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1. Ageing stereotypes and prodromal Alzheimer’s disease (AGING): study protocol for an ongoing randomised clinical study

Author

Ahmed Abbas, Didier Hannequin, Olivier Martinaud, David Wallon, Vincent de la Sayette, Adrien Julian, Marc Paccalin, Julien Cogez, Kim Gauthier, Alexandrine Morand, Frederic Dutheil, Béatrice Alescio-Lautier, José Boucraut, David Clarys, Francis Eustache, Nadine Girard, Eric Guedj, Marie Mazerolle, Aline Zaréa, Pascal Huguet, Bernard F Michel, Béatrice Desgranges, Isabelle Régner, José Broucraut, Boris Dufournet, Carine Giallo, Bernard François Michel, Nathalie Sambuchi, Pierre Branger, Sabine Fradin, Frédérique Grandhomme, Catherine Lalevée, Nadège Loisel, Alice Pélerin, Mélissa Pierre, Vincent de La Sayette, Alain Manrique, Vanessa Baudifier, Foucaud du Boisgueheneuc, Jean-Claude Lecron, Isabelle Merlet, Claudie Ornon, Sandrine Bioux, Evangeline Bliaux, Véronique Hannier, Maud Loubeyre, Dorothée Pouliquen, Muriel Quillard-Muraine, Véronique Paban, Arnaud Weill, Michel Isingrini, Sandrine Kalenzaga, François Rigalleau, Julien Chavant, Florence Fraisse, Mickael Laisney, Shailendra Segobin, Pierre Chausse, Julien Guegan, Guillaume Vallet, Sophie Blanchet, and Pascale Piolino

Subjects
Medicine
Abstract

Introduction The number of older people diagnosed with amnestic mild cognitive impairment (aMCI), the prodromal state of Alzheimer's disease (AD), is increasing worldwide. However, some patients with aMCI never convert to the AD type of dementia, with some remaining stable and others reverting to normal. This overdiagnosis bias has been largely overlooked and gone unexplained. There is ample evidence in the laboratory that negative ageing stereotypes (eg, the culturally shared belief that ageing inescapably causes severe cognitive decline) contribute to the deteriorating cognitive performances of healthy older adults, leading them to perform below their true abilities. The study described here is intended to test for the first time whether such stereotypes also impair patients’ cognitive performances during neuropsychological examinations in memory clinics, resulting in overdiagnosis of aMCI.Methods and analysis The ongoing study is a 4-year randomised clinical trial comparing patients’ physiological stress and cognitive performances during neuropsychological testing in memory clinics. A total of 260 patients attending their first cognitive evaluation will be randomised to either a standard condition of test administration, assumed here to implicitly activate negative ageing stereotypes or a reduced-threat instruction condition designed to alleviate the anxiety arising from these stereotypes. Both groups will be tested with the same test battery and stress biomarkers. For 30 patients diagnosed with aMCI in each group (n=60), biomarkers of neurodegeneration and amyloidopathy will be used to distinguish between aMCI with normal versus abnormal AD biomarkers. A 9-month follow-up will be performed on all patients to identify those whose cognitive performances remain stable, deteriorate or improve.Ethics and dissemination This protocol has been approved by the French National Agency for Medicines and Health Products Safety and the Sud-Est I French Ethics Committee (2017-A00946-47). Results will be published in peer-reviewed journals.Trial registration number NCT03138018.

Published
2019
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2. Primary progressive aphasias associated with C9orf72 expansions: Another side of the story

Author

idier Hannequin, Eino Solje, Sabrina Sayah, Emmanuel Gerardin, Marie Sarazin, Florence Pasquier, Marion Houot, Assi-Hervé Oya, Martine Vercelletto, Julien Lagarde, Marie Noguès-Lassiaille, Marie Chupin, Vincent Deramecourt, Sophie Auriacombe, Agnès Camuzat, Marc Teichmann, Jérémie Pariente, Sophie Ferrieux, Lucette Lacomblez, Mathieu Chastan, Jacques Monteil, Yaohua Chen, Marie-Paule Boncoeur, Lorenzo Cipriano, Anne Bissery, Simona Bottani, David Wallon, Christine Delmaire, Carole Roué-Jagot, Benjamin Le Toullec, Bernard-François Michel, Grégory Petyt, Olivier Martinaud, Philippe Couratier, Dario Saracino, Adeline Rollin-Sillaire, Daisy Rinaldi, Mira Didic, Serge Belliard, Amandine Géraudie, Géraldine Lautrette, Frédérique Etcharry-Bouyx, Xavier Delbeuck, Richard Levy, Frédéric Blanc, Mathieu Ceccaldi, Christel Thauvin-Robinet, Marie-Odile Habert, Eve Benchetrit, Maïté Formaglio, Alexis Brice, Isabelle Le Ber, Charles Duyckaerts, Véronique Golfier, Raffaella Migliaccio, Marie-Anne Mackowiak, Catherine Thomas-Antérion, Anne Bertrand, Olivier Colliot, François Sellal, Claire Boutoleau-Bretonnière, Anne M. Remes, Hugo Bertin, Aurélie Funkiewiez, and Stéphanie Bombois

Subjects
medicine.medical_specialty, C9orf72 Protein, Apraxias, Cognitive Neuroscience, Inferior frontal gyrus, Experimental and Cognitive Psychology, Frontotemporal lobar degeneration, respiratory system, Audiology, medicine.disease, Magnetic Resonance Imaging, Apraxia, Primary progressive aphasia, Aphasia, Primary Progressive, Neuropsychology and Physiological Psychology, Atrophy, C9orf72, medicine, Humans, Speech, Orbitofrontal cortex, Psychology, Language, Frontotemporal dementia
Abstract

C9orf72 repeat expansions are rarely associated with primary progressive aphasias (PPA). In-depth characterization of the linguistic deficits, and the underlying patterns of grey-matter atrophy in PPA associated with the C9orf72 expansions (PPA-C9orf72) are currently lacking. In this study, we comprehensively analyzed a unique series of 16 patients affected by PPA-C9orf72. Eleven patients were issued from two independent French and Finnish cohorts, and five were identified by means of literature review. Voxel-based morphometry (VBM) studies were performed on three of them. This study depicts the spectrum of C9orf72–related aphasic phenotypes, and illustrates their linguistic presentation. The non-fluent/agrammatic variant was the most frequent phenotype in our series (9/16 patients, 56%), with apraxia of speech being the main defining feature. Left frontal lobe atrophy was present in these subjects, peaking in inferior frontal gyrus. Three patients (19%) showed the semantic variant, with progression of atrophy in temporo-polar regions, later involving orbitofrontal cortex. Anterior temporal lobe dysfunction was also particularly relevant in two patients (12.5%) with mixed forms of PPA. Lastly, two patients (12.5%) had unclassifiable PPA with predominating word-finding difficulties. No PPA-C9orf72 patients in our series fulfilled the criteria of the logopenic variant. Importantly, this study underlines the role of C9orf72 mutation in the disruption of the most anterior parts of the language network, including prefrontal and temporo-polar areas. It provides guidelines for C9orf72 testing in PPA patients, with important clinical impact as gene-specific therapies are upcoming.

Published
2021
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3. Challenges in Disease and Health Research Vol. 1

Author

B. M. Duduyemi, A. R. Vhriterhire, Someya Tetsunei, M. Ogiator, D. Dzuachii, N. C. Ahachi, M. Efu, V. I. Ugwu, Kalam Singh Butola, Bernard-François Michel, S. A. Longwam, Béatrice Alescio-Lautier, M. T. Maanongun, Mercy Solomon, Minegishi Yoshinori, B. A. Ojo, P. Abayol, Ayuba Affi, Vasileios Margaritis, Arun Saxena, Dalili Shabbal, C. Ahachi, A. Lukdem, Hellen Kariuki, Bhawna Sethi, Vadim Belenky, E. Agada, A. O. Ojabo, W. T. Yongu, G. Shorun, Aaron Mendelsohn, Deepak Dimri, Aabid A. Ahmed, E. O. Umobong, Nathalie Sambucchi, Ganiyu Amusa, T. Selowo, A. A. Jenrola, Chukwukadibia N. Ahachi, Elmar H. Frangenberg, Caroline Chambon, Peña Betancourt Silvia Denise, George B. Kudolo, Yogesh Kumar, Sasaki Jin-Ichi, Posadas Manzano Eduardo, Neha Prabhakar, I. Okolie, P. Denen-Akaa, B. A. Eke, and B. A. Kobrinskii

Subjects
medicine.medical_specialty, business.industry, Family medicine, medicine, Disease, business
Published
2020
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4. Approximate quantification in young, healthy older adults’, and Alzheimer patients

Author

Patrick Lemaire, Bernard François Michel, Delphine Gandini, Laboratoire de psychologie cognitive (LPC), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
Adult, Male, Aging, medicine.medical_specialty, Adolescent, Cognitive Neuroscience, Experimental and Cognitive Psychology, Disease, Choice Behavior, Developmental psychology, Young Adult, Cognition, Physical medicine and rehabilitation, Arts and Humanities (miscellaneous), Alzheimer Disease, Developmental and Educational Psychology, medicine, Humans, Dementia, Young adult, Cognitive decline, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Estimation, Analysis of Variance, Mathematical Concepts, Middle Aged, medicine.disease, Numero sign, Neuropsychology and Physiological Psychology, [SCCO.PSYC]Cognitive science/Psychology, Visual Perception, Female, Alzheimer's disease, Psychology, Photic Stimulation
Abstract

Forty young adults, 40 healthy older adults, and 39 probable AD patients were asked to estimate small (e.g., 25) and large (e.g., 60) collections of dots in a choice condition and in two no-choice conditions. Participants could choose between benchmark and anchoring strategies on each collection of dots in the choice condition and were required to use either benchmark or anchoring on all configurations in the no-choice conditions (one per strategy). The benchmark strategy involves visual estimation processes whereas the anchoring strategy involves both enumeration and estimation processes. Results showed that strategy use was influenced by collection, participant, and strategy characteristics. Age-related and dementia-related differences were found in both strategy use and strategy execution. The findings have implications for our understanding of aging effects in approximate quantification, strategic variations in Alzheimer's patients, and sources of cognitive decline during early stages of Alzheimer's disease.

Published
2009
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5. TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts

Author

Isabelle Le Ber, Anne De Septenville, Stéphanie Millecamps, Agnès Camuzat, Paola Caroppo, Philippe Couratier, Frédéric Blanc, Lucette Lacomblez, François Sellal, Marie-Céline Fleury, Vincent Meininger, Cécile Cazeneuve, Fabienne Clot, Olivier Flabeau, Eric LeGuern, Alexis Brice, Sophie Auriacombe, Mira Didic, Bruno Dubois, Véronique Golfier, Didier Hannequin, Richard Levy, Bernard-François Michel, Florence Pasquier, Catherine Thomas-Anterion, Michèle Puel, François Salachas, and Martine Vercelletto

Subjects
Aging, Mutation rate, Protein Serine-Threonine Kinases, medicine.disease_cause, Cohort Studies, Mutation Rate, C9orf72, mental disorders, medicine, Missense mutation, Humans, Amyotrophic lateral sclerosis, Loss function, Genetic Association Studies, Optineurin, Genetics, Mutation, business.industry, General Neuroscience, Amyotrophic Lateral Sclerosis, nutritional and metabolic diseases, medicine.disease, nervous system diseases, Frontotemporal Dementia, Neurology (clinical), France, Geriatrics and Gerontology, business, Developmental Biology, Frontotemporal dementia
Abstract

TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%-4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. We identified 5 LoF mutations, in 4 FTD-ALS and 1 ALS patients. We also identified 5 heterozygous missense variants, predicted to be deleterious, in 1 isolated FTD, 1 FTD-ALS, and 3 ALS cases. Our results demonstrate that TBK1 loss-of-function mutations are more frequent in patients with FTD-ALS (10.8%) than in isolated ALS. TBK1 should thus also be sequenced, after exclusion of C9orf72 mutation, in patients presenting FTD, particularly in cases secondarily associated with ALS.

Published
2015

6. Pharmacologie de la maladie d’Alzheimer : vision du futur

Author

Bernard-François Michel, François Sellal, Lucette Lacomblez, Danièle Bentué-Ferrer, Hugo Geerts, Régis Bordet, André Nieoullon, Alexandra Delini-Stula, Hervé Allain, and Géraldine Michel

Subjects
Rivastigmine, Pathology, medicine.medical_specialty, business.industry, Memantine, medicine.disease, Biochemistry of Alzheimer's disease, Drug development, medicine, Galantamine, Dementia, Pharmacology (medical), Alzheimer's disease, business, Donepezil, Neuroscience, medicine.drug
Abstract

Ten years after the introduction of the first drug for the treatment of Alzheimer's disease, tacrine, it seems appropriate to reappraise the pharmacological processes of innovation in the field of research in dementia. The aim of this review is to pinpoint concrete improvements achieved in this field, in terms of experimental methods and clinical evaluation of the compounds, as well as the neurochemistry of the disease and cellular targets deserving of initial consideration. * The article first considers the use of animal models of Alzheimer's disease, which are classified according to two categories: animals with lesions of some neuronal pathways specifically implicated in clinical symptoms (i.e. lesions of the nucleus basalis of Meynert, the origin of cholinergic projections to the cortex underlying memory processes); and transgenic models, which are intended to reproduce some of the neuropathological hallmarks of Alzheimer's disease. Drugs can be tested in animals with such alterations for their effect on neuropathology, neurochemistry and behavioural disturbances. More recently, in silico models have been developed, which offer the possibility of simulating the pharmacodynamic effects of drugs in specific areas of the brain. These experiments are helpful in distinguishing purely symptomatic effects from disease-modifying effects, the latter being the ultimate goal of the modern pharmacology of dementia. * The second breakthrough considered in this article is the codification and standardisation of clinical methods for obtaining a more accurate and earlier diagnosis (the recent introduction of the concept of "Mild Cognitive Impairment", which includes patients who will later develop a true clinical dementia syndrome). In that respect, the determination of the biological markers of Alzheimer's disease (apolipoprotein E, amyloid substance, protein-tau, isoprostane) as well as progress in neuroimaging (functional positron emission tomography [fPET]-scan, single photon emission-computed tomography [SPECT], functional nuclear magnetic resonance [fNMR]) are discussed in terms of their potential as new tools in the early stages of drug development (surrogate markers). The methods used during the comparative clinical trials (phase III) have been elaborated and internationally standardised during the assessment of the different acetylcholinesterase inhibitors (AChE-I), with the knowledge that, since 1994, four of these have been officially approved: tacrine, donepezil, rivastigmine and galantamine; the same methods have been used for developing memantine, a recently-launched modulator of glutamatergic neurotransmission. The validated scales now take into consideration not only the cognitive dimensions of Alzheimer's disease but also the behavioural symptoms, with the introduction of the concept of BPSD (behavioural psychological symptoms of dementia). Some proposals to improve this clinical assessment of anti-dementia drugs are presented here. * The section of this article dealing with prospective issues considers the main pathways of interest in drug innovation and the elucidation of new targets for the future compounds. As well as their symptomatic effects on the different components of cognition, drugs should be neuroprotective and limit the lesions documented in Alzheimer's disease, with the aim of progressing far beyond the amyloid hypothesis (immunisation, beta-sheet breakers, secretase inhibitors). The field of excitotoxicity (which is mainly glutamate dependent) appears fruitful, because of the possibility of pharmacological intervention at the different steps in the excitotoxic process. All the new directions presented in this article support the concept of true disease-modifying agents. In conclusion, this prospective review should be considered as a guide in fostering drug innovation in Alzheimer's disease and related disorders and should help to decrease the gap existing between neuroscience and therapeutics.

Published
2005
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7. Étude contrôlée, en double aveugle, en groupe parallèle, de l’efficacité et de la tolérance de la mémantine (20 mg) versus placebo chez des patients présentant une variante comportementale de démence frontotemporale

Author

Sophie Auriacombe, Patrice Verpillat, C. Volteau, Audrey Gabelle, M. Vercelletto, Lucette Lacomblez, Philippe Couratier, C. Thomas Antérion, M. Puel, Bernard-François Michel, Marie Sarazin, V. Golfier, Claire Boutoleau-Bretonnière, and E. Cerato

Subjects
Neurology, business.industry, Medicine, Neurology (clinical), business
Published
2010
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8. C9ORF72 repeat expansions in the frontotemporal dementias spectrum of diseases: a flow-chart for genetic testing

Author

Patrice Verpillat, Isabelle Le Ber, François Sellal, Michèle Puel, Marie Fleury, Lena Guillot-Noel, Catherine Thomas-Antérion, Sophie Rivaud-Péchoux, Isabelle Wargon, Didier Hannequin, Frédéric Blanc, Vincent Deramecourt, Florence Pasquier, Merle Ruberg, Lucette Lacomblez, Philippe Couratier, Martine Vercelletto, Jérémie Pariente, Cyril Goizet, Alexis Brice, Véronique Golfier, Christel Thauvin-Robinet, Karl Mondon, Olivier Martinaud, Elisabeth Tournier-Lasserve, Eric Berger, William Camu, François Salachas, Bruno Dubois, Mira Didic, Agnès Camuzat, Charles Duyckaerts, Stéphanie Millecamps, Danielle Seilhean, Gabriel Viennet, Bernard-François Michel, Mathilde Sauvée, Vincent Meininger, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Imagerie cérébrale et handicaps neurologiques (ICHN), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Troubles cognitifs vasculaires et dégénératifs - EA 2691 (TCDV), Université de Lille, Droit et Santé, Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Service de Neurologie [CHU Limoges], CHU Limoges, Service de neurologie, Hôpital pasteur [Colmar], Département de neurologie [Lille], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Mémoire de Ressource et Recherche (CMRR), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service de neurologie et de neuropsychologie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), The Mediterranean Institute of Neurobiology, Physiologie et physiopathologie de la motricité chez l'homme, Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Department of Experimental Cardiology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Estrogènes, Expression génique et pathologies du Système Nerveux Central - UFC (E2SNC / ESTROGENES), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neurologie [Lille], Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Saint-Etienne-Hôpital Bellevue, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], 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 Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Pathology, MESH: DNA Repeat Expansion, MESH: Genetic Markers, Primary progressive aphasia, Cohort Studies, 0302 clinical medicine, MESH: Aged, 80 and over, C9orf72, Software Design, Corticobasal degeneration, MESH: Proteins, MESH: Cohort Studies, Aged, 80 and over, MESH: Aged, 0303 health sciences, DNA Repeat Expansion, MESH: Middle Aged, medicine.diagnostic_test, MESH: Genetic Testing, General Neuroscience, Parkinsonism, Age Factors, General Medicine, Middle Aged, Penetrance, Pedigree, Psychiatry and Mental health, Clinical Psychology, Frontotemporal Dementia, Female, Psychology, Frontotemporal dementia, Adult, Genetic Markers, medicine.medical_specialty, MESH: Pedigree, MESH: Frontotemporal Dementia, Progressive supranuclear palsy, 03 medical and health sciences, Sex Factors, MESH: Sex Factors, Internal medicine, mental disorders, medicine, Humans, Genetic Testing, 030304 developmental biology, Genetic testing, Aged, MESH: Age Factors, MESH: Humans, C9orf72 Protein, Proteins, MESH: Adult, medicine.disease, MESH: Male, nervous system diseases, MESH: Software Design, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Geriatrics and Gerontology, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies in the literature (23-50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9-56.1) than in MAPT patients (46.8, 95%CI: 43.0-50.6; p = 0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6-61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed.

Published
2013
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9. Positive effects of computer-based cognitive training in adults with mild cognitive impairment

Author

Caroline Chambon, Veronique Paban, Béatrice Alescio-Lautier, Bernard-François Michel, Cathy Herrera, Laboratoire de Neurosciences intégratives et adaptatives (LNIA), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, medicine.medical_specialty, Aging, Cognitive Neuroscience, education, Experimental and Cognitive Psychology, Neuropsychological Tests, 050105 experimental psychology, law.invention, Memory and attention, Episodic recall, 03 medical and health sciences, Behavioral Neuroscience, [SCCO]Cognitive science, 0302 clinical medicine, Physical medicine and rehabilitation, Randomized controlled trial, law, Alzheimer Disease, Memory, Intervention (counseling), Generalization (learning), medicine, Humans, 0501 psychology and cognitive sciences, Attention, Cognitive Dysfunction, Cognitive decline, Aged, Neuronal Plasticity, training, Recall, 05 social sciences, Cognition, Recognition, Psychology, Cognitive training, 3. Good health, Test (assessment), Recognition, Case-Control Studies, Mental Recall, Female, Neuroplasticity, Psychology, 030217 neurology & neurosurgery, Clinical psychology, Computer-Assisted Instruction
Abstract

International audience; Considering the high risk for individuals with amnestic Mild Cognitive Impairment (A-MCI) to progress towards Alzheimer's disease (AD), we investigated the efficacy of a non-pharmacological intervention, that is, cognitive training that could reduce cognitive difficulties and delay the cognitive decline. For this, we evaluated the efficacy of a 12-week computer-based memory-attention training program based on recognition in subjects with A-MCI and compared their performances with those of A-MCI controls trained in cognitively stimulating activities. The effect of training was assessed by comparing outcome measures in pre- and post-tests 15 days before and after training. To evaluate the duration of training benefits, a follow-up test session was performed 6 months after memory and attention training or cognitively stimulating activities. Outcome measures showed that the trained group, compared to control group, improved episodic recall and recognition. Six months after training, scores remained at the level of the post-test. Since the training program was exclusively based on recognition, our results showed a generalization from recognition to recall processes, which are memory components that represent part of the core cognitive impairments in individuals at risk of converting to AD. Thus, cognitive training based on recognition holds promise as a preventive therapeutic method and could be proposed as a non-pharmacological early-intervention strategy. Future investigations need to focus on methodological constraints and delineating possible neuroplastic mechanisms of action.

Published
2012
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10. Combined measurement of PEDF, haptoglobin and tau in cerebrospinal fluid improves the diagnostic discrimination between alzheimer's disease and other dementias

Author

Guillaume Vicat, Sandra Cobo, Jean-Daniel Abraham, Nicolas Salvetat, Jacques Touchon, Laurence Molina, Sophie Calvayrac-Pawlowski, Bernard-François Michel, Jeannette Fareh, Jean-Michel Verdier, Chantal Mourton-Gilles, Franck Molina, 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), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)

Subjects
Male, Proteomics, MILD COGNITIVE IMPAIRMENT, Health, Toxicology and Mutagenesis, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Clinical Biochemistry, Pilot Projects, medicine.disease_cause, Biochemistry, Severity of Illness Index, 0302 clinical medicine, Cerebrospinal fluid, MARKERS, Neurotrophic factors, OPERATING CHARACTERISTIC CURVES, ROC, OXIDATIVE STRESS, Aged, 80 and over, 0303 health sciences, biology, Haptoglobin, Middle Aged, Frontotemporal Dementia, Biomarker (medicine), Female, DIFFERENTIAL-DIAGNOSIS, Oxidation-Reduction, PHOSPHORYLATED-TAU, Molecular Sequence Data, EPITHELIUM-DERIVED FACTOR, Enzyme-Linked Immunosorbent Assay, tau Proteins, CELL-LINES, CSF, Antibodies, Diagnosis, Differential, 03 medical and health sciences, PEDF, Alzheimer Disease, medicine, Dementia, Humans, Amino Acid Sequence, Nerve Growth Factors, Eye Proteins, Serpins, 030304 developmental biology, Aged, Haptoglobins, business.industry, Dementia, Vascular, Biomarker, medicine.disease, Cognitive Test, Immunology, biology.protein, Differential diagnosis, business, 030217 neurology & neurosurgery, Oxidative stress, Biomarkers, Neurological disease, NEUROTROPHIC FACTOR
Abstract

International audience; Using proteomic approach in cerebrospinal fluid (CSF) we identified pigment epithelium-derived factor (PEDF) and Haptoglobin (Hp) as putative markers that could discriminate between AD and other dementias. ELISA assays were developed to measure the levels of PEDF and Hp in CSF from patients with AD (AD, n=27), non-AD (NAD, n=30) and in non-demented patients (ND, n=27). The combined assessment of PEDF, Hp and Tau levels, using Iterative Marginal Optimization, improved the differential diagnosis of AD, especially in patients with moderate to severe dementia (p

Published
2011
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11. Memantine in behavioral variant frontotemporal dementia: negative results

Author

Martine, Vercelletto, Claire, Boutoleau-Bretonnière, Christelle, Volteau, Michèle, Puel, Sophie, Auriacombe, Marie, Sarazin, Bernard-François, Michel, Philippe, Couratier, Catherine, Thomas-Antérion, Patrice, Verpillat, Audrey, Gabelle, Véronique, Golfier, Evelyne, Cerato, Lucette, Lacomblez, Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Imagerie cérébrale et handicaps neurologiques (ICHN), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], CHU Bordeaux [Bordeaux], Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neurologie [CHU Limoges], CHU Limoges, Neuroépidémiologie Tropicale et Comparée (NETEC), Université de Limoges (UNILIM)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Unité de neuropsychologie, CM2R, CHU Saint-Etienne, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, medicine.medical_specialty, MESH: Frontotemporal Dementia, Neuropsychological Tests, Placebo group, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Double-Blind Method, law, Memantine, Internal medicine, MESH: Memantine, medicine, Clinical endpoint, Dementia, Humans, MESH: Double-Blind Method, 030212 general & internal medicine, Psychiatry, Aged, MESH: Aged, MESH: Humans, MESH: Middle Aged, General Neuroscience, MESH: Neuropsychological Tests, General Medicine, Middle Aged, medicine.disease, MESH: Male, 3. Good health, Clinical trial, Psychiatry and Mental health, Clinical Psychology, Tolerability, Frontotemporal Dementia, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, Geriatrics and Gerontology, Psychology, MESH: Female, 030217 neurology & neurosurgery, medicine.drug, Frontotemporal dementia
Abstract

International audience; We tested the efficacy and tolerability of one-year treatment with memantine (10 mg bid) in behavioral variant frontotemporal dementia (bvFTD). BvFTD patients aged 45 to 75 years, with a Mini-Mental Status Examination (MMSE) score ≥19, were enrolled in a national, randomized, double-blind, placebo-controlled (DBPC), Phase II trial. The primary endpoint was the CIBIC-Plus (Clinician's Interview-Based Impression of Change Plus Caregiver Input). The secondary endpoints included: Neuropsychiatric Inventory (NPI), Frontal Behavioral Inventory (FBI), Mattis Dementia Rating Scale (MDRS), MMSE, Disability Assessment for Dementia (DAD), and the Zarit Burden Inventory (ZBI). Forty-nine patients were analyzed. At baseline, mean age was 65.6 years and mean MMSE was 25.0 (range: 19-30). On the CIBIC-Plus, 52 weeks after baseline, there were no significant differences between the memantine group (n = 23) and the placebo group (n = 26); p = 0.4458; however, 10 patients had worsened in the memantine group versus 17 in the placebo group. For the secondary endpoints there were no differences in the evolution of score between the memantine group and the placebo group (MMSE, p = 0.63); (MDRS, p = 0.95); (NPI, p = 0.25); (ZBI, p = 0.43); (DAD, p = 0.10) except for the FBI score, which was lower in the memantine group (p = 0.0417). Memantine was well-tolerated. This is the first DBPC trial in a large group of bvFTD patients involving neuroprotective treatment. A multinational study with a larger number of patients is now needed in order to verify the results of our study. The trial is registered with ClinicalTrials.gov; number NCT 00200538.

Published
2010
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12. Strategic aspects of young, healthy older adults, and Alzheimer patients arithmetic performance

Author

Phil Allen, Laurence Arnaud, Patrick Lemaire, Bernard François Michel, Laboratoire de psychologie cognitive (LPC), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
Adult, Male, Aging, Cognitive Neuroscience, Experimental and Cognitive Psychology, Disease, Neuropsychological Tests, Education, Strategy selection, Mental Processes, Alzheimer Disease, medicine, Humans, Young adult, Arithmetic, Cognitive decline, ComputingMilieux_MISCELLANEOUS, Strategy execution, Aged, Aged, 80 and over, Middle Aged, medicine.disease, Neuropsychology and Physiological Psychology, [SCCO.PSYC]Cognitive science/Psychology, Female, Alzheimer's disease, Psychology, Mathematics, Photic Stimulation, Psychomotor Performance
Abstract

Forty young adults, 40 healthy older adults, and 23 probable AD patients were asked to solve simple subtraction problems (e.g., 9-3; 14-9) in a choice condition and in a no-choice condition. Participants could choose between retrieval and non-retrieval strategies on each problem in the choice condition and were required to use retrieval on all problems in the no-choice condition. Results showed that arithmetic performance and strategy use were influenced by problem, participant, and strategy characteristics. Age-related differences were found in strategy use and strategy execution. Dementia-related differences were found in strategy execution, but not in strategy selection. AD patients had poorer performance (i.e., larger response times and percent of errors) than age-related controls, with especially low accuracy under no-choice condition. The findings have implications for our understanding of aging effects in arithmetic, strategic variations in Alzheimer's patients, and sources of cognitive decline during early stages of Alzheimer's disease (AD).

Published
2008

13. Amnestic syndrome of the medial temporal type identifies prodromal AD: a longitudinal study

Author

Colette Fabrigoule, Florence Pasquier, M. Puel, Jacques Touchon, Claudine Berr, Marie Sarazin, Marc Verny, Sylvie Legrain, Bernard-François Michel, Bruno Dubois, M. Volteau, J. De Rotrou, Neuro-anatomie fonctionnelle du comportement et de ses troubles, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Service de gérontologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Epidémiologie, santé publique et développement, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR99-ISPED, Département de neurologie [Lille], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de gériatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service de neurologie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte Marguerite, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This work was supported by INSERM U.610, Ministère de la Santé (PHRC, Principal Investigator: Bruno Dubois)., Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Service de Médecine Gériatrique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Service de médecine gériatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Villebrun, Dominique, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, medicine.medical_specialty, Trail Making Test, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Audiology, Neuropsychological Tests, Hippocampus, Sensitivity and Specificity, Benton Visual Retention Test, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Visual memory, Alzheimer Disease, Predictive Value of Tests, medicine, Verbal fluency test, Humans, 030212 general & internal medicine, Longitudinal Studies, Episodic memory, Aged, Recall, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Wechsler Adult Intelligence Scale, Prognosis, Temporal Lobe, Free recall, Early Diagnosis, ROC Curve, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Disease Progression, Parahippocampal Gyrus, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), Amnesia, Psychology, Cognition Disorders, 030217 neurology & neurosurgery, Cognitive psychology
Abstract

Objective: To compare the power of tests assessing different cognitive domains for the identification of prodromal Alzheimer disease (AD) among patients with mild cognitive impairment (MCI). Background: Given the early involvement of the medial temporal lobe, a precocious and specific pattern of memory disorders might be expected for the identification of prodromal AD. Methods: A total of 251 patients with MCI were tested at baseline by a standardized neuropsychological battery, which included the Free and Cued Selective Recall Reminding Test (FCSRT) for verbal episodic memory; the Benton Visual Retention Test for visual memory; the Deno 100 and verbal fluency for language; a serial digit learning test and the double task of Baddeley for working memory; Wechsler Adult Intelligence Scale (WAIS) similarities for conceptual elaboration; and the Stroop test, the Trail Making test, and the WAIS digit symbol test for executive functions. The patients were followed at 6-month intervals for up to 3 years in order to identify those who converted to AD vs those who remained stable over time. Statistical analyses were based on receiver operating characteristic curve and Cox proportional hazards models. Results: A total of 59 subjects converted to AD dementia. The most sensitive and specific test for diagnosis of prodromal AD was the FCSRT. Significant cutoff for the diagnosis was 17/48 for free recall, 40/48 for total recall, and below 71% for index of sensitivity of cueing (% of efficacy of semantic cues for retrieval). Conclusions: The amnestic syndrome of the medial temporal type, defined by the Free and Cued Selective Recall Reminding Test, is able to distinguish patients at an early stage of Alzheimer disease from mild cognitive impairment non-converters. Neurology ® 2007;69:1859–1867

Published
2007
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14. Progranulin null mutations in both sporadic and familial frontotemporal dementia

Author

Michèle Puel, Marleen Van den Broeck, Annie Laquerrière, Marc Cruts, Agnès Camuzat, Martine Vercelletto, Bernard-François Michel, Bruno Dubois, Mira Didic, Patrice Verpillat, Catherine Thomas-Antérion, Véronique Golfier, Alexis Brice, Didier Hannequin, Ilse Gijselinck, Tim De Pooter, Lucette Lacomblez, François Sellal, Dominique Campion, François Salachas, Isabelle Le Ber, Charles Duyckaerts, Christine Van Broeckhoven, Julie van der Zee, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Neurodegenerative Brain Diseases Group, University of Antwerp (UA)-Flanders Interuniversity Institute of Biotechnology, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Department of Genetics, University Hospital, Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Department of Neuropathology, Neuro-anatomie fonctionnelle du comportement et de ses troubles, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de pharmacologie médicale [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, CHU Saint-Etienne, Service de neurologie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte Marguerite, Service de neurologie [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de neurologie et de neuropsychologie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Epilepsies, Lesions Cerebrales et Systemes Neuraux de la Cognition, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Antwerpen, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-06-MRAR-005-01, ANR Maladies Rares DFT-MND, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Université de Rennes (UR), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], and French Research Network on FTD/FTD-MND

Subjects
Male, medicine.disease_cause, Apraxia, 0302 clinical medicine, Progranulins, MESH: Aged, 80 and over, MESH: Genetic Screening, MESH: Codon, Nonsense, Family history, Genetics (clinical), Genetics, Aged, 80 and over, MESH: Aged, 0303 health sciences, Mutation, MESH: Middle Aged, medicine.diagnostic_test, Parkinsonism, Middle Aged, Penetrance, MESH: Dementia, 3. Good health, Pedigree, MESH: tau Proteins, Phenotype, Codon, Nonsense, Intercellular Signaling Peptides and Proteins, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Frontotemporal dementia, MESH: Pedigree, tau Proteins, Biology, MESH: Phenotype, 03 medical and health sciences, mental disorders, medicine, Dementia, Humans, Genetic Testing, MESH: Intercellular Signaling Peptides and Proteins, 030304 developmental biology, Genetic testing, Aged, MESH: Humans, nutritional and metabolic diseases, medicine.disease, MESH: Male, nervous system diseases, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; Frontotemporal dementia (FTD) is the second most frequent type of neurodegenerative dementias. Mutations in the progranulin gene (GRN, PGRN) were recently identified in FTDU-17, an FTD subtype characterized by ubiquitin-immunoreactive inclusions and linkage to chromosome 17q21. We looked for PGRN mutations in a large series of 210 FTD patients (52 familial, 158 sporadic) to accurately evaluate the frequency of PGRN mutations in both sporadic and familial FTD, and FTD with associated motoneuron disease (FTD-MND), as well as to study the clinical phenotype of patients with a PGRN mutation. We identified nine novel PGRN null mutations in 10 index patients. The relative frequency of PGRN null mutations in FTD was 4.8% (10/210) and 12.8% (5/39) in pure familial forms. Interestingly, 5/158 (3.2%) apparently sporadic FTD patients carried a PGRN mutation, suggesting the possibility of de novo mutations or incomplete penetrance. In contrast, none of the 43 patients with FTD-MND had PGRN mutations, supporting that FTDU-17 and FTD-MND are genetically distinct. The clinical phenotype of PGRN mutation carriers was particular because of the wide range in onset age and the frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%) during the course of the disease. This study supports that PGRN null mutations represent a more frequent cause of FTD than MAPT mutations (4.8% vs. 2.9%) but are not responsible for FTD-MND. It also demonstrates that half of the patients with a PGRN mutation in our series had no apparent family history of dementia. Taking this into account, genetic testing should be now considered more systematically, even in patients without obvious familial history of FTD.

Published
2007
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15. Demographic, neurological and behavioural characteristics and brain perfusion SPECT in frontal variant of frontotemporal dementia

Author

Martine Vercelletto, Jacques Pasquier, Agnès Camuzat, Michèle Puel, François Salachas, Patrice Verpillat, Audrey Gabelle, Jean-Albert Lotterie, Lucette Lacomblez, Jean Bochet, Isabelle Le Ber, Marie-Odile Habert, Didier Hannequin, Bruno Dubois, Mira Didic, François Sellal, Marielle Decousus, Pierre Vera, Catherine Thomas-Antérion, Véronique Golfier, M. Volteau, Eric Guedj, Alexis Brice, Anne-Marie Bernard, Christine Magne, Bernard-François Michel, Izzie Jacques Namer, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Central de Biophysique et Médecine Nucléaire, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Neuro-anatomie fonctionnelle du comportement et de ses troubles, Service de Neurologie [CHU de Saint-Étienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine nucléaire [Rouen], CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service de neurologie et de neuropsychologie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Epilepsies, Lesions Cerebrales et Systemes Neuraux de la Cognition, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Médecine Nucléaire - Pierre-Paul Riquet [CHU Toulouse], Pôle imagerie médicale [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Neurologie, Centre hospitalier Saint-Brieuc, Service de médecine nucléaire [Rennes], CRLCC Eugène Marquis (CRLCC), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Service de Médecine Nucléaire [Nantes], Hôpital Laennec, Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Laboratoire de signalisation moléculaire et neurodégénerescence, Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine nucléaire [Strasbourg], CHU Strasbourg, Service de Neurogériatrie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Service de Médecine Nucléaire [Saint-Quentin], Polyclinique Saint-Claude, French research network on FTD/FTD-MND, Centre de neuropsychologie et du langage, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Fédération des Maladies du Système Nerveux, Service de neurologie, Hôpital Bellevue, Service de Pharmacologie médicale [CHU Pitié-Salpêtrière], 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 Marseille (APHM)-Hôpital Sainte Marguerite, Breton, Céline, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de pharmacologie médicale [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Service de Médecine Nucléaire [Toulouse]

Subjects
Male, Pathology, MESH: Social Behavior Disorders, Cross-sectional study, Perfusion scanning, Neuropsychological Tests, 0302 clinical medicine, Age of Onset, MESH: Brain Mapping, MESH: Aged, Brain Mapping, 0303 health sciences, MESH: Middle Aged, Brain, MESH: Neuropsychological Tests, Frontotemporal lobar degeneration, MESH: Cerebrovascular Circulation, Middle Aged, Prognosis, MESH: Dementia, 3. Good health, Cerebrovascular Circulation, MESH: Survival Analysis, Disease Progression, Cardiology, Female, MESH: Disease Progression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Psychology, Perfusion, Frontotemporal dementia, Adult, medicine.medical_specialty, MESH: Age of Onset, MESH: Prognosis, MESH: Tomography, Emission-Computed, Single-Photon, 03 medical and health sciences, MESH: Brain, MESH: Cross-Sectional Studies, Internal medicine, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Survival analysis, Aged, 030304 developmental biology, Tomography, Emission-Computed, Single-Photon, MESH: Humans, Social Behavior Disorders, MESH: Adult, medicine.disease, Survival Analysis, MESH: Male, Cross-Sectional Studies, Disinhibition, MESH: Brain Stem, Dementia, Neurology (clinical), Age of onset, MESH: Female, 030217 neurology & neurosurgery, Brain Stem
Abstract

International audience; We conducted a French multicentric cross-sectional study to describe in detail the demographic, neurological and behavioural characteristics of the frontal variant of frontotemporal dementia (fvFTD) and to characterize the pattern of brain perfusion SPECT in comparison to a healthy control group. A total of 68 fvFTD patients had technetium-99m-ECD brain perfusion SPECT at inclusion, 61 of which also underwent an in-depth evaluation including 70 items assessing behaviour, language and affect/emotion at onset and at inclusion. The mean age-at-onset was 60.4 +/- 7.8 years (35-75). Twenty-six per cent of the patients were older than 65 at onset. A positive familial history consistent with an autosomal dominant inheritance was found in 18% of the patients. At onset, the behavioural profile was predominantly inert in 25% of the patients, disinhibited in 18% and mixed in others. The behavioural features progressed to predominantly mixed or inert forms. Although, inertia was associated with predominant medial frontal and cingulate hypoperfusion, and patients with disinhibition exhibited predominant ventromedial prefrontal and temporal hypoperfusion, there were no major clinical differences between disinhibited and inert patients. Forty-five per cent of the deceased patients survived 8 years (long survival). This shows that the final outcome of fvFTD is highly variable. No clinical factors predictive of short or long survival were identified. Unexpected, however, was the finding that brainstem hypoperfusion distinguished patients with a short survival from patients with long survival. In conclusion, this study shows that fvFTD is clinically a rather homogeneous entity. It also provides evidence that different behavioural presentations at onset are related to different anatomical localizations of degenerative damage. Finally, it demonstrates the prognostic value of brainstem hypoperfusion in a subgroup of patients with a short survival.

Published
2006
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16. Pharmacology of Alzheimer's disease: appraisal and prospects

Author

François Sellal, Hervé Allain, André Nieoullon, Géraldine Michel, Alexandra Delini Stula, Lucette Lacomblez, Danièle Bentué-Ferrer, Bernard François Michel, Régis Bordet, and Hugo Geerts

Subjects
medicine.medical_specialty, Cognitive Neuroscience, Pharmacological Processes, Disease, medicine.disease, Psychiatry and Mental health, Alzheimer Disease, Tacrine, medicine, Dementia, Humans, Geriatrics and Gerontology, Alzheimer's disease, Psychiatry, Psychology, Nootropic Agents, medicine.drug
Abstract

Ten years after the introduction of the first drug, tacrine, in the treatment of Alzheimer’s disease, it seems appropriate to reappraise the pharmacological processes of innovation in the research field of dementia. The aim of this review is to pinpoint concrete improvements achieved in this field, regarding experimental methods and clinical evaluation of the compounds, as well as the neurochemistry of the disease and cellular targets to consider in priority. This review deals with this objective in three parts: (1) assessment of current therapeutics, (2) discussion of the experimental models and clinical practices and (3) prospective drugs of the future. The implementation of considered strategies will require the involvement and close cooperation between political decisions, pharmaceutical companies and the scientific community.

Published
2004

17. Alzheimer's disease: the pharmacological pathway

Author

Bernard-François Michel, Danièle Bentué-Ferrer, Serge Gauthier, Hervé Allain, Olivier Tribut, and Christophe Drieu-La Rochelle

Subjects
Drug, media_common.quotation_subject, Apoptosis, Pharmacology, Antioxidants, Degenerative disease, Alzheimer Disease, Galantamine, medicine, Animals, Humans, Pharmacology (medical), Senile plaques, Excitatory Amino Acid Agents, Nicotinic Agonists, Donepezil, media_common, Hypolipidemic Agents, Rivastigmine, Clinical Trials as Topic, Amyloid beta-Peptides, business.industry, Estrogens, medicine.disease, Mitochondria, Tacrine, Caspases, Cholinesterase Inhibitors, Alzheimer's disease, business, Neuroscience, medicine.drug
Abstract

The current pharmacological treatment of Alzheimer's disease (AD) comes down to four marketed drugs (tacrine, donepezil, rivastigmine and galantamine) all of which are cholinesterase inhibitors, conforming to the cholinergic hypothesis. The future is clearly directed at new biological targets closely linked to the pathophysiology of the disease and more precisely, the pathological hallmark of AD which includes widespread neuronal degeneration, neuritic plaques containing beta-amyloid and tau-rich neurofibrillary tangles. For clinicians, this means that new curative drugs will have to be prescribed early in the course of the disease. This review describes the main entry pathways for drug discovery in AD: (1) supplementation therapy, (2) anti-apoptotic compounds, (3) substances with a mitochondrial impact, (4) anti-amyloid substances, (5) anti-protein aggregation and (6) lipid-lowering drugs. The rapidity at which these compounds will be at our disposal is highly dependent on the policy of the pharmaceutical companies.

Published
2003

18. Alzheimer's disease disrupts arithmetic fact retrieval processes but not arithmetic strategy selection

Author

Patrick Lemaire, Sandrine Duverne, Bernard François Michel, Laboratoire de psychologie cognitive (LPC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
Self-assessment, Adult, Male, Self-Assessment, Cognitive Neuroscience, Experimental and Cognitive Psychology, Disease, Anxiety, Neuropsychological Tests, Severity of Illness Index, 050105 experimental psychology, Developmental psychology, Task (project management), 03 medical and health sciences, 0302 clinical medicine, Strategy selection, Arts and Humanities (miscellaneous), Alzheimer Disease, Developmental and Educational Psychology, medicine, Humans, 0501 psychology and cognitive sciences, Arithmetic, Young adult, Aged, Memory Disorders, Depression, Memoria, 05 social sciences, Cognitive disorder, Age Factors, medicine.disease, Neuropsychology and Physiological Psychology, [SCCO.PSYC]Cognitive science/Psychology, Female, Alzheimer's disease, Psychology, Cognition Disorders, 030217 neurology & neurosurgery, Mathematics
Abstract

International audience; Three groups of healthy younger adults, healthy older adults, and probable AD patients, performed an addition/number comparison task. They compared 128 couples of additions and numbers (e.g., 4 + 9 15) and had to identify the largest item for each problem by pressing one of two buttons located under each item. Manipulations of problem characteristics (i.e., Problem difficulty and splits between correct sums and proposed numbers) enabled us to examine strategy selection and specific arithmetic fact retrieval processes. Results showed that arithmetic facts retrieval processes, which were spared with aging, were impaired in AD patients. However, AD patients were able to switch between strategies across trials according to problem characteristics as well as healthy older adults, and less systematically than healthy younger adults. We discuss implications of these findings for further understanding AD-related differences in arithmetic in particular, and problem solving in general. (C) 2003 Elsevier Science (USA). All rights reserved.

Published
2003
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19. Association between the extended tau haplotype and frontotemporal dementia

Author

Catherine Thomas-Antérion, Bernard-François Michel, Patrice Verpillat, Serge Belliard, Alexis Brice, Didier Hannequin, Michèle Puel, Françoise Clerget-Darpoux, François Sellal, Dominique Campion, Bruno Dubois, Mira Didic, Lucette Lacomblez, Véronique Golfier, Olivier Moreaud, and Agnès Camuzat

Subjects
Oncology, Adult, Male, medicine.medical_specialty, Pathology, Genotype, Tau protein, tau Proteins, Progressive supranuclear palsy, Arts and Humanities (miscellaneous), Internal medicine, mental disorders, medicine, Confidence Intervals, Odds Ratio, Dementia, Corticobasal degeneration, Humans, Aged, biology, Parkinsonism, Haplotype, Middle Aged, medicine.disease, nervous system diseases, Haplotypes, Case-Control Studies, Multivariate Analysis, biology.protein, Female, Neurology (clinical), Alzheimer's disease, Psychology, Frontotemporal dementia
Abstract

Background Recent studies have shown an association between an extended tau haplotype (H1) that covers the entire human tau gene and progressive supranuclear palsy or, more inconsistently, other neurodegenerative disorders, such as corticobasal degeneration, Parkinson disease, Alzheimer disease, and frontotemporal dementia (FTD). In addition, disease-causing mutations in the tau gene on chromosome 17 have been detected in some families with autosomal dominant FTD and parkinsonism. In FTD, the pathological accumulation of the microtubule-associated protein tau suggests that the tau gene may be a genetic risk factor for this disorder. Objective To confirm or refute the association between the H1 haplotype or the H1H1 genotype of the tau gene and FTD. Design Case-control study. Setting Neurology departments of 12 French university hospitals. Participants One hundred unrelated patients with FTD and 79 controls. Methods Tau genotype (contiguous polymorphisms in exons 1, 7, and 13 and in intron 9 used to reconstruct the extended haplotypes H1 and H2). Clinical examination, psychometric testing, laboratory tests, computed tomography and magnetic resonance imaging, single-photon emission computed tomography, and electroencephalography for patients with FTD. Results The H1H1 genotype was significantly overrepresented in patients with FTD compared with controls (62% vs 46%; P = .01, 1-sided; odds ratio adjusted for age and sex, 1.95). After stratification according to apolipoprotein E ( APOE ) genotype, we found a significant interaction between APOE and tau genotypes ( P = .03). Conclusions This study of the largest series of patients with FTD confirms the primary role of tau in FTD and establishes that the H1 haplotype of the tau gene and the E2 allele of APOE interact by an unknown mechanism that increases the risk of FTD.

Published
2002

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