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1. Early neurotransmitters changes in prodromal frontotemporal dementia: A GENFI study

Author: Enrico Premi, Marta Pengo, Irene Mattioli, Valentina Cantoni, Juergen Dukart, Roberto Gasparotti, Emanuele Buratti, Alessandro Padovani, Martina Bocchetta, Emily G. Todd, Arabella Bouzigues, David M. Cash, Rhian S. Convery, Lucy L. Russell, Phoebe Foster, David L. Thomas, John C. van Swieten, Lize C. Jiskoot, Harro Seelaar, Daniela Galimberti, Raquel Sanchez-Valle, Robert Laforce, Jr, Fermin Moreno, Matthis Synofzik, Caroline Graff, Mario Masellis, Maria Carmela Tartaglia, James B. Rowe, Kamen A. Tsvetanov, Rik Vandenberghe, Elizabeth Finger, Pietro Tiraboschi, Alexandre de Mendonça, Isabel Santana, Chris R. Butler, Simon Ducharme, Alexander Gerhard, Johannes Levin, Markus Otto, Sandro Sorbi, Isabelle Le Ber, Florence Pasquier, Jonathan D. Rohrer, Barbara Borroni, Aitana Sogorb Esteve, Carolin Heller, Caroline V. Greaves, Henrik Zetterberg, Imogen J. Swift, Kiran Samra, Rachelle Shafei, Carolyn Timberlake, Thomas Cope, Timothy Rittman, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Vittoria Borracci, Giacomina Rossi, Giorgio Giaccone, Giuseppe Di Fede, Paola Caroppo, Sara Prioni, Veronica Redaelli, David Tang-Wai, Ekaterina Rogaeva, Miguel Castelo-Branco, Morris Freedman, Ron Keren, Sandra Black, Sara Mitchell, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Jackie Poos, Janne M. Papma, Lucia Giannini, Rick van Minkelen, Yolande Pijnenburg, Benedetta Nacmias, Camilla Ferrari, Cristina Polito, Gemma Lombardi, Valentina Bessi, Michele Veldsman, Christin Andersson, Hakan Thonberg, Linn Öijerstedt, Vesna Jelic, Paul Thompson, Tobias Langheinrich, Albert Lladó, Anna Antonell, Jaume Olives, Mircea Balasa, Nuria Bargalló, Sergi Borrego-Ecija, Ana Verdelho, Carolina Maruta, Catarina B. Ferreira, Gabriel Miltenberger, Frederico Simões do Couto, Alazne Gabilondo, Ana Gorostidi, Jorge Villanua, Marta Cañada, Mikel Tainta, Miren Zulaica, Myriam Barandiaran, Patricia Alves, Benjamin Bender, Carlo Wilke, Lisa Graf, Annick Vogels, Mathieu Vandenbulcke, Philip Van Damme, Rose Bruffaerts, Koen Poesen, Pedro Rosa-Neto, Serge Gauthier, Agnès Camuzat, Alexis Brice, Anne Bertrand, Aurélie Funkiewiez, Daisy Rinaldi, Dario Saracino, Olivier Colliot, Sabrina Sayah, Catharina Prix, Elisabeth Wlasich, Olivia Wagemann, Sandra Loosli, Sonja Schönecker, Tobias Hoegen, Jolina Lombardi, Sarah Anderl-Straub, Adeline Rollin, Gregory Kuchcinski, Maxime Bertoux, Thibaud Lebouvier, Vincent Deramecourt, Beatriz Santiago, Diana Duro, Maria João Leitão, Maria Rosario Almeida, Miguel Tábuas-Pereira, and Sónia Afonso
Subjects: Frontotemporal dementia, Frontotemporal lobar degeneration, Genes, Magnetic resonance imaging, Positron emission tomography, Neurotransmitters, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Background: Neurotransmitters deficits in Frontotemporal Dementia (FTD) are still poorly understood. Better knowledge of neurotransmitters impairment, especially in prodromal disease stages, might tailor symptomatic treatment approaches. Methods: In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of Magnetic Resonance Imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission.We included 392 mutation carriers (157 GRN, 164 C9orf72, 71 MAPT), together with 276 non-carrier cognitively healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in mutation carriers (relative to HC) are correlated with specific neurotransmitter systems in prodromal (CDR® plus NACC FTLD = 0.5) and in symptomatic (CDR® plus NACC FTLD≥1) FTD. Results: In prodromal stages of C9orf72 disease, voxel-based brain changes were significantly associated with spatial distribution of dopamine and acetylcholine pathways; in prodromal MAPT disease with dopamine and serotonin pathways, while in prodromal GRN disease no significant findings were reported (p
Published: 2023
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2. AD Course Map charts Alzheimer’s disease progression

Author: Igor Koval, Alexandre Bône, Maxime Louis, Thomas Lartigue, Simona Bottani, Arnaud Marcoux, Jorge Samper-González, Ninon Burgos, Benjamin Charlier, Anne Bertrand, Stéphane Epelbaum, Olivier Colliot, Stéphanie Allassonnière, and Stanley Durrleman
Subjects: Medicine, Science
Abstract: Abstract Alzheimer’s disease (AD) is characterized by the progressive alterations seen in brain images which give rise to the onset of various sets of symptoms. The variability in the dynamics of changes in both brain images and cognitive impairments remains poorly understood. This paper introduces AD Course Map a spatiotemporal atlas of Alzheimer’s disease progression. It summarizes the variability in the progression of a series of neuropsychological assessments, the propagation of hypometabolism and cortical thinning across brain regions and the deformation of the shape of the hippocampus. The analysis of these variations highlights strong genetic determinants for the progression, like possible compensatory mechanisms at play during disease progression. AD Course Map also predicts the patient’s cognitive decline with a better accuracy than the 56 methods benchmarked in the open challenge TADPOLE. Finally, AD Course Map is used to simulate cohorts of virtual patients developing Alzheimer’s disease. AD Course Map offers therefore new tools for exploring the progression of AD and personalizing patients care.
Published: 2021
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3. Intermittent Hypoxia Rewires the Liver Transcriptome and Fires up Fatty Acids Usage for Mitochondrial Respiration

Author: Jonathan Gaucher, Guillaume Vial, Emilie Montellier, Maëlle Guellerin, Sophie Bouyon, Emeline Lemarie, Véronique Pelloux, Anne Bertrand, Karin Pernet-Gallay, Frederic Lamarche, Anne-Laure Borel, Claire Arnaud, Elise Belaidi, Karine Clément, Diane Godin Ribuot, Judith Aron-Wisnewsky, and Jean-Louis Pépin
Subjects: sleep apnea, intermittent hypoxia (IH), liver, transcriptome, mitochondria, Nuclear Respiratory Factor (NRF), Medicine (General), R5-920
Abstract: Sleep Apnea Syndrome (SAS) is one of the most common chronic diseases, affecting nearly one billion people worldwide. The repetitive occurrence of abnormal respiratory events generates cyclical desaturation-reoxygenation sequences known as intermittent hypoxia (IH). Among SAS metabolic sequelae, it has been established by experimental and clinical studies that SAS is an independent risk factor for the development and progression of non-alcoholic fatty liver disease (NAFLD). The principal goal of this study was to decrypt the molecular mechanisms at the onset of IH-mediated liver injury. To address this question, we used a unique mouse model of SAS exposed to IH, employed unbiased high-throughput transcriptomics and computed network analysis. This led us to examine hepatic mitochondrial ultrastructure and function using electron microscopy, high-resolution respirometry and flux analysis in isolated mitochondria. Transcriptomics and network analysis revealed that IH reprograms Nuclear Respiratory Factor- (NRF-) dependent gene expression and showed that mitochondria play a central role. We thus demonstrated that IH boosts the oxidative capacity from fatty acids of liver mitochondria. Lastly, the unbalance between oxidative stress and antioxidant defense is tied to an increase in hepatic ROS production and DNA damage during IH. We provide a comprehensive analysis of liver metabolism during IH and reveal the key role of the mitochondria at the origin of development of liver disease. These findings contribute to the understanding of the mechanisms underlying NAFLD development and progression during SAS and provide a rationale for novel therapeutic targets and biomarker discovery.
Published: 2022
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4. Nobody’s Perfect

Author: Anne Bertrand, Yurika Aonuki, Sihwei Chen, Henry Davis, Joash Gambarage, Laura Griffin, Marianne Huijsmans, Lisa Matthewson, Daniel Reisinger, Hotze Rullmann, Raiane Salles, Michael David Schwan, Neda Todorović, Bailey Trotter, and Jozina Vander Klok
Subjects: tense, aspect, perfect, perfective, experiential, resultative, Language and Literature
Abstract: This paper challenges the cross-linguistic validity of the tense–aspect category ‘perfect’ by investigating 15 languages from eight different families (Atayal, Brazilian Portuguese, Dutch, English, German, Gitksan, Japanese, Javanese, Korean, Mandarin, Niuean, Québec French, St’át’imcets, Swahili, and Tibetan). The methodology involves using the storyboard ‘Miss Smith’s Bad Day’ to test for the availability of experiential, resultative, recent-past, and continuous readings, as well as lifetime effects, result-state cancellability, narrative progression, and compatibility with definite time adverbials. Results show that the target forms in these languages can be classified into four groups: (a) past perfectives; (b) experientials; (c) resultatives; and (d) hybrids (which allow both experiential and resultative readings). It is argued that the main division is between past perfectives, which contain a ‘pronominal’ tense, on the one hand, and the other three groups on the other, which involve existential quantification, either over times (experiential) or over events (resultative). The methodological and typological implications of the findings are discussed. The main conclusion of the study is that there is no universal category of ‘the perfect’, and that instead, researchers should focus on identifying shared semantic components of tense–aspect categories across languages.
Published: 2022
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5. Differential early subcortical involvement in genetic FTD within the GENFI cohort

Author: Martina Bocchetta, Emily G. Todd, Georgia Peakman, David M. Cash, Rhian S. Convery, Lucy L. Russell, David L. Thomas, Juan Eugenio Iglesias, John C. van Swieten, Lize C. Jiskoot, Harro Seelaar, Barbara Borroni, Daniela Galimberti, Raquel Sanchez-Valle, Robert Laforce, Fermin Moreno, Matthis Synofzik, Caroline Graff, Mario Masellis, Maria Carmela Tartaglia, James B. Rowe, Rik Vandenberghe, Elizabeth Finger, Fabrizio Tagliavini, Alexandre de Mendonça, Isabel Santana, Chris R. Butler, Simon Ducharme, Alexander Gerhard, Adrian Danek, Johannes Levin, Markus Otto, Sandro Sorbi, Isabelle Le Ber, Florence Pasquier, Jonathan D. Rohrer, Sónia Afonso, Maria Rosario Almeida, Sarah Anderl-Straub, Christin Andersson, Anna Antonell, Silvana Archetti, Andrea Arighi, Mircea Balasa, Myriam Barandiaran, Nuria Bargalló, Robart Bartha, Benjamin Bender, Alberto Benussi, Maxime Bertoux, Anne Bertrand, Valentina Bessi, Sandra Black, Sergi Borrego-Ecija, Jose Bras, Alexis Brice, Rose Bruffaerts, Agnès Camuzat, Marta Cañada, Valentina Cantoni, Paola Caroppo, Miguel Castelo-Branco, Olivier Colliot, Thomas Cope, Vincent Deramecourt, María de Arriba, Giuseppe Di Fede, Alina Díez, Diana Duro, Chiara Fenoglio, Camilla Ferrari, Catarina B. Ferreira, Nick Fox, Morris Freedman, Giorgio Fumagalli, Aurélie Funkiewiez, Alazne Gabilondo, Roberto Gasparotti, Serge Gauthier, Stefano Gazzina, Giorgio Giaccone, Ana Gorostidi, Caroline Greaves, Rita Guerreiro, Carolin Heller, Tobias Hoegen, Begoña Indakoetxea, Vesna Jelic, Hans-Otto Karnath, Ron Keren, Gregory Kuchcinski, Tobias Langheinrich, Thibaud Lebouvier, Maria João Leitão, Albert Lladó, Gemma Lombardi, Sandra Loosli, Carolina Maruta, Simon Mead, Lieke Meeter, Gabriel Miltenberger, Rick van Minkelen, Sara Mitchell, Katrina Moore, Benedetta Nacmias, Annabel Nelson, Jennifer Nicholas, Linn Öijerstedt, Jaume Olives, Sebastien Ourselin, Alessandro Padovani, Jessica Panman, Janne M. Papma, Yolande Pijnenburg, Cristina Polito, Enrico Premi, Sara Prioni, Catharina Prix, Rosa Rademakers, Veronica Redaelli, Daisy Rinaldi, Tim Rittman, Ekaterina Rogaeva, Adeline Rollin, Pedro Rosa-Neto, Giacomina Rossi, Martin Rossor, Beatriz Santiago, Dario Saracino, Sabrina Sayah, Elio Scarpini, Sonja Schönecker, Elisa Semler, Rachelle Shafei, Christen Shoesmith, Imogen Swift, Miguel Tábuas-Pereira, Mikel Tainta, Ricardo Taipa, David Tang-Wai, Paul Thompson, Hakan Thonberg, Carolyn Timberlake, Pietro Tiraboschi, Philip Van Damme, Mathieu Vandenbulcke, Michele Veldsman, Ana Verdelho, Jorge Villanua, Jason Warren, Carlo Wilke, Ione Woollacott, Elisabeth Wlasich, Henrik Zetterberg, and Miren Zulaica
Subjects: Genetic frontotemporal dementia, MRI imaging, Brain volumetry, Presymptomatic stage, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract: Background: Studies have previously shown evidence for presymptomatic cortical atrophy in genetic FTD. Whilst initial investigations have also identified early deep grey matter volume loss, little is known about the extent of subcortical involvement, particularly within subregions, and how this differs between genetic groups. Methods: 480 mutation carriers from the Genetic FTD Initiative (GENFI) were included (198 GRN, 202 C9orf72, 80 MAPT), together with 298 non-carrier cognitively normal controls. Cortical and subcortical volumes of interest were generated using automated parcellation methods on volumetric 3 T T1-weighted MRI scans. Mutation carriers were divided into three disease stages based on their global CDR® plus NACC FTLD score: asymptomatic (0), possibly or mildly symptomatic (0.5) and fully symptomatic (1 or more). Results: In all three groups, subcortical involvement was seen at the CDR 0.5 stage prior to phenoconversion, whereas in the C9orf72 and MAPT mutation carriers there was also involvement at the CDR 0 stage. In the C9orf72 expansion carriers the earliest volume changes were in thalamic subnuclei (particularly pulvinar and lateral geniculate, 9–10%) cerebellum (lobules VIIa-Crus II and VIIIb, 2–3%), hippocampus (particularly presubiculum and CA1, 2–3%), amygdala (all subregions, 2–6%) and hypothalamus (superior tuberal region, 1%). In MAPT mutation carriers changes were seen at CDR 0 in the hippocampus (subiculum, presubiculum and tail, 3–4%) and amygdala (accessory basal and superficial nuclei, 2–4%). GRN mutation carriers showed subcortical differences at CDR 0.5 in the presubiculum of the hippocampus (8%). Conclusions: C9orf72 expansion carriers show the earliest and most widespread changes including the thalamus, basal ganglia and medial temporal lobe. By investigating individual subregions, changes can also be seen at CDR 0 in MAPT mutation carriers within the limbic system. Our results suggest that subcortical brain volumes may be used as markers of neurodegeneration even prior to the onset of prodromal symptoms.
Published: 2021
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6. Democratic sequences

Author: Mathis, Anne Bertrand
Subjects: Mathematics - Combinatorics, 11K, G.3, G.4
Abstract: Given a countable alphabet and a sountable set pf preset frequency, we construct a sequence where each letter appears with the preaasigned frequency.
Published: 2024

7. Improved cerebral microbleeds detection using their magnetic signature on T2*-phase-contrast: A comparison study in a clinical setting

Author: Takoua Kaaouana, Anne Bertrand, Fatma Ouamer, Bruno Law-ye, Nadya Pyatigorskaya, Ali Bouyahia, Nathalie Thiery, Carole Dufouil, Christine Delmaire, Didier Dormont, Ludovic de Rochefort, and Marie Chupin
Subjects: Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract: Introduction/purpose: In vivo detection of cerebral microbleeds (CMBs) from T2* gradient recalled echo (GRE) magnitude image suffers from low specificity, modest inter-rater reproducibility and is biased by its sensitivity to acquisition parameters. New methods were proposed for improving this identification, but they mostly rely on 3D acquisitions, not always feasible in clinical practice. A fast 2D phase processing technique for computing internal field maps (IFM) has been shown to make it possible to characterize CMBs through their magnetic signature in routine clinical setting, based on 2D multi-slice acquisitions. However, its clinical interest for CMBs identification with respect to more common images remained to be assessed. To do so, systematic experiments were undertaken to compare the ratings obtained by trained observers with several image types, T2* magnitude, Susceptibility Weighted Imaging reconstructions (SWI) and IFM built from the same T2*-weighted acquisition. Materials/methods: 15 participants from the MEMENTO multi-center cohort were selected: six subjects with numerous CMBs (20 ± 6 CMBs), five subjects with a few CMBs (2 ± 1 CMBs) and four subjects without CMB. 2D multi-slice T2* GRE sequences were acquired on Philips and Siemens 3T systems. After pilot experiments, T2* magnitude, Susceptibility Weighted Imaging (SWI) minimum intensity projection (mIP) on three slices and IFM were considered for the rating experiments. A graphical user interface (GUI) was designed in order to consistently display images in random order. Six raters of various background and expertise independently selected “definite” or “possible” CMBs. Rating results were compared with respect to a specific consensus reference, on both lesion and subject type points of view. Results: IFM yielded increased sensitivity and decreased false positives rate (FPR) for CMBs identification compared to T2* magnitude and SWI-mIP images. Inter-rater variability was decreased with IFM when identifying subjects with numerous lesions, with only a limited increase in rating time. IFM thus appears as an interesting candidate to improve CMBs identification in clinical setting. Keywords: Microbleeds, Magnetic susceptibility, Phase MRI, SWI
Published: 2017
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8. An Automated Pipeline for the Analysis of PET Data on the Cortical Surface

Author: Arnaud Marcoux, Ninon Burgos, Anne Bertrand, Marc Teichmann, Alexandre Routier, Junhao Wen, Jorge Samper-González, Simona Bottani, Stanley Durrleman, Marie-Odile Habert, Olivier Colliot, and for the Alzheimer's Disease Neuroimaging Initiative
Subjects: surface analysis, positron emission tomography, PET, brain, neurodegenerative diseases, workflow, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: We present a fully automatic pipeline for the analysis of PET data on the cortical surface. Our pipeline combines tools from FreeSurfer and PETPVC, and consists of (i) co-registration of PET and T1-w MRI (T1) images, (ii) intensity normalization, (iii) partial volume correction, (iv) robust projection of the PET signal onto the subject's cortical surface, (v) spatial normalization to a template, and (vi) atlas statistics. We evaluated the performance of the proposed workflow by performing group comparisons and showed that the approach was able to identify the areas of hypometabolism characteristic of different dementia syndromes: Alzheimer's disease (AD) and both the semantic and logopenic variants of primary progressive aphasia. We also showed that these results were comparable to those obtained with a standard volume-based approach. We then performed individual classifications and showed that vertices can be used as features to differentiate cognitively normal and AD subjects. This pipeline is integrated into Clinica, an open-source software platform for neuroscience studies available at www.clinica.run.
Published: 2018
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9. Structural, Microstructural, and Metabolic Alterations in Primary Progressive Aphasia Variants

Author: Alexandre Routier, Marie-Odile Habert, Anne Bertrand, Aurélie Kas, Martina Sundqvist, Justine Mertz, Pierre-Maxime David, Hugo Bertin, Serge Belliard, Florence Pasquier, Karim Bennys, Olivier Martinaud, Frédérique Etcharry-Bouyx, Olivier Moreaud, Olivier Godefroy, Jérémie Pariente, Michèle Puel, Philippe Couratier, Claire Boutoleau-Bretonnière, Bernard Laurent, Raphaëlla Migliaccio, Bruno Dubois, Olivier Colliot, and Marc Teichmann
Subjects: primary progressive aphasias, cortical thickness, cortical metabolism, tracts, MRI, PET, Neurology. Diseases of the nervous system, RC346-429
Abstract: Neuroimaging studies have described the brain alterations in primary progressive aphasia (PPA) variants (semantic, logopenic, nonfluent/agrammatic). However, few studies combined T1, FDG-PET, and diffusion MRI techniques to study atrophy, hypometabolism, and tract alterations across the three PPA main variants. We therefore explored a large early-stage cohort of semantic, logopenic and nonfluent/agrammatic variants (N = 86) and of 23 matched healthy controls with anatomical MRI (cortical thickness), FDG PET (metabolism) and diffusion MRI (white matter tracts analyses), aiming at identifying cortical and sub-cortical brain alterations, and confronting these alterations across imaging modalities and aphasia variants. In the semantic variant, there was cortical thinning and hypometabolism in anterior temporal cortices, with left-hemisphere predominance, extending toward posterior temporal regions, and affecting tracts projecting to the anterior temporal lobes (inferior longitudinal fasciculus, uncinate fasciculus) and tracts projecting to or running nearby posterior temporal cortices: (superior longitudinal fasciculus, inferior frontal-occipital fasciculus). In the logopenic variant metabolic alterations were more extensive than atrophy affecting mainly the left temporal-parietal junction and extending toward more anterior temporal cortices. Metabolic and tract data were coherent given the alterations of the left superior and inferior longitudinal fasciculus and the left inferior frontal-occipital fasciculus. In the nonfluent/agrammatic variant cortical thinning and hypometabolism were located in the left frontal cortex but Broca's area was only affected on metabolic measures. Metabolic and tract alterations were coherent as reflected by damage to the left uncinate fasciculus connecting with Broca's area. Our findings provide a full-blown statistically robust picture of brain alterations in early-stage variants of primary progressive aphasia which has implications for diagnosis, classification and future therapeutic strategies. They demonstrate that in logopenic and semantic variants patterns of brain damage display a non-negligible overlap in temporal regions whereas they are substantially distinct in the nonfluent/agrammatic variant (frontal regions). These results also indicate that frontal networks (combinatorial syntax/phonology) and temporal networks (lexical/semantic representations) constitute distinct anatomo-functional entities with differential vulnerability to degenerative processes in aphasia variants. Finally, the identification of the specific damage patterns could open an avenue for trans-cranial stimulation approaches by indicating the appropriate target-entry into the damaged language system.
Published: 2018
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10. COGEVIS: A New Scale to Evaluate Cognition in Patients with Visual Deficiency

Author: Claire Meyniel, Dalila Samri, Farah Stefano, Joel Crevoisier, Florence Bonté, Raffaella Migliaccio, Laure Delaby, Anne Bertrand, Marie Odile Habert, Bruno Dubois, Bahram Bodaghi, and Stéphane Epelbaum
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: We evaluated the cognitive status of visually impaired patients referred to low vision rehabilitation (LVR) based on a standard cognitive battery and a new evaluation tool, named the COGEVIS, which can be used to assess patients with severe visual deficits. We studied patients aged 60 and above, referred to the LVR Hospital in Paris. Neurological and cognitive evaluations were performed in an expert memory center. Thirty-eight individuals, 17 women and 21 men with a mean age of 70.3 ± 1.3 years and a mean visual acuity of 0.12 ± 0.02, were recruited over a one-year period. Sixty-three percent of participants had normal cognitive status. Cognitive impairment was diagnosed in 37.5% of participants. The COGEVIS score cutoff point to screen for cognitive impairment was 24 (maximum score of 30) with a sensitivity of 66.7% and a specificity of 95%. Evaluation following 4 months of visual rehabilitation showed an improvement of Instrumental Activities of Daily Living (p=0.004), National Eye Institute Visual Functioning Questionnaire (p=0.035), and Montgomery–Åsberg Depression Rating Scale (p=0.037). This study introduces a new short test to screen for cognitive impairment in visually impaired patients.
Published: 2018
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11. IRC-082451, a novel multitargeting molecule, reduces L-DOPA-induced dyskinesias in MPTP Parkinsonian primates.

Author: Romina Aron Badin, Brigitte Spinnewyn, Marie-Claude Gaillard, Caroline Jan, Carole Malgorn, Nadja Van Camp, Frédéric Dollé, Martine Guillermier, Sabrina Boulet, Anne Bertrand, Marc Savasta, Michel Auguet, Emmanuel Brouillet, Pierre-Etienne Chabrier, and Philippe Hantraye
Subjects: Medicine, Science
Abstract: The development of dyskinesias following chronic L-DOPA replacement therapy remains a major problem in the long-term treatment of Parkinson's disease. This study aimed at evaluating the effect of IRC-082451 (base of BN82451), a novel multitargeting hybrid molecule, on L-DOPA-induced dyskinesias (LIDs) and hypolocomotor activity in a non-human primate model of PD. IRC-082451 displays multiple properties: it inhibits neuronal excitotoxicity (sodium channel blocker), oxidative stress (antioxidant) and neuroinflammation (cyclooxygenase inhibitor) and is endowed with mitochondrial protective properties. Animals received daily MPTP injections until stably parkinsonian. A daily treatment with increasing doses of L-DOPA was administered to parkinsonian primates until the appearance of dyskinesias. Then, different treatment regimens and doses of IRC-082451 were tested and compared to the benchmark molecule amantadine. Primates were regularly filmed and videos were analyzed with specialized software. A novel approach combining the analysis of dyskinesias and locomotor activity was used to determine efficacy. This analysis yielded the quantification of the total distance travelled and the incidence of dyskinesias in 7 different body parts. A dose-dependent efficacy of IRC-082451 against dyskinesias was observed. The 5 mg/kg dose was best at attenuating the severity of fully established LIDs. Its effect was significantly different from that of amantadine since it increased spontaneous locomotor activity while reducing LIDs. This dose was effective both acutely and in a 5-day sub-chronic treatment. Moreover, positron emission tomography scans using radiolabelled dopamine demonstrated that there was no direct interference between treatment with IRC-082451 and dopamine metabolism in the brain. Finally, post-mortem analysis indicated that this reduction in dyskinesias was associated with changes in cFOS, FosB and ARC mRNA expression levels in the putamen. The data demonstrates the antidyskinetic efficacy of IRC-082451 in a primate model of PD with motor complications and opens the way to the clinical application of this treatment for the management of LIDs.
Published: 2013
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12. Micro-MRI study of cerebral aging: ex vivo detection of hippocampal subfield reorganization, microhemorrhages and amyloid plaques in mouse lemur primates.

Author: Anne Bertrand, Adrien Pasquier, Alexandra Petiet, Christopher Wiggins, Audrey Kraska, Nelly Joseph-Mathurin, Fabienne Aujard, Nadine Mestre-Francés, and Marc Dhenain
Subjects: Medicine, Science
Abstract: Mouse lemurs are non-human primate models of cerebral aging and neurodegeneration. Much smaller than other primates, they recapitulate numerous features of human brain aging, including progressive cerebral atrophy and correlation between regional atrophy and cognitive impairments. Characterization of brain atrophy in mouse lemurs has been done by MRI measures of regional CSF volume and by MRI measures of regional atrophy. Here, we further characterize mouse lemur brain aging using ex vivo MR microscopy (31 µm in-plane resolution). First, we performed a non-biased, direct volumetric quantification of dentate gyrus and extended Ammon's horn. We show that both dentate gyrus and Ammon's horn undergo an age-related reorganization leading to a growth of the dentate gyrus and an atrophy of the Ammon's horn, even in the absence of global hippocampal atrophy. Second, on these first MR microscopic images of the mouse lemur brain, we depicted cortical and hippocampal hypointense spots. We demonstrated that their incidence increases with aging and that they correspond either to amyloid deposits or to cerebral microhemorrhages.
Published: 2013
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13. Correction: IRC-082451, a Novel Multitargeting Molecule, Reduces L-DOPA-Induced Dyskinesias in MPTP Parkinsonian Primates.

Author: Romina Aron Badin, Brigitte Spinnewyn, Marie-Claude Gaillard, Caroline Jan, Carole Malgorn, Nadja Van Camp, Frédéric Dollé, Martine Guillermier, Sabrina Boulet, Anne Bertrand, Marc Savasta, Michel Auguet, Emmanuel Brouillet, Pierre-Etienne Chabrier, and Philippe Hantraye
Subjects: Medicine, Science
Published: 2013
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14. Magnetic resonance imaging in primates. The example of the mouse lemur (Microcebus murinus): From detection of pathological aging to therapeutic evaluations

Author: Nelly Joseph-Mathurin, Olene Dorieux, Audrey Kraska, Anne Bertrand, Mathieu Santin, Nadine El Tannir El Tayara, and Marc Dhenain
Subjects: aging, Alzheimer, imaging, mouse lemur, MRI, primates, Science, Zoology, QL1-991
Abstract: Cerebral aging is a major public health issue in our societies as the aged population increases dramatically. It leads in many cases to neurodegenerative diseases such as Alzheimer disease (AD). Rodents and particularly transgenic mice are widely used as models for research on physiopathology of cerebral aging, neurodegenerative diseases and for the evaluation of therapies. However these models do not mimic all the pathophysiological aspects of human diseases. Complementary models such as non-human primates are phylogenetically close to humans and thus more predictive of drug efficiency in humans. Mouse lemur (Microcebus murinus) is a small primate (about 12cm, 100g) described as a useful model of cerebral aging and as a potential model of AD. Indeed several animals develop age-associated cerebral alterations like amyloidosis and other cerebral changes. Non invasive medical imaging methods such as magnetic resonance imaging (MRI) can be used to follow-up brain changes in these animals. In this review, we present how mouse lemurs can be followed-up by MRI and how MRI can be used during therapeutic evaluations and other applications in this model. MR images can be used to follow-up cerebral anatomy in mouse lemurs. It allows for the description of age-associated atrophic processes, age-associated iron accumulation, and vascular anatomy (thanks to MR angiography). Cerebral glucose uptake can be studied in mouse lemurs with other in vivo imaging modalities such as positron emission tomography (PET). In this case, MRI can be used as a support for quantification of radioligand uptake in specific structures. Ex vivo MR imaging is another MR protocol that can be used to describe cerebral aging in lemurs. It provides high resolution 3D histological brain images and allows for studying exquisite anatomical details or microhemorrhages. Finally, MRI can be used to practice cerebral surgery in lemurs and determine coordinates for stereotactic injections. It can also be used during therapeutic interventions by selecting animals to be involved in therapeutic trials and also by following specific MR biomarkers. MRI is thus critical to better characterize cerebral aging in the mouse lemur and to better carry out longitudinal studies in this primate model.
Published: 2011
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15. Bice Curiger

Author: Anne Bertrand
Subjects: General Engineering
Published: 2022

16. Nobody’s Perfect

Author: Klok, Anne Bertrand, Yurika Aonuki, Sihwei Chen, Henry Davis, Joash Gambarage, Laura Griffin, Marianne Huijsmans, Lisa Matthewson, Daniel Reisinger, Hotze Rullmann, Raiane Salles, Michael David Schwan, Neda Todorović, Bailey Trotter, and Jozina Vander
Subjects: tense, aspect, perfect, perfective, experiential, resultative, storyboards, typology
Abstract: This paper challenges the cross-linguistic validity of the tense–aspect category ‘perfect’ by investigating 15 languages from eight different families (Atayal, Brazilian Portuguese, Dutch, English, German, Gitksan, Japanese, Javanese, Korean, Mandarin, Niuean, Québec French, St’át’imcets, Swahili, and Tibetan). The methodology involves using the storyboard ‘Miss Smith’s Bad Day’ to test for the availability of experiential, resultative, recent-past, and continuous readings, as well as lifetime effects, result-state cancellability, narrative progression, and compatibility with definite time adverbials. Results show that the target forms in these languages can be classified into four groups: (a) past perfectives; (b) experientials; (c) resultatives; and (d) hybrids (which allow both experiential and resultative readings). It is argued that the main division is between past perfectives, which contain a ‘pronominal’ tense, on the one hand, and the other three groups on the other, which involve existential quantification, either over times (experiential) or over events (resultative). The methodological and typological implications of the findings are discussed. The main conclusion of the study is that there is no universal category of ‘the perfect’, and that instead, researchers should focus on identifying shared semantic components of tense–aspect categories across languages.
Published: 2022
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17. Sur Les Parties Fractionnaires Des Suites (β n ) n ≥1

Author: Anne Bertrand-Mathis
Subjects: Discrete mathematics, Probability and statistics, General Medicine, Mathematics
Abstract: We show that for an arbitrary sequence of intervals I n with constant length c, there exist real numbers β such that for all n β n belongs to I n modulo one.
Published: 2019

18. Childhood cognitive skill trajectories and suicide by mid-adulthood: an investigation of the 1958 British Birth Cohort

Author: Marie-Claude Geoffroy, Kyle T. Greenway, Massimiliano Orri, Stéphane Richard-Devantoy, Josie-Anne Bertrand, Gustavo Turecki, Chris Power, David Gunnell, McGill Group for Suicide Studies, McGill University = Université McGill [Montréal, Canada]-Douglas Mental Health University Institute, CISSS des Laurentides, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Douglas Research Center, Douglas Mental Health University Institute, Population Health Sciences [Bristol, Royaume-Uni], University of Bristol [Bristol], National Institute of Health Research Biomedical Research Centre [Bristol], University of Bristol [Bristol]-NHS Foundation Trust-University Hospitals Bristol, UCL Great Ormond Street Institute of Child Health [London, UK], Department of educational and counselling psychology, McGill University = Université McGill [Montréal, Canada], DG is supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol, England. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. MO is supported by the European Union's Horizon 2020 research and innovation program under grant agreement No. 793396 and the Canadian Institutes of Health Research. MCG holds a Canada Research Chair (Tier 2) and is supported by the American Foundation for Suicide Prevention (AFSP). Dr Turecki holds a Canada Research Chair (Tier 1) and a NARSAD Distinguished Investigator Award. He is supported by grants from the Canadian Institute of Health Research (CIHR) (FDN148374 and EGM141899). Drs Geoffroy and Turecki are supported by the Fonds de recherche du Québec – Santé (FRQS) through the Quebec Network on Suicide, Mood Disorders and Related Disorders., and European Project: 793396,LIFESPAN
Subjects: Male, Longitudinal study, Adolescent, Intelligence, Poison control, Suicide, Attempted, Suicide prevention, Occupational safety and health, Cohort Studies, 03 medical and health sciences, Cognition, 0302 clinical medicine, Cognitive Abilities, Academic Performance, Injury prevention, Humans, Longitudinal Studies, Cognitive skill, Child, Applied Psychology, Intelligence Tests, Human factors and ergonomics, Middle Aged, United Kingdom, 030227 psychiatry, Suicide, Early-life influences, Psychiatry and Mental health, Reading, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Female, Mathematics, Birth cohort, 030217 neurology & neurosurgery, Demography, Cohort study
Abstract: BackgroundPoor cognitive abilities and low intellectual quotient (IQ) are associated with an increased risk of suicide attempts and suicide mortality. However, knowledge of how this association develops across the life-course is limited. Our study aims to establish whether individuals who died by suicide by mid-adulthood are distinguishable by their child-to-adolescence cognitive trajectories.MethodsParticipants were from the 1958 British Birth Cohort and were assessed for academic performance at ages 7, 11, and 16 and intelligence at 11 years. Suicides occurring by September 2012 were identified from linked national death certificates. We compared mean mathematics and reading abilities and rate of change across 7–16 years for individuals who died by suicide v. those still alive, with and without adjustment for potential early-life confounding factors. Analyses were based on 14 505 participants.ResultsFifty-five participants (48 males) had died by suicide by age 54 years. While males who died by suicide did not differ from participants still alive in reading scores at age 7 [effect size (g) = −0.04, p = 0.759], their reading scores had a less steep improvement up to age 16 compared to other participants. Adjustments for early-life confounding factors explained these differences. A similar pattern was observed for mathematics scores. There was no difference between individuals who died by suicide v. participants still alive on intelligence at 11 years.ConclusionsWhile no differences in tests of academic performance and IQ were observed, individuals who died by suicide had a less steep improvement in reading abilities over time compared to same-age peers.
Published: 2019

19. Intermittent Hypoxia Rewires the Liver Transcriptome and Fires up Fatty Acids Usage for Mitochondrial Respiration

Author: Jonathan Gaucher, Guillaume Vial, Emilie Montellier, Maëlle Guellerin, Sophie Bouyon, Emeline Lemarie, Véronique Pelloux, Anne Bertrand, Karin Pernet-Gallay, Frederic Lamarche, Anne-Laure Borel, Claire Arnaud, Elise Belaidi, Karine Clément, Diane Godin Ribuot, Judith Aron-Wisnewsky, and Jean-Louis Pépin
Subjects: mitochondria, Medicine (General), Nuclear Respiratory Factor (NRF), R5-920, intermittent hypoxia (IH), General Medicine, sleep apnea, liver, transcriptome
Abstract: Sleep Apnea Syndrome (SAS) is one of the most common chronic diseases, affecting nearly one billion people worldwide. The repetitive occurrence of abnormal respiratory events generates cyclical desaturation-reoxygenation sequences known as intermittent hypoxia (IH). Among SAS metabolic sequelae, it has been established by experimental and clinical studies that SAS is an independent risk factor for the development and progression of non-alcoholic fatty liver disease (NAFLD). The principal goal of this study was to decrypt the molecular mechanisms at the onset of IH-mediated liver injury. To address this question, we used a unique mouse model of SAS exposed to IH, employed unbiased high-throughput transcriptomics and computed network analysis. This led us to examine hepatic mitochondrial ultrastructure and function using electron microscopy, high-resolution respirometry and flux analysis in isolated mitochondria. Transcriptomics and network analysis revealed that IH reprograms Nuclear Respiratory Factor- (NRF-) dependent gene expression and showed that mitochondria play a central role. We thus demonstrated that IH boosts the oxidative capacity from fatty acids of liver mitochondria. Lastly, the unbalance between oxidative stress and antioxidant defense is tied to an increase in hepatic ROS production and DNA damage during IH. We provide a comprehensive analysis of liver metabolism during IH and reveal the key role of the mitochondria at the origin of development of liver disease. These findings contribute to the understanding of the mechanisms underlying NAFLD development and progression during SAS and provide a rationale for novel therapeutic targets and biomarker discovery.
Published: 2021

20. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

Author: Barbier, Mathieu, Camuzat, Agnès, Hachimi, Khalid El, Guegan, Justine, Rinaldi, Daisy, Lattante, Serena, Houot, Marion, Sánchez-Valle, Raquel, Sabatelli, Mario, Antonell, Anna, Molina-Porcel, Laura, Clot, Fabienne, Couratier, Philippe, van der Ende, Emma, van der Zee, Julie, Manzoni, Claudia, Camu, William, Cazeneuve, Cécile, Sellal, François, Didic, Mira, Golfier, Véronique, Pasquier, Florence, Duyckaerts, Charles, Rossi, Giacomina, Bruni, Amalia C, Alvarez, Victoria, Gómez-Tortosa, Estrella, de Mendonça, Alexandre, Graff, Caroline, Masellis, Mario, Nacmias, Benedetta, Oumoussa, Badreddine Mohand, Jornea, Ludmila, Forlani, Sylvie, Van Deerlin, Viviana, Rohrer, Jonathan D, Gelpi, Ellen, Rademakers, Rosa, Van Swieten, John, Le Guern, Eric, Van Broeckhoven, Christine, Ferrari, Raffaele, Génin, Emmanuelle, Brice, Alexis, Ber, Le, Isabelle Alexis Brice, Sophie, Auriacombe, Serge, Belliard, Anne, Bertrand, Anne, Bissery, Fre ́ de, ́ ric Blanc, Marie-Paule, Boncoeur, Ste, ́ phanie Bombois, Claire Boutoleau-Bretonnie` re, Agne`, s Camuzat, Mathieu, Ceccaldi, Marie, Chupin, Philippe, Couratier, Olivier, Colliot, Vincent, Deramecourt, Mira, Didic, Bruno, Dubois, Charles, Duyckaerts, Fre ́ de, ́ rique Etcharry-Bouyx, Aure, ́ lie Guignebert-Funkiewiez, Maı ̈te, ́ Formaglio, ́ ronique Golfier, Ve, Marie-Odile, Habert, Didier, Hannequin, Lucette, Lacomblez, Julien, Lagarde, ́ raldine Lautrette, Ge, Isabelle Le Ber, Benjamin Le Toullec, Richard, Levy, Marie-Anne, Mackowiak, Bernard-Franc ̧ois Michel, Florence, Pasquier, Thibaud, Lebouvier, Carole Roue, ́ -Jagot, Christel Thauvin- Robinet, Catherine, Thomas-Anterion, Je ́ re, ́ mie Pariente, Franc ̧ois Salachas, Sabrina, Sayah, Franc ̧ois Sellal, Assi-Herve, ́ Oya, Daisy, Rinaldi, Adeline, Rollin-Sillaire, Martine, Vercelletto, David, Wallon, Armelle, Rametti-Lacroux, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavan, Ramasamy, Kwok, John B. J., Carol Dobson- Stone, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Isabel Herna, ́ ndez, Agustı ́n Ruiz, Merce`, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Diego, Albani, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, ́ n, Jordi Clarimo, Alberto Lleo, ́, Rafael, Blesa, Maria Landqvist Waldo, ̈, Karin, Nilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietro, Pietrini, Edward, Uey, Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, Rowe, James B., Schlachetzki, Johannes C. M., James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Van Deerlin, Vivianna M., Murray, Grossman, Trojanowski, John Q., Julie van der Zee, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle, Leber, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Maria Grazia Spillantini, Morris, Huw R., Patrizia, Rizzu, Peter, Heutink, Snowden, Julie S., Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., David, Knopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, van Swieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Adeline, Rollin, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni., Neurology, Amsterdam Neuroscience - Neurodegeneration, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Dupuytren [CHU Limoges], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Center for Molecular Neurology (VIB-UAntwerp), University of Antwerp (UA), University College of London [London] (UCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Yves le Foll, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Hospital Central de Asturias, Institute of Health Research of Principado de Asturias (ISPA), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Karolinska University Hospital [Stockholm], Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione Don Carlo Gnocchi, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), The French clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS, The International Frontotemporal Dementia Genomics Consortium, The European Early Onset Dementia (EU -EOD) Consortium, Brainbank Neuro-CEB Neuropathology Network, and Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS
Subjects: Adult, Male, TDP-43, C9orf72, SLITRK2, amyotrophic lateral sclerosis, frontotemporal dementia, Nerve Tissue Proteins, Settore MED/03 - GENETICA MEDICA, Polymorphism, Single Nucleotide, Cohort Studies, Genes, X-Linked, 80 and over, Medicine, Dementia, Humans, Allele, Age of Onset, Polymorphism, Aged, Aged, 80 and over, biology, C9orf72 Protein, business.industry, Membrane Proteins, MESH: Frontotemporal Lobar Degeneration / epidemiology, Frontotemporal Lobar, Degeneration / genetics, Genes, X-Linked / genetics, Genome-Wide Association Study / methods, Frontotemporal lobar degeneration, Single Nucleotide, Middle Aged, X-Linked, medicine.disease, Amyotrophic lateral sclerosis, Minor allele frequency, Genes, Immunology, Synaptophysin, biology.protein, Female, MESH: Adult, C9orf72 Protein / genetics, Frontotemporal Lobar Degeneration / diagnosis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, Neurology (clinical), MESH: Humans, Membrane Proteins / genetics, Nerve Tissue Proteins / genetics, Polymorphism, Single Nucleotide / genetics, Age of onset, Frontotemporal Lobar Degeneration, business, Frontotemporal dementia, Genome-Wide Association Study
Abstract: The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.
Published: 2021

21. FHL1 is a major host factor for chikungunya virus infection

Author: Cécile Doyen, Thérèse Couderc, Alexis Brugier, R. Juntas-Morales, Philippe Roingeard, Rabah Ben Yaou, Julien Burlaud-Gaillard, Etienne Simon-Loriere, Mohamed Lamine Hafirassou, Sophia Rafasse, Vasiliya Kril, Pierre-Olivier Vidalain, Laura Pezzi, Gisèle Bonne, Lucie Gueneau, Xavier de Lamballerie, Marc Lecuit, Laurent Meertens, Anne Bertrand-Legout, Beate M. Kümmerer, Ali Amara, Lucie Bonnet-Madin, Thibaud Goupil, Constance Delaugerre, Athena Labeau, Monsef Benkirane, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)), Collège de France (CdF (institution))-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Virology [Bonn, Germany], University of Bonn Medical Centre, Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris] (IP), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Equipe Chimie et Biologie, Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5), Génomique virale et vaccination, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Laboratoire de Virologie [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de maladies infectieuses et tropicales [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service des Maladies infectieuses et tropicales [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This study received funding from the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (ANR-10-LABX-62-IBEID), the ‘Investissements d’Avenir’ program (ANR-10-IHUB-0002, ANR-15-CE15-00029 ZIKAHOST and the INCEPTION program ANR-16-CONV-0005), Institut Pasteur, Inserm and European Research Council. Viruses were provided by the Europe and Virus Archive, which has received funding from the EU Horizon 2020 research and innovation program under grant agreement 653316. The authors thank the EA7310, Laboratoire de Virologie, Université de Corse-Inserm for funding the doctoral position of L.P., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-17-CE15-0029,ZIKAHOST,LES FACTEURS DE L'HÔTE ASSOCIÉS À LA NEUROPATHOGÉNICITÉ DU VIRUS ZIKA(2017), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), Institut National de la Santé et de la Recherche Médicale (INSERM)-Collège de France (CdF (institution))-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), BUISINE, Soline, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, LES FACTEURS DE L'HÔTE ASSOCIÉS À LA NEUROPATHOGÉNICITÉ DU VIRUS ZIKA - - ZIKAHOST2017 - ANR-17-CE15-0029 - AAPG2017 - VALID, and Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs - - INCEPTION2016 - ANR-16-CONV-0005 - CONV - VALID
Subjects: Male, Permissiveness, viruses, Viral pathogenesis, Muscle Proteins, Host-Derived Cellular Factors, Alphavirus, Viral Nonstructural Proteins, Virus Replication, medicine.disease_cause, Virus, Myoblasts, Mice, 03 medical and health sciences, medicine, Animals, Humans, O'nyong-nyong Virus, Chikungunya, Cells, Cultured, 030304 developmental biology, Host factor, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, Multidisciplinary, biology, 030306 microbiology, Intracellular Signaling Peptides and Proteins, virus diseases, Fibroblasts, LIM Domain Proteins, biology.organism_classification, Virology, FHL1, 3. Good health, HEK293 Cells, Viral replication, Host-Pathogen Interactions, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Chikungunya Fever, RNA, Viral, Female, Chikungunya virus, Protein Binding
Abstract: Chikungunya virus (CHIKV) is a re-emerging alphavirus that is transmitted to humans by mosquito bites and causes musculoskeletal and joint pain1,2. Despite intensive investigations, the human cellular factors that are critical for CHIKV infection remain unknown, hampering the understanding of viral pathogenesis and the development of anti-CHIKV therapies. Here we identified the four-and-a-half LIM domain protein 1 (FHL1)3 as a host factor that is required for CHIKV permissiveness and pathogenesis in humans and mice. Ablation of FHL1 expression results in the inhibition of infection by several CHIKV strains and o’nyong-nyong virus, but not by other alphaviruses and flaviviruses. Conversely, expression of FHL1 promotes CHIKV infection in cells that do not normally express it. FHL1 interacts directly with the hypervariable domain of the nsP3 protein of CHIKV and is essential for the replication of viral RNA. FHL1 is highly expressed in CHIKV-target cells and is particularly abundant in muscles3,4. Dermal fibroblasts and muscle cells derived from patients with Emery–Dreifuss muscular dystrophy that lack functional FHL15 are resistant to CHIKV infection. Furthermore, CHIKV infection is undetectable in Fhl1-knockout mice. Overall, this study shows that FHL1 is a key factor expressed by the host that enables CHIKV infection and identifies the interaction between nsP3 and FHL1 as a promising target for the development of anti-CHIKV therapies. FHL1 is a key factor expressed by humans and mice that is required for chikungunya virus infection and is therefore a promising target for the development of therapies against chikungunya virus.
Published: 2019

22. A new milestone for the study of variation in Montréal French: The Hochelaga-Maisonneuve sociolinguistic survey

Author: Anne Bertrand, Mireille Tremblay, Elizabeth Michel, and Hélène Blondeau
Subjects: History, media_common.quotation_subject, Variation, français québécois, Change, Corpus, Temps réel, Real Time, Presentation, Transcription (linguistics), Milestone (project management), Selection (linguistics), Composition (language), Temps apparent, General Environmental Science, media_common, French, language.human_language, Linguistics, Stratified sampling, Changement, Variation (linguistics), Apparent Time, language, General Earth and Planetary Sciences, Québec French
Abstract: This article introduces the 2012 Montréal FRAN-HOMA corpus, collected in the Francophone neighborhood of Hochelaga-Maisonneuve, and how it relates to the heritage corpora of Montréal French collected since the 1970s. We discuss the methodological choices made regarding the composition of this corpus including the historical and demo-linguistic information that led to the selection of the Hochelaga-Maisonneuve neighborhood for fieldwork. A presentation of the socially stratified sample and criteria for participant selection is followed by a discussion on data collection and the sociolinguistic interview. After a brief review of the transcription protocol and the advantages of audio-aligned transcription, we provide two illustrations of the revival of research on linguistic variation made possible by this new corpus. Cet article présente le corpus FRAN-HOMA de Montréal 2012 recueilli dans le quartier francophone d’Hochelaga-Maisonneuve, et son rapport avec les corpus patrimoniaux de français montréalais recueillis depuis les années 1970. Nous discutons des choix méthodologiques effectués concernant la composition de ce corpus, y compris les informations historiques et démo-linguistiques qui ont conduit à la sélection d’Hochelaga-Maisonneuve comme site pour le travail de terrain. Une présentation de l’échantillon socialement stratifié et des critères de sélection des participants est suivie d’une discussion sur la collecte des données et l’entretien sociolinguistique. Après un bref exposé sur le protocole de transcription et les avantages de la transcription audio-alignée, nous fournissons deux illustrations de la relance de la recherche sur la variation linguistique rendue possible par ce nouveau corpus.
Published: 2021

23. Reproducible evaluation of diffusion MRI features for automatic classification of patients with Alzheimer's disease

Author: Jorge Samper-González, Junhao Wen, Alexandre Routier, Stanley Durrleman, Simona Bottani, Sabrina Fontanella, Anne Bertrand, Olivier Colliot, Ninon Burgos, Thomas Jacquemont, Stéphane Epelbaum, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), The research leading to these results has received funding from the program 'Investissements d’avenir' ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Institut Hospitalo-Universitaire-6) ANR-11-IDEX-004 (Agence Nationale de la Recherche-11-Initiative d’Excellence-004, project LearnPETMR number SU-16-R-EMR-16), from the European Union H2020 program (project EuroPOND, grant number 666992, project HBP SGA1 grant number 720270), from the joint NSF/NIH/ANR program 'Collaborative Research in Computational Neuroscience' (project HIPLAY7, grant number ANR-16-NEUC-0001-01), from Agence Nationale de la Recherche (project PREVDEMALS, grant number ANR-14-CE15-0016-07),from the European Research Council (to Dr Durrleman project LEASP, grant number 678304),from the Abeona Foundation (project Brain@Scale), and from the French government under management of Agence Nationale de la Recherche as part of the 'Investissements d’avenir' program, reference ANR-19-P3IA-0001 (PRAIRIE 3IA Institute).J.W. receives financial support from China Scholarship Council (CSC). O.C. is supported by a 'Contrat d’Interface Local' from Assistance Publique-Hôpitaux de Paris (AP-HP). N.B. receives funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. PCOFUND-GA-2013-609102, through the PRESTIGE programme coordinated by Campus France., ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Colliot, Olivier, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Sorbonne Université (SU)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: FOS: Computer and information sciences, Male, Computer Science - Machine Learning, Open-source, Computer science, Diffusion magnetic resonance imaging, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, Quantitative Biology - Quantitative Methods, Machine Learning (cs.LG), [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], 0302 clinical medicine, Statistics - Machine Learning, Preprocessor, Quantitative Methods (q-bio.QM), Aged, 80 and over, Small data, General Neuroscience, Image and Video Processing (eess.IV), 05 social sciences, Brain, Alzheimer's disease, Classification, Reproducibility, 3. Good health, Feature (computer vision), DTI, Female, Smoothing, Information Systems, [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], Feature extraction, Machine Learning (stat.ML), Feature selection, 050105 experimental psychology, 03 medical and health sciences, [INFO.INFO-LG]Computer Science [cs]/Machine Learning [cs.LG], Alzheimer Disease, Image Interpretation, Computer-Assisted, Fractional anisotropy, Machine learning, FOS: Electrical engineering, electronic engineering, information engineering, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, 0501 psychology and cognitive sciences, Aged, business.industry, Pattern recognition, [INFO.INFO-LG] Computer Science [cs]/Machine Learning [cs.LG], Electrical Engineering and Systems Science - Image and Video Processing, FOS: Biological sciences, Artificial intelligence, business, 030217 neurology & neurosurgery, Software, Diffusion MRI
Abstract: Diffusion MRI is the modality of choice to study alterations of white matter. In past years, various works have used diffusion MRI for automatic classification of AD. However, classification performance obtained with different approaches is difficult to compare and these studies are also difficult to reproduce. In the present paper, we first extend a previously proposed framework to diffusion MRI data for AD classification. Specifically, we add: conversion of diffusion MRI ADNI data into the BIDS standard and pipelines for diffusion MRI preprocessing and feature extraction. We then apply the framework to compare different components. First, FS has a positive impact on classification results: highest balanced accuracy (BA) improved from 0.76 to 0.82 for task CN vs AD. Secondly, voxel-wise features generally gives better performance than regional features. Fractional anisotropy (FA) and mean diffusivity (MD) provided comparable results for voxel-wise features. Moreover, we observe that the poor performance obtained in tasks involving MCI were potentially caused by the small data samples, rather than by the data imbalance. Furthermore, no extensive classification difference exists for different degree of smoothing and registration methods. Besides, we demonstrate that using non-nested validation of FS leads to unreliable and over-optimistic results: 0.05 up to 0.40 relative increase in BA. Lastly, with proper FR and FS, the performance of diffusion MRI features is comparable to that of T1w MRI. All the code of the framework and the experiments are publicly available: general-purpose tools have been integrated into the Clinica software package (www.clinica.run) and the paper-specific code is available at: https://github.com/aramis-lab/AD-ML., 51 pages, 5 figure and 6 tables
Published: 2021

24. « A toi appartient le regard et (…) la liaison infinie entre les choses » (sous la dir. de Christine Barthe)

Author: Anne Bertrand
Subjects: General Engineering
Published: 2020

25. Markus Lüpertz, Narcisse et Echo. Discours, essais et poèmes 1961-2019

Author: Anne Bertrand
Subjects: General Engineering
Abstract: En 2007 paraissait a Munster un recueil des ecrits du peintre et sculpteur allemand Markus Lupertz (ne en 1941 a Reichenberg), rediges de 1961 a 2004, reunis par l’historien de l’art et directeur de musee Siegfried Gohr, sous le meme titre que cette volumineuse anthologie francaise (603 p.), qui le continue jusqu’en 2019. Elle s’ouvre sur une preface d’Eric Darragon, egalement specialiste de Georg Baselitz, contemporain de Lupertz. Ce dernier a fait l’objet d’une retrospective au musee d’Art ...
Published: 2020

26. Vincent Bioulès, Journal (1972-2018) : « Dieu, les autres, les femmes, la peinture, la vie enfin… »

Author: Anne Bertrand
Subjects: General Engineering
Published: 2020

27. Copies, écarts et variations dans la création contemporaine (sous la dir. de Céline Cadaureille, Anne Favier)

Author: Anne Bertrand
Subjects: General Engineering
Published: 2020

28. Psychological pain and depression: it's hard to speak when it hurts

Author: Sébastien Guillaume, Josie-Anne Bertrand, Stéphane Richard-Devantoy, Aurélie Cazals, Emilie Olié, Déborah Ducasse, Séverine Béziat, Kyle T. Greenway, Philippe Courtet, Isabelle Jaussent, Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], CISSS des Laurentides, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Adult, Male, medicine.medical_specialty, Pain, Neuropsychological Tests, 03 medical and health sciences, 0302 clinical medicine, Cognition, Phonetics, medicine, Verbal fluency test, Humans, Psychiatry, Depression (differential diagnoses), Depressive Disorder, Major, Depression, Verbal Behavior, verbal fluency, Neuropsychology, Psychological pain, Middle Aged, 030227 psychiatry, Semantics, Psychiatry and Mental health, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Female, Psychology, 030217 neurology & neurosurgery
Abstract: International audience; Objective: To investigate the neuropsychological features of depressed patients reporting high level of psychological pain.Methods: Sixty-two inpatients were included and divided into two groups according to the level of psychological pain assessed by a Likert scale. Cognitive abilities were assessed using the Trail Making Test, the Stroop test, and Verbal Fluency Test (semantic and phonemic verbal fluency). Univariate and multivariate analyses were performed to determine neuropsychological factors associated with a high level of psychological pain.Results: The median level of psychological pain was 8/10. High level of psychological pain was associated with poor phonemic verbal fluency performance in men (p = 0.009), but not in women, even after controlling for confounding factors (age, level of depression, anxiety). Groups did not differ on the Trail Making Test, the Stroop test, or the semantic verbal fluency measure.Conclusion: Psychological pain is a specific clinical entity that should be considered to be more significant than just a symptom of depression. High level of psychological pain appears to be associated with a deficit of phonemic verbal fluency in depressed men. This finding could help to target psychotherapeutic treatments and improve screening.Key pointsPatients with high psychological pain do not differ on the Trail Making Test, the Stroop Test or the Sematic Verbal Fluency Measure to patients with low psychological painHigh psychological pain is associated with a deficit in phonemic verbal fluency in depressed menFuture research should aim to clarify gender differences in psychological pain in participants with and without major depressive disorder, as well as explore the complex relationship between cognition and the different forms of pain (psychological, physical and psychosomatic).
Published: 2020

29. FHL1 is a key player of chikungunya virus tropism and pathogenesis

Author: Meertens, Laurent, primary, Hafirassou, Mohamed Lamine, additional, Couderc, Thérèse, additional, Bonnet-Madin, Lucie, additional, Kril, Vasiliya, additional, Kümmerer, Beate M., additional, Labeau, Athena, additional, Brugier, Alexis, additional, Simon-Loriere, Etienne, additional, Burlaud-Gaillard, Julien, additional, Doyen, Cécile, additional, Pezzi, Laura, additional, Goupil, Thibaud, additional, Rafasse, Sophia, additional, Vidalain, Pierre-Olivier, additional, Legout, Anne Bertrand, additional, Gueneau, Lucie, additional, Juntas-Morales, Raul, additional, Yaou, Rabah Ben, additional, Bonne, Gisèle, additional, de Lamballerie, Xavier, additional, Benkirane, Monsef, additional, Roingeard, Philippe, additional, Delaugerre, Constance, additional, Lecuit, Marc, additional, and Amara, Ali, additional
Published: 2021
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30. Are endocasts reliable proxies for brains? A 3D quantitative comparison of the extant human brain and endocast

Author: Jean Dumoncel, Stanley Durrleman, Edwin John De Jager, Anne Bertrand, Farhana Ebrahim Suleman, Zarina I. Lockhat, Gérard Subsol, Amélie Beaudet, Anna Catherina Oettle, Anthropologie Moléculaire et Imagerie de Synthèse (AMIS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Image & Interaction (ICAR), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Pretoria [South Africa], University of Cambridge [UK] (CAM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Gestionnaire, HAL Sorbonne Université 5, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Histology, Brain shape, [SDV]Life Sciences [q-bio], Surface‐based comparison, Neuroimaging, Biology, Paleoneurology, 03 medical and health sciences, Sulci, 0302 clinical medicine, Imaging, Three-Dimensional, Extant taxon, medicine, Humans, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Original Paper, Fossil Record, Crania, Brain, Cell Biology, Human brain, Anatomy, biology.organism_classification, Original Papers, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Female, Automatic segmentation, 030217 neurology & neurosurgery, Endocast, Developmental Biology, Shape analysis (digital geometry)
Abstract: Endocasts (i.e., replicas of the inner surface of the bony braincase) constitute a critical proxy for qualifying and quantifying variations in brain shape and organization in extinct taxa. In the absence of brain tissues preserved in the fossil record, endocasts provide the only direct evidence of brain evolution. However, debates on whether or not information inferred from the study of endocasts reflects brain shape and organization have polarized discussions in paleoneurology since the earliest descriptions of cerebral imprints in fossil hominin crania. By means of imaging techniques (i.e., MRIs and CT scans) and 3D modelling methods (i.e., surface‐based comparisons), we collected consistent morphological (i.e., shape) and structural (i.e., sulci) information on the variation patterns between the brain and the endocast based on a sample of extant human individuals (N = 5) from the 3D clinical image database of the Steve Biko Academic Hospital in Pretoria (South Africa) and the Hôpitaux Universitaires Pitié Salpêtrière in Paris (France). Surfaces of the brain and endocast of the same individual were segmented from the 3D MRIs and CT images, respectively. Sulcal imprints were automatically detected. We performed a deformation‐based shape analysis to compare both the shape and the sulcal pattern of the brain and the endocast. We demonstrated that there is close correspondence in terms of morphology and organization between the brain and the corresponding endocast with the exception of the superior region. By comparatively quantifying the shape and organization of the brain and endocast, this work represents an important reference for paleoneurological studies., Is the endocast a reliable proxy for reconstructing the brain of fossil specimens? By quantitatively comparing extant human brains and endocasts using MRIs and CT‐scans, here we address this fundamental question and support the significance of fossil endocasts in paleoneurological studies.
Published: 2020

31. Mitochondria in human acute myeloid leukemia cell lines have ultrastructural alterations linked to deregulation of their respiratory profiles

Author: Sylvie Tondeur, Caroline Lo Presti, Karin Pernet-Gallay, Anne Mc Leer, Sandrine Blanchet, Julie Mondet, Pascal Mossuz, Simon Chevalier, and Anne Bertrand
Subjects: 0301 basic medicine, Cancer Research, Mitochondrial disease, Cell, HL-60 Cells, Biology, Mitochondrion, 03 medical and health sciences, Oxygen Consumption, 0302 clinical medicine, Mitophagy, Genetics, medicine, Humans, Molecular Biology, Endoplasmic reticulum membrane, Endoplasmic reticulum, Myeloid leukemia, Cell Biology, Hematology, medicine.disease, Mitochondria, Neoplasm Proteins, Cell biology, Repressor Proteins, Leukemia, Myeloid, Acute, 030104 developmental biology, medicine.anatomical_structure, Apoptosis, 030220 oncology & carcinogenesis, Mutation, K562 Cells
Abstract: Mitochondria not only are essential for cell metabolism and energy supply but are also engaged in calcium homeostasis and reactive oxygen species generation and play a key role in apoptosis. As a consequence, functional mitochondrial disorders are involved in many human cancers including acute myeloid leukemia (AML). However, very few data are available on the deregulation of their number and/or shape in leukemic cells, despite the evident link between ultrastructure and function. In this context, we analyzed the ultrastructural mitochondrial parameters (number per cell, mitochondria area, number of cristae/mitochondria, cristal thickness) in five leukemia cell lines (HEL, HL60, K562, KG1, and OCI-AML3) together with the functional assay of their respiratory profile. First, we describe significant differences in basal respiration, maximal respiration, ATP production, and spare respiratory capacity between our cell lines, confirming the various respiratory profiles among leukemia subtypes. Second, we highlight that these variations are obviously associated with significant interleukemia heterogeneity of the number and/or shape of mitochondria. For instance, KG1, characterized by the smallest number of mitochondria together with reduced cristal diameter, had a particularly deficient respiratory profile. In comparison, the HEL and K562 cell lines, both with high respiratory profiles, harbored the largest number of mitochondria/cells with high cristal diameters. Moreover, we report that K562, carrying the ASXL1 mutation, presents significant mitochondria-endoplasmic reticulum deficiency reflected by decreases in the numbers of matrix granules and mitochondria-associated endoplasmic reticulum membrane (MAM) and mitochondrial-derived vesicle (MDV) precursors, which are implicated in the regulatory pathways of cell mortality via the processes of mitophagy and calcium homeostasis. Contrarily, HL60 carried high levels of matrix granules and MAMs and had a higher sensitivity to drugs targeting mitochondria (rotenone/antimycin). We confirm the implication of ASXL1 mutation in this mitochondria dysregulation through the study of transcript expression (from 415 patients with public data) involved in three mitochondrial pathways: (1) endoplasmic reticulum-mitochondria contacts (MAMs), (2) matrix granule homeostasis, and (3) MDV precursor production. Our study offers new and original data on mitochondria structural alterations linked to deregulation of respiration profiles in AMLs and some genetic characteristics, suggesting that modifications of mitochondrial shape and/or number in leukemic cells participate in chemoresistance and could be a targeted mechanism to regulate their proliferative potential.
Published: 2020

32. Eric Rondepierre, Double feinte. Territoire des fictions secondes

Author: Anne Bertrand
Subjects: General Engineering
Abstract: Artiste mais aussi ecrivain, Eric Rondepierre a largement travaille, depuis le debut des annees 1990, l’idee de fiction qui traverse ses photographies, livres et videos. Il consacre un essai a la notion de « fiction seconde », ainsi definie : « C’est ce degre de la feintise […], et plus particulierement ces courts moments, dans les fictions, ou des personnages, au lieu d’effectuer une action, prennent la decision de la simuler, de la mimer. […]. Exemples : boire un verre sans verre, tirer au ...
Published: 2020

33. Nicolas Bouvier, Du coin de l’œil : écrits sur la photographie

Author: Anne Bertrand
Subjects: General Engineering
Abstract: Nicolas Bouvier (1929-1998) disait : « je fais des photographies sans etre photographe, et j’ecris de temps en temps sans etre veritablement ecrivain. Je crois que si je devais me prevaloir d’une specialite j’opterais pour celle de voyageur. Etre l’œil ou l’esprit qui se promene, observe, compare et ensuite relate, une sorte de temoin ». L’Usage du monde (1963), et ses livres suivants, ont etabli l’auteur suisse comme un des plus curieux, fins, genereux ecrivains-voyageurs. Alexandre Chollier...
Published: 2020

34. Donald Judd Interviews

Author: Anne Bertrand
Subjects: General Engineering
Abstract: En 2016 paraissait le volume Donald Judd Writings, 1056 pages sous couverture rouge cadmium, aujourd’hui rejoint par son jumeau, 1023 pages sous couverture marine, egalement publie, avec la galerie David Zwirner a New York, par la Judd Foundation. Concue en 1977 par l’artiste americain Donald Judd (1928-1994), creee en 1996 et dirigee par ses enfants Flavin et Rainer Judd, elle a pour mission, a Marfa, Texas, comme au 101, Spring Street a New York, de preserver les lieux ou il vecut et travai...
Published: 2020

35. Consequences of Lmna Exon 4 Mutations in Myoblast Function

Author: Gisèle Bonne, Anne Bertrand, Carolina Epifano, Javier Ramón-Azcón, Alberto Martín, Albert G. Castaño, Miguel Ángel Rodríguez-Milla, Déborah Gómez-Domínguez, Fernando de Miguel, Borja Vilaplana-Martí, Sandra Amarilla-Quintana, Ignacio Pérez de Castro, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Instituto de Salud Carlos III [Madrid] (ISC), Universidad Europea de Madrid, Institute for Bioengineering of Catalonia [Barcelona] (IBEC), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institució Catalana de Recerca i Estudis Avançats (ICREA), and Centre de recherche en Myologie – U974 SU-INSERM
Subjects: life_sciences_other, 0301 basic medicine, Laminopathy, [SDV]Life Sciences [q-bio], Mutant, laminopathy, medicine.disease_cause, Muscle Development, LMNA, Myoblasts, Exon, Mice, 0302 clinical medicine, Tecnología médica, lcsh:QH301-705.5, Genetics, Mutation, integumentary system, Cell Differentiation, General Medicine, nuclear envelope, Exons, Lamin Type A, 030220 oncology & carcinogenesis, CRISPR, Female, C2C12, Microtubule-Associated Proteins, Subcellular Fractions, congenital, hereditary, and neonatal diseases and abnormalities, Cell Nucleus Shape, Membrana nuclear, Nuclear Envelope, MAP Kinase Signaling System, Telomere-Binding Proteins, Biology, Distrofias musculares, Article, Cell Line, 03 medical and health sciences, medicine, Animals, Protein kinase B, Cell Nucleus, Biología celular, Base Sequence, Membrane Proteins, medicine.disease, Genética, Clone Cells, 030104 developmental biology, lcsh:Biology (General), Lamin, DNA Damage
Abstract: Laminopathies are causally associated with mutations on the Lamin A/C gene (LMNA). To date, more than 400 mutations in LMNA have been reported in patients. These mutations are widely distributed throughout the entire gene and are associated with a wide range of phenotypes. Unfortunately, little is known about the mechanisms underlying the effect of the majority of these mutations. This is the case of more than 40 mutations that are located at exon 4. Using CRISPR/Cas9 technology, we generated a collection of Lmna exon 4 mutants in mouse C2C12 myoblasts. These cell models included different types of exon 4 deletions and the presence of R249W mutation, one of the human variants associated with a severe type of laminopathy, LMNA-associated congenital muscular dystrophy (L-CMD). We characterized these clones by measuring their nuclear circularity, myogenic differentiation capacity in 2D and 3D conditions, DNA damage, and levels of p-ERK and p-AKT (phosphorylated Mitogen-Activated Protein Kinase 1/3 and AKT serine/threonine kinase 1). Our results indicated that Lmna exon 4 mutants showed abnormal nuclear morphology. In addition, levels and/or subcellular localization of different members of the lamin and LINC (LInker of Nucleoskeleton and Cytoskeleton) complex were altered in all these mutants. Whereas no significant differences were observed for ERK and AKT activities, the accumulation of DNA damage was associated to the Lmna p.R249W mutant myoblasts. Finally, significant myogenic differentiation defects were detected in the Lmna exon 4 mutants. These results have key implications in the development of future therapeutic strategies for the treatment of laminopathies. Ministerio de Ciencia e Innovación (Acción estratégica en Salud intramural PI16III/00017-TPY1348/16). Fundación Andrés Marcio, niños contra la laminopatía (TPY-259/19). 6.600 JCR (2020) Q2, 53/195 Cell Biology 1.220 SJR (2020) Q1, 51/254 Biochemistry, Genetics and Molecular Biology (miscellaneous) No data IDR 2020 UEM
Published: 2020

36. Accuracy of MRI Classification Algorithms in a Tertiary Memory Center Clinical Routine Cohort

Author: Stéphane Epelbaum, Bruno Dubois, Alexandre Morin, Harald Hampel, Marcel Levy, Anne Bertrand, Didier Dormont, Jamila Ahdidan, Olivier Colliot, Marc Teichmann, Sébastian Ströer, Jorge Samper-González, Dalila Samri, Pierrick Coupé, Aline Mendes, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Neuroradiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Instituto Butantan [São Paulo], PICTURA, Laboratoire Bordelais de Recherche en Informatique (LaBRI), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2, Brainreader, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Fédération de neurologie 4, CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Psychiatry, Psychosomatic Medicine and Psychotherapy [Goethe Universität], Goethe-Universität Frankfurt am Main, Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], FRONTlab - Systèmes frontaux : fonctions et dysfonctions (FRONTlab), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), PNRIA, ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), FRONTLAB: Fonctions et dysfonctions de systèmes frontaux [ICM Paris] (FRONTlab), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM)
Subjects: 0301 basic medicine, Signal Processing (eess.SP), FOS: Computer and information sciences, Male, Support Vector Machine, Computer science, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Computer Vision and Pattern Recognition (cs.CV), [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Computer Science - Computer Vision and Pattern Recognition, Quantitative Biology - Quantitative Methods, 0302 clinical medicine, Assessment of cognitive disorders/dementia, All Cognitive Disorders/Dementia, Quantitative Methods (q-bio.QM), Volumetric MRI, medicine.diagnostic_test, General Neuroscience, Image and Video Processing (eess.IV), Brain, General Medicine, Alzheimer's disease, Middle Aged, Clinical routine, Magnetic Resonance Imaging, 3. Good health, Psychiatry and Mental health, Clinical Psychology, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Cohort, Female, Alzheimer’s disease, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Algorithms, MRI, Neuroimaging, 03 medical and health sciences, Magnetic resonance imaging, Alzheimer Disease, Image Interpretation, Computer-Assisted, medicine, FOS: Electrical engineering, electronic engineering, information engineering, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, Electrical Engineering and Systems Science - Signal Processing, Assessment of cognitive disorders/Dementia, Aged, Retrospective Studies, business.industry, Memory clinic, Univariate, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Reproducibility of Results, Pattern recognition, Electrical Engineering and Systems Science - Image and Video Processing, Support vector machine, Statistical classification, 030104 developmental biology, FOS: Biological sciences, Dementia, Artificial intelligence, Geriatrics and Gerontology, business, Cognition Disorders, Classifier (UML), 030217 neurology & neurosurgery, Software, All cognitive disorders/dementia
Abstract: BACKGROUND: Automated volumetry software (AVS) has recently become widely available to neuroradiologists. MRI volumetry with AVS may support the diagnosis of dementias by identifying regional atrophy. Moreover, automatic classifiers using machine learning techniques have recently emerged as promising approaches to assist diagnosis. However, the performance of both AVS and automatic classifiers has been evaluated mostly in the artificial setting of research datasets. OBJECTIVE: Our aim was to evaluate the performance of two AVS and an automatic classifier in the clinical routine condition of a memory clinic. METHODS: We studied 239 patients with cognitive troubles from a single memory center cohort. Using clinical routine T1-weighted MRI, we evaluated the classification performance of: 1) univariate volumetry using two AVS (volBrain and Neuroreader™); 2) Support Vector Machine (SVM) automatic classifier, using either the AVS volumes (SVM-AVS), or whole gray matter (SVM-WGM); 3) reading by two neuroradiologists. The performance measure was the balanced diagnostic accuracy. The reference standard was consensus diagnosis by three neurologists using clinical, biological (cerebrospinal fluid) and imaging data and following international criteria. RESULTS: Univariate AVS volumetry provided only moderate accuracies (46% to 71% with hippocampal volume). The accuracy improved when using SVM-AVS classifier (52% to 85%), becoming close to that of SVM-WGM (52 to 90%). Visual classification by neuroradiologists ranged between SVM-AVS and SVM-WGM. CONCLUSION: In the routine practice of a memory clinic, the use of volumetric measures provided by AVS yields only moderate accuracy. Automatic classifiers can improve accuracy and could be a useful tool to assist diagnosis.
Published: 2020

37. FHL1 is a key player of chikungunya virus tropism and pathogenesis

Author: Beate M. Kümmerer, Laura Pezzi, Mohamed Lamine Hafirassou, Lucie Gueneau, Constance Delaugerre, Gisèle Bonne, Thibaud Goupil, Vasiliya Kril, Monsef Benkirane, Julien Burlaud-Gaillard, Lucie Bonnet-Madin, R. Juntas-Morales, Anne Bertrand Legout, Thérèse Couderc, Laurent Meertens, Etienne Simon-Loriere, Philippe Roingeard, Ali Amara, Marc Lecuit, Rabah Ben Yaou, Sophia Rafasse, Alexis Brugier, Xavier de Lamballerie, Pierre-Olivier Vidalain, Cécile Doyen, Athena Labeau, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Bonn = University of Bonn, Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris] (IP), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes - Paris 5 (UPD5), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Service des Maladies infectieuses et tropicales [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Bonn, Institut Pasteur [Paris], Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), DIAKITE, andrée, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Centre de Recherche en Myologie
Subjects: 0106 biological sciences, 0301 basic medicine, viruses, [SDV]Life Sciences [q-bio], Muscle Proteins, Pathogenesis, MESH: Chikungunya Fever, Viral Nonstructural Proteins, Virus Replication, medicine.disease_cause, 01 natural sciences, Mice, Four and a Half LIM domains 1 Tropism, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Animals, Chikungunya, Host factor, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Intracellular Signaling Peptides and Proteins, virus diseases, General Medicine, MESH: Tropism, LIM Domain Proteins, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Chikungunya virus, MESH: LIM Domain Proteins, Viral protein, Virus infection, Alphavirus, Tropism, Virus, 03 medical and health sciences, MESH: Muscle Proteins, MESH: Intracellular Signaling Peptides and Proteins, medicine, Animals, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Mice, Aedes, MESH: Virus Replication, MESH: Chikungunya virus, biology.organism_classification, Virology, 030104 developmental biology, Infectious disease (medical specialty), Chikungunya Fever, MESH: Viral Nonstructural Proteins, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 010606 plant biology & botany
Abstract: Chikungunya is an infectious disease caused by the chikungunya virus (CHIKV), an alphavirus transmitted to humans by Aedes mosquitoes, and for which there is no licensed vaccine nor antiviral treatments. By using a loss-of-function genetic screen, we have recently identified the FHL1 protein as an essential host factor for CHIKV tropism and pathogenesis. FHL1 is highly expressed in muscles cells and fibroblasts, the main CHIKV-target cells. FHL1 interacts with the viral protein nsP3 and plays a critical role in CHIKV genome amplification. Experiments in vivo performed in FHL1-deficient mice have shown that these animals are resistant to infection and do not develop muscular lesions. Altogether these observations, published in the journal Nature [1], show that FHL1 is a key host factor for CHIKV pathogenesis and identify the interaction between FHL1 and nsP3 as a promising target for the development of new antiviral strategies., Le chikungunya est une maladie infectieuse causée par le virus chikungunya (CHIKV), un alphavirus transmis à l’Homme par les moustiques Aedes et contre lequel il n’existe ni vaccin, ni traitements antiviraux. En utilisant une approche de crible génétique par perte de fonction, nous avons récemment identifié la protéine FHL1 comme un facteur cellulaire essentiel pour le tropisme et la pathogénèse du CHIKV. FHL1 est une molécule présente majoritairement dans les cellules musculaires et les fibroblastes, les cibles privilégiées de CHIKV. FHL1 interagit avec la protéine virale nsP3 et joue un rôle décisif dans le mécanisme d’amplification du génome de CHIKV. Des expériences in vivo chez des souris déficientes pour FHL1 ont montré que ces animaux sont résistants à l’infection et ne développent pas de lésions musculaires. L’ensemble de ces observations publiées dans la revue Nature [1] montrent que FHL1 est un facteur cellulaire clé pour la pathogénèse de CHIKV et identifient l’interaction entre FHL1 et nsp3 comme une cible prometteuse pour le développement de nouvelles stratégies antivirales
Published: 2020

38. A muscle hybrid promoter as a novel tool for gene therapy

Author: Laura Julien, Feriel Azibani, Katarzyna Piekarowicz, Ryszard Rzepecki, Gisèle Bonne, Anne Bertrand, Maud Beuvin, Magdalena Machowska, University of Wrocław [Poland] (UWr), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), This study was supported by Wrocław Research Center EIT+(POIG.01.01.02-02-003/08) from Regional Developmental Fund, COST Actions: BM1002 Nanonet: Nanomechanics of Intermediate Filament Network and CA15214 EuroCellNet: An Integrative Action for Multidisciplinary Studies on Cellular Structural Networks, KP was funded by: National Science Center grant ETIUDA: UMO-2014/12/T/NZ3/00504, Centre de recherche en Myologie – U974 SU-INSERM, and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, lcsh:QH426-470, Transgene, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Myocyte, Skeletal muscles, lcsh:QH573-671, Molecular Biology, Myogenesis, lcsh:Cytology, Cardiac muscle, Skeletal muscle, Heart, AAV, Expression cassette, Cell biology, lcsh:Genetics, 030104 developmental biology, medicine.anatomical_structure, Regulatory sequence, 030220 oncology & carcinogenesis, Myotubes, Molecular Medicine, Desmin, C2C12, Vector, Muscle promoter
Abstract: Gene therapy is a promising strategy to cure rare diseases. The lack of regulatory sequences ensuring specific and robust expression in skeletal and cardiac muscle is a substantial limitation of gene therapy efficiency targeting the muscle tissue. Here we describe a novel muscle hybrid (MH) promoter that is highly active in both skeletal and cardiac muscle cells. It has an easily exchangeable modular structure, including an intronic module that highly enhances the expression of the gene driven by it. In cultured myoblasts, myotubes, and cardiomyocytes, the MH promoter gives relatively stable expression as well as higher activity and protein levels than the standard CMV and desmin gene promoters or the previously developed synthetic or CKM-based promoters. Combined with AAV2/9, the MH promoter also provides a high in vivo expression level in skeletal muscle and the heart after both intramuscular and systemic delivery. It is much more efficient than the desmin-encoding gene promoter, and it maintains the same specificity. This novel promoter has potential for gene therapy in muscle cells. It can provide stable transgene expression, ensuring high levels of therapeutic protein, and limited side effects because of its specificity. This constitutes an improvement in the efficiency of genetic disease therapy. Keywords: muscle promoter, expression cassette, AAV, vector, skeletal muscles, heart, C2C12, myotubes
Published: 2019

39. Gene Therapy via Trans-Splicing for LMNA-Related Congenital Muscular Dystrophy

Author: Marc Bitoun, Sofia Benkhelifa-Ziyyat, Astrid Brull, Bernard Prudhon, Gisèle Bonne, Ludovic Arandel, Feriel Azibani, Esma Ziat, Maud Beuvin, Isabelle Nelson, Arnaud Jollet, Anne Bertrand, Stéphanie Lorain, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, and Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Genetic enhancement, Trans-splicing, Biology, Article, LMNA, 03 medical and health sciences, Exon, 0302 clinical medicine, Drug Discovery, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], LMNA-related congenital muscular dystrophy, lamin A/C, Messenger RNA, trans-splicing, integumentary system, Myogenesis, lcsh:RM1-950, Intron, Lmna, medicine.disease, gene therapy, 3. Good health, 030104 developmental biology, lcsh:Therapeutics. Pharmacology, Cancer research, Congenital muscular dystrophy, Molecular Medicine, 030217 neurology & neurosurgery
Abstract: International audience; We assessed the potential of Lmna-mRNA repair by spliceosome-mediated RNA trans-splicing as a therapeutic approach for LMNA-related congenital muscular dystrophy. This gene therapy strategy leads to reduction of mutated transcript expression for the benefit of corresponding wild-type (WT) transcripts. We developed 5 0-RNA pretrans-splicing molecules containing the first five exons of Lmna and targeting intron 5 of Lmna pre-mRNA. Among nine pre-trans-splicing molecules, differing in the targeted sequence in intron 5 and tested in C2C12 myoblasts, three induced trans-splicing events on endogenous Lmna mRNA and confirmed at protein level. Further analyses performed in primary myotubes derived from an LMNA-related congenital muscular dystrophy (L-CMD) mouse model led to a partial rescue of the mutant phenotype. Finally, we tested this approach in vivo using adeno-associated virus (AAV) delivery in newborn mice and showed that trans-splicing events occurred in WT mice 50 days after AAV delivery, although at a low rate. Altogether, while these results provide the first evidence for reprogramming LMNA mRNA in vitro, strategies to improve the rate of trans-splicing events still need to be developed for efficient application of this therapeutic approach in vivo.
Published: 2018

40. Preclinical Advances of Therapies for Laminopathies

Author: Rabah Ben Yaou, Gisèle Bonne, Anne Bertrand, Louise Benarroch, Enzo Cohen, Antonio Atalaia, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Ben Yaou, Rabah, Centre de Recherche en Myologie, and HAL-SU, Gestionnaire
Subjects: LMNA, [SDV]Life Sciences [q-bio], Adipose tissue, Laminopathy, Review, laminopathy, Striated Muscles, medicine.disease_cause, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, medicine, In patient, Premature ageing, lamin A/C, 030304 developmental biology, therapy, 0303 health sciences, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, treatment, business.industry, General Medicine, Progerin, medicine.disease, preclinical models, 3. Good health, [SDV] Life Sciences [q-bio], progerin, Medicine, HGPS, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: International audience; Laminopathies are a group of rare disorders due to mutation in LMNA gene. Depending on the mutation, they may affect striated muscles, adipose tissues, nerves or are multisystemic with various accelerated ageing syndromes. Although the diverse pathomechanisms responsible for laminopathies are not fully understood, several therapeutic approaches have been evaluated in patient cells or animal models, ranging from gene therapies to cell and drug therapies. This review is focused on these therapies with a strong focus on striated muscle laminopathies and premature ageing syndromes.
Published: 2021

41. Neurite density is reduced in the presymptomatic phase of C9orf72 disease

Author: Anne Bertrand, Daisy Rinaldi, Olivier Colliot, Hui Zhang, Isabelle Le Ber, Alexandre Routier, Stanley Durrleman, Philippe Couratier, Florence Pasquier, Didier Hannequin, Daniel C. Alexander, Marion Houot, Jiaying Zhang, Junhao Wen, Sorbonne Université (SU), Centre for Medical Image Computing (CMIC), University College of London [London] (UCL), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), CHU Rouen, Normandie Université (NU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Pathology, medicine.medical_specialty, Neurite, business.industry, Frontotemporal lobar degeneration, Grey matter, medicine.disease, White matter, [STAT]Statistics [stat], 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, Atrophy, medicine.anatomical_structure, C9orf72, Medicine, Surgery, [INFO]Computer Science [cs], Neurology (clinical), Amyotrophic lateral sclerosis, business, 030217 neurology & neurosurgery, Diffusion MRI
Abstract: ObjectiveTo assess the added value of neurite orientation dispersion and density imaging (NODDI) compared with conventional diffusion tensor imaging (DTI) and anatomical MRI to detect changes in presymptomatic carriers of chromosome 9 open reading frame 72 (C9orf72) mutation.MethodsThe PREV-DEMALS (Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis) study is a prospective, multicentre, observational study of first-degree relatives of individuals carrying the C9orf72 mutation. Sixty-seven participants (38 presymptomatic C9orf72 mutation carriers (C9+) and 29 non-carriers (C9−)) were included in the present cross-sectional study. Each participant underwent one single-shell, multishell diffusion MRI and three-dimensional T1-weighted MRI. Volumetric measures, DTI and NODDI metrics were calculated within regions of interest. Differences in white matter integrity, grey matter volume and free water fraction between C9+ and C9− individuals were assessed using linear mixed-effects models.ResultsCompared with C9−, C9+ demonstrated white matter abnormalities in 10 tracts with neurite density index and only 5 tracts with DTI metrics. Effect size was significantly higher for the neurite density index than for DTI metrics in two tracts. No tract had a significantly higher effect size for DTI than for NODDI. For grey matter cortical analysis, free water fraction was increased in 13 regions in C9+, whereas 11 regions displayed volumetric atrophy.ConclusionsNODDI provides higher sensitivity and greater tissue specificity compared with conventional DTI for identifying white matter abnormalities in the presymptomatic C9orf72 carriers. Our results encourage the use of neurite density as a biomarker of the preclinical phase.Trial registration numberNCT02590276.
Published: 2019

42. Suicidal ideation is common in autosomal dominant Alzheimer's disease at-risk persons

Author: Sulantha Mathotaarachchi, Chathuri Yatawara, Nagaendran Kandiah, Kok Pin Ng, Stéphane Richard-Devantoy, Josie-Anne Bertrand, Pedro Rosa-Neto, Tharick A. Pascoal, Joseph Therriault, Serge Gauthier, Celia M. T. Greenwood, and Lai Jiang
Subjects: Adult, Male, business.industry, Psychological intervention, Neuropsychology, Disease, Ideation, Middle Aged, Risk Assessment, Article, Suicidal Ideation, Psychiatry and Mental health, Cross-Sectional Studies, Alzheimer Disease, Mutation, Medicine, Humans, Geriatric Depression Scale, Female, Geriatrics and Gerontology, medicine.symptom, business, Suicidal ideation, Depressive symptoms, Clinical psychology
Abstract: OBJECTIVES To study the frequency of suicidal ideation and its association with clinical and neurobiological correlates among cognitively intact autosomal dominant Alzheimer's disease (ADAD) at-risk individuals. METHODS/DESIGN In a cross-sectional study of 183 ADAD at-risk individuals (91 mutation carriers and 92 noncarriers), we compared the frequency of suicidal ideation among carriers and noncarriers. Linear mixed-effects models with family-level random effects evaluated the relationships between geriatric depression scale (GDS), neuropsychiatric inventory-questionnaire (NPI-Q), and suicidal ideation scores among all ADAD at-risk individuals. An interaction term was added to the regression models to evaluate the interactions of suicidal ideation and mutation status on neuropsychiatric symptoms. RESULTS Twenty-six (14.20%) ADAD at-risk individuals (13 [14.28%] carriers and 13 [14.13%] noncarriers) had suicidal ideation. The frequency of suicidal ideation did not differ between carriers and noncarriers. Suicidal ideation was associated with higher GDS among all ADAD at-risk individuals. When stratified into mutation carrier status, noncarriers with suicidal ideation had higher GDS than carriers. There was no statistically significant association between suicidal ideation and NPI-Q among ADAD at-risk individuals. Awareness of mutation status, neuropsychological performances, and cerebrospinal fluid AD biomarkers were not associated with suicidal ideation among carriers and noncarriers. CONCLUSIONS Suicidal ideation is common among cognitively intact ADAD at-risk individuals. While ADAD at-risk individuals with suicidal ideation have greater depressive symptoms, noncarriers with suicidal ideation have higher GDS scores than carriers. Interestingly, awareness of the mutation status was not associated with suicidal ideation in our study. Early identification of suicidal thoughts can facilitate timely interventions to prevent suicidal behaviours. Keywords autosomal dominant Alzheimer's diseasedominantly inherited Alzheimer's networkneuropsychiatric symptomssuicidal ideation.
Published: 2019

43. Activity-induced MEMRI cannot detect functional brain anomalies in the APPxPS1-Ki mouse model of Alzheimer’s disease

Author: Yah-Se Abada, Stéphane Epelbaum, Alexandra Petiet, Alexandre Androuin, Myriam Ly, Benoît Delatour, Anne Bertrand, Mathieu Santin, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Centre des Maladies Cognitives et Comportementales [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Neuro-Imagerie de Recherche (CENIR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Mice, 129 Strain, Brain activity and meditation, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, lcsh:Medicine, Mice, Transgenic, Disease, Article, Mice, 03 medical and health sciences, Functional brain, 0302 clinical medicine, Alzheimer Disease, In vivo, medicine, Animals, Dementia, Premovement neuronal activity, lcsh:Science, Neurons, Manganese, Multidisciplinary, medicine.diagnostic_test, business.industry, lcsh:R, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Blood-Brain Barrier, Evaluation Studies as Topic, lcsh:Q, business, Neuroscience, Immediate early gene, 030217 neurology & neurosurgery
Abstract: Alzheimer’s disease (AD) is the most common cause of dementia. Aside neuropathological lesions, abnormal neuronal activity and brain metabolism are part of the core symptoms of the disease. Activity-induced Manganese-Enhanced Magnetic Resonance Imaging (MEMRI) has been proposed as a powerful approach to visualize evoked brain activity in rodents. Here, we evaluated the relevance of MEMRI in measuring neuronal (dys-)function in the APPxPS1 knocked-in (KI) mouse model of AD. Brain anomalies were firstly demonstrated in APPxPS1-Ki mice using cognitive testing (memory impairment) and histological mapping of immediate early gene products (decreased density of fos-positive neurons). Paradoxically, MEMRI analyses were not able to confirm the occurrence of neuronal hypoactivities in vivo. We then performed a neuropathological analysis that highlighted an abnormal increased permeability of the blood-brain barrier (BBB) in APPxPS1-Ki mice. We hypothesized that diffuse weakening of the BBB results in an uncontrolled diffusion of the MR contrast agent and a lack of correlation between manganese accumulation and neuronal activity. These results bring to light a limitation of the activity-induced MEMRI approach when applied to the APPxPS1-Ki mouse model as well as other mouse models harboring a compromised BBB.
Published: 2019

44. Platelets Induce Thymic Stromal Lymphopoietin Production by Endothelial Cells: Contribution to Fibrosis in Human Systemic Sclerosis

Author: Fédération Hospitalo-Universitaire Acronim, Joël Constans, Béatrice Demoures, Julien Seneschal, Cécile Contin-Bordes, Pierre Duffau, Marie-Elise Truchetet, C. Jacquemin, Jean-Luc Pellegrin, Jorge Eduardo Guimaraes, Valérie Jolivel, Christophe Richez, Anne Bertrand, Paôline Laurent, Marie-Sylvie Doutre, Estibaliz Lazaro, Isabelle Douchet, Thierry Schaeverbeke, Patrick Blanco, and Liliane Khoryati
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Thymic stromal lymphopoietin, integumentary system, medicine.diagnostic_test, business.industry, Immunology, Thymic stromal lymphopoietin production, medicine.disease, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, Rheumatology, Dermis, Fibrosis, Biopsy, Skin biopsy, medicine, Immunology and Allergy, Platelet, Platelet activation, business
Abstract: OBJECTIVE To investigate the relationship between vascular damage and fibrosis in systemic sclerosis (SSc) by testing the hypothesis that platelets contribute to skin fibrosis via the activation of human dermal microvascular endothelial cells (HDMECs) and subsequent production of profibrotic mediators. METHODS A total of 203 SSc patients and 30 healthy donors were prospectively enrolled between 2012 and 2015 at the University Hospital of Bordeaux. Immunohistochemistry and immunofluorescence analyses were performed on skin biopsy sections from 18 SSc patients and 5 healthy donors. Serum thymic stromal lymphopoietin (TSLP) levels were measured by enzyme-linked immunosorbent assay in the entire cohort. HDMECs and fibroblasts were purified from biopsy sections. Extracellular matrix production by cultured fibroblasts was assessed by real-time quantitative polymerase chain reaction. RESULTS Serum TSLP levels were significantly increased in SSc patients compared to healthy donors (P
Published: 2016

45. Mutation in lamin A/C sensitizes the myocardium to exercise-induced mechanical stress but has no effect on skeletal muscles in mouse

Author: Alban Vignaud, Karim Wahbi, Adeline Jacquet, Nathalie Mougenot, Arnaud Ferry, Gisèle Bonne, Anne Bertrand, Marie-Elodie Cattin, Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Phénotypage du petit animal (UMS28), Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Cardiologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), HAL-UPMC, Gestionnaire, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Phénotypage du petit animal ( UMS28 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]
Subjects: Male, 0301 basic medicine, Mechanical stress, Dilated cardiomyopathy, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030204 cardiovascular system & hematology, Running, LMNA, Random Allocation, 0302 clinical medicine, Chronic exercise, Gene Knock-In Techniques, Genetics (clinical), [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Lamin Type A, Pathophysiology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Phenotype, medicine.anatomical_structure, Neurology, Congenital muscular dystrophy, A-type lamin, Cardiomyopathy, Dilated, Cardiac function curve, Heterozygote, medicine.medical_specialty, Mice, 129 Strain, L-CMD, Mice, Transgenic, Biology, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Stress, Physiological, Isometric Contraction, Internal medicine, medicine, Animals, RNA, Messenger, Muscle, Skeletal, [SDV.GEN]Life Sciences [q-bio]/Genetics, Myocardium, Skeletal muscle, Heterozygote advantage, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Mutation, Pediatrics, Perinatology and Child Health, Neurology (clinical), [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Lamin
Abstract: International audience; LMNA gene encodes lamin A/C, ubiquitous proteins of the nuclear envelope. They play crucial role in maintaining nuclear shape and stiffness. When mutated, they essentially lead to dilated cardiomyopathy with conduction defects, associated or not with muscular diseases. Excessive mechanical stress sensitivity has been involved in the pathophysiology. We have previously reported the phenotype of LmnadelK32 mice, reproducing a mutation found in LMNA-related congenital muscular dystrophy patients. Heterozygous LmnadelK32/+ (Het) mice develop a progressive dilated cardiomyopathy leading to death between 35 and 70 weeks of age. To investigate the sensitivity of the skeletal muscles and myocardium to chronic exercise-induced stress, Het and wild-type (Wt) mice were subjected to strenuous running treadmill exercise for 5 weeks. Before exercise, the cardiac function of Het mice was similar to Wt-littermates. After the exercise-period, Het mice showed cardiac dysfunction and dilation without visible changes in cardiac morphology, molecular remodelling or nuclear structure compared to Wt exercised and Het sedentary mice. Contrary to myocardium, skeletal muscle ex vivo contractile function remained unaffected in Het exercised mice. In conclusion, the expression of the LmnadelK32 mutation increased the susceptibility of the myocardium to cardiac stress and led to an earlier onset of the cardiac phenotype in Het mice.
Published: 2016

46. Vascular permeability in the RG2 glioma model can be mediated by macropinocytosis and be independent of the opening of the tight junction

Author: Chantal Rémy, Régine Farion, Julie Delaroche, Karin Pernet-Gallay, Anne Bertrand, Emmanuel L. Barbier, Pierre-Henri Jouneau, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie du Cytosquelette, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Neuro-imagerie fonctionnelle et métabolique (ANTE-INSERM U836, équipe 5), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Vascular permeability, Blood–brain barrier, Tight Junctions, Capillary Permeability, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Glioma, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, medicine, Animals, Magnetite Nanoparticles, ComputingMilieux_MISCELLANEOUS, Tight junction, Brain Neoplasms, Chemistry, Pinocytosis, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Original Articles, medicine.disease, Magnetic Resonance Imaging, Ferrosoferric Oxide, Rats, Inbred F344, Extravasation, Amiloride, 030104 developmental biology, medicine.anatomical_structure, Neurology, Blood-Brain Barrier, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Biophysics, Basal lamina, Neurology (clinical), Cardiology and Cardiovascular Medicine, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Neoplasm Transplantation, 030217 neurology & neurosurgery, medicine.drug
Abstract: This study evaluates the extravasation pathways of circulating macromolecules in a rat glioma model (RG2) which was observed by both magnetic resonance imaging using ultrasmall superparamagnetic iron oxide and electron microscopy. Although magnetic resonance imaging signal enhancement was observed as soon as 10 min after injection (9.4% 2 h after injection), electron microscopy showed that endothelial cells were still tightly sealed. However, circulating immunoglobulin G and ultrasmall superparamagnetic iron oxide were found in large membrane compartments of endothelial cells, in the basal lamina (7.4 ± 1.2 gold particles/µm2 in the tumor versus 0.38 ± 0.17 in healthy tissue, p = 1.4.10−5) and between tumoral cells. Altogether, this strongly suggests an active transport mediated by macropinocytosis. To challenge this transport mechanism, additional rats were treated with amiloride, an inhibitor of macropinocytosis, leading to a reduction of membrane protrusions (66%) and of macropinosomes. Amiloride however also opened tumoral tight junctions allowing a larger extravasation of ultrasmall superparamagnetic iron oxide (magnetic resonance imaging signal enhancement of 35.7% 2 h after injection). Altogether, these results suggest that ultrasmall superparamagnetic iron oxide and immunoglobulin G in the RG2 glioma model follow an active extravasation pathway mediated by a macropinocytosis process. Amiloride also appears as a potential strategy to facilitate the extravasation of chemotherapeutic drugs in glioma.
Published: 2016

47. Protein Kinase C Alpha Cellular Distribution, Activity, and Proximity with Lamin A/C in Striated Muscle Laminopathies

Author: Sarah Labib, Wen Yu Wu, Zofia T. Bilińska, Musfira Mohamed-Uvaize, Pierrette M. Bolongo, Frédérique Tesson, Hannah A. Nicolas, Anne Bertrand, Marie-Andrée Akimenko, Gisèle Bonne, Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Centre de recherche en Myologie – U974 SU-INSERM
Subjects: 0301 basic medicine, MAPK/ERK pathway, 030204 cardiovascular system & hematology, Myoblasts, LMNA, Mice, 0302 clinical medicine, Gene expression, Intermediate filament, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, lamin A/C, DCM, integumentary system, Chemistry, [SDV.BA]Life Sciences [q-bio]/Animal biology, General Medicine, protein kinase C alpha, Lamin Type A, Cell biology, medicine.anatomical_structure, embryonic structures, Signal Transduction, congenital, hereditary, and neonatal diseases and abnormalities, Cell type, Protein Kinase C-alpha, L-CMD, MAP Kinase Signaling System, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, EDMD, Article, Cell Line, 03 medical and health sciences, Muscular Diseases, medicine, Animals, Humans, Amino Acid Sequence, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Protein kinase C, [SDV.GEN]Life Sciences [q-bio]/Genetics, Laminopathies, Skeletal muscle, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, striated muscle laminopathies, Muscle, Striated, Rats, 030104 developmental biology, lcsh:Biology (General), Mutation, Lamin
Abstract: Striated muscle laminopathies are cardiac and skeletal muscle conditions caused by mutations in the lamin A/C gene (LMNA). LMNA codes for the A-type lamins, which are nuclear intermediate filaments that maintain the nuclear structure and nuclear processes such as gene expression. Protein kinase C alpha (PKC-&alpha, ) interacts with lamin A/C and with several lamin A/C partners involved in striated muscle laminopathies. To determine PKC-&alpha, &rsquo, s involvement in muscular laminopathies, PKC-&alpha, s localization, activation, and interactions with the A-type lamins were examined in various cell types expressing pathogenic lamin A/C mutations. The results showed aberrant nuclear PKC-&alpha, cellular distribution in mutant cells compared to WT. PKC-&alpha, activation (phos-PKC-&alpha, ) was decreased or unchanged in the studied cells expressing LMNA mutations, and the activation of its downstream targets, ERK 1/2, paralleled PKC-&alpha, activation alteration. Furthermore, the phos-PKC-&alpha, lamin A/C proximity was altered. Overall, the data showed that PKC-&alpha, localization, activation, and proximity with lamin A/C were affected by certain pathogenic LMNA mutations, suggesting PKC-&alpha, involvement in striated muscle laminopathies.
Published: 2020

48. Determinants of adherence and consequences of the transition from adolescence to adulthood among young people with severe haemophilia (TRANSHEMO): study protocol for a multicentric French national observational cross-sectional study

Author: Noémie Resseguier, Natacha Rosso-Delsemme, Any Beltran Anzola, Karine Baumstarck, Vanessa Milien, Laurent Ardillon, Sophie Bayart, Claire Berger, Marie-Anne Bertrand, Christine Biron-Andreani, Annie Borel-Derlon, Sabine Castet, Pierre Chamouni, Ségolène Claeyssens Donadel, Emmanuelle De Raucourt, Dominique Desprez, Céline Falaise, Birgit Frotscher, Valérie Gay, Jenny Goudemand, Yves Gruel, Benoît Guillet, Annie Harroche, Abel Hassoun, Yoann Huguenin, Thierry Lambert, Aurélien Lebreton, Anne Lienhart, Michèle Martin, Sandrine Meunier, Fabrice Monpoux, Guillaume Mourey, Claude Negrier, Philippe Nguyen, Placide Nyombe, Caroline Oudot, Brigitte Pan-Petesch, Benoît Polack, Anne Rafowicz, Antoine Rauch, Delphine Rivaud, Pascale Schneider, Alexandra Spiegel, Cecile Stoven, Brigitte Tardy, Marc Trossaërt, Jean-Baptiste Valentin, Stéphane Vanderbecken, Fabienne Volot, Annelise Voyer-Ebrard, Bénédicte Wibaut, Tanguy Leroy, Thomas Sannie, Hervé Chambost, Pascal Auquier, Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix Marseille Université (AMU), Hématogoie pédiatrique, hôpital Sud, Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire d'Hématologie Biologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Laboratoire d'hématologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Hospitalier de Versailles André Mignot (CHV), Service de pédiatrie, d'hématologie et d'oncologie [Hôpital de La Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d’Hématologie Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Hématologie, Centre Hospitalier Chambéry, Hôpital cardiologique, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Hospitalier Universitaire de Nancy (CHU Nancy), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire de Lyon (CHU Lyon), Service de Pédiatrie médicale - Spécialités médicales [CHU Limoges], CHU Limoges, Hôpital Morvan [Brest], Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Thérapeutique Recombinante Expérimentale (TIMC-IMAG-TheREx), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service d'hémato-immuno-oncologie pédiatrique [Rouen], Groupe de recherche sur la thrombose, pharmacologie des antithrombotiques et situations à risque (GRT), Université Jean Monnet - Saint-Étienne (UJM), Centre hospitalier universitaire de Nantes (CHU Nantes), Groupe de Recherche en Psychologie Sociale (GRePS), Université Lumière - Lyon 2 (UL2), Service d'hématologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Santé Publique, Université de la Méditerranée - Aix-Marseille 2, Ministère des Affaires Sociales et de la Santé, Filière MHEMO, Université Aix-Marseille, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Groupe de recherche sur la thrombose (GRT (EA 3065)), Université Jean Monnet [Saint-Étienne] (UJM), Hôpital Sud, Centre hospitalier de Versailles André-Mignot, 177, rue de Versailles, 78150 Le Chesnay, France, parent, Université de Tours, Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), CHU de Nancy - Hôpitaux de Brabois, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (HOTE GREFFON), Université de Franche-Comté (UFC)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Brest (UBO), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), and Jonchère, Laurent
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, Activities of daily living, Cross-sectional study, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, 0302 clinical medicine, Risk Factors, Academic Performance, Protocol, Early childhood, adherence, adolescents, Young adult, ComputingMilieux_MISCELLANEOUS, Qualitative Research, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, transition, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, 3. Good health, [SDV] Life Sciences [q-bio], Patient Satisfaction, Female, Family Relations, France, Psychosocial, Attitude to Health, Haematology (Incl Blood Transfusion), Adult, young adults, medicine.medical_specialty, Transition to Adult Care, Adolescent, haemophilia, Haemophilia, Hemophilia A, 03 medical and health sciences, Young Adult, Quality of life (healthcare), 030225 pediatrics, medicine, Humans, business.industry, Protective Factors, medicine.disease, Treatment Adherence and Compliance, Cross-Sectional Studies, Social Class, Family medicine, Quality of Life, Observational study, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: IntroductionSevere haemophilia is a rare disease characterised by spontaneous bleeding from early childhood, which may lead to various complications, especially in joints. It is nowadays possible to avoid these complications thanks to substitutive therapies for which the issue of adherence is major. The transition from adolescence to adulthood in young people with severe haemophilia is a critical period as it is associated with a high risk of lack of adherence to healthcare, which might have serious consequences on daily activities and on quality of life.Methods and analysisWe present the protocol for a cross-sectional, observational, multicentric study to assess the differences between adolescents and young adults with severe haemophilia in France through the transition process, especially on adherence to healthcare. This study is based on a mixed methods design, with two complementary and consecutive phases, comparing data from a group of adolescents (aged 14–17 years) with those from a group of young adults (aged 20–29 years). The quantitative phase focuses on the determinants (medical, organisational, sociodemographic and social and psychosocial and behavioural factors) of adherence to healthcare (considered as a marker of the success of transition). The qualitative phase explores participants’ views in more depth to explain and refine the results from the quantitative phase. Eligible patients are contacted by the various Haemophilia Treatment Centres participating in the French national registry FranceCoag.Ethics and disseminationThe study was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2016-A01034-47). Study findings will be disseminated to the scientific and medical community in peer-reviewed journals and presented at scientific meetings. Results will be popularised to be communicated via the French association for people with haemophilia to participants and to the general public.Trial registration numberNCT02866526; Pre-results.
Published: 2018

49. Using diffusion MRI for classification and prediction of Alzheimer's Disease: a reproducible study

Author: Junhao Wen, Jorge Samper-Gonzalez, Simona Bottani, Alexandre Routier, Ninon Burgos, Thomas Jacquemont, Sabrina Fontanella, Stanley Durrleman, Anne Bertrand, Olivier Colliot, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Service de Neuroradiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), WEN, Junhao, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], [INFO.EIAH] Computer Science [cs]/Technology for Human Learning, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, [INFO.EIAH]Computer Science [cs]/Technology for Human Learning, ComputingMilieux_MISCELLANEOUS, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI]
Abstract: International audience
Published: 2018

50. P1‐363: DESIGN OF A DECISION SUPPORT SYSTEM FOR PREDICTING THE PROGRESSION OF ALZHEIMER'S DISEASE

Author: Stanley Durrleman, Anne Bertrand, Didier Dormont, Manon Ansart, and Igor Koval
Subjects: 0303 health sciences, Decision support system, Multivariate statistics, Epidemiology, Computer science, Health Policy, Univariate, Cognition, Disease, Test (assessment), Support vector machine, 03 medical and health sciences, Psychiatry and Mental health, Cellular and Molecular Neuroscience, 0302 clinical medicine, Developmental Neuroscience, Linear regression, Statistics, Neurology (clinical), Geriatrics and Gerontology, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Background: Knowing who will develop Alzheimer's disease (AD) and when is a crucial health issue, that could help treat subjects earlier, using new treatments targeting the earliest stages. We have participated in TADPOLE, a competition based on ADNI data aiming at developing an automatic prognosis system. We propose a method for predicting the time to conversion of MCI subjects to AD and a framework to evaluate such predictions. Method: We decompose the prediction into two steps: first, we monthly predict future values of the cognitive scores of each subject; second, we use them to automatically predict the corresponding disease status, using a Support Vector Machine. For the first step, we compare two approaches: the univariate and the multivariate approach. In the univariate approach, cognitive scores are predicted by linear regression with respect to time for each subject. In the multivariate approach, sociodemographic, cognitive and MRI features of the last visit are used to predict the future cognitive scores. This approach is automatically learned using all visits of training subjects. We evaluate our methods by splitting longitudinal data into training and test subjects. Each test subject is split into observed visits and a future visit, separated by different time periods (mostly 1 to 4 years in the challenge). We want to verify three hypotheses: the multivariate approach outperforms the univariate approach; separating the process into two parts perform better than directly using a classification algorithm; the time to prediction is an important parameter that has to be taken into account. Results: The univariate approach (AUC=82.6%±3.0) performs significantly worse (p=0.0001) than the multivariate approach (AUC=85.5%±2.5). Both perform significantly better (p
Published: 2018

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