References of "Bahri, Mohamed Ali"
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See detailSelf in Dementia
Antoine, Nicolas ULg; Genon, Sarah ULg; Bastin, Christine ULg et al

in Mishara; Corlett, P.; Fletcher, P. (Eds.) et al Phenomenological Neuropsychiatry, How Patient Experience Bridges Clinic with Clinical Neuroscience (in press)

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See detailRegiospecific radiolabelling of Nanofitin on Ni Magnetic Beads with [18F]FBEM and in vivo PET studies
Dammicco, Sylvestre ULg; Goux, Marine; Lemaire, Christian ULg et al

in Nuclear Medicine & Biology (2017)

Introduction: Nanofitins are low molecular weight, single chain and cysteine-free protein scaffolds able to selectively bind a defined biological target. They derive from Sac7d bacterial protein family ... [more ▼]

Introduction: Nanofitins are low molecular weight, single chain and cysteine-free protein scaffolds able to selectively bind a defined biological target. They derive from Sac7d bacterial protein family and are highly stable over a wide range of pH (0-13) and temperature (Tm ~80°C). Their extreme stability, low cost of production and high tolerability for chemical coupling make Nanofitins a very interesting alternative to antibodies and their fragments. Here, a hexahistidine tagged model Nanofitin (H4) directed against hen egg white lysozyme was radiolabelled and injected in mice to provide a baseline biodistribution and pharmacokinetic profiles to support future Nanofitin development programs. Method: A single cysteine residue has been genetically inserted in a model Nanofitin and its regioselective radiolabelling has been performed with 4-[18F]fluorobenzamido-N-ethylamino-maleimide ([18F]FBEM). The synthesis of [18F]FBEM has been completely implemented on a radiosynthesis unit (FastLab) including HPLC purification and formulation. Coupling with the [18F]FBEM has been achieved on a solid support (Ni magnetic beads) allowing rapid purification at room temperature without organic solvent. PET-MRI studies on C57BL/6 mice were conducted after injection of [18F]FBEM-Cys-H4 in order to access the biodistribution of this Nanofitin model. Results: Radiochemical yield (decay corrected) of 54±7% (n=4) was obtained after optimization for coupling the [18F]FBEM to Nanofitin. Pharmacokinetics results of [18F]FBEM-Cys-H4 revealed a fast clearance through the liver and the kidneys. Conclusion: An efficient new method on Ni magnetic beads was developed to radiolabelled his-tagged biomolecules with [18F]FBEM. This procedure was applied on a Nanofitin model Cys-H4 and biodistribution kinetic studies were achieved to evaluate the potential use of Nanofitin for diagnostic imaging. Fast clearance indicates that Nanofitins represent very interesting tools for diagnostic imaging. [less ▲]

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See detailMean and variance of Dynamic Functional Connectivity in Parkinson’s Disease
Baquero Duarte, Katherine Andrea ULg; Guldenmund, Pieter; Rouillard, Maud ULg et al

Poster (2017, June 29)

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See detailComparative assessment of 6-[18F]fluoro-L-m-tyrosine and 6-[18F]fluoro-L-dopa to evaluate dopaminergic presynaptic integrity in a Parkinson’s disease rat model.
Becker, Guillaume ULg; Bahri, Mohamed Ali ULg; Michel, Anne et al

in Journal of Neurochemistry (2017), 141

Because of the progressive loss of nigro-striatal dopaminergic terminals in Parkinson’s disease (PD), in vivo quantitative imaging of dopamine (DA) containing neurons in animal models of PD is of critical ... [more ▼]

Because of the progressive loss of nigro-striatal dopaminergic terminals in Parkinson’s disease (PD), in vivo quantitative imaging of dopamine (DA) containing neurons in animal models of PD is of critical importance in the pre-clinical evaluation of highly awaited disease-modifying therapies. Among existing methods, the high sensitivity of positron emission tomography (PET) is attractive to achieve that goal. The aim of this study was to perform a quantitative comparison of brain images obtained in 6-hydroxydopamine (6-OHDA) lesioned rats using two dopaminergic PET radiotracers, namely [18F]fluoro-3,4-dihydroxyphenyl-L-alanine ([18F]FDOPA) and 6-[18F]fluoro-L-m-tyrosine ([18F]FMT). Because the imaging signal is theoretically less contaminated by metabolites, we hypothesized that the latter would show stronger relationship with behavioural and post-mortem measures of striatal dopaminergic deficiency. We used a within-subject design to measure striatal [18F]FMT and [18F]FDOPA uptake in eight partially lesioned, eight fully lesioned and ten sham-treated rats. Animals were pretreated with an L-aromatic amino acid decarboxylase (AADC) inhibitor. A catechol-O-methyl transferase inhibitor was also given before [18F]FDOPA PET. Quantitative estimates of striatal uptake were computed using conventional graphical Patlak method. Striatal dopaminergic deficiencies were measured with apomorphine-induced rotations and post-mortem striatal DA content. We observed a strong relationship between [18F]FMT and [18F]FDOPA estimates of decreased uptake in the denervated striatum using the tissue-derived uptake rate constant Kc. However, only [18F]FMT Kc succeeded to discriminate between the partial and the full 6-OHDA lesion and correlated well with the post-mortem striatal DA content. This study indicates that the [18F]FMT could be more sensitive, with respect of [18F]FDOPA, to investigate DA terminals loss in 6-OHDA rats, and open the way to in vivo AADC activity targeting in future investigations on progressive PD models. [less ▲]

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See detailRelating pessimistic memory predictions to Alzheimer’s disease brain structure
Genon, Sarah ULg; Simon, Jessica ULg; Bahri, Mohamed Ali ULg et al

Poster (2017, March 23)

Patients with Alzheimer’s disease (AD) show impairment of episodic memory and related metacognitive processes. The present study examined subjective metacognitive judgments preceding objective memory ... [more ▼]

Patients with Alzheimer’s disease (AD) show impairment of episodic memory and related metacognitive processes. The present study examined subjective metacognitive judgments preceding objective memory retrieval and investigated the neural correlates of pessimistic predictions for successfully retrieved memories in AD patients. AD patients and healthy older participants provided predictive judgements on their recognition performance before retrieval of famous (semantic) and recently learned (episodic) names. Correlations between grey matter volume (GMV) in T1 images and behavioural scores were examined with multivariate (PLS) and univariate (GLM) analyses in AD patients. AD patients showed a significant proportion of successful name recognition preceded by pessimistic prediction (Prediction_low_hits) in episodic memory. PLS revealed that behavioural pattern in AD patients was related with a mainly right lateralized pattern of GMV decrease including medial temporal lobe and posterior cingulate cortex, but also right ventrolateral prefrontal cortex (VLPFC). GLM further confirmed that pessimistic prediction negatively correlated with GMV in VLPFC. Thus, impaired monitoring processes (possibly influenced by inaccurate beliefs) allowing inferences about one’s own memory performance are primarily related to decrease GMV in VLPFC in AD patients. [less ▲]

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See detailRelating pessimistic memory predictions to Alzheimer’s disease brain structure
Genon, Sarah ULg; Simon, Jessica ULg; Bahri, Mohamed Ali ULg et al

in Cortex : A Journal Devoted to the Study of the Nervous System & Behavior (2016), 85

Patients with Alzheimer’s disease (AD) show impairment of episodic memory and related metacognitive processes. The present study examined subjective metacognitive judgments preceding objective memory ... [more ▼]

Patients with Alzheimer’s disease (AD) show impairment of episodic memory and related metacognitive processes. The present study examined subjective metacognitive judgments preceding objective memory retrieval and investigated the neural correlates of pessimistic predictions for successfully retrieved memories in AD patients. AD patients and healthy older participants provided predictive judgements on their recognition performance before retrieval of famous (semantic) and recently learned (episodic) names. Correlations between grey matter volume (GMV) in T1 images and behavioural scores were examined with multivariate (PLS) and univariate (GLM) analyses in AD patients. AD patients showed a significant proportion of successful name recognition preceded by pessimistic prediction (Prediction_low_hits) in episodic memory. PLS revealed that behavioural pattern in AD patients was related with a mainly right lateralized pattern of GMV decrease including medial temporal lobe and posterior cingulate cortex, but also right ventrolateral prefrontal cortex (VLPFC). GLM further confirmed that pessimistic prediction negatively correlated with GMV in VLPFC. Thus, impaired monitoring processes (possibly influenced by inaccurate beliefs) allowing inferences about one’s own memory performance are primarily related to decrease GMV in VLPFC in AD patients. [less ▲]

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See detailEVALUATING THE SPECIFICITY OF [18F]UCB-H FOR THE ISOFORM SV2A, COMPARED WITH ISOFORMS SV2B AND SV2C
Serrano Navacerrada, Maria Elisa ULg; Aerts, Joël ULg; Bahri, Mohamed Ali ULg et al

Poster (2016, November 18)

Background: SV2A is the most studied isoform of the Synaptic Vesicle 2 proteins, which are involved in the synaptic vesicle trafficking, being important in normal and pathological process, like the ... [more ▼]

Background: SV2A is the most studied isoform of the Synaptic Vesicle 2 proteins, which are involved in the synaptic vesicle trafficking, being important in normal and pathological process, like the epilepsy (1, 2). [18F]UCB-H was developed like a tool to study the role of this isoform with neuroimaging techniques (3, 4). The objective of this study was to evaluate its specificity to this isoform comparing with the others, through a competition assay in rats with ex-vivo autoradiography and mPET imaging. Methods: Forty male Sprague-Dawley were used in ex-vivo autoradiography experiments (N=20) and in microPET imaging (N=20). Animals were pre-treated 30 minutes before the injection of [18F]UCB-H with a dose IP either of vehicle, Keppra (SV2A ligand), UCB068 (SV2B ligand) or UCB054 (SV2C ligand). Ex-vivo autoradiography was carried out 5 minutes after radiotracer injection while mPET images were acquiring with a dynamic scanner of 1 hour. Data were expressed in Standard Uptake Value and then, the area under the curve was calculated for the total process. Results: In ex-vivo autoradiography, ANOVA of two-ways showed statistical significant differences in brain uptake of [18F]UCB-H among the groups pretreated with Keppra or the ligand for SV2B and the control group. Regarding mPET data, statistical significant differences were found between the group injected with keppra and the rest of groups. Conclusion: Even if a considerable affinity between the ligands UCB068 and UCB054, and the receptor for the isoform SV2A exists, it is only detected during the first 5 minutes (ex-vivo technique), being certainly due to a nonspecific binding. This binding is not strong enough to show a direct competition with the radiotracer during a mPET acquisition. These results allow us to conclude that [18F]UCB-H is a suitable radiotracer for the imaging of the isoform SV2A in vivo, allowing us the clinical study about the molecular base of a disease with a high population impact, like the epilepsy. [less ▲]

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See detailResting-state Network-specific Breakdown of Functional Connectivity during Ketamine Alteration of Consciousness in Volunteers
BONHOMME, Vincent ULg; VANHAUDENHUYSE, Audrey ULg; Demertzi, Athina ULg et al

in Anesthesiology (2016), 125(5), 873-878

Background: Consciousness-altering anesthetic agents disturb connectivity between brain regions composing the resting-state consciousness networks (RSNs). The default mode network (DMn), executive control ... [more ▼]

Background: Consciousness-altering anesthetic agents disturb connectivity between brain regions composing the resting-state consciousness networks (RSNs). The default mode network (DMn), executive control network, salience network (SALn), auditory network, sensorimotor network (SMn), and visual network sustain mentation. Ketamine modifies consciousness differently from other agents, producing psychedelic dreaming and no apparent interaction with the environment. The authors used functional magnetic resonance imaging to explore ketamine-induced changes in RSNs connectivity. Methods: Fourteen healthy volunteers received stepwise intravenous infusions of ketamine up to loss of responsiveness. Because of agitation, data from six subjects were excluded from analysis. RSNs connectivity was compared between absence of ketamine (wake state [W1]), light ketamine sedation, and ketamine-induced unresponsiveness (deep sedation [S2]). Results: Increasing the depth of ketamine sedation from W1 to S2 altered DMn and SALn connectivity and suppressed the anticorrelated activity between DMn and other brain regions. During S2, DMn connectivity, particularly between the medial prefrontal cortex and the remaining network (effect size β [95% CI]: W1 = 0.20 [0.18 to 0.22]; S2 = 0.07 [0.04 to 0.09]), and DMn anticorrelated activity (e.g., right sensory cortex: W1 = −0.07 [−0.09 to −0.04]; S2 = 0.04 [0.01 to 0.06]) were broken down. SALn connectivity was nonuniformly suppressed (e.g., left parietal operculum: W1 = 0.08 [0.06 to 0.09]; S2 = 0.05 [0.02 to 0.07]). Executive control networks, auditory network, SMn, and visual network were minimally affected. Conclusions: Ketamine induces specific changes in connectivity within and between RSNs. Breakdown of frontoparietal DMn connectivity and DMn anticorrelation and sensory and SMn connectivity preservation are common to ketamine and propofol-induced alterations of consciousness. [less ▲]

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See detailEnabling efficient PET imaging of Synaptic Vesicle glycoprotein 2A (SV2A) with a robust and one-step radiosynthesis of a highly potent 18F-labelled ligand ([18F]UCB-H)
Warnier, Corentin ULg; Lemaire, Christian ULg; Becker, Guillaume ULg et al

in Journal of Medicinal Chemistry (2016), 59

We herein describe the straightforward synthesis of a stable pyridyl(4- methoxyphenyl)iodonium salt and its [18F]radiolabelling within a one-step, fully automated and cGMP compliant radiosynthesis of [18F ... [more ▼]

We herein describe the straightforward synthesis of a stable pyridyl(4- methoxyphenyl)iodonium salt and its [18F]radiolabelling within a one-step, fully automated and cGMP compliant radiosynthesis of [18F]UCB-H ([18F]7), a PET tracer for the imaging of Synaptic Vesicle glycoprotein 2A (SV2A). Over the course of one year, 50 automated productions provided 34±2% of injectable [18F]7 from up to 285 GBq (7.7 Ci) of [18F]fluoride in 50 minutes (uncorrected radiochemical yield. Specific Activity = 815±185 GBq/μmol). The successful implementation of our synthetic strategy within routine, high-activity and cGMP productions attests to its practicality and reliability for the production of large doses of [18F]7. In addition to enabling efficient and cost-effective clinical research on a range of neurological pathologies through the imaging of SV2A, this work further demonstrates the real value of iodonium salts for the cGMP 18F-PET tracer manufacturing industry, and their ability to fulfill practical and regulatory requirements in that field. [less ▲]

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See detailBiodistribution of Novel 68Ga-Radiolabelled HER2 Aptamers in Mice
Gijs, Marlies; Becker, Guillaume ULg; Plenevaux, Alain ULg et al

in Journal of Nuclear Medicine and Radiation Therapy (2016), 7(5),

Background: Two novel HER2 aptamers were recently selected with great potential for the in vitro diagnosis of HER2-positive cancer. The goal of this study was to examine the in vivo diagnostic potential ... [more ▼]

Background: Two novel HER2 aptamers were recently selected with great potential for the in vitro diagnosis of HER2-positive cancer. The goal of this study was to examine the in vivo diagnostic potential of these HER2 aptamers. Methods: Both HER2 aptamers were radiolabelled with 68Ga, injected in mice bearing a HER2-positive and HER2-negative tumour and evaluated by PET/MRI. Results: Ex vivo bio distribution analysis revealed high uptake in the blood, tissues and organs, except the brain. Interestingly, this high uptake was explained by the slow blood clearance due to non-specific aptamer binding to blood proteins. We observed accumulation of radioactivity in both tumours in time. Although higher uptake in the HER2-positive tumour compared to the HER2-negative tumour was observed, this was accompanied with more necrosis in the HER2-negative tumour, which was observed by 18FDG PET/CT. Conclusion: This work presents a first step towards the development of 68Ga-labelled aptamers for molecular cancer imaging. [less ▲]

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See detailEffects of aging on task- and stimulus-related cerebral attention networks
Kurth, Sophie ULg; Majerus, Steve ULg; Bastin, Christine ULg et al

in Neurobiology of Aging (2016), 44

Interactions between a dorsal attention (DAN) and a ventral attention cerebral network (VAN) have been reported in young participants during attention or short term memory (STM) tasks. Since it remains an ... [more ▼]

Interactions between a dorsal attention (DAN) and a ventral attention cerebral network (VAN) have been reported in young participants during attention or short term memory (STM) tasks. Since it remains an under-investigated question, age effects on DAN and VAN activity and their functional balance were explored during performance of a STM task. Older and young groups showed similar behavioral patterns of results. At the cerebral level, DAN activation increased as a function of increasing STM load in both groups, suggesting preserved activity in DAN during healthy aging. Age-related over-recruitment in regions of the DAN in the higher task load raised the question of compensation attempt versus less efficient use of neural resources in older adults. Lesser decrease of VAN activation with increasing load and decreased stimulus-driven activation in the VAN, especially in the higher load, in older participants suggested age-related reduced response in the VAN. However, functional connectivity measures showed that VAN was still functionally connected to the DAN in older participants. [less ▲]

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See detailFunction–structure connectivity in patients with severe brain injury as measured by MRI-DWI and FDG-PET
Annen, Jitka ULg; Heine, Lizette ULg; Ziegler, Erik et al

in Human Brain Mapping (2016), 37(11), 3707-3720

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See detailThe influence of COMT single nucleotide polymorphism (rs4680) on the neural substrates of working memory representations maintenance in healthy aging
Manard, Marine ULg; François, Sarah ULg; Bahri, Mohamed Ali ULg et al

Poster (2016, May 10)

The COMT val108/158met polymorphism was associated to the dopaminergic modulation in the brain, and therefore stimulated research on its influence for cognitive functioning and particularly working memory ... [more ▼]

The COMT val108/158met polymorphism was associated to the dopaminergic modulation in the brain, and therefore stimulated research on its influence for cognitive functioning and particularly working memory. First, a general advantage of carrying the met allele was reported. However, many studies used tasks that did not allow efficiently assessing the contribution of manipulation and maintenance processes in working memory, leading to divergent results, in both young and older populations, resulting in debates about the exact phenotypic effect of the COMT polymorphism. Using fMRI, this study was designed to assess the potential effect of the COMT polymorphism on age-related differences in working memory representations maintenance abilities (Sternberg paradigm). Partial Least Squares method was used to determine the brain-behavior correlations at low, intermediate, and high cognitive demands among young and older groups, homozygous for the val or for the met allele. First, young val/val showed some disadvantages at brain and behavioral level compared to their m/m counterparts. However, in older adults subgroups, the m/m participants tended to show greater age-related difference (when compared to younger adults with similar genotype), suggesting an advantage in carrying the val allele when dopamine signaling is not at optimal efficiency (optimal: young/middle adulthood vs suboptimal: childhood or older ages). These results will be discussed in regard to compensating theories and dopaminergic models accounting for the potential effect of COMT polymorphism on stability/flexibility abilities. [less ▲]

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See detailFeasibility study of repetitive diffusion MRI after Neoadjuvant radiotherapy for following tumor microenvironment.
LALLEMAND, François ULg; Leroi, Natacha ULg; Bahri, Mohamed Ali ULg et al

Conference (2016, March 22)

Purpose/Objective. Neoadjuvant radiotherapy (NeoRT) improves tumor local control and tumor resection in many cancers. The timing between the end of the NeoRT and surgery is mostly driven by the occurrence ... [more ▼]

Purpose/Objective. Neoadjuvant radiotherapy (NeoRT) improves tumor local control and tumor resection in many cancers. The timing between the end of the NeoRT and surgery is mostly driven by the occurrence of side effects or the tumor downsizing. We previously demonstrated in an in vivo model that the timing of surgery and the schedule of NeoRT influenced the tumor dissemination. Here, our aim is to evaluate with functional MRI (fMRI) the impact of the radiation treatment on the tumor microenvironment and subsequently to identify non-invasive markers helping to determine the best timing to perform surgery for avoiding tumor spreading. First, we needed to demonstrate the feasibility of repetitive MRI imaging after NeoRT in mice. Material/methods. We used two models of NeoRT we previously developed in mice: MDA-MB 231 and 4T1 cells implanted in the flank of mice. When tumors reached the planned volume, they are irradiated with 2x5 Gy and then surgically removed at different time points after RT. In the mean time between the end of RT and the surgical procedure, mice were imaged in a 9,4T Agilent® MRI. Diffusion Weighted (DW) -MRI was performed every 2 days between RT and surgery. For each tumors we acquired 8 slices of 1 mm thickness and 0.5 mm gap with an “in plane voxel resolution” of 0.5 mm. For DW-MRI, we performed FSEMS (Fast Spin Echo MultiSlice) sequences, with 9 different B-values (from 40 to 1000) and B0, in the 3 main directions. We also performed IVIM (IntraVoxel Incoherent Motion) analysis, in the aim to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor) and subsequently tumor vessels perfusion. Results. As preliminary results, with the MBA-MB 231 we observed a significant increase of F at day 6 after irradiation than a decrease and stabilization until surgery. No other modifications of the MRI signal, ADC, D or D* were observed. We observed similar results with 4T1 cells, F increased at day 3 than returned to initial signal. The difference in the timing of the peak of F can be related to the difference in tumor growth between MBA-MB 231 and 4T1 (four weeks vs one week). Conclusion. For the first time, we demonstrate the feasibility of repetitive fMRI imaging in mice models after NeoRT. With these models, we show a significant peak of the perfusion factor (F) at day 6 or day 3. This change occurs between the two previous time points of surgery demonstrating a difference in the metastatic spreading. Indeed, after a NeoRT of 2X5Gy we observed more metastases in the lung when MDA-MB 231 tumor bearing mice are operated 4 days after RT compared to 11 days. These preliminary results are very promising for identifying noninvasive markers for determining the best timing for surgery. [less ▲]

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See detailEVALUATION OF SV2Alox/Cre TRANSGENIC MICE USING [18F]UCB-H IN VITRO AUTORADIOGRAPHY
Serrano Navacerrada, Maria Elisa ULg; Becker, Guillaume ULg; MENTEN, Catherine ULg et al

Poster (2016, March 09)

Introduction Epilepsy is one of the commonest neurological disorders [1]. Antiepileptic drugs mainly target the SV2A protein [2] but its actual role is still largely unknown. [18F]UCB-H was developed to ... [more ▼]

Introduction Epilepsy is one of the commonest neurological disorders [1]. Antiepileptic drugs mainly target the SV2A protein [2] but its actual role is still largely unknown. [18F]UCB-H was developed to study in vivo SV2A brain proteins [3, 4]. The present pilot study was undertaken to evaluate for the first time in vivo in rats SV2A expression in the Kaïnic Acid (KA) epilepsy model [5]. Although this model is well studied in mice, few reports were devoted to rats. Imaging-wise, rats are very interesting thanks to a bigger brain size (reduction of the partial volume effect). Methods Three male Sprague-Dawley were used, one injected with saline and two with multiple KA injections (3 x 5mg/kg) [6]. 75 days later, when spontaneous seizures started to appear, microPET (Focus 120 ) was performed under isoflurane anesthesia (2.5-3 % in air) for 1 hour with [18F]UCB-H (41 ± 5 MBq IV tail vein) followed by MRI (9.4T Agilent, anatomical T2). Coregistration was done with PMOD 3.6 software. Data were expressed as SUV and areas under the curve were calculated for the different regions. Results [18F]UCB-H microPET images showed an important reduction (20-30%) for SV2A after KA injections mainly localized in amygdala, hippocampus, lateral parietal association cortex and cingulate cortex. The rest of the brain was globally unchanged. MRI revealed atrophy and inflammation in amygdala and hippocampus. Conclusions These preliminary results obtained in KA treated rats showed that [18F]UCB-H was able to detect important modifications for SV2A in relevant regions for epilepsy and appears as a valuable tool to follow in vivo SV2A through longitudinal studies. KA model in rats deserves for further development and validation as a tool for the study of epilepsy. [less ▲]

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