Giovacchini G, Toczek MT, Bonwetsch R, Bagic A, Lang L, Fraser C et al. 5-HT 1A receptors are reduced in temporal lobe epilepsy after partial-volume correction. J Nucl Med 46: 1128-1135

PET Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892-1408, USA.
Journal of Nuclear Medicine (Impact Factor: 6.16). 08/2005; 46(7):1128-35.
Source: PubMed


Preclinical studies suggest that serotonin 1A receptors (5-HT 1A) play a role in temporal lobe epilepsy (TLE). Previous PET studies reported decreased 5-HT 1A binding ipsilateral to epileptic foci but did not correct for the partial-volume effect (PVE) due to structural atrophy.
We used PET with 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl-N-(2-pyridyl)cyclohexanecarboxamide (18F-FCWAY), a 5-HT 1A receptor antagonist, to study 22 patients with TLE and 10 control subjects. In patients, 18F-FDG scans also were performed. An automated MR-based partial-volume correction (PVC) algorithm was applied. Psychiatric symptoms were assessed with the Beck Depression Inventory Scale.
Before PVC, significant (uncorrected P < 0.05) reductions of 18F-FCWAY binding potential (BP) were detected in both mesial and lateral temporal structures, mainly ipsilateral to the seizure focus, in the insula, and in the raphe. Group differences were maximal in ipsilateral mesial temporal regions (corrected P < 0.05). After PVC, differences in mesial, but not lateral, temporal structures and in the insula remained highly significant (corrected P < 0.05). Significant (uncorrected P < 0.05) BP reductions were also detected in TLE patients with normal MR images (n = 6), in mesial temporal structures. After PVC, asymmetries in BP remained significantly greater than for glucose metabolism in hippocampus and parahippocampus. There was a significant inverse relation between the Beck Depression score and the ipsilateral hippocampal BP, both before and after PVC.
Our study shows that in TLE patients, reductions of 5-HT 1A receptor binding in mesial temporal structures and insula are still significant after PVC. In contrast, partial-volume effects may be an important contributor to 5-HT 1A receptor-binding reductions in lateral temporal lobe. Reduction of 5-HT 1A receptors in the ipsilateral hippocampus may contribute to depressive symptoms in TLE patients.

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    • "Since the GABA A receptor is predominantly located in gray matter, rather than white (Heiss and Herholz, 2006), in order to focus on the BP ND in gray matter we used a mask with this high gray matter proportion. Secondly, GABA A receptor BP ND maps were then corrected for partial volume effects on a voxelwise basis by dividing by the gray matter proportion within each voxel following spatial smoothing using a 2.5 mm at FWHM kernel (corresponding to the PET scanner resolution) (Giovacchini et al., 2005; la Fougere et al., 2011). All BP ND values for subsequent analyses were taken from within the masked gray matter region. "
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    • "In addition, when analyses were restricted to cases with an unprovoked ''localized onset'' seizure, depression was 17 times more common among affected cases than among nonseizure controls (Forsgren & Nystrçm, 1990; Hesdorffer et al., 2000); the strong links between temporal or frontal lobe epilepsy and depression are particularly well recognized (Grabowska-Grzyb et al., 2006; García-Morales et al., 2008). Perhaps the more acute neurochemical/structural changes in the brain associated with a partial epileptic focus contribute to depression onset by disrupting neural circuits involved in emotional processing (Giovacchini et al., 2005; Chayasirisobhon, 2009). Epilepsy is treated with a number of antiepileptic drugs (AEDs) according to etiology, age, and pattern of onset, some of which may themselves alter psychobiologic processes (Andersohn et al., 2010; Arana et al., 2010). "
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    • "Estimation of distribution volume (V) was performed with data fitted to a 2 compartment 3 parameter model using metabolite-corrected input arterial function. To correct for structural atrophy, we used an MRI-based partial volume correction (PVC) algorithm (Giovacchini et al 2005). To correct for potential antiepileptic drug (AED) effects on ligand protein binding, we used free fraction corrected V (V/f1) as our binding measure. "
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    ABSTRACT: Memory deficits and depression are common in patients with temporal lobe epilepsy (TLE). Previous positron emission tomography (PET) studies have shown reduced mesial temporal 5HT1A-receptor binding in these patients. We examined the relationships among verbal memory performance, depression, and 5HT1A-receptor binding measured with 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl-N-(2-pyridyl) cyclohexane carboxamide (18FCWAY) PET in a cross-sectional study. We studied 40 patients (24 male; mean age 34.5 ± 10.7 years) with TLE. Seizure diagnosis and focus localization were based on ictal video-electroencephalography (EEG) recording. Patients had neuropsychological testing with Wechsler Adult Intelligence Score III (WAIS III) and Wechsler Memory Score III (WMS III) on stable antiepileptic drug (AED) regimens at least 24 h since the last seizure. Beck Depression Inventory (BDI) scores were obtained. We performed interictal PET with 18FCWAY, a fluorinated derivative of WAY 100635, a highly specific 5HT1A ligand, and structural magnetic resonance imaging (MRI) scans to estimate partial volume and plasma free fraction corrected 18FCWAY volume of distribution (V/f1). Hippocampal V/f1 was significantly lower in area ipsilateral than contralateral to the epileptic focus (73.7 ± 27.3 vs. 95.4 ± 28.4; p < 0.001). We found a significant relation between both left hippocampal 18FCWAY V/f1 (r = 0.41; p < 0.02) and left hippocampal volume (r = 0.36; p < 0.03) and delayed auditory memory score. On multiple regression, there was a significant effect of the interaction of left hippocampal 18FCWAY V/f1 and left hippocampal volume on delayed auditory memory, but not of either alone. High collinearity was present. In an analysis of variance including the side of the seizure focus, the effect of left hippocampal 18FCWAY V/f1 but not focus laterality retained significance. Mean BDI was 8.3 ± 7.0. There was a significant inverse relation between BDI and 18FCWAY V/f1 ipsilateral to the patient's epileptic focus (r = 0.38 p < 0.02). There was no difference between patients with a right or left temporal focus. There was no relation between BDI and immediate or delayed auditory memory. Our study suggests that reduced left hippocampal 5HT1A-receptor binding may play a role in memory impairment in patients with TLE.
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