the A/NA ratio with IMZ and the perfusion reserve in the affected MCA territory. In 2 of 5 patients with a decreased A/NA ratio (<90%) with IMZ, decreased blood flow with preserved perfusion reserve and cerebral hemispheric atrophy were observed, which suggested the influence of neuronal loss due to chronic ischemia.. These findings indicate that IMZ SPECT, which provides new information regarding neuronal damage after ischemic insult to the brain, is useful for evaluating thrombotic cerebral ischemia.

Topics: Amphetamines; Brain; Brain Ischemia; Carotid Stenosis; Case-Control Studies; Cerebrovascular Circulation; Cerebrovascular Disorders; Feasibility Studies; Female; Flumazenil; Humans; Iodine Radioisotopes; Iofetamine; Magnetic Resonance Imaging; Male; Middle Aged; Tomography, Emission-Computed, Single-Photon

Iodine-123-iomazenil (Iomazenil) is a ligand of central type benzodiazepine receptors for single photon emission computed tomography (SPECT). Previously we reported a simple, table look-up method for quantification of its binding potential (BP) by using two SPECT scans and calibrated standard input function with one blood sampling. This method is based on a two-compartment model (K1: influx rate constant; k2: efflux rate constant; Vd (= K1/k2): the total distribution volume corresponding BP), and requires two SPECT scans for calculating both K1 and Vd values. If the K1 value in the two-compartment model can be assumed to be constant, the radioactivity of one SPECT scan at 180 min after injection can be considered to tabulate as a function of Vd for a given K1 value and a given input function, and a table look-up procedure provides the corresponding Vd value. The purpose of this study was to develop a simple, autoradiographic method for quantification of BP by using one SPECT scan and calibrated standard input function with one blood sampling. SPECT studies were performed on 14 patients. A dynamic SPECT scan was initiated following an intravenous bolus injection of Iomazenil. A static SPECT scan was performed at 180 min after the injection. Frequent blood sampling from the brachial artery was performed on all subjects to determine the arterial input function. Simulation studies revealed that errors in calculated Vd values were around +/-10-15% for varied K1 values. A good correlation was observed between total distribution volume values calculated by three-compartment model analysis and those calculated by the present method (r = 0.90), supporting the validity of this method. The present method is simple and applicable for clinical use, and will be able to provide images of BP.

Topics: Adult; Aged; Autoradiography; Brain; Brain Neoplasms; Cerebrovascular Disorders; Computer Simulation; Dementia; Evaluation Studies as Topic; Flumazenil; Humans; Iodine Radioisotopes; Middle Aged; Models, Biological; Nonlinear Dynamics; Receptors, GABA-A; Reproducibility of Results; Tomography, Emission-Computed, Single-Photon

Iodine-123 iomazenil (Iomazenil) is a ligand for central type benzodiazepine receptors that is suitable for single-photon emission tomography (SPET). The purpose of this study was to develop a simple method for the quantification of its binding potential (BP). The method is based on a two-compartment model (K1, influx rate constant; k2', efflux rate constant; VT' (=K1/k2'), the total distribution volumes relative to the total arterial tracer concentration), and requires two SPET scans and one blood sampling. For a given input function, the radioactivity ratio of the early to delayed scans can be considered to tabulate as a function of k2', and a table look-up procedure provides the corresponding k2' value, from which K1 and VT' values are then calculated. The arterial input function is obtained by calibration of the standard input function by the single blood sampling. SPET studies were performed on 14 patients with cerebrovascular diseases, dementia or brain tumours (mean age+/-SD, 56.0+/-12.2). None of the patients had any heart, renal or liver disease. A dynamic SPET scan was performed following intravenous bolus injection of Iomazenil. A static SPET scan was performed at 180 min after injection. Frequent blood sampling from the brachial artery was performed on all subjects for determination of the arterial input function. Two-compartment model analysis was validated for calculation of the VT' value of Iomazenil. Good correlations were observed between VT' values calculated by three-compartment model analysis and those calculated by the present method, in which the scan time combinations (early scan/delayed scan) used were 15/180 min, 30/180 min or 45/180 min (all combinations: r=0.92), supporting the validity of this method. The present method is simple and applicable for clinical use.

Topics: Brain; Brain Neoplasms; Cerebrovascular Disorders; Computer Simulation; Dementia; Flumazenil; Humans; Iodine Radioisotopes; Middle Aged; Receptors, GABA-A; Reproducibility of Results; Tomography, Emission-Computed, Single-Photon

Iomazenil is a specific ligand for central-type benzodiazepine receptors (BZR). In order to determine the clinical significance of the findings of 123I-iomazenil single photon emission tomography (SPET) in cerebrovascular disease (CVD), we compared the cerebral uptake of 123I-iomazenil with oxygen metabolism measured by positron emission tomography (PET). Depending on the severity of the haemodynamic and/or metabolic impairment based on our institutional criteria [a reduction of < 30.6 ml 100g-1 min-1 in cerebral blood flow (CBF) and an increase of > 0.52 in the oxygen extraction fraction (OEF)], the cortical areas were classified into four groups as follows: Group I, normal CBF and OEF; Group II, normal CBF and increased OEF; Group III, reduced CBF and normal OEF; Group IV, reduced CBF and increased OEF. Seven patients (mean age 65 +/- 7 years) with CVD underwent both PET and 123I-iomazenil SPET within 8 days. The ratios of the mean counts in 14 regions of interest in the cerebral cortices to those in the cerebellar cortices (R/C ratios) were compared with the cerebral metabolic rate of oxygen (CMRO2). The R/C ratios of Group IV were lower than those of Group I (P < 0.005). The R/C ratios correlated with CMRO2 in Group III (r = 0.577, P < 0.01) and in Group IV (r = 0.707, P < 0.005), but not in Groups I or II. These results suggests that reduced uptake in 123I-iomazenil SPET reflects oxidative hypometabolism causing neuronal damage in haemodynamically and metabolically impaired areas in patients with CVD. This information may be valuable when deciding therapeutic approaches.

Topics: Aged; Cerebrovascular Circulation; Cerebrovascular Disorders; Flumazenil; Humans; Iodine Radioisotopes; Ligands; Male; Middle Aged; Oxygen Consumption; Receptors, GABA-A; Tomography, Emission-Computed; 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