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2. Association of cerebrospinal fluid α-synuclein with total and phospho-tau181 protein concentrations and brain amyloid load in cognitively normal subjective memory complainers stratified by Alzheimer's disease biomarkers

Author

Audrain, C., Auffret, A., Bakardjian, H., Baldacci, F., Batrancourt, B., Benakki, I., Benali, H., Bertin, H., Bertrand, A., Boukadida, L., Cacciamani, F., Causse, V., Cavedo, E., Cherif Touil, S., Chiesa, P.A., Colliot, O., Dalla Barba, G., Depaulis, M., Dos Santos, A., Dubois, B., Dubois, M., Epelbaum, S., Fontaine, B., Francisque, H., Gagliardi, G., Genin, A., Genthon, R., Glasman, P., Gombert, F., Habert, M.O., Hampel, H., Hewa, H., Houot, M., Jungalee, N., Kas, A., Kilani, M., La Corte, V., Le Roy, F., Lehericy, S., Letondor, C., Levy, M., Lista, S., 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., Thiebaut, M., Uspenskaya, O., Vlaincu, M., Aguilar, L.F., Babiloni, C., Benda, N., Black, K.L., Bokde, A.L.W., Bonuccelli, U., Broich, K., Bun, R.S., Cacciola, F., Castrillo, J., Ceravolo, R., Coman, C.M., Corvol, J.C., Cuello, A.C., Cummings, J.L., Depypere, H., Duggento, A., Durrleman, S., Escott-Price, V., Federoff, H., Ferretti, M.T., Fiandaca, M., Frank, R.A., Garaci, F., 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., Lehéricy, S., Lorenceau, J., Mapstone, M., Neri, C., Nisticò, R., Nyasse-Messene, F., O'Bryant, S.E., Perry, G., Ritchie, C., Rossi, S., Santarnecchi, E., Schneider, L.S., Sporns, O., Toschi, N., Verdooner, S.R., Vergallo, A., Villain, N., Welikovitch, L., Woodcock, J., Younesi, E., Vergallo, Andrea, Bun, René-Sosata, Toschi, Nicola, Baldacci, Filippo, Zetterberg, Henrik, Blennow, Kaj, Cavedo, Enrica, Lamari, Foudil, Habert, Marie-Odile, Dubois, Bruno, Floris, Roberto, Garaci, Francesco, Lista, Simone, and Hampel, Harald

Published
2018
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3. 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
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4. 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
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5. 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
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6. 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
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8. Association of cerebrospinal fluid α-synuclein with total and phospho-tau181 protein concentrations and brain amyloid load in cognitively normal subjective memory complainers stratified by Alzheimer's disease biomarkers

Author

Vergallo, A, Bun, R, Toschi, N, Baldacci, F, Zetterberg, H, Blennow, K, Cavedo, E, Lamari, F, Habert, M, Dubois, B, Floris, R, Garaci, F, Lista, S, Hampel, H, Audrain, C, Auffret, A, Bakardjian, H, Batrancourt, B, Benakki, I, Benali, H, Bertin, H, Bertrand, A, Boukadida, L, Cacciamani, F, Causse, V, Cherif Touil, S, Chiesa, Pa, 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, Mo, 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, Mc, Ratovohery, S, Revillon, M, Rojkova, K, Santos-Andrade, K, Schindler, R, Servera, Mc, Seux, L, Simon, V, Skovronsky, D, Thiebaut, M, Uspenskaya, O, Vlaincu, M, Aguilar, Lf, Babiloni, C, Benda, N, Black, Kl, Bokde, Alw, Bonuccelli, U, Broich, K, Bun, Rs, Cacciola, F, Castrillo, J, Ceravolo, R, Coman, Cm, Corvol, Jc, Cuello, Ac, Cummings, Jl, Depypere, H, Duggento, A, Durrleman, S, Escott-Price, V, Federoff, H, Ferretti, Mt, Fiandaca, M, Frank, Ra, George, N, Giorgi, Fs, Graziani, M, Haberkamp, M, Herholz, K, Karran, E, Kim, Sh, Koronyo, Y, Koronyo-Hamaoui, M, Langevin, T, Lehéricy, S, Lorenceau, J, Mapstone, M, Neri, C, Nisticò, R, Nyasse-Messene, F, O'Bryant, Se, Perry, G, Ritchie, C, Rossi, S, Santarnecchi, E, Schneider, Ls, Sporns, O, Verdooner, Sr, Villain, N, Welikovitch, L, Woodcock, J, Younesi, E, Vergallo, A., Bun, R. -S., Toschi, N., Baldacci, F., Zetterberg, H., Blennow, K., Cavedo, E., Lamari, F., Habert, M. -O., Dubois, B., Floris, R., Garaci, F., Lista, S., Hampel, H., Audrain, C., Auffret, A., Bakardjian, H., Batrancourt, B., Benakki, I., Benali, H., Bertin, H., Bertrand, A., Boukadida, L., Cacciamani, F., Causse, V., Cherif Touil, S., Chiesa, P. A., 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., Thiebaut, M., Uspenskaya, O., Vlaincu, M., Aguilar, L. F., Babiloni, C., Benda, N., Black, K. L., Bokde, A. L. W., Bonuccelli, U., Broich, K., Bun, R. S., Cacciola, F., Castrillo, J., Ceravolo, R., Coman, C. M., Corvol, J. C., Cuello, A. C., Cummings, J. L., Depypere, H., Duggento, A., Durrleman, S., Escott-Price, V., Federoff, H., Ferretti, M. T., Fiandaca, M., Frank, R. A., George, N., Giorgi, F. S., Graziani, M., Haberkamp, M., Herholz, K., Karran, E., Kim, S. H., Koronyo, Y., Koronyo-Hamaoui, M., Langevin, T., Lorenceau, J., Mapstone, M., Neri, C., Nistico, R., Nyasse-Messene, F., O'Bryant, S. E., Perry, G., Ritchie, C., Rossi, S., Santarnecchi, E., Schneider, L. S., Sporns, O., Verdooner, S. R., Villain, N., Welikovitch, L., Woodcock, J., and Younesi, E.

Subjects
0301 basic medicine, Epidemiology, Alzheimer's disease, Amyloid PET, Cerebrospinal fluid, Monocentric, Preclinical, Subjective memory complainers, SUVR, Synergistic, Tau protein, α-Synuclein, chemistry.chemical_compound, 0302 clinical medicine, biology, Health Policy, Settore FIS/07, Settore BIO/14, Pathophysiology, Psychiatry and Mental health, medicine.symptom, medicine.medical_specialty, Amyloid, Asymptomatic, 03 medical and health sciences, Cellular and Molecular Neuroscience, Developmental Neuroscience, Neurology (clinical), Geriatrics and Gerontology, Psychiatry and Mental Health, Internal medicine, mental disorders, medicine, Dementia, Alpha-synuclein, business.industry, Alzheimer's disease biomarkers, medicine.disease, 030104 developmental biology, Endocrinology, nervous system, chemistry, Subjective memory complainer, biology.protein, business, 030217 neurology & neurosurgery
Abstract

Introduction Several neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of α-synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) α-synuclein (α-syn) concentrations in AD compared with other neurodegenerative diseases and healthy controls. Methods The pathophysiological role of CSF α-syn in asymptomatic subjects at risk of AD has not been explored. We performed a large-scale cross-sectional observational monocentric study of preclinical individuals at risk for AD (INSIGHT-preAD). Results We found a positive association between CSF α-syn concentrations and brain β-amyloid deposition measures as mean cortical standard uptake value ratios. We demonstrate positive correlations between CSF α-syn and both CSF t-tau and p-tau 181 concentrations. Discussion Animal models presented evidence, indicating that α-syn may synergistically and directly induce fibrillization of both tau and β-amyloid. Our data indicate an association of CSF α-syn with AD-related pathophysiological mechanisms, during the preclinical phase of the disease.

Published
2018

9. 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

10. 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
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11. Basal Forebrain Volume, but Not Hippocampal Volume, Is a Predictor of Global Cognitive Decline in Patients With Alzheimer's Disease Treated With Cholinesterase Inhibitors

Author

Teipel, Sj, Cavedo, E, Hampel, H, Grothe, Mj, Aguilar, Lf, Babiloni, C, Baldacci, F, Benda, N, Black, Kl, Bokde, Alw, Bonuccelli, U, Broich, K, Bun, Rs, Cacciola, F, Castrillo, J, Ceravolo, R, Chiesa, Pa, Colliot, O, Coman, C, Corvol, J, Cuello, Ac, Depypere, H, Dubois, B, Duggento, A, Durrleman, S, Escott-Price, V, Federoff, H, Ferretti, Mt, Fiandaca, M, Frank, Ra, Garaci, F, Genthon, R, George, N, Giorgi, Fs, Graziani, M, Haberkamp, M, Habert, M, Herholz, K, Karran, E, Kim, Sh, Koronyo, Y, Koronyo-Hamaoui, M, Lamari, F, Langevin, T, Lehericy, S, Lista, S, Lorenceau, J, Mapstone, M, Neri, C, Nistico, R, Nyasse-Messene, F, O'Bryant, Se, Perry, G, Ritchie, C, Rojkova, K, Rossi, S, Saidi, A, Santarnecchi, E, Schneider, Ls, Sporns, O, Toschi, N, Verdooner, Sr, Vergallo, A, Villain, N, Welikovitch, La, Woodcock, J, Younesi, E, and Cummings, Jl

Subjects
Aging, hippocampus, Hippocampus, Neurodegenerative, Alzheimer's Disease, lcsh:RC346-429, cholinergic treatment, memory, 0302 clinical medicine, Medicine and Health Sciences, Psychology, Medicine, Cognitive decline, Episodic memory, basal forebrain, Original Research, Basal forebrain, Settore FIS/07, 05 social sciences, Cognition, IMPAIRMENT, Manchester Institute for Collaborative Research on Ageing, Neurology, Neurological, Cohort, DONEPEZIL, Cardiology, NUCLEUS BASALIS, ADAS-COG, MRI, CHOLINERGIC SYSTEM, medicine.medical_specialty, ResearchInstitutes_Networks_Beacons/MICRA, Clinical Sciences, COMPOSITE SCORE, ATROPHY, 050105 experimental psychology, 03 medical and health sciences, Clinical Research, Internal medicine, Behavioral and Social Science, Acquired Cognitive Impairment, Dementia, 0501 psychology and cognitive sciences, ddc:610, lcsh:Neurology. Diseases of the nervous system, business.industry, Alzheimer's Disease Neuroimaging Initiative, Neurosciences, Alzheimer Precision Medicine Initiative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), prediction, medicine.disease, NEUROIMAGING INITIATIVE ADNI, Brain Disorders, SUBSTANTIA INNOMINATA, executive function, Cholinergic treatment, Executive function, Memory, Prediction, Cholinergic, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Background: Predicting the progression of cognitive decline in Alzheimer's disease (AD) is important for treatment selection and patient counseling. Structural MRI markers such as hippocampus or basal forebrain volumes might represent useful instruments for the prediction of cognitive decline. The primary objective was to determine the predictive value of hippocampus and basal forebrain volumes for global and domain specific cognitive decline in AD dementia during cholinergic treatment.Methods: We used MRI and cognitive data from 124 patients with the clinical diagnosis of AD dementia, derived from the ADNI-1 cohort, who were on standard of care cholinesterase inhibitor treatment during a follow-up period between 0.4 and 3.1 years. We used linear mixed effects models with cognitive function as outcome to assess the main effects as well as two-way interactions between baseline volumes and time controlling for age, sex, and total intracranial volume. This model accounts for individual variation in follow-up times.Results: Basal forebrain volume, but not hippocampus volume, was a significant predictor of rates of global cognitive decline. Larger volumes were associated with smaller rates of cognitive decline. Left hippocampus volume had a modest association with rates of episodic memory decline. Baseline performance in global cognition and memory was significantly associated with hippocampus and basal forebrain volumes; in addition, basal forebrain volume was associated with baseline performance in executive function.Conclusions: Our findings indicate that in AD dementia patients, basal forebrain volume may be a useful marker to predict subsequent cognitive decline during cholinergic treatment.

Published
2018
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12. Visual motion integration for perception and pursuit

Author

Stone, L. S, Beutter, B. R, and Lorenceau, J

Subjects
Life Sciences (General)
Abstract

To examine the relationship between visual motion processing for perception and pursuit, we measured the pursuit eye-movement and perceptual responses to the same complex-motion stimuli. We show that humans can both perceive and pursue the motion of line-figure objects, even when partial occlusion makes the resulting image motion vastly different from the underlying object motion. Our results show that both perception and pursuit can perform largely accurate motion integration, i.e. the selective combination of local motion signals across the visual field to derive global object motion. Furthermore, because we manipulated perceived motion while keeping image motion identical, the observed parallel changes in perception and pursuit show that the motion signals driving steady-state pursuit and perception are linked. These findings disprove current pursuit models whose control strategy is to minimize retinal image motion, and suggest a new framework for the interplay between visual cortex and cerebellum in visuomotor control.

Published
2000
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13. Steady-State Pursuit Is Driven by Object Motion Rather Than the Vector Average of Local Motions

Author

Stone, Leland S, Beutter, B. R, Lorenceau, J. D, and Ahumada, Al

Subjects
Behavioral Sciences
Abstract

We have previously shown that humans can pursue the motion of objects whose trajectories can be recovered only by spatio-temporal integration of local motion signals. We now explore the integration rule used to derive the target-motion signal driving pursuit. We measured the pursuit response of 4 observers (2 naive) to the motion of a line-figure diamond viewed through two vertical bar apertures (0.2 cd/square m). The comers were always occluded so that only four line segments (93 cd/square m) were visible behind the occluding foreground (38 cd/square m). The diamond was flattened (40 & 140 degree vertex angles) such that vector averaging of the local normal motions and vertical integration (e.g. IOC) yield very I or different predictions, analogous to using a Type II plaid. The diamond moved along Lissajous-figure trajectories (Ax = Ay = 2 degrees; TFx = 0.8 Hz; TFy = 0.4 Hz). We presented only 1.25 cycles and used 6 different randomly interleaved initial relative phases to minimize the role of predictive strategies. Observers were instructed to track the diamond and reported that its motion was always coherent (unlike type II plaids). Saccade-free portions of the horizontal and vertical eye-position traces sampled at 240 Hz were fit by separate sinusoids. Pursuit gain with respect to the diamond averaged 0.7 across subjects and directions. The ratio of the mean vertical to horizontal amplitude of the pursuit response was 1.7 +/- 0.7 averaged across subjects (1SD). This is close to the prediction of 1.0 from vertical motion-integration rules, but far from 7.7 predicted by vector averaging and infinity predicted by segment- or terminator-tracking strategies. Because there is no retinal motion which directly corresponds to the diamond's motion, steady-state pursuit of our "virtual" diamond is not closed-loop in the traditional sense. Thus, accurate pursuit is unlikely to result simply from local retinal negative feedback. We conclude that the signal driving steady-state pursuit is not the vector average of local motion signals, but rather a more vertical estimate of object motion, derived in extrastriate cortical areas beyond V1, perhaps NIT or MST.

Published
1997

14. Smooth Pursuit of a Partially Occluded Object

Author

Stone, L. S, Lorenceau, J, Beutter, B. R, and Null, Cynthia H

Subjects
Behavioral Sciences
Abstract

There has long been qualitative evidence that humans can pursue an object defined only by the motion of its parts. We explored this quantitatively using an occluded diamond stimulus. Four subjects (one naive) tracked a line-figure diamond moving along an elliptical path (0.9 Hz) either clockwise (CW) or counterclockwise (CCW) behind either an X-shaped aperture (CROSS) or two vertical rectangular apertures (BARS), which obscured the corners. Although the stimulus consisted of only four line segments (108 cd/square m) moving within a visible aperture (0.2 cd/square m) behind a foreground (38 cd/square m), it is largely perceived as a coherently moving diamond. The inter-saccadic portions of eye-position traces were fit with sinusoids. All subjects tracked object motion with considerable temporal accuracy. The mean phase lag was 5 deg/6 deg (CROSS/BARS) and the mean relative phase between the horizontal and vertical components was +95 deg/+92 deg (CW) and -85 deg/-75 deg (CCW), which is close to perfect. Furthermore, a chi-square analysis showed that 56% of BARS trials were consistent with tracking the correct elliptical shape (p is less than 0.05), although segment motion was purely vertical. These data disprove the main tenet of most models of pursuit: that it is a system that seeks to minimize retinal image motion through negative feedback. Rather, the main drive must be a visual signal which has already integrated spatiotemporal retinal information into an object-motion signal.

Published
1996

43. Method to Quickly Map Multifocal Pupillary Response Fields (mPRF) Using Frequency Tagging.

Author

Lorenceau J, Ajasse S, Barbet R, Boucart M, Chavane F, Lamirel C, Legras R, Matonti F, Rateaux M, Rouland JF, Sahel JA, Trinquet L, Wexler M, and Vignal-Clermont C

Abstract

We present a method for mapping multifocal Pupillary Response Fields in a short amount of time using a visual stimulus covering 40° of the visual angle divided into nine contiguous sectors simultaneously modulated in luminance at specific, incommensurate, temporal frequencies. We test this multifocal Pupillary Frequency Tagging (mPFT) approach with young healthy participants (N = 36) and show that the spectral power of the sustained pupillary response elicited by 45 s of fixation of this multipartite stimulus reflects the relative contribution of each sector/frequency to the overall pupillary response. We further analyze the phase lag for each temporal frequency as well as several global features related to pupil state. Test/retest performed on a subset of participants indicates good repeatability. We also investigate the existence of structural (RNFL)/functional (mPFT) relationships. We then summarize the results of clinical studies conducted with mPFT on patients with neuropathies and retinopathies and show that the features derived from pupillary signal analyses, the distribution of spectral power in particular, are homologous to disease characteristics and allow for sorting patients from healthy participants with excellent sensitivity and specificity. This method thus appears as a convenient, objective, and fast tool for assessing the integrity of retino-pupillary circuits as well as idiosyncrasies and permits to objectively assess and follow-up retinopathies or neuropathies in a short amount of time.

Published
2024
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44. Failed remyelination of the nonhuman primate optic nerve leads to axon degeneration, retinal damages, and visual dysfunction.

Author

Sarrazin N, Chavret-Reculon E, Bachelin C, Felfli M, Arab R, Gilardeau S, Brazhnikova E, Dubus E, Yaha-Cherif L, Lorenceau J, Picaud S, Rosolen S, Moissonnier P, Pouget P, and Baron-Van Evercooren A

Subjects
Animals, Disease Models, Animal, Evoked Potentials, Visual, Macaca fascicularis, Male, Multiple Sclerosis pathology, Reflex, Pupillary, Retina diagnostic imaging, Retina physiopathology, Tomography, Optical Coherence, Axons, Optic Nerve pathology, Remyelination, Retina pathology, Vision Disorders pathology
Abstract

White matter disorders of the central nervous system (CNS), such as multiple sclerosis (MS), lead to failure of nerve conduction and long-lasting neurological disabilities affecting a variety of sensory and motor systems, including vision. While most disease-modifying therapies target the immune and inflammatory response, the promotion of remyelination has become a new therapeutic avenue to prevent neuronal degeneration and promote recovery. Most of these strategies have been developed in short-lived rodent models of demyelination, which spontaneously repair and do not reflect the size, organization, and biology of the human CNS. Thus, well-defined nonhuman primate models are required to efficiently advance therapeutic approaches for patients. Here, we followed the consequence of long-term toxin-induced demyelination of the macaque optic nerve on remyelination and axon preservation, as well as its impact on visual functions. Findings from oculomotor behavior, ophthalmic examination, electrophysiology, and retinal imaging indicate visual impairment involving the optic nerve and retina. These visual dysfunctions fully correlated at the anatomical level, with sustained optic nerve demyelination, axonal degeneration, and alterations of the inner retinal layers. This nonhuman primate model of chronic optic nerve demyelination associated with axonal degeneration and visual dysfunction, recapitulates several key features of MS lesions and should be instrumental in providing the missing link to translate emerging repair promyelinating/neuroprotective therapies to the clinic for myelin disorders, such as MS.

Published
2022
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45. Jumpy and Jerky: When Peripheral Vision Faces Reverse-Phi.

Author

Lorenceau J and Cavanagh P

Abstract

When an annulus in fast apparent motion reverses its contrast over time, the foveal and peripheral percepts are strikingly different. In central vision, the annulus appears to follow the same path as an annulus without flicker, whereas in the periphery, the stimulus seems to randomly jump across the screen. The illusion strength depends on motion speed and reversal rate. Our observations suggest that it results from a balance between conflicting phi and reverse-phi motion, positional uncertainty, and attention. In addition to illustrating the differences between central and peripheral motion processing, this illusion shows that both discrete positional sampling and motion energy combine to generate motion percepts, although with eccentricity dependent weights that are themselves affected by attention., (© The Author(s) 2020.)

Published
2020
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46. Cursive Eye-Writing With Smooth-Pursuit Eye-Movement Is Possible in Subjects With Amyotrophic Lateral Sclerosis.

Author

Lenglet T, Mirault J, Veyrat-Masson M, Funkiewiez A, Amador MDM, Bruneteau G, Le Forestier N, Pradat PF, Salachas F, Vacher Y, Lacomblez L, and Lorenceau J

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder causing a progressive motor weakness of all voluntary muscles, whose progression challenges communication modalities such as handwriting or speech. The current study investigated whether ALS subjects can use Eye-On-Line (EOL), a novel eye-operated communication device allowing, after training, to voluntarily control smooth-pursuit eye-movements (SPEM) so as to eye-write in cursive. To that aim, ALS participants ( n = 12) with preserved eye-movements but impaired handwriting were trained during six on-site visits. The primary outcome of the study was the recognition of eye-written digits (0-9) from ALS and healthy control subjects by naïve "readers." Changes in oculomotor performance and the safety of EOL were also evaluated. At the end of the program, 69.4% of the eye-written digits from 11 ALS subjects were recognized by naïve readers, similar to the 67.3% found for eye-written digits from controls participants, with however, large inter-individual differences in both groups of "writers." Training with EOL was associated with a transient fatigue leading one ALS subject to drop out the study at the fifth visit. Otherwise, itching eyes was the most common adverse event (3 subjects). This study shows that, despite the impact of ALS on the motor system, most ALS participants could improve their mastering of eye-movements, so as to produce recognizable eye-written digits, although the eye-traces sometimes needed smoothing to ease digit legibility from both ALS subjects and control participants. The capability to endogenously and voluntarily generate eye-traces using EOL brings a novel way to communicate for disabled individuals, allowing creative personal and emotional expression.

Published
2019
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47. Effects of pupillary responses to luminance and attention on visual spatial discrimination.

Author

Ajasse S, Benosman RB, and Lorenceau J

Subjects
Adult, Female, Humans, Male, Optics and Photonics, Vision, Ocular, Young Adult, Attention physiology, Light, Pupil physiology, Reflex, Pupillary radiation effects, Spatial Processing physiology
Abstract

The optic quality of the eyes is, at least in part, determined by pupil size. Large pupils let more light enter the eyes, but degrade the point spread function, and thus the spatial resolution that can be achieved (Campbell & Gregory, 1960). In natural conditions, the pupil is mainly driven by the luminance (and possibly the color and contrast) at the gazed location, but is also modulated by attention and cognitive factors. Whether changes in eyes' optics related to pupil size modulation by luminance and attention impacts visual processing was assessed in two experiments. In Experiment 1, we measured pupil size using a constantly visible display made of four disks with different luminance levels, with no other task than fixating the disks in succession. The results confirmed that pupil size depends on the luminance of the gazed stimulus. Experiment 2, using similar settings as Experiment 1, used a two-interval forced-choice design to test whether discriminating high spatial frequencies that requires covert attention to parafoveal stimuli is better during the fixation of bright disks that entails a small pupil size, and hence better eyes' optics, as compared to fixating dark disks that entails a large pupil size, and hence poorer eyes' optics. As in Experiment 1, we observed large modulations of pupil size depending on the luminance of the gazed stimulus, but pupil dynamics was more variable, with marked pupil dilation during stimulus encoding, presumably because the demanding spatial frequency discrimination task engaged attention. However, discrimination performance and mean pupil size were not correlated. Despite this lack of correlation, the slopes of pupil dilation during stimulus encoding were correlated to performance, while the slopes of pupil dilation during decision-making were not. We discuss these results regarding the possible functional roles of pupil size modulations.

Published
2018
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48. A novel method of inducing endogenous pupil oscillations to detect patients with unilateral optic neuritis.

Author

Lamirel C, Ajasse S, Moulignier A, Salomon L, Deschamps R, Gueguen A, Vignal C, Cochereau I, and Lorenceau J

Subjects
Adult, Female, Humans, Male, Middle Aged, Optic Neuritis physiopathology, Photic Stimulation, ROC Curve, Reflex, Pupillary radiation effects, Young Adult, Optic Neuritis diagnosis, Pupil radiation effects
Abstract

Purpose: To use and test a new method of inducing endogenously generated pupillary oscillations (POs) in patients with unilateral optic neuritis (ON), to describe a signal analysis approach quantifying pupil activity and to evaluate the extent to which POs permit to discriminate patients from control participants., Method: Pupil size was recorded with an eye-tracker and converted in real time to modulate the luminance of a stimulus (a 20° disk) presented in front of participants. With this biofeedback setting, an increasing pupil size transforms into a high luminance, entraining a pupil constriction that in turn decreases the stimulus luminance, and so on, resulting in endogenously generated POs. POs were recorded for 30 seconds in the affected eye, in the fellow eye and in binocular conditions with 22 patients having a history of unilateral ON within a period of 5 years, and with 22 control participants. Different signal analysis methods were used to quantify the power and frequency of POs., Results: On average, pupil size oscillated at around 1 Hz. The amplitude of POs appears not to be a reliable marker of ON. In contrast, the frequency of POs was significantly lower, and was more variable over time, in the patients' affected eye, as compared to their fellow eye and to the binocular condition. No such differences were found in control participants. Receiver operating characteristic analyses based on the frequency and the variability of POs to classify patients and control participants gave an area under the curve of 0.82, a sensitivity of 82% (95%CI: 60%-95%) and a specificity of 77% (95%CI: 55%-92%)., Conclusions: The new method used to induce POs allowed characterizing the visual afferent pathway defect in ON patients with encouraging accuracy. The method was fast, easy to use, only requiring that participants look ahead, and allows testing many stimulus parameters (e.g. color, stimulus location, size, etc)., Competing Interests: The authors have declared that no competing interests exist.

Published
2018
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49. Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology.

Author

Hampel H, Toschi N, Babiloni C, Baldacci F, Black KL, Bokde ALW, Bun RS, Cacciola F, Cavedo E, Chiesa PA, Colliot O, Coman CM, Dubois B, Duggento A, Durrleman S, Ferretti MT, George N, Genthon R, Habert MO, Herholz K, Koronyo Y, Koronyo-Hamaoui M, Lamari F, Langevin T, Lehéricy S, Lorenceau J, Neri C, Nisticò R, Nyasse-Messene F, Ritchie C, Rossi S, Santarnecchi E, Sporns O, Verdooner SR, Vergallo A, Villain N, Younesi E, Garaci F, and Lista S

Subjects
Animals, Brain diagnostic imaging, Humans, Neurology, Neurophysiology, Systems Biology, Translational Research, Biomedical, Alzheimer Disease diagnosis, Alzheimer Disease therapy, Precision Medicine
Abstract

The Precision Neurology development process implements systems theory with system biology and neurophysiology in a parallel, bidirectional research path: a combined hypothesis-driven investigation of systems dysfunction within distinct molecular, cellular, and large-scale neural network systems in both animal models as well as through tests for the usefulness of these candidate dynamic systems biomarkers in different diseases and subgroups at different stages of pathophysiological progression. This translational research path is paralleled by an "omics"-based, hypothesis-free, exploratory research pathway, which will collect multimodal data from progressing asymptomatic, preclinical, and clinical neurodegenerative disease (ND) populations, within the wide continuous biological and clinical spectrum of ND, applying high-throughput and high-content technologies combined with powerful computational and statistical modeling tools, aimed at identifying novel dysfunctional systems and predictive marker signatures associated with ND. The goals are to identify common biological denominators or differentiating classifiers across the continuum of ND during detectable stages of pathophysiological progression, characterize systems-based intermediate endophenotypes, validate multi-modal novel diagnostic systems biomarkers, and advance clinical intervention trial designs by utilizing systems-based intermediate endophenotypes and candidate surrogate markers. Achieving these goals is key to the ultimate development of early and effective individualized treatment of ND, such as Alzheimer's disease. The Alzheimer Precision Medicine Initiative (APMI) and cohort program (APMI-CP), as well as the Paris based core of the Sorbonne University Clinical Research Group "Alzheimer Precision Medicine" (GRC-APM) were recently launched to facilitate the passageway from conventional clinical diagnostic and drug development toward breakthrough innovation based on the investigation of the comprehensive biological nature of aging individuals. The APMI movement is gaining momentum to systematically apply both systems neurophysiology and systems biology in exploratory translational neuroscience research on ND.

Published
2018
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50. Continuous Auditory Feedback of Eye Movements: An Exploratory Study toward Improving Oculomotor Control.

Author

Boyer EO, Portron A, Bevilacqua F, and Lorenceau J

Abstract

As eye movements are mostly automatic and overtly generated to attain visual goals, individuals have a poor metacognitive knowledge of their own eye movements. We present an exploratory study on the effects of real-time continuous auditory feedback generated by eye movements. We considered both a tracking task and a production task where smooth pursuit eye movements (SPEM) can be endogenously generated. In particular, we used a visual paradigm which enables to generate and control SPEM in the absence of a moving visual target. We investigated whether real-time auditory feedback of eye movement dynamics might improve learning in both tasks, through a training protocol over 8 days. The results indicate that real-time sonification of eye movements can actually modify the oculomotor behavior, and reinforce intrinsic oculomotor perception. Nevertheless, large inter-individual differences were observed preventing us from reaching a strong conclusion on sensorimotor learning improvements.

Published
2017
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