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1. Advantages and disadvantages of the use of the CSF Amyloid β (Aβ) 42/40 ratio in the diagnosis of Alzheimer’s Disease

Author

Markus Otto, Henrik Zetterberg, Piotr Lewczuk, Oskar Hansson, Sylvain Lehmann, Clinical Memory Research Unit [Malmö, Suède], Department of Clinical Sciences [Malmö, Suède], Lund University [Malmö, Suède]-Lund University [Malmö, Suède], Memory Clinic [Malmö, Suède], Skåne University Hospital [Malmö, Suède], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Neurology [Ulm, Allemagne], Universität Ulm - Ulm University [Ulm, Allemagne], Clinical Neurochemistry Laboratory [Göteborg, Suède], Department of Psychiatry and Neurochemistry [Goteborg], Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg]-Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg], Department of Neurodegenerative Disease [Londres, Royaume-Uni], Institute of Neurology [London], University College of London [London] (UCL)-University College of London [London] (UCL), UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), Department of Psychiatry and Psychotherapy [Erlangen, Allemagne], Universitätsklinikum Erlangen [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU)-Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Department of Neurodegeneration Diagnostics [Bialystok, Pologne], Medical University of Bialystok [Bialystok, Pologne], Lab for Clinical Neurochemistry and Neurochemical Dementia Diagnostics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU)-Friedrich-Alexander Universität Erlangen-Nürnberg (FAU)-Universitätsklinikum Erlangen [Erlangen, Allemagne], Fujirebio Europe sponsored this paper, however, it had no influence on its factual content. PL was supported by the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. OH has acquired research support (for the institution) from Roche, GE Healthcare, Biogen, AVID Radiopharmaceuticals, Fujirebio and Euroimmun. HZ’s research is supported by the Swedish Research Council, the European Research Council, the Knut and Alice Wallenberg Foundation, the Olav Thon Foundation, the UK Dementia Research Institute at UCL and Swedish State Support for Clinical Research (ALFGBG)., Lund University [Lund]-Lund University [Lund], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Medical University of Białystok (MUB), and Bodescot, Myriam

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Neurology, Amyloid β, Cognitive Neuroscience, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Diagnostic accuracy, Disease, Review, Aβ 42/40 ratio, Alzheimer's Disease, lcsh:RC346-429, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Medizinische Fakultät, Alzheimer Disease, Internal medicine, medicine, Dementia, Humans, ddc:610, Alzheimer’s Disease, Cognitive impairment, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biochemical markers, lcsh:Neurology. Diseases of the nervous system, Cerebrospinal Fluid, Amyloid beta-Peptides, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, business.industry, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, Peptide Fragments, 030104 developmental biology, Aβ42/40 ratio, Neurology (clinical), business, 030217 neurology & neurosurgery, Amyloidβ Peptides, Biomarkers
Abstract

International audience; The cerebrospinal fluid (CSF) biochemical markers (biomarkers) Amyloidβ 42 (Aβ42), total Tau (T-tau) and Tau phosphorylated at threonine 181 (P-tau181) have proven diagnostic accuracy for mild cognitive impairment and dementia due to Alzheimer's Disease (AD). In an effort to improve the accuracy of an AD diagnosis, it is important to be able to distinguish between AD and other types of dementia (non-AD). The concentration ratio of Aβ42 to Aβ40 (Aβ42/40 Ratio) has been suggested to be superior to the concentration of Aβ42 alone when identifying patients with AD. This article reviews the available evidence on the use of the CSF Aβ42/40 ratio in the diagnosis of AD. Based on the body of evidence presented herein, it is the conclusion of the current working group that the CSF Aβ42/40 ratio, rather than the absolute value of CSF Aβ42, should be used when analysing CSF AD biomarkers to improve the percentage of appropriately diagnosed patients.

Published
2019

2. Using florbetapir positron emission tomography to explore cerebrospinal fluid cut points and gray zones in small sample sizes

Author

Ps, Weston, Rw, Paterson, Modat M, Burgos N, Mj, Cardoso, Magdalinou N, Lehmann M, Jc, Dickson, Barnes A, Jb, Bomanji, Kayani I, David Cash, Ourselin S, Toombs J, Mp, Lunn, Cj, Mummery, Jd, Warren, Mn, Rossor, Nc, Fox, Zetterberg H, Jm, Schott, Centre for Medical Image Computing (CMIC), University College of London [London] (UCL), Department of Neurodegenerative Disease, Alzheimer Scotland Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UCL Institute of neurology, UCL Institute of Neurology, Department of Psychiatry and Neurochemistry [Goteborg], and Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg]

Subjects
Cerebrospinal fluid, Amyloid PET, Phosphorylated tau, mental disorders, Diagnosis, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Neuroimaging, Tau, Cut points, Aβ
Abstract

00002; International audience; Introduction We aimed to assess the feasibility of determining Alzheimer's disease cerebrospinal fluid (CSF) cut points in small samples through comparison with amyloid positron emission tomography (PET). Methods Twenty-three individuals (19 patients, four controls) had CSF measures of amyloid beta (Aβ)1–42 and total tau/Aβ1–42 ratio, and florbetapir PET. We compared CSF measures with visual and quantitative (standardized uptake value ratio [SUVR]) PET measures of amyloid. Results Seventeen of 23 were amyloid-positive on visual reads, and 14 of 23 at an SUVR of ≥1.1. There was concordance (positive/negative on both measures) in 20 of 23, of whom 19 of 20 were correctly classified at an Aβ1–42 of 630 ng/L, and 20 of 20 on tau/Aβ1–42 ratio (positive ≥0.88; negative ≤0.34). Three discordant cases had Aβ1–42 levels between 403 and 729 ng/L and tau/Aβ1–42 ratios of 0.54–0.58. Discussion Comparing amyloid PET and CSF biomarkers provides a means of assessing CSF cut points in vivo, and can be applied to small sample sizes. CSF tau/Aβ1–42 ratio appears robust at predicting amyloid status, although there are gray zones where there remains diagnostic uncertainty.

Published
2015

3. Comparing biological markers of Alzheimer's disease across blood fraction and platforms: Comparing apples to oranges

Author

Sid E. O'Bryant, Simone Lista, Robert A. Rissman, Melissa Edwards, Fan Zhang, James Hall, Henrik Zetterberg, Simon Lovestone, Veer Gupta, Neill Graff‐Radford, Ralph Martins, Andreas Jeromin, Stephen Waring, Esther Oh, Mitchel Kling, Laura D. Baker, Harald Hampel, ISTAART Blood Based Biomarker Professional Interest Area, University of North Texas Health Science Center [Fort Worth], Institute for Aging and Alzheimer’s Disease Research [Fort Worth] (IAADR), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), AXA Research Fund, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), UC San Diego School of Medicine, University of North Texas (UNT), UCL Institute of neurology, UCL Institute of Neurology, Department of Psychiatry and Neurochemistry [Goteborg], Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg], Psychiatry Institute, King‘s College London, Center of Excellence for Alzheimer's Disease Research and Care, Mayo Clinic [Jacksonville], Quanterix Corp, Essentia Institute of Rural Health, Texas Alzheimer's Research and Care Consortium, Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine Baltimore, Perelman School of Medicine, University of Pennsylvania [Philadelphia], Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center, Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), University of Pennsylvania, and HAL-UPMC, Gestionnaire

Subjects
Serum, 0301 basic medicine, Aging, Pathology, Disease, lcsh:Geriatrics, Neurodegenerative, lcsh:RC346-429, Plasma, chemistry.chemical_compound, 0302 clinical medicine, Pancreatic polypeptide, Alzheimer's Disease including Alzheimer's Disease Related Dementias, Meso Scale Discovery, Multiplex, Biomarker discovery, Diagnostics, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Factor VII, Interleukin, Blood-Based Biomarkers, Alzheimer's disease, Psychiatry and Mental health, Blood, medicine.medical_specialty, Preanalytic processing, 03 medical and health sciences, Clinical Research, Acquired Cognitive Impairment, Genetics, medicine, Serum amyloid A, Multiplex assay platform, lcsh:Neurology. Diseases of the nervous system, Rules Based Medicine, business.industry, Beta-2 microglobulin, Neurosciences, Proteins, Standardization, Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, lcsh:RC952-954.6, 030104 developmental biology, chemistry, Immunology, Dementia, Neurology (clinical), business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

International audience; Introduction : This study investigated the comparability of potential Alzheimer's disease (AD) biomarkers across blood fractions and assay platforms.Methods : Nonfasting serum and plasma samples from 300 participants (150 AD patients and 150 controls) were analyzed. Proteomic markers were obtained via electrochemiluminescence or Luminex technology. Comparisons were conducted via Pearson correlations. The relative importance of proteins within an AD diagnostic profile was examined using random forest importance plots.Results : On the Meso Scale Discovery multiplex platform, 10 of the 21 markers shared >50% of the variance across blood fractions (serum amyloid A R2 = 0.99, interleukin (IL)10 R2 = 0.95, fatty acid-binding protein (FABP) R2 = 0.94, I309 R2 = 0.94, IL-5 R2 = 0.94, IL-6 R2 = 0.94, eotaxin3 R2 = 0.91, IL-18 R2 = 0.87, soluble tumor necrosis factor receptor 1 R2 = 0.85, and pancreatic polypeptide R2 = 0.81). When examining protein concentrations across platforms, only five markers shared >50% of the variance (beta 2 microglobulin R2 = 0.92, IL-18 R2 = 0.80, factor VII R2 = 0.78, CRP R2 = 0.74, and FABP R2 = 0.70).Discussion : The current findings highlight the importance of considering blood fractions and assay platforms when searching for AD relevant biomarkers.

Published
2016

4. Possible association between the androgen receptor gene and autism spectrum disorder.: Association between androgen receptor gene and autism

Author

Henrik Anckarsäter, Elias Eriksson, Lina Jonsson, Susanne Henningsson, Carina Gillberg, Elin Ljunggren, Maria Råstam, Mikael Landén, Kent Thuresson, Gudrun Nygren, Lars Westberg, Christopher Gillberg, Catalina Betancur, Jonas Melke, Marion Leboyer, Department of Pharmacology, University of Gothenburg (GU), Department of Child and Adolescent Psychiatry, Forensic Psychiatry, Stockholm Center for Psychiatric Research, Karolinska Institutet [Stockholm], Department of Psychiatry and Neurochemistry [Goteborg], Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg], Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, and This work has been supported by the Swedish Research Council (6588, 8668 and 2006-3449), the Wilhelm and Martina Lundgren Foundation, the INSERM, Fondation Orange and the Brain Power Consortium, and by the Swedish Knowledge Foundation through the Industrial PhD programme in Medical Bioinformatics at the Strategy and Development Office at Karolinska Institutet. We would like to thank The SWEGENE Göteborg Genomics Core Facility platform, funded by a grant from the Knut and Alice Wallenberg Foundation.

Subjects
Adult, Male, Linkage disequilibrium, Adolescent, Genotype, Endocrinology, Diabetes and Metabolism, autism, Biology, Linkage Disequilibrium, polymorphism, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Gene Frequency, GGN repeat, medicine, Pervasive developmental disorder, Humans, Family, Genetic Predisposition to Disease, Autistic Disorder, Allele, Child, Allele frequency, Biological Psychiatry, 030304 developmental biology, CAG repeat, Genetics, 0303 health sciences, Polymorphism, Genetic, Endocrine and Autonomic Systems, androgens, Transmission disequilibrium test, Middle Aged, medicine.disease, rs6152, Developmental disorder, Psychiatry and Mental health, Receptors, Androgen, Autism spectrum disorder, Case-Control Studies, Child, Preschool, testosterone, Autism, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030217 neurology & neurosurgery
Abstract

International audience; Autism is a highly heritable disorder but the specific genes involved remain largely unknown. The higher prevalence of autism in men than in women, in conjunction with a number of other observations, has led to the suggestion that prenatal brain exposure to androgens may be of importance for the development of this condition. Prompted by this hypothesis, we investigated the potential influence of variation in the androgen receptor (AR) gene on the susceptibility for autism. To this end, 267 subjects with autism spectrum disorder and 617 controls were genotyped for three polymorphisms in exon 1 of the AR gene: the CAG repeat, the GGN repeat and the rs6152 SNP. In addition, parents and affected siblings were genotyped for 118 and 32 of the cases, respectively. Case-control comparisons revealed higher prevalence of short CAG alleles as well as of the A allele of the rs6152 SNP in female cases than in controls, but revealed no significant differences with respect to the GGN repeat. Analysis of the 118 families using transmission disequilibrium test, on the other hand, suggested an association with the GGN polymorphism, the rare 20-repeat allele being undertransmitted to male cases and the 23-repeat allele being overtransmitted to female cases. Sequencing of the AR gene in 46 patients revealed no mutations or rare variants. The results lend some support for an influence of the studied polymorphisms on the susceptibility for autism, but argue against the possibility that mutations in the AR gene are common in subjects with this condition.

Published
2009

5. The Road Ahead to Cure Alzheimer’s Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across all Stages and Target Populations

Author

Ara S. Khachaturian, Sid E. O'Bryant, Lon S. Schneider, Bruno Vellas, M. Thiebaut de Schotten, Bruno Dubois, Simone Lista, Zaven S. Khachaturian, C. R. Jack, Keith A. Johnson, Harald Hampel, William E. Klunk, Miia Kivipelto, J. Cummings, Henrik Zetterberg, Karl Herholz, Karl Broich, Sandrine Andrieu, Adriaan A. Lammertsma, Alexander Drzezga, Kaj Blennow, Reisa A. Sperling, Jean-François Mangin, Stefan J. Teipel, Olivier Colliot, Giovanni B. Frisoni, Arun L.W. Bokde, Paul S. Aisen, Philippe Amouyel, Hovagim Bakardjian, Enrica Cavedo, Radiology and nuclear medicine, NCA - neurodegeneration, Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Prevent Alzheimer’s Disease 2020 [Rockville] (PAD 2020), Department of Neurosciences [San Diego], University of California [San Diego] (UC San Diego), University of California-University of California, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institute of Brain, Behaviour and Mental Health, University of Manchester [Manchester], Department of Radiology [Rochester], Mayo Clinic [Rochester], Center for Alzheimer Research and Treatment [Boston], Harvard Medical School [Boston] (HMS), Lou Ruvo Center for Brain Health [Las Vegas], Cleveland Clinic, Department of Psychiatry and Neurochemistry [Goteborg], Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg], Institute for Aging and Alzheimer’s Disease Research [Fort Worth] (IAADR), University of North Texas Health Science Center [Fort Worth], IRCCS San Giovanni, Laboratory of Epidemiology and Neuroimaging, Brescia, Alzheimer’s & Dementia [Rockville], Karolinska Institutet [Stockholm], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Federal Institute of Drugs and Medical Devices [Bonn], Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'épidémiologie [Toulouse], CHU Toulouse [Toulouse], Natbrainlab, Department of Forensic and Neurodevelopmental Sciences, Institute of psychiatry-King‘s College London, Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Laboratoire de Neuroimagerie Assistée par Ordinateur (LNAO), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Radiology and Nuclear Medicine [Amsterdam], VU University Medical Center [Amsterdam], Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Psychosomatic Medicine [Rostock], University of Rostock, Department of Nuclear Medicine [Cologne], University Hospital of Cologne [Cologne], Institute of Neuroscience, Trinity College Dublin-Trinity College Dublin-Discipline of Psychiatry [Dublin], School of Medicine [Dublin], Trinity College Dublin-Trinity College Dublin-School of Medicine [Dublin], Trinity College Dublin, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), Fédération de neurologie 4, Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Keck School of Medicine [Los Angeles], University of Southern California (USC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Epidémiologie clinique et santé publique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Pierre et Marie Curie - Paris 6 (UPMC)-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 Pierre et Marie Curie - Paris 6 (UPMC)-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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Colliot, Olivier

Subjects
Oncology, medicine.medical_specialty, prevention trials, Neuroimaging, Disease, Article, 03 medical and health sciences, ddc:616.89, 0302 clinical medicine, Atrophy, Internal medicine, Medicine, Dementia, ddc:610, Alzheimer’s Disease, Biomarker discovery, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing, 030304 developmental biology, 0303 health sciences, neuroimaging, business.industry, biomarkers, Prevention Trials, molecular imaging, medicine.disease, Molecular Imaging, 3. Good health, Clinical trial, Biomarker (medicine), business, Alzheimer’s disease, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Neuroscience, Biomarkers, 030217 neurology & neurosurgery, Tractography
Abstract

Alzheimer's disease (AD) is a slowly progressing non-linear dynamic brain disease in which pathophysiological abnormalities, detectable in vivo by biological markers, precede overt clinical symptoms by many years to decades. Use of these biomarkers for the detection of early and preclinical AD has become of central importance following publication of two international expert working group's revised criteria for the diagnosis of AD dementia, mild cognitive impairment (MCI) due to AD, prodromal AD and preclinical AD. As a consequence of matured research evidence six AD biomarkers are sufficiently validated and partly qualified to be incorporated into operationalized clinical diagnostic criteria and use in primary and secondary prevention trials. These biomarkers fall into two molecular categories: biomarkers of amyloid-beta (Aβ) deposition and plaque formation as well as of tau-protein related hyperphosphorylation and neurodegeneration. Three of the six gold-standard ("core feasible) biomarkers are neuroimaging measures and three are cerebrospinal fluid (CSF) analytes. CSF Aβ 1-42 (Aβ1-42), also expressed as Aβ1-42 : Aβ1- 40 ratio, T-tau, and P-tau Thr181 & Thr231 proteins have proven diagnostic accuracy and risk enhancement in prodromal MCI and AD dementia. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up. Magnetic resonance imaging (MRI) at increasing field strength and resolution allows detecting the evolution of distinct types of structural and functional abnormality pattern throughout early to late AD stages. Anatomical or volumetric MRI is the most widely used technique and provides local and global measures of atrophy. The revised diagnostic criteria for “prodromal AD” and "mild cognitive impairment due to AD" include hippocampal atrophy (as the fourth validated biomarker), which is considered an indicator of regional neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both in regions of interest, such as the hippocampus and in an exploratory fashion, observer and hypothesis-indedendent, throughout the entire brain. Evolving modalities such as diffusion-tensor imaging (DTI) and advanced tractography as well as resting-state functional MRI provide useful additionally useful measures indicating the degree of fiber tract and neural network disintegration (structural, effective and functional connectivity) that may substantially contribute to early detection and the mapping of progression. These modalities require further standardization and validation. The use of molecular in vivo amyloid imaging agents (the fifth validated biomarker), such as the Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the detection of early AD pathological processes and associated neurodegeneration. How to use, interpret, and disclose biomarker results drives the need for optimized standardization. Multimodal AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping fashion. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. AD biomarkers can be combined to increase accuracy or risk. A list of genetic risk factors is increasingly included in secondary prevention trials to stratify and select individuals at genetic risk of AD. Although most of these biomarker candidates are not yet qualified and approved by regulatory authorities for their intended use in drug trials, they are nonetheless applied in ongoing clinical studies for the following functions: (i) inclusion/exclusion criteria, (ii) patient stratification, (iii) evaluation of treatment effect, (iv) drug target engagement, and (v) safety. Moreover, novel promising hypothesis-driven, as well as exploratory biochemical, genetic, electrophysiological, and neuroimaging markers for use in clinical trials are being developed. The current state-of-the-art and future perspectives on both biological and neuroimaging derived biomarker discovery and development as well as the intended application in prevention trials is outlined in the present publication.

Published
2014

6. Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Author

Lars Bertram, Hovagim Bakardjian, Stéphane Epelbaum, Alexander Drzezga, Paul S. Aisen, Robert Nisticò, Alexis Brice, Kaj Blennow, Charles Duyckaerts, Karl Broich, Stefan J. Teipel, Stéphane Lehéricy, Francesco Giuseppe Garaci, Bruno Dubois, Simone Lista, Zaven S. Khachaturian, Olivier Colliot, Harald Hampel, Henrik Zetterberg, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Department of Psychosomatic Medicine [Rostock], University of Rostock, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS San Raffaele Pisana), Department of Physiology and Pharmacology [Rome], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Department of Psychiatry and Neurochemistry [Goteborg], Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg], Department of Vertebrate Genomics [Berlin], Max-Planck-Institut für Molekulare Genetik (MPIMG), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Department of Nuclear Medicine [Cologne], University Hospital of Cologne [Cologne], Algorithms, models and methods for images and signals of the human brain (ARAMIS), Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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 Pierre et Marie Curie - Paris 6 (UPMC)-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), Federal Institute of Drugs and Medical Devices [Bonn], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Prevent Alzheimer’s Disease 2020 [Rockville] (PAD 2020), Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Laboratoire de Neuropathologie Raymond Escourolle, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Department of Neurosciences [San Diego], University of California-University of California, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
CSF/blood biomarkers, Psychological intervention, Disease, Bioinformatics, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Clinical trials, alzheimer's disease, clinical trials, csf/blood biomarkers, pet imaging markers, structural/functional mri markers, Alzheimer Disease, Structural/functional MRI markers, Medicine, Humans, ddc:610, 030304 developmental biology, Pharmacology, 0303 health sciences, Alzheimer's disease, PET imaging markers, Biological Markers, Clinical Trials as Topic, Operationalization, Conceptualization, therapy [Alzheimer Disease], business.industry, Perspective (graphical), Settore BIO/14, medicine.disease, 3. Good health, Clinical trial, Clinical therapy, business, Neuroscience, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, 030217 neurology & neurosurgery, metabolism [Alzheimer Disease], Biomarkers, metabolism [Biomarkers]
Abstract

International audience; Recent advances in understanding the molecular mechanisms underlying various paths toward the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD.

Published
2014

7. Possible association between the androgen receptor gene and autism spectrum disorder

Author

Henningsson, Susanne, Jonsson, Lina, Ljunggren, Elin, Westberg, Lars, Gillberg, Carina, Råstam, Maria, Anckarsäter, Henrik, Nygren, Gudrun, Landén, Mikael, Thuresson, Kent, Betancur, Catalina, Leboyer, Marion, Gillberg, Christopher, Eriksson, Elias, Melke, Jonas, Guellaen, Georges, Department of Pharmacology, University of Gothenburg (GU), Department of Child and Adolescent Psychiatry, Forensic Psychiatry, Stockholm Center for Psychiatric Research, Karolinska Institutet [Stockholm], Department of Psychiatry and Neurochemistry [Goteborg], Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg], Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, and This work has been supported by the Swedish Research Council (6588, 8668 and 2006-3449), the Wilhelm and Martina Lundgren Foundation, the INSERM, Fondation Orange and the Brain Power Consortium, and by the Swedish Knowledge Foundation through the Industrial PhD programme in Medical Bioinformatics at the Strategy and Development Office at Karolinska Institutet. We would like to thank The SWEGENE Göteborg Genomics Core Facility platform, funded by a grant from the Knut and Alice Wallenberg Foundation.

Subjects
CAG repeat, GGN repeat, testosterone, autism, androgens, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], polymorphism, rs6152
Abstract

International audience; Autism is a highly heritable disorder but the specific genes involved remain largely unknown. The higher prevalence of autism in men than in women, in conjunction with a number of other observations, has led to the suggestion that prenatal brain exposure to androgens may be of importance for the development of this condition. Prompted by this hypothesis, we investigated the potential influence of variation in the androgen receptor (AR) gene on the susceptibility for autism. To this end, 267 subjects with autism spectrum disorder and 617 controls were genotyped for three polymorphisms in exon 1 of the AR gene: the CAG repeat, the GGN repeat and the rs6152 SNP. In addition, parents and affected siblings were genotyped for 118 and 32 of the cases, respectively. Case-control comparisons revealed higher prevalence of short CAG alleles as well as of the A allele of the rs6152 SNP in female cases than in controls, but revealed no significant differences with respect to the GGN repeat. Analysis of the 118 families using transmission disequilibrium test, on the other hand, suggested an association with the GGN polymorphism, the rare 20-repeat allele being undertransmitted to male cases and the 23-repeat allele being overtransmitted to female cases. Sequencing of the AR gene in 46 patients revealed no mutations or rare variants. The results lend some support for an influence of the studied polymorphisms on the susceptibility for autism, but argue against the possibility that mutations in the AR gene are common in subjects with this condition.

Published
2009

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