Benzodiazepine receptors in normal human brain, in Parkinson''s disease and in progressive supranuclear palsy

Benzodiazepine receptors have been characterized in human brain. They have been localized mainly in the cerebral cortex and a synaptosomal enrichment was observed after brain fractionation by differential centrifugation. Benzodiazepine receptors were studied in Parkinson's disease and in progressive supranuclear palsy (PSP). In both diseases, the [3H]flunitrazepam specific binding was unchanged when compared to control groups (Bmax and KD values) except in the caudate nucleus of parkinsonian patients where an increase of the specific binding was observed. The subcellular distribution profile of benzodiazepine receptors in Parkinson's disease was similar to that of controls. gamma-Aminobutyric acid (GABA) still enhanced the [3H]flunitrazepam-specific binding (increase of binding affinity), indicating that the functional link between GABA and benzodiazepine receptors remained intact in Parkinson's disease. The present results suggest that benzodiazepine receptors in human striatum are localized on neuronal elements which do not degenerate in Parkinson's disease and PSP.     

Central Benzodiazepine/γ-Aminobutyric AcidA Receptors in Idiopathic Generalized Epilepsy: An [11C]Flumazenil Positron Emission Tomography Study

Summary: Purpose: Previous [¹¹C]flumazenil (FMZ) positron emission tomography (PET) investigations in patients with idiopathic generalized epilepsy (IGE) have demonstrated nonsignificant global cortical decreases in central benzodiazepine γ-aminobutyric acid, (GABA_A) receptor (cBZR) binding or focal decreases in the thalamus and increases in the cerebellar nuclei with no changes in cerebral cortex. We previously reported lower [¹¹C]FMZ binding in cerebral cortex of IGE patients treated with valproate (VPA) than in cerebral cortex of controls. We now report high-resolution three-dimensional [¹¹C]FMZ PET studies in a larger number of subjects using an improved method to detect differences in cBZR between IGE patients and controls and a more powerful longitudinal design to determine the functional effect of VPA.
Methods: We compared parametric images of [¹¹C]FMZ volume of distribution (FMZVD) in 10 IGE patients before and after addition of VPA and in 20 normal subjects.
Results: Mean FMZVD was significantly higher in the cerebral cortex (11%, p = 0.009), thalamus (14%, p = 0.018), and cerebellum (15%, p = 0.027) of the 10 IGE patients as compared with that of 20 normal controls. Using statistical parametric mapping, no significant areas of focal abnormality of FMZVD were detected. Addition of VPA was not associated with a significant change in mean FMZVD in any brain area.
Conclusions: Our finding of increased FMZVD in IGE could reflect microdysgenesis or a state of cortical hyperexcitability. Our data suggest that short-term VPA therapy does not affect the number of available cBZR in patients with IGE.     

Localization of type I benzodiazepine receptors to postsynaptic densities in bovine brain

The subcellular localization of central-type benzodiazepine receptors in bovine cerebral cortex, cerebellum, hippocampus, and corpus striatum has been studied. In all regions except for the corpus striatum, benzodiazepine receptors are most highly enriched in purified postsynaptic densities (PSDs) prepared by Triton X-100/hypotonic lysis of purified synaptosomal plasma membranes. Benzodiazepine receptor enrichment in PSDs varies regionally, following the order cerebellum (approximately 8.5-fold enriched relative to crude P2 membranes) greater than cerebral cortex greater than hippocampus greater than striatum (no significant enrichment); the percentage of putative type I benzodiazepine receptors in each of these brain regions follows the same rank order. In cerebral cortex, analysis of displacement of the benzodiazepine antagonist [3H]Ro-15-1788 by the type I-selective drug CL-218,872 reveals that PSDs contain type I benzodiazepine receptors exclusively; other subcellular fractions contain mixtures of type I and type II benzodiazepine receptors. Benzodiazepine receptors in PSDs resist further extraction with detergent but can be solubilized with detergent containing greater than or equal to 0.2 M NaCl. The enrichment of detergent-resistant/detergent-plus-salt extractable type I benzodiazepine receptors in PSDs might account in part for the differential solubilization of type I and type II benzodiazepine receptors from crude brain membranes previously reported. The benzodiazepine-binding protein in cerebral cortical PSDs was identified by photoaffinity labeling with [3H]flunitrazepam followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and fluorography. The PSD benzodiazepine-binding protein is identical in molecular weight to the binding protein from whole brain; partial tryptic and alpha-chymotryptic fingerprints are also very similar in PSDs and whole brain.     

Imaging of [C]-labelled RO 15-1788 binding to benzodiazepine receptors in the human brain by positron emission tomography

The benzodiazepine antagonist Ro 15-1788 was labelled with [¹¹C] and examined for possible use as ligand for PET scan studies on benzodiazepine receptors in the brain of cynomolgus monkeys and human subjects. [¹¹C] Ro 15-1788 allowed the in vivo visualization of benzodiazepine receptor binding in cerebral and cerebellar cortical areas as well as in basal brain nuclei in PET scan images. [¹¹C] Ro 15-1788 exhibited a high ratio of specific benzodiazepine receptor binding (cerebral cortex) to non-specific binding (pons) and the kinetics of binding should be satisfactory for quantitative clinical PET scan studies using [¹¹C]. The in vivo binding of [¹¹C] Ro 15-1788 in the cerebral cortex of cynomolgus monkeys and healthy human subjects was reduced by approximately 90% within 10 min after the intravenous injection of a high dose of unlabelled Ro 15-1788 (0.5 mg/kg i.v.). Different areas of the healthy human brain showed an approximately 10-fold variation in maximal [¹¹C] Ro 15-1788 binding that corresponded to the previously known distribution of benzodiazepine receptors in these regions. The highest degree of binding was obtained in the medial occipital cerebral cortex followed by frontal cortex, cerebellum, thalamus, striatum and pons. Two psychiatric patients with anxiety syndromes who had been treated for a long time with high doses of benzodiazepines had roughly the same degree of maximal [¹¹C] Ro 15-1788 binding in brain regions as the healthy subjects but the rate of decline of [¹¹C] Ro 15-1788 in the brain was higher. This indicates that there is measurable competition between [¹¹C] Ro 15-1788 binding and clinical benzodiazepine concentrations in the body fluids of psychiatric patients. The results demonstrate that [¹¹C] Ro 15-1788 should be a valuable tool for quantitative analyses of benzodiazepine receptor characteristics and receptor occupancy in the brain of patients with neuropsychiatric disorders.     

Glucose and [11C]flumazenil positron emission tomography abnormalities of thalamic nuclei in temporal lobe epilepsy

OBJECTIVES: To analyze interictal patterns of thalamic nuclei glucose metabolism and benzodiazepine receptor binding in patients with medically intractable temporal lobe epilepsy (TLE) using high-resolution 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and [11C]flumazenil (FMZ) PET. BACKGROUND: Structural and glucose metabolic abnormalities of the thalamus are considered important in the pathophysiology of TLE. The differential involvement of various thalamic nuclei in humans is not known. METHODS: Twelve patients with TLE underwent volumetric MRI, FDG and FMZ PET, and prolonged video-EEG monitoring. Normalized values and asymmetries of glucose metabolism and FMZ binding were obtained in three thalamic regions (dorsomedial nucleus [DMN], pulvinar, and lateral thalamus [LAT]) defined on MRI and copied to coregistered, partial-volume-corrected FDG and FMZ PET images. Hippocampal and amygdaloid FMZ binding asymmetries and thalamic volumes also were measured. RESULTS: The DMN showed significantly lower glucose metabolism and FMZ binding on the side of the epileptic focus. The LAT showed bilateral hypermetabolism and increased FMZ binding. There was a significant correlation between the FMZ binding asymmetries of the DMN and amygdala. The PET abnormalities were associated with a significant volume loss of the thalamus ipsilateral to the seizure focus. CONCLUSIONS: Decreased [11C]flumazenil (FMZ) binding and glucose metabolism of the dorsomedial nucleus (DMN) are common and have strong lateralization value for the seizure focus in human temporal lobe epilepsy. Decreased benzodiazepine receptor binding can be due to neuronal loss, as suggested by volume loss, but also may indicate impaired gamma-aminobutyric acid (GABA)ergic transmission in the DMN, which has strong reciprocal connections with other parts of the limbic system. Increased glucose metabolism and FMZ binding in the lateral thalamus could represent an upregulation of GABA-mediated inhibitory circuits.     

Positron emission tomography in presurgical localization of epileptic foci

The success of cortical resection for intractable epilepsy of neocortical origin is highly dependent on the accurate presurgical delineation of the regions responsible for generating seizures. In addition to EEG and structural imaging studies, functional neuroimaging such as positron emission tomography (PET) can assist lateralization and localization of epileptogenic cortical areas. In the presented studies, objectively delineated focal PET abnormalities have been analyzed in patients (mostly children) with intractable epilepsy, using two different tracers: 2-deoxy-2-[18F]fluoro-D-glucose (FDG), that measures regional brain glucose metabolism, and [11C]flumazenil (FMZ), that binds to GABAA receptors. The PET abnormalities were correlated with scalp and intracranial EEG findings, structural brain abnormalities, as well as surgical outcome data. In patients with extratemporal foci and no lesion on MRI, FMZ PET was more sensitive than FDG PET for identification of the seizure onset zone defined by intracranial EEG monitoring. In contrast, seizures commonly originated from the border of hypometabolic cortex detected by FDG PET suggesting that such areas are most likely epileptogenic, and should be addressed if subdural EEG is applied to delineate epileptic cortex. In patients with cortical lesions, perilesional cortex with decreased FMZ binding was significantly smaller than corresponding areas of glucose hypometabolism, and correlated well with spiking cortex. Extent of perilesional hypometabolism, on the other hand, showed a correlation with the life-time number of seizures suggesting a seizure-related progression of brain dysfunction. FMZ PET proved to be also very sensitive for detection of dual pathology (coexistence of an epileptogenic cortical lesion and hippocampal sclerosis). This has a major clinical importance since resection of both the cortical lesion and the atrophic hippocampus is required to achieve optimal surgical results. Finally, the author demonstrated that in patients with neocortical epilepsy, FDG PET abnormalities correctly regionalize the epileptogenic area, but their size is not related to the extent of epileptogenic tissue to be removed. In contrast, complete resection of cortex with decreased FMZ binding predicts good surgical outcome suggesting that application of FMZ PET can improve surgical results in selected patients with intractable epilepsy of neocortical origin.     

Decreased binding of [11C]flumazenil in Angelman syndrome patients with GABA(A) receptor beta3 subunit deletions

We used positron emission tomography (PET) to study brain [11C]flumazenil (FMZ) binding in four Angelman syndrome (AS) patients. Patients 1 to 3 had a maternal deletion of 15q11-q13 leading to the loss of beta3 subunit of gamma-aminobutyric acidA/benzodiazepine (GABA(A)/BZ) receptor, whereas Patient 4 had a mutation in the ubiquitin protein ligase (UBE3A) saving the beta3 subunit gene. [11C]FMZ binding potential in the frontal, parietal, hippocampal, and cerebellar regions was significantly lower in Patients 1 to 3 than in Patient 4. We propose that the 15q11-q13 deletion leads to a reduced number of GABA(A)/BZ receptors, which could partly explain the neurological deficits of the AS patients.     

The correlation between cerebral glucose metabolism and benzodiazepine receptor density in the acute vegetative state

This paper compares the results of parallel positron emission tomography (PET) studies of regional cerebral glucose metabolism with the radiotracer 18F-fluorodeoxyglucose (FDG) and benzodiazepine receptor (BZR) density by PET using the BZR ligand 11C-flumazenil (FMZ), a tracer of neuronal integrity, in nine patients with acute vegetative state (AVS, duration <1 month). Overall glucose utilization was significantly reduced in AVS in comparison with age-matched controls (global metabolic rate for glucose 26 micromol/100 g/min in AVS vs. 31 micromol/100 g/min in controls). FMZ-PET demonstrated a considerable reduction of BZR binding sites in all cortical regions that grossly corresponded to the extent of reduction of cerebral glucose metabolism assessed with FDG-PET, whilst the cerebellum was spared from neuronal loss. In controls, cortical relative flumazenil binding was not lower than five times the average white matter activity, whilst in AVS, nearly all values were below this threshold. There was no relevant overlap of the data of relative flumazenil binding between both groups. The comparison of FDG- and FMZ-PET findings in AVS demonstrates that alterations of cerebral glucose consumption do not represent mere functional inactivation, but irreversible structural brain damage.     

Positron emission tomographic studies of cerebral benzodiazepine-receptor binding in chronic alcoholics

Positron emission tomography was used with [¹¹C] flumazenil (FMZ) and [¹⁸F] fluorodeoxyglucose to study GABA type A/benzodiazepine (GABA-A/BDZ) receptors and cerebral metabolic rates for glucose (1CMRglc) in 17 male patients with severe chronic alcoholism (ALC), 8 with (ACD) and 9 without alcoholic cerebellar degeneration (non-ACD). In comparison with male normal controls of similar ages, the ALC group had significantly reduced FMZ ligand influx (K₁), FMZ distribution volume (DV), and 1CMRglc bilaterally in the medial frontal lobes, including superior frontal gyrus and rostral cingulate gyrus; the ACD group had significant reductions of K₁, DV, and ICMRglc bilaterally in the same distribution, and also in the superior cerebellar vermis; and the non-ACD group had significant reductions of K₁, DV, and ICMRglc bilaterally in the same regions of the frontal lobes but not in the superior cerebellar vermis. When compared with the non-ACD group, the ACD group had significant reductions of K₁ and DV bilaterally in the superior cerebellar vermis. The results suggest that severe chronic alcoholism damages neurons containing GABA-A/BDZ receptors in the superior medial apsects of the frontal lobes, and in patients with clinical signs of ACD, neurons containing GABA-A/BDZ receptors in the superior cerebellar vermis.     

Measurement of the 11C-flumazenil binding in the visual cortex predicts the prognosis of hemianopia

In order to determine whether functional neuroimaging studies can predict the prognosis of hemianopia due to organic cerebral disorders, we studied 8 patients (6 men and 2 women; age, 56.0+/-8.6 years) with homonymous hemianopia and compared them with 15 normal subjects (6 men and 9 women; age, 54.3+/-4.4 years). The cerebral glucose metabolism and 11C-flumazenil (FMZ) binding were measured by positron emission tomography, more than 1 month after the onset of the condition. Bilateral regions of interest (ROIs) were selected in the striate cortex, extrastriate cortex, cuneus and thalamus. Further, semi-quantitative data on the cerebral glucose metabolism and FMZ binding were obtained for the ROIs and compared with the data obtained for homologous regions in the contralateral hemisphere by calculating the ipsilateral/contralateral (I/C) ratio. The I/C ratios for the cerebral glucose metabolism and FMZ binding in the striate cortex were significantly low in the patients (glucose metabolism, P<0.0005; FMZ binding, P<0.005), while the ratio for the FMZ binding in the cuneus increased (P<0.0005). We observed that 5 patients, whose I/C ratio for the FMZ binding in the striate cortex was >0.850, experienced an improvement in their visual field, while that 3 patients with lower I/C ratios did not. The FMZ-PET may be useful to predict the prognosis of hemianopia in the chronic phase.     

11C-Flumazenil positron emission tomography demonstrates reduction of both global and local cerebral benzodiazepine receptor binding in a patient with Stiff Person Syndrome

Stiff Person Syndrome (SPS) is a rare autoimmune disorder associated with antibodies against glutamic acid decarboxylase (GAD-Ab), the key enzyme in γ-aminobutyric acid synthesis (GABA). In order to investigate the role of cerebral benzodiazepinereceptor binding in SPS, we performed [¹¹C]flumazenil (FMZ) positron emission tomography (PET) in a female patient with SPS compared to nine healthy controls. FMZ is a radioligand to the postsynaptic central benzodiazepine receptor which is co-localized with the GABA-A receptor. In the SPS patient, we found a global reduction of cortical FMZ binding. In addition, distinct local clusters of reduced radiotracer binding were observed. These data provide first in vivo evidence for a reduced postsynaptic GABA-A receptor availability which may reflect the loss of GABAergic neuronal inhibition in SPS.     

Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography.

The in vivo kinetic behavior of [11C]flumazenil ([11C]FMZ), a non-subtype-specific central benzodiazepine antagonist, is characterized using compartmental analysis with the aim of producing an optimized data acquisition protocol and tracer kinetic model configuration for the assessment of [11C]FMZ binding to benzodiazepine receptors (BZRs) in human brain. The approach presented is simple, requiring only a single radioligand injection. Dynamic positron emission tomography data were acquired on 18 normal volunteers using a 60- to 90-min sequence of scans and were analyzed with model configurations that included a three-compartment, four-parameter model, a three-compartment, three-parameter model, with a fixed value for free plus nonspecific binding; and a two-compartment, two-parameter model. Statistical analysis indicated that a four-parameter model did not yield significantly better fits than a three-parameter model. Goodness of fit was improved for three- versus two-parameter configurations in regions with low receptor density, but not in regions with moderate to high receptor density. Thus, a two-compartment, two-parameter configuration was found to adequately describe the kinetic behavior of [11C]FMZ in human brain, with stable estimates of the model parameters obtainable from as little as 20-30 min of data. Pixel-by-pixel analysis yields functional images of transport rate (K1) and ligand distribution volume (DV"), and thus provides independent estimates of ligand delivery and BZR binding.     

Neurotransmitter receptor localizations: Brain lesion induced alterations in benzodiazepine, GABA, β-adrenergic and histamine H1-receptor binding

Selective neuronal lesions have been utilized in efforts to localize binding sites in rat brain for β-adrenergic, γ-aminobutyric acid (GABA), histamine H₁ and benzodiazepine receptors. The various receptors respond differentially to lesions both in extent of change and in time course. After kainate lesions in the corpus striatum, benzodiazepine receptors are depleted up to 45% at 45–78 days but are unaffected after 7 days. By contrast striatal GABA receptors are increased at 7 days but depleted at later times. Thus both striatal benzodiazepine and GABA receptors appear to be associated at least in part with intrinsic neurons.In the cerebellum both benzodiazepine and GABA receptors are reduced in kainate treated rats and in Nervous mice, mutants which lack Purkinje cells. The most pronounced dissimilarity between benzodiazepine and GABA receptors occurs in Weaver mice, which selectively lack granule cells and display a 60% reduction in GABA receptors but a 40% augmentation in benzodiazepine receptors. A major portion of cerebellar GABA receptors, therefore, appear to be localized to granule cells.Striatal β-adrenergic receptors are reduced following intrastriatal kainate injections but are unaffected by cerebral cortex ablation, suggesting an association with intrinsic neurons but not with axon terminals of the corticostriate pathway. While intraventricular injections of 6-hydroxydopamine enhance [³H]dihydroalprenolol binding to β-adrenergic receptors in the cerebral cortex and hippocampus, such binding is not augmented in the corpus striatum, brain stem, midbrain or thalamus-hypothalamus by this treatment. Moreover, medial forebrain bundle lesions, which destroy ascending adrenergic neurons, fail to alter cerebral cortical or striatal β-adrenergic receptors. Thus denervation-elicited increase in β-adrenergic receptors vary with brain region and the type of denervating lesion.Histamine H₁-receptors are the most resistant of all to neuronal lesions. In the corpus striatum [³H]mepyramine binding is unaffected by cerebral cortex ablation, nigral injections of 6-hydroxydopamine or brain stem hemisection. In the hippocampus, medial forebrain bundle lesions, intrahippocampal kainate injection, and fimbria and fornix transection largely fail to alter [³H]mepyramine binding. Accordingly, a major portion of these receptors may be associated with nonneuronal elements such as glia or blood vessels.     

In vivo [11C] flumazenil-PET correlates with ex vivo [3H] flumazenil autoradiography in hippocampal sclerosis

By using [¹¹C]flumazenil-positron emission tomography ([¹¹C]FMZ-PET), we have previously shown that reductions of central benzodiazepine receptors (cBZRs) are restricted to the hippocampus in mesial temporal lobe epilepsy (mTLE) caused by unilateral hippocampal sclerosis (HS). Receptor autoradiographic studies on resected hippocampal specimens from the same patients demonstrated loss of cBZRs that was over and above loss of neurons in the CA1 subregion. Here, we report the first direct comparison of in vivo cBZR binding with [¹¹C]FMZ-PET and ex vivo binding using [³H]FMZ autoradiography. We applied a magnetic resonance imaging-based method for partial volume effect correction to the PET images of [¹¹C]FMZ volume of distribution ([¹¹C]FMZ V_d) obtained in 10 patients with refractory mTLE due to unilateral, hisologically verifed HS. Saturation autoradiography was performed on the hippocampal specimens obtained from the same patients, allowing calculation of receptor availability ([³H]FMZ B_max). After correction for partial volume effect, [¹¹C]FMZ V_d in the body of epileptogenic hippocampus was reduced by a mean of 42.1% compred with normal controls. [³H]FMZ b_max, determined autoradiographically from the same hippocampal tissue, was reduced by a mean of 42.7% compared with control hippocampi. Absolute in vivo and ex vivo measurements of cBZR binding for the body of the hippocampus were significantly correlated in each individual. Our study demonstrates that reduction of available cBZR on remaining neuron in HS can be reliably detected in vivo by using [¹¹C]FMZ-PET after correction for partial volume effect.     

Adrenalectomy prevents the stress-induced decrease in in vitro [H]Ro15-1788 binding to GABAA benzodiazepine receptors in the mouse

The effect of a single or repeated swim stress on in vivo benzodiazepine receptor binding to various brain regions in adrenalectomized and sham-operated (control) mice was assessed using the benzodiazepine receptor antagonist, [³H]Ro15-1788. In sham-operated mice the binding of [³H]Ro15-1788 to benzodiazepine receptors was reduced in the hippocampus and hypothalamus (single or repeated stress) and cerebral cortex (repeated swim stress) compared to non-stressed mice. In contrast, no alterations in [³H]Ro15-1788 binding were observed in any brain region in adrenalectomized mice after either single or repeated swim stress. These data suggest that an intact hypothalamic-pituitary-adrenal axis is required for the stress-induced decrease in benzodiazepine receptor occupancy measured using the in vivo binding method.     

Benzodiazepine receptors in human brain: characterization, subcellular localization and solubilization

1. Benzodiazepine receptors have been characterized in human brain mainly using [3H]-Ro 15-1788 and [3H]-flunitrazepam. Both ligands present a very high affinity for the receptor sites (Kd values of 0.56 and 1.53 nM respectively). 2. GABA enhanced the affinity of [3H]-flunitrazepam and [3H]-diazepam, but not that of [3H]-Ro 15-1788 and [3H]-methyl-beta-carboline 3-carboxylate for their specific binding sites as well in cerebral as in cerebellar human cortex. 3. Subcellular distribution of the benzodiazepine receptors revealed a main synaptosomal localization in human cerebral cortex, cerebellum and striatum. 4. Solubilized benzodiazepine receptors were obtained using 0.5% sodium deoxycholate and were characterized with [3H]-Ro 15-1788. The solubilized receptors are still coupled to GABA receptors since the [3H]-flunitrazepam specific binding was enhanced in the presence of micromolar concentrations of GABA.     

Huntington's disease: increased number and altered regulation of benzodiazepine receptor complexes in frontal cerebral cortex

The properties of benzodiazepine receptors in samples of six areas of cerebral cortex from patients and controls matched with respect to age, sex, and postmortem delay have been studied by in vitro radioligand binding techniques. A statistically significant 30 to 40% increase in the number of benzodiazepine and allosterically linked GABA-A receptors is observed in the midfrontal cortex (A9/A10), but in no other cortical region examined. The degree of enhancement of [3H]diazepam binding by a given dose of GABA or pentobarbital is significantly reduced in Huntington's disease midfrontal cortex. As in the case of receptor number changes, other cortical regions examined show less prominent changes in regulation of benzodiazepine binding by GABA or pentobarbital. Direct identification of the benzodiazepine binding subunit by photoaffinity labeling with [3H]flunitrazepam reveals a single species of apparent molecular weight 51 kD in patients and controls, suggesting that gross changes in structure of the benzodiazepine binding subunit do not account for the observed alterations in benzodiazepine receptor regulation.     

Impaired benzodiazepine receptor binding in peri-lesional cortex of patients with symptomatic epilepsies studied by [(11)C]-flumazenil PET.

Individual benzodiazepine receptor (BZR) binding of peri-lesional cortex was investigated in symptomatic epilepsies. Eleven patients aged 19-44 years were studied whose diagnosis was established by medical history, clinical, electroencephalographic, and magnetic resonance imaging (MRI) findings. Three-dimensional [11C]-flumazenil (FMZ) positron emission tomography and MRI scans were obtained and coregistered. Lesions (five low-grade brain tumours, one AV malformation, one cavernoma, one cystic lesion of unknown aetiology, one traumatic brain injury, one post-operative and one post-haemorrhagic defect) were outlined on individual MRI scans. Adjacent to those lesions, and in homologous contralateral structures, FMZ binding was analysed in four pairs of cortical 9 x 9-mm regions of interest (ROIs) placed on transaxial and coronal slices, respectively, as well as in the lesion volume and its mirror region. Percentage asymmetry ratios were calculated and those at or outside the 90-110% range were operationally defined significant. Peri-lesional FMZ binding asymmetries ranged from 70 to 125%, lesional asymmetries from 38 to 82%. Only one patient showed no significant change, whilst nine exhibited significant reductions of FMZ binding in at least one ROI (3 x 1, 4 x 2, 1 x 3, 1 x 4), and significant increases were observed in two ROIs of another patient. Therefore, peri-lesional disturbances of BZR binding are common but variable in location. Because a close correlation between regional decreases in FMZ binding and spiking activity was recently demonstrated in neocortical epilepsies, abnormal peri-lesional FMZ binding may bear some relation to the mechanisms of epileptogenesis in symptomatic epilepsies.     

Electroclinical correlates of flumazenil and fluorodeoxyglucose PET abnormalities in lesional epilepsy

OBJECTIVE: To analyze the clinical utility of [11C]flumazenil (FMZ) PET to detect perilesional and remote cortical areas of abnormal benzodiazepine receptor binding in relation to MRI, 2-deoxy-2-[18F]fluoro-d-glucose (FDG) PET, and electrocorticographic (ECoG) findings as well as clinical characteristics of the epilepsy in epileptic patients with brain lesion. BACKGROUND: The success of resective surgery in patients with medically intractable epilepsy and brain lesion depends not only on removal of the lesion itself but also on the reliable presurgical delineation of the epileptic cortex that commonly extends beyond it. PET could provide a noninvasive identification of such epileptogenic areas. METHODS: Seventeen patients underwent high resolution MRI, FDG and FMZ PET, and presurgical EEG evaluation, including chronic intracranial ECoG monitoring or intraoperative ECoG. Regional cortical FDG/FMZ PET abnormalities were defined on partial volume-corrected PET images using an objective method based on a semiautomated definition of areas with abnormal asymmetry. Structural lesions were defined on coregistered MRI. The marked PET abnormalities visualized on three-dimensional cortical surface were compared with each other, to the extent of MRI-defined lesion, as well as to ECoG findings. RESULTS: The mean surface extent of FMZ PET abnormalities was significantly larger than the corresponding structural lesions, but it was significantly smaller than areas of glucose hypometabolism. The size of perilesional FDG PET abnormalities showed a correlation with the lifetime number of seizures (r = 0.93, p = 0.001). The extent of perilesional FMZ PET abnormalities was independent of the seizure number and showed an excellent correspondence with spiking cortex, the resection of which resulted in seizure-free outcome in all but one operated patient. Remote FMZ PET abnormalities (n = 6) were associated with early age at seizure onset (p = 0.048) and appeared in ipsilateral synaptically connected regions from the lesion area. CONCLUSIONS: Three-dimensional surface-rendered FMZ PET is able to delineate perilesional epileptic cortex, and it may be especially useful to localize such areas in patients with extensive perilesional glucose hypometabolism associated with a large number of seizures. Remote FMZ PET abnormalities in patients with early onset and long duration of epilepsy might represent secondary epileptogenesis, but this requires further study.     

Increase in central and peripheral benzodiazepine receptors following surgery

[3H]Flunitrazepam, [3H]PK 11195, [3H]quinuclidinyl benzilate (QNB) and monoamine oxidase (MAO) A and B activity were measured in male rats 1, 3 and 7 days following laparotomy. The surgery resulted in the up-regulation of central benzodiazepine (BZ) receptors in cerebral cortex and of peripheral BZ binding sites in brain and kidney on the first and third days after operation. This increase was followed by a decrease to normal range 7 days after the surgical procedure. [3H]QNB binding to muscarinic receptors in the cerebral cortex as well as MAO A and B activity in rat cerebral cortex and kidney were not affected by the surgical manipulation. The modulatory effect of surgery on BZ receptors corresponds to stages of the healing process in surgical wounds.