References of "Plenevaux, Alain"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailAnxiety-like features and spatial memory problems as a consequence of hippocampal SV2A expression.
Serrano Navacerrada, Maria Elisa ULiege; Bartholomé, Odile ULiege; Van den Ackerveken, Priscillia et al

in PLoS ONE (2019)

The Synaptic Vesicle Protein 2A (SV2A) is a transmembrane protein whose presence is reduced both in animal models and in patients with chronic epilepsy. Besides its implication in the epileptic process ... [more ▼]

The Synaptic Vesicle Protein 2A (SV2A) is a transmembrane protein whose presence is reduced both in animal models and in patients with chronic epilepsy. Besides its implication in the epileptic process, the behavioural consequences of the changes in its expression remain unclear. The purpose of our research is to better understand the possible role(s) of this protein through the phenotype of cKO (Grik4 Cre+/-, SV2A lox/lox) mice, male and female, which present a specific decrease of SV2A expression levels in the hippocampal glutamatergic neurons but without any epileptic seizures. In this study, we compare the cKO mice with cHZ (Grik4 Cre+/-, SV2A lox/+) and WT (Grik4 Cre+/+, SV2A lox/lox) mice through a battery of tests, used to evaluate different features: the anxiety-related features (Elevated Plus Maze), the locomotor activity (Activity Chambers), the contextual fear-related memory (Contextual Fear Conditioning), and the spatial memory (Barnes Maze). Our results showed statistically significant differences in the habituation to a new environment, an increase in the anxiety levels and spatial memory deficit in the cHZ and cKO groups, compared to the WT group. No statistically significant differences due to the genotype appeared in the spontaneous locomotor activity or the fear-linked memory. However, sexual differences were observed in this last feature. These results highlight not only an important role of the SV2A protein in the cognitive and anxiety problems typically encountered in epileptic patients, but also a possible role in the symptomatology of other neurodegenerative diseases, such as the Alzheimer’s disease. [less ▲]

Detailed reference viewed: 23 (3 ULiège)
Full Text
Peer Reviewed
See detailChanges in Whole Brain Dynamics and Connectivity Patterns during Sevoflurane- and Propofol-induced Unconsciousness Identified by Functional Magnetic Resonance Imaging
Golkowski, Daniel; Larroque, Stephen ULiege; Vanhaudenhuyse, Audrey et al

in Anesthesiology (2019), 130(6), 898-911

Background: A key feature of the human brain is its capability to adapt flexibly to changing external stimuli. This capability can be eliminated by general anesthesia, a state characterized by ... [more ▼]

Background: A key feature of the human brain is its capability to adapt flexibly to changing external stimuli. This capability can be eliminated by general anesthesia, a state characterized by unresponsiveness, amnesia, and (most likely) unconsciousness. Previous studies demonstrated decreased connectivity within the thalamus, frontoparietal, and default mode networks during general anesthesia. We hypothesized that these alterations within specific brain networks lead to a change of communication between networks and their temporal dynamics. Methods: We conducted a pooled spatial independent component analysis of resting-state functional magnetic resonance imaging data obtained from 16 volunteers during propofol and 14 volunteers during sevoflurane general anesthesia that have been previously published. Similar to previous studies, mean z-scores of the resulting spatial maps served as a measure of the activity within a network. Additionally, correlations of associated time courses served as a measure of the connectivity between networks. To analyze the temporal dynamics of between-network connectivity, we computed the correlation matrices during sliding windows of 1 min and applied k-means clustering to the matrices during both general anesthesia and wakefulness. Results: Within-network activity was decreased in the default mode, attentional, and salience networks during general anesthesia (P < 0.001, range of median changes: –0.34, –0.13). Average between-network connectivity was reduced during general anesthesia (P < 0.001, median change: –0.031). Distinct between-network connectivity patterns for both wakefulness and general anesthesia were observed irrespective of the anesthetic agent (P < 0.001), and there were fewer transitions in between-network connectivity patterns during general anesthesia (P < 0.001, median number of transitions during wakefulness: 4 and during general anesthesia: 0). Conclusions: These results suggest that (1) higher-order brain regions play a crucial role in the generation of specific between-network connectivity patterns and their dynamics, and (2) the capability to interact with external stimuli is represented by complex between-network connectivity patterns. [less ▲]

Detailed reference viewed: 23 (8 ULiège)
Full Text
Peer Reviewed
See detailEvaluating the In Vivo Specificity of [18F]UCB-H for the SV2A Protein, Compared with SV2B and SV2C in Rats Using microPET.
Serrano Navacerrada, Maria Elisa ULiege; Becker, Guillaume ULiege; Bahri, Mohamed Ali ULiege et al

in Molecules (2019), 24(9), 1705

The synaptic vesicle protein 2 (SV2) is involved in synaptic vesicle trafficking. The SV2A isoform is the most studied and its implication in epilepsy therapy led to the development of the first SV2A PET ... [more ▼]

The synaptic vesicle protein 2 (SV2) is involved in synaptic vesicle trafficking. The SV2A isoform is the most studied and its implication in epilepsy therapy led to the development of the first SV2A PET radiotracer [18F]UCB-H. The objective of this study was to evaluate in vivo, using microPET in rats, the specificity of [18F]UCB-H for SV2 isoform A in comparison with the other two isoforms (B and C) through a blocking assay. Twenty Sprague Dawley rats were pre-treated either with the vehicle, or with specific competitors against SV2A (levetiracetam), SV2B (UCB5203) and SV2C (UCB0949). The distribution volume (Vt, Logan plot, t* 15 min) was obtained with a population-based input function. The Vt analysis for the entire brain showed statistically significant differences between the levetiracetam group and the other groups (p < 0.001), but also between the vehicle and the SV2B group (p < 0.05). An in-depth Vt analysis conducted for eight relevant brain structures confirmed the statistically significant differences between the levetiracetam group and the other groups (p < 0.001) and highlighted the superior and the inferior colliculi along with the cortex as regions also displaying statistically significant differences between the vehicle and SV2B groups (p < 0.05). These results emphasize the in vivo specificity of [18F]UCB-H for SV2A against SV2B and SV2C, confirming that [18F]UCB-H is a suitable radiotracer for in vivo imaging of the SV2A proteins with PET. [less ▲]

Detailed reference viewed: 18 (7 ULiège)
Full Text
Peer Reviewed
See detailTumor modifications recorded with IVIM and DCE-MRI after Neoadjuvant radiotherapy.
LALLEMAND, François ULiege; LEROI, Natacha ULiege; Bahri, Mohamed Ali ULiege et al

in Radiotherapy and Oncology (2019, April), 133(Supplement 1), 284-285

Purpose or Objective Neoadjuvant radiotherapy (NeoRT) improves tumor local control and facilitates tumor resection in many cancers. We hypothesized anti-cancer treatments (i.e. radiotherapy) modify tumor ... [more ▼]

Purpose or Objective Neoadjuvant radiotherapy (NeoRT) improves tumor local control and facilitates tumor resection in many cancers. We hypothesized anti-cancer treatments (i.e. radiotherapy) modify tumor microenvironment and could potentially impact distant metastases occurrence. Previously, we developed a pre-clinical model demonstrating an impact of NeoRT schedule and the timing of surgery on metastatic spreading (Leroi et al. Oncotarget 2015). Here, we aim to identify by fMRI noninvasive markers reflecting NeoRT related tumor microenvironment modifications that could predict the best timing for performing surgery and avoiding tumor spreading. Material and Methods To briefly delineate the NeoRT model, MDA-MB 231 tumor cells implanted in the flank of SCID mice were locally irradiated with 2x5Gy when tumor reached 100mm3 and then surgically removed at different time points. We performed fMRI, Diffusion Weighted (DW) and Dynamic Contract enhancement (DCE) – MRI, before RT and every 2 days between RT and surgery. 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 Bvalue (from 40 to 1000) and B0. We performed IVIM (IntraVoxel Incoherent Motion) analysis to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor) and subsequently tumor vessels perfusion. For DCE-MRI, we performed a T1 mapping with multiple TR and DCE acquisition with 200 repetitions of 3 sec each and gadolinium IV injection after 10 repetitions. We performed semi-quantitative analysis. We validated tumor perfusion by immunochemistry with injection of FITC-dextran IV 3 min before surgery and CD31 labelling. Human Ki67 was used for lung metastases labelling and quantification. Results After the tumor irradiation, we observed a significant and transient increase at day 6 (60% of the basal value (n=6, p<0,05)) of F and D* parameters related to perfusion. The other parameters of the DW-MRI, ADC and D presented no modifications. The sham irradiated tumors used as control showed no modifications of all fMRI parameters. At the same timing, 6 days post-radiotherapy, DCE-MRI significantly demonstrated a WhashinSlope (n=13, p<0,05) increase. Immunochemistry confirmed the increase of tumor perfusion when surgery is performed at day 6. The sham irradiated tumors never demonstrated such changes. Finally, when surgery is performed on tumor increased perfusion measured by fMRI, it demonstrated a burst of lung metastasis compared to the other timings. Conclusion We showed a significant difference in perfusion-related parameters with fMRI and immunochemistry at a specific time point after NeoRT. These modifications are correlated with an increase of metastasis spreading related to surgery procedure. These results open new perspectives in the personalized medicine and MRI guided surgery timing after NeoRT. [less ▲]

Detailed reference viewed: 19 (3 ULiège)
Full Text
Peer Reviewed
See detailFully Automated Synthesis and Evaluation of [ 18 F]BPAM121: Potential of an AMPA Receptor Positive Allosteric Modulator as PET Radiotracer
Manos-Turvey, A.; Becker, Guillaume ULiege; Francotte, Pierre ULiege et al

in ChemMedChem (2019), 14(7), 788-795

Alzheimer's disease (AD) remains a significant burden on society. In the search for new AD drugs, modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are of particular ... [more ▼]

Alzheimer's disease (AD) remains a significant burden on society. In the search for new AD drugs, modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are of particular interest, as loss of synaptic AMPARs has been linked to AD learning and memory deficits. Previously reported fluorine-containing BPAM121, an AMPA positive allosteric modulator (pam) with high activity, low toxicity, and slow metabolism, was considered to be a perfect 18 F-labeled candidate for positron emission tomography (PET) AD diagnostic investigations. For the preclinical use of this compound, an automated synthesis avoiding human radiation exposure was developed. The detailed production of [ 18 F]BPAM121 in relatively high quantity using a commercial FASTlab synthesizer from GE Healthcare coupled with a full set of quality controls is presented, along with procedures for the synthesis of the tosylated precursor and the fluorinated reference. To evaluate the clinical usefulness of [ 18 F]BPAM121 as a potential AD diagnostic, some in vivo studies in mice were then realized, alongside blocking and competition studies. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim [less ▲]

Detailed reference viewed: 18 (2 ULiège)
Full Text
Peer Reviewed
See detailWheel-running exercise before and during gestation against acute and sensitized cocaine psychomotor-activation in offspring.
Lespine, Louis-Ferdinand ULiege; Plenevaux, Alain ULiege; Tirelli, Ezio ULiege

in Behavioural Brain Research (2019), 363

While animal research has consistently reported preventive effects of exercise against drug abuse vulnerability, little is known about the influence of the developmental stage during which exercise is ... [more ▼]

While animal research has consistently reported preventive effects of exercise against drug abuse vulnerability, little is known about the influence of the developmental stage during which exercise is displayed on addictive drugs responsiveness. This study aimed to determine whether prenatal exercise could attenuate acute cocaine reactivity and psychomotor sensitization in youth offspring. We used a split-plot factorial design where C57BL/6 J females were randomly assigned into sedentary or exercised (wheel-running) conditions before and during gestation, the wheels being removed on gestational day 18. Offspring were weaned, gendered and individually housed on 24–28 days old. At 38–42 days old, they were tested for their acute psychomotor responsiveness to 8 mg/kg cocaine and their initiation of sensitization over 8 additional once-daily administrations, the long-term expression of sensitization occurring 30 days later. Adolescent females born from exercised mothers were much less responsive to the acute psychomotor-stimulating effect of cocaine than those born from sedentary mothers (d=0.75, p=0.02), whereas there was no evidence for such a difference in males (d=0.34, p=0.17). However, we did not find sizeable attenuating effects of prenatal exercise on the initiation and the long-term expression of the psychomotor-activating effect of cocaine, in either sex (Cohen’s ds varying from −0.13 to 0.39). These results suggest that prenatal exercise may induce initial protection against cocaine responsiveness in youth females, a finding that warrants further research. [less ▲]

Detailed reference viewed: 27 (5 ULiège)
Full Text
Peer Reviewed
See detailQuantification of [18F]UCB-H Binding in the Rat Brain: From Kinetic Modelling to Standardised Uptake Value
Serrano Navacerrada, Maria Elisa ULiege; Bahri, Mohamed Ali ULiege; Becker, Guillaume ULiege et al

in Molecular Imaging and Biology (2018)

Purpose: [18F]UCB-H is a specific positron emission tomography (PET) biomarker for the Synaptic Vesicle protein 2A (SV2A), the binding site of the antiepileptic drug levetiracetam. With a view to ... [more ▼]

Purpose: [18F]UCB-H is a specific positron emission tomography (PET) biomarker for the Synaptic Vesicle protein 2A (SV2A), the binding site of the antiepileptic drug levetiracetam. With a view to optimising acquisition time and simplifying data analysis with this radiotracer, we compared two parameters: the distribution volume (Vt) obtained from Logan graphical analysis using a Population-Based Input Function, and the Standardised Uptake Value (SUV). Procedures: Twelve Sprague Dawley male rats, pre-treated with three different doses of levetiracetam were employed to develop the methodology. Three additional kainic acid (KA) treated rats (temporal lobe epilepsy model) were also used to test the procedure. Image analyses focused on: (i) length of the dynamic acquisition (90 versus 60 min); (ii) correlations between Vt and SUV over 20-min consecutive time-frames; (iii) and (iv) evaluation of differences between groups using the Vt and the SUV; and (v) preliminary evaluation of the methodology in the KA epilepsy model. Results: A large correlation between the Vt issued from 60 to 90-min acquisitions was observed. Further analyses highlighted a large correlation (r 9 0.8) between the Vt and the SUV. Equivalent differences between groups were detected for both parameters, especially in the 20–40 and 40– 60-min time-frames. The same results were also obtained with the epilepsy model. Conclusions: Our results enable the acquisition setting to be changed from a 90-min dynamic to a 20-min static PET acquisition. According to a better image quality, the 20–40-min time-frame appears optimal. Due to its equivalence to the Vt, the SUV parameter can be considered in order to quantify [18F]UCB-H uptake in the rat brain. This work, therefore, establishes a starting point for the simplification of SV2A in vivo quantification with [18F]UCB-H, and represents a step forward to the clinical application of this PET radiotracer. [less ▲]

Detailed reference viewed: 28 (9 ULiège)
Full Text
Peer Reviewed
See detailTHE SV2A PROTEIN: IMAGING SYNAPTIC DENSITY DURING THE PROGRESSION OF THE TEMPORAL LOBE EPILEPSY IN THE KASE RAT MODEL
Serrano Navacerrada, Maria Elisa ULiege; Bahri, Mohamed Ali ULiege; Becker, Guillaume ULiege et al

Poster (2018, October 18)

Introduction The temporal lobe epilepsy (TLE) is the most common epileptic disorder. New antiepileptic drugs target the Synaptic Vesicle protein 2A (SV2A) (1). Nevertheless, the prevailing literature ... [more ▼]

Introduction The temporal lobe epilepsy (TLE) is the most common epileptic disorder. New antiepileptic drugs target the Synaptic Vesicle protein 2A (SV2A) (1). Nevertheless, the prevailing literature addressing the relation between this protein and the epilepsy is limited (2, 3). This study provides insights on the role of the SV2A protein during the four stages of TLE (4, 5), throughout its in vivo study with the [18F]UCB-H radiotracer (6). Methods Twenty-four male Sprague-Dawley were subjected to multiple injections (7) of i) Saline (Sham), or ii) 5mg/kg of Kainic Acid (KA). The rats not reacting to KA (NKA) were also scanned. In each TLE stages, a [18F]UCB-H dynamic scan was performed, followed by a T2-structural MRI. EEG recordings were performed to determine the number of crises. Data processing was done with PMOD 3.6. Results were expressed as SUV and statistically analyzed with the SPSS and the SPM. Results During the acute phase, statistically significant differences were found between Sham and KA in striatum, cerebellum, and medulla. In the latent phase, these SUV differences were detected between the NKA and KA in the same regions along with hippocampus and thalamus. When the spontaneous crises started, these group differences became statistically significant in all the regions but the cortex. During the chronic phase, all the regions showed statistically significant differences between groups. Furthermore, the voxel-wise analysis highlighted statistically significant differences in voxels at the level of amygdala and hippocampus. Conclusions These results show that [18F]UCB-H is able to detect early modifications in SV2A expression (3 days after the TLE model creation), in particular in regions implicated in the epileptic process. This radiotracer can potentially be used as a suitable biomarker for the early detection of the epileptic disease, being able to distinguish between stages in this neurodegenerative disease. [less ▲]

Detailed reference viewed: 36 (4 ULiège)
Full Text
Peer Reviewed
See detailSound production and sonic apparatus in deep-living cusk-eels (Genypterus chilensis and Genypterus maculatus)
Parmentier, Eric ULiege; Bahri, Mohamed Ali ULiege; Plenevaux, Alain ULiege et al

in Deep-Sea Research. Part I, Oceanographic Research Papers (2018)

Cusk-eels (Ophidiidae) are known sound producers, but many species live in deep water where sounds are difficult to record. For these species sonic ability has been inferred from inner anatomy. Genypterus ... [more ▼]

Cusk-eels (Ophidiidae) are known sound producers, but many species live in deep water where sounds are difficult to record. For these species sonic ability has been inferred from inner anatomy. Genypterus (subfamily Ophidiinae) are demersal fishes inhabiting the continental shelf and slope at depths between 50 and 800 m. Males and females G. maculatus have been maintained together in a tank and 9 unsexed specimens of G. chilensis in a second tank, providing a valuable opportunity to record the sounds of living species usually found at great depths. Genypterus chilensis and G. maculatus respectively produced one and two sound types mainly between 7 and 10 pm. Sound 1 in Genypterus maculatus consists of trains of pulses that vary in amplitude and pulse period; call 2 sounded like a growl that results from the rapid emission of pulses that define sound 1. Genypterus chilensis produced a growl having an unusual feature since the first peak of the second pulse has always greater amplitude than all other peaks. These sounds are probably related to courtship behavior since floating eggs are found after night calls. The anatomical structures of the sound-producing organ in both species present an important panel of highly derived characters including three pairs of sonic muscles, a neural arch that pivots on the first vertebral body and a thick swimbladder with unusual features. Sonic structures are similar between species and between sexes. Therefore both biological sexes are capable of sound production although precedent from shallow ophidiids and sonic fishes in general suggests that males are more likely to produce courtship calls. This study reports two main types of information. It demonstrates that two deep-living species are capable of sound production, which is a pioneer step in the acoustic study of deep-sea fauna. Recorded sounds should also help to locate fish in open sea. As these species are currently used to diversify the aquaculture industry in Chile, deeper studies on their acoustic behavior should also help to target spawning period and to identify mature specimens. [less ▲]

Detailed reference viewed: 32 (6 ULiège)
Full Text
See detailEPILEPSY AND THE SV2A PROTEIN: new insights about the disease.
Serrano Navacerrada, Maria Elisa ULiege; Raedt, Robrecht; Becker, Guillaume ULiege et al

Conference (2018, September 13)

Around two million of people worldwide are affected by neurodegenerative diseases, such as Alzheimer, Parkinson or Epilepsy. Despite the social and the economic impact of these diseases, their causes ... [more ▼]

Around two million of people worldwide are affected by neurodegenerative diseases, such as Alzheimer, Parkinson or Epilepsy. Despite the social and the economic impact of these diseases, their causes still remain unclear. In the case of the epilepsy, for example, around 25% of the patients suffer drug-resistant epilepsy, for which there is no medicament able to mitigate the epileptic crises or the associated symptomatology, such as cognitive problems and mood disorders. In 1974, UCB Pharma synthetized a new antiepileptic drug with a high therapeutic index: the Levetiracetam. The target of this medicament is the Synaptic Vesicle Protein 2A (SV2A) whose specific role in the pathology is still unknown. The main goal of my thesis is to better understand the relationship between this protein and the epilepsy. On the one hand, the production and phenotyping of conditional knockout mice for the SV2A protein allowed us to discover a possible implication of this protein in the spatial memory and anxiety process, an important part of the epileptic symptomatology. On the other hand, the synthesis of the radiotracer [18F]UCB-H, with a high affinity for the SV2A protein, enabled the in vivo evaluation (with the mPET technique) of a rat model of the temporal lobe epilepsy through the disease process. Results showed a strong correlation between the severity of the epilepsy (EEG technique) and the SV2A levels in different brain regions, highlighting the importance of this protein in the development of the disease. In summary, although further studies in humans are necessary, this protein emerges as an important key in clinical diagnosis and medical research, being implicated in all the aspects of the epileptic disease. [less ▲]

Detailed reference viewed: 67 (5 ULiège)
Full Text
See detailEPILEPSY AND THE SV2A PROTEIN: new insights about the disease.
Serrano Navacerrada, Maria Elisa ULiege; Raedt, Robrecht; Becker, Guillaume ULiege et al

Conference (2018, September 13)

Around two million of people worldwide are affected by neurodegenerative diseases, such as Alzheimer, Parkinson or Epilepsy. Despite the social and the economic impact of these diseases, their causes ... [more ▼]

Around two million of people worldwide are affected by neurodegenerative diseases, such as Alzheimer, Parkinson or Epilepsy. Despite the social and the economic impact of these diseases, their causes still remain unclear. In the case of the epilepsy, for example, around 25% of the patients suffer drug-resistant epilepsy, for which there is no medicament able to mitigate the epileptic crises or the associated symptomatology, such as cognitive problems and mood disorders. In 1974, UCB Pharma synthetized a new antiepileptic drug with a high therapeutic index: the Levetiracetam. The target of this medicament is the Synaptic Vesicle Protein 2A (SV2A) whose specific role in the pathology is still unknown. The main goal of my thesis is to better understand the relationship between this protein and the epilepsy. On the one hand, the production and phenotyping of conditional knockout mice for the SV2A protein allowed us to discover a possible implication of this protein in the spatial memory and anxiety process, an important part of the epileptic symptomatology. On the other hand, the synthesis of the radiotracer [18F]UCB-H, with a high affinity for the SV2A protein, enabled the in vivo evaluation (with the mPET technique) of a rat model of the temporal lobe epilepsy through the disease process. Results showed a strong correlation between the severity of the epilepsy (EEG technique) and the SV2A levels in different brain regions, highlighting the importance of this protein in the development of the disease. In summary, although further studies in humans are necessary, this protein emerges as an important key in clinical diagnosis and medical research, being implicated in all the aspects of the epileptic disease. [less ▲]

Detailed reference viewed: 22 (4 ULiège)
Full Text
Peer Reviewed
See detailDecrease in SV2A expression in the hippocampus involves changes in cognition and anxiety-like features.
Serrano Navacerrada, Maria Elisa ULiege; Bartholomé, Odile ULiege; Van Den Ackerveken, Priscilla ULiege et al

Poster (2018, July)

The Synaptic Vesicle Protein 2A (SV2A) is a transmembrane protein whose link with the epilepsy has been reported in multiples articles. However, the behavioral consequences of the decrease in its ... [more ▼]

The Synaptic Vesicle Protein 2A (SV2A) is a transmembrane protein whose link with the epilepsy has been reported in multiples articles. However, the behavioral consequences of the decrease in its expression remain still unclear. The purpose of our research is to better understand the role of this protein through the evaluation of cKO (Grik4 +/-, SV2A lox/lox) mice of both sexes, which present a specific decrease in the hippocampus. After a first evaluation of the SV2A levels in the hippocampus with the in vitro [18F]UCB-H autoradiography, differences in brain metabolism were assessed with [18F]FDG in mPET and ex vivo autoradiography. Finally, the phenotype of cKO mice was analyzed with a behavioral test battery. Our results showed a strong reduction of SV2A expression in the whole hippocampus of cKO mice, with regard to the WT mice, not accompanied by statistically significant differences in brain metabolism between groups, either in vivo or ex vivo. No statistically significant differences were found in spontaneous locomotor activity or fear-linked memory. However, cKO males showed significant more anxiety than WT (less percent of entries in open arms) and females presented spatial memory deficits measured in the Barnes Maze (less time spend in quadrant during the test). These results could explain the comorbidity between anxiety, memory impairment and epilepsy present both in animal models and in humans, suggesting an important role of SV2A in the symptomatology of other neurodegenerative diseases, such as the Alzheimer disease, or in anxiety-related pathologies. [less ▲]

Detailed reference viewed: 33 (2 ULiège)
Full Text
Peer Reviewed
See detailThe severe deficiency of the somatotrope GHRH/GH/IGF1 axis of Ghrh-/- mice is associated with an important splenic atrophy and relative B lymphopenia
Bodart, Gwennaëlle ULiege; Farhat, Khalil ULiege; Charlet-Renard, Jeanne de Chantal ULiege et al

in Frontiers in Endocrinology (2018), 9(Art. 296),

A debate is still open about the precise control exerted by the somatotrope GH-releasing hormone (GHRH)/growth hormone (GH)/insulin-like growth factor 1 axis on the immune system. The objective of this ... [more ▼]

A debate is still open about the precise control exerted by the somatotrope GH-releasing hormone (GHRH)/growth hormone (GH)/insulin-like growth factor 1 axis on the immune system. The objective of this study was to directly address this question through the use of Ghrh−/− mice that exhibit a severe deficiency of their somatotrope axis. After control backcross studies and normalization for the reduced global weight of transgenic mice, no difference in weight and cellularity of the thymus was observed in Ghrh−/− mice when compared with C57BL/6 wild-type (WT) control mice. Similarly, no significant change was observed in frequency and number of thymic T cell subsets. In the periphery, Ghrh−/− mice exhibited an increase in T cell proportion associated with a higher frequency of sjTREC and naïve T cells. However, all Ghrh−/− mice displayed an absolute and relative splenic atrophy, in parallel with a decrease in B cell percentage. GH supplementation of transgenic mice for 6 weeks induced a significant increase in their global as well as absolute and relative splenic weight. Interestingly, the classical thymus involution following dexamethasone administration was shown to recover in WT mice more quickly than in mutant mice. Altogether, these data show that the severe somatotrope deficiency of Ghrh−/− mice essentially impacts the spleen and B compart- ment of the adaptive immune system, while it only marginally affects thymic function and T cell development. [less ▲]

Detailed reference viewed: 36 (16 ULiège)
Full Text
Peer Reviewed
See detailTumor microenvironment modifications recorded with IVIM perfusion analysis after radiotherapy.
LALLEMAND, François ULiege; LEROI, Natacha ULiege; Bahri, Mohamed Ali ULiege et al

in Radiotherapy and Oncology (2018, April), 127(Supplement 1), 1285-1286

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

Purpose or Objective Neoadjuvant radiotherapy (NeoRT) improves tumor local control and facilitates tumor resection in many cancers. The timing between the end of the NeoRT and surgery is driven by the occurrence of side effects or the tumor downsizing. Some clinical studies demonstrated that the timing of surgery and the RT schedule influence tumor dissemination and subsequently patient overall survival (Acta Oncol 2006). Previously, we developed a pre-clinical model demonstrating an impact of NeoRT schedule and the timing of surgery on metastatic spreading (Oncotarget 2015). Here, we used functional MRI (fMRI) to record tumor microenvironment modifications after NeoRT. We aim to get non-invasive markers to establish the best timing to perform surgery and avoiding tumor spreading. Material and Methods Based on our NeoRT model, MDA-MB 231 and 4T1 cells were implanted in the flank of SCID and BalbC mice, respectively. We locally irradiated (PXI, X-Rad SmART) tumors with 2x5Gy and then surgically removed at different time points after RT. We acquired fMRI (9,4T Agilent) before and after RT. Diffusion Weighted (DW) - MRI was performed every 2 days between RT and surgery. For each tumor, 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-value (from 40 to 1000) and B0, in the 3 main directions. We performed IVIM (IntraVoxel Incoherent Motion) analysis to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor) and subsequently tumor vessels perfusion. Results With the MDA-MB 231, we observed a significant and transient increase (60% of the basal value (n=6, p<0,05)) of F and D* parameters related to perfusion. The other parameters of the DW-MRI, ADC and D presented no modification. We observed similar results with 4T1 cells, where F increased at day 3 (55% of the basal value, n=10, p<0,05) then returned to initial level. The difference in timing for the peak of F (day 6 vs day 3) could be related to the difference in tumor growth according to the cell line (four weeks for MDA-MB 231 cells vs one week for 4T1 cells). We also observed a decrease of hypoxia (pimonidazole staining) when surgery was performed on the peak but vascular architecture was not affected. Moreover, performing surgery during F and D* peak, in the MDA-MB 231model, is associated with an increase of lung metastases: 115% and 187% compared to a surgery performed before or after the peak. Conclusion We demonstrated the feasibility of repetitive fMRI imaging in preclinical models after NeoRT. We showed a significant difference in perfusion-related parameters (D* and F) at a specific time point depending of tumor cells correlated with tumor metastases. We demonstrated the feasibility of Image Guided Surgery for decreasing tumor metastases after NeoRT. [less ▲]

Detailed reference viewed: 15 (0 ULiège)
Full Text
Peer Reviewed
See detailBrain modifications after stereotactic radiotherapy recorded by Functional MRI.
LALLEMAND, François ULiege; LEROI, Natacha ULiege; Bahri, Mohamed Ali ULiege et al

in Radiotherapy and Oncology (2018, April), 127(Supplement 1), 582

Purpose or Objective Brain irradiation is commonly used in malignant diseases (i.e. metastases or Glioblastoma) and in benign diseases (i.e. meningioma, epilepsy, vestibular schwannoma or Parkinson ... [more ▼]

Purpose or Objective Brain irradiation is commonly used in malignant diseases (i.e. metastases or Glioblastoma) and in benign diseases (i.e. meningioma, epilepsy, vestibular schwannoma or Parkinson disease). The use of stereotactic radiosurgery (SRS) allows the administration of very high doses in a single fraction (e.g. 120Gy), in a small brain volume. After irradiation, morphological and functional cerebral changes occur depending on the total dose, dose per fraction and the irradiated brain volume. The aim of this work is to use f-MRI to record adult normal brain tissue modification after irradiation with different radiotherapy doses and schedules and to identify new parameters of brain radio-damages. Material and Methods With a dedicated small animal radiotherapy device allowing IGRT (PXI, X-Rad SmART), we specifically irradiated with a 2mm-collimator, mimicking SRS, a small part of adult brain mice (n=72), known to have no impact on vital function, with dose schedules: 1X20Gy, 3X10Gy, 4X5Gy and no RT as control. We imaged brain mice longitudinally with a dedicated 9.4-T MRI (Agilent). Imaging was realized once before as reference level and after irradiation every month for the first 6 months and every 3 months during one year. For each mouse we acquired 14 slices of 1 mm thickness and 0.5 mm gap with an “in plane voxel resolution” of 0.5 mm. We performed T1-weighted, T2-weighted, T1-mapping, T2-mapping and DW-MRI. For DW-MRI, we performed Fast Spin Echo MultiSlice sequences, with 9 different B-value and B0 (from 20 to 1000). We performed IntraVoxel Incoherent Motion (IVIM) analysis to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor). Results Only mice irradiated with 120Gy showed brain modifications in T1 and T2 anatomic images and in T1 mapping, ADC, D and F but no changes were recorded in D* or T2 mapping. All these changes started 5 weeks after SRS and then stabilized after 7 weeks. The mean values for the control group were stable during the 5 months (ADC 0,73μm²/ms; D 0,66μm²/ms; F 4,67%, T1 1,25 sec). For the 120Gy group, values were significantly higher after 5 weeks (Δ = compared to the control group) with ADC 1,66μm²/ms (Δ=151%); D 1,37μm²/ms (Δ=107%); F 18,84% (Δ=303%); T1 1,99 sec (Δ=59%). No specific behaviour changes were observed during all the experiment. Conclusion In this work, we studied normal brain modifications after SRS therapy with anatomical and functional MRI. SRS doses and schedules in this work reflected those used in clinic for tumor treatment or functional SRS. We showed an increase of ADC value 5 weeks after one single dose of 120Gy, compared to normal brain tissue. These results are consistent with radio-necrosis. In addition, we highlighted an increase of IVIM parameters D and F and an increase of T1 mapping in radio-necrosis area. These results increase the numbers of MRI parameters that could be used for following brain damage after radiation. [less ▲]

Detailed reference viewed: 14 (2 ULiège)
Full Text
Peer Reviewed
See detail[18F]UCB-H BINDING QUANTIFICATION IN RAT BRAIN: FROM MODELLING TO SUV
Serrano Navacerrada, Maria Elisa ULiege; Bahri, Mohamed Ali ULiege; Becker, Guillaume ULiege et al

Poster (2018, March 22)

Introduction Image quantification in Positron Emission Tomography (PET) is usually achieved through the invasive and sometimes infeasible arterial blood sampling [1, 2]. Alternative methods have been ... [more ▼]

Introduction Image quantification in Positron Emission Tomography (PET) is usually achieved through the invasive and sometimes infeasible arterial blood sampling [1, 2]. Alternative methods have been proposed, but a validation of their results is necessary [3, 4]. In the scope of improving the use of [18F]UCB-H, a specific biomarker for the Synaptic Vesicle protein 2A (SV2A) [5, 6, 7, 8], we have compared the distribution volume (VT) obtained through full kinetic modelling using a Population Based Input Function (PBIF) [9], and the Standardized Uptake Value (SUV). Methods Twelve Sprague Dawley male rats were pre-treated with vehicle (saline), 1 or 10 mg/kg of SV2A ligand (Keppra®, IP). Thirty minutes later, [18F]UCB-H was injected (IV) and a 90 min microPET dynamic acquisition was started followed by a T2 structural MRI. Primary image analysis was focused in examining tracer measurement stability through 10 min time windows. Subsequently, we calculated the correlation between VT (90 minutes) and SUV values over consecutive 20-minute time frames searching for the optimal frame to perform a static acquisition [10]. Finally, we did a supplementary test-retest static acquisition, from 60 to 80 minutes, in order to test group differences in SUV. Results/Discussion Evaluation of ten minutes time windows showed more stability in VT than in SUV measures, for all the groups. This change in signal seems to decrease in late time frames. We found also a strong correlation (R2>0.6) between dynamic VT and twenty minutes frame SUV, especially between 20 min and 60 min. From this, we can infer that an optimal frame to perform a static acquisition with [18F]UCB-H would be between 50 and 80 minutes. Using a static acquisition from 60 to 80 minutes, the SUV highlighted statistically significant differences between the group injected with vehicle and the other groups (p<0.01), but not between groups pre-treated with 1mg/kg and 10mg/kg of Keppra®. Conclusions Our work shows that a strong correlation between the SUV and the VT parameter based on a PBIF does exist. This opens the way to a possible simplification for SV2A in vivo imaging with [18F]UCB-H. Despite the fact that SUV is affected by many factors [11] and that it can overestimate results relative to VT [10], it is able to detect important differences in SV2A expression. Based on these results, SUV could become an interesting and easy to obtain parameter to study group differences in the context of several diseases. References 1. Acton PD et al. Radiologic Clinics of North America. 2004; 42(6):1055. 2. Kinahan PE & Fletcher JW. Seminars in Ultrasound, CT and MRI 2010; 31(6): 496. 3. Heurling K et al. Brain Res. 2017; 1670:220. 4. Tomasi G et al. Molecular Imaging and Biology. 2012; 14(2):131. 5. Bretin F et al. EJNMMI res. 2013; 3(1):35. 6. Warnock GI et al. J Nucl Med. 2014; 55(8):1336. 7. Bretin F et al. Molecular Imaging and Biology. 2015; 17(4):557. 8. Salmon E et al. Alzheimer's & Dementia. 2017; 13(7):781. 9. Becker G et al. Molecular Pharmaceutics. 2017; 14(8):2719. 10. Lockhart SN et al. PLoS One. 2016; 11(6):e0158460. 11. Boellaard R. J Nucl Med. 2009; 50(Suppl 1):11S-20S. Acknowledgement 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. [less ▲]

Detailed reference viewed: 62 (11 ULiège)
Full Text
Peer Reviewed
See detailSexual dimorphism in the sonic system and otolith morphology of Neobythites gilli (Ophidiiformes)
Parmentier, Eric ULiege; Boistel, Renaud; Bahri, Mohamed Ali ULiege et al

in Journal of Zoology (2018), 305

Detailed reference viewed: 26 (3 ULiège)
Full Text
Peer Reviewed
See detailIncreased hippocampal volume in exercising mice: comparison of control conditions with in vivo voxel based morphometry
Becker, Guillaume ULiege; Lespine, Louis-Ferdinand ULiege; Bahri, Mohamed Ali ULiege et al

Poster (2018, March)

Introduction Both human and animal studies have shown that physical exercise (primarily aerobic exercise) may have facilitating effects on brain plasticity and cognition. In rodents, improvements of ... [more ▼]

Introduction Both human and animal studies have shown that physical exercise (primarily aerobic exercise) may have facilitating effects on brain plasticity and cognition. In rodents, improvements of various forms of learning and memory induced by wheel-running have been associated with numerous neuroplastic changes such as increased hippocampal neurogenesis. A few studies, using magnetic resonance imaging (MRI), consistently reported hippocampal volumetric increase relative to non-exercising mice. However, the control group is commonly limited either to a locked wheel or no wheel. Methods In the present study, we intended to test whether 6 weeks of voluntary wheel-running exercise during adulthood induced a detectable volumetric change in mice brain in comparison to non-exercised control mice housed either with a locked wheel or without such wheel. 54 C57Bl6 males were randomly assigned to one of the three groups and individually housed for 6 weeks before imaging session. MRI (Agilent 9.4T) acquisition consisted in 3D T2 volume sequence (voxel size: 0.21 mm isotropic) using a dedicated surface coil receiver. We used Dartel soware for the preprocessing of the data, and the Voxel Based Morphometry was done with SPM mouse toolbox (F test, threshold p < .001 uncor). A small volume correction was applied to limit the analysis to the hippocampus. Results/Discussion VBM analysis shows significant clusters with increased grey matter volume in the hippocampus (cluster sizes 1531 and 3460, p < .001) when we compare the wheel vs locked wheel groups. Regarding the wheel vs no wheel comparison, significant clusters were observed in the hippocampus (cluster sizes 955 and 238, p < .001). Interestingly, no dierences were found when we compare the two control groups (locked wheel vs no wheel). Conclusions In this study, we replicate previous studies depicting an increased hippocampal volume under physical exercise in mice using VBM. Moreover, we certified here that attempting to study the impact of physical exercise on brain volume, control groups with a locked wheel or no wheel are equivalent. [less ▲]

Detailed reference viewed: 37 (13 ULiège)
Full Text
See detailNanofitin as a New Molecular-Imaging Agent for the Diagnosis of Epidermal Growth Factor Receptor Over-Expressing Tumors
Goux, Marine; Becker, Guillaume ULiege; Gorre, Harmony et al

Scientific conference (2018, January 19)

In this study, we provide the first report of the use of the Nanofitin scaffold for generating targeted PET radiotracers, using the anti-EGFR B10 Nanofitin as proof-of-concept. 18F-FBEM-Cys-B10 shows a ... [more ▼]

In this study, we provide the first report of the use of the Nanofitin scaffold for generating targeted PET radiotracers, using the anti-EGFR B10 Nanofitin as proof-of-concept. 18F-FBEM-Cys-B10 shows a favorable in vivo profile. The posibility to drive Nanofitin molecular recognition capability, over a fast and tunable in vitro selection system could facilitate the development of valuable PET-based companion diagnostics. [less ▲]

Detailed reference viewed: 18 (1 ULiège)