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1. Phenotype and imaging features associated with APP duplications

Author

Lou Grangeon, Camille Charbonnier, Aline Zarea, Stephane Rousseau, Anne Rovelet-Lecrux, David Bendetowicz, Marion Lemaitre, Cécile Malrain, Muriel Quillard-Muraine, Kevin Cassinari, David Maltete, Jeremie Pariente, Olivier Moreaud, Eloi Magnin, Benjamin Cretin, Marie-Anne Mackowiak, Adeline Rollin Sillaire, Martine Vercelletto, Elsa Dionet, Olivier Felician, Pauline Rod-Olivieri, Catherine Thomas-Antérion, Gaelle Godeneche, Mathilde Sauvée, Leslie Cartz-Piver, Isabelle Le Ber, Valérie Chauvire, Therèse Jonveaux, Anna-Chloé Balageas, Annie Laquerriere, Charles Duyckaerts, Anne Vital, Andre Maues de Paula, David Meyronet, Lucie Guyant-Marechal, Didier Hannequin, Elisabeth Tournier-Lasserve, Dominique Campion, CNR-MAJ collaborators, Gaël Nicolas, and David Wallon

Subjects
Cerebral amyloid angiopathy, Alzheimer disease, APP duplication, Cerebral MRI, Autosomal dominant, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers. Methods Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls. Results Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aβ42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia. Discussion Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA.

Published
2023
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2. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases.

Author

Hélène-Marie Lanoiselée, Gaël Nicolas, David Wallon, Anne Rovelet-Lecrux, Morgane Lacour, Stéphane Rousseau, Anne-Claire Richard, Florence Pasquier, Adeline Rollin-Sillaire, Olivier Martinaud, Muriel Quillard-Muraine, Vincent de la Sayette, Claire Boutoleau-Bretonniere, Frédérique Etcharry-Bouyx, Valérie Chauviré, Marie Sarazin, Isabelle le Ber, Stéphane Epelbaum, Thérèse Jonveaux, Olivier Rouaud, Mathieu Ceccaldi, Olivier Félician, Olivier Godefroy, Maite Formaglio, Bernard Croisile, Sophie Auriacombe, Ludivine Chamard, Jean-Louis Vincent, Mathilde Sauvée, Cecilia Marelli-Tosi, Audrey Gabelle, Canan Ozsancak, Jérémie Pariente, Claire Paquet, Didier Hannequin, Dominique Campion, and collaborators of the CNR-MAJ project

Subjects
Medicine
Abstract

BackgroundAmyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series.Methods and findingsWe report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification.ConclusionsOur findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.

Published
2017
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3. Lipid and hemolysis parameters predicting acute chest syndrome in adulthood with sickle cell disease

Author

Guillaume Feugray, Maximilien Grall, Cécile Dumesnil, Valéry Brunel, Ygal Benhamou, Muriel Quillard Muraine, and Paul Billoir

Subjects
Sickle cell disease, Acute chest syndrome, Lipid parameters, Inflammatory, Hemolysis, Nutritional diseases. Deficiency diseases, RC620-627
Abstract

Abstract Sickle cell disease (SCD) is a lifelong blood disorder affecting approximately 100,000 people in the United States and is one of the most common monogenic diseases. A serious complication of SCD is acute chest syndrome (ACS). ACS is a condition with a high rate of morbidity and mortality. The aim of the study was to assess hemolysis and lipid parameters in a cohort of confirmed SCD patients to predict ACS development in the following year. Standard lipid were performed (triglycerides, total cholesterol, high-density cholesterol, low-density cholesterol) panel to calculate of non-HDL-C, large buoyant LDL cholesterol (lbLDL-C) and small dense LDL cholesterol (sdLDL-C) with Sampson equation. Hemolysis and hematologic parameters were also evaluated. Among 91 patients included between September 2018 and June 2021, thirty-seven patients had history of ACS and 6 patients developed ACS during following year. In unadjusted logistic regression, total bilirubin was associated with ACS occurrence (RR: 1.2 [1.05–1.51] p = 0.013). Concerning lipid profile, non-HDL-C (RR: 0.87 [0.0.67–0.99] p = 0.04) and sdLDL-C (RR: 0.78 [0.49–0.96] p = 0.03) were associated with ACS occurrence decrease. C-reactive protein was associated with ACS occurrence (RR: 1.27 [1.065–1.85] p = 0.011). Based on these findings, this study demonstrated that several biomarker easily available can be used at steady state to predict ACS in the following year. The validation of these results are required to ensure the reproducibility of the findings.

Published
2024
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5. Cerebrospinal Fluid Profile of Tau, Phosphorylated Tau, Aβ42, and Aβ40 in Probable Cerebral Amyloid Angiopathy

Author

Lou Grangeon, Claire Paquet, Stéphanie Guey, Aline Zarea, Olivier Martinaud, Maud Rotharmel, David Maltête, Muriel Quillard-Muraine, Gael Nicolas, Camille Charbonnier, Hugues Chabriat, and David Wallon

Subjects
Amyloid beta-Peptides, General Neuroscience, tau Proteins, General Medicine, Peptide Fragments, Psychiatry and Mental health, Clinical Psychology, Cerebral Amyloid Angiopathy, Alzheimer Disease, mental disorders, Humans, Geriatrics and Gerontology, Biomarkers, Retrospective Studies
Abstract

Background: There is no consensus regarding the diagnostic value of cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers in cerebral amyloid angiopathy (CAA). Objective: To describe the CSF levels of Aβ42, Aβ40, total protein Tau, and phosphorylated-Tau (p-Tau) in a large series of probable CAA patients and to compare with AD patients in order to identify a specific pattern in CAA but also to look for correlations with the neuroimaging profile. Methods: We retrospectively included from 2 French centers probable CAA patients according to modified Boston criteria who underwent lumbar puncture (LP) with CSF AD biomarker quantifications. Two neurologists independently analyzed all MRI sequences. A logistic regression and Spearman’s correlation coefficient were used to identify correlation between MRI and CSF biomarkers in CAA. Results: We included 63 probable CAA and 27 AD patients. Among CAA 50.8% presented with decreased Aβ42 level associated with elevated p-Tau and/or Tau, 34.9% with isolated decreased Aβ42 level and 14.3% patients with normal Aβ42 level. Compared to AD, CAA showed lower levels of Tau (p = 0.008), p-Tau (p = 0.004), and Aβ40 (p = 0.001) but similar Aβ42 level (p = 0.07). No correlation between Aβ42 or Aβ40 levels and neuroimaging was found. Conclusion: CSF biomarkers may improve the accuracy of the modified Boston criteria with altered profile in 85% of the patients fulfilling revised Boston criteria for probable CAA. Aβ40 appears as an interesting selective biomarker in differential diagnosis.

Published
2022

6. Contribution of cerebrospinal fluid Alzheimer biomarkers to the diagnosis of Creutzfeldt‐Jakob disease

Author

Elise Faraut, Maïté Formaglio, Audrey Gabelle, Lou Grangeon, Eloi Magnin, Olivier Martinaud, Claire Boutoleau‐Bretonnière, Emmanuel Cognat, Muriel Quillard‐Muraine, David Maltête, and David Wallon

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2021

7. International initiative for harmonization of cerebrospinal fluid diagnostic comments in Alzheimer's disease

Author

Mari L DeMarco, Clementine Gondolf, Léonor Nogueira, Michael Khalil, Koen Poesen, Aurélie Bedel, Andreas Jeromin, Marie-Céline Blanc, Daniel Alcolea, Markus Otto, Agnieszka Kulczyńska-Przybik, Marc Suárez-Calvet, Benoit Rucheton, Muriel Quillard-Muraine, Hermann Esselmann, Maria Bjerke, Alberto Lleó, Anne Fogli, Frédérique Grandhomme, Olivier Bousiges, Federico Verde, M D'Onofrio, Oriol Grau-Rivera, Ashvini Keshavan, Hayrettin Tumani, Melanie Hart, Isabelle Quadrio, Sylvain Lehmann, Albert Puig‐Pijoan, Lucie Vaudran, Marcel M. Verbeek, Lucilla Parnetti, Peter Koertvelyessy, Catherine Malaplate, Armand Perret-Liaudet, Henrik Zetterberg, Jens Wiltfang, Lisa Vermunt, Chinedu T. Udeh-Momoh, Katell Poec, Claire Paquet, Magda Tsolaki, Barbara Mroszko, Jean-Baptiste Oudart, Jean-Louis Laplanche, Sebastiaan Engelborghs, Miles D. Chapman, Elodie Bouaziz Amar, Jonathan Vogelgsang, Susanna Schraen, Edith Bigot-Corbel, Elisabetta Galloni, Adelina Orellana, Constance Delaby, Anne Beaume, Diane Dufour-Rainfray, and Charlotte E. Teunissen

Subjects
medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Harmonization, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Cerebrospinal fluid, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Intensive care medicine, business
Published
2020

8. Phenotypes associated with MAPT duplications

Author

Stéphane Epelbaum, Muriel Quillard-Muraine, David Wallon, Dominique Campion, François Sellal, Antoine Bonnevalle, Gaël Nicolas, Michel Bottlaender, Susana Boluda, Marie Sarazin, Camille Heitz, Isabelle Le Ber, Didier Hannequin, Thérèse Rivasseau Jonveaux, Anne-Claire Richard, Anne Rovelet-Lecrux, Stéphane Rousseau, Charles Duyckaerts, Julien Lagarde, Olivier Quenez, Camille Charbonnier, Eloi Magnin, and Mathieu Chastan

Subjects
Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology, Biology, Phenotype
Published
2020

9. Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer’s Disease Before 51 Years

Author

Aline Zarea, Eloi Magnin, Stéphane Epelbaum, Claire Paquet, Valérie Chauviré, Florence Pasquier, Anne Boland, Marie Sarazin, David Wallon, Bruno Salomon, Dominique Campion, Olivier Godefroy, Olivier Martinaud, Mathilde Sauvée, Sophie Auriacombe, Cecilia Marelli, Frédérique Etcharry-Bouyx, Gaël Nicolas, Jean-François Deleuze, Anne-Claire Richard, Vincent de la Sayette, Audrey Gabelle, Thérèse Rivasseau Jonveaux, Stéphane Rousseau, Jérémie Pariente, Mathieu Ceccaldi, Maïté Formaglio, Anne Rovelet-Lecrux, Didier Hannequin, Adeline Rollin-Sillaire, Bernard Croisile, Isabelle Le Ber, Morgane Lacour, Olivier Quenez, Olivier Rouaud, Muriel Quillard-Muraine, Claire Boutoleau-Bretonnière, 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), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), CHU Rouen, Normandie Université (NU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de neurologie [Rouen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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), Laboratoire de Neurosciences Fonctionnelles et Pathologies (LNFP), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [Lyon], CHU Lyon, Hospices Civils de Lyon (HCL), 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 Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut National de la Santé et de la Recherche Médicale (INSERM), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie François JACOB (JACOB), 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 du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and 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)

Subjects
0301 basic medicine, Male, MESH: Mutation, 03 medical and health sciences, Amyloid beta-Protein Precursor, 0302 clinical medicine, MESH: Whole Exome Sequencing, Alzheimer Disease, Risk Factors, MESH: Risk Factors, MESH: Amyloid beta-Protein Precursor, PSEN2, Genotype, Genetic variation, Presenilin-2, Exome Sequencing, medicine, PSEN1, Presenilin-1, Humans, Early-onset Alzheimer's disease, Genetic Predisposition to Disease, Risk factor, Allele, Exome sequencing, Genetics, MESH: Humans, MESH: Middle Aged, business.industry, General Neuroscience, MESH: Genetic Predisposition to Disease, General Medicine, Middle Aged, medicine.disease, MESH: Presenilin-1, MESH: Male, 3. Good health, MESH: Presenilin-2, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Female, Geriatrics and Gerontology, business, MESH: Female, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract

International audience; Background:Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer’s disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants.Objective:To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. Methods:We first screened PSEN1, PSEN2, and APP in 154 EOAD patients with an onset before 51 years and a negative family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2, SORL1, and ABCA7. Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved. Results:Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1, 4 TREM2, and 9 ABCA7. MC presented an earlier disease onset (p

Published
2019

10. Diagnosis associated with Tau higher than 1200 pg/mL: Insights from the clinical and laboratory practice

Author

C Malaplate-Armand, Frédéric Blanc, Jean-Louis Laplanche, Constance Delaby, Eloi Magnin, Jacques Hugon, Audrey Gabelle, David Wallon, S. Schraen, Julien Dumurgier, Claire Paquet, Bernard Sablonnière, Elodie Bouaziz-Amar, Muriel Quillard-Muraine, Olivier Bousiges, Sylvain Lehmann, Katell Peoc'h, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpitaux Universitaire Saint-Louis, Lariboisière, Fernand-Widal, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, CHU Rouen, Normandie Université (NU), Laboratoire de neurosciences cognitives et adaptatives (LNCA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Biochimie et de Biologie Moléculaire [AP-HP Hôpital Lariboisière] (Inserm U942), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Service de neurologie [Rouen], Normandie Université (NU)-Normandie Université (NU), CCSD, Accord Elsevier, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Clinical Biochemistry, Tau protein, Context (language use), tau Proteins, Disease, Biochemistry, Diagnosis, Differential, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Cerebrospinal fluid, Internal medicine, Medicine, Dementia, Humans, Medical diagnosis, Aged, Aged, 80 and over, biology, Lewy body, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Biochemistry (medical), [SCCO.NEUR] Cognitive science/Neuroscience, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, 14-3-3 protein, General Medicine, Middle Aged, Alzheimer's disease, medicine.disease, Phosphoproteins, Creutzfeldt-Jakob disease, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Female, business, Laboratories, Biomarkers, Frontotemporal dementia
Abstract

International audience; Context: Cerebrospinal fluid (CSF) biomarkers are valuable tools for the diagnosis of neurological diseases. We aimed to investigate within a retrospective multicentric study the final diagnosis associated with very high CSF Tau levels and to identify patterns of biomarkers that would differentiate them in clinical practice, to help clinical biologists into physicians' counseling.Patients and methods: Within the national multicentric network ePLM, we included 1743 patients from January 1, 2008, to December 31, 2013, with CSF biomarkers assayed by the same Innotest assays (protein Tau, phospho-Tau [pTau], and Aβ 1-42). We identified 205 patients with protein Tau concentration higher than 1200 pg/mL and final diagnosis.Results: Among those patients, 105 (51.2%) were suffering from Alzheimer's disease, 37 (18%) from sporadic Creuztfeldt-Jakob disease, and 63 (30.7%) from other neurological diseases including paraneoplastic/ central nervous system tumor, frontotemporal dementia, other diagnoses, amyloid angiopathy, Lewy body dementia, and infections of the central nervous system. Phospho-Tau, Aβ1-42 and Aβ1-42/pTau values differed significantly between the three groups of patients (p < .001). An Aβ1-42/pTau ratio between 4.7 and 9.7 was suggestive of other neurological diseases (threshold in AD: 8.3). CSF 14-3-3 was useful to discriminate Alzheimer's disease from Creuztfeldt-Jakob disease in case of Aβ1-42 concentrations 60 pg/mL.Conclusion: This work emphasizes the interest of a well-thought-out interpretation of CSF biomarkers in neurological diseases, particularly in the case of high Tau protein concentrations in the CSF.

Published
2019

11. Differential Diagnosis of Dementia with High Levels of Cerebrospinal Fluid Tau Protein

Author

Muriel Quillard-Muraine, Didier Hannequin, Olivier Martinaud, Jean-Louis Laplanche, Lou Grangeon, Gaël Nicolas, Bertrand Bourre, Claire Paquet, Katell Peoc'h, Florence Pasquier, Stéphanie Bombois, Jacques Hugon, Emmanuel Gerardin, Romain Lefaucheur, David Maltête, Julien Dumurgier, Mary Jan, and David Wallon

Subjects
0301 basic medicine, Male, Pathology, Creutzfeldt-Jakob Syndrome, 0302 clinical medicine, Cerebrospinal fluid, Age of Onset, Phosphorylation, Aged, 80 and over, biology, General Neuroscience, General Medicine, Middle Aged, Psychiatry and Mental health, Clinical Psychology, Frontotemporal Dementia, Biomarker (medicine), Female, France, Frontotemporal dementia, Adult, Lewy Body Disease, medicine.medical_specialty, Tau protein, tau Proteins, Diagnosis, Differential, 03 medical and health sciences, Sex Factors, Alzheimer Disease, Internal medicine, mental disorders, medicine, Dementia, Humans, Vascular dementia, Aged, Retrospective Studies, Lewy body, business.industry, Dementia, Vascular, medicine.disease, nervous system diseases, 030104 developmental biology, biology.protein, Geriatrics and Gerontology, Differential diagnosis, business, Mental Status Schedule, 030217 neurology & neurosurgery, Biomarkers
Abstract

BACKGROUND: Total Tau concentration in cerebrospinal fluid (CSF) is widely used as a biomarker in the diagnosis of neurodegenerative process primarily in Alzheimer's disease (AD). A particularly high Tau level may indicate AD but may also be associated with Creutzfeldt-Jakob disease (CJD). In such situations little is known about the distribution of differential diagnoses. OBJECTIVE: Our study aimed to describe the different diagnoses encountered in clinical practice for patients with dementia and CSF Tau levels over 1000 pg/ml. We studied the p-Tau/Tau ratio to specify its ability to distinguish AD from CJD. METHODS: Patients (n = 202) with CSF Tau levels over 1000 pg/ml were recruited in three memory clinics in France. All diagnoses were made using the same diagnostic procedure and criteria. RESULTS: Patients were diagnosed with AD (n = 148, 73.2%), mixed dementia (n = 38, 18.8%), CJD, vascular dementia (n = 4, 2.0% for each), Lewy body dementia, and frontotemporal dementia (n = 3, 1.5% for each). Dispersion of CSF Tau levels clearly showed an overlap between all diagnoses. Using the p-Tau/Tau ratio suggestive of CJD (

Published
2016

12. A diagnostic scale for Alzheimer’s disease based on cerebrospinal fluid biomarker profiles

Author

Frédéric Blanc, Eloi Magnin, Constance Delaby, Julien Dumurgier, Florence Pasquier, Jean-Louis Laplanche, Jacques Touchon, Muriel Quillard-Muraine, Carole Miguet-Alfonsi, Barbara Jung, Audrey Gabelle, Sylvain Lehmann, Stéphanie Bombois, Jacques Hugon, David Wallon, Susanna Schraen, Nathalie Philippi, Dominique Campion, Olivier Bousiges, Claire Paquet, Benjamin Cretin, Didier Hannequin, Katell Peoc'h, Olivier Vercruysse, and Bernard Sablonnière

Subjects
Oncology, medicine.medical_specialty, Pathology, Neurology, Cognitive Neuroscience, Clinical Neurology, Disease, Primary progressive aphasia, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Internal medicine, medicine, 030304 developmental biology, 0303 health sciences, business.industry, Geriatrics gerontology, Research, Memory clinic, Cognition, medicine.disease, 3. Good health, Biomarker (medicine), Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Introduction The relevance of the cerebrospinal fluid (CSF) biomarkers for the diagnosis of Alzheimer’s disease (AD) and related disorders is clearly established. However, the question remains on how to use these data, which are often heterogeneous (not all biomarkers being pathologic). The objective of this study is to propose to physicians in memory clinics a biologic scale of probabilities that the patient with cognitive impairments has an Alzheimer’s disease (AD) pathologic process. Methods For that purpose, we took advantage of the multicenter data of our Paris-North, Lille, and Montpellier (PLM) study, which has emerged through the initial sharing of information from these memory centers. Different models combining the CSF levels of amyloid-β 42, tau, and p-tau(181) were tested to generate categories of patients with very low (75%), and very high predictive values (>90%) for positive AD. In total, 1,273 patients (646 AD and 627 non-AD) from six independent memory-clinic cohorts were included. Results A prediction model based on logistic regressions achieved a very good stratification of the population but had the disadvantages of needing mathematical optimization and being difficult to use in daily clinical practice. Remarkably, a simple and intuitive model based on the number (from zero to three) of three pathologic CSF biomarkers resulted in a very efficient predictive scale for AD in patients seen in memory clinics. The scale’s overall predictive value for AD for the different categories were as follows: class 0, 9.6% (95% confidence interval (CI), 6.0% to 13.2%); class 1, 24.7% (95% CI, 18.0% to 31.3%); class 2, 77.2% (95% CI, 67.8% to 86.5%); and class 3, 94.2% (95% CI, 90.7% to 97.7%). In addition, with this scale, significantly more patients were correctly classified than with the logistic regression. Its superiority in model performance was validated by the computation of the net reclassification index (NRI). The model was also validated in an independent multicenter dataset of 408 patients (213 AD and 195 non-AD). Conclusions In conclusion, we defined a new scale that could be used to facilitate the interpretation and routine use of multivariate CSF data, as well as helping the stratification of patients in clinical research trials.

Published
2014

13. Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: An international overview

Author

Constance Delaby, Charlotte E. Teunissen, Kaj Blennow, Daniel Alcolea, Ivan Arisi, Elodie Bouaziz Amar, Anne Beaume, Aurélie Bedel, Giovanni Bellomo, Edith Bigot‐Corbel, Maria Bjerke, Marie‐Céline Blanc‐Quintin, Mercè Boada, Olivier Bousiges, Miles D Chapman, Mari L. DeMarco, Mara D'Onofrio, Julien Dumurgier, Diane Dufour‐Rainfray, Sebastiaan Engelborghs, Hermann Esselmann, Anne Fogli, Audrey Gabelle, Elisabetta Galloni, Clémentine Gondolf, Frédérique Grandhomme, Oriol Grau‐Rivera, Melanie Hart, Takeshi Ikeuchi, Andreas Jeromin, Kensaku Kasuga, Ashvini Keshavan, Michael Khalil, Peter Körtvelyessy, Agnieszka Kulczynska‐Przybik, Jean‐Louis Laplanche, Piotr Lewczuk, Qiao‐Xin Li, Alberto Lleó, Catherine Malaplate, Marta Marquié, Colin L. Masters, Barbara Mroczko, Léonor Nogueira, Adelina Orellana, Markus Otto, Jean‐Baptiste Oudart, Claire Paquet, Federico Paolini Paoletti, Lucilla Parnetti, Armand Perret‐Liaudet, Katell Peoc'h, Koen Poesen, Albert Puig‐Pijoan, Isabelle Quadrio, Muriel Quillard‐Muraine, Benoit Rucheton, Susanna Schraen, Jonathan M. Schott, Leslie M. Shaw, Marc Suárez‐Calvet, Magda Tsolaki, Hayrettin Tumani, Chinedu T Udeh‐Momoh, Lucie Vaudran, Marcel M Verbeek, Federico Verde, Lisa Vermunt, Jonathan Vogelgsang, Jens Wiltfang, Henrik Zetterberg, Sylvain Lehmann, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Universitat Autònoma de Barcelona (UAB), Hospital de la Santa Creu i Sant Pau, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Amsterdam UMC - Amsterdam University Medical Center, Vrije Universiteit Amsterdam [Amsterdam] (VU), Sahlgrenska Academy at University of Gothenburg [Göteborg], European Brain Research Institute [Rome, Italy] (EBRI), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Bordeaux [Bordeaux], Università degli Studi di Perugia = University of Perugia (UNIPG), Centre hospitalier universitaire de Nantes (CHU Nantes), Vrije Universiteit Brussel (VUB), University of Antwerp (UA), Hôpital Cochin [AP-HP], Universitat Internacional de Catalunya [Barcelona] (UIC), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Laboratoire de Biochimie et de Biologie Moléculaire, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), University of British Columbia (UBC), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Medical Center Göttingen (UMG), CHU Clermont-Ferrand, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), IMIM-Hospital del Mar, Generalitat de Catalunya, Niigata University, Medical University of Graz, Freie Universität Berlin, Humboldt University Of Berlin, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Medical University of Białystok (MUB), Universitätsklinikum Erlangen [Erlangen], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Universität Ulm - Ulm University [Ulm, Allemagne], Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Hôpital Beaujon [AP-HP], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), CHU Rouen, Normandie Université (NU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Excellence Laboratory LabEx DISTALZ, University of Pennsylvania, Aristotle University of Thessaloniki, Imperial College London, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Radboud University Medical Center [Nijmegen], McLean Hospital [Belmont, Ma.], Harvard Medical School [Boston] (HMS), Universidade de Aveiro, Sahlgrenska University Hospital [Gothenburg], UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), Institute of Neurology [London], Laboratory Medicine, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Neuroinfection & -inflammation, Neurology, Clinical Biology, Clinical sciences, and Neuroprotection & Neuromodulation

Subjects
Epidemiology, Neuroscience(all), [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Clinical Neurology, tau Proteins, cerebrospinal fluid [Amyloid beta-Peptides], Cellular and Molecular Neuroscience, Developmental Neuroscience, Alzheimer Disease, Humans, ddc:610, cerebrospinal fluid [Peptide Fragments], clinical report, cerebrospinal fluid biomarkers, consensus approach, Amyloid beta-Peptides, Health Policy, diagnosis [Alzheimer Disease], Alzheimer's disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Peptide Fragments, cerebrospinal fluid [Alzheimer Disease], Psychiatry and Mental health, cerebrospinal fluid [Biomarkers], cerebrospinal fluid [tau Proteins], harmonization, Neurology (clinical), Human medicine, Geriatrics and Gerontology, Alzheimer’s disease, Biomarkers
Abstract

Introduction: the current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests. Methods: We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients. Results: the (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis. Discussion: this is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD. This manuscript was facilitated by the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART), through the Biofluid Based Biomarkers Professional Interest Area (BBB-PIA). The views and opinions expressed in this publication represent those of the authors and do not necessarily reflect those of the BBB-PIA membership, ISTAART, or the Alzheimer's Association. The authors thank the French Society of Clinical Biology, the ISTAART BBB-PIA, and the Society for Neurochemistry and Clinical CSF analysis for their help in initiating this work. Constance Delaby received no support for the present manuscript. Charlotte Teunissen received the following grants during the last 36 months: Research of CET is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 [MIRIADE], and JPND), Health Holland, the Dutch Research Council (ZonMw), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, Alzheimer Association. CT and WF are recipients of ABOARD, which is a public-private partnership receiving funding from ZonMw (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD. ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. IV is appointed on a research grant by Alzheimer Nederland (NL-17004). She received no support for the present manuscript. Kaj Blennow is supported by the Swedish Alzheimer Foundation (#AF-742881) and Hjärnfonden, Sweden (#FO2017-0243). He received no support for the present manuscript. Daniel Alcolea received funding from Institute of Health Carlos III (ISCIII), Spain PI18/00435 and INT19/00016, and by the Department of Health Generalitat de Catalunya PERIS program SLT006/17/125. He received no support for the present manuscript. Ivan Arisi was partly supported by: Fondo Ordinario Enti (FOE D.M 865/2019) funds in the framework of a collaboration agreement between the Italian National Research Council and EBRI (2019-2021); POR (Operative Program Lazio Region, Italy) FESR (European Program Regional Development) 2014-2020, Public Notice “LIFE 2020” MODIAG Project. Elodie Bouaziz-Amar received no support for the present manuscript. Anne Beaume received no support for the present manuscript. Aurélie Bedel received no support for the present manuscript. Giovanni Bellomo is supported by University of Perugia, CIRMMP, IRST Istituto Romagnolo per lo Studio e la Cura dei Tumori, Innuvatech srl. He received no support for the present manuscript. Edith Bigot-Corbel received no support for the present manuscript. Maria Bjerke received no support for the present manuscript. Marie-Céline Blanc-Quintin received no support for the present manuscript. Mercè Boada received support from LA CAIXA, IMI, ISCIII H2020 the European Union/EFPIA Innovative Medicines Initiative Joint Undertaking MOPEAD project (Grants No. 115985) and is also supported by national grant, PI17/01474 from Acción Estratégica en Salud, integrated into the Spanish National Plan of R+D+I and founded by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- “Una manera de Hacer Europa”). She received no support for the present manuscript. Olivier Bousigues is supported by A2MCL Alsace Alzheimer. He received no support for the present manuscript. Miles D. Chapman received no support for the present manuscript. Mari L. DeMarco is supported by the Michael Smith Foundation for Health Research, Brain Canada (Canada Brain Research Fund), Health Canada, Women's Brain Health Initiative, Alzheimer Society of Canada, St. Paul's Foundation, Djavad Mowafaghian Centre for Brain Health at the University of British Columbia and the Canadian Consortium for Neurodegeneration and Aging; with all funds provided to the University of British Columbia. Mara D'Onofrio was partly supported by Fondo Ordinario Enti (FOE D.M 865/2019) funds in the framework of a collaboration agreement between the Italian National Research Council POR (Operative Program Lazio Region, Italy) FESR (European Program Regional Development) 2014-2020, Public Notice “LIFE 2020″, MODIAG Project. She received no support for the present manuscript. Julien Dumurgier received no support for the present manuscript. Diane Dufour received no support for the present manuscript. Sebastiaan Engelborghs is supported for various projects: Research Project GSKE/FMRE, Research Project FWO Vlaanderen, PhD fellowship FWO Vlaanderen (n = 3), VLAIO PhD fellowship. He received no support for the present manuscript. Hermann Esselmann received no support for the present manuscript. Anne Fogli received no support for the present manuscript. Audrey Gabelle received no support for the present manuscript. Elisabetta Galloni received no support for the present manuscript. Clémentine Gondolf received no support for the present manuscript. Frédérique Grandhomme received no support for the present manuscript. Oriol Grau-Rivera receives grants from the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-33437), and from the Alzheimer's Association Research Fellowship Program (2019-AARF-644568). He received no support for the present manuscript. Melanie Hart receives UCLH Biomedical Research Centre support from NIHR (Neurosciences). She received no support for the present manuscript. Takeshi Ikeuchi received the following grants to his institution AMED: 21dk0207049, 21dk0207045, 21ek0109545, 20ek0109350, 20ek0109392. He received no support for the present manuscript. Andreas Jeromin received no support for the present manuscript. Kensaku Kasuga received no support for the present manuscript. Ashvini Keshavan is supported by the Weston Brain Institute/Selfridges Foundation grant UB170045. She received no support for the present manuscript. Michael Khalil received unrestricted research grants from Biogen and Novartis. He received no support for the present manuscript. Peter Körtvelyessy received no support for the present manuscript. Agnieszka Kulczynska-Przybik received no support for the present manuscript. Jean-Louis Laplanche received no support for the present manuscript. Qiao-Xin Li received no support for the present manuscript. Alberto Lleó is supported by grants from Generalitat de Catalunya (PERIS SLT002/16/00408), Instituto de Salud Carlos III (PI17/01896), Instituto de Salud Carlos III CIBERNED. He received no support for the present manuscript. Catherine Malaplate received no support for the present manuscript. Marta Marquié is supported by the Instituto de Salud Carlos III (ISCIII) Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de hacer Europa) grant PI19/00335. She received no support for the present manuscript. Colin M. Masters received no support for the present manuscript. Barbara Mroczko received a grant from The Binding Site Group and Biokom Diagnostyka. She received no support for the present manuscript. Léonor Nogueira received no support for the present manuscript. Adelina Orellana received no support for the present manuscript. Markus Otto is supported by BMBF, Thierry Latran foundation, EU, DFG. He received no support for the present manuscript. Jean-Baptiste Oudart is supported by Astrazeneca grant for a research program on EGFR targeted therapy resistance in NSCLC. He received no support for the present manuscript. Claire Paquet received no support for the present manuscript. Federico Paolini received no support for the present manuscript. Lucilla Parnetti received no support for the present manuscript. Armand Perret-Liaudet received no support for the present manuscript. Katell Peoc'h is supported by contract with Siemens Healthineers. She received no support for the present manuscript. Koen Poesen received no support for the present manuscript. Albert Puig-Pijoan received no support for the present manuscript. Isabelle Quadrio received no support for the present manuscript. Murielle Quillard-Muraine received no support for the present manuscript. Benoît Rucheton received no support for the present manuscript. Susanne Schraen received no support for the present manuscript. Jonathan M. Schott is supported by the Medical Research Council, Alzheimer's Research UK, Weston Brain Institute, British Heart Foundation, Alzheimer's Association. He received no support for the present manuscript. Leslie M. Shaw is supported by NIA for ADNI Biomarker Core, UPENN ADRC Biomarker Corr, MJ Fox PPMI for CSF Biomarker measurements, Roche for IIS study of AD biomarkers. He received no support for the present manuscript. Marc Suárez-Calvet receives funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant agreement No. 948677). He also receives funding from the Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I). He received no support for the present manuscript. Magda Tsolaki received no support for the present manuscript. Hayrettin Tumani is supported by Alexion, Bayer, Biogen, Celgene, Genzyme-Sanofi, Merck, Novartis, Roche, Teva. He received no support for the present manuscript. Chinedu T Udeh-Momoh is supported by Alzheimer research UK (Project Grant). He received no support for the present manuscript. Lucie Vaudran received no support for the present manuscript. Marcel M. Verbeek is supported by the BIONIC project (no. 733050822, which has been made possible by ZonMw within the framework of “Memorabel,” the research and innovation program for dementia, as part of the Dutch national “Deltaplan for Dementia”: zonmw.nl/dementiaresearch), and the CAFÉ project (the National Institutes of Health, USA, grant number 5R01NS104147-02). The BIONIC project is a consortium of Radboudumc, LUMC, ADX Neurosciences, and University of Rhode Island University. MM Verbeek is also supported by a grant from the Selfridges Group Foundation. He received no support for the present manuscript. Federico Verde received no support for the present manuscript. Lisa Vermunt is supported by Alzheimer Nederland. She received no support for the present manuscript. Jonathan Volgesgang is supported by Clinician Scientist Research Fellowship, German Research Foundation (Deutsche Forschungsgesellschaft, project number: 413501650; 09/01/2019-02/28/2021); Eric Dorris Memorial Fellowship (McLean Hospital; 07/01/2020-06/30/2021). He received no support for the present manuscript. Jens Wiltfang is supported by Federal Ministry of Education and Research (BMBF) State of Lower Saxony; He received no support for the present manuscript. Henrik Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. He received no support for the present manuscript. Sylvain Lehmann received no support for the present manuscript.

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

Author

Gauthier, Kim, Morand, Alexandrine, Dutheil, Frederic, Alescio-Lautier, Béatrice, Boucraut, José, Clarys, David, Eustache, Francis, Girard, Nadine, Guedj, Eric, Mazerolle, Marie, Paccalin, Marc, de la Sayette, Vincent, Zaréa, Aline, Huguet, Pascal, Michel, Bernard F, Desgranges, Béatrice, Régner, Isabelle, Laboratoire de psychologie cognitive (LPC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), 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), Laboratoire de Psychologie Sociale et Cognitive (LAPSCO), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Service Santé Travail Environnement [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Neurosciences sensorielles et cognitives (NSC), Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Institut de Neurosciences de la Timone (INT), Centre de Recherches sur la Cognition et l'Apprentissage (CeRCA), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Institut FRESNEL (FRESNEL), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Imagerie MOléculaire pour applications THéranostiques personnalisées (IMOTHEP), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE), Maison des Sciences de l'Homme et de l'Environnement Claude Nicolas Ledoux (UAR 3124) (MSHE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de Neurologie Comportementale [Hôpital Sainte Marguerite - APHM], Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), This study was supported by a grant from the French National Research Agency (ANR) (grant no. ANR-16-CE36-0005-01)., Collaborators Members of AGING Consortium: Hospitals : José Broucraut, Boris Dufournet, Carine Giallo, Nadine Girard, Eric Guedj, Bernard François Michel, Nathalie Sambuchi (Marseille Public Hospitals, France: central site), Pierre Branger, Julien Cogez, Sabine Fradin, Frédérique Grandhomme, Catherine Lalevée, Nadège Loisel, Olivier Martinaud, Alice Pélerin, Mélissa Pierre, Vincent de La Sayette (Caen University Hospital, France), Alain Manrique (Cyceron Biomedical Imaging Centre, Caen, France), Vanessa Baudifier, Foucaud du Boisgueheneuc, Adrien Julian, Jean-Claude Lecron, Isabelle Merlet, Claudie Ornon, Marc Paccalin (Poitiers University Hospital, France), Sandrine Bioux, Evangeline Bliaux, Didier Hannequin, Véronique Hannier, Maud Loubeyre, Dorothée Pouliquen, Muriel Quillard-Muraine, David Wallon, Aline Zaréa (Rouen University Hospital, France). Laboratories : Kim Gauthier, Isabelle Régner (Cognitive Psychology Laboratory, Aix Marseille Univ, Marseille, France), Béatrice Alescio-Lautier, Véronique Paban, Arnaud Weill (Sensory and Cognitive Neuroscience Laboratory, Aix Marseille Univ ‑ CNRS, Marseille, France), David Clarys, Michel Isingrini, Sandrine Kalenzaga, François Rigalleau (Centre for Research on Cognition and Learning, CNRS ‑ Poitiers University ‑ Tours University, Poitiers, France), Ahmed Abbas, Julien Chavant, Béatrice Desgranges, Francis Eustache, Florence Fraisse, Mickael Laisney, Alexandrine Morand, Shailendra Segobin (Neuropsychology and Human Memory Imaging research unit, Caen University Hospital ‑ Caen Normandy University ‑ PSL Research University ‑ EPHE ‑ INSERM, Caen, France), Pierre Chausse, Frédéric Dutheil, Julien Guegan, Pascal Huguet, Guillaume Vallet (Social and Cognitive Psychology Laboratory, University of Clermont Auvergne ‑ CNRS, Clermont-Ferrand, France), Sophie Blanchet, Pascale Piolino (Memory and Cognition, Institute of Psychology and Centre for Psychiatriy and Neurosciences, INSERM ‑ University of Paris Descartes, Paris, France), Marie Mazerolle (Psychology Department and Laboratory, University of Bourgundy Franche-Comté, France)., ANR-16-CE36-0005,AGING,Impact potentiel des stéréotypes du vieillissement sur l'évaluation des déficits mnésiques et le repérage de l'état prodromal de la maladie d'Alzheimer(2016), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Département de Médecine Nucléaire [AP-HM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)- Hôpital Nord [CHU - APHM], Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), 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), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Maison des Sciences de l'Homme et de l'Environnement Claude Nicolas Ledoux (MSHE), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), Eustache, Francis, Impact potentiel des stéréotypes du vieillissement sur l'évaluation des déficits mnésiques et le repérage de l'état prodromal de la maladie d'Alzheimer - - AGING2016 - ANR-16-CE36-0005 - AAPG2016 - VALID, Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Université de Poitiers, and Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Aging, Stereotyping, diagnosis, Neuropsychological Tests, aging stereotypes, amyloid PET, [SCCO]Cognitive science, mild cognitive impairment, Neurology, Memory, stereotype threat, Protocol, Humans, Regression Analysis, Cognitive Dysfunction, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer disease, Randomized Controlled Trials as Topic
Abstract

International audience; 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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