Distribution Of Benzodiazepine Receptors Research Articles

Progressive Cortical Neuronal Damage and Extracranial-Intracranial Bypass Surgery in Patients with Misery Perfusion.

Misery perfusion may cause selective neuronal damage in atherosclerotic ICA or MCA disease. Bypass surgery can improve misery perfusion and may prevent neuronal damage. On the other hand, surgery conveys a risk for neuronal damage. The purpose of this retrospective study was to determine whether progression of cortical neuronal damage in surgically treated patients with misery perfusion is larger than that in surgically treated patients without misery perfusion or medically treated patients with misery perfusion. We evaluated the distribution of benzodiazepine receptors twice by using PET and 11C-labeled flumazenil in 18 surgically treated patients with atherosclerotic ICA or MCA disease (9 with misery perfusion and 9 without) and no perioperative stroke before and after bypass surgery; in 8 medically treated patients with misery perfusion and no intervening ischemic event; and in 7 healthy controls. We quantified abnormal decreases in the benzodiazepine receptors of the cerebral cortex within the MCA distribution and compared changes in the benzodiazepine receptor index among the 3 groups. The change in the benzodiazepine receptor index in surgically treated patients with misery perfusion (27.5 ± 15.6) during 7 ± 5 months was significantly larger than that in surgically treated patients without misery perfusion (-5.2 ± 9.4) during 6 ± 4 months (P < .001) and in medically treated patients with misery perfusion (3.2 ± 15.4) during 16 ± 6 months (P < .01). Progression of cortical neuronal damage in surgically treated patients with misery perfusion and no perioperative stroke may occur and may be larger than that in medically treated patients with misery perfusion and no intervening ischemic event.

Unique Distribution of Benzodiazepine Receptors in the Brain during the First Two Years of Life

Background: ¹²³I-iomazenil (IMZ) single-photon emission computed tomography (SPECT) is a tool for evaluating epileptic foci and brain damage. To apply the method to children, information regarding the age-specific expression of benzodiazepine receptors (BDZ-Rs) is required. Unfortunately, there is no information currently available for children <2 years of age. Methods: We used IMZ SPECT once in infants aged 3-8 months and again at 2 years of age in order to describe the maturational changes in BDZ-R distribution. Results: No neurological deficits were found in any of the infants at the first examination. The BDZ-Rs were more dominantly distributed in the occipital lobe than in the frontal lobe before the age of 2 years. The frontal-occipital gradients of the distribution were obvious in children <8 months of age. Magnetic resonance imaging showed a spreading of myelination toward the frontal lobes simultaneously with BDZ-R expression. Conclusion: Information regarding the alteration in the BDZ-R distribution pattern is useful when assessing infantile epilepsy and brain injury. The age-related pattern of BDZ-R distribution could correspond with myelination, cerebral blood flow, metabolism and behavioral development.

Progressive Cortical Neuronal Damage and Chronic Hemodynamic Impairment in Atherosclerotic Major Cerebral Artery Disease.

Cross-sectional studies suggest that chronic hemodynamic impairment may cause selective cortical neuronal damage in patients with atherosclerotic internal carotid artery or middle cerebral artery occlusive disease. The purpose of this longitudinal study was to determine whether the progression of cortical neuronal damage, evaluated as a decrease in central benzodiazepine receptors (BZRs), is associated with hemodynamic impairment at baseline or hemodynamic deterioration during follow-up. We evaluated the distribution of BZRs twice using positron emission tomography and (11)C-flumazenil over time in 80 medically treated patients with atherosclerotic internal carotid artery or middle cerebral artery occlusive disease that had no ischemic episodes during follow-up. Using 3D stereotactic surface projections, we quantified abnormal decreases in the BZRs in the cerebral cortex within the middle cerebral artery distribution and correlated changes in the BZR index with the mean hemispheric values of hemodynamic parameters obtained from (15)O gas positron emission tomography. In the hemisphere affected by arterial disease, the BZR index in 40 patients (50%) was increased during follow-up (mean 26±20 months). In multivariable logistic regression analyses, increases in the BZR index were associated with the decreased cerebral blood flow at baseline and an increased oxygen extraction fraction during follow-up. Increases in the oxygen extraction fraction during follow-up were associated with a lack of statin use. In patients with atherosclerotic internal carotid artery or middle cerebral artery disease, the progression of cortical neuronal damage was associated with hemodynamic impairment at baseline and hemodynamic deterioration during follow-up. Statin use may be beneficial against hemodynamic deterioration and therefore neuroprotective.

Role of I-123-iomazenil SPECT imaging in drug resistant epilepsy with complex partial seizures.

Fifteen patients with therapy resistant partial complex seizures with no structural lesions were examined interictally with 123-I-IOMAZENIL SPECT for measurement of benzodiazepine receptor distribution and with 99m-Tc-HMPAO SPECT for measurement of cerebral blood flow distribution. Regional abnormalities were correlated with the seizure onset patterns in EEG later recorded with implanted subdural strips. SPECT scans were made immediately after and at 1 and 2 h after intravenous injection of 123-I-Iomazenil. During that time there was a continuous change from an immediate flow-related distribution toward a more specific receptor distribution. The decay of radioactivity of I-123 in the brain was linear over time. Two patients on benzodiazepine treatment showed much faster elimination and showed no focal abnormalities. Eight patients with clear-cut unifocal seizure onset showed concordant focal benzodiazepine defects. These patients showed a progressive focus/homotopic non-focus enhancement over time much larger than the HMPAO scans in the same patients. Also the estimated focal area of abnormality was more restricted in the Iomazenil scans than in HMPAO scans. Five patients had more complex seizure onset patterns. In these patients a mismatch between the locations of abnormalities in Iomazenil and HMPAO scans were often found but benzodiazepine receptor abnormalities were more circumscribed also in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased regional cerebral blood flow but normal distribution of GABA A receptor in the visual cortex of subjects with early-onset blindness

Before the completion of visual development, visual deprivation impairs synaptic elimination in the visual cortex. The purpose of this study was to determine whether the distribution of central benzodiazepine receptor (BZR) is also altered in the visual cortex in subjects with early-onset blindness. Positron emission tomography was carried out with [ 15O]water and [ 11C]flumazenil on six blind subjects and seven sighted controls at rest. We found that the CBF was significantly higher in the visual cortex for the early-onset blind subjects than for the sighted control subjects. However, there was no significant difference in the BZR distribution in the visual cortex for the subject with early-onset blindness than for the sighted control subjects. These results demonstrated that early visual deprivation does not affect the distribution of GABA A receptors in the visual cortex with the sensitivity of our measurements. Synaptic elimination may be independent of visual experience in the GABAergic system of the human visual cortex during visual development.

18F]Fluoroethylflumazenil: a novel tracer for PET imaging of human benzodiazepine receptors.

5-(2'-[18F]Fluoroethyl)flumazenil ([18F]FEF) is a fluorine-18 labelled positron emission tomography (PET) tracer for central benzodiazepine receptors. Compared with the established [11C]flumazenil, it has the advantage of the longer half-life of the fluorine-18 label. After optimisation of its synthesis and determination of its in vitro receptor affinities, we performed first PET studies in humans. PET studies in seven healthy human volunteers were performed on a Siemens ECAT EXACT whole-body scanner after injection of 100-280 MBq [L8F]FEF. In two subjects, a second PET scan was conducted after pretreatment with unlabelled flumazenil (1 mg or 2.5 mg i.v., 3 min before tracer injection). A third subject was studied both with [18F]FEF and with [11C]flumazenil. Brain radioactivity was measured for 60-90 min p.i. and analysed with a region of interest-oriented approach and on a voxelwise basis with spectral analysis. Plasma radioactivity was determined from arterial blood samples and metabolites were determined by high-performance liquid chromatography. In human brain, maximum radioactivity accumulation was observed 4 +/- 2 min p.i., with a fast clearance kinetics resulting in 50% and 20% of maximal activities at about 10 and 30 min, respectively. [18F]FEF uptake followed the known central benzodiazepine receptor distribution in the human brain (occipital cortex >temporal cortex >cerebellum >thalamus >pons). Pretreatment with unlabelled flumazenil resulted in reduced tracer uptake in all brain areas except for receptor-free reference regions like the pons. Parametric images of distribution volume and binding potential generated on a voxelwise basis revealed two- to three-fold lower in vivo receptor binding of [18F]FEF compared with [11C]flumazenil, while relative uptake of [18F]FEF was higher in the cerebellum, most likely owing to its relatively higher affinity for benzodiazepine receptors containing the alpha6 subunit. Metabolism of [18F]FEF was very rapid. Polar metabolites represented about 50%-60% of total plasma radioactivity at 5 min and 80%-90% at 20 min p.i. Although [11C]flumazenil has some advantages over [18F]FEF (higher affinity, slower metabolism, slower kinetics), our results indicate that [18F]FEF is a suitable PET ligand for quantitative assessment of central benzodiazepine receptors, which can be used independently of an on-site cyclotron.

Decreased benzodiazepine receptor density in the cerebellum of early blind human subjects

As a first approach to study the effect of early visual deprivation in the GABA-ergic inhibitory system, the distribution of benzodiazepine receptors (BZR) was accurately estimated using [ 11C]flumazenil ([ 11C]FMZ). Measurements were carried out in five subjects who became blind early in life and in five sighted control subjects. The interactions between [ 11C]FMZ and BZR were described using a non-linear compartmental analysis which permitted to estimate the BZR synaptic density independently of other model parameters. The distribution of BZR in the visual areas and other cortical regions of blind subjects was qualitatively and quantitatively similar to that of controls. However, the BZR density in the cerebellum was significantly lower in blind than in control subjects ( P<0.01). Our findings suggest that modifications of the cerebellar neural circuitry may be concomitant to the already observed compensatory reorganization in cerebral areas of blind subjects.

Intrasubject correlation between static scan and distribution volume images for [11C]flumazenil PET.

Accumulation of [11C]flumazenil (FMZ) reflects central nervous system benzodiazepine receptor (BZR). We searched for the optimal time for a static PET scan with FMZ as semi-quantitative imaging of BZR distribution. In 10 normal subjects, a dynamic series of decay-corrected PET scans was performed for 60 minutes, and the arterial blood was sampled during the scan to measure radioactivity and labeled metabolites. We generated 13 kinds of "static scan" images from the dynamic scan in each subject, and analyzed the pixel correlation for these images versus distribution volume (DV) images. We also analyzed the time for the [11C]FMZ in plasma and tissue to reach the equilibrium. The intra-subject pixel correlation demonstrated that the "static scan" images for the period centering around 30 minutes post-injection had the strongest linear correlation with the DV image. The ratio of radioactivity in the cortex to that in the plasma reached a peak at 40 minutes after injection. Considering the physical decay and patient burden, we conclude that the decay corrected static scan for [11C]FMZ PET as semi-quantitative imaging of BZR distribution is to be optimally acquired from 20 to 40 minutes after injection.

Hypoexpression of Benzodiazepine Receptors in the Amygdala of Neophobic BALB/c Mice Compared to C57BL/6 Mice

The distribution of benzodiazepine receptors in the brain of neophobic BALB/c mice was studied by autoradiographic analysis using [ 3H]-diazepam and compared to that of the same receptors of the “nonemotional” C57BL/6 mice. This technique revealed no significant interstrain difference except for a lower density of diazepam binding sites in the amygdala of BALB/c mice. Therefore, the expression of benzodiazepine receptors in the amygdala of the two strains of mice were quantified by binding studies on brain membranes. The amygdala of BALB/c mice exhibited a fivefold decrease in the density of benzodiazepine receptors compared to C57BL/6 mice. These results suggest that the trait anxiety (neophobia) that characterizes BALB/c mice could be due, at least in part, to a genetic modulation of benzodiazepine receptor expression in the amygdala, a structure known to be strongly involved in fear behavior.

Decreased density of GABA-A receptors in the left sensorimotor cortex in akinetic catatonia: investigation of in vivo benzodiazepine receptor binding

OBJECTIVESCatatonia is a psychomotor syndrome with concomittant akinesia and anxiety which both respond almost immediately to benzodiazepines such as lorazepam. The benzodiazepine receptor distribution was therefore investigated in akinetic catatonia...

Benzodiazepine receptor imaging with iomazenil SPECT in aphasic patients with cerebral infarction.

To investigate the relationship between prognosis of aphasia and neuronal damage in the cerebral cortex, we evaluated the distribution of central-type benzodiazepine receptor (BZR) binding in post-stroke aphasics with [123I]iomazenil and SPECT. We performed iomazenil SPECT in six aphasic patients (aged from 45 to 75 years; all right-handed) with unilateral left cerebral infarction. Three patients showed signs of Broca's aphasia and the other three Wernicke's aphasia. Cerebral blood flow (CBF) imaging was performed with [123I]iodoamphetamine (IMP). The regions of interest (ROIs) on both images were set in the cerebral cortex, cerebellar cortex and language-relevant area in both hemispheres. Three patients were classified in the mild prognosis group and the other three in the moderate prognosis group. The left language-relevant area was more closely concerned with the difference in aphasic symptoms than the right one in both BZR and CBF distribution, but the ipsilateral to the contralateral ratio (I/C ratio) in the language-relevant areas in the BZR distribution was significantly lower in the moderate prognosis group than in the mild prognosis group, although no difference was seen for these values between the two groups in the CBF distribution. These results suggest that BZR imaging, which makes possible an increase in neuronal cell viability in the cerebral cortex, is useful not only for clarifying the aphasic symptoms but also for evaluating the prognosis of aphasia in patients with cerebral infarction.

Alterations of benzodiazepine receptors in type II alcoholic subjects measured with SPECT and [123I]iomazenil.

Alterations in cortical benzodiazepine receptor density have been described in postmortem and in vivo studies of alcoholic subjects. The authors attempted to replicate these findings using single photon emission computed tomography and the benzodiazepine receptor radiotracer [123I]iomazenil. They measured the distribution volume of benzodiazepine receptors in 11 recently detoxified patients with type II alcoholism and 11 healthy comparison subjects. The tracer was given as a bolus followed by a continuous infusion to achieve sustained binding equilibrium at the benzodiazepine receptors. Data were analyzed by using a region of interest method (regions of interest were identified on coregistered magnetic resonance imaging scans) and by a pixel-by-pixel method (distribution volume maps were analyzed with statistical parametric mapping for between-group differences). The region of interest analysis revealed that alcoholic patients had significantly lower benzodiazepine distribution volume than comparison subjects in the frontal, anterior cingulate, and cerebellar cortices. Statistical parametric mapping revealed two large excursions in which the distribution volume in alcoholic patients was significantly lower than in comparison subjects: the anterior cingulate, extending into the right middle frontal gyrus, and the left occipital cortex. Benzodiazepine receptor distribution volume is significantly lower in several cortical regions and the cerebellum in alcoholic subjects than in healthy comparison subjects. These results are consistent with previous reports and might indicate either a toxic effect of alcoholism on benzodiazepine receptors or a vulnerability factor for developing alcoholism.

I-123 iomazenil SPECT in patients with mental disorders.

The purpose of this study is visual evaluation of the distribution of I-123 iomazenil in the brains of patients with various types of mental disorder and to examine whether chronic administration of a clinical dose of benzodiazepine (BZ) affects the binding of I-123 iomazenil to BZ receptors (BZR). The subjects were 10 patients with mental disorders (3 males and 7 females) with a mean age of 26.8 yrs (range 19-39 yrs). Four of 10 patients were administered BZ for over 3 months and the other six were free of BZ for over one month. The SPECT images were obtained at 5-25 min (early) and 170-190 min (delayed), after the bolus i.v. injection of 167 MBq of I-123 iomazenil, with a triple-head gamma camera. The images were visually evaluated and the washout ratios of each region were calculated. In visual analysis, abnormalities were recognized in 5 patients on the delaye SPECT. The abnormalities were recognized more frequently in the superior frontal lobe. The washout ratio was higher in the BZ (+) patient group than in the BZ (-) patient group. I-123 iomazenil is useful, because the SPECT image with I-123 iomazenil reflects the distribution of BZR on the brain and provides the different information from that obtained with perfusion SPECT, X-ray CT or MRI. The rapid washout of I-123 iomazenil from the brains of BZ (+) patients suggests that chronic administration of a clinical dose of BZ affects the binding of I-123 iomazenil to BZR.

Benzodiazepine receptor distribution and diazepam binding in schizophrenia: an exploratory study

Clinical studies indicate that patients with acute schizophrenia may benefit from benzodiazepine treatment. Therefore we investigated the benzodiazepine receptor distribution and diazepam binding in 20 patients with DSM-III schizophrenia using single photon emission computed tomography (SPECT) with iomazenil as the ligand. In each patient, two SPECT images were obtained: SPECT 1 was obtained 2 h after intravenous injection of 200 MBq I-123-iomazenil. Following SPECT 1, patients received 10 mg diazepam intravenously. Twenty min later, SPECT 2 was started. The highest iomazenil uptake was found in the occipital cortex followed by the frontal and temporal cortices. Baseline iomazenil uptake in the medial frontal cortex was significantly ( P < 0.05) correlated with the BPRS total score ( r = 0.46). Diazepam injection led to a significant activity decrease in iomazenil binding which was greatest in the frontal regions of interest. With respect to the medial frontal cortex, this effect was significantly ( P < 0.05) more pronounced in patients with a remitting than a chronic course of the disorder. These findings suggest that changes of the benzodiazepine receptor system in the frontal cortex may be associated with severity and chronicity of schizophrenia.

Immunohistochemical localization of the β2 and β3 subunits of the GABAA receptor in the basolateral amygdala of the rat and monkey

The basolateral amygdala has a strong intrinsic inhibitory system mediated by GABAA receptors and is the main site of the anxiolytic actions of benzodiazepines. In an effort to identify the anatomical susbstrates for these transmitter and drug actions, immunohistochemical techniques were used to analyse the neuronal localization of the β2 and β3 receptor subunits of the GABAA–benzodiazepine receptor complex in the rat and monkey basolateral amygdala. The overall pattern of GABAA–benzodiazepine receptor immunoreactivity was very similar in both species. The density of the immunoreactivity in the neuropil varied in different nuclei of the basolateral amygdaloid complex. In both species the neuropil of the lateral nucleus exhibited the most robust staining. Immunoreactivity was also seen in neuronal perikarya and dendrites where it was localized to the cytoplasm and/or surface membrane. The cell type with the strongest immunoreactivity was a subpopulation of small non-pyramidal neurons that had numerous thin dendrites. Other larger non-pyramidal neurons were also stained. Pyramidal neurons in the rat and monkey basolateral amygdala exhibited light to moderate perikaryal staining that varied in different nuclei.The results of this study indicate that the pattern of GABAA–benzodiazepine receptor immunoreactivity in the neuropil of the rat and monkey basolateral amygdala closely resembled the distribution of benzodiazepine receptors localized in previous radioligand autoradiographic studies. The finding of intense immunoreactivity in subpopulations of non-pyramidal neurons suggests the existence of disinhibitory mechanisms which may be important for the activation of basolateral amygdaloid projection neurons.

Heterogeneous distribution of benzodiazepine receptors among rat neostriatal neurones.

1. The effects of benzodiazepine receptor (BZR) agonist were investigated in dissociated rat neostriatal neurones by a conventional whole-cell patch recording configuration at room temperature. 2. The dissociated neurones, with a longest somatic diameter of larger than 25 microns, were classified as 'large neurones', while those having soma measuring less than 15 microns were described as 'small neurones'. Large neurones were intensely positive for acetylcholinesterase staining, whereas the small ones were not. 3. CL218,872 enhanced the GABA response in both the large and small neurones with similar EC50S. However, the potentiation efficacy of CL218,872 in large neurones was larger than that of small ones. 4. Zolpidem also potentiated the GABA response in both neuronal populations with similar EC50S. This compound also enhanced the GABA response more strongly in large neurones than in small ones. 5. Zopiclone exerted a prominent potentiation in large neurones, although no difference was seen in the EC50S in the large and small neurones. 6. It was concluded that the BZR in large neurones had a different pharmacological property from that in small ones and that the BZR agonists showed a prominent difference, not in EC50, but in the potentiation efficacy between these neuronal populations.

Central benzodiazepine receptor distribution after subcortical hemorrhage evaluated by means of [123I]iomazenil and SPECT.

[123I]Iomazenil is a single-photon emission computed tomography (SPECT) tracer that selectively binds to central benzodiazepine receptor in the neuron membrane. With this ligand, we studied the central benzodiazepine receptor distribution in the cortex remote from subcortical hematoma in intracerebral hemorrhage patients. Four patients with unilateral putaminal hemorrhage and one patient with right thalamic hemorrhage were studied (mean +/- 1 SD age, 50.0 +/- 8.8 years). The initial volume of hematoma ranged from 4.3 to 31.0 mL (mean +/- 1 SD, 17.5 +/- 12.3 mL). SPECT images obtained 3 hours after intravenous administration of [123I]iomazenil (167 MBq/750 ng) were analyzed. In three patients, perfusion was evaluated with [123I]IMP. On SPECT images, the radioactivity ratio of the ipsilateral to the contralateral cerebral cortex (I/C ratio) or of the contralateral to the ipsilateral cerebellar hemisphere (C/I ratio) was measured. The I/C ratio for iomazenil was significantly decreased compared with unity in the temporal lobe (0.84 +/- 0.08, P < .01) and the parietal lobe (0.87 +/- 0.10, P < .05), but the C/I ratio in the cerebellum (1.00 +/- 0.03) was not. The C/I ratio for perfusion in the cerebellar cortex (0.83 +/- 0.04, P < .01) was significantly decreased compared with that in normal subjects. Central benzodiazepine receptor-[123I]iomazenil binding was decreased in the ipsilateral cerebral cortex remote from the subcortical hematoma. This preliminary result may facilitate further study of the potential damage of the cortical neurons remote from subcortical hematoma.

Dynamic SPECT imaging after injection of the benzodiazepine receptor ligand [ 123I]iomazenil in healthy human subjects

Previous work suggests that iomazenil (formerly known as Ro 16–0154) is a useful ligand for static imaging of the benzodiazepine (BZ) receptor with single photon emission computed tomography (SPECT). The present study evaluated the feasibility of dynamic SPECT imaging of cerebral radioactivity following intravenous [ 123I]iomazenil injection in healthy human subjects, in preparation for future receptor quantitation studies. Maximal brain uptake was reached approximately 25–30 minutes after i.v. administration of the radioligand and represented approximately 12% of the injected dose. The regional distribution of radioactive densities was consistent with the known distribution of BZ receptors in human brain, with highest uptake localized over the occipital area. Washout of cortical radioactivity was regionally variable but relatively slow, with a half-life of approximately 4 hours after the time of peak radioactivity. In summary, [ 123I]iomazenil is a promising SPECT radioligand for the BZ receptor, with high brain uptake, relatively slow washout of radioactivity and appropriate regional distribution.

Parametric in vivo imaging of benzodiazepine receptor distribution in human brain.

Emission computed tomographic methods for the in vivo quantification of radioligand-binding sites in human brain have previously been limited either by a lack of correction for possible effects of altered ligand transport or by highly complicated physiological models that preclude display of binding data in a detailed anatomical format. We investigated the application of a simplified compartmental model to the kinetic analysis of in vivo ligand binding to central benzodiazepine receptors. The human brain distribution of [11C]flumazenil, as determined by dynamic positron emission tomography, combined with metabolite-corrected arterial blood samples, permitted estimations of local cerebral ligand transport and of receptor binding. This approach allows calculation of transport and binding "maps" on a pixel-by-pixel basis, resulting in the display of binding data in a familiar tomographic format while maintaining much of the physiological accuracy inherent in more complex methods. The results obtained in a study of 6 normal volunteers revealed good interindividual precision, with coefficients of variation between 10 and 15% of mean regional values, suggesting the utility of this approach in future clinical studies of benzodiazepine receptor binding.

Acute effects of ethanol on regional brain glucose metabolism and transport

To evaluate the effects of ethanol in the human brain, we tested six normal subjects and six alcoholics using positron emission tomography and 2-deoxy-2-[ 18F]-fluoro-D-glucose (FDG) under baseline conditions and 24 hours later after ethanol administration (1 g/kg). Ethanol inhibited cortical and cerebellar glucose metabolism with relative sparing of the basal ganglia and corpus callosum. This inhibition was more pronounced in the alcoholics than in the controls. Measurement of the constants for glucose transport and utilization showed that decreased glucose metabolism was due to a reduction in glucose phosphorylation and not to a change of glucose transport into the tissue. The pattern of regional metabolic inhibition by alcohol paralleled the distribution of benzodiazepine receptors in the human brain.