Browsing by Author "Vivash, L"

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    [18F]-Flumazenil: a γ-aminobutyric acid A–specific PET radiotracer for the localisation of drug resistant temporal lobe epilepsy
    (Society of Nuclear Medicine and Molecular Imaging, 2013-07-15) Vivash, L; Grégoire, MC; Lau, EW; Ware, RE; Binns, D; Roselt, P; Bouilleret, V; Myers, DE; Cook, MJ; Hicks, RJ; O’Brien, TJ
    Studies report that 11C-flumazenil (FMZ) PET more specifically localizes the epileptogenic zone in patients with medically refractory focal epilepsy than 18F-FDG PET. However, practical aspects of 11C use limit clinical application. We report a phase I/IIa study assessing the clinical use of 18F-FMZ PET for the localization of the epileptogenic zone in patients with drug-resistant temporal lobe epilepsy (TLE). Receptor binding was quantified using kinetic modeling that did not require arterial sampling. Methods: Dynamic 18F-FMZ PET and static interictal 18F-FDG PET scans were compared in healthy controls (n = 17 for 18F-FMZ and n = 20 for 18F-FDG) and TLE patients with mesial temporal sclerosis on MR imaging (MTS, n = 12) and with normal MR imaging (NL TLE, n = 19). Masked visual assessment of images was undertaken. Parametric images of 18F-FMZ binding potential (BPND) were generated using the simplified reference tissue model. Region-of-interest analysis on coregistered MR images and statistical parametric mapping were used to quantify 18F-FMZ BPND and 18F-FDG uptake in the temporal lobe. Results: The visual assessment of static standardized uptake value images showed 18F-FMZ PET to have high specificity (16/17 [94%]) and moderate sensitivity (21/31 [68%]) for the localization of the epileptogenic zone, with a more restricted abnormality than 18F-FDG PET. However, the 18F-FMZ standardized uptake value images were falsely localizing in 3 of 31 patients (10%). Region-of-interest analysis demonstrated reductions in ipsilateral hippocampal 18F-FMZ BPND in patients with either MTS or NL TLE, compared with controls subjects. Ipsilateral hippocampal 18F-FMZ BPND was independent of both hippocampal volume and 18F-FDG uptake, whereas ipsilateral hippocampal volume was correlated with 18F-FDG uptake (r2 = 0.69, P < 0.0001). Statistical parametric mapping analysis demonstrated decreased uptake in 14 of 31 (45%) cases with 18F-FMZ PET and 18 of 29 (62%) with 18F-FDG PET. Cluster size was significantly smaller on 18F-FMZ than 18F-FDG images (37 vs. 160 voxels, P < 0.01). Conclusion: 18F-FMZ PET has potential as a clinical tool for the localization of the epileptogenic zone in the presurgical evaluation of drug-resistant TLE, providing information complementary to 18F-FDG PET, with a more restricted region of abnormality. © 2013 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
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    Development of [18F]-Flumazenil-PET for localisation of the epileptogenic zone in patients with medically refractory focal epilepsy
    (Springer, 2010-10-11) Vivash, L; Grégoire, MC; Dedeurwaerdere, S; Bouilleret, V; Roselt, P; Lau, EW; Ware, RE; Binns, D; Katsifis, A; Hicks, RJ; Myers, DE; O'Brien, TJ
    Introduction: Studies of GABAA/central benzodiazepine receptor (GABAA/cBZR) distribution in the CNS using [11C]-flumazenil-PET (FMZ-PET) have enabled localisation of the epileptogenic zone (EZ) in patients with medically refractory epilepsy. [11C]-FMZ-PET images show a more restricted region of abnormality with increased sensitivity when compared with FDG-PET. However, use of [11C]-FMZ in routine clinical practice has been hindered by practical limitations of [11C]. The aim of the current study is to develop an [18F]-radiolabelled FMZ tracer with high specificity and improved imaging quality for EZ localisation in routine clinical practice. Methods: Preclinical studies: Presaturation, displacementand uptake PET scans were performed to define the kinetics of [18F]-FMZ binding in non-epileptic rats (n=8). Bmax (receptor density) and KD (binding affinity) were then quantified in the brains of epileptic (n=9; kainic acid-induced model of temporal lobe epilepsy) vs. non-epileptic control animals (n=10). Clinical study: 4 patient groups have been studied; healthy controls (n=20), patients with well-localised TLE from MRI scans (n=10), patients with lateralised TLE(n=7), and patients with other focal epilepsies (n=4). Each participant underwent a single 60 minute dynamic [18F]-FMZ-PET scan. Patients also underwent an FDG-PET scan. Blinded visual assessment of images to locate the EZ was performed. Parametric images of binding potential (BP) were generated. Datasets were processed using ROI analysis and SPM to assess differences in BP between patients and controls and localisation of the EZ in patients. Results:[18F]-FMZ was shown to be a suitable PET radiotracer for imaging GABAA/cBZR in vivo, with reversible and competitive binding and low non-specific binding. [18F]-FMZ-PET reliably detected decreased Bmax in the hippocampi of epilepticrats (left 16.3, right 15.9) compared with controls (left 20.9, right 19.8, p=0.022, p=0.049), with no change in KD (left 8.24 vs 8.46, p=0.82, right 7.43vs 8.07 p=0.56). There were no changes in whole brain Bmax or KD. To date the visual assessment of the clinical data has shown [18F]-FMZ-PET to have high sensitivity (100%) and positive predictive value (100%) for the EZ in patients, with a more restricted localisation of the EZ compared to FDG-PET. Quantitative analysis is ongoing. Conclusions: The pre-clinical studies have demonstrated that [18F]-FMZ-PET is a reliable radiotracer for quantification of CNSGABAA/cBZR expression in vivo. Preliminary analysis in our current clinical study indicates that [18F]-FMZ-PET also has excellent imaging characteristics in humans, and shows promise as a new clinical tool for localising the EZ in TLE patients. © 2020 Springer Nature Switzerland AG
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    In vivo measurement of hippocampal GABAA/cBZR density with [18F]-Flumazenil PET for the study of disease progression in an animal model of temporal lobe epilepsy
    (Public Library of Science, 2014-01-21) Vivash, L; Grégoire, MC; Bouilleret, V; Berard, A; Wimberley, CA; Binns, D; Roselt, P; Katsifis, A; Myers, DE; Hicks, RJ; O'Brien, TJ; Dedeurwaerdere, S
    Purpose Imbalance of inhibitory GABAergic neurotransmission has been proposed to play a role in the pathogenesis of temporal lobe epilepsy (TLE). This study aimed to investigate whether [18F]-flumazenil ([18F]-FMZ) PET could be used to non-invasively characterise GABAA/central benzodiazepine receptor (GABAA/cBZR) density and affinity in vivo in the post-kainic acid status epilepticus (SE) model of TLE. Methods Dynamic [18F]-FMZ -PET scans using a multi-injection protocol were acquired in four male wistar rats for validation of the partial saturation model (PSM). SE was induced in eight male Wistar rats (10 weeks of age) by i.p. injection of kainic acid (7.5–25 mg/kg), while control rats (n = 7) received saline injections. Five weeks post-SE, an anatomic MRI scan was acquired and the following week an [18F]-FMZ PET scan (3.6–4.6 nmol). The PET data was co-registered to the MRI and regions of interest drawn on the MRI for selected structures. A PSM was used to derive receptor density and apparent affinity from the [18F]-FMZ PET data. Key Findings The PSM was found to adequately model [18F]-FMZ binding in vivo. There was a significant decrease in hippocampal receptor density in the SE group (p<0.01), accompanied by an increase in apparent affinity (p<0.05) compared to controls. No change in cortical receptor binding was observed. Hippocampal volume reduction and cell loss was only seen in a subset of animals. Histological assessment of hippocampal cell loss was significantly correlated with hippocampal volume measured by MRI (p<0.05), but did not correlate with [18F]-FMZ binding. Significance Alterations to hippocampal GABAA/cBZR density and affinity in the post-kainic acid SE model of TLE are detectable in vivo with [18F]-FMZ PET and a PSM. These changes are independent from hippocampal cell and volume loss. [18F]-FMZ PET is useful for investigating the role that changes GABAA/cBZR density and binding affinity play in the pathogenesis of TLE. © 2014 Vivash et al.
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    In-vivo imaging characteristics of two fluorinated flumazenil radiotracers in the rat
    (Springer, 2009-06) Dedeurwaerdere, S; Grégoire, MC; Vivash, L; Roselt, P; Binns, D; Fookes, CJR; Greguric, I; Pham, TQ; Loc'h, C; Katsifis, A; Hicks, RJ; O'Brien, TJ; Myers, DE
    Purpose: [11C]Flumazenil shows promise as a clinical and research PET radiotracer to image changes in GABAA central benzodiazepine receptor (cBZR), but its widespread use has been limited by practical limitations of [11C]. This study evaluated the imaging characteristics of two fluorinated PET radiotracers in rats in vivo: [18F]fluoroflumazenil ([18F]FFMZ) and [18F]flumazenil ([18F]FMZ). Methods: PET acquisitions were performed on a small-animal scanner following injection of [18F]FFMZ in nine rats and [18F]FMZ in eight rats. The following treatments were investigated: (1) injection of the tracer dose, (2) presaturation then injection of the tracer dose, and (3) injection of the tracer dose followed by a displacement injection. Unchanged tracer was measured in plasma and brain structures in four animals 10 and 30 min after injection, and ex-vivo autoradiography was also performed. Results: For both [18F]FFMZ and [18F]FMZ maximal brain activity peaked rapidly, and was highest in the hippocampus (1.12±0.06 SUV, 1.24±0.10 SUV, respectively), and lowest in the pons (1.00±0.07 SUV, 1.03±0.09 SUV, respectively). By 50 min after injection, maximal uptake for [18F]FFMZ and [18F]FMZ had decreased in the hippocampus to 18±3% and 80±1% (p<0.01), respectively. The presaturation and displacement studies showed a higher nonspecific component for [18F]FFMZ than for [18F]FMZ. Metabolite studies showed that at 30 min only 10% of the signal was from [18F]FFMZ in the brain. This nonspecific binding was apparent on autoradiography. In contrast, [18F]FMZ accounted for >70% of the signal in the brain, which resulted in well-defined regional binding on autoradiography. Conclusion These results demonstrate that [18F]FMZ is a superior radiotracer to [18F]FFMZ for in-vivo PET imaging of the GABAA/cBZR, having slower metabolism and leading to lower concentrations of metabolites in the brain that results in a substantially better signal-to-noise ratio. © 2009, Springer.