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.     

Similarity and robustness of PET and SPECT binding parameters for benzodiazepine receptors.

The single photon emission computed tomography (SPECT) radiotracer [123I]iomazenil is used to assess benzodiazepine receptor binding parameters. These measurements are relative indices of benzodiazepine receptor concentration (B'max). To evaluate the ability of such indices in accurately accessing the B'max the authors compared them with absolute values of B'max, measured using positron emission tomography (PET). The authors performed SPECT, PET, and magnetic resonance imaging (MRI) studies on a group composed of seven subjects. For SPECT studies, the authors administered a single injection of [123I]iomazenil and estimated the total and specific distribution volumes (DV(T SPECT), DV(S SPECT)) and the binding potential (BP) using unconstrained (BP(SPECT)) and constrained (BP(C SPECT)) compartmental models. For PET studies, the authors used a multiinjection approach with [11C]flumazenil and unlabeled flumazenil to estimate absolute values of receptor concentration, B'max, and some other binding parameters. The authors studied the correlation of different binding parameters with B'max. To study the robustness of the binding parameter measurements at the pixel level, the authors applied a wavelet-based filter to improve signal-to-noise ratio of time-concentration curves, and the calculated kinetic parameters were used to build up parametric images. For PET data, the B'max and the DV(PET) were highly correlated (r = 0.988). This confirms that it is possible to use the DV(PET) to access benzodiazepine receptor density. For SPECT data, the correlation between DV(SPECT) estimated using a two- and three-compartment model was also high (r = 0.999). The DV(T SPECT) and BP(C SPECT) parameters estimated with a constrained three-compartment model or the DV(T'SPECT) parameter estimated with a two-compartment model were also highly correlated to the B'max parameter estimated with PET. Finally, the robustness of the binding parameters allowed the authors to build pixel-by-pixel parametric images using SPECT data.     

PET measures of benzodiazepine receptors in progressive supranuclear palsy

OBJECTIVE: To evaluate the integrity of neurons containing benzodiazepine receptors in metabolically affected regions of the brain in patients with clinically diagnosed progressive supranuclear palsy (PSP). METHODS: The cerebral distribution of [11C]flumazenil (FMZ), a ligand that binds to the gamma-aminobutyric acid A (GABAA) receptor, and [18F]fluorodeoxyglucose (FDG), a measure of local cerebral glucose metabolism, was determined with PET in 12 patients with PSP and 10 normal control subjects. Tracer kinetic analysis was applied to quantify data and analysis was performed using three-dimensional stereotactic surface projections and stereotactically determined volumes of interest. RESULTS: There was a global reduction in FMZ binding of 13%, with a reduction in the anterior cingulate gyrus of 20% (p = 0.004), where glucose metabolic rates also showed the greatest reduction. CONCLUSIONS: PSP causes loss of benzodiazepine receptors in the cerebral cortex. Consistent with postmortem studies, the authors did not find significant changes in FMZ binding in subcortical nuclei that exhibit the most pathologic change. This study suggests that both loss of intrinsic neurons containing benzodiazepine receptors and deafferentation of the cerebral cortex from distant brain regions contribute to cerebral cortical hypometabolism in PSP.     

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.     

Relationship between EEG and positron emission tomography abnormalities in clinical epilepsy.

Positron emission tomography (PET) is a relatively noninvasive neuroimaging method by means of which a large variety of human brain functions can be assessed. Localized neurochemical abnormalities detected by PET were found in patients with partial epilepsy and suggested the use of this modality for localizing epileptogenic regions of the brain. The clinical usefulness of PET is determined by its sensitivity and specificity for identifying epileptogenic areas as defined by ictal surface and intracranial EEG recordings. The findings obtained from comparative EEG and glucose PET data are reviewed with special emphasis on patients undergoing presurgical evaluation because of medically intractable temporal and extratemporal lobe epilepsy. The utility of glucose PET studies for identifying regions of seizure onset is presented, and the limited specificity of glucose metabolic abnormalities for the detection of various EEG patterns in clinical epilepsy is discussed. The authors review the available intracranial EEG and PET comparisons using [11C]flumazenil (FMZ) PET, a tracer for the assessment of tau-amino-butyric acid/benzodiazepine receptor function. They also summarize their experience with [11C]flumazenil PET in identifying cortical regions that show various ictal and interictal cortical EEG abnormalities in patients with extratemporal seizure origin. Finally, the authors demonstrate that further development of new PET tracers, such as alpha-[11C]methyl-L-tryptophan, is feasible and clinically useful and may increase the number of patients in whom PET studies can replace invasive EEG monitoring.     

Postnatal maturation of human GABAA receptors measured with positron emission tomography

During brain development in nonhuman primates, there are large changes in GABAA receptor binding and subunit expression. An understanding of human GABAA receptor ontogeny is highly relevant in elucidating the pathophysiology of neurodevelopmental disorders in which GABAergic mechanisms play a role as well as in understanding differences that occur during development in the pharmacology of drugs acting on this system. We have measured age-related changes in the brain distribution of the GABAA receptor complex in vivo using positron emission tomography (PET) in epileptic children under evaluation for surgical treatment. PET imaging was performed using the tracer [11C]flumazenil (FMZ), a ligand that binds to alpha subunits of the GABAA receptor. FMZ binding was quantified using a two-compartment model yielding values for the volume of distribution (VD) of the tracer in tissue. All brain regions studied showed the highest value for FMZ VD at the youngest age measured (2 years), and the values then decreased exponentially with age. Medial temporal lobe structures, primary visual cortex, and thalamus showed larger differences between values for age 2 years and adults (approximately 50% decrease) than did basal ganglia, cerebellum, and other cortical regions (25-40% decreases). Furthermore, subcortical regions reached adult values earlier (14-17.5 years) than did cortical regions (18-22 years). The ontogeny data of FMZ VD from children may contribute to understanding regional differences in synaptic plasticity as well as improve rational therapeutic use of drugs acting at the GABAA receptor in the pediatric population.     

Uptake and utilization of [beta-11C]5-hydroxytryptophan in human brain studied by positron emission tomography.

The immediate precursor in the serotonin synthetic route, 5-hydroxytryptophan (5-HTP), labeled with 11C in the beta position, has become available for studies using positron emission tomography (PET) to examine serotonin formation in human brain. Normalized uptake and intracerebral utilization of tracer amounts of [beta-11C]5-HTP were studied twice in six healthy male volunteers, three of them before and after pharmacological pretreatments. The kinetic model defines regional utilization as the relative regional radioactivity accumulation rate. Repeat studies showed good reproducibility. Pretreatments with benserazide, p-chlorophenylalanine (PCPA), and unlabeled 5-HTP all significantly increased uptake of [beta-11C]5-HTP. The utilization rates in both striatal and frontal cortex were higher than those in the surrounding brain, indicating that PET studies using [beta-11C]5-HTP as a ligand quantitate selective processes in the utilization of 5-HTP. We tentatively interpret uptake and utilization as a measure of brain serotonin turnover, the selectivity of which was shown by pharmacological interventions in vivo.     

Age-related changes in muscarinic cholinergic receptors in the living brain: a PET study using N-[11C]methyl-4-piperidyl benzilate combined with cerebral blood flow measurement in conscious monkeys

The effects of changes in regional cerebral blood flow (rCBF) with aging on muscarinic cholinergic receptor binding were evaluated with [15O]H(2)O and N-[11C]methyl-4-piperidyl benzilate (4-MPB) in the living brains of young (5.9+/-1.8 years old) and aged (19.0+/-3.3 years old) monkeys (Macaca mulatta) in the conscious state using high-resolution positron emission tomography (PET). For quantitative analysis of receptor binding in vivo with [11C]4-MPB, metabolite-corrected arterial plasma radioactivity curves were obtained as an input function into the brain, and graphical Patlak plot analysis was applied. In addition, two-compartment model analysis using the radioactivity curve in the cerebellum as an input function (reference analysis) was also applied to determine the distribution volume (DV=K(1)/k(2)') for [11C]4-MPB. With metabolite-corrected arterial input, Patlak plot analysis of [11C]4-MPB indicated a regionally specific decrease in muscarinic cholinergic receptor binding in vivo in the frontal and temporal cortices as well as the striatum in aged compared with young animals, showing no correlation with the degree of reduced rCBF. In contrast, on the reference analysis with cerebellar input of [11C]4-MPB, all regions assayed except the pons showed a significant age-related decrease of DV, and the degree of reduction of DV was correlated with that of rCBF. These results demonstrated the usefulness of kinetic analysis of [11C]4-MPB with metabolite-corrected arterial input, not with reference region's input, as an indicator of the aging process of cortical muscarinic cholinergic receptors in vivo measured by PET with less blood flow dependency.     

Positron emission tomography measures of benzodiazepine receptors in Huntington's disease

We performed positron emission tomographic (PET) measurements of the regional distribution volume of benzodiazepine receptors and regional glucose metabolism in 6 drug-free patients with early Huntington's disease following injection of [¹¹C] flumazenil, a nonsubtype selective central benzodiazepine receptor antagonist, and ¹⁸F-2-fluoro-2-deoxy-D -glucose, respectively. Flumazenil data were analyzed with a recently developed two-compartment, two-parameter tracer kinetic model. Benzodiazepine receptor density is related to distribution volume for flumazenil. In comparison with a group of healthy volunteers, benzodiazepine receptor density was significantly decreased in the caudate nucleus. Glucose metabolism was significantly reduced not only in the caudate nucleus but also in the putamen and thalamus. The changes in benzodiazepine receptor density observed in the caudate nucleus are commensurate with data obtained in postmortem autoradiographic studies of receptor density. Based on such postmortem studies we also anticipated changes in putamen and thalamic benzodiazepine receptor density. However, relatively little is known on receptor changes in early Huntington's disease, because the autoradiographic data available were obtained mostly in patients with advanced disease. The decreased glucose metabolism in the caudate and putamen agrees well with previously published results of PET studies, whereas metabolic impairment of the thalamus has not yet been described in Huntington's disease. The present study suggests that regional metabolism and γ-aminobutyric acid (GABA)-benzodiazepine receptor changes in subcortical structures of patients with early Huntington's disease do not occur with the same time course: Caudate benzodiazepine receptor density is already severely impaired when other subcortical structures reveal only minor abnormalities. Impairment of neuronal metabolism seems to predate GABA/benzodiazepine receptor changes since the putamen and thalamus demonstrate metabolic impairment without detectable loss of benzodiazepine receptor density.     

[11C]PBR28 radiotracer kinetics are not driven by alterations in cerebral blood flow

The positron emission tomography (PET) radiotracer [¹¹C]PBR28 has been increasingly used to image the translocator protein (TSPO) as a marker of neuroinflammation in a variety of brain disorders. Interrelatedly, similar clinical populations can also exhibit altered brain perfusion, as has been shown using arterial spin labelling in magnetic resonance imaging (MRI) studies. Hence, an unsolved debate has revolved around whether changes in perfusion could alter delivery, uptake, or washout of the radiotracer [¹¹C]PBR28, and thereby influence outcome measures that affect interpretation of TSPO upregulation. In this simultaneous PET/MRI study, we demonstrate that [¹¹C]PBR28 signal elevations in chronic low back pain patients are not accompanied, in the same regions, by increases in cerebral blood flow (CBF) compared to healthy controls, and that areas of marginal hypoperfusion are not accompanied by decreases in [¹¹C]PBR28 signal. In non-human primates, we show that hypercapnia-induced increases in CBF during radiotracer delivery or washout do not alter [¹¹C]PBR28 outcome measures. The combined results from two methodologically distinct experiments provide support from human data and direct experimental evidence from non-human primates that changes in CBF do not influence outcome measures reported by [¹¹C]PBR28 PET imaging studies and corresponding interpretations of the biological meaning of TSPO upregulation.     

Development of a tracer kinetic plasma input model for (R)-[11C]PK11195 brain studies.

(R)-[(11)C]PK11195 ([1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl]-3-isoquinoline carboxamide) is a ligand for the peripheral benzodiazepine receptor, which, in the brain, is mainly expressed on activated microglia. Using both clinical studies and Monte Carlo simulations, the aim of this study was to determine which tracer kinetic plasma input model best describes (R)-[(11)C]PK11195 kinetics. Dynamic positron emission tomography (PET) scans were performed on 13 subjects while radioactivity in arterial blood was monitored online. Discrete blood samples were taken to generate a metabolite corrected plasma input function. One-tissue, two-tissue irreversible, and two-tissue reversible compartment models, with and without fixing K(1)/k(2) ratio, k(4) or blood volume to whole cortex values, were fitted to the data. The effects of fixing parameters to incorrect values were investigated by varying them over a physiologic range and determining accuracy and reproducibility of binding potential and volume of distribution using Monte Carlo simulations. Clinical data showed that a two-tissue reversible compartment model was optimal for analyzing (R)-[(11)C]PK11195 PET brain studies. Simulations showed that fixing the K(1)/k(2) ratio of this model provided the optimal trade-off between accuracy and reproducibility. It was concluded that a two-tissue reversible compartment model with K(1)/k(2) fixed to whole cortex value is optimal for analyzing (R)-[(11)C]PK11195 PET brain studies.     

Altered in vitro and in vivo flumazenil binding in human epileptogenic neocortex.

In vitro and in vivo parameters of flumazenil (FMZ) binding were measured in spiking and nonspiking neocortex identified by intraoperative electrocorticography in epileptic patients who underwent cortical resection for seizure control. In vitro measures of receptor affinity (K(D)), number (Bmax) and laminar distribution for [3H]-FMZ binding in the epileptic focus (n = 38) were compared to nonspiking cortex from a subgroup of the patients (n = 12) and to tissue obtained from trauma patients (n = 5). The in vitro binding parameters were compared to in vivo [11C]-FMZ binding measured with positron emission tomography (PET) (n = 19). The Bmax was higher in the 38 spiking tissues as compared to the 12 nonspiking tissues (P = .012). Paired comparison of spiking versus nonspiking binding in the 12 patients from whom nonspiking tissue was available showed increases in both K(D) (P = .037) and Bmax (P = .0047) in spiking cortex. A positive correlation was found between K(D) and Bmax values for 38 patients (r = 0.55, P < .0001), the magnitude of the K(D) increase being twice that of the Bmax increase. In addition, there was a significant correlation between the asymmetry indices of the in vivo FMZ binding on PET and in vitro K(D) of spiking cortex (n = 19, r = 0.52, P = .02). The laminar distribution of [3H]-FMZ showed increased FMZ binding in cortical layers V-VI in spiking cortex compared to nonspiking and control cortex. The increased receptor number in spiking cortical layers V-VI may be a compensatory mechanism to decreased GABAergic input. The increased Bmax in spiking cortex was accompanied by a larger decrease in the affinity of FMZ for the receptor suggesting that decreased FMZ binding in the epileptic focus measured with PET is due to a decrease in the affinity of the tracer for the receptor.     

Positron emission tomographic measurement of cerebral blood flow and permeability-surface area product of water using [15O]water and [11C]butanol

We have previously adapted Kety's tissue autoradiographic method for measuring regional CBF in laboratory animals to the measurement of CBF in humans with positron emission tomography (PET) and H2(15)O. Because this model assumes diffusion equilibrium between tissue and venous blood, the use of a diffusion-limited tracer, such as H2(15)O, may lead to an underestimation of CBF. We therefore validated the use of [11C]butanol as an alternative freely diffusible tracer for PET. We then used it in humans to determine the underestimation of CBF that occurs with H2(15)O, and thereby were able to calculate the extraction Ew and permeability-surface area product PSw of H2(15)O. Measurements of the permeability of rhesus monkey brain to [11C]butanol, obtained by means of an intracarotid injection, external detection technique, demonstrated that this tracer is freely diffusible up to a CBF of at least 170 ml/min-100 g. CBF measured in baboons with the PET autoradiographic method and [11C]butanol was then compared with CBF measured in the same animals with a standard residue detection method. An excellent correspondence was obtained between both of these measurements. Finally, paired PET measurements of CBF were made with both H2(15)O and [11C]butanol in 17 normal human subjects. Average global CBF was significantly greater when measured with [11C]butanol (53.1 ml/min-100 g) than with H2(15)O (44.4 ml/min-100 g). Average global Ew was 0.84 and global PSw was 104 ml/min-100 g. Regional measurements showed a linear relationship between local PSw and CBF, while Ew was relatively uniform throughout the brain. Simulations were used to determine the potential error associated with the use of an incorrect value for the brain-blood partition coefficient for [11C]butanol and to calculate the effect of tissue heterogeneity and errors in flow measurement on the calculation of PSw.     

Intracranial EEG versus flumazenil and glucose PET in children with extratemporal lobe epilepsy

OBJECTIVE: To compare abnormalities determined in 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and [11C]flumazenil (FMZ) PET images with intracranial EEG data in patients with extratemporal lobe epilepsy. BACKGROUND: Although PET studies with FDG and FMZ are being used clinically to localize epileptogenic regions in patients with refractory epilepsy, the electrophysiologic significance of the identified PET abnormalities remains poorly understood. METHODS: We studied 10 patients, mostly children (4 boys, 6 girls, aged 2 to 19 years; mean age, 11 years), who underwent FDG and FMZ PET scans, intracranial EEG monitoring, and cortical resection for intractable epilepsy. EEG electrode positions relative to the brain surface were determined from MRI image volumes. Cortical areas of abnormal glucose metabolism or FMZ binding were determined objectively based on asymmetry measures derived from homotopic cortical areas at three asymmetry thresholds. PET data were then coregistered with the MRI and overlaid on the MRI surface. A receiver operating characteristics (ROC) analysis was performed to determine the specificity and sensitivity of PET-defined abnormalities against the gold standard of intracranial EEG data. RESULTS: FMZ PET detected at least part of the seizure onset zone in all subjects, whereas FDG PET failed to detect the seizure onset region in two of 10 patients. The area under the ROC curves was higher for FMZ than FDG PET for both seizure onset (p = 0.01) and frequent interictal spiking (p = 0.04). Both FMZ and FDG PET showed poor performance for detection of rapid seizure spread (area under the ROC curve not significantly different from 0.5). CONCLUSIONS: [11C]flumazenil (FMZ) PET is significantly more sensitive than 2-deoxy-2-[18F]fluoro-D-glucose (FDG) PET for the detection of cortical regions of seizure onset and frequent spiking in patients with extratemporal lobe epilepsy, whereas both FDG and FMZ PET show low sensitivity in the detection of cortical areas of rapid seizure spread. The application of PET, in particular FMZ PET, in guiding subdural electrode placement in refractory extratemporal lobe epilepsy will enhance coverage of the epileptogenic zone.     

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.     

PET imaging of human gliomas with ligands for the peripheral benzodiazepine binding site

Human gliomas were imaged in vivo using ligands for the peripheral-type benzodiazepine binding site (or omega 3 binding site) and positron emission tomography (PET). Although gliomas have a high density of the peripheral-type benzodiazepine binding site, PET scans with a selective ligand for this site, [11C] Ro5-4864, failed to demonstrate higher radioactivity levels in human gliomas than in brain. In vitro studies of surgically removed specimens of human glioma demonstrated little binding of Ro5-4864 but high levels of binding of another selective ligand, PK 11195. Scans with [11C]PK 11195 demonstrated increased radioactivity in glioma compared to brain in 8 of 10 patients. Radioactivity in tumor and the ratios of radioactivity in tumor to that in remote gray and in white matter correlated significantly with the specific activity of [11C]PK 11195, suggesting that accumulation represents saturable high-affinity binding. We conclude that the PK 11195 manifests greater binding than Ro5-4864 to the peripheral-type benzodiazepine binding site on human gliomas and that human gliomas can be successfully imaged using [11C]PK 11195 and PET.     

Multiparametric assessment of acute and subacute ischemic neuronal damage: A small animal positron emission tomography study with rat photochemically induced thrombosis model

We evaluated sequential changes in rat brain function up to 14 days after focal ischemic insult with a small animal positron emission tomography (PET). Unilateral focal ischemic cerebral damage was induced by left middle cerebral artery occlusion with a photochemically induced thrombosis (PIT) method. PET scans were conducted with [¹¹C](R)‐PK11195 ([¹¹C](R)‐PK) for peripheral benzodiazepine receptor (PBR), [¹¹C]flumazenil ([¹¹C]FMZ) for central benzodiazepine receptor (CBR), and [¹⁸F]fluoro‐2‐deoxy‐D ‐glucose ([¹⁸F]FDG) for glucose metabolism at before (as “Normal”) and after PIT. At 1 and 3 days after PIT, [¹⁸F]FDG indicated lower uptake in the infarct area. Interestingly, unexpectedly high‐[¹⁸F]FDG uptake was observed in the peri‐infarct area surrounding the infarct area at day 7. The high‐[¹⁸F]FDG uptake region completely overlapped with the high‐[¹¹C](R)‐PK uptake region at day 7, which resulted in the underestimation of neuronal damage. Immunohistochemical data also suggested that the high‐[¹⁸F]FDG uptake peak at day 7 was caused by inflammation including microglial cell activation. In contrast, imaging with [¹¹C]FMZ indicated cortical neuronal damage on days 7 and 14 without any disturbance by microglial formation. These results indicated that [¹⁸F]FDG might not be a suitable ligand for ischemic neuronal damage detection from acute to subacute phases. Synapse, 2010. © 2010 Wiley‐Liss, Inc.     

Clinical utility of 11C-flumazenil positron emission tomography in intractable temporal lobe epilepsy

BACKGROUND: 11C-flumazenil (FMZ) positron emission tomography (PET) is a new entrant into the armamentarium for pre-surgical evaluation of patients with intractable temporal lobe epilepsy (TLE). AIMS: To analyze the clinical utility of FMZ PET to detect lesional and remote cortical areas of abnormal benzodiazepine receptor binding in relation to magnetic resonance imaging (MRI), 2-Deoxy-2 [18F] fluoro-D-glucose, (18F FDG) PET, electrophysiological findings and semiology of epilepsy in patients with intractable TLE. MATERIALS AND METHODS: Patients underwent a high resolution MRI, prolonged Video-EEG monitoring before 18F FDG and 11C FMZ PET studies. Regional cortical FMZ PET abnormalities were defined on co-registered PET images using an objective method based on definition of areas of abnormal asymmetry (asymmetry index {AI}>10%). SETTINGS AND DESIGN: Prospective. STATISTICAL ANALYSIS: Student's "t" test. RESULTS: Twenty patients (Mean age: 35.2 years [20-51]; M:F=12:8) completed the study. Mean age at seizure onset was 10.3 years (birth-38 years); mean duration, 23.9 years (6-50 years). Concordance with the MRI lesion was seen in 10 patients (nine with hippocampal sclerosis and one with tuberous sclerosis). In the other 10, with either normal or ambiguous MRI findings, FMZ and FDG uptake were abnormal in all, concordant with the electrophysiological localization of the epileptic foci. Remote FMZ PET abnormalities (n=18) were associated with early age of seizure onset (P=0.005) and long duration of epilepsy (P=0.01). CONCLUSIONS: FMZ-binding asymmetry is a sensitive method to detect regions of epileptic foci in patients with intractable TLE.     

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.     

Quantitative analysis for estimating binding potential of the peripheral benzodiazepine receptor with [(11)C]DAA1106.

[(11)C]DAA1106 is a potent and selective ligand for the peripheral benzodiazepine receptor (PBR) with high affinity. It has been reported that the density of PBR is related to brain damage, so a reliable tracer method for the evaluation of PBR would be of use. We evaluated a quantification method of [(11)C]DAA1106 binding in simulated data and human brain data. In the simulation study, the reliability of parameters estimated from the nonlinear least-squares (NLS) method, graphical analysis (GA), and multilinear analysis (MA) was evaluated. In GA, variation of the estimated distribution volume (DV) was small. However, DV was underestimated as noise increased. In MA, bias was smaller, and variation of the estimated DV was larger than in GA. In NLS, although variation was larger than in GA, it was small enough in regions of interest analysis, and not only DV but also binding potential (BP), determined from the k(3)/k(4) without any constraint, could be estimated. The variation of BP estimated with NLS became larger as k(3) or k(4) became smaller. In human studies with normal volunteers, regions of interest were drawn on several brain regions, BP was calculated by NLS, and DV was also estimated by NLS, GA, and MA. As a result, DVs estimated with each method were well correlated. However, there was no correlation between BP with NLS and DV with NLS, GA, and MA, because of the variation of K(1)/k(2) between individuals. In conclusion, BP is estimated most reliably by NLS with the two-tissue compartment model.