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52. 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
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54. Recurrence of an early postzygotic rescue of an inherited unbalanced translocation resulting in mosaic segmental uniparental isodisomy of chromosome 11q in siblings

Author

Alice Goldenberg, Gaël Nicolas, Maud Blanluet, Sandra Chantot-Bastaraud, Gabriella Vera, Boris Keren, Géraldine Joly-Helas, Thierry Frebourg, Didier Hannequin, Jean-Pierre Siffroi, Kévin Cassinari, Nathalie Le Meur, Bertrand Mace, Pascal Chambon, Couvet, Sandrine, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UF de Génétique chromosomique [CHU Trousseau], CHU Trousseau [APHP], Service de Génétique médicale [CHU Pitié-Salpêtrière], and CHU Pitié-Salpêtrière [AP-HP]

Subjects
MESH: Abnormalities, Multiple, MESH: Chromosome Deletion, [SDV]Life Sciences [q-bio], MESH: Chromosomes, Human, Pair 2, Chromosomal translocation, Chromosomal rearrangement, postzygotic, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, MESH: Cervical Vertebrae, Germline, MESH: Intellectual Disability, MESH: Uniparental Disomy, Gene duplication, Genetics, medicine, MESH: In Situ Hybridization, Fluorescence, Genetics (clinical), MESH: Humans, medicine.diagnostic_test, MESH: Genetic Predisposition to Disease, MESH: Scoliosis, Chromosome, Karyotype, MESH: Male, MESH: Translocation, Genetic, MESH: Siblings, [SDV] Life Sciences [q-bio], MESH: Karyotyping, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Uniparental Isodisomy, rescue, unbalanced translocation, MESH: Chromosome Banding, MESH: Chromosomes, mosaic, MESH: Mosaicism, MESH: Kyphosis, MESH: Chromosomes, Human, Pair 11, MESH: Female, Fluorescence in situ hybridization
Abstract

Balanced translocations are associated with a risk of transmission of unbalanced chromosomal rearrangements in the offspring. Such inherited chromosomal abnormalities are typically non-mosaic as they are present in the germline. We report the recurrence in two siblings of a mosaicism for a chromosomal rearrangement inherited from their asymptomatic father who carried a balanced t(2;11)(q35;q25) translocation. Both siblings exhibited a similar phenotype including intellectual disability, dysmorphic features, kyphoscoliosis, and cervical spinal stenosis. Karyotyping, fluorescence in situ hybridization and SNP array analysis of blood lymphocytes of both siblings identified two cell lines: one carrying a 2q35q37.3 duplication and a 11q25qter deletion (~90% cells), and one carrying an 11q uniparental isodisomy of maternal origin (~10% cells). We hypothesize that these mosaics were related to a postzygotic rescue mechanism which unexpectedly recurred in both siblings.

Published
2021
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57. Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes

Author

Schramm, Catherine, Charbonnier, Camille, Zaréa, Aline, Lacour, Morgane, Wallon, David, Boland, Anne, Deleuze, Jean-François, Olaso, Robert, Alarcon, Flora, Campion, Dominique, Nuel, Grégory, Nicolas, Gaël, Collaborators Daniela Andriuta, Pierre, Anthony, Sophie, Auriacombe, Anna-Chloé, Balageas, Guillaume, Ballan, Mélanie, Barbay, Emilie, Beaufils, Yannick, Béjot, Serge, Belliard, Marie, Benaiteau, Karim, Bennys, Frédéric, Blanc, Stéphanie, Bombois, Claire Boutoleau Bretonnière, Pierre, Branger, Jasmine, Carlier, Leslie, Cartz-Piver, Pascaline, Cassagnaud, Giovanni, Castelnovo, Christine, Champion, Annabelle, Chaussenot, Mathieu, Ceccaldi, Valérie, Chauviré, Yaohua, Chen, Julien, Cogez, Emmanuel, Cognat, Fabienne, Contegal-Callier, Lea, Corneille, Philippe, Couratier, Hélène, Courtemanche, Benjamin, Cretin, Charlotte, Crinquette, Bernard, Croisille, Benjamin, Dauriat, Sophie, Dautricourt, Vincent de la Sayette, Astrid De Liège, Marie De Verdal, Didier, Deffond, Benoit, Delpont, Florence, Demurger, Vincent, Deramecourt, Céline, Derollez, Mira, Didic, Giulia, Diemert, Elsa, Dionet, Philippe, Diraison, Aude, Doan, Martine Doco Fenzy, Boris, Dufournet, Julien, Dumurgier, Hélène, Durand, Anas, Dutray, Frédérique, Etcharry-Bouyx, Maté, Formaglio, Audrey, Gabelle, Anne, Gainche-Salmon, Jean-Claude, Getenet, Emmanuelle, Ginglinger, Olivier, Godefroy, Mathilde, Graber, Chloé, Gregoire, Stephan, Grimaldi, Julien, Gueniat, Claude, Gueriot, Sophie, Haffen, Lorraine, Hamelin, Didier, Hannequin, Cezara, Hanta, Clémence, Hardy, Geoffroy, Hautecloque, Camille, Heitz, Claire, Hourregue, Thérèse, Jonveaux, Snejana, Jurici, Catia, Khoumri, Lejla, Koric, Pierre, Krolak-Salmon, Pierre, Labauge, Morgane, Lacour, Julien, Lagarde, Hélène-Marie, Lanoiselée, Brice, Laurens, Isabelle Le Ber, Gwenaël Le Guyader, Amélie, Leblanc, Thibaud, Lebouvier, Anas, Lippi, Marie-Anne, Mackowiak, Eloi, Magnin, Cecilia, Marelli, Olivier, Martinaud, Aurélien, Maureille, Emilie, Milongo-Rigal, Sophie, Mohr, Hélène, Mollion, Olivier, Moreaud, Alexandre, Morin, Gaël, Nicolas, Julia, Nivelle, Camille, Noiray, Elisabeth, Ollagnon-Roman, Claire, Paquet, Jérémie, Pariente, Florence, Pasquier, Alexandre, Perron, Nathalie, Philippi, Virginie, Pichon, Vincent, Planche, Céline, Poirsier, Marie, Rafiq, Pauline, Rod-Olivieri, Adeline, Rollin-Sillaire, Carole, Roué-Jagot, Dario, Saracino, Marie, Sarazin, Mathilde, Sauvée, François, Sellal, Lila Sirven Villaros, Christel, Thauvin, Camille, Tisserand, Christophe, Tomasino, Cédric, Turpinat, Laurène Van Damme, Olivier, Vercruysse, Alice, Voilly, Nathalie, Wagemann, David, Wallon, Aline, Zarea, Shahzad, Ahmad, Philippe, Amouyel, Claudine, Berr, Anne, Boland, Paola, Bossu, Femke, Bouwman, Jose, Bras, Dominique, Campion, Camille, Charbonnier, Jordi, Clarimon, Antonio, Daniele, Jean-François, Dartigues, Stéphanie, Debette, Jean-François, Deleuze, Nicola, Denning, Oriol, Dols-Icardo, Nick, C Fox, Daniela, Galimberti, Emmanuelle, Génin, Hans, Gille, Benjamin, Grenier-Boley, Detelina, Grozeva, Rita, Guerreiro, John, J Hardy, Clive, Holmes, Henne, Holstege, Marc, Hulsman, Holger, Hummerich, M Arfan Ikram, M Kamran Ikram, Iris, Jansen, Amit, Kawalia, Robert, Kraaij, Jean-Charles, Lambert, Marc, Lathrop, Afina, W Lemstra, Alberto, Lleo, Lauren, Luckcuck, Marcel M A, M Mannens, Rachel, Marshall, Carlo, Masullo, Simon, Mead, Mecocci, Patrizia, Alun, Meggy, Merel, O Mol, Kevin, Morgan, Benedetta, Nacmias, Penny, J Norsworthy, Pau, Pastor, Olivier, Quenez, Alfredo, Ramirez, Rachel, Raybould, Richard, Redon, Marcel J, T Reinders, Anne-Claire, Richard, Steffi, G Riedel-Heller, Fernando, Rivadeneira, Stéphane, Rousseau, Natalie, S Ryan, Salha, Saad, Pascual, Sanchez-Juan, Philip, Scheltens, Jonathan, M Schott, Davide, Seripa, Daoud, Sie, Rebecca, Sims, Erik, Sistermans, Sandro, Sorbi, Resie van Spaendonk, Gianfranco, Spalleta, Nicćolo, Tesi, Betty, Tijms, André, G Uitterlinden, Wiesje, M van der Flier, Sven, J van der Lee, Cornelia, M van Duijn, Jeroen G, J van Rooij, John, C van Swieten, Pieter, J de Visser, Michael, Wagner, and Julie, Williams

Subjects
Genotype, Membrane Transport Proteins, Penetrance, Lifetime risk, Pedigree, Expectation-maximization algorithm, Settore MED/26 - NEUROLOGIA, Apolipoproteins E, Missing genotypes, Alzheimer Disease, Case-Control Studies, SORL1, Alzheimer, Genetics, Humans, Molecular Medicine, Molecular Biology, LDL-Receptor Related Proteins, APOE, Genetics (clinical)
Abstract

Background Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE-ε4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1-LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1-LoF variants, stratified by APOE-ε4, derived from the Rotterdam study (N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1-LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE-ε4-stratified SORL1-LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1-LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE-ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1-LoF variant carriers in case-control study data. Conclusions We conclude that SORL1-LoF variants should be interpreted in light of APOE genotypes for future clinical applications.

Published
2022
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58. La contrebande d'armes à feu au Canada : influence et contrôle sous une perspective transnationale

Author

Hannequin-Bouchard, Catherine and Côté-Boucher, Karine

Subjects
Firearms, Organized crime, Border security, Crime organisé, Contrôle, Armes à feu, Smuggling, Control, Sécurité frontalière, Contrebande, Criminalité transnationale, Transnational crime
Abstract

La prolifération des armes à feu illégales en territoire canadien a un impact sur l’augmentation de la violence armée observée au cours des dernières années. La mobilité des armes illégales au Canada a été étudiée par des chercheurs. Toutefois, le sujet des sources alimentant ce marché illicite n’a été que très peu abordé au sein de la littérature scientifique. L’une des possibilités reliées à cette thématique présente les États-Unis comme source d’approvisionnement en armes à feu illégales au Canada. C’est à travers cette idée que s’inscrit l’objectif principal de ce mémoire. En effet, cette étude vise une recontextualisation de la problématique du trafic d’armes à feu au Canada en tant qu’enjeu sécuritaire transnational selon le postulat identifiant les États-Unis comme la principale source d’alimentation du marché noir des armes à feu au Canada. Afin de répondre à cet objectif, nous décrivons d’abord l’environnement au travers duquel s’articulent les dynamiques de contrebande d’armes à feu au Canada. Ensuite, nous portons notre regard sur la réponse institutionnelle reliée au contrôle et à la lutte contre le trafic transfrontalier d’armes à feu. Une méthodologie qualitative basée sur l’analyse d’entretiens semi-dirigés avec des acteurs impliqués au sein d’organisations d’application de la loi, de rapports et de documents gouvernementaux ainsi que de documentation juridique a été utilisée dans le cadre de cette étude. Les résultats découlant des analyses présentées dans ce mémoire permettent tout d’abord de contextualiser l’enjeu de la contrebande transfrontalière d’armes à feu entre les États-Unis et les Canada ainsi que les efforts des organisations d’application de la loi en matière de contrôle. Ils permettent également de mettre en lumière les disparités existantes entre la nécessité d’une utilisation efficiente du renseignement et la réalité sur le terrain. En effet, les lacunes quant à la collecte et à l’analyse des données reliées à la contrebande transfrontalière d’armes à feu ont un impact sur le ciblage et l’orientation des mesures visant à lutter contre cet enjeu., The proliferation of illegal firearms on Canadian soil has had an impact on the increase in gun violence observed in recent years. The mobility of illegal firearms in Canada has been studied by researchers. However, the topic of the sources of this illicit market has received very little attention in the scientific literature. One of the possibilities related to this theme presents the United States as a source of supply of illegal firearms in Canada. It is through this idea that the main objective of this thesis lies. Indeed, this study aims to recontextualize the problem of firearms trafficking in Canada as a transnational security issue based on the premise that the United States is the main source of supply for the black market in firearms in Canada. More specifically, in such a context, firearms would be brought into Canada through cross-border smuggling. First, we define the environment through which the dynamics of firearms smuggling in Canada are articulated. Secondly, we examine the institutional response to controlling and combating cross-border firearms trafficking. A qualitative methodology based on the analysis of semi-structured interviews with actors involved in law enforcement organizations, government reports and documents, and legal documentation was used in this study. The results of the analyses presented in this paper first contextualize the issue of cross-border firearms smuggling between the United States and Canada and the control efforts of law enforcement agencies. They also highlight the disparities between the need for efficient use of intelligence and the reality of the operational environment. Gaps in data collection and analysis related to crossborder firearms smuggling have an impact on the targeting and direction of measures to combat this issue.

Published
2022

59. Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimerʼs and Parkinsonʼs diseases

Author

Ferrari, Raffaele, Wang, Yunpeng, Vandrovcova, Jana, Guelfi, Sebastian, Witeolar, Aree, Karch, Celeste M, Schork, Andrew J, Fan, Chun C, Brewer, James B, Momeni, Parastoo, Schellenberg, Gerard D, Dillon, William P, Sugrue, Leo P, Hess, Christopher P, Yokoyama, Jennifer S, Bonham, Luke W, Rabinovici, Gil D, Miller, Bruce L, Andreassen, Ole A, Dale, Anders M, Hardy, John, Desikan, Rahul S, Hernandez, D G, Nalls, M A, Rohrer, J D, Ramasamy, A, Kwok, J B J, Dobson-Stone, C, Schofield, P R, Halliday, G M, Hodges, J R, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, N J, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, K, Nilsson, C, Mackenzie, I R A, Hsiung, G-Y R, Mann, D M A, Grafman, J, Morris, C M, Attems, J, Griffiths, T D, McKeith, I G, Thomas, A J, Pietrini, P, Huey, E D, Wassermann, E M, Baborie, A, Jaros, E, Tierney, M C, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, J B, Schlachetzki, J C M, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, V M, Grossman, M, Trojanowski, J Q, van der Zee, J, Cruts, M, Van Broeckhoven, C, Cappa, S F, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, J E, Hjermind, L E, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, M N, Fox, N C, Warren, J D, Spillantini, M G, Morris, H R, Rizzu, P, Heutink, P, Snowden, J S, Rollinson, S, Richardson, A, Gerhard, A, Bruni, A C, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, M E, Smirne, N, Rademakers, R, Baker, M, Dickson, D W, Graff-Radford, N R, Petersen, R C, Knopman, D, Josephs, K A, Boeve, B F, Parisi, J E, Seeley, W W, Karydas, A M, Rosen, H, van Swieten, J C, Dopper, E G P, Seelaar, H, Pijnenburg, Y A L, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, A A, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, H-H, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, and Singleton, A B

Published
2017
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64. Clinical follow-up of corticotomy-accelerated Invisalign orthodontic treatment with Dental Monitoring

Author

Nathan Moreau, Emmanuel Racy, Ronan Hannequin, and Elea Ouadi

Subjects
Orthodontics, Class iii malocclusion, business.industry, Treatment options, Sagittal split osteotomy, 030206 dentistry, Smartphone application, 03 medical and health sciences, 0302 clinical medicine, Tooth movement, Medicine, business, 030217 neurology & neurosurgery, Corticotomy
Abstract

The demand for fast and invisible treatment options for adults has grown. Treatment protocols involving clear aligners in association with alveolar corticotomy have been developed in response to this demand. Alveolar corticotomy surgery can accelerate orthodontic tooth movement, but good clinical follow-up is crucial and can become cumbersome as the frequency of aligner changes accelerates. Clinical monitoring with patient-managed software can be of assistance in such cases. We present the ortho-surgical treatment of a healthy 21-year-old woman with Class III malocclusion who was treated with corticotomy-accelerated presurgical decompensation and clear aligners, followed by mandibular sagittal split osteotomy. Alveolar corticotomy surgery was performed and the aligners were changed every 4 days. Clinical follow-up of aligner-mediated tooth movement was managed with a patient-managed smartphone application, allowing early interception and correction of minute orthodontic movement errors. Such errors would have been difficult to detect considering the rapidity of aligner change when accelerated by alveolar corticotomy. Clinical follow-up with a patient-managed smartphone application could thus allow for better and easier management of corticotomy-accelerated clear aligner orthodontic treatment.

Published
2020
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65. The Short and Fast Step Test: A functional tool to assess anaerobic metabolism in rehabilitated coronary patients

Author

D. Besson, Jean-Marie Casillas, Aurélie Gudjoncik, A. Hannequin, Anaïs Gouteron, and Davy Laroche

Subjects
Male, medicine.medical_specialty, Psychometrics, Oxygen debt, Oxygen Consumption, Internal medicine, Humans, Medicine, Orthopedics and Sports Medicine, Anaerobiosis, Cardiac Rehabilitation, Exercise Tolerance, business.industry, Rehabilitation, Middle Aged, Exercise Therapy, Patient Outcome Assessment, Treatment Outcome, Cardiovascular Diseases, Exercise Test, Step test, Cardiology, Feasibility Studies, Female, business, Anaerobic exercise
Published
2020
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66. FDG PET and CT radiomics in diagnosis and prognosis of non-small-cell lung cancer

Author

Pascal Hannequin, Chantal Decroisette, Pascale Kermanach, Giulia Berardi, and Vincent Bourbonne

Subjects
Oncology
Abstract

Our patients were retrospectively considered. They all had a FDG PET-CT and immuno-histo-chemistry (IHC) to assess PD-L1 expression at the beginning of the disease. A prognosis univariate and multivariate Cox survival analyses was performed for overall survival (OS) and progression free survival (PFS) prediction, including a training/testing procedure. Two sets of 47 PET and 47 CT radiomics features (RFs) were extracted. Difference between RFs according to PD-L1 expression, the histology status and the stage level were tested using suited non parametric statistical tests and the receiver operating characteristics (ROC) curve and the area under curve (AUC).From 2017 to 2019, 212 NSCLC patients treated in our institution were included. The main conventional prognostic variables were stage and gender with a low added prognostic value in the models including PET and CT RFs. Neither PET nor CT RFs were significant to separate the different levels of PD-L1 expression. Several RFs differ between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) tumours and a large number of PET and CT RFs are significantly linked to patient stage.In our population, PET and CT RFs show their intrinsic power to predict survival but do not significantly improve OS and PFS prediction in the different multivariate models, in comparison to conventional data. It would seem necessary to carry out one's own survival analysis before determining a radiomics signature.

Published
2022

67. Exploring Links Between Psychosis and Frontotemporal Dementia Using Multimodal Machine Learning: Dementia Praecox Revisited

Author

Koutsouleris, Nikolaos, Pantelis, Christos, Kambeitz, Joseph, Toivonen, Anna, Turtonen, Otto, Botterweck, Sonja, Kluthausen, Norman, Antoch, Gerald, Caspers, Julian, Wittsack, Hans-Jörg, Blasi, Giuseppe, Pergola, Giulio, Caforio, Grazia, Salokangas, Raimo K R, Fazio, Leonardo, Quarto, Tiziana, Gelao, Barbara, Romano, Raffaella, Andriola, Ileana, Falsetti, Andrea, Barone, Marina, Passiatore, Roberta, Sangiuliano, Marina, Surmann, Marian, Hietala, Jarmo, Bienek, Olga, Dannlowski, Udo, Solana, Ana Beatriz, Abraham, Manuela, Schirmer, Timo, Ferro, Adele, Re, Marta, Sberna, Maurizio, D'Agostino, Armando, Del Fabro, Lorenzo, Bertolino, Alessandro, Perna, Giampaolo, Nobile, Maria, Balestrieri, Matteo, Bonivento, Carolina, Cabras, Giuseppe, Fabbro, Franco, Delvecchio, Giuseppe, Maggioni, Eleonora, Squarcina, Letizia, Gritti, Davide, Brambilla, Paolo, Rossetti, Maria Gloria, Ferrari, Raffaele, Hernandez, Dena Michelle Godwin, Nalls, Michael, Rohrer, Jonathan, Ramasamy, Adaikalavan, Kwok, John, Dobson-Stone, Carol, Brooks, William, Schofield, Peter, Upthegrove, Rachel, Halliday, Glenda, Hodges, John, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Wood, Stephen J, Cruchaga, Carlos, Cairns, Nigel, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Lencer, Rebekka, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Landqvist Waldö, Maria, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R.A., Hsiung, Ging-Yuek, Mann, David, Borgwardt, Stefan, Grafman, Jordan, Morris, Christopher, Attems, Johannes, McKeith, Ian, Thomas, Alan, Pietrini, Pietro, Huey, Edward, Wassermann, Eric, Baborie, Atik, Jaros, Evelyn, Maj, Carlo, Tierney, Michael, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Velakoulis, Dennis, Nöthen, Markus M., Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James, Schlachetzki, Johannes, Uphill, James, Collinge, John, Degenhardt, Franziska, Mead, Simon, Van Deerlin, Vivianna, Marschhauser, Anke, Regenbrecht, Frank, Thoene-Otto, Angelika, Gordulla, Jannis, Ballarini, Tommaso, Engel, Annerose, Pino, Daniele, Leuthold, Dominique, Polyakova, Maryna, Naumann, Heike, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Van Broeckhofen, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Mueller, Karsten, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Villringer, Arno, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N, Fox, Nick C, Warren, Jason D, Spillantini, Maria Grazia, Morris, Huw R, Rizzu, Patrizia, Heutink, Peter, Danek, Adrian, Snowden, Julie S, Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C, Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Fassbender, Klaus, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W, Graff-Radford, Neill R, Petersen, Ronald C, Knopman, David S, Josephs, Keith A, Fliessbach, Klaus, Boeve, Bradley F, Parisi, Joseph E, Seeley, William W, Miller, Bruce L, Karydas, Anna M, Rosen, Howard, van Swieten, John C, Dopper, Elise Gp, Seelaar, Harro, Pijnenburg, Yolande Al, Jahn, Holger, Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A, Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Kornhuber, Johannes, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B, McGuire, Philip, Landwehrmeyer, Bernhard, Hardy, John, Momeni, Parastoo, Barthel, Henryk, Elisa, Semler, Jolina, Lombardi, Christine, von Arnim, Felix, Oberahauser, Kai, Schumacher, Jan, Lehmbeck, Juan-Manuel, Maler, Anderl-Straub, Sarah, Tanja, Richter-Schmidinger, Anke, Hammer-Kaspereit, Timo, Oberstein, Felix, Müller-Sarnowski, Carola, Roßmeier, Albert, Ludolph, Jan, Kassubek, Anja, Schneider, Johannes, Levin, Prudlo, Johannes, Synofzik, Matthis, Wiltfang, Jens, Riedl, Lina, Diehl-Schmid, Janine, Otto, Markus, Meisenzahl, Eva, Falkai, Peter, Dwyer, Dominic B, Schroeter, Matthias L, Consortium, the PRONIA, Haas, Shalaila, Hasan, Alkomiet, Hoff, Claudius, Khanyaree, Ifrah, Melo, Aylin, Muckenhuber-Sternbauer, Susanna, Köhler, Yanis, Urquijo-Castro, Maria-Fernanda, Öztürk, Ömer, Penzel, Nora, Rangnick, Adrian, von Saldern, Sebastian, Spangemacher, Moritz, Tupac, Ana, Weiske, Johanna, Wosgien, Antonia, Krämer, Camilla, Blume, Karsten, Paul, Riya, Hedderich, Dennis, Julkowski, Dominika, Kaiser, Nathalie, Lichtenstein, Thorsten, Milz, Ruth, Nikolaides, Alexandra, Pilgram, Tanja, Seves, Mauro, Wassen, Martina, Andreou, Christina, Dong, Sen, Egloff, Laura, Harrisberger, Fabienne, Heitz, Ulrike, Lenz, Claudia, Leanza, Letizia, Mackintosh, Amatya, Smieskova, Renata, Studerus, Erich, Walter, Anna, Widmayer, Sonja, Popovic, David, Day, Chris, Lowri Griffiths, Sian, Iqbal, Mariam, Pelton, Mirabel, Mallikarjun, Pavan, Stainton, Alexandra, Lin, Ashleigh, Lalousis, Paris, Denissoff, Alexander, Ellilä, Anu, Oeztuerk, Oemer, From, Tiina, Heinimaa, Markus, Ilonen, Tuula, Jalo, Päivi, Laurikainen, Heikki, Luutonen, Antti, Mäkela, Akseli, Paju, Janina, Pesonen, Henri, Säilä, Reetta-Liina, International FTD-Genetics Consortium (IFGC), German Frontotemporal Lobar Degeneration (FTLD) Consortium, PRONIA Consortium, and International FTD-Genetics Consortium Consortium

Subjects
Adult, Male, Medizin, genetics [Alzheimer Disease], genetics [Psychotic Disorders], Neuropsychological Tests, diagnostic imaging [Frontotemporal Dementia], diagnostic imaging [Psychotic Disorders], Machine Learning, methods [Magnetic Resonance Imaging], Brain, Female, Humans, Magnetic Resonance Imaging, Alzheimer Disease, Frontotemporal Dementia, Psychotic Disorders, Schizophrenia, pathology [Brain], genetics [Schizophrenia], ddc:610, diagnostic imaging [Brain], genetics [Frontotemporal Dementia], Settore MED/25 - Psichiatria, Psychiatry and Mental health, diagnostic imaging [Schizophrenia], diagnostic imaging [Alzheimer Disease]
Abstract

Weitere Nicht-UDE Autoren sind nicht genannt. Importance: The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far. Objective: To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD). Design, Setting, and Participants: This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration. Data were collected from January 1996 to July 2019 and analyzed between April 2020 and April 2022. Main Outcomes and Measures: Case assignments based on diagnostic patterns; sociodemographic, clinical, and biological data; 2-year functional outcomes and genetic separability of patients with CHR and ROD with high vs low pattern expression; and pattern progression from baseline to follow-up MRI scans in patients with nonrecovery vs preserved recovery. Results: Of 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. The bvFTD pattern comprising prefrontal, insular, and limbic volume reductions was more expressed in patients with schizophrenia (65 of 157 [41.2%]) and major depression (22 of 102 [21.6%]) than the temporo-limbic AD patterns (28 of 157 [17.8%] and 3 of 102 [2.9%], respectively). bvFTD expression was predicted by high body mass index, psychomotor slowing, affective disinhibition, and paranoid ideation (R2= 0.11). The schizophrenia pattern was expressed in 92 of 108 patients (85.5%) with bvFTD and was linked to the C9orf72 variant, oligoclonal banding in the cerebrospinal fluid, cognitive impairment, and younger age (R2= 0.29). bvFTD and schizophrenia pattern expressions forecasted 2-year psychosocial impairments in patients with CHR and were predicted by polygenic risk scores for frontotemporal dementia, AD, and schizophrenia. Findings were not associated with AD or accelerated brain aging. Finally, 1-year bvFTD/schizophrenia pattern progression distinguished patients with nonrecovery from those with preserved recovery. Conclusions and Relevance: Neurobiological links may exist between bvFTD and psychosis focusing on prefrontal and salience system alterations. Further transdiagnostic investigations are needed to identify shared pathophysiological processes underlying the neuroanatomical interface between the 2 disease spectra.

Published
2022
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68. An Autopsy Case of Amyotrophic Lateral Sclerosis with Waldenström Macroglobulinemia and Anti-MAG Gammopathy

Author

Snejana Jurici, Annie Laquerrière, Anne-Laure Bedat-Millet, Fabrice Jardin, Lucile Musset, Jean-Michel Vallat, Didier Hannequin, and Olivier Martinaud

Subjects
Amyotrophic lateral sclerosis, Anti-MAG, Waldenström macroglobulinemia, Neurology. Diseases of the nervous system, RC346-429
Abstract

We report the case of a 71-year-old woman with typical signs of bulbar amyotrophic lateral sclerosis (ALS) associated with immunoglobulin M (IgM) monoclonal gammopathy and anti-MAG (myelin-associated glycoprotein) antibodies. This unusual association between ALS and anti-MAG antibodies has previously been reported in a single case. Our present case, at neuropathological examination, demonstrated no causative link between anti-MAG antibodies and ALS.

Published
2011
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69. 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
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78. Contribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls

Author

Hannequin, Didier, Campion, Dominique, Wallon, David, Martinaud, Olivier, Zarea, Aline, Nicolas, Gaël, Rollin-Sillaire, Adeline, Bombois, Stéphanie, Mackowiak, Marie-Anne, Deramecourt, Vincent, Pasquier, Florence, Michon, Agnès, Le Ber, Isabelle, Dubois, Bruno, Godefroy, Olivier, Etcharry-Bouyx, Frédérique, Chauviré, Valérie, Chamard, Ludivine, Berger, Eric, Magnin, Eloi, Dartigues, Jean-Francois, Auriacombe, Sophie, Tison, François, Sayette, Vincent de la, Castan, Dominique, Dionet, Elsa, Sellal, Francois, Rouaud, Olivier, Thauvin, Christel, Moreaud, Olivier, Sauvée, Mathilde, Formaglio, Maïté, Mollion, Hélène, Roullet-Solignac, Isabelle, Vighetto, Alain, Croisile, Bernard, Didic, Mira, Félician, Olivier, Koric, Lejla, Ceccaldi, Mathieu, Gabelle, Audrey, Marelli, Cecilia, Labauge, Pierre, Jonveaux, Thérèse, Vercelletto, Martine, Boutoleau-Bretonnière, Claire, Castelnovo, Giovanni, Paquet, Claire, Dumurgier, Julien, Hugon, Jacques, De Boisgueheneuc, Foucauld, Belliard, Serge, Bakchine, Serge, Sarazin, Marie, Barrellon, Marie-Odile, Laurent, Bernard, Blanc, Frédéric, Pariente, Jérémie, Jurici, Snejana, Bellenguez, Céline, Charbonnier, Camille, Grenier-Boley, Benjamin, Quenez, Olivier, Le Guennec, Kilan, Chauhan, Ganesh, Rousseau, Stéphane, Richard, Anne Claire, Boland, Anne, Bourque, Guillaume, Munter, Hans Markus, Olaso, Robert, Meyer, Vincent, Letenneur, Luc, Redon, Richard, Dartigues, Jean-François, Tzourio, Christophe, Frebourg, Thierry, Lathrop, Mark, Deleuze, Jean-François, Genin, Emmanuelle, Amouyel, Philippe, Debette, Stéphanie, and Lambert, Jean-Charles

Published
2017
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79. Deletion of the progranulin gene in patients with frontotemporal lobar degeneration or Parkinson disease

Author

Anne Rovelet-Lecrux, Vincent Deramecourt, Solenn Legallic, Claude-Alain Maurage, Isabelle Le Ber, Alexis Brice, Jean-Charles Lambert, Thierry Frébourg, Didier Hannequin, Florence Pasquier, and Dominique Campion

Subjects
Progranulin, Deletion, Frontotemporal lobar degeneration, Parkinson disease, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Progranulin gene (PGRN) mutations cause ubiquitin-positive frontotemporal lobar degeneration linked to chromosome 17 (FTLDU-17). The spectrum of known mutations strongly suggests that neurodegeneration results from a partial loss of PGRN function and leads to the hypothesis that PGRN gene deletions could be present in a subset of patients. We analysed 63 unrelated French patients with frontotemporal lobar degeneration (FTLD) for PGRN gene dosage alteration by quantitative multiplex PCR of short fluorescent fragments (QMPSF). We identified in one patient with typical PGRN neuropathology a near complete deletion, removing exons 1–11, of the PGRN gene. This deletion, which resulted from a nonhomologous recombination event, was equally present in one affected sister presenting with Parkinson disease (PD). This observation provides a final argument that PGRN mutations exert their pathogenic effect through haploinsufficiency and underlines the diversity of clinical presentations associated with these PGRN alterations.

Published
2008
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80. Association study of the GAB2 gene with the risk of developing Alzheimer's disease

Author

Julien Chapuis, Didier Hannequin, Florence Pasquier, Peter Bentham, Alexis Brice, Isabelle Leber, Thierry Frebourg, Jean-François Deleuze, Emmanuelle Cousin, Uma Thaker, Philippe Amouyel, David Mann, Corinne Lendon, Dominique Campion, and Jean-Charles Lambert

Subjects
Alzheimer, GAB2, APOE, Polymorphism, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

The first genome-wide association in Alzheimer's disease (AD) suggested that the GAB2 gene rs2373115 polymorphism may be a strong risk factor in APOE ɛ4-carriers. We failed to detect an association of rs2373115 with the risk of developing AD in three populations (totalling 1406 controls and 1749 AD cases) whatever the APOE status, even if we observed a slight tendency for an increase of the GG genotype (OR (GG versus GT+TT)=1.3, 95% CI 1.0–1.6, p=0.09) and the G allele frequency (OR=1.3, 95%CI 1.0–1.6, p=0.05) in ɛ4-carriers. In addition, the rs2373115 did not modulate the extent of tau phosphorylation in the brain of 89 AD cases. The GAB2 gene is at best a minor genetic determinant of AD.

Published
2008
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81. Is the Short and Fast Step Test a safe and feasible tool for exploring anaerobic capacities of individuals with coronary heart disease in clinical practice?

Author

Anaïs Gouteron, Lucie Rigaud, Davy Laroche, A. Hannequin, Elea Ksiazek, D. Besson, Paul Ornetti, Mathieu Gueugnon, Jean-Marie Casillas, and Isabelle Fournel

Subjects
education.field_of_study, medicine.medical_specialty, Activities of daily living, Rehabilitation, business.industry, Intraclass correlation, medicine.medical_treatment, Population, Reproducibility of Results, Coronary Disease, Physical Therapy, Sports Therapy and Rehabilitation, Context (language use), Confidence interval, Exercise Test, Physical therapy, Humans, Medicine, Anaerobiosis, Prospective Studies, business, Prospective cohort study, education, Anaerobic exercise
Abstract

Background While its importance in daily living, the anaerobic metabolism is not taken into account in clinical practice. The lack of validated functional performance tests for patients with chronic disabilities may explain this defect. In this context, the Short and Fast Step Test (SFST) was recently developed and validated in healthy volunteers. Aim The purpose of this study was to investigate the safety, feasibility and reliability of the SFST, a functional test exploring anaerobic metabolism in coronary patients during cardiac rehabilitation. Design This study was a monocentric prospective study. Settings This study took place in the rehabilitation center of the University Hospital Center of Dijon, France. Population 44 coronary patients, addressed for a first cardiac rehabilitation, were included in this protocol. Methods All participants performed three SFST: T1 and T2 (including respiratory gas exchange) the first day of the program and T3 after 3 to 7 days. SFST consists of walking up and down a 17.5cm-high step as many times as possible in 1 minute. Safety was assessed by the percentage of patients who performed the SFST without reporting a fall, or muscular or cardiovascular events. Feasibility was evaluated by the percentage of patients who succeeded in doing the SFST. Reliability was assessed with the number of raised steps in same condition (T1-T3) and different conditions (T1-T2) using a 2-way intraclass correlation coefficient (ICC). Values were given with their 90% confidence interval [90%CI]. Results The safety was 95.2% [85.8;99.2] for T1, 88.1% [76.6;95.2] for T2 and 90.4% [79.5;96.7] for T3. 100% [93,1;100] of participants completed T1 and T2, 92.9% [82.6;98] T3. An ICC of 0.74 [0.60;0.84] was observed between T1 and T3 and of 0.87 [0.79;0.92] between T1 and T2. Conclusions This study demonstrates the good safety, feasibility and reliability of the SFST to assess anaerobic metabolism in coronary patients in a rehabilitation program. Clinical rehabilitation impact These results show that the SFST seems suitable for the evaluation of brief submaximal functional capacity in daily activities. It offers a real possibility to assess such capacity during the cardiac rehabilitation routine.

Published
2021
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84. Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Author

Thomas Roux, Mathieu Barbier, Mélanie Papin, Claire-Sophie Davoine, Sabrina Sayah, Giulia Coarelli, Perrine Charles, Cecilia Marelli, Livia Parodi, Christine Tranchant, Cyril Goizet, Stephan Klebe, Ebba Lohmann, Lionel Van Maldergem, Christine van Broeckhoven, Marie Coutelier, Christelle Tesson, Giovanni Stevanin, Charles Duyckaerts, Alexis Brice, Alexandra Durr, Frédéric Darios, Sylvie Forlani, Pitié-Salpêtrière Site, Guillaume Banneau, Cécile Cazeneuve, Bertrand Fontaine, Jean-Philippe Azulay, Odile Boesfplug-Tanguy, Didier Hannequin, Jamilé Hazan, Andrea Burgo, Christophe Verny, Michel Koenig, Pierre Labauge, Karine N’guyen, Diana Rodriguez, Soraya Belarbi, Abdelmadjid Hamri, Meriem Tazir, Sylvia Boesch, Massimo Pandolfo, Jardim Laura, Velina Guergueltcheva, Ivalo Tournev, Olga Lucia Pedraza Linarès, Jørgen E. Nielsen, Kirsten Svenstrup, Maha Zaki, Peter Bauer, Lüdger Schöls, Rebecca Schüle, Alexander Lossos, Maria-Teresa Bassi, Manuela Basso, Enrico Bertini, Alfredo Brusco, Carlo Casali, Giorgio Casari, Chiara Criscuolo, Alessandro Filla, Laura Orsi, Filippo M. Santorelli, Enza Maria Valente, Marinela Vavla, Giovanni Vazza, André Megarbane, Ali Benomar, Berry Kremer, Willeke Van Roon-Mom, Richard Roxburgh, Anne Kjersti Erichsen, Chantal Tallaksen, Isabel Alonso, Paula Coutinho, José Léal Loureiro, Jorge Sequeiros, Mustapha Salih, Vladimir S. Kostic, Idoia Rouco Axpe, Liena Elsayed, Martin Arce Paucar, Samir Roumani, Soong Bing-Wen, Evan Reid, Nethisinghe Suran, Thomas Warner, Nicholas Wood, 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), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], 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), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-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), CHU Strasbourg, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), University of Tübingen, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), University of Antwerp (UA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), SPATAX Network, Roux, T., Barbier, M., Papin, M., Davoine, C. -S., Sayah, S., Coarelli, G., Charles, P., Marelli, C., Parodi, L., Tranchant, C., Goizet, C., Klebe, S., Lohmann, E., Van Maldergen, L., van Broeckhoven, C., Coutelier, M., Tesson, C., Stevanin, G., Duyckaerts, C., Brice, A., Durr, A., Darios, F., Forlani, S., Site, P. -S., Banneau, G., Cazeneuve, C., Fontaine, B., Azulay, J. -P., Boesfplug-Tanguy, O., Hannequin, D., Hazan, J., Burgo, A., Verny, C., Koenig, M., Labauge, P., N'Guyen, K., Rodriguez, D., Belarbi, S., Hamri, A., Tazir, M., Boesch, S., Pandolfo, M., Laura, J., Guergueltcheva, V., Tournev, I., Pedraza Linares, O. L., Nielsen, J. E., Svenstrup, K., Zaki, M., Bauer, P., Schols, L., Schule, R., Lossos, A., Bassi, M. -T., Basso, M., Bertini, E., Brusco, A., Casali, C., Casari, G., Criscuolo, C., Filla, A., Orsi, L., Santorelli, F. M., Valente, E. M., Vavla, M., Vazza, G., Megarbane, A., Benomar, A., Kremer, B., Van Roon-Mom, W., Roxburgh, R., Erichsen, A. K., Tallaksen, C., Alonso, I., Coutinho, P., Loureiro, J. L., Sequeiros, J., Salih, M., Kostic, V. S., Rouco Axpe, I., Elsayed, L., Paucar, M. A., Roumani, S., Bing-Wen, S., Reid, E., Suran, N., Warner, T., and Wood, N.

Subjects
Male, Pathology, MESH: Ataxia, Purkinje cell, Medizin, MESH: Cognitive Dysfunction, 0302 clinical medicine, spinocerebellar ataxia, ATP-Dependent Proteases, SCA48, Medicine, Genetics (clinical), 0303 health sciences, Penetrance, 3. Good health, MESH: Cerebellar Ataxia, MESH: ATPases Associated with Diverse Cellular Activities, medicine.anatomical_structure, Spinocerebellar ataxia, Female, medicine.symptom, Frontotemporal dementia, medicine.medical_specialty, Ataxia, Cerebellar Ataxia, MESH: Spinocerebellar Ataxias, Ubiquitin-Protein Ligases, Neuropathology, 03 medical and health sciences, MESH: ATP-Dependent Proteases, Atrophy, Humans, Spinocerebellar Ataxias, Cognitive Dysfunction, 030304 developmental biology, cognitive impairment, SCAR16, STUB1, MESH: Humans, Cerebellar ataxia, business.industry, medicine.disease, MESH: Ubiquitin-Protein Ligases, MESH: Male, ATPases Associated with Diverse Cellular Activities, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Human medicine, business, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; Purpose: Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48).Methods: We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance.Results: STUB1 variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% of STUB1 variant carriers, including five families with Huntington or frontotemporal dementia disease-like phenotypes associated with ataxia, while no STUB1 variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of a STUB1 heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening of STUB1 variants revealed new features: (1) the majority of patients were women (70%) and (2) "second hits" in AFG3L2, PRKCG, and TBP were detected in three families suggesting synergic effects.Conclusion: Our results reveal an unexpectedly frequent (7%) implication of STUB1 among dominantly inherited cerebellar ataxias, and suggest that the penetrance of STUB1 variants could be modulated by other factors, including sex and variants in other ataxia-related genes.

Published
2020
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86. Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

Author

Swarup, Vivek, Hinz, Flora I., Rexach, Jessica E., Noguchi, Ken-ichi, Toyoshiba, Hiroyoshi, Oda, Akira, Hirai, Keisuke, Sarkar, Arjun, Seyfried, Nicholas T., Cheng, Chialin, Haggarty, Stephen J., Ferrari, Raffaele, Rohrer, Jonathan D., Ramasamy, Adaikalavan, Hardy, John, Hernandez, Dena G., Nalls, Michael A., Singleton, Andrew B., Kwok, John B. J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cairns, Nigel J., Cruchaga, Carlos, Binetti, Giuliano, Ghidoni, Roberta, Benussi, Luisa, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Jaros, Evelyn, Pietrini, Pietro, Huey, Edward D., Wassermann, Eric M., Tierney, Michael C., Baborie, Atik, Pastor, Pau, Ortega-Cubero, Sara, Razquin, Cristina, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter St., Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C. M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., Pickering-Brown, Stuart, Momeni, Parastoo, van der Zee, Julie, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Leber, Isabelle, Brice, Alexis, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Gasparoni, Gilles, Pichler, Sabrina, Ibach, Bernd, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Gerhard, Alexander, Richardson, Anna, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, Seeley, William W., van Swieten, John C., Dopper, Elise G. P., Seelaar, Harro, Pijnenburg, Yolande A. L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Ferrucci, Luigi, Kapogiannis, Dimitrios, Lah, James J., Levey, Allan I., Kondou, Shinichi, Geschwind, Daniel H., Int Frontotemporal Dementia Gen, Swarup, Vivek, Hinz, Flora I., Rexach, Jessica E., Noguchi, Ken-ichi, Toyoshiba, Hiroyoshi, Oda, Akira, Hirai, Keisuke, Sarkar, Arjun, Seyfried, Nicholas T., Cheng, Chialin, Haggarty, Stephen J., Ferrari, Raffaele, Rohrer, Jonathan D., Ramasamy, Adaikalavan, Hardy, John, Hernandez, Dena G., Nalls, Michael A., Singleton, Andrew B., Kwok, John B. J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cairns, Nigel J., Cruchaga, Carlo, Binetti, Giuliano, Ghidoni, Roberta, Benussi, Luisa, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Grafman, Jordan, Morris, Christopher M., Attems, Johanne, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Jaros, Evelyn, Pietrini, Pietro, Huey, Edward D., Wassermann, Eric M., Tierney, Michael C., Baborie, Atik, Pastor, Pau, Ortega-Cubero, Sara, Razquin, Cristina, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagioti, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter St., Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C. M., Uphill, Jame, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., Pickering-Brown, Stuart, Momeni, Parastoo, van der Zee, Julie, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Leber, Isabelle, Brice, Alexi, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthia, Mayhaus, Manuel, Gasparoni, Gille, Pichler, Sabrina, Ibach, Bernd, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Gerhard, Alexander, Richardson, Anna, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, Seeley, William W., van Swieten, John C., Dopper, Elise G. P., Seelaar, Harro, Pijnenburg, Yolande A. L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Ferrucci, Luigi, Kapogiannis, Dimitrio, Lah, James J., Levey, Allan I., Kondou, Shinichi, and Geschwind, Daniel H.

Subjects
Proteomics, Genetics and Molecular Biology (all), 0301 basic medicine, Messenger, Gene regulatory network, Inbred C57BL, Biochemistry, Transgenic, Mice, 0302 clinical medicine, Gene Regulatory Networks, Regulation of gene expression, Cell Death, Drug discovery, Neurodegeneration, Neurodegenerative Diseases, General Medicine, Chemistry, Frontotemporal Dementia, 030220 oncology & carcinogenesis, Frontotemporal dementia, Evolution, Systems biology, Genetic Vectors, Animals, Dementia, Disease Models, Animal, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs, RNA, Messenger, Reproducibility of Results, Transcriptome, tau Proteins, Evolution, Molecular, Computational biology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, microRNA, medicine, Biochemistry, Genetics and Molecular Biology (all), Animal, Molecular, medicine.disease, 030104 developmental biology, Disease Models, RNA, Human medicine
Abstract

Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.

Published
2018
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87. 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
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88. 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
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89. A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

Author

Zhang M1, 2 3, Ferrari R4, Tartaglia MC3, 5 6, Keith J7, Surace EI8, Wolf U9, Sato C3, Grinberg M3, Liang Y3, Xi Z3, Dupont K3, McGoldrick P3, Weichert A3, McKeever PM3, Schneider R3, 6 7, McCorkindale MD4, Manzoni C10, Rademakers R11, Graff-Radford NR12, Dickson DW11, Parisi JE13, Boeve BF14, Petersen RC14, Miller BL15, Seeley WW16, van Swieten JC17, van Rooij J17, Pijnenburg Y18, van der Zee J19, Van Broeckhoven C19, Le Ber I21, Van Deerlin V23, Suh E23, Rohrer JD24, Mead S25, Graff C26, Öijerstedt L26, Pickering-Brown S28, Rollinson S28, Rossi G29, Tagliavini F30, Brooks WS31, Dobson-Stone C32, Halliday GM32, Hodges JR32, Piguet O34, Binetti G36, Benussi L37, Ghidoni R37, Nacmias B38, Sorbi S38, Bruni AC40, Galimberti D41, Scarpini E41, Rainero I42, Rubino E42, Clarimon J43, Lleó A43, Ruiz A45, Hernández I45, Pastor P46, Diez-Fairen M46, Borroni B48, Pasquier F49, Deramecourt V49, Lebouvier T49, Perneczky R50, 51 52, Diehl-Schmid J50, Grafman J53, Huey ED55, Mayeux R55, Nalls MA57, Hernandez D57, Singleton A57, Momeni P58, Zeng Z59, Hardy J4, Robertson J3, Zinman L6, 7, Rogaeva E3, 6, International FTD-Genomics Consortium (IFGC), Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JBJ, Dobson-Stone C, Brooks WS, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Hernández I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Albani D, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimón J, Lleó A, Blesa R, Wald Ouml ML, Nilsson K, Nilsson C, Mackenzie IRA, Hsiung GR, Mann DMA, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wassermann EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky R, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, St George-Hyslop P, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JCM, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossman M, Trojanowski JQ, van der Zee J, Van Broeckhoven C, Cappa SF, Leber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Grazia Spillantini M, Morris HR, Rizzu P, Heutink P, Snowden JS, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Elena Conidi M, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Petersen RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Miller BL, Karydas AM, Rosen H, van Swieten JC, Dopper EGP, Seelaar H, Pijnenburg YAL, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebouvier T, Kapogiannis D, Ferrucci L, Pickering-Brown S, Singleton AB, Hardy J, Momeni P, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Neurology, Divisions, Zhang, M1, 2, 3, Ferrari, R4, Tartaglia, Mc3, 5, 6, Keith, J7, Surace, Ei8, Wolf, U9, Sato, C3, Grinberg, M3, Liang, Y3, Xi, Z3, Dupont, K3, Mcgoldrick, P3, Weichert, A3, Mckeever, Pm3, Schneider, R3, 6, 7, Mccorkindale, Md4, Manzoni, C10, Rademakers, R11, Graff-Radford, Nr12, Dickson, Dw11, Parisi, Je13, Boeve, Bf14, Petersen, Rc14, Miller, Bl15, Seeley, Ww16, van Swieten, Jc17, van Rooij, J17, Pijnenburg, Y18, van der Zee, J19, Van Broeckhoven, C19, Le Ber, I21, Van Deerlin, V23, Suh, E23, Rohrer, Jd24, Mead, S25, Graff, C26, Öijerstedt, L26, Pickering-Brown, S28, Rollinson, S28, Rossi, G29, Tagliavini, F30, Brooks, Ws31, Dobson-Stone, C32, Halliday, Gm32, Hodges, Jr32, Piguet, O34, Binetti, G36, Benussi, L37, Ghidoni, R37, Nacmias, B38, Sorbi, S38, Bruni, Ac40, Galimberti, D41, Scarpini, E41, Rainero, I42, Rubino, E42, Clarimon, J43, Lleó, A43, Ruiz, A45, Hernández, I45, Pastor, P46, Diez-Fairen, M46, Borroni, B48, Pasquier, F49, Deramecourt, V49, Lebouvier, T49, Perneczky, R50, 51, 52, Diehl-Schmid, J50, Grafman, J53, Huey, Ed55, Mayeux, R55, Nalls, Ma57, Hernandez, D57, Singleton, A57, Momeni, P58, Zeng, Z59, Hardy, J4, Robertson, J3, Zinman, L6, Rogaeva, E3, International FTD-Genomics Consortium, (IFGC), Ferrari, R, Hernandez, Dg, Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Brooks, W, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Wald Ouml, Ml, Nilsson, K, Nilsson, C, Mackenzie, Ira, Hsiung, Gr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wassermann, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, Vm, Grossman, M, Trojanowski, Jq, van der Zee, J, Van Broeckhoven, C, Cappa, Sf, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Grazia Spillantini, M, Morris, Hr, Rizzu, P, Heutink, P, Snowden, J, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Elena Conidi, M, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Petersen, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten, Jc, Dopper, Egp, Seelaar, H, Pijnenburg, Yal, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, Ab, Hardy, J, Momeni, P, and Int FTD-Genomics Consortium IFGC

Subjects
Male, Heterozygote, amyotrophic lateral sclerosis, Genotype, genetic association, Age of onset, Polymorphism, Single Nucleotide, frontotemporal dementia, age of onset, C9orf72, Humans, amyotrophic lateral sclerosi, Aged, C9orf72 Protein, Original Articles, DNA Methylation, Middle Aged, Amyotrophic lateral sclerosis, Gene Expression Regulation, Genetic association, CpG Islands, Female, Human medicine, Neurology (clinical), Frontotemporal dementia
Abstract

Discovery of disease age-of-onset modifiers is important for clinical trials and drug design. Zhang et al. perform a genome-wide analysis of epigenetic functional polymorphisms and identify an association between the C6orf10/LOC101929163 locus and age of FTD/ALS onset. The risk allele may be associated with a pro-inflammatory state in the brain., The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

Published
2018
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90. Clinical and neuropathological diversity of tauopathy in MAPT duplication carriers

Author

Isabelle Le Ber, Marie Sarazin, Olivier Quenez, Florence Clavaguera, Catherine Schramm, Anne Rovelet-Lecrux, Camille Heitz, Mathieu Mula, Stéphane Epelbaum, Susana Boluda, Charles Duyckaerts, Manon Thierry, Didier Hannequin, Magalie Lecourtois, Serge Marty, Michel Bottlaender, Julien Lagarde, David Wallon, Natsuko Nakamura, François Sellal, Antoine Bonnevalle, Laetitia Miguel, Gaël Nicolas, Stéphane Rousseau, Dominique Campion, Thérèse Rivasseau Jonveaux, Aline Zarea, Eloi Magnin, 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neurologie de la mémoire et du langage [CHU Ste Anne], Université Paris Descartes - Paris 5 (UPD5), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), LaBoratoire d'Imagerie biOmédicale MultimodAle Paris-Saclay (BIOMAPS), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité BioMaps (BIOMAPS), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Proband, Adult, Male, Pathology, medicine.medical_specialty, Heterozygote, [SDV]Life Sciences [q-bio], Tau protein, tau Proteins, Pathology and Forensic Medicine, Progressive supranuclear palsy, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Extrapyramidal symptoms, Alzheimer Disease, Basal ganglia, medicine, Humans, Cognitive Dysfunction, Age of Onset, ComputingMilieux_MISCELLANEOUS, Inclusion Bodies, biology, business.industry, Brain, Middle Aged, medicine.disease, 030104 developmental biology, Tauopathies, Chromosomal region, biology.protein, Female, Neurology (clinical), Tauopathy, Alzheimer's disease, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Microduplications of the 17q21.31 chromosomal region encompassing the MAPT gene, which encodes the Tau protein, were identified in patients with a progressive disorder initially characterized by severe memory impairment with or without behavioral changes that can clinically mimic Alzheimer disease. The unique neuropathological report showed a primary tauopathy, which could not be unanimously classified in a given known subtype, showing both 4R- and 3R-tau inclusions, mainly within temporal cortical subregions and basal ganglia, without amyloid deposits. Recently, two subjects harboring the same duplication were reported with an atypical extrapyramidal syndrome and gait disorder. To decipher the phenotypic spectrum associated with MAPT duplications, we studied ten carriers from nine families, including two novel unrelated probands, gathering clinical (n = 10), cerebrospinal fluid (n = 6), MRI (n = 8), dopamine transporter scan (n = 4), functional (n = 5), amyloid (n = 3) and Tau-tracer (n = 2) PET imaging data as well as neuropathological examination (n = 4). Ages at onset ranged from 37 to 57 years, with prominent episodic memory impairment in 8/10 patients, associated with behavioral changes in four, while two patients showed atypical extrapyramidal syndrome with gait disorder at presentation, including one with associated cognitive deficits. Amyloid imaging was negative but Tau imaging showed significant deposits mainly in both mesiotemporal cortex. Dopaminergic denervation was found in 4/4 patients, including three without extrapyramidal symptoms. Neuropathological examination exclusively showed Tau-immunoreactive lesions. Distribution, aspect and 4R/3R tau aggregates composition suggested a spectrum from predominantly 3R, mainly cortical deposits well correlating with cognitive and behavioral changes, to predominantly 4R deposits, mainly in the basal ganglia and midbrain, in patients with prominent extrapyramidal syndrome. Finally, we performed in vitro seeding experiments in HEK-biosensor cells. Morphological features of aggregates induced by homogenates of three MAPT duplication carriers showed dense/granular ratios graduating between those induced by homogenates of a Pick disease and a progressive supranuclear palsy cases. These results suggest that MAPT duplication causes a primary tauopathy associated with diverse clinical and neuropathological features.

Published
2021
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91. Correction: Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Author

Roux, Thomas, primary, Barbier, Mathieu, additional, Papin, Mélanie, additional, Davoine, Claire-Sophie, additional, Sayah, Sabrina, additional, Coarelli, Giulia, additional, Charles, Perrine, additional, Marelli, Cecilia, additional, Parodi, Livia, additional, Tranchant, Christine, additional, Goizet, Cyril, additional, Klebe, Stephan, additional, Lohmann, Ebba, additional, Van Maldergem, Lionel, additional, van Broeckhoven, Christine, additional, Coutelier, Marie, additional, Tesson, Christelle, additional, Stevanin, Giovanni, additional, Duyckaerts, Charles, additional, Brice, Alexis, additional, Durr, Alexandra, additional, Darios, Frédéric, additional, Forlani, Sylvie, additional, Site, Pitié-Salpêtrière, additional, Banneau, Guillaume, additional, Cazeneuve, Cécile, additional, Fontaine, Bertrand, additional, Azulay, Jean-Philippe, additional, Boesfplug-Tanguy, Odile, additional, Hannequin, Didier, additional, Hazan, Jamilé, additional, Burgo, Andrea, additional, Verny, Christophe, additional, Koenig, Michel, additional, Labauge, Pierre, additional, N’guyen, Karine, additional, Rodriguez, Diana, additional, Belarbi, Soraya, additional, Hamri, Abdelmadjid, additional, Tazir, Meriem, additional, Boesch, Sylvia, additional, Pandolfo, Massimo, additional, Laura, Jardim, additional, Guergueltcheva, Velina, additional, Tournev, Ivalo, additional, Pedraza Linarès, Olga Lucia, additional, Nielsen, Jørgen E., additional, Svenstrup, Kirsten, additional, Zaki, Maha, additional, Bauer, Peter, additional, Schöls, Lüdger, additional, Schüle, Rebecca, additional, Lossos, Alexander, additional, Bassi, Maria-Teresa, additional, Basso, Manuela, additional, Bertini, Enrico, additional, Brusco, Alfredo, additional, Casali, Carlo, additional, Casari, Giorgio, additional, Criscuolo, Chiara, additional, Filla, Alessandro, additional, Orsi, Laura, additional, Santorelli, Filippo M., additional, Valente, Enza Maria, additional, Vavla, Marinela, additional, Vazza, Giovanni, additional, Megarbane, André, additional, Benomar, Ali, additional, Kremer, Berry, additional, Van Roon-Mom, Willeke, additional, Roxburgh, Richard, additional, Erichsen, Anne Kjersti, additional, Tallaksen, Chantal, additional, Alonso, Isabel, additional, Coutinho, Paula, additional, Loureiro, José Léal, additional, Sequeiros, Jorge, additional, Salih, Mustapha, additional, Kostic, Vladimir S, additional, Rouco Axpe, Idoia, additional, Elsayed, Liena, additional, Paucar, Martin Arce, additional, Roumani, Samir, additional, Bing-Wen, Soong, additional, Reid, Evan, additional, Suran, Nethisinghe, additional, Warner, Thomas, additional, and Wood, Nicholas, additional

Published
2021
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92. Clinical and genetic characteristics of late-onset Huntington's disease

Author

Oosterloo, Mayke, Bijlsma, Emilia K., van Kuijk, Sander MJ., Minkels, Floor, de Die-Smulders, Christine EM., Bachoud-Lévi, Anne-Catherine, Bentivoglio, Anna-Rita, Biunno, Ida, Bonelli, Raphael M., Bronzova, Juliana, Burgunder, Jean-Marc, Dunnett, Stephen B., Ferreira, Joaquim J., Frich, Jan, Giuliano, Joe, Handley, Olivia J., Heiberg, Arvid, Illarioshkin, Sergey, Illmann, Torsten, Klempir, Jiri, Landwehrmeyer, G. Bernhard, Levey, Jamie, Mclean, Tim, Nielsen, Jørgen E., Koivisto, Susana Pro, Päivärinta, Markku, Pålhagen, Sven, Quarrell, Oliver, Ramos-Arroyo, Maria, Roos, Raymund A. C., Saft, Carsten, Sebastián, Ana Rojo, Tabrizi, Sarah J., Vandenberghe, Wim, Verellen-Dumoulin, Christine, Uhrova, Tereza, Wahlström+, Jan, Zaremba, Jacek (formerly Rödig, Verena, Baake, Barth, Katrin, Garde, Monica Bascuñana, Becanovic, Kristina, Bernard, Tomáš, Betz, Sabrina, Bos, Reineke, Come, Adrien, Guedes, Leonor Correia, Callaghan, Jenny, Capodarca, Selene, Charpentier, Sébastien, Vieira da Silva, Wildson, Di Renzo, Martina, Ecker, Daniel, Finisterra, Ana Maria, Fullam, Ruth, Genoves, Camille, Gilling, Mette, Horta, Andrea, Hvalstedt, Carina, Held, Christine, Hussain, Hasina, Koppers, Kerstin, Lamanna, Claudia, Laurà, Matilde, Descals, Asunción Martínez, Martinez-Horta, Saul, Mestre, Tiago, Minster, Sara, Monza, Daniela, Münkel, Kristina, Mütze, Lisanne, Oehmen, Martin, Padieu, Helene, Paterski, Laurent, Peppa, Nadia, Rindal, Beate, Rogers, Dawn, Røren (formerly Heinonen), Niini, Salgueiro, Ana, Šašinková, Pavla, Seliverstov, Yury, Taylor, Catherine, Timewell, Erika, Townhill, Jenny, Cubillo, Patricia Trigo, van Walsem, Marleen R., Witjes-Ané, Marie-Noelle, Witkowski, Grzegorz, Wright, Abigail, Yudina, Elizaveta, Zielonka, Daniel, Zielonka, Eugeniusz, Zinzi, Paola, Hecht, Karen, Herranhof, Brigitte, Holl (formerly Hödl), Anna, Kapfhammer, Hans-Peter, Koppitz, Michael, Lilek, Sabine, Magnet, Markus, Müller, Nicole, Otti, Daniela, Painold, Annamaria, Reisinger, Karin, Scheibl, Monika, Schöggl, Helmut, Ullah, Jasmin, Braunwarth, Eva-Maria, Brugger, Florian, Buratti, Lisa, Hametner, Eva-Maria, Hepperger, Caroline, Holas, Christiane, Hotter, Anna, Hussl, Anna, Larcher, Barbara, Mahlknecht, Philipp, Müller, Christoph, Pinter, Bernadette, Poewe, Werner, Reiter, Eva-Magdalena, Seppi, Klaus, Sprenger, Fabienne, Wenning, Gregor, Ladurner, Gunther, Lilek, Stefan, Sinadinosa, Daniela, Staffen, Wolfgang, Walleczek, Anna Maria, Linder, Christoph, Pirker, Walter, Liessens, Dirk, Calmeyn, Godelinde, Somers, Nele, Delvaux, Isabelle, Boogaerts, Andrea, Flamez, Anja, de Raedt, Sylvie, Alaerts, Nick, Slama, Hichem, Supiot, Frédéric, Constant, Eric, Gillardin, Anne-Françoise, Léonard, Marie-Claude, van de Wyngaerde, Françoise, Dupuis, Michel, Minet, Cécile, Ribaï, Pascale, Van Paemel, Dominique, van Reijen, Dimphna, Weckx, Petra, Kaiserova, Michaela, Šenkárová, Zuzana, Bezdíček, Ondřej, Klempíř, Jiří, Klempířová, Olga, Majerová-Ibarburu, Veronika, Nikolai, Tomáš, Roth, Jan, Stárková, Irena, Madsen, Louise Hasselstrøm, Møller, Anette Torvin, Hjermind, Lena, Jacobsen, Oda, Larsen, Ida Unmack, Lindquist, Suzanne, Nielsen, Jørgen, Regeur, Lisbeth, Roos, Peter, Stockholm, Jette, Vangsted-Hansen, Christina, Vinther-Jensen, Tua, Lolk, Annette, Lundsgaard, Marianne, Wermuth, Lene, Andersson, Christian, Nyberg, Clara, Sundblom, Jimmy, Peippo, Maarit, Sipponen, Marjatta, Bruun, Anu, Hartikainen, Paivi, Mäkipää, Seija, Ollokainen, Mari, Åman, Jaana, Kärppä, Mikko, Ignatius, Jaakko, Jääskeläinen, Outi, Kajula, Outi, Moilanen, Jukka, Mustonen, Aki, Santala, Maire, Eklund, Pia, Hiivola, Heli, Hyppönen, Hannele, Martikainen, Kirsti, Ojala, Marjut, Tähkäpää, Sirkku, Tuuha, Katri, Allain, Philippe, Bonneau, Dominique, Bost, Marie, Gohier, Bénédicte, Guérid, Marie-Anne, Olivier, Audrey, Prouzet, Julie, Prundean, Adriana, Scherer-Gagou, Clarisse, Verny, Christophe, Babiloni, Blandine, Bled, Déborah, Debruxelles, Sabrina, Duché, Charlotte, Fraisse, Sonia, Goizet, Cyril, Jameau, Laetitia, Lafoucrière, Danielle, Spampinato, Umberto, Couttier, Julien, Debilly, Bérengère, Delaigue, Christine, Derost, Philippe, Durif, Franck, Germain, Véronique, Legendre, Perrine, Loiseau, Sylvie, Marques, Ana, Ulla, Miguel, Vidal, Tiphaine, Badei, Farideh, Boissé, Marie-Françoise, Boudali, Lotfi, Cleret de Langavant, Laurent, Lemoine, Laurie, Morgado, Graca, Youssov, Katia, Annic, Agnès, Barthélémy, Recka, De Bruycker, Christelle, Cabaret, Maryline, Carette, Anne-Sophie, Carrière, Nicolas, Decorte, Eric, Defebvre, Luc, Delliaux, Marie, Delval, Arnaud, Depelchin, Alizé, Destee, Alain, Dewulf-Pasz, Nelly, Dondaine, Thibaut, Dugauquier, Florence, Dujardin, Kathy, Hopes, Lucie, Krystkowiak, Pierre, Lemaire, Marie-Hélène, Manouvrier, Sylvie, Mutez, Eugénie, Peter, Mireille, Plomhause, Lucie, Sablonnière, Bernard, Simonin, Clémence, Tard, Céline, Thibault-Tanchou, Stéphanie, Vuillaume, Isabelle, Bellonet, Marcellin, Blin, Stéphanie, Chen, Simone, Masmoudi, Kamel, Morin, Gilles, Roussel, Martine, Tir, Mélissa, Schüler, Béatrice, Wannepain, Sandrine, Zouitina, Yassine, Azulay, Jean-Philippe, Delfini, Marie, Eusebio, Alexandre, Fluchere, Frédérique, Guenam, Aicha, Mundler, Laura, Nguyen, Karine, Benaich, Sandra, Brice, Alexis, Boster, Sarah, Charles, Perrine, Durr, Alexandra, Ewenczyk, Claire, Francisque, Hélène, Jauffret, Céline, Justo, Damian, Kassar, Abdulrahman, Klebe, Stephan, Lesne, Fabien, Milani, Paolo, Monin, Marie-Lorraine, Monnier, Tiffany, Roze, Emmanuel, Tataru, Alina, Tchikviladzé, Maya, Bioux, Sandrine, Bliaux, Evangeline, Girard, Carole, Guyant-Maréchal, Lucie, Hannequin, Didier, Hannier, Véronique, Jourdain, Séverine, Maltête, David, Pouliquen, Dorothée, Anheim, Mathieu, Barun, Nadia, Lagha-Boukbiza, Ouhaid, Longato, Nadine, Marcel, Christophe, Phillipps, Clélie, Rudolf, Gabrielle, Steinmetz, Gisèle, Tranchant, Christine, Wagner, Caroline, Zimmermann, Marie-Agathe, Blondeau, Leily, Calvas, Fabienne, Cheriet, Samia, Delabaere, Helène, Demonet, Jean-François, Marquine, Laurent, Pariente, Jérémie, Pierre, Michèle, Pomies, Elsa, Rolland, Sandrine, Souyris, Corinne, Kosinski, Christoph Michael, Milkereit, Eva, Probst, Daniela, Reetz, Kathrin, Sass, Christian, Schiefer, Johannes, Schlangen, Christiane, Werner, Cornelius J., Beuth, Markus, Gelderblom, Harald, Priller, Josef, Prüß, Harald, Spruth, Eike, Thiel, Silvia, Andrich, Jürgen, Ellrichmann, Gisa, Herrmann, Lennard, Hoffmann, Rainer, Kaminski, Barbara, Kraus, Peter, Stamm, Christiane, Ganos, Christos, Stubbe, Lars, Tadic, Vera, Tübing, Jennifer, Lange, Herwig, Bosredon, Cecile, Hunger, Ulrike, Löhle, Matthias, Maass, Antonia, Ossig, Christiana, Schmidt, Simone, Storch, Alexander, Wolz, Annett, Wolz, Martin, Kohl, Zacharias, Kozay, Christina, Winkler, Jürgen, Bergmann, Ulrike, Böringer, Regina, Capetian, Philipp, Kammel, Gerit, Lambeck, Johann, Mächtel, Miriam, Meier, Simone, Rijntjes, Michel, Zucker, Birgit, Boelmans, Kai, Goerendt, Ines, Heinicke, Walburgis, Hidding, Ute, Lewerenz, Jan, Münchau, Alexander, Orth, Michael, Schmalfeld, Jenny, Zittel, Simone, Diercks, Gabriele, Dressler, Dirk, Francis, Flverly, Gayde-Stephan, Sabine, Gorzolla, Heike, Kramer, Bianca, Minschke, Rebecca, Schrader, Christoph, Tacik, Pawel, Ribbat+, Michael, Longinus, Bernhard, Möller, Carsten, Bürk, Katrin, Lüsebrink, Antje, Mühlau, Mark, Peinemann, Alexander, Städtler, Michael, Weindl, Adolf, Winkelmann, Juliane, Ziegler, Cornelia, Bechtel, Natalie, Beckmann, Heike, Bohlen, Stefan, Göpfert, Nicole, Hölzner, Eva, Reilmann, Ralf, Rohm, Stefanie, Rumpf, Silke, Schepers, Sigrun, Weber, Nathalia, Bachmeier, Michael, Dose, Matthias, Hofstetter, Nina, Marquard, Ralf, Mühlbäck, Alzbeta, Buck, Andrea, Connemann, Julia, Geitner, Carolin, Kesse, Andrea, Landwehrmeyer, Bernhard, Lezius, Franziska, Nepper, Solveig, Niess, Anke, Schneider, Ariane, Schwenk, Daniela, Süssmuth, Sigurd, Trautmann, Sonja, Vogel, Melanie, Weydt, Patrick, Musacchio, Thomas, Leypold, Christine, Nöth, Kerstin, Cormio, Claudia, Difruscolo, Olimpia, Franco, Giovanni, Nuzzi, Angela, Sciruicchio, Vittorio, Serpino, Claudia, de Tommaso, Marina, Calandra-Buonaura, Giovanna, Capellari, Sabina, Cortelli, Pietro, Gallassi, Roberto, Poda, Roberto, Scaglione, Cesa, Agosti, Chiara, Barlati, Sergio, Compostella, Silvia, Marchina, Eleonora, Padovani, Alessando, Figorilli, Michela, Marrosu, Francesco, Muroni, Antonella, Piras, Valeria, Vacca, Melisa, Bertini, Elisabetta, Bartoli, Caterina, Fortunato, Fernanda, Ghelli, Elena, Ginestroni, Andrea, Mechi, Claudia, Paganini, Marco, Piacentini, Silvia, Pradella, Silvia, Romoli, Anna Maria, Sorbi, Sandro, Abbruzzese, Giovanni, Bandettini di Poggio, Monica, Ferrandes, Giovanna, Mandich, Paola, Marchese, Roberta, Di Maria, Emilio, Tamburini, Tiziano, Albanese, Alberto, Castagliuolo, Simona, Castaldo, Anna, Di Donato, Stefano, Di Bella, Daniela, Gellera, Cinzia, Genitrini, Silvia, Mariotti, Caterina, Nanetti, Lorenzo, Panzeri, Marta, Paridi, Dominga, Soliveri, Paola, Spagnolo, Francesca, Taroni, Franco, Tomasello, Chiara, De Michele, Giuseppe, Di Maio, Luigi, Rinaldi, Carlo, Massarelli, Marco, Peluso, Silvio, Roca, Alessandro, Russo, Cinzia Valeria, Salvatore, Elena, Sorrentino, Pierpaolo, Tucci, Tecla, Cannella, Milena, Codella, Valentina, De Gregorio, Francesca, De Nicola, Annunziata, Elifani, Francesca, Esposito, Chiara, Martino, Tiziana, Mazzante, Irene, Petrollini, Martina, Simonelli, Maria, Vezza, Maurizio, Squitieri, Ferdinando, D'Alessio, Barbara, Lovo, Francesca, Bentivoglio, Anna Rita, Bove, Francesco, Catalli, Claudio, Di Giacopo, Raffaella, Fasano, Alfonso, Frontali, Marina, Guidubaldi, Arianna, Ialongo, Tamara, Jacopini, Gioia, Loria, Giovanna, Modoni, Anna, Petracca, Martina, Piano, Carla, Chiara, Piccininni, Quaranta, Davide, Romano, Silvia, Soleti, Francesco, Solito, Marcella, Spadaro, Maria, Torlizzi, Flavia, Coarelli, Giulia, Ferraldeschi, Michela, Ristori, Giovanni, van Hout, Monique S. E., van Vugt, Jeroen P. P., Marit de Weert, A., Verhoeven, Marloes, Dekker, Meike, Klooster, Jesper, Leenders, Nico, van Oostrom, Joost, Kremer, Berry, Baake, Verena, van den Bogaard, Simon J. A., Dumas, Eve M., t Hart, Ellen P., Hogenboom, Marye, Jacobs, Milou, Jurgens, Caroline, Kampstra, Anne, Schoonderbeek, Anne, Witjes-Ané, Marie-Noëlle, Duits, Annelien, Waber, Mirella, Verstappen, Carla, Blinkenberg, Ellen Økland, Hauge, Erik, Tyvoll, Hilde, Aaserud, Olaf, Aanonsen, Nils Olaf, Bjørgo, Kathrine, Borgerød, Nancy, Dramstad, Elisabeth, Fannemel, Madeleine, Frich, Jan C., Gørvell, Per F., Haggag, Kathrine, Johannessen, Cecilie Haggag, Retterstøl, Lars, Røsby, Oddveig, Rummel, Jutta, Sikiric, Alma, Stokke, Bodil, van Walsem, Marleen, Wehus, Ragnhild, Arntsen, Vibeke, Bjørnevoll, Inga, Sando, Sigrid Botne, Haug, Marte Gjøl, Størseth, Hanna Haugan, Østern, Rune, Paulsen, Julie, Dziadkiewicz, Artur, Konkel, Agnieszka, Narożańska, Ewa, Nowak, Malgorzata, Robowski, Piotr, Sitek, Emilia, Slawek, Jaroslaw, Soltan, Witold, Szinwelski, Michal, Arkuszewski, Michał, Błaszczyk, Magdalena, Boczarska-Jedynak, Magdalena, Ciach-Wysocka, Ewelina, Gorzkowska, Agnieszka, Jasińska-Myga, Barbara, Kaczmarczyk, Aleksandra, Kłodowska – Duda, Gabriela, Opala, Grzegorz, Rudzińska, Monika, Stompel, Daniel, Banaszkiewicz, Krzysztof, Boćwińska, Dorota, Bojakowska-Jaremek, Kamila, Dec, Małgorzata, Grabska, Natalia, Krawczyk, Malgorzata, Kubowicz, Ewelina, Malec-Litwinowicz, Michalina, Stenwak, Agata, Szczudlik, Andrzej, Szczygieł, Elżbieta, Wójcik, Magdalena, Wasielewska, Anna, Anna Bryl, Jacek Anioła, Ciesielska, Anna, Klimberg, Aneta, Marcinkowski, Jerzy, Samara, Husam, Sempołowicz, Justyna, Wiśniewski, Bartłomiej, Gogol (formerly Kalbarczyk), Anna, Janik, Piotr, Jamrozik, Zygmunt, Kaminska, Anna, Kwiecinski+, Hubert, Antczak, Jakub, Jachinska, Katarzyna, Krysa, Wioletta, Rakowicz, Maryla, Rola, Rafal, Ryglewicz, Danuta, Sienkiewicz-Jarosz, Halina, Stępniak, Iwona, Sułek, Anna, Zaremba, Jacek, Zdzienicka, Elzbieta, Ziora-Jakutowicz, Karolina, Januário, Cristina, Júlio, Filipa, Almeida, Manuel, Calado, Ana, Dias, Margarida, Morgado, Joana, Semedo, Cristina, Coelho, Miguel, Magalhães, Andreia, Mendes, Tiago, Neutel, Dulce, Rodrigues, Filipe, Valadas, Anabela, Costa, Cristina, Cardoso, Helena, Santos, Mariana, Cação, Gonçalo, Cavaco, Sara, Damásio, Joana, Fernandes, Joana, Gonçalves, Alexandra, Loureiro, Rui, Moreira, Inês, Magalhães, Marina, Salgado, Paula, Andrade, Carlos, Costa, Andreia, Garrett, Carolina, Gago, Miguel, Guimarães, Joana, Massano, João, Meireles, Joana, Monteiro, Ana, Khasanova, Diana, Zalyalova, Zuleykha, Klyushnikov, Sergey, Sidorova, Olga, Smirnov, Oleg, Antonova, Victoria, Kopishinskaya, Svetlana, Korotysh, Maria, Magzhanov, Rim, Saifullina, Elena, Kurbatov, Sergey, Solis, Pilar, Herrera, Carmen Durán, Moreno, Patrocinio Garcia, Bas, Jordi, Busquets, Núria, Calopa, Matilde, Classen, Serge Jaumà, Dedichá, Nadia Rodríguez, Buongiorno, María Teresa, María, Andrés de la Cerda Santa, Muñoz, Esteban, Santacruz, Pilar, Barbera, Miquel Aguilar, Pardo, Sonia Arribas, Guia, Dolors Badenes, Calzado, Noemi, Hernanz, Laura Casas, Tartari Díaz-Zorita, Juan Pablo, Catena, Judit López, Ferrer, Pilar Quiléz, Carruesco, Gemma Tome, Robert, Misericordia Floriach, Viladrich, Cèlia Mareca, Roca, Elvira, Ruiz Idiago, Jesús Miguel, Riballo, Antonio Villa, Campolongo, Antonia, Fernandez de Bobadilla, Ramon, Bojarsky, Jaime Kulisevsky, Pagonabarraga, Javier, Perez, Jesus Perez, Ribosa, Roser, Villa, Carolina, Acera Gil, Maria Angeles, Corrales, Koldo Berganzo, Gomez Esteban, Juan Carlos, González, Amaia, Merino, Beatriz Tijero, Cubo, Esther, Polo, Cecilia Gil, Mariscal, Natividad, Sánchez, Jesús, Romero, Sandra Gutierrez, Arbelo, José Matías, Malo de Molina, Rocío, Martín, Idaira, Periañez, Juan Manuel, Udaeta, Beatriz, Alonso-Frech, Fernando, Loarte, María del Valle, Barrero, Francisco, Morales, Blas, Frades, Belén, Villanueva, Marina Ávila, Zea Sevilla, Maria Ascension, Fenollar, María del Mar, García-Ramos García, Rocío, Villanueva, Clara, Bascuñana, Mónica, Ventura, Marta Fatás, Caldentey, Juan García, Ribas, Guillermo García, García de Yébenes, Justo, López-Sendón Moreno, José Luis, Barral, Verónica Mañanes, Feliz, Cici, García Ruíz, Pedro José, García, Ana, López, Rosa Guerrero, Bárcenas, Antonio Herranz, Martínez-Descals, Asunción, Pueyo, Angel Martínez, Martin, Veronica Puertas, Martínez, Noelia Rodríguez, Montojo, Teresa, Sainz Artiga, María José, Sánchez, Vicenta, Alarcón, María Dolores, Almagro, Carmen Antúnez, Diéguez, Esther, Fortuna, Lorenza, Legaz, Agustina, Manzanares, Salvadora, Muñoz, Juan Marín, Antequera Torres, María Martirio, Perea, Fuensanta Noguera, Vivancos, Laura, González, Sonia, Guisasola, Luis Menéndez, Prieto, Marta Para, Ribacoba, René, Salvador, Carlos, Lozano, Pablo Sánchez, Ramirez, Inés Legarda, Benito, Dolors Moragues, Arques, Penelope Navas, Lopera, Monica Rodriguez, Pastor, Barbara Vives, Gaston, Itziar, Garcia-Amigot, Fermin, Martinez-Jaurrieta, Maria Dolores, Ramos-Arroyo, Maria Antonia, Adarmes, Astrid, Bernal-Escudero, Maravilla, Carrillo, Fátima, Jesús, Silvia, Mir, Pablo, Vargas-González, Laura, Hermoso, Fátima Damas, García Moreno, José Manuel, Jaramillo, Javier Abril, Lucena, Carolina Mendez, Pacheco Cortegana, Eva María, Peña, José Chacón, Redondo, Luis, Sánchez, Violeta Sánchez, Fernandez, Cristina Melgar, Romero Lemos, María Dolores, Mata, Maite Paredes, Casado, Rocío Villagrán, Bosca, Maria, Burguera, Juan Andres, Brugada, Francisco Castera, Millán Salvador, Jose Maria, Vilaplana, Carmen Peiró, Solís, Pilar, Figuerola, Begoña Jeweinat, Palanca, Paloma Millan, Diago, Elena Bellosta, López del Val, Javier, Martinez, Laura Martinez, López, Elena, Høsterey-Ugander, Ulrika, Fredlund, Gunnel, Constantinescu, Radu, Lewin, Kajsa, Neleborn-Lingefjärd, Liselotte, Berglund, Maria, Berglund, Peter, Linnsand, Petra, Petersén, Åsa, Reimer, Jan, Widner, Håkan, Esmaeilzadeh, Mouna, Tedroff, Joakim, Winnberg, Elisabeth, Benaminov, Stanislav, Björnsson, Elisabeth, Merrick, Daniel, Paucar, Martin, Svenningsson, Per, Wallden, Tina, Berglund, Måns, Loutfi, Ghada, Olofsson, Carina, Stattin, Eva-Lena, Westman, Laila, Wikström, Birgitta, Ekwall, Camilla, Göller, Marie-Lousie, Johansson, Anders, Niemelä, Valter, Nyholm, Dag, Wiklund, Leif, Koehli, Jessica, Stebler, Yanik, Kaelin, Alain, Romero, Irene, Schüpbach, Michael, Zaugg, Sabine Weber, Esposito, Federica, Good, Jean-Marc, Paus, Karin, Vingerhoets, Francois, Wider+, Christian, Jung, Hans H., Petersen, Jens A., Ligon-Auer, Maria, Mihaylova, Violeta, Downie, Lorna, Jack, Roisin, Matheson, Kirsty, Miedzybrodzka, Zosia, Rae, Daniela, Simpson, Sheila A., Summers, Fiona, Ure, Alexandra, Vaughan, Vivien, Harrower, Timothy, Vernon, Nathan, Akhtar, Shahbana, Crooks, Jenny, Curtis, Adrienne, de Souza (Keylock), Jenny, Piedad, John, Rickards, Hugh, Wright, Jan, Haig-Brown, Diane, Craven, Janet, Pallett, Andrew, Simpson, Steve, Weekes, Rebecca, Coulthard, Elizabeth, Gethin, Louise, Hayward, Beverley, Sieradzan, Kasia, Barker, Roger A., O'Keefe, Deidre, Gerrtiz (nee Di Pietro), Anna, Fisher, Kate, Goodman, Anna, Hill, Susan, Mason, Sarah, Swain, Rachel, Guzman, Natalie Valle, Busse, Monica, Butcher, Cynthia, Dunnett, Stephen, Clenaghan, Catherine, Hunt, Sarah, Jones, Lesley, Jones, Una, Khalil, Hanan, Owen, Michael, Price, Kathleen, Rosser, Anne, Goudie, David, Buchanan, Lindsay, Mcfadyen, Paula, Tonner, Alison, Taylor, Anne-Marie, Edwards, Maureen, Carrie, Ho, Mcgill, Marie, Porteous, Mary, Pearson, Pauline, Irvine, Sarah, Brockie, Peter, Foster, Jillian, Johns, Nicola, Mckenzie, Sue, Rothery, Jean, Thomas, Gareth, Yates, Shona, Neumann, Christian, Patterson, Kirsten, Thomson, David, Deith, Catherine, Ireland, Jane, Ritchie, Stuart, Brown, Pauline, Burrows, Liz, Fletcher, Amy, Harding, Alison, Harrison, Kaye, Laver, Fiona, Silva, Mark, Thomson, Aileen, Chu, Carol, Evans, Carole, Gallentree, Deena, Hamer, Stephanie, Kraus, Alison, Markova, Ivana, Raman, Ashok, Rowett, Liz, Andrew, Alyson, Frost, Julie, Noad, Rupert, Cosgrove, Jeremy, Gallantree, Deena, Hobson, Emma, Jamieson, Stuart, Longthorpe, Mandy, Musgrave, Hannah, Peacy, Caroline, Toscano, Jean, Wild, Sue, Yardumian, Pam, Clayton, Carole, Dipple, Heather, Freire-Patino, Dawn, Hallam, Caroline, Middleton, Julia, Alusi, Sundus, Davies, Rhys, Foy, Kevin, Gerrans, Emily, Pate, Louise, Anjum, Uruj, Coebergh, Jan, Eddy, Charlotte, Lahiri, Nayana, Mcentagart, Meriel, Patton, Michael, Peterson, Maria, Rose, Sarah, Andrews, Thomasin, Dougherty, Andrew, Golding, Charlotte, Kavalier, Fred, Laing, Hana, Lashwood, Alison, Robertson, Dene, Ruddy, Deborah, Santhouse, Alastair, Whaite, Anna, Gosling (nee Brown), Stefanie, Bruno, Stefania, Chu, Elvina, Doherty, Karen, Haider, Salman, Hensman, Davina, Lewis, Monica, Novak, Marianne, Patel, Aakta, Robertson, Nicola, Rosser, Elisabeth, Tabrizi, Sarah, Taylor, Rachel, Warner, Thomas, Wild, Edward, Ackermann, Oda, Duport, Sophie, Scott, Adrienne, Stoy, Nicholas, Vaughn, Jenny, Arran, Natalie, Bek, Judith, Craufurd, David, Hare, Marianne, Howard, Liz, Huson, Susan, Johnson, Liz, Jones, Mary, Krishnamoorthy, Ashok, Murphy, Helen, Oughton, Emma, Partington-Jones, Lucy, Sollom, Andrea, Snowden, Julie, Stopford, Cheryl, Thompson, Jennifer, Trender-Gerhard, Iris, Verstraelen (formerly Ritchie), Nichola, Westmoreland, Leann, Cass, Ginette, Davidson, Lynn, Davison, Jill, Fullerton, Neil, Holmes, Katrina, Komati, Suresh, Mcdonnell, Sharon, Mohammed, Zeid, Morgan, Karen, Savage, Lois, Singh, Baldev, Wood, Josh, Knight, Caroline, O'Neill, Mari, Purkayastha, Debasish Das, Nemeth, Andrea H., Siuda, Gill, Valentine, Ruth, Dixon, Kathryn, Armstrong, Richard, Harrison, David, Hughes, Max, Large, Sandra, Donovan, John O., Palmer, Amy, Parkinson, Andrew, Soltysiak, Beverley, Timings, Leanne, Williams, Josh, Burn, John, Bailey, Wendy, Coleman, Caroline, Majeed, Tahir, Verstraelen (Ritchie), Nicola, Barrett, Wendy, Aileen, Ho, Bandmann, Oliver, Bradbury, Alyson, Fairtlough, Helen, Fillingham, Kay, Foustanos, Isabella, Gill, Paul, Kazoka, Mbombe, O'Donovan, Kirsty, Nevitt, Louise, Taylor, Cat, Tidswell, Katherine, Kipps, Christopher, Mackinnon, Lesley, Agarwal, Veena, Hayward, Elaine, Gunner, Kerry, Harris, Kayla, Anderson, Mary, Heywood, Melanie, Keys, Liane, Smalley, Sarah, El-Nimr, George, Duffell, Allison, Wood, Sue, Kennedy (nee Smith), Karen, Gowers, Lesley, Powell, Kingsley, Bethwaite, Pamela, Edwards, Rachel, Fuller, Kathleen, Phillips, Michelle, Tan, Louis, Lau, Puay Ngoh, Pica, Emmanuel, Roos, Raymund AC., Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), MUMC+: KIO Kemta (9), Epidemiologie, RS: CAPHRI - R2 - Creating Value-Based Health Care, Klinische Genetica, MUMC+: DA KG Polikliniek (9), and RS: GROW - R4 - Reproductive and Perinatal Medicine

Subjects
Male, HD, 0301 basic medicine, Pediatrics, Neurology, Huntingtin Protein/genetics, FEATURES, Disease, Neuropsychological Tests, 0302 clinical medicine, Cognitive Dysfunction/psychology, Medicine, Family history, Postural Balance, Huntington Disease/genetics, Huntingtin Protein, education.field_of_study, Chorea/physiopathology, Huntington's disease, Sensation Disorders/physiopathology, Middle Aged, Dystonia, Settore MED/26 - NEUROLOGIA, Huntington Disease, neurodegenerative disorders, Sensation Disorders, Disease Progression, Female, medicine.symptom, Adult, medicine.medical_specialty, Population, Age of onset, Late-onset Huntington's disease, Geriatrics and Gerontology, Neurology (clinical), 03 medical and health sciences, AGE, Chorea, Humans, Cognitive Dysfunction, education, Dystonia/physiopathology, Gait Disorders, Neurologic/physiopathology, Gait Disorders, Neurologic, business.industry, medicine.disease, Gait, 030104 developmental biology, Trinucleotide Repeat Expansion, business, 030217 neurology & neurosurgery, Balance problems
Abstract

Background: The frequency of late-onset Huntington's disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P

Published
2019
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93. Comparison of Pittsburgh compound B and florbetapir in cross‐sectional and longitudinal studies

Author

William S. Brooks, Ivonne Jimenez-Velazques, Jérémie Pariente, Andrei G. Vlassenko, William E. Klunk, Robert A. Koeppe, Serge Gauthier, Smiljana Milosavljevic-Ristic, Guoqiao Wang, Michel Bottlaender, Roger Clarnette, Shauna H. Yuan, Raquel Sánchez-Valle, Russ C. Hornbeck, Ging-Yuek Robin Hsiung, Gregory Klein, Clifford R. Jack, Colin L. Masters, Nelly Joseph-Mathurin, Bruno Dubois, Barbara J. Snider, Shaney Flores, Douglas Galasko, David Wallon, Chengjie Xiong, Tammie L.S. Benzinger, Stephen Salloway, Christopher H. van Dyck, Sarah B. Berman, Brian A. Gordon, Catherine J. Mummery, Michael J. Fulham, John C. Morris, Yi Su, John M. Ringman, Randall J. Bateman, Jared R. Brosch, Martin R. Farlow, Benjamin Speidel, Suman Jayadev, Erik D. Roberson, Didier Hannequin, Lawrence S. Honig, Eric McDade, and Mario Masellis

Subjects
Positron emission tomography, Multivariate statistics, Amyloid, PiB, Amyloid pet, Neuroimaging, lcsh:Geriatrics, Imaging data, lcsh:RC346-429, Amyloid imaging, White matter, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Nuclear magnetic resonance, Genetics, medicine, Centiloid, lcsh:Neurology. Diseases of the nervous system, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, business.industry, Significant difference, Neurosciences, Florbetapir, lcsh:RC952-954.6, Psychiatry and Mental health, medicine.anatomical_structure, chemistry, Neurology (clinical), business, Pittsburgh compound B, 030217 neurology & neurosurgery
Abstract

Introduction Quantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B–based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design. Methods Pittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally. Results Global amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers. Discussion Although the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.

Published
2019
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94. Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification

Author

Nicolas, Gaël, Pottier, Cyril, Charbonnier, Camille, Guyant-Maréchal, Lucie, Le Ber, Isabelle, Pariente, Jérémie, Labauge, Pierre, Ayrignac, Xavier, Defebvre, Luc, Maltête, David, Martinaud, Olivier, Lefaucheur, Romain, Guillin, Olivier, Wallon, David, Chaumette, Boris, Rondepierre, Philippe, Derache, Nathalie, Fromager, Guillaume, Schaeffer, Stéphane, Krystkowiak, Pierre, Verny, Christophe, Jurici, Snejana, Sauvée, Mathilde, Vérin, Marc, Lebouvier, Thibaud, Rouaud, Olivier, Thauvin-Robinet, Christel, Rousseau, Stéphane, Rovelet-Lecrux, Anne, Frebourg, Thierry, Campion, Dominique, Hannequin, Didier, Ahtoy, Patrick, Anheim, Mathieu, Augustin, Jérôme, Ayrignac, Xavier, Bille-Turc, Françoise, Campion, Dominique, Chaumette, Boris, Clanet, Michel, Defebvre, Luc, Defer, Gilles, Derache, Nathalie, Didic, Mira, Durif, Franck, Flamand-Roze, Emmanuel, Fromager, Guillaume, Giroud, Maurice, Goldenberg, Alice, Guillin, Olivier, Guyant-Maréchal, Lucie, Hannequin, Didier, Hubsch, Cécile, Jurici, Snejana, Krystkowiak, Pierre, Labauge, Pierre, Layet, Antoine, Le Ber, Isabelle, Lebouvier, Thibaud, Lefaucheur, Romain, Maltête, David, Morcamp, Olivier Martinaud Donald, Nicolas, Gaël, Ozkul, Ozlem, Pariente, Jérémie, Pottier, Cyril, Rondepierre, Philippe, Rouaud, Olivier, Sallé, Brigitte, Sauvée, Mathilde, Schaeffer, Stéphane, Thauvin-Robinet, Christel, Thomas-Antérion, Catherine, Tranchant, Christine, Triquenot, Aude, Vaschalde, Yvan, Vérin, Marc, Verny, Christophe, Vidailhet, Marie, and Wallon, David

Published
2013
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97. Adult-onset genetic leukoencephalopathies: A MRI pattern-based approach in a comprehensive study of 154 patients

Author

Ayrignac, Xavier, Carra-Dalliere, Clarisse, Menjot de Champfleur, Nicolas, Denier, Christian, Aubourg, Patrick, Bellesme, Celine, Castelnovo, Giovanni, Pelletier, Jean, Audoin, Bertrand, Kaphan, Elsa, de Seze, Jerome, Collongues, Nicolas, Blanc, Frederic, Chanson, Jean-Baptiste, Magnin, Eloi, Berger, Eric, Vukusic, Sandra, Durand-Dubief, Francoise, Camdessanche, Jean-Philippe, Cohen, Mickael, Lebrun-Frenay, Christine, Brassat, David, Clanet, Michel, Vermersch, Patrick, Zephir, Helene, Outteryck, Olivier, Wiertlewski, Sandrine, Laplaud, David-Axel, Ouallet, Jean-Christophe, Brochet, Bruno, Goizet, Cyril, Debouverie, Marc, Pittion, Sophie, Edan, Gilles, Deburghgraeve, Véronique, Le Page, Emmanuelle, Verny, Christophe, Amati-Bonneau, Patrizia, Bonneau, Dominique, Hannequin, Didier, Guyant-Maréchal, Lucie, Derache, Nathalie, Louis Defer, Gilles, Moreau, Thibault, Giroud, Maurice, Guennoc, Anne Marie, Clavelou, Pierre, Taithe, Frédérique, Mathis, Stephane, Neau, Jean-Philippe, Magy, Laurent, Devoize, Jean Louis, Bataillard, Marc, Masliah-Planchon, Julien, Dorboz, Imen, Tournier-Lasserve, Elisabeth, Levade, Thierry, Boespflug Tanguy, Odile, and Labauge, Pierre

Published
2015
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98. 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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100. Plasma NfL levels and longitudinal change rates in

Author

Dario, Saracino, Karim, Dorgham, Agnès, Camuzat, Daisy, Rinaldi, Armelle, Rametti-Lacroux, Marion, Houot, Fabienne, Clot, Philippe, Martin-Hardy, Ludmila, Jornea, Carole, Azuar, Raffaella, Migliaccio, Florence, Pasquier, Philippe, Couratier, Sophie, Auriacombe, Mathilde, Sauvée, Claire, Boutoleau-Bretonnière, Jérémie, Pariente, Mira, Didic, Didier, Hannequin, David, Wallon, Olivier, Colliot, Bruno, Dubois, Alexis, Brice, Richard, Levy, and Sylvie, Forlani

Subjects
Adult, Aged, 80 and over, Male, C9orf72 Protein, Amyotrophic Lateral Sclerosis, Middle Aged, Progranulins, Neurofilament Proteins, Frontotemporal Dementia, Disease Progression, Humans, Female, Neurogenetics, Aged
Abstract

Objective Neurofilament 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. Methods We 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. Results pNfL levels increased with age in controls, from ~5 to~18 pg/mL (p

Published
2021

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