Search

Your search keyword '"Benda N."' showing total 9 results
Start Over Author "Benda N." Topic humans
9 results on '"Benda N."'

1. Aptamarker prediction of brain amyloid-β status in cognitively normal individuals at risk for Alzheimer’s disease

Author

Penner, G, Lecocq, S, Chopin, A, Vedoya, X, Lista, S, Vergallo, A, Cavedo, E, Lejeune, F, Dubois, B, Hampel, H, Bakardjian, H, Benali, H, Bertin, H, Bonheur, J, Boukadida, L, Boukerrou, N, Chiesa, Pa, Colliot, O, Dubois, M, Epelbaum, S, Gagliardi, G, Genthon, R, Habert, M, Houot, M, Kas, A, Lamari, F, Levy, M, Metzinger, C, Mochel, F, Nyasse, F, Poisson, C, Potier, M, Revillon, M, Santos, A, Andrade, Ks, Sole, M, Surtee, M, de Schotten, Mt, Younsi, N, Afshar, M, Aguilar, Lf, Akman-Anderson, L, Aremas, J, Avila, J, Babiloni, C, Baldacci, F, Batrla, R, Benda, N, Black, Kl, Bokde, Alw, Bonuccelli, U, Broich, K, Cacciola, F, Caraci, F, Caruso, G, Castrillo, J, Ceravolo, R, Corbo, M, Corvol, J, Cuello, Ac, Cummings, Jl, Depypere, H, Duggento, A, Emanuele, E, Escott-Price, V, Federoff, H, Ferretti, Mt, Fiandaca, M, Frank, Ra, Garaci, F, Geerts, H, Giacobini, E, Giorgi, Fs, Goetzl, Ej, Graziani, M, Haberkamp, M, Hanisch, B, Herholz, K, Hernandez, F, Imbimbo, Bp, Kapogiannis, D, Karran, E, Kiddle, Sj, Kim, Sh, Koronyo, Y, Koronyo-Hamaoui, M, Langevin, T, Lehericy, S, Lemercier, P, Llavero, F, Lorenceau, J, Lucia, A, Mango, D, Mapstone, M, Neri, C, Nistico, R, O'Bryant, Se, Palermo, G, Perry, G, Ritchie, C, Rossi, S, Saidi, A, Santarnecchi, E, Schneider, Ls, Sporns, O, Toschi, N, Valenzuela, Pl, Vellas, B, Verdooner, Sr, Villain, N, Giudici, Kv, Watling, M, Welikovitch, La, Woodcock, J, Younesi, E, Zugaza, Jl, Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Gasset, Maria

Subjects
Male, Aging, Amyloid β, MESH: SELEX Aptamer Technique, [SDV]Life Sciences [q-bio], Oligonucleotides, Artificial Gene Amplification and Extension, Disease, Neurodegenerative, Alzheimer's Disease, Pathology and Laboratory Medicine, Biochemistry, Polymerase Chain Reaction, Diagnostic Radiology, Negative selection, Medical Conditions, Mathematical and Statistical Techniques, 0302 clinical medicine, MESH: Aged, 80 and over, MESH: Early Diagnosis, 80 and over, Medicine and Health Sciences, Biomarker discovery, Tomography, Aged, 80 and over, MESH: Aged, screening and diagnosis, 0303 health sciences, Multidisciplinary, Nucleotides, Mathematical Models, Radiology and Imaging, SELEX Aptamer Technique, Settore MED/37 - Neuroradiologia, Neurodegenerative Diseases, MESH: Case-Control Studies, MESH: Amyloid beta-Peptides, Detection, Neurology, Neurological, Medicine, Biomedical Imaging, Female, Biotechnology, 4.2 Evaluation of markers and technologies, Research Article, Amyloid, General Science & Technology, Imaging Techniques, Science, Aptamer, Neuroimaging, and over, Computational biology, Biology, Research and Analysis Methods, 03 medical and health sciences, Clinical Research, Diagnostic Medicine, Alzheimer Disease, Mental Health and Psychiatry, Acquired Cognitive Impairment, Humans, Risk factor, Molecular Biology Techniques, Molecular Biology, Aged, 030304 developmental biology, Amyloid beta-Peptides, MESH: Humans, Prevention, Neurosciences, Alzheimer Precision Medicine Initiative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Biology and Life Sciences, Omics, MESH: Male, Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, Early Diagnosis, Case-Control Studies, MESH: Biomarkers, Dementia, INSIGHT-preAD study group, MESH: Female, Biomarkers, Positron Emission Tomography, 030217 neurology & neurosurgery, MESH: Alzheimer Disease, Neuroscience
Abstract

International audience; The traditional approach to biomarker discovery for any pathology has been through hypothesis-based research one candidate at a time. The objective of this study was to develop an agnostic approach for the simultaneous screening of plasma for consistent molecular differences between a group of individuals exhibiting a pathology and a group of healthy individuals. To achieve this, we focused on developing a predictive tool based on plasma for the amount of brain amyloid-β deposition as observed in PET scans. The accumulation of brain amyloid-β (Aβ) plaques is a key risk factor for the development of Alzheimer's disease. A contrast was established between cognitively normal individuals above the age of 70 that differed for the amount of brain amyloid-β observed in PET scans (INSIGHT study group). Positive selection was performed against a pool of plasma from individuals with high brain amyloid and negative selection against a pool of plasma from individuals with low brain amyloid This enriched, selected library was then applied to plasma samples from 11 individuals with high levels of brain amyloid and 11 individuals with low levels of brain Aβ accumulation. Each of these individually selected libraries was then characterized by next generation sequencing, and the relative frequency of 10,000 aptamer sequences that were observed in each selection was screened for ability to explain variation in brain amyloid using sparse partial least squares discriminant analysis. From this analysis a subset of 44 aptamers was defined, and the individual aptamers were synthesized. This subset was applied to plasma samples from 70 cognitively normal individuals all above the age of 70 that differed for brain amyloid deposition. 54 individuals were used as a training set, and 15 as a test set. Three of the 15 individuals in the test set were mis-classified resulting in an overall accuracy of 80% with 86% sensitivity and 75% specificity. The aptamers included in the subset serve directly as biomarkers, thus we have named them Aptamarkers. There are two potential applications of these results: extending the predictive capacity of these aptamers across a broader range of individuals, and/or using the individual aptamers to identify targets through covariance analysis and reverse omics approaches. We are currently expanding applications of the Aptamarker platform to other diseases and target matrices.

Published
2021

2. Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease

Author

Chiesa P. A., Cavedo E., Vergallo A., Lista S., Potier M. -C., Habert M. -O., Dubois B., Thiebaut de Schotten M., Hampel H., Audrain C., Auffret A., Bakardjian H., Baldacci F., Batrancourt B., Benakki I., Benali H., Bertin H., Bertrand A., Boukadida L., Cacciamani F., Causse V., Cherif Touil S., Colliot O., Dalla Barba G., Depaulis M., Dos Santos A., Dubois M., Epelbaum S., Fontaine B., Francisque H., Gagliardi G., Genin A., Genthon R., Glasman P., Gombert F., Habert M. O., Hewa H., Houot M., Jungalee N., Kas A., Kilani M., La Corte V., Le Roy F., Lehericy S., Letondor C., Levy M., Lowrey M., Ly J., Makiese O., Masetti I., Mendes A., Metzinger C., Michon A., Mochel F., Nait Arab R., Nyasse F., Perrin C., Poirier F., Poisson C., Potier M. C., Ratovohery S., Revillon M., Rojkova K., Santos-Andrade K., Schindler R., Servera M. C., Seux L., Simon V., Skovronsky D., Uspenskaya O., Vlaincu M., Aguilar L. F., Babiloni C., Benda N., Black K. L., Bokde A. L. W., Bonuccelli U., Broich K., Cacciola F., Castrillo J., Ceravolo R., Corvol J. -C., Claudio Cuello A., Cummings J. L., Depypere H., Duggento A., Durrleman S., Escott-Price V., Federoff H., Teresa Ferretti M., Fiandaca M., Frank R. A., Garaci F., Geerts H., George N., Giorgi F. S., Graziani M., Haberkamp M., Herholz K., Karran E., Kim S. H., Koronyo Y., Koronyo-Hamaoui M., Lamari F., Langevin T., Lorenceau J., Mango D., Mapstone M., Neri C., Nistico R., O'Bryant S. E., Palermo G., Perry G., Ritchie C., Rossi S., Saidi A., Santarnecchi E., Schneider L. S., Sporns O., Toschi N., Verdooner S. R., Villain N., Welikovitch L. A., Woodcock J., Younesi E., 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), Service de Neuroradiologie [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), Treat SVD, Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), sans affiliation, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), 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), Université de Bordeaux (UB), Service de neurologie 1 [CHU Pitié-Salpétrière], 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 médecine nucléaire [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre des Maladies Cognitives et Comportementales [Paris], Fraunhofer Center for Assistive Information and Communication Solutions [Porto] (Fraunhofer AICOS), Fraunhofer (Fraunhofer-Gesellschaft), Ariana Pharmaceuticals, McGill University = Université McGill [Montréal, Canada], Universidad Autonoma de Madrid (UAM), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], University of Pisa - Università di Pisa, Federal Institute of Drugs and Medical Devices [Bonn], Discipline of Psychiatry [Dublin], School of Medicine [Dublin], Trinity College Dublin-Trinity College Dublin, Universita degli Studi di Messina, University of Catania [Italy], University of Cambridge [UK] (CAM), Lou Ruvo Center for Brain Health [Las Vegas], Cleveland Clinic, Università degli Studi di Roma Tor Vergata [Roma], University of Pavia, Cardiff University, Universität Zürich [Zürich] = University of Zurich (UZH), University of California [Irvine] (UCI), University of California, Siemens Healthineers, Digital Services, Digital Technology and Innovation, In Silico Biosciences (ISB), Abdus Salam International Centre for Theoretical Physics [Trieste] (ICTP), University of California [San Francisco] (UCSF), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Manchester [Manchester], National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Abbvie Inc. [North Chicago], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, University of Britsh Columbia [Vancouver], Cedars-Sinai Medical Center, Functional Neuromodulation, CIBER de Enfermedades Raras (CIBERER), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Brain Research Institute [Rome, Italy] (EBRI), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute for Aging and Alzheimer’s Disease Research [Fort Worth] (IAADR), University of North Texas Health Science Center [Fort Worth], University of Auckland [Auckland], University of Edinburgh, Università degli Studi di Siena = University of Siena (UNISI), Harvard Medical School [Boston] (HMS), Keck School of Medicine [Los Angeles], University of Southern California (USC), Indiana State University, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), NeuroVision Imaging, Fondation pour la Recherche sur Alzheimer, Center for Drug Evaluation and Research (CDER), European Society for Translational Medicine (EUSTM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Explorations Fonctionnelles Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de médecine nucléaire [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Fraunhofer AICOS [Porto], McGill University, Sapienza University [Rome], University of Zürich [Zürich] (UZH), Università degli Studi di Roma 'La Sapienza' [Rome], CHU Pitié-Salpêtrière [APHP], Service de neuro-radiologie [CHU Pitié-Salpêtrière], Università degli Studi di Siena (UNISI), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-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 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), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), 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], Service de Médecine nucléaire [CHU Pitié-Salpétrière], Universidad Autónoma de Madrid (UAM), 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), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Sans affiliation, 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), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Università degli Studi di Messina = University of Messina (UniMe), Università degli Studi di Pavia = University of Pavia (UNIPV), University of California [Irvine] (UC Irvine), University of California (UC), University of California [San Francisco] (UC San Francisco), University of British Columbia [Vancouver], Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Chiesa, P. A., Cavedo, E., Vergallo, A., Lista, S., Potier, M. -C., Habert, M. -O., Dubois, B., Thiebaut de Schotten, M., Hampel, H., Audrain, C., Auffret, A., Bakardjian, H., Baldacci, F., Batrancourt, B., Benakki, I., Benali, H., Bertin, H., Bertrand, A., Boukadida, L., Cacciamani, F., Causse, V., Cherif Touil, S., Colliot, O., Dalla Barba, G., Depaulis, M., Dos Santos, A., Dubois, M., Epelbaum, S., Fontaine, B., Francisque, H., Gagliardi, G., Genin, A., Genthon, R., Glasman, P., Gombert, F., Habert, M. O., Hewa, H., Houot, M., Jungalee, N., Kas, A., Kilani, M., La Corte, V., Le Roy, F., Lehericy, S., Letondor, C., Levy, M., Lowrey, M., Ly, J., Makiese, O., Masetti, I., Mendes, A., Metzinger, C., Michon, A., Mochel, F., Nait Arab, R., Nyasse, F., Perrin, C., Poirier, F., Poisson, C., Potier, M. C., Ratovohery, S., Revillon, M., Rojkova, K., Santos-Andrade, K., Schindler, R., Servera, M. C., Seux, L., Simon, V., Skovronsky, D., Uspenskaya, O., Vlaincu, M., Aguilar, L. F., Babiloni, C., Benda, N., Black, K. L., Bokde, A. L. W., Bonuccelli, U., Broich, K., Cacciola, F., Castrillo, J., Ceravolo, R., Corvol, J. -C., Claudio Cuello, A., Cummings, J. L., Depypere, H., Duggento, A., Durrleman, S., Escott-Price, V., Federoff, H., Teresa Ferretti, M., Fiandaca, M., Frank, R. A., Garaci, F., Geerts, H., George, N., Giorgi, F. S., Graziani, M., Haberkamp, M., Herholz, K., Karran, E., Kim, S. H., Koronyo, Y., Koronyo-Hamaoui, M., Lamari, F., Langevin, T., Lorenceau, J., Mango, D., Mapstone, M., Neri, C., Nistico, R., O'Bryant, S. E., Palermo, G., Perry, G., Ritchie, C., Rossi, S., Saidi, A., Santarnecchi, E., Schneider, L. S., Sporns, O., Toschi, N., Verdooner, S. R., Villain, N., Welikovitch, L. A., Woodcock, J., Younesi, E., and Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Apolipoprotein E, Epidemiology, Brain activity and meditation, Precuneus, Disease, Neuropsychological Tests, Hippocampus, Cohort Studies, [SCCO]Cognitive science, 0302 clinical medicine, Medicine, Longitudinal Studies, Default mode network, ComputingMilieux_MISCELLANEOUS, Brain Mapping, Subjective memory complaints, Brain functional dynamic, Health Policy, Precision medicine, fMRI, Settore BIO/14, Brain, Brain functional dynamics, Alzheimer's disease, Magnetic Resonance Imaging, Temporal Lobe, Frontal Lobe, Psychiatry and Mental health, medicine.anatomical_structure, Cohort, Biomarker (medicine), Female, Amyloid, 03 medical and health sciences, Cellular and Molecular Neuroscience, Apolipoproteins E, Developmental Neuroscience, Alzheimer Disease, Humans, Aged, Resting state fMRI, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, 030104 developmental biology, Neurology (clinical), Geriatrics and Gerontology, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

Introduction The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood. Methods In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years. Results Widespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E e4 (APOE e4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status. Discussion For the first time, we demonstrated that the pleiotropic biological effect of the APOE e4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions.

Published
2019

3. Age and sex impact plasma NFL and t-Tau trajectories in individuals with subjective memory complaints: a 3-year follow-up study

Author

Baldacci, F., Lista, S., Manca, M. L., Chiesa, P. A., Cavedo, E., Lemercier, P., Zetterberg, H., Blennow, K., Habert, M. -O., Potier, M. C., Dubois, B., Vergallo, A., Hampel, H., Bakardjian, H., Benali, H., Bertin, H., Bonheur, J., Boukadida, L., Boukerrou, N., Chiesa, P., Colliot, O., Dubois, M., Epelbaum, S., Gagliardi, G., Genthon, R., Houot, M., Kas, A., Lamari, F., Levy, M., Metzinger, C., Mochel, F., Nyasse, F., Poisson, C., Potier, M. -C., Revillon, M., Santos, A., Andrade, K. S., Sole, M., Surtee, M., de Schotten, M. T., Younsi, N., Afshar, M., Aguilar, L. F., Akman-Anderson, L., Arenas, J., Avila, J., Babiloni, C., Batrla, R., Benda, N., Black, K. L., Bokde, A. L. W., Bonuccelli, U., Broich, K., Cacciola, F., Caraci, F., Caruso, G., Castrillo, J., Ceravolo, R., Corbo, M., Corvol, J. -C., Claudio, A., Cummings, J. L., Depypere, H., Duggento, A., Emanuele, E., Escott-Price, V., Federoff, H., Ferretti, M. T., Fiandaca, M., Frank, R. A., Garaci, F., Geerts, H., Giacobini, E., Giorgi, F. S., Goetzl, E. J., Graziani, M., Haberkamp, M., Hanisch, B., Herholz, K., Hernandez, F., Imbimbo, B. P., Kapogiannis, D., Karran, E., Kiddle, S. J., Kim, S. H., Koronyo, Y., Koronyo-Hamaoui, M., Langevin, T., Lehericy, S., Llavero, F., Lorenceau, J., Lucia, A., Mango, D., Mapstone, M., Neri, C., Nistico, R., O'Bryant, S. E., Palermo, G., Perry, G., Ritchie, C., Rossi, S., Saidi, A., Santarnecchi, E., Schneider, L. S., Sporns, O., Toschi, N., Valenzuela, P. L., Vellas, B., Verdooner, S. R., Villain, N., Virecoulon Giudici, K., Watling, M., Welikovitch, L. A., Woodcock, J., Younesi, E., Zugaza, J. L., Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), 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), University of Pisa - Università di Pisa, 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), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Sahlgrenska Academy at University of Gothenburg [Göteborg], University College of London [London] (UCL), UK Dementia Research Institute (UK DRI), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de médecine nucléaire [CHU Pitié-Salpétrière], 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 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)

Subjects
Male, BIOMARKER, 0301 basic medicine, Oncology, Aging, Neurology, [SDV]Life Sciences [q-bio], Disease, Neurodegenerative, Alzheimer's Disease, Medical and Health Sciences, lcsh:RC346-429, MESH: Cognitive Dysfunction, Alzheimer’s disease, Biomarkers, Mild cognitive impairment, Neurofilament light chain, Subjective memory complainers, Tau, 0302 clinical medicine, Neurofilament Proteins, Medicine and Health Sciences, BRAIN, MESH: Neurofilament Proteins, RISK, Settore FIS/07, NEURODEGENERATION, Cognition, ASSOCIATION, MESH: Follow-Up Studies, Alzheimer's disease, MESH: Amyloid beta-Peptides, MESH: tau Proteins, ALZHEIMERS-DISEASE, POSITIVITY, Neurological, Cohort, Biomarker (medicine), Female, medicine.medical_specialty, Cognitive Neuroscience, tau Proteins, Subjective, Affect (psychology), VALIDATION, lcsh:RC321-571, subjective memory complainers, mild cognitive impairment, biomarkers, s disease, 03 medical and health sciences, memory complainers, Clinical Research, Alzheimer Disease, Internal medicine, NEUROFILAMENT LIGHT-CHAIN, Acquired Cognitive Impairment, medicine, Humans, Cognitive Dysfunction, Vitamin B12, Allele, Alzheimer&#8217, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, lcsh:Neurology. Diseases of the nervous system, Amyloid beta-Peptides, MESH: Humans, business.industry, Research, Prevention, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer Precision Medicine Initiative, COGNITIVE IMPAIRMENT, MESH: Male, Brain Disorders, 030104 developmental biology, MESH: Biomarkers, Dementia, Neurology (clinical), business, INSIGHT-preAD study group, MESH: Female, MESH: Alzheimer Disease, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Background Plasma neurofilament light (NFL) and total Tau (t-Tau) proteins are candidate biomarkers for early stages of Alzheimer’s disease (AD). The impact of biological factors on their plasma concentrations in individuals with subjective memory complaints (SMC) has been poorly explored. We longitudinally investigate the effect of sex, age, APOE ε4 allele, comorbidities, brain amyloid-β (Aβ) burden, and cognitive scores on plasma NFL and t-Tau concentrations in cognitively healthy individuals with SMC, a condition associated with AD development. Methods Three hundred sixteen and 79 individuals, respectively, have baseline and three-time point assessments (at baseline, 1-year, and 3-year follow-up) of the two biomarkers. Plasma biomarkers were measured with an ultrasensitive assay in a mono-center cohort (INSIGHT-preAD study). Results We show an effect of age on plasma NFL, with women having a higher increase of plasma t-Tau concentrations compared to men, over time. The APOE ε4 allele does not affect the biomarker concentrations while plasma vitamin B12 deficiency is associated with higher plasma t-Tau concentrations. Both biomarkers are correlated and increase over time. Baseline NFL is related to the rate of Aβ deposition at 2-year follow-up in the left-posterior cingulate and the inferior parietal gyri. Baseline plasma NFL and the rate of change of plasma t-Tau are inversely associated with cognitive score. Conclusion We find that plasma NFL and t-Tau longitudinal trajectories are affected by age and female sex, respectively, in SMC individuals. Exploring the influence of biological variables on AD biomarkers is crucial for their clinical validation in blood.

Published
2020

4. β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification

Author

Hampel, H., Lista, S., Vanmechelen, E., Zetterberg, H., Giorgi, F. S., Galgani, A., Blennow, K., Caraci, F., Das, B., Yan, R., Vergallo, A., Aguilar, L. F., Akman-Anderson, L., Arenas, J., Avila, J., Babiloni, C., Baldacci, F., Batrla, R., Benda, N., Black, K. L., Bokde, A. L. W., Bonuccelli, U., Broich, K., Cacciola, F., Caruso, G., Castrillo, J., Cavedo, E., Ceravolo, R., Chiesa, P. A., Corbo, M., Corvol, J. -C., Cuello, A. C., Cummings, J. L., Depypere, H., Dubois, B., Duggento, A., Emanuele, E., Escott-Price, V., Federoff, H., Ferretti, M. T., Fiandaca, M., Frank, R. A., Garaci, F., Geerts, H., Giacobini, E., Goetzl, E. J., Graziani, M., Haberkamp, M., Habert, M. -O., Hanisch, B., Herholz, K., Hernandez, F., Imbimbo, B. P., Kapogiannis, D., Karran, E., Kiddle, S. J., Kim, S. H., Koronyo, Y., Koronyo-Hamaoui, M., Langevin, T., Lehericy, S., Lemercier, P., Llavero, F., Lorenceau, J., Lucia, A., Mango, D., Mapstone, M., Neri, C., Nistico, R., O'Bryant, S. E., Palermo, G., Perry, G., Ritchie, C., Rossi, S., Saidi, A., Santarnecchi, E., Schneider, L. S., Sporns, O., Toschi, N., Valenzuela, P. L., Vellas, B., Verdooner, S. R., Villain, N., Virecoulon Giudici, K., Watling, M., Welikovitch, L. A., Woodcock, J., Younesi, E., and Zugaza, J. L.

Subjects
BIOMARKER, 0301 basic medicine, Aging, Neurology, Fluid biomarkers, Axonal damage, context of use, Review, Alzheimer’s disease, Amyloid-β pathway, BACE1, clinical trials, fluid biomarkers, neurodegeneration, Disease, Neurodegenerative, Bioinformatics, Medical and Health Sciences, lcsh:RC346-429, Clinical trials, 0302 clinical medicine, PP-BETA, Medicine and Health Sciences, Aspartic Acid Endopeptidases, Context of use, Neurodegeneration, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Biomarkers, Humans, Alzheimer Disease, RISK, screening and diagnosis, CORRELATE, Settore FIS/07, AMYLOID-PRECURSOR PROTEIN, Alzheimer's disease, Detection, Neurological, State of art, Biomarker (medicine), EXPRESSION, medicine.medical_specialty, Cognitive Neuroscience, lcsh:RC321-571, 03 medical and health sciences, CEREBROSPINAL-FLUID, Clinical Research, BETA-SECRETASE BACE1, mental disorders, Acquired Cognitive Impairment, medicine, Adverse effect, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, lcsh:Neurology. Diseases of the nervous system, Mechanism (biology), business.industry, Prevention, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Amyloid-beta pathway, medicine.disease, Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, Clinical trial, Good Health and Well Being, 030104 developmental biology, Dementia, Alzheimer’s Precision Medicine Initiative, Neurology (clinical), TAU, business, 030217 neurology & neurosurgery, GENERATION
Abstract

β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-β pathway in Alzheimer’s disease (AD). A robust body of evidence demonstrates an association between cerebrospinal fluid/blood BACE1 biomarkers and core pathophysiological mechanisms of AD, such as brain protein misfolding and aggregration, neurodegeneration, and synaptic dysfunction.In pharmacological trials, BACE1 candidate biomarkers may be applied to a wide set of contexts of use (CoU), including proof of mechanism, dose-finding, response and toxicity dose estimation. For clinical CoU, BACE1 biomarkers show good performance for prognosis and disease prediction.The roadmap toward validation and qualification of BACE1 biomarkers requires standardized pre-analytical and analytical protocols to reduce inter-site variance that may have contributed to inconsistent results.BACE1 biomarker-drug co-development programs, including biomarker-guided outcomes and endpoints, may support the identification of sub-populations with a higher probability to benefit from BACE1 inhibitors with a reduced risk of adverse effects, in line with the evolving precision medicine paradigm.

Published
2020

5. Blood-based systems biology biomarkers for next-generation clinical trials in Alzheimer’s disease

Author

Hampel, H, Vergallo, A, Afshar, M, Akman-Anderson, L, Arenas, J, Benda, N, Batrla, R, Broich, K, Caraci, F, Cuello, Ac, Emanuele, E, Haberkamp, M, Kiddle, Sj, Lucia, A, Mapstone, M, Verdooner, Sr, Woodcock, J, Lista, S, Aguilar, Lf, Babiloni, C, Baldacci, F, Black, Kl, Bokde, Alw, Bonuccelli, U, Cacciola, F, Castrillo, J, Cavedo, E, Ceravolo, R, Chiesa, Pa, Corvol, J, Cummings, Jl, Depypere, H, Dubois, B, Duggento, A, Escott-Price, V, Federoff, H, Ferretti, Mt, Fiandaca, M, Frank, Ra, Garaci, F, Geerts, H, Giorgi, Fs, Goetzl, Ej, Graziani, M, Habert, M, Herholz, K, Kapogiannis, D, Karran, E, Kim, Sh, Koronyo, Y, Koronyo-Hamaoui, M, Langevin, T, Lehericy, S, Lorenceau, J, Mango, D, Neri, C, Nistico, R, O'Bryant, Se, Palermo, G, Perry, G, Ritchie, C, Rossi, S, Saidi, A, Santarnecchi, E, Schneider, Ls, Sporns, O, Toschi, N, Villain, N, Welikovitch, La, and Younesi, E

Subjects
biomarker-drug codevelopment, Systems biology, Alzheimer's disease, systems biology, precision medicine, blood-based biomarker, context of use, pathophysiology, clinical trial, predictive biomarker, Druggability, Eligibility Determination, Disease, Computational biology, 03 medical and health sciences, 0302 clinical medicine, Drug Development, Alzheimer Disease, Humans, Medicine, Clinical Trials as Topic, business.industry, Clinical study design, Settore FIS/07, Precision medicine, Treatment efficacy, 030227 psychiatry, Clinical trial, Early Diagnosis, Alzheimer’s disease, DECIPHER, Original Article, business, Biomarkers
Abstract

Alzheimer's disease (AD)-a complex disease showing multiple pathomechanistic alterations-is triggered by nonlinear dynamic interactions of genetic/epigenetic and environmental risk factors, which, ultimately, converge into a biologically heterogeneous disease. To tackle the burden of AD during early preclinical stages, accessible blood-based biomarkers are currently being developed. Specifically, next-generation clinical trials are expected to integrate positive and negative predictive blood-based biomarkers into study designs to evaluate, at the individual level, target druggability and potential drug resistance mechanisms. In this scenario, systems biology holds promise to accelerate validation and qualification for clinical trial contexts of use-including proof-of-mechanism, patient selection, assessment of treatment efficacy and safety rates, and prognostic evaluation. Albeit in their infancy, systems biology-based approaches are poised to identify relevant AD "signatures" through multifactorial and interindividual variability, allowing us to decipher disease pathophysiology and etiology. Hopefully, innovative biomarker-drug codevelopment strategies will be the road ahead towards effective disease-modifying drugs. .La Enfermedad de Alzheimer (EA) es una enfermedad compleja que presenta múltiples alteraciones patomecánicas, que se desencadena por interacciones dinámicas no lineales de factores de riesgo genéticos / epigenéticos y ambientales, los que, en definitiva, convergen en una enfermedad biológicamente heterogénea. Para hacer frente a la carga de la EA durante las etapas preclínicas tempranas, actualmente se están desarrollando biomarcadores sanguíneos de fácil accesibilidad. Específicamente, se espera que los ensayos clínicos de próxima generación integren biomarcadores sanguíneos predictivos tanto positivos como negativos en los diseños de los estudios para evaluar, a nivel individual, la capacidad de la droga objetivo y los posibles mecanismos de resistencia a los medicamentos. En este contexto, la biología de sistemas promete acelerar la validación y la calificación de su empleo en los ensayos clínicos, incluida la prueba del mecanismo, la selección de pacientes, la evaluación de la eficacia del tratamiento y los porcentajes de seguridad, y la evaluación pronóstica. A pesar de estar en sus comienzos, los enfoques basados en la biología de sistemas están preparados para identificar “firmas” de EA relevantes a través de la variabilidad multifactorial e interindividual, lo que nos permite descifrar la fisiopatología y la etiología de la enfermedad. Ojalá, las estrategias innovadoras conjuntas del desarrollo de biomarcadores y de medicamentos sean el camino adecuado para conseguir fármacos eficaces que modifiquen la enfermedad.La maladie d’Alzheimer (MA) — maladie complexe présentant des altérations nombreuses pathomécaniques — est déclenchée par des interactions dynamiques non linéaires entre des facteurs de risques génétiques et épigénétiques et environnementaux qui, au bout du compte, aboutissent à une maladie biologiquement hétérogène. Pour réduire la charge de morbidité de la MA durant ses premiers stades précliniques, des biomarqueurs sanguins sont actuellement développés. Spécifiquement, la prochaine génération d’essais cliniques devrait intégrer ces biomarqueurs sanguins positifs ou négatifs prédictifs de la maladie dans des études qui auront pour but d’évaluer, à un niveau individuel, des cibles pouvant être traitées par des candidats médicaments et de potentiels mécanismes de résistance à ces médicaments. Dans ce contexte, la biologie des systèmes devrait permettre d’accélérer la validation et la qualification de leur utilisation dans les études cliniques – incluant la preuve du mécanisme d’action, la sélection des patients, la confirmation de l’efficacité du traitement et son niveau de sécurité, ainsi que l’évaluation pronostique. Bien que nous en soyons au tout début, les approches reposant sur la biologie des systèmes sont sur le point d’identifier des « signatures » pertinentes de la MA grâce à des variables multifactorielles et interindividuelles, qui nous permettront d’élucider la pathophysiologie et l’étiologie de la maladie. Avec un peu de chance, les stratégies innovantes de codéveloppement de biomarqueurs et de médicaments nous mèneront vers des médicaments efficaces pour lutter contre la maladie.

Published
2019

6. Brain Aβ load association and sexual dimorphism of plasma BACE1 concentrations in cognitively normal individuals at risk for AD

Author

Vergallo, A., Houot, M., Cavedo, E., Lemercier, P., Vanmechelen, E., De Vos, A., Habert, M. -O., Potier, M. -C., Dubois, B., Lista, S., Hampel, H., Bakardjian, H., Benali, H., Bertin, H., Bonheur, J., Boukadida, L., Boukerrou, N., Chiesa, P., Colliot, O., Dubois, M., Epelbaum, S., Gagliardi, G., Genthon, R., Habert, M. O., Kas, A., Lamari, F., Levy, M., Metzinger, C., Mochel, F., Nyasse, F., Poisson, C., Potier, M. C., Revillon, M., Santos, A., Andrade, K. S., Sole, M., Surtee, M., Thiebaud de Schotten, M., Younsi, N., Afshar, M., Flores Aguilar, L., Akman-Anderson, L., Arenas, J., Avila, J., Babiloni, C., Baldacci, F., Batrla, R., Benda, N., Black, K. L., Bokde, A. L. W., Bonuccelli, U., Broich, K., Cacciola, F., Caraci, F., Castrillo, J., Ceravolo, R., Chiesa, P. A., Corvol, J. -C., Claudio Cuello, A., Cummings, J. L., Depypere, H., Duggento, A., Emanuele, E., Escott-Price, V., Federoff, H., Teresa Ferretti, M., Fiandaca, M., Frank, R. A., Garaci, F., Geerts, H., Giorgi, F. S., Goetzl, E. J., Graziani, M., Haberkamp, M., Marie-Odile, H., Herholz, K., Hernandez, F., Kapogiannis, D., Karran, E., Kiddle, S. J., Kim, S. H., Koronyo, Y., Koronyo-Hamaoui, M., Langevin, T., Lehericy, S., Lucia, A., Lorenceau, J., Mango, D., Mapstone, M., Neri, C., Nistico, R., O'Bryant, S. E., Palermo, G., Perry, G., Ritchie, C., Rossi, S., Saidi, A., Santarnecchi, E., Schneider, L. S., Sporns, O., Toschi, N., Verdooner, S. R., Villain, N., Welikovitch, L. A., Woodcock, J., Younesi, E., Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), 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), 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), Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Service de médecine nucléaire [CHU Pitié-Salpétrière]

Subjects
Male, 0301 basic medicine, Apolipoprotein E, Epidemiology, [SDV]Life Sciences [q-bio], PROGRESSION, Disease, Cognition, 0302 clinical medicine, Amyloid precursor protein, Medicine and Health Sciences, Aspartic Acid Endopeptidases, medicine.diagnostic_test, biology, Health Policy, Settore BIO/14, Brain, Alzheimer's disease, Healthy Volunteers, 3. Good health, GENOTYPE, ALZHEIMERS-DISEASE, Psychiatry and Mental health, Positron emission tomography, Cohort, Biomarker (medicine), Female, EXPRESSION, medicine.medical_specialty, BIOMARKERS, Standardized uptake value, 03 medical and health sciences, Cellular and Molecular Neuroscience, Sexual dimorphism, Apolipoproteins E, Sex Factors, Developmental Neuroscience, Alzheimer Disease, Internal medicine, mental disorders, medicine, Humans, BACE1 biomarkers, Aged, Plasma BACE1, DECLINE, Amyloid beta-Peptides, business.industry, 030104 developmental biology, Endocrinology, Positron-Emission Tomography, Disease modifying, biology.protein, Neurology (clinical), Amyloid Precursor Protein Secretases, Geriatrics and Gerontology, business, Biomarkers, 030217 neurology & neurosurgery
Abstract

Introduction: Successful development of effective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1)-targeted therapies for early stages of Alzheimer's disease requires biomarker-guided intervention strategies. Methods: We investigated whether key biological factors such as sex, apolipoprotein E (APOE epsilon 4) allele, and age affect longitudinal plasma BACE1 concentrations in a large monocenter cohort of individuals at risk for Alzheimer's disease. We explored the relationship between plasma BACE1 concentrations and levels of brain amyloid-beta (A beta) deposition, using positron emission tomography global standard uptake value ratios. Results: Baseline and longitudinal mean concentrations of plasma BACE1 were significantly higher in women than men. We also found a positive significant impact of plasma BACE1 on baseline A beta-positron emission tomography global standard uptake value ratios. Discussion: Our results suggest a sexual dimorphism in BACE1-related upstream mechanisms of brain A beta production and deposition. We argue that plasma BACE1 should be considered in further biomarker validation and qualification studies as well as in BACE1 clinical trials. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.

Published
2019

7. Advanced methods for dose and regimen finding during drug development:Summary of the EMA /EFPIA workshop on dose finding (London 4-5 December 2014)

Author

Musuamba, F. T., Manolis, E., Holford, N., Cheung, S. Y. A., Friberg, Lena E, Ogungbenro, K., Posch, M., Yates, J. W. T., Berry, S., Thomas, N., Corriol-Rohou, S., Bornkamp, B., Bretz, F., Hooker, Andrew, Van der Graaf, P. H., Standing, J. F., Hay, J., Cole, S., Gigante, V., Karlsson, K., Dumortier, T., Benda, N., Serone, F., Das, S., Brochot, A., Ehmann, F., Hemmings, R., and Rusten, I. Skottheim

Subjects
Clinical Trials as Topic, Dose-Response Relationship, Drug, Pharmaceutical Preparations, Research Design, Drug Discovery, White Paper, Animals, Humans, Pharmacology and Toxicology, Models, Theoretical, Farmakologi och toxikologi
Abstract

Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late-stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well-established and regulatory-acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4-5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP-Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)-based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well-designed dose-finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale.

Published
2017

8. [Prevalence and follow-up of psychiatric diseases in internal medicine departments]

Author

Johannes Wancata, Benda N, and Hajji M

Subjects
Adult, Male, Adolescent, Neurotic Disorders, Substance-Related Disorders, Mental Disorders, Neurocognitive Disorders, Sick Role, Comorbidity, Length of Stay, Middle Aged, Hospitals, General, Patient Readmission, Adjustment Disorders, Patient Admission, Austria, Humans, Female
Abstract

While several surveys have shown that psychiatric disorders are common in non-psychiatric hospital departments, information on the course of psychiatric morbidity during the hospital stay is still lacking. Therefore, in two medical hospital departments in Austria we investigated the course of illness in 265 patients staying in the hospital for more than four weeks. Patients were interviewed using the Clinical Interview Schedule. At admission, prevalence of all psychiatric disorders was 46.0%. During the four weeks after admission, mentally well were discharged from hospital more frequently than mentally ill. Among those staying in the hospital after four weeks, prevalence was 51.4%. In the intervening period, the incidence (9.5%) was slightly lower than the rate of remission (12.4%). At both assessments, organic mental illness was the most frequent diagnosis followed by neurotic and adjustment disorders. Thus, in spite of the slightly higher rate of remission than incidence, the overall psychiatric prevalence increased during the first four weeks after admission because of the earlier discharges of the mentally well. In conclusion, our results show that point-prevalence surveys not regarding disease course give an incomplete impression of psychiatric morbidity in non-psychiatric hospital departments.

9. [Diagnosis and differential diagnosis of consciousness disorders from the psychiatric viewpoint]

Author

Semler B, Benda N, Ramskogler K, and Henrik Walter

Subjects
Diagnosis, Differential, Patient Care Team, Psychotropic Drugs, Substance-Related Disorders, Mental Disorders, Consciousness Disorders, Humans, Drug Overdose, Alcoholic Intoxication
Abstract

Diagnosis and differential diagnosis of disturbance of consciousness are often difficult, especially when occurring in the course of psychiatric diseases. Apart from discord in defining the term of consciousness it is not always easy to distinguish between qualitative and quantitative alterations of the disorders. The performance of an exact interview and a thorough clinical examination allows an estimation of the degree of dimming of consciousness as well as the possible causes. Disorder of Consciousness is often found in patients carrying out substance abuse but also in the course of other psychiatric diseases such as depression, schizophrenia, personality disorders and dissociative disorders. This article is dealing with the clinical approach towards patients experiencing alterations or disturbances of consciousness and is also trying to communicate innovations in the field of psychiatric diagnostics.

Catalog

Books, media, physical & digital resources
See catalog results