Browsing by Author "Dedeurwaerdere, S"

Now showing 1 - 7 of 7
  • No Thumbnail Available
    Item
    Characterisation of peripheral benzodiazepine receptors changes in early phase of epileptogenesis in the rat with PET and [18F]PBR111
    (Society of Nuclear Medicine, 2009-05) Grégoire, MC; Dedeurwaerdere, S; Callaghan, PD; Loc'h, C; Pham, TQ; Katsifis, A
    The current project aims at investigating the role of microglial activation in epileptogenesis by estimating PBR changes in the rat brain with a new and highly specific PBR ligand, [18F]PBR111, during the early phase, i.e. one week after status epilepticus induced by kainic acid (KA). Methods Four controls and 6 KA rats were scanned for 180 minutes with our small animal PET/CT under a triple-injection protocol. The results presented here cover only the first 60 minutes after injection of 0.06nmoles of [18F]PBR111. Arterial blood samples were withdrawn and metabolite corrected plasma time-activity curves were derived. Each CT and PET data were co-registered to an age and strain matched rat brain atlas containing 25 Regions-Of-Interest (ROIs). The Volume of Distribution (Vd) were calculated for each region. Whole-brain-normalised Vd (nVd) were also calculated to assess local variations. Results Compared to controls, KA-treated rats show a 2 to 3-fold increase of the Vd in all brain areas except the midbrain. No significant asymmetry was detected (< 9%), so the ROIs were grouped. Normalized Vd values (Table 1) show that Amygdala, Striata, Thalamus and Hippocampus are predominantly involved. No significant changes were detected in the midbrain and all cortical areas. Estimates of receptors densitiy (Bmax) and apparent affinity (KdVr) will be calculated from the full kinetics (three phases) and reported later. Conclusions This in vivo imaging study has identified significant microglial activation during early epileptogenesis in several brain regions which are known to play a key role in chronic epilepsy.
  • No Thumbnail Available
    Item
    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
  • Thumbnail Image
    Item
    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.
  • No Thumbnail Available
    Item
    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.
  • No Thumbnail Available
    Item
    Increased brain metabolism after acute administration of the synthetic cannabinoid HU210: A small animal PET imaging study with (18)F-FDG
    (Elsevier, 2012-02-10) Nguyen, VH; Verdurand, M; Dedeurwaerdere, S; Wang, HQ; Zahra, D; Grégoire, MC; Zavitsanou, K
    Cannabis use has been shown to alter brain metabolism in both rat models and humans although the observations between both species are conflicting. In the present study, we examined the short term effects of a single-dose injection of the synthetic cannabinoid agonist HU210 on glucose metabolism in the rat brain using small animal (18)F-2-fluoro-deoxyglucose (FDG) Positron Emission Tomography (PET) 15min (Day 1) and 24h (Day 2) post-injection of the agonist in the same animal. Young adult male Wistar rats received an intra-peritoneal injection of HU210 (100μg/kg, n=7) or vehicle (n=5) on Day 1. Approximately 1mCi of (18)F-FDG was injected intravenously into each animal at 15min (Day 1) and 24h (Day 2) post-injection of HU210. A 5-min Computer Tomography (CT) scan followed by a 20-min PET scan was performed 40min after each (18)F-FDG injection. Standardised Uptake Values (SUVs) were calculated for 10 brain regions of interest (ROIs). Global increased SUVs in the whole brain, hence global brain metabolism, were observed following HU210 treatment on Day 1 compared to the controls (21%, P<0.0001), but not in individual brain regions. On Day 2, however, no statistically significant differences were observed between the treated and control groups. At the 24h time point (Day 2), SUVs in the HU210 treated group returned to control levels (21-30% decrease compared to Day 1), in all ROIs investigated (P<0.0001). In the control group, SUVs did not differ between the two acquisition days in all brain regions. The present results suggest that high-dose HU210 increases brain glucose metabolism in the rat brain shortly after administration, in line with normalised human in vivo studies, an effect that was no longer apparent 24h later. Copyright © 2011 Elsevier Inc. All rights reserved.
  • Thumbnail Image
    Item
    Mapping the early inflammation process that leads to epilepsy in rodents
    (Australian Nuclear Science and Technology Organisation, 2009-01-09) Callaghan, PD; Dedeurwaerdere, S; Grégoire, MC; Pham, TQ; Katsifis, A
    Imaging of the living brain using Positron Emission Tomography (PET), a noninvasive, sensitive and quantitative imaging methodology, allows us to investigate neurobiological mechanisms involved in the onset of the neurological disease. Our work has focused on investigating the pre-symptomatic neuroinflammatory processes (called epileptogenesis) that lead development of chronic seizures, in an animal model of epilepsy. We have used our in-house radiotracer (18F-PBR111) which is highly specific for receptors expressed in the inflammatory response within the brain. Performing pre-clinical PET imaging with this radioligand allowed us to map and quantify neuroinflammation in vivo, and to correlate this with full in vitro assessment of the neuroinflammation response. The in vivo ligand binding patterns highly correlate with the structures involved in the generation of seizures, and these data reflect the in vitro data, illustrating that the PET binding represents true neuroinflammation. Thus, longitudinal PET studies will be possible in order to follow-up the evolution of the inflammatory regions during the onset of the disease, and test new preventive therapies that modulate this disease process.
  • Thumbnail Image
    Item
    PET imaging of brain inflammation during early epileptogenesis in a rat model of temporal lobe epilepsy
    (Springer-Velag, 2012-11-08) Dedeurwaerdere, S; Callaghan, PD; Pham, TQ; Rahardjo, GL; Amhaoul, H; Berghofer, PJ; Quinlivan, M; Mattner, F; Loc'h, C; Katsifis, A; Grégoire, MC
    Background Recently, inflammatory cascades have been suggested as a target for epilepsy therapy. Positron emission tomography (PET) imaging offers the unique possibility to evaluate brain inflammation longitudinally in a non-invasive translational manner. This study investigated brain inflammation during early epileptogenesis in the post-kainic acid-induced status epilepticus (KASE) model with post-mortem histology and in vivo with [18F]-PBR111 PET. Methods Status epilepticus (SE) was induced (N = 13) by low-dose injections of KA, while controls (N = 9) received saline. Translocator protein (TSPO) expression and microglia activation were assessed with [125I]-CLINDE autoradiography and OX-42 immunohistochemistry, respectively, 7 days post-SE. In a subgroup of rats, [18F]-PBR111 PET imaging with metabolite-corrected input function was performed before post-mortem evaluation. [18F]-PBR111 volume of distribution (V t) in volume of interests (VOIs) was quantified by means of kinetic modelling and a VOI/metabolite-corrected plasma activity ratio. Results Animals with substantial SE showed huge overexpression of TSPO in vitro in relevant brain regions such as the hippocampus and amygdala (P < 0.001), while animals with mild symptoms displayed a smaller increase in TSPO in amygdala only (P < 0.001). TSPO expression was associated with OX-42 signal but without obvious cell loss. Similar in vivo [18F]-PBR111 increases in V t and the simplified ratio were found in key regions such as the hippocampus (P < 0.05) and amygdala (P < 0.01). Conclusion Both post-mortem and in vivo methods substantiate that the brain regions important in seizure generation display significant brain inflammation during epileptogenesis in the KASE model. This work enables future longitudinal investigation of the role of brain inflammation during epileptogenesis and evaluation of anti-inflammatory treatments. © 2012, Springer.