References of "Bahri, Mohamed Ali"
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See detailNeuro-functional correlates of the protective effects of exercise against cocaine sensitization and dopamine D2 receptors density: a [18F]Fallypride microPET study.
Becker, Guillaume ULiege; Lespine, Louis-Ferdinand ULiege; Serrano Navacerrada, Maria Elisa ULiege et al

in Molecular Imaging & Biology (in press)

Preclinical studies suggest that free access to a running wheel can attenuate behavioural effects of addictive drugs such as psychomotor sensitization to cocaine in rodents. This phenomenon has an ... [more ▼]

Preclinical studies suggest that free access to a running wheel can attenuate behavioural effects of addictive drugs such as psychomotor sensitization to cocaine in rodents. This phenomenon has an integral role in the process of drug addiction in craving and relapse (Steketee and Kalivas, 2011). Free wheel-running was recently shown to be efficacious at preventing the initiation or the long-term expression of psychomotor sensitization to cocaine in mice or rats (Diaz et al., 2013; Geuzaine and Tirelli, 2014). In the present study, we investigated the neuro-functional correlates of the protection against psychomotor sensitization to cocaine afforded by free wheel-running on dopaminergic neurotransmission, using microPET imaging with [18F]Fallypride, a Dopamine 2 receptor (D2R) antagonist. Sixty-four 28-day-old female C57BL/6J mice were randomly assigned to one of the two housing conditions, defined by the presence or the absence of a running wheel in the cage over a 6-week pre-testing period. Since mice from the two types of housing received either saline (controls) or cocaine (8 mg/kg, i.p.) during testing (9 once-daily sessions to establish sensitization plus 1 single session to test its expression), a basic 2x2 randomized blocks design was generated (2-way ANOVA and planned comparisons; n=10). Experimentation lasted 85 days, with a 42-day period of pre-testing and a 3-week interval preceding the test for long-term expression of sensitization (LTES). All mice underwent a microPET (Focus 120, Siemens) the day after the LTES. The microPET protocol consisted of a 60 min. dynamic acquisition after the injection of 10 MBq of [18F]Fallypride in the tail vein. Wheel-running strongly and significantly attenuated LTES (interaction) to cocaine (Cohen’s d=1.63; t(21)=3.75, p<.001) and cocaine-treated mice exhibited a clear-cut and significant increase (main effect) of the [18F]Fallypride BP (d=0.88, t(31)=2.45, p =.02). Wheel-running induced an overall moderate-sized decrease (main effect) of the [18F]Fallypride BP, but without achieving statistical significance (d=0.64, t(31)=1.79, p =.08). These findings suggest that LTES is associated with an increase of the [18F]Fallypride BP in the mouse striatum, probably reflecting an increase in postsynaptic D2R density in this region. Also, the protecting effect of free running on psychomotor sensitization goes together with a decrease in D2R density in the striatum of exercised mice. We intend to complement the present study with an identical experiment to reach a total number of 80 mice (n=20). This will confer to our study a sufficient power (80%) for the main effect of wheel-running exercise on [18F]Fallypride BP to be detected at an alpha-level of 5%. Finally, autoradiography studies, performed on the same mice with [18F]Fallypride, will strengthen our in vivo results. [less ▲]

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See detailSelf in Dementia
Antoine, Nicolas ULiege; Genon, Sarah ULiege; Bastin, Christine ULiege 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 detailMeasuring brain synaptic vesicle protein 2A with positron emission tomography and [18F]UCB-H.
Bahri, Mohamed Ali ULiege; Plenevaux, Alain ULiege; Aerts, Joël ULiege et al

in Alzheimer’s & Dementia: Translational Research & Clinical Interventions (2017), 4(4), 481-486

Introduction: Brain distribution of synaptic vesicle protein 2Awas measured with fluorine-18 UCBH ([18F]UCB-H) and positron emission tomography (PET). Methods: Images of synaptic density were acquired in ... [more ▼]

Introduction: Brain distribution of synaptic vesicle protein 2Awas measured with fluorine-18 UCBH ([18F]UCB-H) and positron emission tomography (PET). Methods: Images of synaptic density were acquired in healthy volunteers (two young participants and two seniors). Input function was measured by arterial blood sampling (arterial input function) and derived from PET images using carotid activity (image-derived input function). Logan graphical analysis was used to estimate regional synaptic vesicle protein 2A distribution volume. Results: [18F]UCB-H uptake was ubiquitous in cortical and subcortical gray matter. Arterial input function and image-derived input function provided regional distribution volume with a high linear relationship. Discussion: The cerebral distribution of [18F]UCB-H is similar to that recently observed with carbon-11 UCB-J ([11C]UCB-J). An accurate [18F]UCB-H quantification can be performed without invasive arterial blood sampling when no suitable reference region is available, using dynamic PET carotid activity. Brain synaptic density can be studied in vivo in normal and pathological aging. [less ▲]

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See detailNanofitin as a New Molecular-Imaging Agent for the Diagnosis of 2 Epidermal Growth Factor Receptor Over-Expressing Tumors.
Goux, Marine; Becker, Guillaume ULiege; Gorré, Harmony et al

in Bioconjugate Chemistry (2017), 28(9), 2361-2371

Epidermal growth-factor receptor (EGFR) is involved in cell growth and proliferation and is over-expressed in malignant tissues. Although anti-EGFR-based immunotherapy became a standard of care for ... [more ▼]

Epidermal growth-factor receptor (EGFR) is involved in cell growth and proliferation and is over-expressed in malignant tissues. Although anti-EGFR-based immunotherapy became a standard of care for patients with EGFR-positive tumors, this strategy of addressing cancer tumors by targeting EGFR with monoclonal antibodies is less-developed for patient diagnostic and monitoring. Indeed, antibodies exhibit a slow blood clearance, which is detrimental for positron emission tomography (PET) imaging. New molecular probes are proposed to overcome such limitations for patient monitoring, making use of low-molecular-weight protein scaffolds as alternatives to antibodies, such as Nanofitins with better pharmacokinetic profiles. Anti-EGFR Nanofitin B10 was reformatted by genetic engineering to exhibit a unique cysteine moiety at its C-terminus, which allows the development of a fast and site-specific radiolabeling procedure with 18F−4-fluorobenzamido-N-ethylamino-maleimide (18F−FBEM). The in vivo tumor targeting and imaging profile of the anti-EGFR Cys−B10 Nanofitin was investigated in a double-tumor xenograft model by static small-animal PET at 2 h after tail-vein injection of the radiolabeled Nanofitin 18F−FBEM−Cys−B10. The image showed that the EGFR- positive tumor (A431) is clearly delineated in comparison to the EGFR-negative tumor (H520) with a significant tumor-to-background contrast. 18F−FBEM−Cys−B10 demonstrated a significantly higher retention in A431 tumors than in H520 tumors at 2.5 h post-injection with a A431-to-H520 uptake ratio of 2.53 ± 0.18 and a tumor-to-blood ratio of 4.55 ± 0.63. This study provides the first report of Nanofitin scaffold used as a targeted PET radiotracer for in vivo imaging of EGFR-positive tumor, with the anti-EGFR B10 Nanofitin used as proof-of-concept. The fast generation of specific Nanofitins via a fully in vitro selection process, together with the excellent imaging features of the Nanofitin scaffold, could facilitate the development of valuable PET-based companion diagnostics. [less ▲]

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

Poster (2017, June 29)

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See detailPharmacokinetic characterization of [18F]UCB-H PET radiopharmaceutical in the rat brain.
Becker, Guillaume ULiege; Warnier, Corentin; Serrano Navacerrada, Maria Elisa ULiege et al

in Molecular Pharmaceutics (2017), 14(8), 2719-2725

The synaptic vesicle glycoprotein 2A (SV2A), a protein essential to the proper nervous system function, is found in presynaptic vesicles. Thus, SV2A targeting, using dedicated radiotracers combined with ... [more ▼]

The synaptic vesicle glycoprotein 2A (SV2A), a protein essential to the proper nervous system function, is found in presynaptic vesicles. Thus, SV2A targeting, using dedicated radiotracers combined with positron emission tomography (PET), allows the assessment of synaptic density in the living brain. The first-in-class fluorinated SV2A specific radioligand, [18F]UCB-H, is now available at high-activity through an efficient radiosynthesis compliant with the current good manufacturing practices (cGMP). We report here a non-invasive method to quantify [18F]UCB-H binding in rat brain with microPET. Validation study in rats confirmed the need of high enantiomeric purity to target SV2A in vivo. We demonstrated the reliability of a population-based input function to quantify SV2A in preclinical microPET setting. Finally, we investigated the in vivo metabolism of [18F]UCB-H and confirmed the negligible amount of radiometabolites in the rat brain. Hence, the in vivo quantification of SV2A using [18F]UCB-H microPET seems a promising tool for the assessment of the synaptic density in the rat brain, and opens the way for longitudinal follow-up in neurodegenerative diseases rodents’ models. [less ▲]

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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 ULiege; Bahri, Mohamed Ali ULiege; 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 detailFunctional correlates of the protective effects of free wheel-running against cocaine psychomotor sensitization on dopamine D2 receptors: a [18F]Fallypride microPET study.
Becker, Guillaume ULiege; Lespine, Louis-Ferdinand ULiege; Bahri, Mohamed Ali ULiege et al

Conference (2017, April 05)

Preclinical studies suggest that free access to a running wheel can attenuate the behavioural responsiveness to addictive drugs in rodents. Regarding the behavioural responsiveness to drugs, psychomotor ... [more ▼]

Preclinical studies suggest that free access to a running wheel can attenuate the behavioural responsiveness to addictive drugs in rodents. Regarding the behavioural responsiveness to drugs, psychomotor sensitization has an integral role in the process of drug addiction in craving and relapse (Steketee and Kalivas, 2011). Free wheel-running was recently shown to be efficacious at preventing the initiation or the long-term expression of psychomotor sensitization to cocaine in mice or rats (Diaz et al., 2013; Geuzaine and Tirelli, 2014). In the present study, we investigated the neuro-functional correlates of the protection against psychomotor sensitization to cocaine afforded by free wheel-running on dopaminergic neurotransmission, using microPET imaging with [18F]Fallypride, a Dopamine 2 receptor (D2R) antagonist. We used a total of 32 female C57BL/6J mice. At 28 days of age, the mice were randomly assigned to on of the two experimental housing conditions, defined by the presence or the absence of a running wheel in the cage (pre-testing period: 6 weeks). Since mice from the two types of housing received either saline or cocaine (8 mg/kg, i.p.) during testing (9 days), a basic 2*2 factorial design was generated (two-way ANOVA). The whole experimentation lasted 85 days, included the 42-days pre-testing period and the 3 weeks (housing condition, no injection) between the testing and the long-term expression of sensitization (LTES). All mice underwent a microPET (Focus 120, Siemens) the day after the LTES. The microPET protocol consisted of a 60 min. dynamic acquisition after the injection of 10 MBq of [18F]Fallypride in the tail vein. We observe a strong attenuating effect of exercise on the expression of sensitization to cocaine (Effect Size = 2.66 at p < .001 one-tailed, N.B: Effect Size is the mean difference in standard deviation units). Regarding the microPET outcomes ([18F]Fallypride Binding Potential, BP), we have a significant increase of the [18F]Fallypride BP for the cocaine-treated mice, compared to the saline-injected mice (Effect Size = 0.78 at p = .02 one-tailed). We observe a decrease tendency of the [18F]Fallypride BP in the exercise condition compared to the sedentary condition (ES = 0.48 at p = .09 one-tailed). These findings indicate that LTES is associated with an increase of the [18F]Fallypride BP in the mouse striatum, probably reflecting an increase in postsynaptic D2R density in this region. Besides that, the protecting effect of free running on psychomotor sensitization goes together with a decrease in D2R density in the striatum of exercised mice. Those data will be augmented with identical sub-experiment. All data will be pooled together to reach a total number of 64 mice (n = 16 per group). [less ▲]

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See detailRelating pessimistic memory predictions to Alzheimer’s disease brain structure
Genon, Sarah ULiege; Simon, Jessica ULiege; Bahri, Mohamed Ali ULiege 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 detailNoninvasive quantification of [18F]UCB-H binding using microPET and population-based input function.
Becker, Guillaume ULiege; Warnier, C; Serrano Navacerrada, Maria Elisa ULiege et al

Poster (2017, February 19)

Introduction: [18F]UCB-H is a validated radiotracer with a high affinity for the synaptic vesicle glycoprotein 2A (SV2A), known as the binding site of the antiepileptic drug levetiracetam [1, 2]. Due to ... [more ▼]

Introduction: [18F]UCB-H is a validated radiotracer with a high affinity for the synaptic vesicle glycoprotein 2A (SV2A), known as the binding site of the antiepileptic drug levetiracetam [1, 2]. Due to the absence of reference region, the major drawback of SV2A microPET imaging in the living rat brain is the invasiveness and the complexity of the arterial input function measurement needed for a full quantification. We provide here evaluation of a population-based input function (PBIF) to estimate input function of [18F]UCB-H. Methods: Standard arterial input functions were measured with an arteriovenous shunt and a β-microprobe system from eight anesthetized Sprague-Dawley (SD) rats, as previously described [2]. The distribution volume (Vt) for [18F]UCB-H was calculated with Logan graphic analysis. After normalization, all individual AIFs were averaged to provide the PBIF, and the Logan graphical analysis was computed on each individual rat using the PBIF instead of individual AIF. Correlations analyses were computed between Vt obtained with each methods (individual AIF vs PBIF). Finally, another cohort of five SD rats was scanned with [18F]UCB-H, and Vt were computed using the PBIF and Logan analysis. Single blood samples were harvested at 15 min after radiotracer injection, just to ensure the consistency of the metabolic parent fraction. Results: The Vt computed with individual AIFs were higly consistent with previously reported values, so are the Vt computed with the PBIF [2]. Individual AIFs Vt and PBIF Vt are highly correlated through all brain areas for the height subjects (r2 =0.9). Coefficients of variance are slightly higher with the PBIF method compare to the individual AIF method (14 % and 9 % respectively for the whole brain). Finally, Vt measurement in the second cohort were consistent with previously reported values, and the metabolization profile matched the parent fraction described by Warnock and coll. [2]. Conclusions: The present study described a method for the noninvasive estimation of the AIF using a PBIF, carrying a potential that might substitute for conventional invasive, indivi- dual AIF measurement. We propose that this method can provide a reasonable solution for longitudinal quantitative [18F]UCB-H microPET studies. [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 ULiege; Becker, Guillaume ULiege; Bahri, Mohamed Ali ULiege et al

Poster (2017, February 01)

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 detailSedation of Patients With Disorders of Consciousness During Neuroimaging: Effects on Resting State Functional Brain Connectivity.
KIRSCH, Murielle ULiege; Guldenmund, Pieter; Bahri, Mohamed Ali ULiege et al

in Anesthesia and Analgesia (2017), 124(2),

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See detailIN VIVO STUDY OF THE SV2A PROTEIN IN THE KAINIC ACID EPILEPSY RAT MODEL
Serrano Navacerrada, Maria Elisa ULiege; Becker, Guillaume ULiege; Bahri, Mohamed Ali ULiege et al

Poster (2017)

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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See detailIN VIVO STUDY OF THE SV2A PROTEIN IN AN EPILEPTIC RAT MODEL
Serrano Navacerrada, Maria Elisa ULiege; Becker, Guillaume ULiege; Bahri, Mohamed Ali ULiege et al

Poster (2017)

Introduction Epilepsy is one of the commonest neurological disorders, affecting more than 60 million people worldwide [1]. New and effective antiepileptic drugs mainly target the SV2A protein [2] but its ... [more ▼]

Introduction Epilepsy is one of the commonest neurological disorders, affecting more than 60 million people worldwide [1]. New and effective antiepileptic drugs mainly target the SV2A protein [2] but its actual role is still largely unknown. [18F]UCB-H was developed as a tool to study in vivo the brain expression of this isoform [3, 4]. Due to the fact that only post-mortem studies were reported so far [5] the present pilot study was undertaken in order to evaluate for the first time in vivo in rats the SV2A expression in the validated Kaïnic Acid (KA) epilepsy model [6]. Methods Three male Sprague-Dawley were used, one injected with saline (Sham) and two with multiple KA systemic injections (5mg/kg x 3) [9]. SV2A brain levels were estimated at day 75, when spontaneous seizures started to appear. Animals were anesthetized (2.5 to 3 % isoflurane), and scanned for 1 hour with [18F]UCB-H (41 ± 5 MBq IV tail vein) in a Focus 120 microPET system and with MRI (9.4T Agilent, anatomical T2). Coregistration was done with PMOD 3.6 software. Data were expressed in 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 in KA treated rats presenting spontaneous seizures showed that [18F]UCB-H microPET was able to detect important reductions for the SV2A proteins in relevant regions for epilepsy [5]. Accordingly to this, we can infer that the KA model in rats deserves for further development and validation as a tool for the study of epilepsy. [18F]UCB-H appears as a valuable tool to follow in vivo SV2A proteins through longitudinal protocols and in turn to better understand its actual role in epilepsy. References/acknowledgements This work was funded by University of Liège, F.R.S.-FNRS, Walloon Region and UCB Pharma. Alain Plenevaux is research director from F.R.S.-FNRS. [1] Alexopoulos, Epileptology, 2004 [2] Hamann et al., Eur J Pharmacol, 2008 [3] Bretin et al., Molecular Imaging and Biology, 2015 [4] Warnock et al., J Nucl Med., 2014 [5] Wang et al., J Mol Neurosci., 2014 [6] Hellier et al., Epilepsy Res., 1998 [less ▲]

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See detail[18F]UCB-H RADIOTRACER AS A TOOL TO UNDERSTAND THE ROLE OF THE SV2A PROTEIN
Serrano Navacerrada, Maria Elisa ULiege; Becker, Guillaume ULiege; Bahri, Mohamed Ali ULiege et al

Poster (2017)

Background: SV2A is the most studied isoform of the Synaptic Vesicle 2 proteins, which are involved in the synaptic vesicle trafficking, being important both in normal as in pathological process (1, 2 ... [more ▼]

Background: SV2A is the most studied isoform of the Synaptic Vesicle 2 proteins, which are involved in the synaptic vesicle trafficking, being important both in normal as in pathological process (1, 2). Until now, only one study in vivo has been reported, showing a reduction of SV2A levels in the epilepsy (3). [18F]UCB-H was developed like a current tool to study the role of SV2A with in vivo techniques (4, 5), and as a tool in clinical investigations. The objective of this research was to evaluate the radiotracer 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. Standard Uptake Value (SUV) and Distribution Volume (VT) were calculated and the correlation between both parameters was determined. 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. Pearson Correlation between SUV and VT was strong, with a value of 0.955. 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. 1) Van Vliet et al., 2009. Epilepsia 2) Crèvecœur et al., 2013. BMC Neurosci. 3) Finnema et al., 2016; Sci Transl Med. 4) Bretin et al., 2013.EJNMMI Res 5) Bretin et al., 2015.Mol Imaging Biol [less ▲]

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See detailAltered functional brain connectivity in patients with visually induced dizziness
Van Ombergen, Angelique; Heine, Lizette ULiege; Jillings, Steven et al

in NeuroImage (2017), 14

Background: Vestibular patients occasionally report aggravation or triggering of their symptoms by visual stimuli, which is called visually induced dizziness (VID). These patients therefore experience ... [more ▼]

Background: Vestibular patients occasionally report aggravation or triggering of their symptoms by visual stimuli, which is called visually induced dizziness (VID). These patients therefore experience dizziness, discomfort, disorientation and postural unsteadiness. The underlying pathophysiology of VID is still poorly understood. Objective: The aimof the current explorative study was to gain a first insight in the underlying neural aspects of VID. Methods:We included 10 VID patients and 10 healthymatched controls, all ofwhich underwent a resting state fMRI scan session. Changes in functional connectivitywere explored bymeans of the intrinsic connectivity contrast (ICC). Seed-based analysis was subsequently performed in visual and vestibular seeds. Results: We found a decreased functional connectivity in the right central operculum (superior temporal gyrus), as well as increased functional connectivity in the occipital pole in VID patients as compared to controls in a hypothesis-free analysis. A weaker functional connectivity between the thalamus and most of the right putamen was measured in VID patients in comparison to controls in a seed-based analysis. Furthermore, also by means of a seed-based analysis, a decreased functional connectivity between the visual associative area and the left parahippocampal gyrus was found in VID patients. Additionally,we found increased functional connectivity between thalamus and occipital and cerebellar areas in the VID patients, as well as between the associative visual cortex and both middle frontal gyrus and precuneus. Conclusions:We found alterations in the visual and vestibular cortical network in VID patients that could underlie the typical VID symptoms such as a worsening of their vestibular symptoms when being exposed to challenging visual stimuli. These preliminary findings provide the first insights into the underlying functional brain connectivity in VID patients. Future studies should extend these findings by employing larger sample sizes, by investigating specific task-based paradigms in these patients and by exploring the implications for treatment. [less ▲]

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See detailFlow dynamics at the origin of thin clayey sand lacustrine turbidites: Examples from Lake Hazar, Turkey
Hage, Sophie; Hubert, Aurelia ULiege; Lamair, Laura ULiege et al

in Sedimentology (2017)

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