Positron Emission Tomography with [11C]Deuterium-Deprenyl in Temporal Lobe Epilepsy

Summary: We performed positron emission tomography (PET) with [¹¹C]deuterium-deprenyl in 9 patients with temporal lobe epilepsy (TLE) undergoing evaluation for possible epilepsy surgery. Seven patients had unilateral and 2 had bilateral mesiotemporal epileptic foci based on the preoperative investigation including ictal EEG discharges and PET with 2-[¹⁸F]fluoro-2-deoxyglucose (FDG). Deprenyl is an irreversible inhibitor of mono-amine oxidase type B (MAO-B) with a very high affinity for the enzyme. In the brain, MAO-B is preferentially located in astrocytes, and a previous in vitro study showed increased binding of the ligand in sclerotic hippocampi. Dynamically acquired N-[methyl-¹¹C]-a, a-di-deutero-L-deprenyl distributions in PET images were analyzed graphically, and the focus regions were assessed visually on the PET images. In addition, the accumulation rate and distribution volume of the tracer relative to the cerebellar cortex were measured in standardized homologous temporal regions by semiquantitative methods. Uptake of [¹¹C]deuterium-deprenyl was significantly increased in the epileptogenic temporal lobes, both apparently and semiquantitatively. By calculating mean inter-lobar ratios, we identified the temporal lobe containing the epileptic focus in six unilateral cases. One case was ambiguous but was not falsely localized. The two bilateral cases were correctly identified as such. Our results suggest that PET with [¹¹C]deuterium-deprenyl might be a useful method for identification of epileptogenic temporal lobes.     

Benzodiazepine-GABAA Receptors in Idiopathic Generalized Epilepsy Measured with [11C]Flumazenil and Positron Emission Tomography

Summary The neurochemical basis of absence seizures and the mechanism of their suppression by valproate (VPA) are uncertain. We used positron emission tomography (PET) to determine whether an abnormality of [¹¹C]flumazenil binding to benzodiazepine (BZD)-GABA_A receptors exists in patients with childhood and juvenile absence epilepsy and to examine the effects of VPA on [¹¹C] flumazenil binding. The regional cerebral volume of distribution ( V _d) of [¹¹C]flumazenil in patients not treated with VPA was not different from that in normal controls; V _d was lower in patients treated with VPA, and the number of receptors available for binding was significantly reduced in such patients as compared with normal controls. There was no evidence of a primary abnormality of the BZD-GABA, receptor in childhood and juvenile absence epilepsy (CAE/JAE), but the data suggest that treatment with VPA is associated with a reduction in [¹¹C]flumazenil binding that may be relevant to its mode of action in CAE/JAE.     

Striatal kinetics of [11C]-(+)-nomifensine and 6-[18F]fluoro-L-dopa in Parkinson''s disease measured with positron emission tomography

The kinetics in brain of the dopamine reuptake blocking agent [11C]-(+)-nomifensine and the L-dopa analogue 6-[18F]fluoro-L-dopa were compared in 3 patients with idiopathic Parkinson's disease and age-matched healthy volunteers using positron emission tomography. Regional uptake was analyzed and quantified according to a 3-compartment model. Retention of both tracers in striatal regions of the parkinsonian patients were reduced compared with the healthy volunteers mainly in the putamen, while the caudate nucleus was only mildly affected. The reductions were considerably less than the decrease previously reported postmortem for striatal dopamine content in the basal ganglia of patients with Parkinson's disease. A fairly constant ratio between 6-[18F]fluoro-L-dopa utilization and [11C]-(+)-nomifensine binding in the caudate nucleus and the putamen were found in both groups unrelated to the size of the estimated parameters. This indicates that a limiting factor for the utilization of exogenous levodopa in Parkinson's disease may be a reduced transport capacity for the amino acid into the dopaminergic terminals.     

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.     

[11ClFlumazenil PET in Patients with Epilepsy with Dual Pathology

PURPOSE: Coexistence of hippocampal sclerosis and a potentially epileptogenic cortical lesion is referred to as dual pathology and can be responsible for poor surgical outcome in patients with medically intractable partial epilepsy. [11C]Flumazenil (FMZ) positron emission tomography (PET) is a sensitive method for visualizing epileptogenic foci. In this study of 12 patients with dual pathology, we addressed the sensitivity of FMZ PET to detect hippocampal abnormalities and compared magnetic resonance imaging (MRI) with visual as well as quantitative FMZ PET findings. METHODS: All patients underwent volumetric MRI, prolonged video-EEG monitoring, and glucose metabolism PET before the FMZ PET. MRI-coregistered partial volume-corrected PET images were used to measure FMZ-binding asymmetries by using asymmetry indices (AIs) in the whole hippocampus and in three (anterior, middle, and posterior) hippocampal subregions. Cortical sites of decreased FMZ binding also were evaluated by using AIs for regions with MRI-verified cortical lesions as well as for non-lesional areas with visually detected asymmetry. RESULTS: Abnormally decreased FMZ binding could be detected by quantitative analysis in the atrophic hippocampus of all 12 patients, including three patients with discordant or inconclusive EEG findings. Decreased FMZ binding was restricted to only one subregion of the hippocampus in three patients. Areas of decreased cortical FMZ binding were obvious visually in all patients. Decreased FMZ binding was detected visually in nonlesional cortical areas in four patients. The AIs for these nonlesional regions with visual asymmetry were significantly lower than those for regions showing MRI lesions (paired t test, p = 0.0075). CONCLUSIONS: Visual as well as quantitative analyses of FMZ-binding asymmetry are sensitive methods to detect decreased benzodiazepine-receptor binding in the hippocampus and neocortex of patients with dual pathology. MRI-defined hippocampal atrophy is always associated with decreased FMZ binding, although the latter may be localized to only one sub-region within the hippocampus. FMZ PET abnormalities can occur in areas with normal appearance on MRI, but FMZ-binding asymmetry of these regions is lower when compared with that of lesional areas. FMZ PET can be especially helpful when MRI and EEG findings of patients with intractable epilepsy are discordant.     

Functional Neuroimaging with Positron Emission Tomography

Summary: Epilepsy research using positron emission tomography (PET) has provided considerable new information about ictal and interictal dysfunctions in human epilepsy. Neuroreceptor mapping with PET ligands has revealed altered central benzodiazepine receptor and opiate receptor densities in partial epilepsies interictally, and regional increases in endogenous opioid peptide concentrations during absence seizures. Imaging of perfusion and glucose metabolism during cognitive processing has shown interictal abnormalities of regional activation in partial and generalized epilepsies. The diagnostically robust patterns of interictal glucose hypometabolism are not adequately explained by macrostructural and microstructural alterations in temporal lobe epilepsy. Current investigations of the pathophysiology of interictal hypometabolism must address ultrastructural and neurochemical factors. Clinical PET in pre-surgical evaluation of medically refractory epilepsies remains an active area of research, but remarkably little antiepileptic drug research has exploited PET techniques.     

Estimation of regional cerebral utilization of [11C]-L-3, 4-dihydroxy-phenylalanine (DOPA) in the primate by positron emission tomography

The intracerebral kinetics of [11C]-labelled L-3,4-dihydroxyphenylalanine, L-DOPA, was investigated in rhesus monkeys by positron emission tomography (PET). Through the labelling of the L-DOPA molecule in different positions and observation of a series of pharmacological challenges it was possible to establish that the kinetic conversion of the radiotracer in the striatum represents the process of decarboxylation to [11C]-labelled dopamine. The rate constant for this process can be estimated using a two-compartment model. The use of [11C]-L-DOPA and PET will thus provide a possibility for in vivo studies of blood-brain barrier transport of the amino acid as well as for the estimation of the ability for brain tissue to decarboxylate the tracer by the action of aromatic L-amino acid decarboxylase.     

Cortical Benzodiazepine Receptor Changes are Related to Frequency of Partial Seizures: A Positron Emission Tomography Study

Measurements of benzodiazepine (BZD) receptor density with positron emission tomography (PET) are a promising method of identifying and localizing epileptogenic regions. We investigated whether the pattern of BZD receptor changes depends on seizure frequency, studying 19 patients with matching seizure semiology but different rates of seizure occurrence, using [₁₁C] flumaze-nil as the ligand. All patients had partial epilepsy and normal magnetic resonance imaging (MRI) of the brain. The visually determined PET focus, characterized by reduced BZD receptor density, corresponded to the epileptogenic focuslseizure onset region in all patients. The degree of BZD receptor reduction showed a positive correlation with seizure frequency. Patients with daily seizures differed from those with fewer seizures in two aspects: (a) the degree and extent of BZD receptor reduction was more pronounced, and (b) BZD receptors were also reduced in the primary projection areas of the focus. Flumazenil-PET reliably identifies epileptogenic brain regions in patients with partial seizures. In addition, flurna-zenil-PET can distinguish patients with frequent seizures. The method therefore is not only suitable for noninvasive localization of the seizure focus, but also may provide a biochemical marker of epileptogenicity.     

[18F]FDG-PET and Whole-Scalp MEG Localization of Epileptogenic Cortex

PURPOSE: To evaluate combined [18F]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and 122-channel whole-scalp magnetoencephalography (MEG) in lateralizing the epileptogenic cortex in patients whose routine presurgical evaluations gave discordant results about the location of the epileptic focus. METHODS: Nine patients (five women, four men) aged 13-40 years were studied. Subdural EEG (SEEG) was recorded from eight patients. Six patients were operated on. RESULTS: In seven of nine patients, PET and MEG agreed in localizing the epileptogenic cortex. When PET and MEG were in congruence, SEEG agreed with the findings. In five of six operated-on patients, PET and MEG results were congruent, and the outcome of the operation was successful. Two patients had discordant PET and MEG results. In one patient, PET showed bitemporal hypometabolism, whereas MEG showed epileptiform activity in the right parietal lobe. The surgical outcome of the palliative temporal lobectomy was poor. Another patient had unilateral temporal hypometabolism in PET and bitemporal activity in MEG. She was not operated on. CONCLUSIONS: In most patients, PET and MEG were congruent in locating the epileptogenic cortex. Thus the combination of these techniques may provide useful support for the localization of the seizure onset and reduce the need for invasive procedures.     

Regional increases in [11 C]flumazenil binding after epilepsy surgery

Introduction – Animal experiments suggest that epileptic seizures alter the expression of mRNA for neuro-receptors. PET measurements with [¹¹ C]flumazenil show that patients with partial seizures have a reduced density of benzodiazepine (BZ) receptors in the epileptogenic regions (ER) and some of the target areas for seizure activity, the so called projection areas. Recent data suggest that the degree of BZ receptor reduction in ER is correlated to seizure frequency. We therefore hypothesized that seizure activity can alter the BZ receptor binding, and that some of these changes could normalize when the seizures disappeared. Methods – In 4 patients whose seizures were generated by mesial temporal lobe structures, BZ receptor density was measured with [¹¹ C]flumazenil PET before, and 1 year after the epilepsy surgery and cessation of seizures. By use of a computerized anatomical brain atlas the same regions were analyzed in both PET scans, and the results related to data from 7 healthy controls. Results – Presurgical PET scans showed reductions in BZ receptor density in the epileptogenic region and some of its primary projection areas. Other cortical regions had normal values. Postsurgically, the calculated BZ receptor density normalized (29±17% increase) in several of the affected projection areas, whereas the values in other cortical regions remained unaltered. Conclusion – Regional reductions in BZ receptor density may be dynamic and related to seizures. The present preliminary observations encourage further studies on seizure-related changes in regional receptor binding in humans.     

Cerebral uptake and utilization of therapeutic [β-11C]-L-DOPA in Parkinson''s disease measured by positron emission tomography. Relations to motor response

Cerebral uptake and utilization of levodopa was measured in eight patients with idiopathic Parkinson's disease (PD) by [beta-11C]-L-DOPA and positron emission tomography (PET). By adding pharmacological doses of unlabelled levodopa to the radioactive solution it was possible to evaluate the clinical effect simultaneously with the cerebral kinetics of the drug. Additionally, in two of the patients with advanced PD, investigations with the dopamine re-uptake blocker [11C]-(+)-nomifensine and PET were carried out to get a measure of the density of striatal dopaminergic nerve-terminals. The brain uptake of [beta-11C]-L-DOPA was inversely correlated to the sum of large neutral amino acids in plasma. In the eight PD patients studied with [beta-11C]-L-DOPA striatal k3, which reflects the ability for striatal tissue to decarboxylate the tracer by the action of aromatic L-amino acid decarboxylase (AADC), was decreased 35% compared to healthy subjects. It was demonstrated that, in the patients with advanced PD and motor fluctuations on oral L-DOPA medication, reversal of parkinsonian symptoms occurred at very low striatal tissue dopamine concentrations. In the two very advanced patients studied with [11C]-(+)-nomifensine the striatal binding of the tracer was 50% reduced.     

Changes in GABAA receptor properties in amygdala kindled animals: in vivo studies using [11C]flumazenil and positron emission tomography

Purpose: The purpose of the present investigation was to quantify alterations in GABA_A receptor density in vivo in rats subjected to amygdala kindling. Methods: The GABA_A receptor density was quantified by conducting a [¹¹C]flumazenil (FMZ) positron emission tomography (PET) study according to the full saturation method, in which each animal received a single injection of FMZ to fully saturate the GABA_A receptors. Subsequently, the concentration‐time curves of FMZ in blood [using high‐pressure liquid chromatography with UV detector (HPLC‐UV) or high‐performance liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS)] and brain (with PET‐scanning) were analyzed by population modeling using a pharmacokinetic model, containing expressions to describe the time course of FMZ in blood and brain. Results: The GABA_A receptor density (B_max) in kindled rats was decreased by 36% compared with controls. This is consistent with a reduction of 28% in electroencephalography (EEG) effect of midazolam in the same animal model, suggesting that a reduced number of GABA_A receptors underlies the decreased efficacy of midazolam. Furthermore, receptor affinity (K_D) was not changed, but the total volume of distribution in the brain (V_Br), is increased to 178% of control after kindling, which might indicate an alteration in the transport of FMZ across the blood–brain barrier. Conclusions: Both the GABA_A receptor density (B_max), and possibly also the blood–brain barrier transport of FMZ (V_Br) are altered after kindling. Furthermore, this study indicates the feasibility of conducting PET studies for quantifying moderate changes in GABA_A receptor density in a rat model of epilepsy in vivo.     

Effect of Valproate on Cerebral Metabolism and Blood Flow: An 18F-2-Deoxyglusose and 15O Water Positron Emission Tomography Study

Summary: We compared the effect of valproate (VPA) on cerebral metabolic rate for glucose (CMRGlc) and cerebral blood flow (CBF), measured with ¹⁸F-2–deoxyglucose (^I8FDG) and ¹⁵O water positron emission tomography (PET), in 10 normal volunteers. Mean VPA dose was 17.7 mg/kg, and mean VPA level was 82.1 mg/L (±16.5) for 4 weeks. VPA reduced global CMRGlc by 9.4% (9.60 2 0.76 vs. 8.59 ± 1.02 mg Glc/min/100 g, p < 0.05) and regionally in all anatomic areas (p < 0.05 for 11 of 26 areas). VPA diminished global CBF by 14.9% (56.55 ± 6.70 vs. 47.48 ± 4.42 ml/min/100 g, p < 0.002) and regionally in all anatomic areas (p < 0.05 for 12 of 26 areas). No significant correlation was noted between VPA level and either global CMRGlc or CBF. The effect of VPA on global CMRGlc is similar to that of carbamazepine (CBZ) and phenytoin but less than that of phenobarbital, Valium, or combination therapy with VPA and CBZ. VPA reduced regional CBF (rCBF) but not CMRGlc in the thalamus, an effect that may be associated with VPA's mechanism of action against generalized seizures.     

Effect of Seizures on Cerebral Blood Flow Measured with 15–H2O and Positron Emission Tomography

Summary: To study quantitative alterations in regional cerebral blood flow (rCBF) accompanying seizures, and to assess the utility of ictal activation PET scanning as a noninvasive clinical tool for localization of epileptogenic foci, we used pentylenetetrazole (F'TZ) to induce seizures during ¹⁵O-water positron emission tomography (PET) CBF measurement in 15 patients with uncontrolled complex partial seizures (CPS) who had been referred for surgical evaluation. Continuous EEG monitoring was performed during the PET scans. After baseline scans were obtained, each patient was injected with 150–300 mg PTZ. Two patients had generalized tonic-clonic seizures (GTCs). CBF increases were asymmetrical. Two patients (in 1 the seizure occurred spontaneously, without PTZ injection) who had CPS had bitemporal 70–80% increases in CBF. Thalamic CBF increased during both CPS and GTCS. Five patients had an increase in focal EEG in-terictal abnormality, accompanied by focal flow decreases in 3. PTZ injection not accompanied by clinical seizures did not increase CBF. Partial seizures may be associated with bilateral increases in CBF, and subcortical gray regions are involved in ictal activation.     

PET visualization of microglia in multiple sclerosis patients using [11C]PK11195

Activated microglia are involved in the immune response of multiple sclerosis (MS). The peripheral benzodiazepine receptor (PBR) is expressed on microglia and up-regulated after neuronal injury. [11C]PK11195 is a positron emission tomography (PET) radioligand for the PBR. The objective of the present study was to investigate [11C]PK11195 imaging in MS patients and its additional value over magnetic resonance imaging (MRI) concerning the immuno-pathophysiological process. Seven healthy and 22 MS subjects were included. Semiquantitative [11C]PK11195 uptake values were assessed with normalization on cortical grey matter. Uptake in Gadolinium-lesions was significantly increased compared with normal white matter. Uptake in T2-lesions was generally decreased, suggesting a PBR down-regulation. However, uptake values increased whenever a clinical or MR-relapse was present, suggestive for a dynamic process with a transient PBR up-regulation. During disease progression, an increase of normal-appearing white matter (NAWM) uptake was found, propagating NAWM as the possible real burden of disease. In conclusion, [11C]PK11195 and PET are able to demonstrate inflammatory processes with microglial involvement in MS.