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1. Long-COVID cognitive impairments and reproductive hormone deficits in men may stem from GnRH neuronal deathResearch in context

Author: Florent Sauve, Sreekala Nampoothiri, Sophie A. Clarke, Daniela Fernandois, Caio Fernando Ferreira Coêlho, Julie Dewisme, Edouard G. Mills, Gaetan Ternier, Ludovica Cotellessa, Cristina Iglesias-Garcia, Helge Mueller-Fielitz, Thibaud Lebouvier, Romain Perbet, Vincent Florent, Marc Baroncini, Ariane Sharif, June Ereño-Orbea, Maria Mercado-Gómez, Asis Palazon, Virginie Mattot, Florence Pasquier, Sophie Catteau-Jonard, Maria Martinez-Chantar, Erik Hrabovszky, Mercé Jourdain, Dominique Deplanque, Annamaria Morelli, Giulia Guarnieri, Laurent Storme, Cyril Robil, François Trottein, Ruben Nogueiras, Markus Schwaninger, Pascal Pigny, Julien Poissy, Konstantina Chachlaki, Claude-Alain Maurage, Paolo Giacobini, Waljit Dhillo, S. Rasika, and Vincent Prevot
Subjects: COVID-19, GnRH, Neurodevelopment, Cognition, Infertility, Hypothalamus, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: We have recently demonstrated a causal link between loss of gonadotropin-releasing hormone (GnRH), the master molecule regulating reproduction, and cognitive deficits during pathological aging, including Down syndrome and Alzheimer's disease. Olfactory and cognitive alterations, which persist in some COVID-19 patients, and long-term hypotestosteronaemia in SARS-CoV-2-infected men are also reminiscent of the consequences of deficient GnRH, suggesting that GnRH system neuroinvasion could underlie certain post-COVID symptoms and thus lead to accelerated or exacerbated cognitive decline. Methods: We explored the hormonal profile of COVID-19 patients and targets of SARS-CoV-2 infection in post-mortem patient brains and human fetal tissue. Findings: We found that persistent hypotestosteronaemia in some men could indeed be of hypothalamic origin, favouring post-COVID cognitive or neurological symptoms, and that changes in testosterone levels and body weight over time were inversely correlated. Infection of olfactory sensory neurons and multifunctional hypothalamic glia called tanycytes highlighted at least two viable neuroinvasion routes. Furthermore, GnRH neurons themselves were dying in all patient brains studied, dramatically reducing GnRH expression. Human fetal olfactory and vomeronasal epithelia, from which GnRH neurons arise, and fetal GnRH neurons also appeared susceptible to infection. Interpretation: Putative GnRH neuron and tanycyte dysfunction following SARS-CoV-2 neuroinvasion could be responsible for serious reproductive, metabolic, and mental health consequences in long-COVID and lead to an increased risk of neurodevelopmental and neurodegenerative pathologies over time in all age groups. Funding: European Research Council (ERC) grant agreements No 810331, No 725149, No 804236, the European Union Horizon 2020 research and innovation program No 847941, the Fondation pour la Recherche Médicale (FRM) and the Agence Nationale de la Recherche en Santé (ANRS) No ECTZ200878 Long Covid 2021 ANRS0167 SIGNAL, Agence Nationale de la recherche (ANR) grant agreements No ANR-19-CE16-0021-02, No ANR-11-LABEX-0009, No. ANR-10-LABEX-0046, No. ANR-16-IDEX-0004, Inserm Cross-Cutting Scientific Program HuDeCA, the CHU Lille Bonus H, the UK Medical Research Council (MRC) and National Institute of Health and care Research (NIHR).
Published: 2023
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2. SpliceAI-visual: a free online tool to improve SpliceAI splicing variant interpretation

Author: Jean-Madeleine de Sainte Agathe, Mathilde Filser, Bertrand Isidor, Thomas Besnard, Paul Gueguen, Aurélien Perrin, Charles Van Goethem, Camille Verebi, Marion Masingue, John Rendu, Mireille Cossée, Anne Bergougnoux, Laurent Frobert, Julien Buratti, Élodie Lejeune, Éric Le Guern, Florence Pasquier, Fabienne Clot, Vasiliki Kalatzis, Anne-Françoise Roux, Benjamin Cogné, and David Baux
Subjects: Medicine, Genetics, QH426-470
Abstract: Abstract SpliceAI is an open-source deep learning splicing prediction algorithm that has demonstrated in the past few years its high ability to predict splicing defects caused by DNA variations. However, its outputs present several drawbacks: (1) although the numerical values are very convenient for batch filtering, their precise interpretation can be difficult, (2) the outputs are delta scores which can sometimes mask a severe consequence, and (3) complex delins are most often not handled. We present here SpliceAI-visual, a free online tool based on the SpliceAI algorithm, and show how it complements the traditional SpliceAI analysis. First, SpliceAI-visual manipulates raw scores and not delta scores, as the latter can be misleading in certain circumstances. Second, the outcome of SpliceAI-visual is user-friendly thanks to the graphical presentation. Third, SpliceAI-visual is currently one of the only SpliceAI-derived implementations able to annotate complex variants (e.g., complex delins). We report here the benefits of using SpliceAI-visual and demonstrate its relevance in the assessment/modulation of the PVS1 classification criteria. We also show how SpliceAI-visual can elucidate several complex splicing defects taken from the literature but also from unpublished cases. SpliceAI-visual is available as a Google Colab notebook and has also been fully integrated in a free online variant interpretation tool, MobiDetails ( https://mobidetails.iurc.montp.inserm.fr/MD ). Graphical abstract
Published: 2023
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3. Frequency and topography of small cerebrovascular lesions in vascular and in mixed dementia: a post-mortem 7-tesla magnetic resonance imaging study with neuropathological correlates

Author: Jacques De Reuck, Florent Auger, Nicolas Durieux, Vincent Deramecourt, Claude-Alain Maurage, Charlotte Cordonnier, Florence Pasquier, Didier Leys, and Regis Bordet
Subjects: post-mortem 7.0-tesla MRI, vascular dementia, mixed dementia, topographic distribution of small cerebrovascular lesions, cortical microbleeds, cortical microinfarcts, white matter changes, lacunar infarcts, Medicine
Abstract: Introduction : Mixed dementia (MixD) refers to a combination of definite Alzheimer’s disease (AD) and vascular encephalopathy. The existence of a “pure” type of vascular dementia (VaD) is controversial. There is a need to find magnetic resonance imaging (MRI) characteristics allowing the distinction between VaD and MixD. The present post-mortem 7.0-tesla MRI compares the frequency or severity and the topography of the small cerebrovascular lesions in brains of patients with VaD and with MixD. Material and methods : Based on neuropathological criteria, 14 brains were classified as VaD, 24 as MixD and 11 as controls. Three coronal sections of a cerebral hemisphere and a horizontal section of a cerebellar hemisphere underwent T2 and T2* 7.0-tesla MRI examination. The mean values and topographic distribution of white matter changes (WMCs), lacunar infarcts (LIs), cortical microbleeds (CoMBs) and cortical microinfarcts (CoMIs) were determined and compared between the different groups. Results : Compared to the controls, both VaD and MixD brains had significantly more severe WMCs and increased numbers of CoMBs and CoMIs. Lacunar infarcts predominated only in the VaD cases. On mutual comparison of VaD and MixD brains, CoMBs and CoMIs predominated in the frontal lobe and the cerebellum of VaD, while were mainly present in the occipital lobe of MixD. White matter changes predominated in the temporal lobe of MixD cases. Lacunar infarcts were significantly increased in the corona radiata and putamen of VaD patients. Conclusions : The present post-mortem MRI study shows clear differences in the distribution and the types of cerebrovascular lesions on high-field MRI, confirming that VaD and MixD are different diseases.
Published: 2017
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4. How many patients are eligible for disease-modifying treatment in Alzheimer’s disease? A French national observational study over 5 years

Author: Didier Hannequin, Florence Pasquier, Bruno Dubois, David Wallon, Julien Dumurgier, Stéphane Epelbaum, Thérèse Jonveaux, Annick Besozzi, Stéphane Pouponneau, Caroline Hommet, Laetitia Berly, Adrien Julian, Marc Paccalin, Julie Bellet, Claire Boutoleau-Bretonniere, Thiphaine Charriau, Olivier Rouaud, Olivier Madec, Aurélie Mouton, Renaud David, Samir Bekadar, Roxane Fabre, and Walter Deberdt
Subjects: Medicine
Abstract: ObjectiveWe aimed to study the epidemiology of the prodromal and mild stages of Alzheimer’s disease (AD) patients who are eligible for clinical trials with disease-modifying therapies.SettingsWe analysed two large complementary databases to study the incidence and characteristics of this population on a nationwide scope in France from 2014 to 2018. The National Alzheimer Database contains data from 357 memory centres and 90 private neurologists. Data from 2014 to 2018 have been analysed.ParticipantsPatients, 50–85 years old, diagnosed with AD who had an Mini-Mental State Exam (MMSE) score of ≥20 were included. We excluded patients with mixed and non-AD neurocognitive disorders.Primary outcome measureDescriptive statistics of the population of interest was the primary measure.ResultsIn the National Alzheimer Database, 550 198 patients were assessed. Among them, 72 174 (13.1%) were diagnosed with AD and had an MMSE ≥20. Using corrections for specificity of clinical diagnosis of AD, we estimated that about 50 000 (9.1%) had a prodromal or mild AD. In the combined electronic clinical records database of 11 French expert memory centres, a diagnosis of prodromal or mild AD, certified by the use of cerebrospinal fluid AD biomarkers, could be established in 195 (1.3%) out of 14 596 patients.ConclusionsAD was not frequently diagnosed at a prodromal or mild dementia stage in France in 2014 to 2018. Diagnosis rarely relied on a pathophysiological marker even in expert memory centres. National databases will be valuable to monitor early stage AD diagnosis efficacy in memory centres when a disease-modifying treatment becomes available.
Published: 2019
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5. ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease

Author: Florent Letronne, Geoffroy Laumet, Anne-Marie Ayral, Julien Chapuis, Florie Demiautte, Mathias Laga, Michel E. Vandenberghe, Nicolas Malmanche, Florence Leroux, Fanny Eysert, Yoann Sottejeau, Linda Chami, Amandine Flaig, Charlotte Bauer, Pierre Dourlen, Marie Lesaffre, Charlotte Delay, Ludovic Huot, Julie Dumont, Elisabeth Werkmeister, Franck Lafont, Tiago Mendes, Franck Hansmannel, Bart Dermaut, Benoit Deprez, Anne-Sophie Hérard, Marc Dhenain, Nicolas Souedet, Florence Pasquier, David Tulasne, Claudine Berr, Jean-Jacques Hauw, Yves Lemoine, Philippe Amouyel, David Mann, Rebecca Déprez, Frédéric Checler, David Hot, Thierry Delzescaux, Kris Gevaert, and Jean-Charles Lambert
Subjects: Alzheimer, APP, ADAM30, Amyloid, Metabolism, LTP, Medicine, Medicine (General), R5-920
Abstract: Although several ADAMs (A disintegrin-like and metalloproteases) have been shown to contribute to the amyloid precursor protein (APP) metabolism, the full spectrum of metalloproteases involved in this metabolism remains to be established. Transcriptomic analyses centred on metalloprotease genes unraveled a 50% decrease in ADAM30 expression that inversely correlates with amyloid load in Alzheimer's disease brains. Accordingly, in vitro down- or up-regulation of ADAM30 expression triggered an increase/decrease in Aβ peptides levels whereas expression of a biologically inactive ADAM30 (ADAM30mut) did not affect Aβ secretion. Proteomics/cell-based experiments showed that ADAM30-dependent regulation of APP metabolism required both cathepsin D (CTSD) activation and APP sorting to lysosomes. Accordingly, in Alzheimer-like transgenic mice, neuronal ADAM30 over-expression lowered Aβ42 secretion in neuron primary cultures, soluble Aβ42 and amyloid plaque load levels in the brain and concomitantly enhanced CTSD activity and finally rescued long term potentiation alterations. Our data thus indicate that lowering ADAM30 expression may favor Aβ production, thereby contributing to Alzheimer's disease development.
Published: 2016
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6. The topography of cortical microbleeds in frontotemporal lobar degeneration: a post-mortem 7.0-tesla magnetic resonance study

Author: Jacques De Reuck, Florent Auger, Nicolas Durieux, Vincent Deramecourt, Claude-Alain Maurage, Florence Lebert, Didier Leys, Charlotte Cordonnier, Florence Pasquier, and Regis Bordet
Subjects: 7.0-tesla magnetic resonance imaging, topography of post-mortem cortical microbleeds, frontotemporal lobar degeneration, neurodegenerative diseases, Medicine
Abstract: Introduction : Cerebrovascular lesions are rare in frontotemporal lobar degeneration (FTLD), in contrast to other neurodegenerative diseases. Cortical microbleeds (CoMBs) are frequent in Alzheimer’s disease, in particular in cases associated with cerebral amyloid angiopathy. The present study investigates the gyral topographic distribution of CoMBs in post-mortem FTLD brains with 7.0-tesla magnetic resonance imaging. Material and methods : The distribution of CoMBs in 11 post-mortem FTLD brains and in 12 control brains was compared on T2*-GRE MRI of six coronal sections of a cerebral hemisphere. The mean values of CoMBs were determined in twenty-two different gyri. The findings were correlated to those separately observed on neuropathological examination. Results : As a whole there was a trend of more CoMBs in the prefrontal section of FTLD as well as of the control brains. CoMBs were significantly increased in the superior frontal gyrus and the insular cortex (p ≤ 0.001) and also in the inferior frontal gyrus and the superior temporal gyrus (p ≤ 0.01). Conclusions : CoMBs in FTLD are only increased in the regions mainly affected by the neurodegenerative lesions. They probably do not reflect additional cerebrovascular disease.
Published: 2016
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7. Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial.

Author: Brian Lawlor, Ricardo Segurado, Sean Kennelly, Marcel G M Olde Rikkert, Robert Howard, Florence Pasquier, Anne Börjesson-Hanson, Magda Tsolaki, Ugo Lucca, D William Molloy, Robert Coen, Matthias W Riepe, János Kálmán, Rose Anne Kenny, Fiona Cregg, Sarah O'Dwyer, Cathal Walsh, Jessica Adams, Rita Banzi, Laetitia Breuilh, Leslie Daly, Suzanne Hendrix, Paul Aisen, Siobhan Gaynor, Ali Sheikhi, Diana G Taekema, Frans R Verhey, Raffaello Nemni, Flavio Nobili, Massimo Franceschi, Giovanni Frisoni, Orazio Zanetti, Anastasia Konsta, Orologas Anastasios, Styliani Nenopoulou, Fani Tsolaki-Tagaraki, Magdolna Pakaski, Olivier Dereeper, Vincent de la Sayette, Olivier Sénéchal, Isabelle Lavenu, Agnès Devendeville, Gauthier Calais, Fiona Crawford, Michael Mullan, and NILVAD Study Group
Subjects: Medicine
Abstract: BACKGROUND:This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. METHODS AND FINDINGS:NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and
Published: 2018
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8. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases.

Author: Hélène-Marie Lanoiselée, Gaël Nicolas, David Wallon, Anne Rovelet-Lecrux, Morgane Lacour, Stéphane Rousseau, Anne-Claire Richard, Florence Pasquier, Adeline Rollin-Sillaire, Olivier Martinaud, Muriel Quillard-Muraine, Vincent de la Sayette, Claire Boutoleau-Bretonniere, Frédérique Etcharry-Bouyx, Valérie Chauviré, Marie Sarazin, Isabelle le Ber, Stéphane Epelbaum, Thérèse Jonveaux, Olivier Rouaud, Mathieu Ceccaldi, Olivier Félician, Olivier Godefroy, Maite Formaglio, Bernard Croisile, Sophie Auriacombe, Ludivine Chamard, Jean-Louis Vincent, Mathilde Sauvée, Cecilia Marelli-Tosi, Audrey Gabelle, Canan Ozsancak, Jérémie Pariente, Claire Paquet, Didier Hannequin, Dominique Campion, and collaborators of the CNR-MAJ project
Subjects: Medicine
Abstract: BackgroundAmyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series.Methods and findingsWe report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification.ConclusionsOur findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.
Published: 2017
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9. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.

Author: Valentina Escott-Price, Céline Bellenguez, Li-San Wang, Seung-Hoan Choi, Denise Harold, Lesley Jones, Peter Holmans, Amy Gerrish, Alexey Vedernikov, Alexander Richards, Anita L DeStefano, Jean-Charles Lambert, Carla A Ibrahim-Verbaas, Adam C Naj, Rebecca Sims, Gyungah Jun, Joshua C Bis, Gary W Beecham, Benjamin Grenier-Boley, Giancarlo Russo, Tricia A Thornton-Wells, Nicola Denning, Albert V Smith, Vincent Chouraki, Charlene Thomas, M Arfan Ikram, Diana Zelenika, Badri N Vardarajan, Yoichiro Kamatani, Chiao-Feng Lin, Helena Schmidt, Brian Kunkle, Melanie L Dunstan, Maria Vronskaya, United Kingdom Brain Expression Consortium, Andrew D Johnson, Agustin Ruiz, Marie-Thérèse Bihoreau, Christiane Reitz, Florence Pasquier, Paul Hollingworth, Olivier Hanon, Annette L Fitzpatrick, Joseph D Buxbaum, Dominique Campion, Paul K Crane, Clinton Baldwin, Tim Becker, Vilmundur Gudnason, Carlos Cruchaga, David Craig, Najaf Amin, Claudine Berr, Oscar L Lopez, Philip L De Jager, Vincent Deramecourt, Janet A Johnston, Denis Evans, Simon Lovestone, Luc Letenneur, Isabel Hernández, David C Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M Goate, Nathalie Fiévet, Matthew J Huentelman, Michael Gill, Kristelle Brown, M Ilyas Kamboh, Lina Keller, Pascale Barberger-Gateau, Bernadette McGuinness, Eric B Larson, Amanda J Myers, Carole Dufouil, Stephen Todd, David Wallon, Seth Love, Ekaterina Rogaeva, John Gallacher, Peter St George-Hyslop, Jordi Clarimon, Alberto Lleo, Anthony Bayer, Debby W Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, Petra Proitsi, John Collinge, Sandro Sorbi, Florentino Sanchez Garcia, Nick C Fox, John Hardy, Maria Candida Deniz Naranjo, Paolo Bosco, Robert Clarke, Carol Brayne, Daniela Galimberti, Elio Scarpini, Ubaldo Bonuccelli, Michelangelo Mancuso, Gabriele Siciliano, Susanne Moebus, Patrizia Mecocci, Maria Del Zompo, Wolfgang Maier, Harald Hampel, Alberto Pilotto, Ana Frank-García, Francesco Panza, Vincenzo Solfrizzi, Paolo Caffarra, Benedetta Nacmias, William Perry, Manuel Mayhaus, Lars Lannfelt, Hakon Hakonarson, Sabrina Pichler, Minerva M Carrasquillo, Martin Ingelsson, Duane Beekly, Victoria Alvarez, Fanggeng Zou, Otto Valladares, Steven G Younkin, Eliecer Coto, Kara L Hamilton-Nelson, Wei Gu, Cristina Razquin, Pau Pastor, Ignacio Mateo, Michael J Owen, Kelley M Faber, Palmi V Jonsson, Onofre Combarros, Michael C O'Donovan, Laura B Cantwell, Hilkka Soininen, Deborah Blacker, Simon Mead, Thomas H Mosley, David A Bennett, Tamara B Harris, Laura Fratiglioni, Clive Holmes, Renee F A G de Bruijn, Peter Passmore, Thomas J Montine, Karolien Bettens, Jerome I Rotter, Alexis Brice, Kevin Morgan, Tatiana M Foroud, Walter A Kukull, Didier Hannequin, John F Powell, Michael A Nalls, Karen Ritchie, Kathryn L Lunetta, John S K Kauwe, Eric Boerwinkle, Matthias Riemenschneider, Mercè Boada, Mikko Hiltunen, Eden R Martin, Reinhold Schmidt, Dan Rujescu, Jean-François Dartigues, Richard Mayeux, Christophe Tzourio, Albert Hofman, Markus M Nöthen, Caroline Graff, Bruce M Psaty, Jonathan L Haines, Mark Lathrop, Margaret A Pericak-Vance, Lenore J Launer, Christine Van Broeckhoven, Lindsay A Farrer, Cornelia M van Duijn, Alfredo Ramirez, Sudha Seshadri, Gerard D Schellenberg, Philippe Amouyel, Julie Williams, and Cardiovascular Health Study (CHS)
Subjects: Medicine, Science
Abstract: BACKGROUND:Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. PRINCIPAL FINDINGS:In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. SIGNIFICANCE:The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
Published: 2014
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10. Association of Amyotrophic Lateral Sclerosis and Alzheimer’s Disease: New Entity or Coincidence? A Case Series

Author: Claire Paquet, Pierre Lozeron, Elodie Bouaziz-Amar, Florence Pasquier, Vincent Deramecourt, Eloi Magnin, Agathe Vrillon, and David Wallon
Subjects: Pathology, medicine.medical_specialty, Amyloid, business.industry, General Neuroscience, General Medicine, Disease, Neuropathology, medicine.disease, Psychiatry and Mental health, Clinical Psychology, Cerebrospinal fluid, medicine, Geriatrics and Gerontology, Amyotrophic lateral sclerosis, business, Episodic memory, Pathological, Frontotemporal dementia
Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia have a strong clinical, genetic, and pathological connection but association of ALS with Alzheimer’s disease (AD) is seldom reported. We report a series of 5 cases of AD associated with ALS. Our patients presented with cognitive deterioration with episodic memory impairment meeting criteria for AD. ALS occurred subsequently in all cases and its phenotype was not homogenous. Amyloid process was confirmed in four cases with cerebrospinal fluid biomarkers. One case underwent postmortem exam, demonstrating hallmarks lesions of both diseases. This series highlights that ALS-AD phenotype could be a specific underexplored entity.
Published: 2021

11. Primary progressive aphasias associated with C9orf72 expansions: Another side of the story

Author: idier Hannequin, Eino Solje, Sabrina Sayah, Emmanuel Gerardin, Marie Sarazin, Florence Pasquier, Marion Houot, Assi-Hervé Oya, Martine Vercelletto, Julien Lagarde, Marie Noguès-Lassiaille, Marie Chupin, Vincent Deramecourt, Sophie Auriacombe, Agnès Camuzat, Marc Teichmann, Jérémie Pariente, Sophie Ferrieux, Lucette Lacomblez, Mathieu Chastan, Jacques Monteil, Yaohua Chen, Marie-Paule Boncoeur, Lorenzo Cipriano, Anne Bissery, Simona Bottani, David Wallon, Christine Delmaire, Carole Roué-Jagot, Benjamin Le Toullec, Bernard-François Michel, Grégory Petyt, Olivier Martinaud, Philippe Couratier, Dario Saracino, Adeline Rollin-Sillaire, Daisy Rinaldi, Mira Didic, Serge Belliard, Amandine Géraudie, Géraldine Lautrette, Frédérique Etcharry-Bouyx, Xavier Delbeuck, Richard Levy, Frédéric Blanc, Mathieu Ceccaldi, Christel Thauvin-Robinet, Marie-Odile Habert, Eve Benchetrit, Maïté Formaglio, Alexis Brice, Isabelle Le Ber, Charles Duyckaerts, Véronique Golfier, Raffaella Migliaccio, Marie-Anne Mackowiak, Catherine Thomas-Antérion, Anne Bertrand, Olivier Colliot, François Sellal, Claire Boutoleau-Bretonnière, Anne M. Remes, Hugo Bertin, Aurélie Funkiewiez, and Stéphanie Bombois
Subjects: medicine.medical_specialty, C9orf72 Protein, Apraxias, Cognitive Neuroscience, Inferior frontal gyrus, Experimental and Cognitive Psychology, Frontotemporal lobar degeneration, respiratory system, Audiology, medicine.disease, Magnetic Resonance Imaging, Apraxia, Primary progressive aphasia, Aphasia, Primary Progressive, Neuropsychology and Physiological Psychology, Atrophy, C9orf72, medicine, Humans, Speech, Orbitofrontal cortex, Psychology, Language, Frontotemporal dementia
Abstract: C9orf72 repeat expansions are rarely associated with primary progressive aphasias (PPA). In-depth characterization of the linguistic deficits, and the underlying patterns of grey-matter atrophy in PPA associated with the C9orf72 expansions (PPA-C9orf72) are currently lacking. In this study, we comprehensively analyzed a unique series of 16 patients affected by PPA-C9orf72. Eleven patients were issued from two independent French and Finnish cohorts, and five were identified by means of literature review. Voxel-based morphometry (VBM) studies were performed on three of them. This study depicts the spectrum of C9orf72–related aphasic phenotypes, and illustrates their linguistic presentation. The non-fluent/agrammatic variant was the most frequent phenotype in our series (9/16 patients, 56%), with apraxia of speech being the main defining feature. Left frontal lobe atrophy was present in these subjects, peaking in inferior frontal gyrus. Three patients (19%) showed the semantic variant, with progression of atrophy in temporo-polar regions, later involving orbitofrontal cortex. Anterior temporal lobe dysfunction was also particularly relevant in two patients (12.5%) with mixed forms of PPA. Lastly, two patients (12.5%) had unclassifiable PPA with predominating word-finding difficulties. No PPA-C9orf72 patients in our series fulfilled the criteria of the logopenic variant. Importantly, this study underlines the role of C9orf72 mutation in the disruption of the most anterior parts of the language network, including prefrontal and temporo-polar areas. It provides guidelines for C9orf72 testing in PPA patients, with important clinical impact as gene-specific therapies are upcoming.
Published: 2021

12. Dissemination in time and space in presymptomatic granulin mutation carriers: a GENFI spatial chronnectome study

Author: Sandro Sorbi, Vince D. Calhoun, James B. Rowe, Isabelle Le Ber, Matthis Synofzik, Roberto Gasparotti, Martina Bocchetta, Enrico Premi, Dave Cash, Alexandre de Mendonça, Armin Iraji, Johannes Levin, Stefano Gazzina, A. Danek, Lize C. Jiskoot, Marcello Giunta, Alexander Gerhard, Markus Otto, Raquel Sánchez-Valle, Emily Todd, Genetic Frontotemporal dementia Initiative, Isabel Santana, Silvana Archetti, Rhian S Convery, Robert Laforce, Srinivas Rachakonda, Florence Pasquier, Fermin Moreno, John C. van Swieten, Georgia Peakman, Elizabeth Finger, Jonathan D. Rohrer, Christopher C Butler, Daniela Galimberti, Alberto Benussi, Carmela Tartaglia, Rik Vandenberghe, Caroline Graff, Mario Masellis, Fabrizio Tagliavini, Barbara Borroni, Simon Ducharme, Genetic Frontotemporal dementia Initiative (GENFI), Neurology, and Clinical Genetics
Subjects: Adult, Male, resting-state functional MRI, Heterozygote, Aging, Time Factors, Dissemination in time, Spatial Behavior, spatial chronnectome, Granulin, Biology, Research initiative, frontotemporal dementia, Executive Function, dynamic functional network connectivity, Frontotemporal Dementia, GRN mutation, medicine, Humans, Default mode network, Granulins, General Neuroscience, Brain, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Asymptomatic Diseases, Mutation, Mutation (genetic algorithm), Female, Neurology (clinical), Geriatrics and Gerontology, Neuroscience, Insula, Language network, Developmental Biology, Frontotemporal dementia
Abstract: The presymptomatic brain changes of granulin (GRN) disease, preceding by years frontotemporal dementia, has not been fully characterized. New approaches focus on the spatial chronnectome can capture both spatial network configurations and their dynamic changes over time. To investigate the spatial dynamics in 141 presymptomatic GRN mutation carriers and 282 noncarriers from the Genetic Frontotemporal dementia research Initiative cohort. We considered time-varying patterns of the default mode network, the language network, and the salience network, each summarized into 4 distinct recurring spatial configurations. Dwell time (DT) (the time each individual spends in each spatial state of each network), fractional occupacy (FO) (the total percentage of time spent by each individual in a state of a specific network) and total transition number (the total number of transitions performed by each individual in a specifict state) were considered. Correlations between DT, FO, and transition number and estimated years from expected symptom onset (EYO) and clinical performances were assessed. Presymptomatic GRN mutation carriers spent significantly more time in those spatial states characterised by greater activation of the insula and the parietal cortices, as compared to noncarriers (p < 0.05, FDR-corrected). A significant correlation between DT and FO of these spatial states and EYO was found, the longer the time spent in the spatial states, the closer the EYO. DT and FO significantly correlated with performances at tests tapping processing speed, with worse scores associated with increased spatial states’ DT. Our results demonstrated that presymptomatic GRN disease presents a complex dynamic reorganization of brain connectivity. Change in both the spatial and temporal aspects of brain network connectivity could provide a unique glimpse into brain function and potentially allowing a more sophisticated evaluation of the earliest disease changes and the understanding of possible mechanisms in GRN disease.
Published: 2021

13. A multimodal, longitudinal study of cognitive heterogeneity in early‐onset Alzheimer's disease

Author: Florence Pasquier, Grégory Kuchcinski, Stéphanie Bombois, Xavier Delbeuck, Cécile Bordier, Renaud Lopes, Adeline Rollin-Sillaire, Emilie Skrobala, and Marianne Pollet
Subjects: Apolipoprotein E, Pediatrics, medicine.medical_specialty, Longitudinal study, medicine.diagnostic_test, business.industry, Neuroimaging, Cognition, Neuropsychological test, Disease, Neuropsychological Tests, medicine.disease, Neurology, Alzheimer Disease, Cohort, medicine, Humans, Early-onset Alzheimer's disease, Longitudinal Studies, Neurology (clinical), business
Abstract: BACKGROUND AND PURPOSE Alzheimer's disease (AD) is a heterogeneous pathology. Young patients with AD are particularly likely to have an atypical presentation. The objectives of the present cluster analysis were to determine whether patients with early-onset AD (EOAD) had several distinct cognitive profiles and to compare the resulting clusters with regard to clinical, neuroimaging, and laboratory characteristics. METHODS We collected cognitive, behavioural, functional, neuroimaging, and laboratory data on 72 patients meeting the criteria for probable mild EOAD. The patients were first classified into clinical phenotype groups by a multidisciplinary board of clinicians. The patients' cognitive and functional decline was monitored for 24 months. A k-means clustering analysis was then used to determine clusters on the basis of the patients' neuropsychological test results. RESULTS Two distinct clusters were identified: the patients in the first cluster (C1, n = 38) had a predominant memory impairment, whereas patients in the second (C2, n = 34) did not. Dyslipidaemia and the presence of ɛ4 apolipoprotein E allele were more frequent in C1, whereas the cognitive and functional decline was faster in the patients in C2. Moreover, posterior brain abnormalities were more severe in patients in C2 than in patients in C1. CONCLUSIONS By applying a k-means clustering analysis, we identified two clusters of patients in an EOAD cohort. The clusters differed with regard to certain clinical, imaging, and laboratory characteristics. This clustering procedure might be of value for managing patients with EOAD in general and for identifying those at risk of more rapid decline in particular.
Published: 2021

14. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease

Author: Christopher H. van Dyck, Roger Clarnette, Susan Mills, John C. Morris, Carlos Cruchaga, Anna Santacruz, Ging-Yuek Robin Hsiung, Roy Yaari, Suman Jayadev, Caroline Giacobino, William S. Brooks, Robert A. Koeppe, Raquel Sánchez-Valle, Anne M. Fagan, Eric McDade, Sarah B. Berman, Catherine J. Mummery, Florence Pasquier, Scott M. Berry, Randall J. Bateman, Brian A. Gordon, Jorge J. Llibre-Guerra, Maïté Formaglio, Paul S. Aisen, Paulo Fontoura, Mark A. Mintun, Bruno Dubois, Erik D. Roberson, Kelley Coalier, Ronald G. Thomas, Martin R. Farlow, John R. Sims, Serge Gauthier, Douglas Galasko, Mario Masellis, G. Mustafa Surti, Barbara A. Wendelberger, Guoqiao Wang, James J. Lah, Yan Li, David B. Clifford, David Wallon, Paul Delmar, Alison Goate, Rachelle S. Doody, Didier Hannequin, Stephen Salloway, Geoffrey A. Kerchner, Karen C. Holdridge, Ivonne Z. Jimenez-Velazquez, Janice M. Hitchcock, Monika Baudler, Lawrence S. Honig, Tammie L.S. Benzinger, Clifford R. Jack, Peter J. Snyder, Scott W. Andersen, J. Pariente, Andrew J. Aschenbrenner, Jason Hassenstab, Richard J. Perrin, Colin L. Masters, Chengjie Xiong, Jared R. Brosch, and B. Joy Snider
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Disease, Antibodies, Monoclonal, Humanized, Placebo, Asymptomatic, Article, General Biochemistry, Genetics and Molecular Biology, law.invention, Placebos, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Alzheimer Disease, law, Internal medicine, medicine, Humans, Solanezumab, Cognitive decline, Amyloid beta-Peptides, Dose-Response Relationship, Drug, business.industry, General Medicine, Middle Aged, 030104 developmental biology, 030220 oncology & carcinogenesis, Disease Progression, Biomarker (medicine), Female, medicine.symptom, Gantenerumab, business, Biomarkers, medicine.drug
Abstract: Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.
Published: 2021

15. Is Fall Risk Systematically Evaluated in Memory Clinics? A National Survey of Practice in France

Author: Florence Pasquier, Victoire Leroy, Pierre Krolak-Salmon, Bertrand Fougère, Françcois Puisieux, Naiara Demnitz, Yaohua Chen, 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), CHU Lille, Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Elderly Health Service, Hôpital des Charpennes [CHU - HCL], Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Éducation Éthique Santé EA 7505 (EES), and Université de Tours (UT)
Subjects: Male, Risk, medicine.medical_specialty, Specialty, Standardized test, Computer-assisted web interviewing, Timed Up and Go test, Risk Assessment, [SHS]Humanities and Social Sciences, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Outpatient clinic, Dementia, 030212 general & internal medicine, Practice Patterns, Physicians', Geriatric Assessment, Postural Balance, Aged, Aged, 80 and over, Memory Disorders, business.industry, General Neuroscience, Memory clinic, General Medicine, medicine.disease, Psychiatry and Mental health, Clinical Psychology, Health Care Surveys, Family medicine, Accidental Falls, Female, France, Geriatrics and Gerontology, business, Neurocognitive, 030217 neurology & neurosurgery
Abstract: International audience; Background: Falls are a major health problem in older persons but are still under-diagnosed and challenging to prevent. Current guidelines do not target high-risk populations, especially people living with dementia. In France, people with neurocognitive disorders are mainly referred to memory clinics (MCs). Objective: We aimed to survey the routine practice of physicians working in MCs regarding fall risk assessment. Methods: We conducted a cross-sectional survey in France from January to May 2019 among physicians working in MCs, through an anonymous online questionnaire: twenty-seven questions about the physician’s background and their practice of fall risk assessment, especially use of clinical and paraclinical tools. We compared the results according to the age and the specialty of the physician. Results: We obtained 171 responses with a majority of women (60%) and geriatricians (78%). All age classes and all French regions were represented. Most of respondents (98.8%) stated that they address gait and/or falls in outpatient clinic and 95.9%in day hospitals. When asked about how they assess fall risk, fall history (83%) and gait examination (68.4%) were the most widely used, while orthostatic hypotension (24%) and clinical standardized tests (25.7%) were less common. Among standardized tests, One-leg Balance, Timed Up and Go Test, and gait speed measurements were the most used. Geriatricians had more complete fall risk assessment than neurologists (e.g., 56%versus 13%for use of standardized tests, p
Published: 2021

16. ATG2B/GSKIP in de novo acute myeloid leukemia (AML): high prevalence of germline predisposition in French West Indies

Author: Jean-Edouard Martin, Christine Bellanné-Chantelot, Olivier Caron, Pascal Fuseau, Nathalie Auger, Barbara Schmaltz-Panneau, Sophie Cotteret, Stéphane de Botton, Christophe Willekens, Florence Pasquier, Christophe Marzac, Jean-Baptiste Micol, Jean Pegliasco, Maureen Lopez, William Vainchenker, Adel Ben-Ali, Véronique Saada, Carole Bourdin, Flore Salviat, Odile Bera, Sabine Khalife-Hachem, Isabelle Plo, Cristina Castilla-Llorent, Philippe Helias, Jean-Côme Meniane, Samy Chraibi, and Raouf Ben-Abdelali
Subjects: Cancer Research, High prevalence, Adult patients, business.industry, De novo acute, Myeloid leukemia, Hematology, Germline, Oncology, hemic and lymphatic diseases, Immunology, Genetic predisposition, Medicine, business, West indies
Abstract: Genetic predisposition to acute myeloid leukemia (AML) concerns a minority of adult patients. Development of high-throughput sequencing technologies over the last ten years allowed identification o...
Published: 2021

17. Effects of azacitidine in 93 patients with IDH1/2 mutated acute myeloid leukemia/myelodysplastic syndromes: a French retrospective multicenter study

Author: Claude Preudhomme, Cyril Quivoron, Sophie Broutin, Emmanuelle Clappier, Aline Renneville, S. de Botton, Christophe Willekens, Angelo Paci, Ramy Rahmé, Julien Rossignol, Pierre Fenaux, Laurence Simon, Raphael Itzykson, Alice Marceau, Eyal C. Attar, Véronique Saada, Mark G. Frattini, Jean-Baptiste Micol, Madalina Uzunov, Florence Pasquier, Laurent Pascal, Thorsten Braun, Emmanuel Raffoux, Matthieu Duchmann, Julia Delahousse, V. Vidal, Virginie Penard-Lacronique, and Lionel Adès
Subjects: Cancer Research, Myeloid, IDH1, business.industry, Myelodysplastic syndromes, Azacitidine, Myeloid leukemia, Hematology, medicine.disease, IDH2, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Isocitrate dehydrogenase, Oncology, Multicenter study, 030220 oncology & carcinogenesis, medicine, Cancer research, business, 030215 immunology, medicine.drug
Abstract: Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations in Myeloid Neoplams (MNs) exhibit DNA hypermethylation via 2-hydroxyglutarate (2HG) over-production. Clinical impact of azacitidine (AZA) re...
Published: 2020

18. Sedative Load in Community-Dwelling Older Adults with Mild–Moderate Alzheimer’s Disease: Longitudinal Relationships with Adverse Events, Delirium and Falls

Author: Dyer, Adam H, Murphy, Claire, Lawlor, Brian, Kennelly, Sean, P NILVAD StudyGroup: Brian Lawlor, Ricardo, Segurado, Sean, Kennelly, Marcel G, M Olde Rikkert, Robert, Howard, Florence, Pasquier, Anne, Börjesson-Hanson, Magda, Tsolaki, Ugo, Lucca, D William Molloy, Robert, Coen, Matthias, W Riepe, János, Kálmán, Rose Anne Kenny, Fiona, Cregg, Sarah, O'Dwyer, Cathal, Walsh, Jessica, Adams, Rita, Banzi, Laetitia, Breuilh, Leslie, Daly, Suzanne, Hendrix, Paul, Aisen, Siobhan, Gaynor, Ali, Sheikhi, Diana, G Taekema, Frans, R Verhey, Raffaello, Nemni, Nobili, FLAVIO MARIANO, Massimo, Franceschi, Frisoni, Giovanni, Zanetti, Orazio, Anastasia, Konsta, Orologas, Anastasios, Styliani, Nenopoulou, Fani, Tsolaki-Tagaraki, Magdolna, Pakaski, Olivier, Dereeper, Olivier, Sénéchal, Agnès, Devendeville, Gauthier, Calais, Fiona, Crawford, Michael, Mullan, Pauline, Aalten, Maria, A Berglund, Jurgen, A Claassen, Rianne, A De Heus, Daan L, K De Jong, Olivier, Godefroy, Siobhan, Hutchinson, Aikaterini, Ioannou, Michael, Jonsson, Annette, Kent, Jürgen, Kern, Petros, Nemtsas, Minoa-Kalliopi, Panidou, Laila, Abdullah, Angelina, M Santoso, Gerrita, J van Spijker, Martha, Spiliotou, Georgia, Thomoglou, and Anders, Wallin
Subjects: Male, medicine.medical_specialty, Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1], medicine.drug_class, Sedation, Rate ratio, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Internal medicine, medicine, Humans, Hypnotics and Sedatives, Cognitive Dysfunction, Pharmacology (medical), 030212 general & internal medicine, Cognitive decline, Adverse effect, Aged, Aged, 80 and over, business.industry, Incidence, Delirium, Drug Utilization, Sedative, Cohort, Accidental Falls, Female, Independent Living, Geriatrics and Gerontology, medicine.symptom, business, 030217 neurology & neurosurgery, Antipsychotic Agents, Cohort study
Abstract: Older adults are frequently prescribed medications with sedative effects, which are associated with numerous adverse consequences. However, the prevalence and longitudinal associations of sedative medication use in community-dwelling older adults with mild–moderate Alzheimer’s disease (AD) has not been explored to date. Our objective was to assess the prevalence of sedative medication use in community-dwelling older adults with mild–moderate AD and examine the longitudinal association between sedative medication use and adverse events (AEs). The association between baseline sedative load (SL) and AEs, unscheduled healthcare utilisation, delirium and falls was assessed in older adults with mild–moderate AD over 18 months using secondary analysis of NILVAD trial data (collected from 2014 to 2016). Baseline medication use was assessed, and the SL model was applied to each participant’s medication individually. The SL model classifies medications into one of four categories: (1) primary sedatives, (2) medications with a sedating component or prominent side effect, (3) medications with sedation as a potential adverse reaction and (4) all other medications with no known sedative side effects. Medications in group 1 were assigned an SL score of 2, those in group 2 were assigned an SL score of 1, and those in categories 3 and 4 an SL score of 0. SL scores for each medication participants were taking were summed and the total SL calculated as an arithmetic sum of individual medications score. A total SL score ≥ 3 was classed as high. Statistical analysis was conducted using Poisson regression and mixed-effects linear regression, with adjustment for important clinical covariates. We also assessed the impact of SL on dementia progression and cognitive decline. Over half (55.7% [284/510]) of those with mild–moderate AD (age 72.8 ± 8.3 years, 61.9% female) were prescribed a regular medication with sedation as a primary effect or prominent side effect, with 22.2% (113/510) having a high SL (≥ 3). The most common medications contributing to SL were antidepressants, antipsychotics, anxiolytics and hypnotics. Over 18 months, increasing baseline SL was associated with incident AEs (incidence rate ratio [IRR] 1.15; 95% confidence interval [CI] 1.11–1.19; p < 0.001), serious AEs (IRR 1.23; 95% CI 1.11–1.36; p < 0.001) and unscheduled general practitioner visits (IRR 1.23; 95% CI 1.13–1.34; p < 0.001). Further, increasing SL was associated with a greater likelihood of incident delirium (IRR 1.30; 95% CI 1.11–1.53; p < 0.001) and falls (IRR 1.20; 95% CI 1.03–1.42; p = 0.02). Associations persisted after robust covariate adjustment. SL was not associated with accelerated cognitive decline or AD progression. In the current study, over half of older adults with mild–moderate AD were prescribed at least one drug with a sedative effect, and a significant minority had a high SL. Increasing baseline SL was associated with a greater likelihood of incident AEs, delirium and falls, highlighting the need for optimal prescribing in this potentially vulnerable cohort.
Published: 2020

19. Ivosidenib for the treatment of relapsed or refractory acute myeloid leukemia with an IDH1 mutation

Author: Claude Chahine, Florence Pasquier, Christophe Marzac, and Stéphane de Botton
Subjects: Pharmacology, Poor prognosis, IDH1, Oncogene, business.industry, Myeloid leukemia, Refractory, hemic and lymphatic diseases, IDH1 Mutation, Drug Discovery, Genetics, Cancer research, Molecular Medicine, Medicine, business, neoplasms
Abstract: Management of acute myeloid leukemia (AML) remains challenging, especially for relapsed or refractory (R/R) AML patients who display poor prognosis with conventional therapies. This underlined the ...
Published: 2020

20. Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders

Author: Florence Pasquier, Mathieu Vandenbulcke, John R. Hodges, Mario Masellis, Alan J. Lerner, Chiadi U. Onyike, Yolande A.L. Pijnenburg, Wendy Kelso, Dennis Velakoulis, Fiona Kumfor, Carole Azuar, Robert Laforce, Peter Pressman, John C. van Swieten, Ratnavalli Ellajosyula, Jan Van den Stock, Calvin Trieu, Dhamidhu Eratne, Leonardo Cruz de Souza, Daniela Galimberti, Everard G. B. Vijverberg, Bradley F. Boeve, Maria Landqvist Waldö, Howard J. Rosen, Olivier Piguet, Rik Vandenberghe, Alexander Santillo, Annemiek Dols, Flora Gossink, Harro Seelaar, Ramon Landin-Romero, Mario F. Mendez, Elio Scarpini, Caroline Dallaire-Théroux, David C. Perry, Janine Diehl-Schmid, Simon Ducharme, Edward D. Huey, Michael Hornberger, Paulo Caramelli, Emma Devenney, Manabu Ikeda, Sandra Baez, Isabelle Le Ber, Richard Levy, APH - Mental Health, Amsterdam Neuroscience - Neurodegeneration, Neurology, and Psychiatry
Subjects: Male, Delayed Diagnosis, Neuropsychological Tests, Neurodegenerative, frontotemporal dementia, Medical and Health Sciences, Diagnosis, differential diagnosis, Neuropsychological assessment, guidelines, Review Articles, Neurologic Examination, screening and diagnosis, medicine.diagnostic_test, Psychiatric assessment, Mental Disorders, Corrigenda, Magnetic Resonance Imaging, psychiatry, Frontotemporal Dementia (FTD), Detection, Mental Health, Schizophrenia, Frontotemporal Dementia, Neurological, Major depressive disorder, Female, Frontotemporal dementia, 4.2 Evaluation of markers and technologies, medicine.medical_specialty, Neuroimaging, Diagnosis, Differential, Fluorodeoxyglucose F18, Clinical Research, Behavioral and Social Science, medicine, Acquired Cognitive Impairment, Dementia, Humans, Medical history, Bipolar disorder, Psychiatry, Neurology & Neurosurgery, business.industry, Prevention, Psychology and Cognitive Sciences, Neurosciences, biomarkers, medicine.disease, Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, Positron-Emission Tomography, Differential, Neurology (clinical), business
Abstract: The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5–6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.
Published: 2020

21. A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers

Author: Yolande A.L. Pijnenburg, Alessandro Padovani, Lieke H.H. Meeter, Rita Guerreiro, Mathieu Vandenbulcke, Rose Bruffaerts, Sonja Schönecker, Sofia Bergström, Florence Pasquier, Mikel Tainta, Beatriz Santiago, Roberto Gasparotti, Maria Rosário Almeida, Núria Bargalló, Abbe Ullgren, Martina Bocchetta, James B. Rowe, Pietro Tiraboschi, Robart Bartha, Rachelle Shafei, Benjamin Bender, Anna Månberg, Enrico Premi, Sergi Borrego-Écija, Sandro Sorbi, Christopher C Butler, Rick van Minkelen, Alberto Benussi, Marta Cañada, Carlo Wilke, Christin Andersson, Caroline Graff, Isabel Santana, Elisa Semler, Valentina Bessi, Miren Zulaica, Benedetta Nacmias, Tobias Langheinrich, Christen Shoesmith, Philip Van Damme, Camilla Ferrari, Martin Rosser, Pedro Rosa-Neto, Alexandre de Mendonça, Jennifer M. Nicholas, Catharina Prix, Sebastien Ourselin, Michele Veldsman, Jessica L. Panman, Håkan Thonberg, Jennie Olofsson, Paul M. Thompson, Ana Gorostidi, Andrea Arighi, Raquel Sánchez-Valle, Anna Antonell, Vesna Jelic, Ana Verdelho, Sara Mitchell, Janne M. Papma, Alina Díez, Giuliano Binetti, Rhian S Convery, Silvana Archetti, Ekaterina Rogaeva, Michela Pievani, C. Ferreira, Hans-Otto Karnath, Veronica Redaelli, Giuseppe Di Fede, Giovanni B. Frisoni, Carolina Maruta, Giacomina Rossi, Jaume Olives, Simon Ducharme, Roberta Ghidoni, Alexander Gerhard, Ron Keren, Johannes Levin, Sandra V. Loosli, Jose Bras, Isabelle Le Ber, Emily Todd, Robert Laforce, Sónia Afonso, Matthis Synofzik, Alazne Gabilondo, Elizabeth Finger, Thomas E. Cope, Paola Caroppo, Jorge Villanua, Diana Duro, Georgia Peakman, Giorgio G. Fumagalli, Serge Gauthier, Mario Masellis, Markus Otto, Caroline V. Greaves, Carolyn Timberlake, Harro Seelaar, Ione O.C. Woollacott, Sara Prioni, Jason D. Warren, Cristina Polito, Miguel Tábuas-Pereira, David F. Tang-Wai, Carmela Tartaglia, Linn Öijerstedt, Luisa Benussi, Barbara Borroni, Ricardo Taipa, Albert Lladó, Mircea Balasa, Rosa Rademakers, Lize C. Jiskoot, Miguel Castelo-Branco, Julia Remnestål, Fabrizio Tagliavini, Giorgio Giaccone, Maria João Leitão, Henrik Zetterberg, Valentina Cantoni, Daniela Galimberti, Sarah Anderl-Straub, Simon Mead, Myriam Barandiaran, Adrian Danek, Timothy Rittman, Chiara Fenoglio, Katrina M. Moore, David M. Cash, Rik Vandenberghe, Peter Nilsson, Elisabeth Wlasich, John C. van Swieten, Morris Freedman, Sandra E. Black, Carolin Heller, Stefano Gazzina, Gabriel Miltenberger, Fermin Moreno, Nick C. Fox, David L. Thomas, Jonathan D. Rohrer, Begoña Indakoetxea, Tobias Hoegen, Gemma Lombardi, Elio Scarpini, Bergström, Sofia [0000-0003-2910-4754], Apollo - University of Cambridge Repository, Neurology, Amsterdam Neuroscience - Neurodegeneration, Genetic Frontotemporal Dementia Initiative (GENFI), Jiskoot, Lize (Beitragende*r), Rowe, James B. (Beitragende*r), de Mendonça, Alexandre (Beitragende*r), Tagliavini, Fabrizio (Beitragende*r), Santana, Isabel (Beitragende*r), Le Ber, Isabelle (Beitragende*r), Levin, Johannes (Beitragende*r), Danek, Adrian (Beitragende*r), Otto, Markus (Beitragende*r), Frisoni, Giovanni (Beitragende*r), Ghidoni, Roberta (Beitragende*r), Sorbi, Sandro (Beitragende*r), Pasquier, Florence (Beitragende*r), Jelic, Vesna (Beitragende*r), Andersson, Christin (Beitragende*r), Afonso, Sónia (Beitragende*r), Almeida, Maria Rosario (Beitragende*r), Anderl-Straub, Sarah (Beitragende*r), Antonell, Anna (Beitragende*r), Archetti, Silvana (Beitragende*r), Arighi, Andrea (Beitragende*r), Balasa, Mircea (Beitragende*r), Barandiaran, Myriam (Beitragende*r), Bargalló, Nuria (Beitragende*r), Bartha, Robart (Beitragende*r), Bender, Benjamin (Beitragende*r), Benussi, Alberto (Beitragende*r), Benussi, Luisa (Beitragende*r), Bessi, Valentina (Beitragende*r), Binetti, Giuliano (Beitragende*r), Black, Sandra (Beitragende*r), Bocchetta, Martina (Beitragende*r), Borrego-Ecija, Sergi (Beitragende*r), Bras, Jose (Beitragende*r), Bruffaerts, Rose (Beitragende*r), Cañada, Marta (Beitragende*r), Cantoni, Valentina (Beitragende*r), Caroppo, Paola (Beitragende*r), Cash, David (Beitragende*r), Castelo-Branco, Miguel (Beitragende*r), Convery, Rhian (Beitragende*r), Cope, Thomas (Beitragende*r), Di Fede, Giuseppe (Beitragende*r), Díez, Alina (Beitragende*r), Duro, Diana (Beitragende*r), Fenoglio, Chiara (Beitragende*r), Ferrari, Camilla (Beitragende*r), Ferreira, Catarina B. (Beitragende*r), Fox, Nick (Beitragende*r), Freedman, Morris (Beitragende*r), Fumagalli, Giorgio (Beitragende*r), Gabilondo, Alazne (Beitragende*r), Gasparotti, Roberto (Beitragende*r), Gauthier, Serge (Beitragende*r), Gazzina, Stefano (Beitragende*r), Giaccone, Giorgio (Beitragende*r), Gorostidi, Ana (Beitragende*r), Greaves, Caroline (Beitragende*r), Guerreiro, Rita (Beitragende*r), Heller, Carolin (Beitragende*r), Hoegen, Tobias (Beitragende*r), Indakoetxea, Begoña (Beitragende*r), Karnath, Hans-Otto (Beitragende*r), Keren, Ron (Beitragende*r), Langheinrich, Tobias (Beitragende*r), Leitão, Maria João (Beitragende*r), Lladó, Albert (Beitragende*r), Lombardi, Gemma (Beitragende*r), Loosli, Sandra (Beitragende*r), Maruta, Carolina (Beitragende*r), Mead, Simon (Beitragende*r), Meeter, Lieke (Beitragende*r), Miltenberger, Gabriel (Beitragende*r), van Minkelen, Rick (Beitragende*r), Mitchell, Sara (Beitragende*r), Moore, Katrina (Beitragende*r), Nacmias, Benedetta (Beitragende*r), Nicholas, Jennifer (Beitragende*r), Olives, Jaume (Beitragende*r), Ourselin, Sebastien (Beitragende*r), Padovani, Alessandro (Beitragende*r), Panman, Jessica (Beitragende*r), Papma, Janne M. (Beitragende*r), Peakman, Georgia (Beitragende*r), Pievani, Michela (Beitragende*r), Pijnenburg, Yolande (Beitragende*r), Polito, Cristina (Beitragende*r), Premi, Enrico (Beitragende*r), Prioni, Sara (Beitragende*r), Prix, Catharina (Beitragende*r), Rademakers, Rosa (Beitragende*r), Redaelli, Veronica (Beitragende*r), Rittman, Tim (Beitragende*r), Rogaeva, Ekaterina (Beitragende*r), Rosa-Neto, Pedro (Beitragende*r), Rossi, Giacomina (Beitragende*r), Rosser, Martin (Beitragende*r), Santiago, Beatriz (Beitragende*r), Scarpini, Elio (Beitragende*r), Schönecker, Sonja (Beitragende*r), Semler, Elisa (Beitragende*r), Shafei, Rachelle (Beitragende*r), Shoesmith, Christen (Beitragende*r), Tábuas-Pereira, Miguel (Beitragende*r), Tainta, Mikel (Beitragende*r), Taipa, Ricardo (Beitragende*r), Tang-Wai, David (Beitragende*r), Thomas, David L. (Beitragende*r), Thompson, Paul (Beitragende*r), Thonberg, Håkan (Beitragende*r), Timberlake, Carolyn (Beitragende*r), Tiraboschi, Pietro (Beitragende*r), Todd, Emily (Beitragende*r), Van Damme, Philip (Beitragende*r), Vandenbulcke, Mathieu (Beitragende*r), Veldsman, Michele (Beitragende*r), Verdelho, Ana (Beitragende*r), Villanua, Jorge (Beitragende*r), Warren, Jason (Beitragende*r), Wilke, Carlo (Beitragende*r), Woollacott, Ione (Beitragende*r), Wlasich, Elisabeth (Beitragende*r), Zetterberg, Henrik (Beitragende*r), and Zulaica, Miren (Beitragende*r)
Subjects: medicine.medical_specialty, Neurology, NEFM, Medizin, genetics [Mutation], LASSO, Biology, Aquaporin 4 (AQP4), Neurosecretory protein VGF (VGF), DISEASE, genetics [Progranulins], Cellular and Molecular Neuroscience, Progranulins, CEREBROSPINAL-FLUID, C9orf72, ddc:570, medicine, CRITERIA, Humans, Neuronal pentraxin 2 (NPTX2), RC346-429, genetics [Frontotemporal Dementia], Molecular Biology, Pathological, Genetics, Science & Technology, Neurosciences, RC952-954.6, Brain, Neurofilament medium polypeptide (NEFM), medicine.disease, Molecular medicine, Cerebrospinal fluid, Aquaporin 4, Geriatrics, Suspension bead array, Frontotemporal Dementia, Mutation, Mutation (genetic algorithm), Neurosciences & Neurology, Neurology. Diseases of the nervous system, Neurology (clinical), Life Sciences & Biomedicine, Random forest, Biomarkers, Research Article, Frontotemporal dementia
Abstract: Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Supplementary Information: Additional file 1 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; Additional file 2 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; both files are available online at https://doi.org/10.1186/s13024-021-00499-4 Copyright © The Author(s) 2021. Background: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods: A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results: When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion: In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD. This study has received support from the Swedish FTD initiative funded by the Schörling Family Foundation. This work was also funded by KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, grants from Vetenskapsrådet Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Åhlén foundation, Demensfonden, Stohnes foundation, Gamla Tjänarinnor and Stockholm County Council ALF. Furthermore, support was received by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project, the JPND GENFI-PROX grant (2019-02248), the Dioraphte Foundation [grant numbers 09-02-00]; the Association for Frontotemporal Dementias Research Grant 2009; The Netherlands Organization for Scientific Research (NWO) (grant HCMI 056-13-018); ZonMw Memorabel (Deltaplan Dementie), (project numbers 733 050 103 and 733 050 813); JPND PreFrontAls consortium (project number 733051042). JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. M.S. was supported by the JPND grant “GENFI-prox” (by DLR/BMBF to M. S, joint with JDR., J.vS., M.O., B.B. and C.G.). Open Access funding provided by Royal Institute of Technology.
Published: 2021

22. The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis

Author: Florence Pasquier, Daniela Fernandois, Gaetan Ternier, Paolo Giacobini, Sreekala Nampoothiri, Virginie Mattot, Vincent Florent, Claude-Alain Maurage, S. Rasika, Eleonora Deligia, Marc Baroncini, Florent Sauve, Romain Perbet, Vincent Prevot, Monica Imbernon, François Trottein, Caio Coelho, CHU Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), FHU 1,000 Days for Health [Lille], Université de Lille, European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), and Mattot, Virginie
Subjects: 0303 health sciences, business.industry, Viral pathogenesis, [SDV]Life Sciences [q-bio], Human brain, 3. Good health, Olfactory bulb, [SDV] Life Sciences [q-bio], Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Hypothalamus, Immunology, Medicine, Brainstem, Animal studies, business, 030217 neurology & neurosurgery, 030304 developmental biology, Hormone
Abstract: Most patients with COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), display neurological symptoms, and respiratory failure in certain cases could be of extra-pulmonary origin. Hypothalamic neural circuits play key roles in sex differences, diabetes, hypertension, obesity and aging, all risk factors for severe COVID-19, besides being connected to olfactory/gustative and brainstem cardiorespiratory centers. Here, human brain gene-expression analyses and immunohistochemistry reveal that the hypothalamus and associated regions express angiotensin-converting enzyme 2 and transmembrane proteinase, serine 2, which mediate SARS-CoV-2 cellular entry, in correlation with genes or pathways involved in physiological functions or viral pathogenesis. A post-mortem patient brain shows viral invasion and replication in both the olfactory bulb and the hypothalamus, while animal studies indicate that sex hormones and metabolic diseases influence this susceptibility.
Published: 2021

23. Frontline Consolidation with Blinatumomab for High-Risk Philadelphia-Negative Acute Lymphoblastic Adult Patients. Early Results from the Graall-2014-QUEST Phase 2

Author: Rathana Kim, Nicolas Boissel, Hervé Dombret, Florence Van Obbergh, Sébastien Maury, Carlos Graux, Yosr Hicheri, Laure Farnault, Yves Chalandon, Thibaut Leguay, Thomas Cluzeau, Cedric Pastoret, Alban Villate, Emmanuelle Clappier, Françoise Huguet, Philippe Rousselot, Martine Escoffre-Barbe, Florence Pasquier, Marie Balsat, Anne Thiebaut-Bertrand, Mathilde Hunault, Eric Delabesse, Patrice Chevallier, Véronique Lhéritier, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Catholique de Louvain = Catholic University of Louvain (UCL), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Henri Mondor [Créteil], CHU Pontchaillou [Rennes], Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Hospitalier de Versailles André Mignot (CHV), Hôpitaux Universitaires de Genève (HUG), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), and Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Oncology, Philadelphia negative, medicine.medical_specialty, Adult patients, Consolidation (soil), business.industry, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Biology, Hematology, Biochemistry, Early results, Internal medicine, Medicine, Blinatumomab, business, medicine.drug
Abstract: Introduction: Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) with high-risk genetics and/or measurable residual disease (MRD) are at high-risk of disease recurrence. In the previous GRAALL-2005 study, we identified KMT2A rearrangements (KMT2A-r), IKZF1 intragenic deletion (IKZF1del) and post-induction (TP1, week 6) MRD ≥ 0.01% as independent factors to predict relapse in Ph-negative B-cell precursor (BCP) ALL (Beldjord K, Blood 2014). In the GRAALL-2014 trial, high-risk (HR) patients were thus defined by the presence of at least one of these three factors. Among them, only those with higher MRD levels defined as TP1-MRD ≥ 0.1% and/or week 12 (TP2) MRD ≥ 0.01% were considered at very high risk (VHR) and proposed allogeneic hematopoietic stem cell transplant (alloSCT) in first remission (Dhedin et al., Blood 2015). Since October 2018, all these patients were eligible to be included in the GRAALL-2014-QUEST phase 2 study to receive blinatumomab as part of consolidation and maintenance phases or as a bridge to transplant. Methods: From October 2018 to December 2020, 95 patients with high-risk Ph-negative BCP-ALL without central nervous system involvement at diagnosis and in continuous complete remission after induction and consolidation 1, were prospectively included to start blinatumomab at week 12. One patient was excluded because of T-ALL phenotype (with CD19 aberrant expression). Patients with alloSCT indication and a stem cell source received blinatumomab 28 microg/d administered by continuous intravenous infusion (cIV) until transplant. A minimum of 4 weeks blinatumomab was recommended before proceeding to transplantation. All other patients received 5 cycles of blinatumomab 28 microg/day cIV (for 28 days), during consolidation 2 and 3 and at months 1/3/5 of the maintenance phase respectively. The primary objective was disease-free survival (DFS). Secondary objectives included post-blinatumomab MRD response at TP3 (after consolidation 2 or before alloSCT), overall survival (OS), and safety. Early results are reported here. Results: Median age was 35 years old (range, 18-60). Median white blood cell count (WBC) at diagnosis was 12 G/L (range, 1-449). Oncogenetic analyses allowed classifying ALL as Ph-like (18%), KMT2A-r (17%), DUX4/ERGdel (13%), ZNF384-r (11%), low hypodiploidy/near triploidy (7%), B-other (26%) or unknown (9%). An IKZF1del was found in 37/93 (40%). A TP1-MRD ≥ 0.01% was found in 46/94 patients (49%). Final risk group was HR for 45 patients and VHR for 49 patients. Last pre-blinatumomab MRD was Conclusion. In patients wih high-risk BCP-ALL, blinatumomab added to consolidation is safe and gives promising results. A comparison to similar patients treated in the same GRAALL-2014 study before October 2018 is planned with a longer follow-up. Figure 1 Figure 1. Disclosures Boissel: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; Servier: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; CELGENE: Honoraria; JAZZ Pharma: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Delabesse: Astellas: Consultancy; Novartis: Consultancy. Dombret: Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; NOVARTIS: Research Funding; pfizer: Honoraria, Research Funding; servier: Research Funding; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Blinatumomab in frontline high-risk acute lymphoblastic leukemia
Published: 2021

24. 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

25. Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial

Author: Peter A. Ljubenkov, Mary Koestler, Florence Pasquier, Dana Hilt, Beth Ann Haynes, Renaud La Joie, Lauren Edwards, Bradley F. Boeve, Jacob Hesterman, Ira J. Goodman, Leonardo Iaccarino, Rik Vandenberghe, Catherine J. Mummery, Marco Onofrj, Sophie Auriacombe, Henry Riordan, Gerhard Koenig, Julio C. Rojas, Hans J Moebius, Adam L. Boxer, Giovanni B. Frisoni, Scott M. McGinnis, Gary Wisniewski, Ken Marek, Didier Hannequin, Murray Grossman, John C. van Swieten, Holger Patzke, Isabelle Le Ber, Baruch Harris, Barbara Borroni, University of California [San Francisco] (UCSF), University of California, Mayo Clinic [Rochester], ASST Spedali Civili of Brescia, University of Brescia, Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Pennsylvania [Philadelphia], Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Excellence Laboratory LabEx DISTALZ, University College of London [London] (UCL), University Hospitals Leuven [Leuven], Leuven Brain Institute [Leuven, Belgium] (LBI), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), 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), CHU Rouen, Normandie Université (NU), Massachusetts General Hospital, Charlestown, MA, USA, Massachusetts Alzheimer's Disease Research Center, CHU Bordeaux [Bordeaux], University 'G. d'Annunzio' of Chieti-Pescara [Chieti and Pescara, Italy], GlaxoSmithKline [King of Prussia] (GSK), University of California [San Francisco] (UC San Francisco), University of California (UC), University of Pennsylvania, Lille Neurosciences & Cognition - U 1172 (LilNCog), 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), 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), and Neurology
Subjects: Oncology, Male, Haploinsufficiency, law.invention, 0302 clinical medicine, Progranulins, Randomized controlled trial, law, Organic Chemicals, media_common, Original Investigation, 0303 health sciences, PLASMA, General Medicine, Middle Aged, CEREBROSPINAL-FLUID BIOMARKERS, DEGENERATION, 3. Good health, Online Only, Tolerability, Neurology, Frontotemporal Dementia, Female, Life Sciences & Biomedicine, Frontotemporal dementia, Adult, medicine.medical_specialty, Clinical Dementia Rating, Biological Availability, Placebo, SEQUENCE, 03 medical and health sciences, Medicine, General & Internal, Internal medicine, General & Internal Medicine, mental disorders, medicine, media_common.cataloged_instance, Humans, European union, 030304 developmental biology, Aged, Science & Technology, business.industry, MUTATIONS, Research, FRONTOTEMPORAL DEMENTIA, medicine.disease, Clinical trial, Histone Deacetylase Inhibitors, SEVERITY, Pharmacodynamics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, 030217 neurology & neurosurgery
Abstract: Key Points Question What is the safety, tolerability, pharmacodynamic, and pharmacokinetic profile of the histone deacetylase inhibitor FRM-0334 in participants with progranulin gene (GRN) haploinsufficiency? Findings In this randomized placebo-controlled clinical trial including 27 participants with GRN haploinsufficiency, FRM-0334 was safe and well tolerated; however, it failed to increase plasma progranulin and cerebrospinal fluid progranulin and failed to demonstrate dose-dependent oral bioavailability. Meaning The studied formulation of FRM-0334 should not be investigated in future clinical trials enrolling participants with GRN haploinsufficiency; this study did not fully address the potential of histone deacetylase inhibition to alter GRN expression., This randomized clinical trial investigates the pharmacokinetic and pharmacodynamic profile, tolerability, and safety of the histone deacetylase inhibitor FRM-0334 in people with progranulin gene haploinsufficiency., Importance Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. Objective To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)–positron emission tomography (PET), in individuals with GRN haploinsufficiency. Design, Setting, and Participants In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. Interventions Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. Main Outcomes and Measures Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). Results A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, –10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, –0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer’s Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = −3.6 × 10−2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, −4.9 × 10−2 to −2.2 × 10−2; P
Published: 2021

26. Therapy-related myeloid neoplasms following treatment with PARP inhibitors: new molecular insights

Author: Sylvain Garciaz, Olivier Caron, Amine Belhabri, Norbert Vey, Jacques Vargaftig, Veronique Verge, Sophie Cotteret, S. de Botton, Flore Salviat, Suzette Delaloge, Iléana Antony-Debré, Patricia Pautier, Christophe Marzac, Sarah Bertoli, Florence Pasquier, Jean-Baptiste Micol, Sabine Khalife-Hachem, Alexandra Leary, Etienne Rouleau, A Renneville, M Kfoury, Filippo Rosselli, Thomas Grinda, Christian Recher, Madalina Uzunov, Jean-Edouard Martin, Gabriel Etienne, Institut Gustave Roussy (IGR), Université Paris-Saclay, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Curie [Paris], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Léon Bérard [Lyon], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Intégrité du génome et cancers (IGC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Oncologie gynécologique, Institut Bergonié [Bordeaux], UNICANCER, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), and NUNES, Jacques A
Subjects: Myeloid, DNA Repair, Poly ADP ribose polymerase, [SDV]Life Sciences [q-bio], MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, Poly(ADP-ribose) Polymerase Inhibitors, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Text mining, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, Humans, Medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Ovarian Neoplasms, 0303 health sciences, Therapy related, business.industry, Hematology, 3. Good health, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Female, Poly(ADP-ribose) Polymerases, business
Abstract: International audience; No abstract available
Published: 2021

27. Three-year changes of cortical 18F-FDG in amnestic vs. non-amnestic sporadic early-onset Alzheimer’s disease

Author: Xavier Leclerc, Xavier Delbeuck, Adeline Rollin Sillaire, Renaud Lopes, Alice Jaillard, Franck Semah, Grégory Kuchcinski, Matthieu Vanhoutte, Rachid Fahmi, and Florence Pasquier
Subjects: Fluorodeoxyglucose, medicine.diagnostic_test, business.industry, Central nervous system, Neuropsychology, Physiology, Physical examination, General Medicine, Disease, medicine.disease, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, medicine.anatomical_structure, 030220 oncology & carcinogenesis, medicine, Biomarker (medicine), Radiology, Nuclear Medicine and imaging, Early-onset Alzheimer's disease, business, medicine.drug
Abstract: To examine and compare longitudinal changes of cortical glucose metabolism in amnestic and non-amnestic sporadic forms of early-onset Alzheimer’s disease and assess potential associations with neuropsychological performance over a 3-year period time. Eighty-two participants meeting criteria for early-onset (
Published: 2019

28. Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms

Author: Pierre Hirsch, Barbara Schmaltz-Panneau, Jean-Henri Bourhis, Caroline Deswarte, Christophe Marzac, Christine Bellanné-Chantelot, Jean-Baptiste Micol, Christine Delaunay-Darivon, Flore Sicre de Fontbrune, Hélène Guermouche, Albert Najman, William Vainchenker, Céline Lemaitre, Jean-Côme Meniane, Eolia Brissot, Florence Pasquier, Philippe Pellet, Gwendoline Leroy, François Delhommeau, Patrick R. Benusiglio, Samy Chraibi, Isabelle Plo, Olivier Caron, Pascal Fuseau, Simona Lapusan, Pascale Cony-Makhoul, Odile Bera, Chrystelle Colas, Jean Pegliasco, Graciela Rabadan Moraes, and Françoise Isnard
Subjects: 0301 basic medicine, Adult, Male, Cancer Research, Myeloid, Adolescent, DNA Copy Number Variations, Vesicular Transport Proteins, Autophagy-Related Proteins, Biology, Germline, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Gene Duplication, Gene duplication, medicine, Biomarkers, Tumor, Humans, Gene, Dominance (genetics), Aged, Retrospective Studies, Chromosomes, Human, Pair 14, Myeloproliferative Disorders, Essential thrombocythemia, Myeloid leukemia, Hematology, Middle Aged, medicine.disease, Prognosis, Repressor Proteins, Survival Rate, Haematopoiesis, Leukemia, Myeloid, Acute, 030104 developmental biology, medicine.anatomical_structure, Germ Cells, Oncology, 030220 oncology & carcinogenesis, Case-Control Studies, Myelodysplastic Syndromes, Mutation, Cancer research, Female, Disease Susceptibility, Clonal Hematopoiesis, Follow-Up Studies
Abstract: The germline predisposition associated with the autosomal dominant inheritance of the 14q32 duplication implicating ATG2B/GSKIP genes is characterized by a wide clinical spectrum of myeloid neoplasms. We analyzed 12 asymptomatic carriers and 52 patients aged 18-74 years from six families, by targeted sequencing of 41 genes commonly mutated in myeloid malignancies. We found that 75% of healthy carriers displayed early clonal hematopoiesis mainly driven by TET2 mutations. Molecular landscapes of patients revealed two distinct routes of clonal expansion and leukemogenesis. The first route is characterized by the clonal dominance of myeloproliferative neoplasms (MPN)-driver events associated with TET2 mutations in half of cases and mutations affecting splicing and/or the RAS pathway in one-third of cases, leading to the early development of MPN, mostly essential thrombocythemia, with a high risk of transformation (50% after 10 years). The second route is distinguished by the absence of MPN-driver mutations and leads to AML without prior MPN. These patients mostly harbored a genomic landscape specific to acute myeloid leukemia secondary to myelodysplastic syndrome. An unexpected result was the total absence of DNMT3A mutations in this cohort. Our results suggest that the germline duplication constitutively mimics hematopoiesis aging by favoring TET2 clonal hematopoiesis.
Published: 2021

29. Investigating the association between cancer and the risk of dementia: Results from the Memento cohort

Author: Mathieu Ceccaldi, Audrey Gabelle, Bruno Dubois, Carole Dufouil, David Wallon, Olivier Hanon, Armelle Gentric, Pierre Krolak-Salmon, Yannick Béjot, Geneviève Chêne, Olivier Godefroy, Jonviea D Chamberlain, Anaïs Rouanet, Florence Pasquier, 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Mémoire de Ressources et de Recherches (CMRR), Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Bordeaux [Bordeaux], Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), and Gestionnaire, HAL Sorbonne Université 5
Subjects: Male, medicine.medical_specialty, media_common.quotation_subject, Neuropsychological Tests, illness-death model, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, illness‐death model, 0302 clinical medicine, Developmental Neuroscience, Internal medicine, Neoplasms, Epidemiology, medicine, Dementia, Humans, cancer, Cognitive Dysfunction, selection bias, 030212 general & internal medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Mortality, Research Articles, media_common, Aged, Selection bias, business.industry, Health Policy, Hazard ratio, Cancer, Cognition, Alzheimer's disease, medicine.disease, Confidence interval, 3. Good health, Psychiatry and Mental health, Cohort, Female, epidemiology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), France, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Research Article, dementia
Abstract: International audience; IntroductionStudies on the association of cancer and risk of dementia are inconclusive due to result heterogeneity and concerns of survivor bias and unmeasured confounding.MethodsThis study uses data from the Memento cohort, a French multicenter cohort following persons with either mild or isolated cognitive complaints for a median of 5 years. Illness‐death models (IDMs) were used to estimate transition‐specific hazard ratios (HRs) and 95% confidence intervals (CIs) for incident cancer in relation to dementia from time since study entry.ResultsThe analytical sample (N = 2258) excluded 65 individuals without follow‐up information. At the end of follow‐up, 286 individuals were diagnosed with dementia, 166 with incident cancer, and 95 died. Incident cancer was associated with a reduced risk of dementia (HR = 0.58, 95% CI = 0.35‐0.97), with a corresponding E‐value of 2.84 (lower CI = 1.21).DiscussionThis study supports a protective relationship between incident cancer and dementia, encouraging further investigations to understand potential underlying mechanisms.
Published: 2021

30. Real-life experience with CPX-351 and impact on the outcome of high-risk AML patients: a multicentric French cohort

Author: Patrice Chevallier, Alexis Caulier, Gabrielle Roth-Guepin, Xavier Thomas, Pierre-Yves Dumas, Yosr Hicheri, Florence Pasquier, Sarah Bertoli, Jean-Baptiste Micol, Edmond Chiche, Thomas Cluzeau, Ramy Rahmé, Arnaud Pigneux, Magalie Joris, Patrick Auberger, Pierre Peterlin, Caroline Lejeune, Ollivier Legrand, Mohamad Mohty, Norbert Vey, Caroline Bonmati, Lionel Ades, Michael Loschi, Christian Recher, Emmanuel Raffoux, Alexis Genthon, Université Côte d'Azur - Faculté de Médecine (UCA Faculté Médecine), Université Côte d'Azur (UCA), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire, F-33000 Bordeaux, France., BMGIC, U1035 INSERM, University of Bordeaux, Bordeaux, France, Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, CHU Saint-Eloi, CHU Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service d'Hématologie, CHU Nice, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Laboratoire d'Hématologie et d'Immunologie [CHU Saint-Antoine], Hopital Saint-Louis [AP-HP] (AP-HP), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Picardie Jules Verne (UPJV), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), University of Lausanne (UNIL), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), XLIM (XLIM), Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux [Bordeaux], Institut Gustave Roussy (IGR), Université Paris-Saclay, Département d'hématologie [Gustave Roussy], Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Cancérologie Lucien Neuwirth, CHU Saint-Etienne, Université Paris Cité (UPCité), and DESSAIVRE, Louise
Subjects: Adult, Oncology, medicine.medical_specialty, Multivariate analysis, Daunorubicin, [SDV]Life Sciences [q-bio], Internal medicine, hemic and lymphatic diseases, medicine, Humans, Aged, Retrospective Studies, Response rate (survey), Myeloid Neoplasia, business.industry, Cytarabine, Myeloid leukemia, Hematology, Minimal residual disease, Transplantation, [SDV] Life Sciences [q-bio], Leukemia, Myeloid, Acute, Cohort, business, medicine.drug
Abstract: CPX-351 is a liposomal formulation of cytarabine and daunorubicin approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML). We retrospectively analyzed the efficacy and safety of CPX-351 in a real-world setting in 103 patients from 12 French centers, including the evaluation of molecular abnormalities at baseline and minimal residual disease (MRD) in responding patients, compared with a historical data set from Bordeaux-Toulouse DATAML registry. A favorable safety profile was observed, with a low frequency of alopecia (11%) and gastrointestinal toxicity (50%). The overall response rate after induction was 59%, and MRD
Published: 2021

31. Primary Progressive Aphasia Associated With GRN Mutations: New Insights Into the Nonamyloid Logopenic Variant

Author: Bruno Dubois, Audrey Gabelle, François Sellal, Jérémie Pariente, Marie Sarazin, Agnès Camuzat, Raffaella Migliaccio, Frédérique Etcharry-Bouyx, Amandine Geraudie, Sophie Ferrieux, Simona Bottani, Carole Roué-Jagot, Mira Didic, Florence Pasquier, Leila Sellami, Alexis Brice, Olivier Colliot, Fabienne Clot, Marc Teichmann, Didier Hannequin, Christel Thauvin-Robinet, Claire Boutoleau-Bretonnière, Julien Lagarde, Cinzia Coppola, David Wallon, Richard Levy, Marie Noguès-Lassiaille, Dario Saracino, Aurélie Funkiewiez, Maria Luisa Gorno-Tempini, Olivier Martinaud, Isabelle Le Ber, Marion Houot, Stéphane Epelbaum, Sophie Auriacombe, Alexandre Morin, Vincent Deramecourt, Ftd-Als, Philippe Couratier, Daisy Rinaldi, Saracino, Dario, Ferrieux, Sophie, Noguès-Lassiaille, Marie, Houot, Marion, Funkiewiez, Aurélie, Sellami, Leila, Deramecourt, Vincent, Pasquier, Florence, Couratier, Philippe, Pariente, Jérémie, Géraudie, Amandine, Epelbaum, Stéphane, Wallon, David, Hannequin, Didier, Martinaud, Olivier, Clot, Fabienne, Camuzat, Agnè, Bottani, Simona, Rinaldi, Daisy, Auriacombe, Sophie, Sarazin, Marie, Didic, Mira, Boutoleau-Bretonnière, Claire, Thauvin-Robinet, Christel, Lagarde, Julien, Roué-Jagot, Carole, Sellal, Françoi, Gabelle, Audrey, Etcharry-Bouyx, Frédérique, Morin, Alexandre, Coppola, Cinzia, Levy, Richard, Dubois, Bruno, Brice, Alexi, Colliot, Olivier, Luisa Gorno-Tempini, Maria, Teichmann, Marc, Migliaccio, Raffaella, Le Ber, Isabelle, 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), CHU Lille, CHU Limoges, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), 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), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropsychologie et imagerie de la mémoire humaine (NIMH), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Charles Foix [AP-HP], 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), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), GHU AP-HP Centre Université de Paris, Hôpitaux Civils de Colmar, Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), University of the Study of Campania Luigi Vanvitelli, University of California [San Francisco] (UC San Francisco), University of California (UC), The research leading to these results received funding from the Investissements davenir ANR-11-INBS-0011. This work was funded by the Programme Hospitalier de Recherche Clinique (PHRC) FTLD-exome (to ILB, promotion by Assistance Publique Hôpitaux de Paris), PHRC Predict-PGRN (to ILB, promotion by Assistance Publique Hôpitaux de Paris)., ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Admin, Oskar, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, 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], 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), CHU Toulouse [Toulouse], 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), 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), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of California [San Francisco] (UCSF), University of California, 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), 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), and Normandie Université (NU)-Normandie Université (NU)-École Pratique des Hautes Études (EPHE)
Subjects: Oncology, medicine.medical_specialty, Apraxia, 050105 experimental psychology, Primary progressive aphasia, 03 medical and health sciences, Dementia aphasia, 0302 clinical medicine, Atrophy, Gyrus, Aphasia, Agrammatism, Internal medicine, medicine, 0501 psychology and cognitive sciences, Prospective cohort study, business.industry, 05 social sciences, respiratory system, medicine.disease, medicine.anatomical_structure, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract: ObjectiveTo determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with GRN (progranulin) mutations and to study their neuroanatomic correlates.MethodsPatients with PPA carrying GRN mutations (PPA-GRN) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA.ResultsAmong the 235 patients with PPA, 45 (19%) carried GRN mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%).ConclusionsThis study shows that the most frequent PPA variant associated with GRN mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. GRN testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming GRN gene–specific therapies.
Published: 2021

32. Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications

Author: Fabienne Clot, Florence Pasquier, Didier Hannequin, Olivier Colliot, Armelle Rametti-Lacroux, Sophie Auriacombe, Raffaella Migliaccio, Ludmila Jornea, Marion Houot, Agnès Camuzat, Carole Azuar, Alexis Brice, Mathilde Sauvée, Philippe Martin-Hardy, Richard Levy, Philippe Couratier, Isabelle Le Ber, Jérémie Pariente, Claire Boutoleau-Bretonnière, Karim Dorgham, Dario Saracino, Bruno Dubois, Mira Didic, Daisy Rinaldi, Prev-Demals, David Wallon, Predict-PGRN study groups, Ftd-Als, Sylvie Forlani, 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), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), 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), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], 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 Lille 2 - Faculté de Médecine, CHU Limoges, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU), CIC - Nantes, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Institut de Neurosciences des Systèmes (INS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Hôpital de la Timone [CHU - APHM] (TIMONE), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), The research leading to these results received funding from the ’Investissements d’avenir’ ANR-11- INBS-0011. This work was partially funded by the Programme Hospitalier de Recherche Clinique (PHRC) Predict- PGRN (to ILB, promotion by Assistance Publique–Hôpitaux de Paris), the PHRC FTLD- exome (to ILB, promotion by Assistance Publique–Hôpitaux de Paris), by the ANR- PRTS PREV- DEMALS project (to ILB, grant number ANR-14- CE15-0016-07, promotion by Assistance Publique–Hôpitaux de Paris) and the Fondation Vaincre Alzheimer (to ILB, grant number FR-17035)., ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), 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), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Faculté de Médecine Henri Warembourg - Université de Lille, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Saracino, Dario, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées
Subjects: Oncology, 0303 health sciences, medicine.medical_specialty, business.industry, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Disease progression, Youden's J statistic, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, Therapeutic trial, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, C9orf72, Internal medicine, Medicine, Biomarker (medicine), Surgery, Neurology (clinical), Amyotrophic lateral sclerosis, business, Trial registration, 030217 neurology & neurosurgery, 030304 developmental biology, Frontotemporal dementia
Abstract: ObjectiveNeurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages.MethodsWe analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical–genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index.ResultspNfL levels increased with age in controls, from ~5 to~18 pg/mL (pGRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades.ConclusionsThis study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression.Trial registration numbersNCT02590276 and NCT04014673.
Published: 2021

33. Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes

Author: Lianne M. Reus, Bogdan Pasaniuc, Danielle Posthuma, Toni Boltz, Yolande A.L. Pijnenburg, Roel A. Ophoff, Raffaele Ferrari, Dena G. Hernandez, Michael A. Nalls, Jonathan D. Rohrer, Adaikalavan Ramasamy, John B.J. Kwok, Carol Dobson-Stone, William S. Brooks, Peter R. Schofield, Glenda M. Halliday, John R. Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Isabel Hernández, Agustín Ruiz, Mercè Boada, Barbara Borroni, Alessandro Padovani, Carlos Cruchaga, Nigel J. Cairns, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Gianluigi Forloni, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Elio Scarpini, Jordi Clarimón, Alberto Lleó, Rafael Blesa, Maria Landqvist Waldö, Karin Nilsson, Christer Nilsson, Ian R.A. Mackenzie, Ging-Yuek R. Hsiung, David M.A. Mann, Jordan Grafman, Christopher M. Morris, Johannes Attems, Timothy D. Griffiths, Ian G. McKeith, Alan J. Thomas, Pietro Pietrini, Edward D. Huey, Eric M. Wassermann, Atik Baborie, Evelyn Jaros, Michael C. Tierney, Pau Pastor, Cristina Razquin, Sara Ortega-Cubero, Elena Alonso, Robert Perneczky, Janine Diehl-Schmid, Panagiotis Alexopoulos, Alexander Kurz, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Ekaterina Rogaeva, Peter St. George-Hyslop, Giacomina Rossi, Fabrizio Tagliavini, Giorgio Giaccone, James B. Rowe, Johannes C.M. Schlachetzki, James Uphill, John Collinge, Simon Mead, Adrian Danek, Vivianna M. Van Deerlin, Murray Grossman, John Q. Trojanowski, Julie van der Zee, Christine Van Broeckhoven, Stefano F. Cappa, Isabelle Le Ber, Didier Hannequin, Véronique Golfier, Martine Vercelletto, Alexis Brice, Benedetta Nacmias, Sandro Sorbi, Silvia Bagnoli, Irene Piaceri, Jørgen E. Nielsen, Lena E. Hjermind, Matthias Riemenschneider, Manuel Mayhaus, Bernd Ibach, Gilles Gasparoni, Sabrina Pichler, Wei Gu, Martin N. Rossor, Nick C. Fox, Jason D. Warren, Maria Grazia Spillantini, Huw R. Morris, Patrizia Rizzu, Peter Heutink, Julie S. Snowden, Sara Rollinson, Anna Richardson, Alexander Gerhard, Amalia C. Bruni, Raffaele Maletta, Francesca Frangipane, Chiara Cupidi, Livia Bernardi, Maria Anfossi, Maura Gallo, Maria Elena Conidi, Nicoletta Smirne, Rosa Rademakers, Matt Baker, Dennis W. Dickson, Neill R. Graff-Radford, Ronald C. Petersen, David Knopman, Keith A. Josephs, Bradley F. Boeve, Joseph E. Parisi, William W. Seeley, Bruce L. Miller, Anna M. Karydas, Howard Rosen, John C. van Swieten, Elise G.P. Dopper, Harro Seelaar, Philip Scheltens, Giancarlo Logroscino, Rosa Capozzo, Valeria Novelli, Annibale A. Puca, Massimo Franceschi, Alfredo Postiglione, Graziella Milan, Paolo Sorrentino, Mark Kristiansen, Huei-Hsin Chiang, Caroline Graff, Florence Pasquier, Adeline Rollin, Vincent Deramecourt, Florence Lebert, Dimitrios Kapogiannis, Luigi Ferrucci, Stuart Pickering-Brown, Andrew B. Singleton, John Hardy, Parastoo Momeni, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Child and Adolescent Psychiatry / Psychology, Erasmus MC other, Neurology, Psychiatry, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), and Amsterdam Neuroscience - Neurodegeneration
Subjects: 0301 basic medicine, Candidate gene, 17q21.31 inversion region, Dorsolateral prefrontal cortex, Expression quantitative trait loci (eQTL), Frontotemporal dementia, SEC22B, Transcriptome-wide association study, Semantic dementia, Gene Expression, Locus (genetics), Biology, 03 medical and health sciences, 0302 clinical medicine, Progressive nonfluent aphasia, mental disorders, medicine, Humans, Gene, Biological Psychiatry, Genetics, nutritional and metabolic diseases, medicine.disease, Genetic architecture, nervous system diseases, 030104 developmental biology, medicine.anatomical_structure, Frontotemporal Dementia, 030217 neurology & neurosurgery
Abstract: Background: The etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach. Methods: FUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold. Results: We identified 73 significant gene–tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed. Conclusions: We identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.
Published: 2021

34. Clinical relevance of brain atrophy subtypes categorization in memory clinics

Author: Olivier Godefroy, François Tison, Yannick Béjot, Frédéric Blanc, David Wallon, Vincent Bouteloup, Clara Fischer, Marie-Odile Habert, Bruno Dubois, Mathilde Sauvée, Geneviève Chêne, Cédric Annweiler, Olivier Hanon, Vincent Planche, Carole Dufouil, J. Delrieu, Marie Chupin, Audrey Gabelle, Isabelle Jalenques, Pierre Krolak-Salmon, Matthieu Ceccaldi, Claire Paquet, Isabelle Bourdel-Marchasson, Florence Pasquier, Jean-François Mangin, Centre de résonance magnétique des systèmes biologiques (CRMSB), and Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)
Subjects: Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Epidemiology, [SDV]Life Sciences [q-bio], Ambulatory Care Facilities, Hippocampus, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Atrophy, Developmental Neuroscience, Alzheimer Disease, mental disorders, Humans, Medicine, Dementia, Cognitive decline, ComputingMilieux_MISCELLANEOUS, Aged, Memory Disorders, Lewy body, business.industry, Health Policy, Brain, Cognition, medicine.disease, Magnetic Resonance Imaging, Psychiatry and Mental health, 030104 developmental biology, Categorization, Cohort, Female, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, business, 030217 neurology & neurosurgery
Abstract: Introduction The clinical relevance of brain atrophy subtypes categorization in non-demented persons without a priori knowledge regarding their amyloid status or clinical presentation is unknown. Methods A total of 2083 outpatients with either subjective cognitive complaint or mild cognitive impairment at study entry were followed during 4 years (MEMENTO cohort). Atrophy subtypes were defined using baseline magnetic resonance imaging (MRI) and previously described algorithms. Results Typical/diffuse atrophy was associated with faster cognitive decline and the highest risk of developing dementia and Alzheimer's disease (AD) over time, both in the whole analytic sample and in amyloid-positive participants. Hippocampal-sparing and limbic-predominant atrophy were also associated with incident dementia, with faster cognitive decline in the limbic predominant atrophy group. Lewy body dementia was more frequent in the hippocampal-sparing and minimal/no atrophy groups. Discussion Atrophy subtypes categorization predicted different subsequent patterns of cognitive decline and rates of conversion to distinct etiologies of dementia in persons attending memory clinics.
Published: 2020

35. Current status and quantitative results of the AMYPAD prognostic and natural history study

Author: Juan Domingo Gispert, Pablo Martinez-Lage, Laure Saint-Aubert, Lisa Ford, Miia Kivipelto, José Luis Molinuevo, Florence Pasquier, Lyduine Collij, Philip Scheltens, Bruno Dubois, Marta Marquié, Katherine R. Gray, Julien Dumurgier, Rik Vandenberghe, Fiona Heeman, Craig W. Ritchie, Oriol Grau-Rivera, Peter Connelly, Frederik Barkhof, Michael Schöll, Giovanni B. Frisoni, Isadora Lopes Alves, Andrew W. Stephens, Bruno Vellas, Christopher Buckley, Pierre Payoux, Mercè Boada, Audrey Gabelle, Gemma Salvadó, Gill Farrar, Claire Boutoleau-Bretonnière, and Bernard Hanseeuw
Subjects: medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Disease progression, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Physical medicine and rehabilitation, Developmental Neuroscience, Neuroimaging, medicine, Neurology (clinical), Tracking (education), Geriatrics and Gerontology, business, Natural history study
Published: 2020

36. Pathways involved in the relationship between resilience and cognitive function: The Memento cohort

Author: Geneviève Chêne, Pierre Krolak Salmon, Claire Paquet, Audrey Gabelle, Florence Pasquier, Leslie Grasset, Frédéric Blanc, Cédric Annweiler, Olivier Hanon, Mathieu Ceccaldi, Carole Dufouil, Bruno Vellas, and Bruno Dubois
Subjects: Gerontology, medicine.medical_specialty, Epidemiology, Health Policy, Cognition, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Cohort, medicine, Neurology (clinical), Geriatrics and Gerontology, Resilience (network), Psychology
Published: 2020

37. Greater than the sum: Federated analyses in Alzheimer’s disease using the Human Brain Project Medical Informatics Platform (MIP)

Author: Florence Pasquier, Jean-François Démonet, Ferath Kherif, Thierry Phenix, Philippe Ryvlin, Alberto Redolfi, Jerome Chaptinel, Arseny A. Sokolov, and Melanie Leroy
Subjects: medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Developmental cognitive neuroscience, Disease, Human Brain Project, Health informatics, Clinical neurology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Neuroimaging, medicine, Medical physics, Neurology (clinical), Geriatrics and Gerontology, business, Health policy
Published: 2020

38. The impact of culture on neuropsychological performance: A global social cognition study across 12 countries

Author: Anne Botzung, Sandra Baez, Ricardo F. Allegri, Begoña Indakoetxea, Catalina Trujillo, Lucia Crivelli, Fermin Moreno, Andrea Slachevsky, Sol Fittipaldi, Leonardo Cruz de Souza, Frédéric Blanc, François Quesque, Johan S. Grisales, Gada Musa, Alberto Benussi, Olga Iakovlena, Michael Hornberger, Maxime Bertoux, María Florencia Clarens, Antoine Coutrot, Antônio Lúcio Teixeira, Galina Prianishnikova, Junhua Liang, Thomas Duning, Ismael Calandri, David Huepe, Juan F. Cardona, Lina Zhao, Myriam Barandiaran, Luciana Cassimiro, Elena Lyashenko, Nahuel Magrath, Patricia Lillo, Paulo Caramelli, Thibaud Lebouvier, Anna Morozova, Nathalie Philippi, Carol Hudon, Florence Pasquier, Nadezda Veryugina, Adolfo M. García, Maura Cosseddu, Agustín Ibáñez, Fen Wang, Emma Flanagan, Hannah Mulet‐Perreault, Millena Vieira Brandão Moura, Carolina Delgado, Lucas Sedeño, Jennifer Kemp, Alejandra Neely-Prado, Sharon Cox, Mônica Sanches Yassuda, Andreas Johnen, and Barbara Borroni
Subjects: Epidemiology, Health Policy, media_common.quotation_subject, Neuropsychology, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Social cognition, Multiculturalism, medicine, Dementia, Neurology (clinical), Geriatrics and Gerontology, Psychology, media_common, Clinical psychology
Published: 2020

39. CSF biomarkers in neuropathological Alzheimer's disease

Author: Vincent Deramecourt, Thibaud Lebouvier, Claude Alain Maurage, Florence Pasquier, and Melanie Leroy
Subjects: Pathology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Neuropathology, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Csf biomarkers, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published: 2020

40. Overview of dominantly inherited AD and top‐line DIAN‐TU results of solanezumab and gantenerumab

Author: Didier Hannequin, Jared R. Brosch, B. Joy Snider, Anna Santacruz, Anne M. Fagan, Suman Jayadev, William S. Brooks, Colin L. Masters, Erik D. Roberson, Mario Masellis, Susan Mills, Christopher H. Dyck, Florence Pasquier, Paulo Fontoura, Bruno Dubois, Monika Baudler, Lawrence S. Honig, Doug R. Galasko, James J. Lah, Peter J. Snyder, David Wallon, Geoffrey A. Kerchner, Eric McDade, Guoqiao Wang, Andrew J. Aschenbrenner, Jason Hassenstab, Roy Yaari, Ghulam M. Surti, Raquel Sánchez-Valle, Jérémie Pariente, Stephen Salloway, Carlos Cruchaga, Randall J. Bateman, Ivonne Z. Jimenez-Velazquez, Robert A. Koeppe, John C. Morris, Serge Gauthier, Clifford R. Jack, Sarah B. Berman, Alison Goate, Catherine J. Mummery, Martin R. Farlow, Karen C. Holdridge, Rachelle S. Doody, Tammie L.S. Benzinger, Scott W. Andersen, Chengjie Xiong, Ging-Yuek Robin Hsiung, Roger Clarnette, Paul Delmar, Maïté Formaglio, Mark A. Mintun, Kelley Coalier, John R. Sims, Brian A. Gordon, and David B. Clifford
Subjects: Physics, Epidemiology, Health Policy, Geometry, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Neurology (clinical), Solanezumab, Geriatrics and Gerontology, Line (text file), Gantenerumab, medicine.drug
Published: 2020

41. Association of Alzheimer's disease and amyotrophic lateral sclerosis: A series of cases and review of the literature

Author: Pierre Lozeron, Florence Pasquier, David Wallon, Vincent Deramecourt, Agathe Vrillon, Elodie Bouaziz Amar, and Claire Paquet
Subjects: medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Disease, medicine.disease, Dermatology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Amyotrophic lateral sclerosis, business, Association (psychology)
Published: 2020

42. Alzheimer's disease phenotypes misdiagnosed with frontotemporal lobar degeneration: A retrospective neuropathologic study

Author: Claude Alain Maurage, Melanie Leroy, Florence Pasquier, Simon Lecerf, Vincent Deramecourt, Florence Lebert, and Thibaud Lebouvier
Subjects: Pathology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Neuropathology, Frontotemporal lobar degeneration, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Clinical phenotype, business
Published: 2020

43. Dementia with Lewy bodies: Characteristics of the prodromal stage in a nationwide longitudinal cohort

Author: Anne Botzung, Izzie Jacques Namer, Carole Dufouil, Frédéric Blanc, Jean-François Dartigues, Catherine Martin-Hunyadi, Jean-François Mangin, Marie Chupin, Clara Fischer, Marie-Odile Habert, Paulo Loureiro de Sousa, Claire Paquet, Vincent Bouteloup, Mathieu Ceccaldi, Nathalie Philippi, Pierre Krolak Salmon, Florence Pasquier, Renaud David, David Wallon, Geneviève Chêne, Catherine Demuynck, Olivier Bousiges, Stéphane Kremer, Catherine Belin, Timothée Albasser, Olivier Moreaud, Mathilde Sauvée, Benjamin Cretin, and Audrey Gabelle
Subjects: medicine.medical_specialty, Epidemiology, Dementia with Lewy bodies, Behavioral neurology, business.industry, Health Policy, Prodromal Stage, Neuropsychiatry, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Longitudinal cohort, Psychiatry, business
Published: 2020

44. lncRNAs as a novel source of diagnostic applications for early Alzheimer’s disease and other dementia types

Author: Moira Marizzoni, Hüseyin Firat, Sabrina Danilin, Frédéric Blanc, Eloi Magnin, Jean-François Démonet, Hakan Gurvit, Bruno Dubois, Giovanni B. Frisoni, Eric Schordan, Florence Pasquier, Stéphanie Boutillier, François Sellal, Sami Ait Abbi Nazi, Jean Christophe Bier, Saliha Moussaoui, Audrey Gabelle, Catherine Mutter, Renaud David, and Adrian Ivanoiu
Subjects: Epidemiology, business.industry, Health Policy, Disease, medicine.disease, Bioinformatics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Neuroimaging, medicine, Dementia, Neurology (clinical), Geriatrics and Gerontology, business
Published: 2020

45. Solanezumab in‐depth outcomes

Author: Roger Clarnette, Ivonne Z. Jimenez-Velazquez, Ghulam M. Surti, Suman Jayadev, Anne M. Fagan, Clifford R. Jack, Peter J. Snyder, Christopher H. van Dyck, Erik D. Roberson, Guoqiao Wang, Mario Masellis, David B. Clifford, Chengjie Xiong, Randall J. Bateman, Jérémie Pariente, Tammie L.S. Benzinger, Ging-Yuek Robin Hsiung, Serge Gauthier, Rachelle S. Doody, Paul Delmar, Didier Hannequin, Doug R. Galasko, Sarah B. Berman, Florence Pasquier, Robert A. Koeppe, James J. Lah, Carlos Cruchaga, Paulo Fontoura, Alison Goate, Eric McDade, Raquel Sánchez-Valle, David Wallon, Dian‐Tu Study Team, Catherine J. Mummery, Colin L. Masters, Jared R. Brosch, Maïté Formaglio, B. Joy Snider, Susan Mills, Monika Baudler, Lawrence S. Honig, Bruno Dubois, John C. Morris, Kelley Coalier, Brian A. Gordon, Stephen Salloway, Andrew J. Aschenbrenner, Jason Hassenstab, Anna Santacruz, William S. Brooks, Geoffrey A. Kerchner, and Martin R. Farlow
Subjects: Oncology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, medicine, Neurology (clinical), Solanezumab, Geriatrics and Gerontology, business, Gantenerumab, medicine.drug
Published: 2020

46. Plasma microRNA signature in presymptomatic and symptomatic subjects with C9orf72 -associated frontotemporal dementia and amyotrophic lateral sclerosis

Author: Noémie Robil, Agnès Camuzat, Vincent Anquetil, Isabelle Le Ber, Ivan Moszer, Florence Pasquier, Philippe Couratier, Emmanuelle Becker, Ludmila Jornea, David Wallon, Olivier Colliot, Dario Saracino, Sylvie Forlani, Thomas Gareau, Daisy Rinaldi, Virgilio Kmetzsch, Pierre de la Grange, Dynamics, Logics and Inference for biological Systems and Sequences (Dyliss), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes 1 (UR1), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), 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), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), Service de Neurologie [CHU Limoges], CHU Limoges, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Rouen, Université de Lille, Département de neurologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), GenoSplice [Paris], FRONTLAB: Fonctions et dysfonctions de systèmes frontaux [ICM Paris] (FRONTlab), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-14-CE15-0016,PREV-DEMALS,Prédire pour prévenir les démences frontotemporales (DFT) et la sclérose latérale amyotrophique (SLA)(2014), ANR-11-INBS-0013,IFB (ex Renabi-IFB),Institut français de bioinformatique(2011), 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), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), 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), École pratique des hautes études (EPHE), Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), FRONTlab - Systèmes frontaux : fonctions et dysfonctions (FRONTlab), Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Kmetzsch, Virgilio, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, Appel à projets générique - Prédire pour prévenir les démences frontotemporales (DFT) et la sclérose latérale amyotrophique (SLA) - - PREV-DEMALS2014 - ANR-14-CE15-0016 - Appel à projets générique - VALID, Infrastructures - Institut français de bioinformatique - - IFB (ex Renabi-IFB)2011 - ANR-11-INBS-0013 - INBS - VALID, Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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), and 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)
Subjects: Oncology, medicine.medical_specialty, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Chromosome 9, Disease, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], C9orf72, Internal medicine, microRNA, medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Amyotrophic lateral sclerosis, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Mutation, business.industry, medicine.disease, [STAT.ML] Statistics [stat]/Machine Learning [stat.ML], Psychiatry and Mental health, Surgery, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract: ObjectiveTo identify potential biomarkers of preclinical and clinical progression in chromosome 9 open reading frame 72 gene (C9orf72)-associated disease by assessing the expression levels of plasma microRNAs (miRNAs) in C9orf72 patients and presymptomatic carriers.MethodsThe PREV-DEMALS study is a prospective study including 22 C9orf72 patients, 45 presymptomatic C9orf72 mutation carriers and 43 controls. We assessed the expression levels of 2576 miRNAs, among which 589 were above noise level, in plasma samples of all participants using RNA sequencing. The expression levels of the differentially expressed miRNAs between patients, presymptomatic carriers and controls were further used to build logistic regression classifiers.ResultsFour miRNAs were differentially expressed between patients and controls: miR-34a-5p and miR-345-5p were overexpressed, while miR-200c-3p and miR-10a-3p were underexpressed in patients. MiR-34a-5p was also overexpressed in presymptomatic carriers compared with healthy controls, suggesting that miR-34a-5p expression is deregulated in cases with C9orf72 mutation. Moreover, miR-345-5p was also overexpressed in patients compared with presymptomatic carriers, which supports the correlation of miR-345-5p expression with the progression of C9orf72-associated disease. Together, miR-200c-3p and miR-10a-3p underexpression might be associated with full-blown disease. Four presymptomatic subjects in transitional/prodromal stage, close to the disease conversion, exhibited a stronger similarity with the expression levels of patients.ConclusionsWe identified a signature of four miRNAs differentially expressed in plasma between clinical conditions that have potential to represent progression biomarkers for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. This study suggests that dysregulation of miRNAs is dynamically altered throughout neurodegenerative diseases progression, and can be detectable even long before clinical onset.Trial registration numberNCT02590276.
Published: 2020

47. Scedosporiosis/lomentosporiosis observational study (SOS): Clinical significance of Scedosporium species identification

Author: Boris Melloni, Benoit Roze, Lilia Hasseine, Jacques-Olivier Bay, Laurence Delhaes, Dominique Toubas, Gaelle Guillerm, Xavier Iriart, Thomas Similowski, Valérie Letscher-Bru, Liana Carausu, Adela Angoulvant, Eric Caumes, Marie-Elisabeth Bougnoux, Yves Leprince, Taieb Chouaki, Cécile Molucon-Chabrot, Eric Dannaoui, Hervé Dutronc, Youssef El-Samad, Florent Morio, Morgane Mourguet, Alexandre Alanio, Berengere Gruson, Pierre Cahen, Stéphane Ranque, Anne Boullié, Julie Bonhomme, Violaine Noel, Françoise Dromer, Elisabeth Chachaty, Felipe Suarez, Beate Heym, François Bissuel, Cécile Jensen, Jean-Pierre Gangneux, Emmanuelle Mouchon, Philippe Zann, Patricia Mariani, Bernard Bouteille, Véronique Leflon-Guibout, Dea Garcia-Hermoso, Anne Scemla, Stéphane Blanche, Agnes Lefort, Dorothée Raoux-Barbot, Didier Bronnimann, Olivier Lortholary, Matthieu Revest, Fanny Lanternier, Philippe Poirier, Luc Quaesaet, Marie Machouart, Françoise Botterel-Chartier, Viviane Queyrel-Moranne, Thomas Perpoint, Anne De Tinteniac, Pascale Penn, Ana Presedo, Marie Balsat, Anne Huynh, Lelia Escaut, Noémie Gadaud, Antoine Huguenin, Martine Gari-Toussaint, Sophie Brun, Jean-Marie Forel, Blandine Rammaert, Nicole Desbois, Alain Delmer, Valérie Moal, Arnaud Fekkar, Damien Hoinard, Elizabeth Rivaud, Delphine Lancement, Laurence Pougnet, Valérie Zeller, Jacques Grill, Florence Pasquier, Fabrice Larosa, Jean-François Papon, Nina Arakelyan-Laboure, Thomas Daix, Catherine Cordonnier, Nicolas Limal, Patrick Lutz, Laurence Maulin, Céline Nourrisson, Stéphane Bretagne, Françoise Uettwiller, Florence Ader, Céline Dieval, Nicolas Traversier, Sophie Bayle, Sorya Belaz, Frédéric Villega, Flore Sicre De Fontbrune, Didier Poisson, Olivier Moquet, Guillaume Martin-Blondel, Kamel Laribi, Delphine Horeau-Langlard, Gilles Nevez, Stéphanie Branger, Audrey Hessel, Philippe Herman, Jérémie Orain, Emilie Catherinot, Frédéric Mechai, Cristina Audoly, Frédéric Gabriel, Jean-François Velly, Caroline Fritz, Muriel Alvarez, Romain Guillemain, Pascal Turlure, Grégoire Leclerc, Frederic Pene, Lionel Mannone, Frédéric Grenouillet, Yoann Prevot, Louis-Jean Couderc, Isabelle Degasne, Giovanna Ingenuo, Joséphine Dorin, Florence Persat, Pierre-Marie Roger, Nathalie Brieu, David Boutoille, Pierre Frange, Nicolas Paleiron, Christophe Joubert, Laurent Hustache-Mathieu, Raoul Herbrecht, Frédéric Janvier, Lenaïg Le Clech, Cécile Gautier, Joelle Guitard, Nicolas Durrleman, Romain Guery, Stéphane De Botton, Sophie Cassaing, Marine Paul, Rachel Brault, Claire Briere-Bellier, Catherine Kauffmann-Lacroix, Nicolas Engrand, Audrey Berric, Hôpital Henri Mondor, Diane Bouvry, André Paugam, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Victor Segalen - Bordeaux 2, Université Paris Cité (UPCité), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier du Pays d'Aix, CHU Amiens-Picardie, The National Reference Center for Invasive Mycoses and Antifungals is supported in part by Santé Publique France and Institut Pasteur., Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris], and Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP]
Subjects: Adult, Male, medicine.medical_specialty, Antifungal Agents, Adolescent, LOMENTOSPORA PROLIFICANS, Lomentospora prolificans, Microbial Sensitivity Tests, Neutropenia, Scedosporium sp, Scedosporium, Young Adult, 03 medical and health sciences, Scedosporium species, Internal medicine, Humans, Medicine, Clinical significance, Child, Mycological Typing Techniques, scedosporiosis, Phylogeny, Fungemia, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Aged, Retrospective Studies, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, 030306 microbiology, business.industry, Infant, Newborn, Infant, Scedosporium apiospermum, General Medicine, Middle Aged, medicine.disease, cardiovascular localization, 3. Good health, Infectious Diseases, Child, Preschool, outcome, Female, Observational study, France, business, Invasive Fungal Infections
Abstract: International audience; Scedosporiosis/lomentosporiosis is a devastating emerging fungal infection. Our objective was to describe the clinical pattern and to analyze whether taxonomic grouping of the species involved was supported by differences in terms of clinical presentations or outcomes. We retrospectively studied cases of invasive scedosporiosis in France from 2005 through 2017 based on isolates characterized by polyphasic approach. We recorded 90 cases, mainly related to Scedosporium apiospermum (n = 48), S. boydii/S. ellipsoideum (n = 20), and Lomentospora prolificans (n = 14). One-third of infections were disseminated, with unexpectedly high rates of cerebral (41%) and cardiovascular (31%) involvement. In light of recent Scedosporium taxonomic revisions, we aimed to study the clinical significance of Scedosporium species identification and report for the first time contrasting clinical presentations between infections caused S. apiospermum, which were associated with malignancies and cutaneous involvement in disseminated infections, and infections caused by S. boydii, which were associated with solid organ transplantation, cerebral infections, fungemia, and early death. The clinical presentation of L. prolificans also differed from that of other species, involving more neutropenic patients, breakthrough infections, fungemia, and disseminated infections. Neutropenia, dissemination, and lack of antifungal prescription were all associated with 3-month mortality. Our data support the distinction between S. apiospermum and S. boydii and between L. prolificans and Scedosporium sp. Our results also underline the importance of the workup to assess dissemination, including cardiovascular system and brain. Lay Summary Scedosporiosis/lomentosporiosis is a devastating emerging fungal infection. Our objective was to describe the clinical pattern and to analyze whether taxonomic grouping of the species involved was supported by differences in terms of clinical presentations or outcomes.
Published: 2020

48. Visit-to-Visit Blood Pressure Variability Is Associated With Cognitive Decline and Incident Dementia: The S.AGES Cohort

Author: Nicolas Danchin, Bruno Falissard, Philippe Cestac, Jean-Sébastien Vidal, Matthieu Piccoli, Florence Pasquier, Gilles Berrut, Françoise Forette, Philippe Bertin, Emmanuelle Corruble, Brigitte Sallerin, Rissane Ourabah, Linda Benattar-Zibi, Michel Pinget, Laure Rouch, Geneviève Derumeaux, and Olivier Hanon
Subjects: Male, Mean arterial pressure, medicine.medical_specialty, Blood Pressure, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Cognition, Internal medicine, Internal Medicine, Medicine, Dementia, Humans, Cognitive Dysfunction, Cognitive decline, Aged, Aged, 80 and over, business.industry, Proportional hazards model, Incidence, Hazard ratio, Blood Pressure Determination, medicine.disease, Mental Status and Dementia Tests, Pulse pressure, Blood pressure, Cohort, Cardiology, Disease Progression, Female, business, 030217 neurology & neurosurgery
Abstract: To investigate the impact of visit-to-visit systolic blood pressure variability (BPV), diastolic BPV, mean arterial pressure variability, and pulse pressure variability on cognitive decline and incident dementia in noninstitutionalized patients aged ≥65 years. A total of 3319 subjects from the S.AGES (Sujets AGÉS—Aged Subjects) cohort underwent clinical examinations every 6 months during 3 years. Variability was evaluated using standard deviation (SD), coefficient of variation, average real variability, successive variation, variation independent of mean, and residual SD. Cognition was assessed using the Mini-Mental State Examination and dementia with the Diagnostic Statistical Manual of Mental Disorders. Linear mixed models and Cox proportional hazards models were used. Higher systolic BPV was associated with poorer cognition independently of baseline SBP: adjusted 1-SD increase of coefficient of variation: β (SE)=−0.12 (0.06), P =0.04. Similar results were observed for diastolic BPV and mean arterial pressure variability: β (SE)=−0.20 (0.06), P P =0.02). Among the 3319 subjects, 93 (2.8%) developed dementia. Higher systolic BPV was associated with greater dementia risk (adjusted 1-SD increase of coefficient of variation: hazard ratios=1.23 [95% CI, 1.01–1.50], P =0.04). Similar results were found for diastolic BPV and mean arterial pressure variability ( P
Published: 2020

49. Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

Author: Manuel Mayhaus, Sandro Sorbi, Peter R. Schofield, A. Rollin, A. Karydas, Alessandro Padovani, Gilles Gasparoni, Peter St George-Hyslop, Carol Dobson-Stone, Stefano F. Cappa, D. S. Knopman, John Hardy, John R. Hodges, Graziella Milan, Florence Pasquier, Christopher Morris, Edward D. Huey, Marc Cruts, Y.A.L. Pijnenburg, R. C. Petersen, Elisa Rubino, P. Scheltens, Vincent Deramecourt, Neil Graff-Radford, Elio Scarpini, Ting Wang, Panagiotis Alexopoulos, Peter Heutink, Lena E. Hjermind, AB Singleton, Jordan Grafman, Elizabeth Thompson, Adrian Danek, Pietro Pietrini, Raffaele Ferrari, Innocenzo Rainero, C. Van Broeckhoven, Rosa Capozzo, Adaikalavan Ramasamy, J. van der Zee, Eric M. Wassermann, Karin Nilsson, Ging-Yuek Robin Hsiung, J. C. van Swieten, Ping Zeng, Rosa Rademakers, Siro Bagnoli, Amalia C. Bruni, Anna Richardson, Dimitrios Kapogiannis, Ian R. A. Mackenzie, Martin N. Rossor, Bruce L. Miller, Roberta Ghidoni, Raffaele Maletta, Massimo Franceschi, Rafael Blesa, Vivianna M. Van Deerlin, Christer Nilsson, Glenda M. Halliday, Jordi Clarimón, John Q. Trojanowski, Michael Tierney, Valeria Novelli, Agustín Ruiz, Didier Hannequin, Giorgio Giaccone, Elise G.P. Dopper, Nicoletta Smirne, F Tagliavini, I. Leber, Julie S. Snowden, Sara Rollinson, Alexis Brice, Ian G. McKeith, John E. Nielsen, Paolo Sorrentino, Véronique Golfier, Maura Gallo, Lauren Bartley, B. F. Boeve, Giancarlo Logroscino, Elena Alonso, Lorenzo Pinessi, Matt Baker, Nigel J. Cairns, Matthias Riemenschneider, William S. Brooks, Alexander Gerhard, Mark Kristiansen, Eric Haan, Israel Hernandez, Ekaterina Rogaeva, Jason D. Warren, Thibaud Lebouvier, Nick C. Fox, Stuart Pickering-Brown, Giacomina Rossi, Carlos Cruchaga, G. Binetti, Maria Landqvist Waldö, William W. Seeley, Jonathan D. Rohrer, Keith A. Josephs, Diego Albani, Wei Gu, Huei-Hsin Chiang, Luigi Ferrucci, H. Zhao, Howie Rosen, Pau Pastor, Alfredo Postiglione, Evelyn Jaros, Livia Bernardi, Dena G. Hernandez, Alberto Lleó, James B. Rowe, Parastoo Momeni, Maria Serpente, Huw R. Morris, Timothy D. Griffiths, Maria Grazia Spillantini, Alan J. Thomas, Maria Elena Conidi, M. Anfossi, Sabrina Pichler, Martine Vercelletto, Murray Grossman, Johannes C. M. Schlachetzki, Gianluigi Forloni, Dennis W. Dickson, Chiara Fenoglio, Olivier Piguet, John B.J. Kwok, Benedetta Nacmias, Harro Seelaar, Robert Perneczky, A. Baborie, Patrizia Rizzu, Y. Gao, Simon Mead, Janine Diehl-Schmid, Sara Ortega-Cubero, Mike A. Nalls, Daniela Galimberti, Annibale Alessandro Puca, Cristina Razquin, Mercè Boada, Johannes Attems, Luisa Benussi, Chiara Cupidi, Irene Piaceri, Xinghao Yu, Joseph E. Parisi, Alexander Kurz, John Collinge, James Uphill, Barbara Borroni, Francesca Frangipane, Caroline Graff, Bernd Ibach, D. M. A. Mann, Amsterdam Neuroscience - Neurodegeneration, Human genetics, Neurology, Apollo - University of Cambridge Repository, and Int FTD-Genomics Consortium IFGC
Subjects: 0301 basic medicine, Oncology, lcsh:Medicine, Genome-wide association study, Neurodegenerative, 631/208, 0302 clinical medicine, Leukocytes, Odds Ratio, 2.1 Biological and endogenous factors, Aetiology, Amyotrophic lateral sclerosis, lcsh:Science, Telomerase, Telomere Shortening, education.field_of_study, Multidisciplinary, 692/617, article, Mendelian Randomization Analysis, Amyotrophic Lateral Sclerosis, Asian Continental Ancestry Group, Cholesterol, European Continental Ancestry Group, Genome-Wide Association Study, Humans, Lipoproteins, LDL, Polymorphism, Single Nucleotide, Proportional Hazards Models, Telomere, Frontotemporal Dementia, Single Nucleotide, Neurology, Engineering sciences. Technology, 692/499, medicine.medical_specialty, Lipoproteins, 692/308, Population, White People, LDL, Mendelian randomization (MR) , leukocyte telomere length (LTL) , amyotrophic lateral sclerosis (ALS), 03 medical and health sciences, Medical research, Rare Diseases, Asian People, Internal medicine, Mendelian randomization, Genetics, medicine, Polymorphism, education, Genetic association, business.industry, Proportional hazards model, International FTD-Genomics Consortium, lcsh:R, Neurosciences, Odds ratio, medicine.disease, Computational biology and bioinformatics, Brain Disorders, 030104 developmental biology, Risk factors, lcsh:Q, 631/114, ALS, business, ddc:600, 030217 neurology & neurosurgery
Abstract: Funder: QingLan Research Project of Jiangsu for Outstanding Young Teachers, Funder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical University, Funder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical University, We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.
Published: 2020

50. The Influence of Baseline Alzheimer's Disease Severity on Cognitive Decline and CSF Biomarkers in the NILVAD Trial

Author: Marcel G. M. Olde Rikkert, Michael Mullan, Ghania Ait-Ghezala, Daniel Paris, Laila Abdullah, Kaj Blennow, Florence Pasquier, Magda Tsolaki, Fiona Crawford, Suzanne Hendrix, Anders Wallin, Anne Börjesson-Hanson, Sean Kennelly, and Brian A. Lawlor
Subjects: 0301 basic medicine, medicine.medical_specialty, mild Alzheimer's disease, Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1], Clinical Dementia Rating, Placebo, lcsh:RC346-429, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, cerebrospinal fluid Aβ42/Aβ40 ratios, Internal medicine, mental disorders, medicine, Neurogranin, Cognitive decline, lcsh:Neurology. Diseases of the nervous system, Original Research, business.industry, Confounding, nilvadipine, exploratory analysis, cognitive decline, Nilvadipine, 3. Good health, Clinical trial, 030104 developmental biology, Neurology, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Contains fulltext : 220566.pdf (Publisher’s version ) (Open Access) We examined the effects of a dihydropyridine calcium channel blocker nilvadipine with anti-inflammatory properties on cognition and cerebrospinal fluid (CSF) biomarkers by baseline Alzheimer's disease (AD) severity. Exploratory analyses were performed on the dataset (n = 497) of a phase III randomized placebo-controlled trial to examine the response to nilvadipine in AD subjects stratified by baseline AD severity into very mild (MMSE >/= 25), mild (MMSE 20-24) and moderate AD (MMSE < 20). The outcome measures included total and subscale scores of the Alzheimer's Disease Assessment Scale Cognitive 12 (ADAS-Cog 12), the Clinical Dementia Rating Scale sum of boxes (CDR-sb) and the AD composite score (ADCOMS). Cerebrospinal fluid biomarkers Abeta38, Abeta40, Abeta42, neurofilament light chain (NFL), neurogranin, YKL-40, total tau and P181 tau (ptau) were measured in a subset of samples (n = 55). Regression analyses were adjusted for confounders to specifically examine the influence of nilvadipine and baseline AD severity on cognitive outcomes over 78-weeks. Compared to their respective placebo-controls, nilvadipine-treated, very mild AD subjects showed less decline, whereas moderate AD subjects showed a greater cognitive decline on the ADAS-Cog 12 test and the ADCOMS. A lower decline was observed after nilvadipine treatment for a composite memory trait in very mild AD subjects and a composite language trait in mild AD subjects. Cerebrospinal fluid Abeta42/Abeta40 ratios were increased in mild AD and decreased in moderate AD patients treated with nilvadipine, compared to their respective controls. Among moderate AD subjects, levels of ptau, total tau, neurogranin and YKL-40 increased in subjects treated with nilvadipine compared to placebo. These studies suggest that baseline AD severity influenced the treatment outcome in the NILVAD trial and that future clinical trials of nilvadipine should be restricted to mild and very mild AD patients. Trial Registration: NCT02017340 Registered 20 December 2013, https://clinicaltrials.gov/ct2/show/NCT02017340 EUDRACT Reference Number 2012-002764-27 Registered 04 February 2013, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-002764-27.
Published: 2020

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