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Alzheimer Disease: HELP
Articles by Anne M. Fagan
Based on 152 articles published since 2010
(Why 152 articles?)
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Between 2010 and 2020, A. Fagan wrote the following 152 articles about Alzheimer Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7
1 Review Current state of Alzheimer's fluid biomarkers. 2018

Molinuevo, José Luis / Ayton, Scott / Batrla, Richard / Bednar, Martin M / Bittner, Tobias / Cummings, Jeffrey / Fagan, Anne M / Hampel, Harald / Mielke, Michelle M / Mikulskis, Alvydas / O'Bryant, Sid / Scheltens, Philip / Sevigny, Jeffrey / Shaw, Leslie M / Soares, Holly D / Tong, Gary / Trojanowski, John Q / Zetterberg, Henrik / Blennow, Kaj. ·BarcelonaBeta Brain Research Center, Fundació Pasqual Maragall, Universitat Pompeu Fabra, Barcelona, Spain. · Unidad de Alzheimer y otros trastornos cognitivos, Hospital Clinic-IDIBAPS, Barcelona, Spain. · Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia. · Roche Centralised and Point of Care Solutions, Roche Diagnostics International, Rotkreuz, Switzerland. · Neuroscience Therapeutic Area Unit, Takeda Development Centre Americas Ltd, Cambridge, MA, USA. · Genentech, A Member of the Roche Group, Basel, Switzerland. · Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA. · Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA. · AXA Research Fund and Sorbonne University Chair, Paris, France. · Sorbonne University, GRC No 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France. · Brain and Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Paris, France. · Department of Neurology, Institute of Memory and Alzheimer's Disease (IM2A), Pitié-Salpêtrière Hospital, AP-HP, Paris, France. · Departments of Epidemiology and Neurology, Mayo Clinic, Rochester, MN, USA. · Biomarkers, Biogen, Cambridge, MA, USA. · Department of Pharmacology and Neuroscience; Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX, USA. · Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands. · Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland. · Department of Pathology and Laboratory Medicine, and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA. · Clinical Development Neurology, AbbVie, North Chicago, IL, USA. · Lundbeck, Deerfield, IL, USA. · Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. · Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. · Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal Campus, Sahlgrenska University Hospital, 431 80, Mölndal, Sweden. · Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK. · UK Dementia Research Institute at UCL, London, UK. · Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. kaj.blennow@neuro.gu.se. · Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal Campus, Sahlgrenska University Hospital, 431 80, Mölndal, Sweden. kaj.blennow@neuro.gu.se. ·Acta Neuropathol · Pubmed #30488277.

ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.

2 Review Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry. 2018

Lewczuk, Piotr / Riederer, Peter / O'Bryant, Sid E / Verbeek, Marcel M / Dubois, Bruno / Visser, Pieter Jelle / Jellinger, Kurt A / Engelborghs, Sebastiaan / Ramirez, Alfredo / Parnetti, Lucilla / Jack, Clifford R / Teunissen, Charlotte E / Hampel, Harald / Lleó, Alberto / Jessen, Frank / Glodzik, Lidia / de Leon, Mony J / Fagan, Anne M / Molinuevo, José Luis / Jansen, Willemijn J / Winblad, Bengt / Shaw, Leslie M / Andreasson, Ulf / Otto, Markus / Mollenhauer, Brit / Wiltfang, Jens / Turner, Martin R / Zerr, Inga / Handels, Ron / Thompson, Alexander G / Johansson, Gunilla / Ermann, Natalia / Trojanowski, John Q / Karaca, Ilker / Wagner, Holger / Oeckl, Patrick / van Waalwijk van Doorn, Linda / Bjerke, Maria / Kapogiannis, Dimitrios / Kuiperij, H Bea / Farotti, Lucia / Li, Yi / Gordon, Brian A / Epelbaum, Stéphane / Vos, Stephanie J B / Klijn, Catharina J M / Van Nostrand, William E / Minguillon, Carolina / Schmitz, Matthias / Gallo, Carla / Lopez Mato, Andrea / Thibaut, Florence / Lista, Simone / Alcolea, Daniel / Zetterberg, Henrik / Blennow, Kaj / Kornhuber, Johannes / Anonymous11351124. ·a Department of Psychiatry and Psychotherapy , Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg , Erlangen , Germany. · b Department of Neurodegeneration Diagnostics , Medical University of Białystok , and Department of Biochemical Diagnostics , University Hospital of Białystok , Białystok , Poland. · c Center of Mental Health, Clinic and Policlinic of Psychiatry, Psychosomatics and Psychotherapy , University Hospital Würzburg , Würzburg , Germany. · d Institute for Healthy Aging , University of North Texas Health Science Center , Fort Worth , TX , USA. · e Department of Neurology , Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center , Nijmegen , The Netherlands. · f Department of Laboratory Medicine , Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer center , Nijmegen , The Netherlands. · g Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Salpêtrièrie Hospital, INSERM UMR-S 975 (ICM), Paris 6 University , Paris , France. · h Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience , Alzheimer Center Limburg, Maastricht University , Maastricht , The Netherlands. · i Department of Neurology , Alzheimer Centre, Amsterdam Neuroscience VU University Medical Centre , Amsterdam , The Netherlands. · j Institute of Clinical Neurobiology , Vienna , Austria. · k Reference Center for Biological Markers of Dementia (BIODEM) , University of Antwerp , Antwerp , Belgium. · l Department of Neurology and Memory Clinic , Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken , Antwerp , Belgium. · m Department of Psychiatry and Psychotherapy , University of Bonn , Bonn , Germany. · n Institute of Human Genetics , University of Bonn , Bonn , Germany. · o Department of Psychiatry and Psychotherapy , University of Cologne , Cologne , Germany. · p Section of Neurology, Center for Memory Disturbances, Lab of Clinical Neurochemistry , University of Perugia , Perugia , Italy. · q Department of Radiology , Mayo Clinic , Rochester , MN , USA. · r Neurochemistry Lab and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience , VU University Medical Center Amsterdam , Amsterdam , The Netherlands. · s AXA Research Fund & UPMC Chair , Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Inserm, CNRS, Institut du Cerveau et de la Moelle Épinière (ICM), Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Hôpital Pitié-Salpêtrière, Boulevard de l'hôpital , Paris , France. · t Department of Neurology , Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona , Barcelona , Spain. · u Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas , CIBERNED , Spain. · v German Center for Neurodegenerative Disorders (DZNE) , Bonn , Germany. · w Center for Brain Health, Department of Psychiatry , NYU Langone Medical Center , New York , NY , USA. · x Knight Alzheimer's Disease Research Center , Washington University School of Medicine , Saint Louis , MO , USA. · y Department of Neurology , Washington University School of Medicine , Saint Louis , MO , USA. · z Barcelonabeta Brain Research Center , Pasqual Maragall Foundation , Barcelona , Spain. · aa Alzheimer's Disease and Other Cognitive Disorders Unit , Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) , Barcelona , Spain. · ab Karolinska Institutet , Department NVS, Center for Alzheimer Research, Division of Neurogeriatrics , Huddinge , Sweden. · ac Department of Pathology and Laboratory Medicine, Perelman School of Medicine , University of Pennsylvania , Philadelphia , PA , USA. · ad Clinical Neurochemistry Laboratory , Sahlgrenska University Hospital , Mölndal , Sweden. · ae Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry , The Sahlgrenska Academy at the University of Gothenburg , Mölndal , Sweden. · af Department of Neurology , University of Ulm , Ulm , Germany. · ag Paracelsus-Elena-Klinik, Kassel and University Medical Center Göttingen, Department of Neurology , Göttingen , Germany. · ah Department of Psychiatry & Psychotherapy , University of Göttingen , Göttingen , Germany. · ai German Center for Neurodegenerative Diseases (DZNE) , Göttingen , Germany. · aj iBiMED, Medical Sciences Department , University of Aveiro , Aveiro , Portugal. · ak Nuffield Department of Clinical Neurosciences , University of Oxford , Oxford , UK. · al Clinical Dementia Centre, Department of Neurology , University Medical School , Göttingen , Germany. · am Laboratory of Neurosciences , National Institute on Aging/National Institutes of Health (NIA/NIH) , Baltimore , MD , USA. · an Department of Radiology , Washington University School of Medicine , Saint Louis , MO , USA. · ao Department of Neurosurgery, HSC T-12/086 , Stony Brook University , New York , NY , USA. · ap Departamento de Ciencias Celulares y Moleculares/Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía , Universidad Peruana Cayetano Heredia , Lima , Peru. · aq Chair of Psychoneuroimmunoendocrinology , Maimonides University , Buenos Aires , Argentina. · ar Department of Psychiatry , University Hospital Cochin-Site Tarnier 89 rue d'Assas, INSERM 894, Faculty of Medicine Paris Descartes , Paris , France. · as Department of Molecular Neuroscience , UCL Institute of Neurology , London , UK. ·World J Biol Psychiatry · Pubmed #29076399.

ABSTRACT: In the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimer's disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-β positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.

3 Review Neurological manifestations of autosomal dominant familial Alzheimer's disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS). 2016

Tang, Mengxuan / Ryman, Davis C / McDade, Eric / Jasielec, Mateusz S / Buckles, Virginia D / Cairns, Nigel J / Fagan, Anne M / Goate, Alison / Marcus, Daniel S / Xiong, Chengjie / Allegri, Ricardo F / Chhatwal, Jasmeer P / Danek, Adrian / Farlow, Martin R / Fox, Nick C / Ghetti, Bernardino / Graff-Radford, Neill R / Laske, Christopher / Martins, Ralph N / Masters, Colin L / Mayeux, Richard P / Ringman, John M / Rossor, Martin N / Salloway, Stephen P / Schofield, Peter R / Morris, John C / Bateman, Randall J / Anonymous9491124. ·Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA. · Department of Biostatistics, Washington University School of Medicine, Saint Louis, MO, USA. · Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA. · Department of Radiology, Washington University School of Medicine, Saint Louis, MO, USA. · Neurological Research Institute Raúl Carrea, Buenos Aires, Argentina. · Department of Neurology, Center for Alzheimer Research and Treatment, Brigham and Women's Hospital and Massachusetts General Hospital, Boston, MA, USA. · Neurologische Klinik Ludwig-Maximilians-Universität Munich, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany. · Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA. · Dementia Research Centre, University College London Institute of Neurology, London, UK. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. · Department of Neurology, Mayo Clinic, Jacksonville, FL, USA. · German Center for Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, Tübingen, Germany. · Centre of Excellence for Alzheimer's Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, WA, Australia. · Mental Health Research Institute, University of Melbourne, Parkville, VIC, Australia. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA. · Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA. · Department of Neurology, Butler Hospital, Warren Alpert Medical School, Brown University, Providence, RI, USA. · Neuroscience Research Australia and University of New South Wales, Sydney, NSW, Australia. · Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA. Electronic address: batemanr@wustl.edu. ·Lancet Neurol · Pubmed #27777020.

ABSTRACT: BACKGROUND: Autosomal dominant familial Alzheimer's disease (ADAD) is a rare disorder with non-amnestic neurological symptoms in some clinical presentations. We aimed to compile and compare data from symptomatic participants in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) with those reported in the literature to estimate the prevalences of non-amnestic neurological symptoms in participants with ADAD. METHODS: We prospectively collected data from the DIAN-OBS database, which recruited participants from study centres in the USA, Europe, and Australia, between Feb 29, 2008, and July 1, 2014. We also did a systematic review of publications to extract individual-level clinical data for symptomatic participants with ADAD. We used data for age of onset (from first report of cognitive decline), disease course from onset to death, and the presence of 13 neurological findings that have been reported in association with ADAD. Using multivariable linear regression, we investigated the prevalences of various non-amnestic neurological symptoms and the contributions of age of onset and specific mutation type on symptoms. FINDINGS: The DIAN-OBS dataset included 107 individuals with detailed clinical data (forming the DIAN-OBS cohort). Our systematic review yielded 188 publications reporting on 1228 symptomatic individuals, with detailed neurological examination descriptions available for 753 individuals (forming the published data cohort). The most prevalent non-amnestic cognitive manifestations in participants in the DIAN-OBS cohort were those typical of mild to moderate Alzheimer's disease, including visual agnosia (55·1%, 95% CI 45·7-64·6), aphasia (57·9%, 48·6-67·3), and behavioural changes (61·7%, 51·5-70·0). Non-amnestic cognitive manifestations were less prevalent in the published data cohort (eg, visual agnosia [5·6%, 3·9-7·2], aphasia [23·0%, 20·0-26·0], and behavioural changes [31·7%, 28·4-35·1]). Prevalence of non-cognitive neurological manifestations in the DIAN-OBS cohort was low, including myoclonus and spasticity (9·3%, 95% CI 3·8-15·0), and seizures (2·8%, 0·5-5·9) and moderate for parkinsonism (11·2%, 5·3-17·1). By constrast, prevalence was higher in the published data cohort for myoclonus and spasticity (19·4%, 16·6-22·2 and 15·0%, 12·5-17·6, respectively), parkinsonism (12·5%, 10·1-15·0), and seizures (20·3%, 17·4-23·2). In an analysis of the published data cohort, ischaemic stroke was more prevalent at older ages of onset of symptoms of ADAD (odds ratio 1·09 per 1 year increase in age of onset, 95% CI 1·04-1·14, p=0·0003); and motor symptoms were more common at younger age of onset (myoclonus 0·93, 0·90-0·97, p=0·0007; seizures 0·95, 0·92-0·98, p=0·0018; corticobulbar deficits 0·91, 0·86-0·96, p=0·0012; and cerebellar ataxia 0·82, 0·74-0·91, p=0·0002). In the DIAN-OBS cohort, non-cognitive symptoms were more common at more severe stages of disease. INTERPRETATION: The non-cognitive clinical manifestations of Alzheimer's disease seem to affect a small proportion of participants with mild to moderate ADAD, and are probably influenced by disease severity, environmental, and genetic factors. When evaluating patients with potential ADAD, clinicians should note that cognitive symptoms typical of sporadic Alzheimer's disease are the most consistent finding, with some patients manifesting non-cognitive neurological symptoms. Future work is needed to determine the environmental and genetic factors that cause these neurological symptoms. FUNDING: National Institutes of Health and German Center for Neurodegenerative Diseases.

4 Review Suspected non-Alzheimer disease pathophysiology--concept and controversy. 2016

Jack, Clifford R / Knopman, David S / Chételat, Gaël / Dickson, Dennis / Fagan, Anne M / Frisoni, Giovanni B / Jagust, William / Mormino, Elizabeth C / Petersen, Ronald C / Sperling, Reisa A / van der Flier, Wiesje M / Villemagne, Victor L / Visser, Pieter J / Vos, Stephanie J B. ·Department of Radiology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA. · Department of Neurology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA. · INSERM, Université de Caen, EPHE, CHU de Caen, U1077, Caen, France. · Department of Pathology, Mayo Clinic and Foundation, 4500 San Pablo Road South, Jacksonville, Florida 32224, USA. · Department of Neurology, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 4488 Forest Park Avenue, Suite 101, St Louis, Missouri 63108, USA. · University Hospitals and University of Geneva, Rue Gabrielle-Perret-Gentil 4, 1205 Genève, Switzerland. · Helen Wills Neuroscience Institute, University of California Berkeley, 175 Li Ka Shing Center, Berkeley, California 94720, USA. · Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, Massachusetts 02115, USA. · Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, PO Box 7057, 1007 MB Amsterdam, Netherlands. · Department of Molecular Imaging &Therapy, Centre for PET, Austin Health, 145 Studley Road, PO Box 5555 Melbourne, Victoria, Australia 3084. · Department of Psychiatry and Neuropsychology, Institute of Mental Health and Neuroscience, Maastricht University, PO Box 616 MD Maastricht, Netherlands. ·Nat Rev Neurol · Pubmed #26782335.

ABSTRACT: Suspected non-Alzheimer disease pathophysiology (SNAP) is a biomarker-based concept that applies to individuals with normal levels of amyloid-β biomarkers in the brain, but in whom biomarkers of neurodegeneration are abnormal. The term SNAP has been applied to clinically normal individuals (who do not meet criteria for either mild cognitive impairment or dementia) and to individuals with mild cognitive impairment, but is applicable to any amyloid-negative, neurodegeneration-positive individual regardless of clinical status, except when the pathology underlying neurodegeneration can be reliably inferred from the clinical presentation. SNAP is present in ∼23% of clinically normal individuals aged >65 years and in ∼25% of mildly cognitively impaired individuals. APOE*ε4 is underrepresented in individuals with SNAP compared with amyloid-positive individuals. Clinically normal and mildly impaired individuals with SNAP have worse clinical and/or cognitive outcomes than individuals with normal levels of neurodegeneration and amyloid-β biomarkers. In this Perspectives article, we describe the available data on SNAP and address topical controversies in the field.

5 Review Autosomal Dominant Alzheimer Disease: A Unique Resource to Study CSF Biomarker Changes in Preclinical AD. 2015

Schindler, Suzanne Elizabeth / Fagan, Anne M. ·Department of Neurology, Knight Alzheimer's Disease Research Center, Hope Center for Neurological Disorders, Washington University School of Medicine , St. Louis, MO , USA. ·Front Neurol · Pubmed #26175713.

ABSTRACT: Our understanding of the pathogenesis of Alzheimer disease (AD) has been greatly influenced by investigation of rare families with autosomal dominant mutations that cause early onset AD. Mutations in the genes coding for amyloid precursor protein (APP), presenilin 1 (PSEN-1), and presenilin 2 (PSEN-2) cause over-production of the amyloid-β peptide (Aβ) leading to early deposition of Aβ in the brain, which in turn is hypothesized to initiate a cascade of processes, resulting in neuronal death, cognitive decline, and eventual dementia. Studies of cerebrospinal fluid (CSF) from individuals with the common form of AD, late-onset AD (LOAD), have revealed that low CSF Aβ42 and high CSF tau are associated with AD brain pathology. Herein, we review the literature on CSF biomarkers in autosomal dominant AD (ADAD), which has contributed to a detailed road map of AD pathogenesis, especially during the preclinical period, prior to the appearance of any cognitive symptoms. Current drug trials are also taking advantage of the unique characteristics of ADAD and utilizing CSF biomarkers to accelerate development of effective therapies for AD.

6 Review Biomarkers of Alzheimer's disease and mild cognitive impairment: a current perspective. 2015

Lewczuk, Piotr / Mroczko, Barbara / Fagan, Anne / Kornhuber, Johannes. ·Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: Piotr.Lewczuk@uk-erlangen.de. · Department of Neurodegeneration Diagnostics, Medical University of Bialystok, Bialystok, Poland; Department of Biochemical Diagnostics, University Hospital in Bialystok, Bialystok, Poland. · The Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University, St. Louis, MO, USA. · Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany. ·Adv Med Sci · Pubmed #25579841.

ABSTRACT: A growing body of evidence supports the application of the neurochemical dementia diagnostics (NDD) biomarkers for the diagnosis of dementing conditions. Biomarkers of Alzheimer's disease (AD) were recently classified as these reflecting amyloid β pathology (decreased CSF concentrations of Aβ42 and/or positive Aβ PET scan) and these reflecting neurodegeneration (increased CSF Tau concentrations, decreased uptake of FDG on FDG-PET, and cerebral atrophy on structural MRI). Particularly important seems the role of the biomarkers in the early diagnosis of AD, as the first pathophysiologic events observable in the CSF and amyloid β-PET occur years and perhaps decades before the onset of the earliest clinical symptoms. Therefore, the NDD tools enable the diagnosis of AD already in the early preclinical stage. This review summarizes pathophysiology underlying the CSF biomarkers, following a discussion of their role in the current guidelines for the diagnostic procedures.

7 Review Guidelines for the standardization of preanalytic variables for blood-based biomarker studies in Alzheimer's disease research. 2015

O'Bryant, Sid E / Gupta, Veer / Henriksen, Kim / Edwards, Melissa / Jeromin, Andreas / Lista, Simone / Bazenet, Chantal / Soares, Holly / Lovestone, Simon / Hampel, Harald / Montine, Thomas / Blennow, Kaj / Foroud, Tatiana / Carrillo, Maria / Graff-Radford, Neill / Laske, Christoph / Breteler, Monique / Shaw, Leslie / Trojanowski, John Q / Schupf, Nicole / Rissman, Robert A / Fagan, Anne M / Oberoi, Pankaj / Umek, Robert / Weiner, Michael W / Grammas, Paula / Posner, Holly / Martins, Ralph / Anonymous3110808. ·Institute for Aging & Alzheimer's Disease Research and Department of Internal Medicine, University of North Texas Health Science Center, Fort Worth, TX, USA. Electronic address: sid.o'bryant@unthsc.edu. · Centre of Excellence for Alzheimer's Disease Research & Care, School of Medical Sciences, Edith Cowan University, Joondalup, WA, Australia. · Nordic Bioscience Biomarkers and Research, Neurodegenerative Diseases, Herlev, Denmark. · Department of Psychology, University of North Texas, Denton, TX, USA. · Quanterix, Inc., Lexington, MA, USA. · AXA Research Fund & UPMC Chair, Paris, France. · Department of Old Age Psychiatry, King's College London, Institute of Psychiatry, London, UK. · Bristol-Myers Squibb, Wallingford, CT, USA. · AXA Research Fund & UPMC Chair, Paris, France; Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, Institut dela Mémoire et de la Maladie d'Alzheimer (IM2A) & Institut du Cerveau et dela Moelle épinière (ICM), Département de Neurologie, Hôpital de laPitié- Salpétrière, Paris, France; Département de Neurologie, Institut du Cerveau et de la Moelle épinière (ICM), Hôpital de la Pitié-Salpétrière, Paris, France. · Department of Pathology, University of Washington, Seattle, WA, USA. · Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, University of Goteborg, Sahlgrenska University Hospital, Molndal, Sweden. · Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. · Alzheimer's Association, Chicago, IL, USA. · Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL, USA. · Department of Neurodegeneration, Center of Neurology, Section for Dementia Research, Hertie-Institute of Clinical Brain Research, University of Tubingen, Tubingen, Germany. · Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · Department of Epidemiology, Joseph P Mailman School of Public Health, Columbia University, New York, NY, USA. · Alzheimer's Disease Cooperative Study, Department of Neurosciences, UCSD School of Medicine, La Jolla, CA, USA. · Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. · Meso Scale Discovery, Rockville, MD, USA. · Department of Medicine, Radiology and Psychiatry, University of California, San Francisco, CA, USA. · Texas Tech University Health Science Center, Garrison Institute on Aging, Lubbock, TX, USA. · Pfizer Inc., New York, NY, USA. ·Alzheimers Dement · Pubmed #25282381.

ABSTRACT: The lack of readily available biomarkers is a significant hindrance toward progressing to effective therapeutic and preventative strategies for Alzheimer's disease (AD). Blood-based biomarkers have potential to overcome access and cost barriers and greatly facilitate advanced neuroimaging and cerebrospinal fluid biomarker approaches. Despite the fact that preanalytical processing is the largest source of variability in laboratory testing, there are no currently available standardized preanalytical guidelines. The current international working group provides the initial starting point for such guidelines for standardized operating procedures (SOPs). It is anticipated that these guidelines will be updated as additional research findings become available. The statement provides (1) a synopsis of selected preanalytical methods utilized in many international AD cohort studies, (2) initial draft guidelines/SOPs for preanalytical methods, and (3) a list of required methodological information and protocols to be made available for publications in the field to foster cross-validation across cohorts and laboratories.

8 Review Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer's disease. 2015

Blennow, Kaj / Dubois, Bruno / Fagan, Anne M / Lewczuk, Piotr / de Leon, Mony J / Hampel, Harald. ·Department of Neuroscience and Physiology, Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, University of Gothenburg, Mölndal, Sweden. Electronic address: Kaj.Blennow@neuro.gu.se. · Institute for Memory and Alzheimer's Disease, Institute of Neurology, Pitié-Salpêtrière Hospital Group, Pierre and Marie Curie University, Paris, France. · Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. · Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany. · Department of Psychiatry, New York University School of Medicine, New York, NY, USA; Centre for Brain Health, New York University School of Medicine, New York, NY, USA. ·Alzheimers Dement · Pubmed #24795085.

ABSTRACT: Several potential disease-modifying drugs for Alzheimer's disease (AD) have failed to show any effect on disease progression in clinical trials, conceivably because the AD subjects are already too advanced to derive clinical benefit from treatment and because diagnosis based on clinical criteria alone introduces a high misdiagnosis rate. Thus, well-validated biomarkers for early detection and accurate diagnosis are crucial. Low cerebrospinal fluid (CSF) concentrations of the amyloid-β (Aβ1-42) peptide, in combination with high total tau and phosphorylated tau, are sensitive and specific biomarkers highly predictive of progression to AD dementia in patients with mild cognitive impairment. However, interlaboratory variations in the results seen with currently available immunoassays are of concern. Recent worldwide standardization efforts and quality control programs include standard operating procedures for both preanalytical (e.g., lumbar puncture and sample handling) and analytical (e.g., preparation of calibration curve) procedures. Efforts are also ongoing to develop highly reproducible assays on fully automated instruments. These global standardization and harmonization measures will provide the basis for the generalized international application of CSF biomarkers for both clinical trials and routine clinical diagnosis of AD.

9 Review Progress update: fluid and imaging biomarkers in Alzheimer's disease. 2014

Sutphen, Courtney L / Fagan, Anne M / Holtzman, David M. ·Department of Neurology, Washington University School of Medicine, St. Louis, Missouri; Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri. · Department of Neurology, Washington University School of Medicine, St. Louis, Missouri; Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri; Department of Development Biology (DMH), Washington University School of Medicine, St. Louis, Missouri. Electronic address: holtzman@neuro.wustl.edu. ·Biol Psychiatry · Pubmed #24012326.

ABSTRACT: Alzheimer's disease (AD) is a growing health crisis around the world. Although significant progress has been made in our understanding of AD pathogenesis, there is currently no effective treatment to delay onset or prevent the disease. The focus has now shifted to the identification and treatment of AD in the early clinical stages as well as before cognitive symptoms emerge-during the long preclinical stage. It is possible that diagnosis of individuals with AD will be more accurate when clinical symptoms and signs are combined with biomarkers, which can improve both the diagnostic and prognostic accuracy of AD and its differentiation from the other neurodegenerative diseases. This review discusses fluid and imaging biomarkers that have shown promise in such areas, as well as some of the current challenges that face the field.

10 Review Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial. 2013

Mills, S M / Mallmann, J / Santacruz, A M / Fuqua, A / Carril, M / Aisen, P S / Althage, M C / Belyew, S / Benzinger, T L / Brooks, W S / Buckles, V D / Cairns, N J / Clifford, D / Danek, A / Fagan, A M / Farlow, M / Fox, N / Ghetti, B / Goate, A M / Heinrichs, D / Hornbeck, R / Jack, C / Jucker, M / Klunk, W E / Marcus, D S / Martins, R N / Masters, C M / Mayeux, R / McDade, E / Morris, J C / Oliver, A / Ringman, J M / Rossor, M N / Salloway, S / Schofield, P R / Snider, J / Snyder, P / Sperling, R A / Stewart, C / Thomas, R G / Xiong, C / Bateman, R J. ·DIAN-TU, Washington University, 660, S. Euclid Avenue, Campus Box 8111, St. Louis, MO 63108, USA. ·Rev Neurol (Paris) · Pubmed #24016464.

ABSTRACT: The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.

11 Review Fluid biomarkers in Alzheimer disease. 2012

Blennow, Kaj / Zetterberg, Henrik / Fagan, Anne M. ·Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Mölndal, SE-431 80 Mölndal, Sweden. kaj.blennow@neuro.gu.se ·Cold Spring Harb Perspect Med · Pubmed #22951438.

ABSTRACT: Research progress has provided detailed understanding of the molecular pathogenesis of Alzheimer disease (AD). This knowledge has been translated into new drug candidates with putative disease-modifying effects, which are now being tested in clinical trials. The promise of effective therapy has created a great need for biomarkers able to detect AD in the predementia phase, because drugs will probably be effective only if neurodegeneration is not too advanced. In this chapter, cerebrospinal fluid (CSF) and plasma biomarkers are reviewed. The core CSF biomarkers total tau (T-tau), phosphorylated tau (P-tau) and the 42 amino acid form of β-amyloid (Aβ42) reflect AD pathology, and have high diagnostic accuracy to diagnose AD with dementia and prodromal AD in mild cognitive impairment cases. The rationale for the use of CSF biomarkers to identify and monitor the mechanism of action of new drug candidates is also outlined in this chapter.

12 Review Upcoming candidate cerebrospinal fluid biomarkers of Alzheimer's disease. 2012

Fagan, Anne M / Perrin, Richard J. ·Department of Neurology, Washington University School of Medicine, 660 South Euclid Ave., St Louis, MO 63110, USA. fagana@neuro.wustl.edu ·Biomark Med · Pubmed #22917147.

ABSTRACT: Dementia due to Alzheimer's disease (AD) is estimated to reach epidemic proportions by the year 2030. Given the limited accuracy of current AD clinical diagnosis, biomarkers of AD pathologies are currently being sought. Reductions in cerebrospinal fluid levels of β-amyloid 42 (a marker of amyloid plaques) and elevations in tau species (markers of neurofibrillary tangles and/or neurodegeneration) are well-established as biomarkers useful for AD diagnosis and prognosis. However, novel markers for other features of AD pathophysiology (e.g., β-amyloid processing, neuroinflammation and neuronal stress/dysfunction) and for other non-AD dementias are required to improve the accuracy of AD disease diagnosis, prognosis, staging and therapeutic monitoring (theragnosis). This article discusses the potential of several promising novel cerebrospinal fluid analytes, highlights the next steps critical for advancement in the field, and provides a prediction on how the field may evolve in 5-10 years.

13 Review Cerebrospinal fluid biomarkers of Alzheimer's disease. 2010

Fagan, Anne M / Holtzman, David M. ·Department of Neurology, Hope Center for Neuological Disorder, Washington University, School of Medicine, St. Louis, MO 63110, USA. fagana@neuro.wustl.edu ·Biomark Med · Pubmed #20361010.

ABSTRACT: Alzheimer's disease will reach epidemic proportions within the next 20-30 years if left unchecked. Currently, there are no treatments that prevent or slow Alzheimer's disease but many are being developed. Parallel efforts to develop biomarkers to aid in disease diagnosis and prognosis, and assess disease risk are currently underway. Clinicopathological and biomarker studies have demonstrated that Alzheimer's disease pathology can be detected preclinically. Using biomarkers to identify affected individuals prior to the onset of clinical symptoms and associated synaptic/neuronal loss should enable novel clinical trial design and early mechanism-based therapeutic intervention. This article summarizes the most promising cerebrospinal fluid biomarkers, highlights novel applications and current challenges, and provides a prediction on how the field may evolve in 5-10 years.

14 Clinical Trial Tau and Aβ imaging, CSF measures, and cognition in Alzheimer's disease. 2016

Brier, Matthew R / Gordon, Brian / Friedrichsen, Karl / McCarthy, John / Stern, Ari / Christensen, Jon / Owen, Christopher / Aldea, Patricia / Su, Yi / Hassenstab, Jason / Cairns, Nigel J / Holtzman, David M / Fagan, Anne M / Morris, John C / Benzinger, Tammie L S / Ances, Beau M. ·Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, USA. · Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, USA. Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA. · Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, USA. · Department of Mathematics, Washington University in St. Louis, St. Louis, MO 63110, USA. · Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, USA. Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA. · Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, USA. Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA. Department of Pathology, Washington University in St. Louis, St. Louis, MO 63110, USA. · Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, USA. Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA. Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA. · Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, USA. Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA. Department of Pathology, Washington University in St. Louis, St. Louis, MO 63110, USA. Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA. · Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, USA. Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA. Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO 63110, USA. · Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, USA. Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, USA. Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA. Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA. bances@wustl.edu. ·Sci Transl Med · Pubmed #27169802.

ABSTRACT: Alzheimer's disease (AD) is characterized by two molecular pathologies: cerebral β-amyloidosis in the form of β-amyloid (Aβ) plaques and tauopathy in the form of neurofibrillary tangles, neuritic plaques, and neuropil threads. Until recently, only Aβ could be studied in humans using positron emission tomography (PET) imaging owing to a lack of tau PET imaging agents. Clinical pathological studies have linked tau pathology closely to the onset and progression of cognitive symptoms in patients with AD. We report PET imaging of tau and Aβ in a cohort of cognitively normal older adults and those with mild AD. Multivariate analyses identified unique disease-related stereotypical spatial patterns (topographies) for deposition of tau and Aβ. These PET imaging tau and Aβ topographies were spatially distinct but correlated with disease progression. Cerebrospinal fluid measures of tau, often used to stage preclinical AD, correlated with tau deposition in the temporal lobe. Tau deposition in the temporal lobe more closely tracked dementia status and was a better predictor of cognitive performance than Aβ deposition in any region of the brain. These data support models of AD where tau pathology closely tracks changes in brain function that are responsible for the onset of early symptoms in AD.

15 Article Neurofilament Light Predicts Decline in Attention but Not Episodic Memory in Preclinical Alzheimer's Disease. 2020

Aschenbrenner, Andrew J / Gordon, Brian A / Fagan, Anne M / Schindler, Suzanne E / Balota, David A / Morris, John C / Hassenstab, Jason J. ·Charles F. and Joanne Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. · Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA. · Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, USA. ·J Alzheimers Dis · Pubmed #32144992.

ABSTRACT: BACKGROUND: Cerebrospinal fluid tau and neurofilament light (NfL) are two biomarkers of neurodegeneration in Alzheimer's disease. Previous reports have shown that the influence of tau on cognitive decline depends on levels of amyloid burden whereas NfL predicts decline independently of amyloid. Most studies use a global cognitive composite as the primary outcome, and it is unknown if critical cognitive domain scores are similarly sensitive to rates of decline due to neurodegeneration. OBJECTIVE: To examine the unique contribution of amyloid, tau, and NfL to rates of cognitive decline in multiple cognitive composites in a cognitively healthy, middle-aged to older adult cohort. METHODS: A total of 255 participants (55% female; mean age = 66.2 years, range = 42.5-86.7 years) completed CSF studies and serial cognitive assessments to measure global cognition, episodic memory, and attentional control. Linear mixed effects models were used to examine rates of change on each composite score as a function of baseline biomarker levels. RESULTS: Total tau predicted decline in attention regardless of amyloid status, but the relationship to global cognition and episodic memory was dependent on amyloid, replicating prior literature. NfL predicted decline in attention and global cognition, but not memory, and this effect was independent of amyloid status. CONCLUSIONS: These findings suggest that NfL can be used to monitor cognitive decline in aging and Alzheimer's disease and that an attentional control composite may be a better outcome for tracking general neurodegenerative effects on cognition.

16 Article Resting State Functional Connectivity Signature Differentiates Cognitively Normal from Individuals Who Convert to Symptomatic Alzheimer's Disease. 2020

Wisch, Julie K / Roe, Catherine M / Babulal, Ganesh M / Schindler, Suzanne E / Fagan, Anne M / Benzinger, Tammie L / Morris, John C / Ances, Beau M. ·Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA. · Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. · Hope Center, Washington University in Saint Louis, St. Louis, MO, USA. · Department of Radiology, Washington University in St. Louis St. Louis, MO, USA. ·J Alzheimers Dis · Pubmed #32144983.

ABSTRACT: BACKGROUND: Changes in resting state functional connectivity (rs-fc) occur in Alzheimer's disease (AD), but few longitudinal rs-fc studies have been performed. Most studies focus on single networks and not a global measure of rs-fc. Although the amyloid tau neurodegeneration (AT(N)) framework is increasingly utilized by the AD community, few studies investigated when global rs-fc signature changes occur within this model. OBJECTIVE: 1) Identify a global rs-fc signature that differentiates cognitively normal (CN) individuals from symptomatic AD. 2) Assess when longitudinal changes in rs-fc occur relative to conversion to symptomatic AD. 3) Compare rs-fc with amyloid, tau, and neurodegeneration biomarkers. METHODS: A global rs-fc signature composed of intra-network connections was longitudinally evaluated in a cohort of cognitively normal participants at baseline (n = 335). Biomarkers, including cerebrospinal fluid (Aβ42 and tau), structural magnetic resonance imaging, and positron emission tomography were obtained. RESULTS: Global rs-fc signature distinguished CN individuals from individuals who developed symptomatic AD. Changes occurred nearly four years before conversion to symptomatic AD. The global rs-fc signature most strongly correlated with markers of neurodegeneration. CONCLUSION: The global rs-fc signature changes near symptomatic onset and is likely a neurodegenerative biomarker. Rs-fc changes could serve as a biomarker for evaluating potential therapies for symptomatic conversion to AD.

17 Article Predicting sporadic Alzheimer's disease progression via inherited Alzheimer's disease-informed machine-learning. 2020

Franzmeier, Nicolai / Koutsouleris, Nikolaos / Benzinger, Tammie / Goate, Alison / Karch, Celeste M / Fagan, Anne M / McDade, Eric / Duering, Marco / Dichgans, Martin / Levin, Johannes / Gordon, Brian A / Lim, Yen Ying / Masters, Colin L / Rossor, Martin / Fox, Nick C / O'Connor, Antoinette / Chhatwal, Jasmeer / Salloway, Stephen / Danek, Adrian / Hassenstab, Jason / Schofield, Peter R / Morris, John C / Bateman, Randall J / Anonymous61125 / Anonymous71125 / Ewers, Michael. ·Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany. · Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität LMU, Munich, Germany. · Department of Radiology, Washington University in St. Louis, St. Louis, Missouri, USA. · Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, Missouri, USA. · Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, Missouri, USA. · Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri, USA. · Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA. · Munich Cluster for Systems Neurology, Munich, Germany. · German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. · Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany. · Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri, USA. · Department of Psychological and Brain Sciences, Washington University, St. Louis, Missouri, USA. · The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia. · Dementia Research Centre, University College London, Queen Square, London, UK. · Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA. · Department of Neurology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA. · Neuroscience Research Australia, Randwick, New South Wales, Australia. · School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia. · ADNI Consortium members are listed in the appendix. · DIAN Consortium members are listed in the appendix. ·Alzheimers Dement · Pubmed #32043733.

ABSTRACT: INTRODUCTION: Developing cross-validated multi-biomarker models for the prediction of the rate of cognitive decline in Alzheimer's disease (AD) is a critical yet unmet clinical challenge. METHODS: We applied support vector regression to AD biomarkers derived from cerebrospinal fluid, structural magnetic resonance imaging (MRI), amyloid-PET and fluorodeoxyglucose positron-emission tomography (FDG-PET) to predict rates of cognitive decline. Prediction models were trained in autosomal-dominant Alzheimer's disease (ADAD, n = 121) and subsequently cross-validated in sporadic prodromal AD (n = 216). The sample size needed to detect treatment effects when using model-based risk enrichment was estimated. RESULTS: A model combining all biomarker modalities and established in ADAD predicted the 4-year rate of decline in global cognition (R DISCUSSION: Our independently validated machine-learning model predicted cognitive decline in sporadic prodromal AD and may substantially reduce sample size needed in clinical trials in AD.

18 Article Spatial navigation ability predicts progression of dementia symptomatology. 2020

Levine, Taylor F / Allison, Samantha L / Stojanovic, Marta / Fagan, Anne M / Morris, John C / Head, Denise. ·Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, Missouri. · Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. · Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin. · Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, Missouri. · Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, Missouri. · Neurology Department, Washington University in St. Louis, St. Louis, Missouri. · Radiology Department, Washington University in St. Louis, St. Louis, Missouri. ·Alzheimers Dement · Pubmed #32043719.

ABSTRACT: INTRODUCTION: Spatial navigation deficits are observed in Alzheimer's disease cross-sectionally, but prediction of longitudinal clinical decline has been less examined. METHODS: Cognitive mapping (CM) was assessed in 95 participants and route learning (RL) was assessed in 65 participants at baseline. Clinical progression over an average of 4 to 5 years was assessed using the clinical dementia rating (CDR) scale. Relative predictive ability was compared to episodic memory, hippocampus, and cerebrospinal fluid biomarkers (phosphorylated tau/amyloid β 42 (ptau RESULTS: CM and RL were predictors of clinical progression (P's < 0.032). All measures, except RL-Learning remained predictors with episodic memory in models (P's < 0.048). Only RL-Retrieval remained a predictor when ptau DISCUSSION: Baseline spatial navigation performance may be appropriate for assessing risk of clinical progression.

19 Article Concordance of Lumipulse cerebrospinal fluid t-tau/Aβ42 ratio with amyloid PET status. 2020

Kaplow, June / Vandijck, Manu / Gray, Julia / Kanekiyo, Michio / Huyck, Els / Traynham, C J / Esquivel, Rianne / Fagan, Anne M / Luthman, Johan. ·Eisai Inc., Woodcliff Lake, NJ, USA. · Fujirebio Europe, Ghent, Belgium. · Department of Neurology, Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO, USA. · Fujirebio Diagnostics Inc., Malvern, PA, USA. ·Alzheimers Dement · Pubmed #31914216.

ABSTRACT: INTRODUCTION: Cerebrospinal fluid (CSF) biomarkers can identify individuals with Alzheimer's disease (AD) pathology (eg, amyloid plaques, neurofibrillary tangles), but defined analyte cut-points using high-throughput automated assays are necessary for general clinical use. METHODS: CSF amyloid β42 peptide (Aβ42), t-tau, and t-tau/Aβ42 were quantified by the Lumipulse platform in two test cohorts (A/B: Eisai BAN2401-201/MISSION AD E2609-301/302, n = 138; C: Knight Alzheimer's Disease Research Center (ADRC), n = 198), and receiver operating characteristic (ROC) curve analyses defined cut-points corresponding best to amyloid determinations using positron emission tomography (PET) imaging. The best-performing cut-point was then validated as a predictor of amyloid status in an independent cohort (D: MISSION AD E2609-301/302, n = 240). RESULTS: Virtually identical t-tau/Aβ42 cut-points (∼0.54) performed best in both test cohorts and with similar accuracy (areas under ROC curve [AUCs] [A/B: 0.95; C: 0.94]). The cut-point yielded an overall percent agreement with amyloid PET of 85.0% in validation cohort D. DISCUSSION: Lumipulse CSF biomarker measures with validated cut-points have clinical utility in identifying AD pathology.

20 Article Functional connectivity among brain regions affected in Alzheimer's disease is associated with CSF TNF-α in APOE4 carriers. 2020

Contreras, Joey Annette / Aslanyan, Vahan / Sweeney, Melanie D / Sanders, Lianne M J / Sagare, Abhay P / Zlokovic, Berislav V / Toga, Arthur W / Han, S Duke / Morris, John C / Fagan, Anne / Massoumzadeh, Parinaz / Benzinger, Tammie L / Pa, Judy. ·Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, CA, USA. · Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, USA. · Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, CA, USA; Department of Human Movement Sciences, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. · Family Medicine, Neurology, Psychology, and Gerontology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. · Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO, USA; Department of Neurology, Washington University, St Louis, MO, USA. · Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO, USA. · Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO, USA; Department of Radiology and Neurological Surgery, Washington University, St. Louis, MO, USA. · Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, CA, USA. Electronic address: judypa@usc.edu. ·Neurobiol Aging · Pubmed #31870643.

ABSTRACT: It is now recognized that understanding how neuroinflammation affects brain function may provide new insights into Alzheimer's pathophysiology. Tumor necrosis factor (TNF)-α, an inflammatory cytokine marker, has been implicated in Alzheimer's disease (AD), as it can impair neuronal function through suppression of long-term potentiation. Our study investigated the relationship between cerebrospinal fluid TNF-α and functional connectivity (FC) in a cohort of 64 older adults (μ age = 69.76 years; 30 cognitively normal, 34 mild AD). Higher cerebrospinal fluid TNF-α levels were associated with lower FC among brain regions important for high-level decision-making, inhibitory control, and memory. This effect was moderated by apolipoprotein E-ε4 (APOE4) status. Graph theory metrics revealed there were significant differences between APOE4 carriers at the node level, and by diagnosis at the network level suggesting global brain network dysfunction in participants with AD. These findings suggest proinflammatory mechanisms may contribute to reduced FC in regions important for high-level cognition. Future studies are needed to understand the role of inflammation on brain function and clinical progression, especially in APOE4 carriers.

21 Article The Relation Between Personality and Biomarkers in Sensitivity and Conversion to Alzheimer-Type Dementia. 2019

Duchek, Janet M / Aschenbrenner, Andrew J / Fagan, Anne M / Benzinger, Tammie L S / Morris, John C / Balota, David A. ·Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, USA. · Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, USA. · The Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, USA. · Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, USA. · Department of Neurological Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA. ·J Int Neuropsychol Soc · Pubmed #31822309.

ABSTRACT: OBJECTIVES: The present study explored relationships among personality, Alzheimer's disease (AD) biomarkers, and dementia by addressing the following questions: (1) Does personality discriminate healthy aging and earliest detectable stage of AD? (2) Does personality predict conversion from healthy aging to early-stage AD? (3) Do AD biomarkers mediate any observed relationships between personality and dementia status/conversion? METHODS: Both self- and informant ratings of personality were obtained in a large well-characterized longitudinal sample of cognitively normal older adults (N = 436) and individuals with early-stage dementia (N = 74). Biomarkers included amyloid imaging, hippocampal volume, cerebral spinal fluid (CSF) Aβ42, and CSF tau. RESULTS: Higher neuroticism, lower conscientiousness, along with all four biomarkers strongly discriminated cognitively normal controls from early-stage AD individuals. The direct effects of neuroticism and conscientiousness were only mediated by hippocampal volume. Conscientiousness along with all biomarkers predicted conversion from healthy aging to early-stage AD; however, none of the biomarkers mediated the relationship between conscientiousness and conversion. Conscientiousness predicted conversion as strongly as the biomarkers, with the exception of hippocampal volume. CONCLUSIONS: Conscientiousness and to a lesser extent neuroticism serve as important independent behavioral markers for AD risk.

22 Article A harmonized longitudinal biomarkers and cognition database for assessing the natural history of preclinical Alzheimer's disease from young adulthood and for designing prevention trials. 2019

Xiong, Chengjie / Luo, Jingqin / Agboola, Folasade / Li, Yan / Albert, Marilyn / Johnson, Sterling C / Koscik, Rebecca L / Masters, Colin L / Soldan, Anja / Villemagne, Victor L / Li, Qiao-Xin / McDade, Eric M / Fagan, Anne M / Massoumzadeh, Parinaz / Benzinger, Tammie / Hassenstab, Jason / Bateman, Randall J / Morris, John C / Anonymous2061068. ·Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: chengjie@wustl.edu. · Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA; Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA; Siteman Cancer Center Biostatistics Core Washington University School of Medicine, St. Louis, MO, USA. · Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. · Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Wisconsin Alzheimer's Institute and Alzheimer's Disease Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA; Geriatric Research Education and Clinical Center, William S Middleton Veterans Memorial Hospital, Madison, WI, USA. · Wisconsin Alzheimer's Institute and Alzheimer's Disease Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA. · The Florey Institute, University of Melbourne, Melbourne, Australia. · Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia. · Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. · Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. · Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA. · Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Departments of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. ·Alzheimers Dement · Pubmed #31506247.

ABSTRACT: INTRODUCTION: Large longitudinal biomarkers database focusing on middle age is needed for Alzheimer's disease (AD) prevention. METHODS: Data for cerebrospinal fluid analytes, molecular imaging of cerebral fibrillar β-amyloid with positron emission tomography, magnetic resonance imaging-based brain structures, and clinical/cognitive outcomes were harmonized across eight AD biomarker studies. Statistical power was estimated. RESULTS: The harmonized database included 7779 participants with clinical/cognitive data: 3542 were 18∼65 years at the baseline, 5865 had longitudinal cognitive data for a median of 4.7 years, 2473 participated in the cerebrospinal fluid studies (906 had longitudinal data), 2496 participated in the magnetic resonance imaging studies (1283 had longitudinal data), and 1498 participated in the positron emission tomography amyloid studies (849 had longitudinal data). The database provides adequate power for detecting early biomarker changes, and demonstrates the feasibility of AD prevention trials on middle-aged individuals. DISCUSSION: The harmonized database is an optimum resource to design AD prevention trials decades before symptomatic onset.

23 Article Vascular risk factors are associated with longitudinal changes in cerebrospinal fluid tau markers and cognition in preclinical Alzheimer's disease. 2019

Bos, Isabelle / Vos, Stephanie J B / Schindler, Suzanne E / Hassenstab, Jason / Xiong, Chengjie / Grant, Elizabeth / Verhey, Frans / Morris, John C / Visser, Pieter Jelle / Fagan, Anne M. ·Department of Psychiatry & Neuropsychology, Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands. · Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. · Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA. · Department of Psychiatry & Neuropsychology, Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands; Alzheimer Center, VU University Medical Center, Amsterdam, the Netherlands. · Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: fagana@wustl.edu. ·Alzheimers Dement · Pubmed #31378575.

ABSTRACT: INTRODUCTION: Vascular factors increase the risk of Alzheimer's disease (AD). We investigated the associations between such factors, longitudinal AD cerebrospinal fluid biomarkers, and cognition. METHODS: 433 cognitively normal participants were classified into four biomarker groups using their baseline amyloid (A+/-) and tau status (T+/-). 184 participants had undergone serial cerebrospinal fluid collection. Frequencies of risk factors and the Framingham Risk Score (FRS) were compared, and we tested the influence of risk factors on change in biomarker concentrations and cognition. RESULTS: The absence of obesity, presence of hypertension, and a high FRS were associated with an increase in tau levels, particularly in A+T+ individuals. Risk factors were not associated with amyloid. Depression was associated with higher cognitive scores, whereas high FRS was associated with lower scores and a faster decline. DISCUSSION: Our results demonstrate that vascular risk factors may enhance neurodegeneration but not amyloid accumulation in preclinical AD.

24 Article Developing a Spatial Navigation Screening Tool Sensitive to the Preclinical Alzheimer Disease Continuum. 2019

Allison, Samantha L / Rodebaugh, Thomas L / Johnston, Chiharu / Fagan, Anne M / Morris, John C / Head, Denise. ·Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, Missouri, USA. · Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, Missouri, USA. · Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, Missouri, USA. · Neurology Department, Washington University in St. Louis, St. Louis, Missouri, USA. · Radiology Department, Washington University in St. Louis, St. Louis, Missouri, USA. ·Arch Clin Neuropsychol · Pubmed #31197326.

ABSTRACT: OBJECTIVE: There remains a need for a non-invasive and cost-effective screening measure that could be administered prior to the provision of a lumbar puncture or positron emission tomography scan for the detection of preclinical Alzheimer disease (AD). Previous findings suggest that a hippocampally-based spatial navigation task may be effective for screening individuals for the preclinical AD continuum (i.e., low cerebrospinal fluid (CSF) Aβ42). Unfortunately, this task took 1.5-2 hours to administer, which would be time-prohibitive in a clinical setting. Therefore, the goal of this study was to compare psychometric properties of six spatial navigation-related tasks in order to take the next steps in developing a clinically appropriate screening measure. METHODS: Psychometric properties (i.e., reliability, diagnostic accuracy, validity) of a modified version of the cognitive mapping task, two binding tasks, a visual perspective taking task, and self- and informant report versions of a questionnaire were examined in a sample of 91 clinically normal (CN) individuals. CSF Aβ42 and ptau181 were available for 30 individuals. RESULTS: The learning phase of the cognitive mapping task and the self-report questionnaire were sensitive to identifying individuals in the preclinical AD continuum (93% and 87% sensitivity, 60% and 67% specificity, respectively). These two measures also demonstrated good test-retest stability (intraclass correlation coefficients = .719 and .838, respectively) and internal consistency (Cronbach's αs = .825 and .965, respectively). CONCLUSIONS: These findings suggest that a self-report questionnaire and aspects of a cognitive mapping task may be particularly appropriate for development as screening tools for identifying individuals in the preclinical AD continuum.

25 Article Quantification of white matter cellularity and damage in preclinical and early symptomatic Alzheimer's disease. 2019

Wang, Qing / Wang, Yong / Liu, Jingxia / Sutphen, Courtney L / Cruchaga, Carlos / Blazey, Tyler / Gordon, Brian A / Su, Yi / Chen, Charlie / Shimony, Joshua S / Ances, Beau M / Cairns, Nigel J / Fagan, Anne M / Morris, John C / Benzinger, Tammie L S. ·Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Knight Alzheimer's Disease Research Center, 4488 Forest Park, Suite 101, St. Louis, MO 63108, USA. · Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Knight Alzheimer's Disease Research Center, 4488 Forest Park, Suite 101, St. Louis, MO 63108, USA; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biomedical Engineering, Washington University School of Engineering & Applied Science, St. Louis, MO 63015, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: wangyong@wustl.edu. · Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA. · Knight Alzheimer's Disease Research Center, 4488 Forest Park, Suite 101, St. Louis, MO 63108, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. · Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA. · Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA. · Banner Alzheimer's Institute, Phoenix, AZ 85006, USA. · Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA. · Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Knight Alzheimer's Disease Research Center, 4488 Forest Park, Suite 101, St. Louis, MO 63108, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. · Knight Alzheimer's Disease Research Center, 4488 Forest Park, Suite 101, St. Louis, MO 63108, USA; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. · Knight Alzheimer's Disease Research Center, 4488 Forest Park, Suite 101, St. Louis, MO 63108, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. · Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Knight Alzheimer's Disease Research Center, 4488 Forest Park, Suite 101, St. Louis, MO 63108, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA. ·Neuroimage Clin · Pubmed #30901713.

ABSTRACT: Interest in understanding the roles of white matter (WM) inflammation and damage in the pathophysiology of Alzheimer disease (AD) has been growing significantly in recent years. However, in vivo magnetic resonance imaging (MRI) techniques for imaging inflammation are still lacking. An advanced diffusion-based MRI method, neuro-inflammation imaging (NII), has been developed to clinically image and quantify WM inflammation and damage in AD. Here, we employed NII measures in conjunction with cerebrospinal fluid (CSF) biomarker classification (for β-amyloid (Aβ) and neurodegeneration) to evaluate 200 participants in an ongoing study of memory and aging. Elevated NII-derived cellular diffusivity was observed in both preclinical and early symptomatic phases of AD, while disruption of WM integrity, as detected by decreased fractional anisotropy (FA) and increased radial diffusivity (RD), was only observed in the symptomatic phase of AD. This may suggest that WM inflammation occurs earlier than WM damage following abnormal Aβ accumulation in AD. The negative correlation between NII-derived cellular diffusivity and CSF Aβ

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