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      Astrocyte biomarker signatures of amyloid-β and tau pathologies in Alzheimer’s disease

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      1 , 2 , 1 , 1 , 1 , 3 , 3 , 4 , 2 , 5 , 6 , 3 , 5 , 5 , 6 , 7 , 8 , 2 , 2 , 3 , 3 , 3 , 3 , 3 , 3 , 3 , 3 , 3 , 3 , 1 , 1 , 1 , 1 , 3 , 5 , 6 , 5 , 6 , 9 , 10 , 11 , 2 , 1 , 5 , 6 , 2 , 12 , 13 , 3 , 1 ,
      Molecular Psychiatry
      Nature Publishing Group UK
      Biomarkers, Diseases, Neuroscience

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          Abstract

          Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer’s disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-β (Aβ) and tau pathologies. We assessed 121 individuals across the aging and AD clinical spectrum with positron emission tomography (PET) brain imaging for Aβ ([ 18F]AZD4694) and tau ([ 18F]MK-6240), as well as CSF GFAP and YKL-40 measures. We observed that higher CSF GFAP levels were associated with elevated Aβ-PET but not tau-PET load. By contrast, higher CSF YKL-40 levels were associated with elevated tau-PET but not Aβ-PET burden. Structural equation modeling revealed that CSF GFAP and YKL-40 mediate the effects of Aβ and tau, respectively, on hippocampal atrophy, which was further associated with cognitive impairment. Our results suggest the existence of distinct astrocyte biomarker signatures in response to brain Aβ and tau accumulation, which may contribute to our understanding of the complex link between reactive astrogliosis heterogeneity and AD progression.

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          STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets

          Abstract Proteins and their functional interactions form the backbone of the cellular machinery. Their connectivity network needs to be considered for the full understanding of biological phenomena, but the available information on protein–protein associations is incomplete and exhibits varying levels of annotation granularity and reliability. The STRING database aims to collect, score and integrate all publicly available sources of protein–protein interaction information, and to complement these with computational predictions. Its goal is to achieve a comprehensive and objective global network, including direct (physical) as well as indirect (functional) interactions. The latest version of STRING (11.0) more than doubles the number of organisms it covers, to 5090. The most important new feature is an option to upload entire, genome-wide datasets as input, allowing users to visualize subsets as interaction networks and to perform gene-set enrichment analysis on the entire input. For the enrichment analysis, STRING implements well-known classification systems such as Gene Ontology and KEGG, but also offers additional, new classification systems based on high-throughput text-mining as well as on a hierarchical clustering of the association network itself. The STRING resource is available online at https://string-db.org/.
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            lavaan: AnRPackage for Structural Equation Modeling

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              The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

              The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia. Copyright © 2011. Published by Elsevier Inc.
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                Author and article information

                Contributors
                PASCOAL@pitt.edu
                Journal
                Mol Psychiatry
                Mol Psychiatry
                Molecular Psychiatry
                Nature Publishing Group UK (London )
                1359-4184
                1476-5578
                10 August 2022
                10 August 2022
                2022
                : 27
                : 11
                : 4781-4789
                Affiliations
                [1 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, Department of Psychiatry, , University of Pittsburgh, ; Pittsburgh, PA USA
                [2 ]GRID grid.8532.c, ISNI 0000 0001 2200 7498, Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, ; Porto Alegre, RS Brazil
                [3 ]GRID grid.14709.3b, ISNI 0000 0004 1936 8649, Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer’s Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-Montréal; Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, , McGill University, ; Montreal, QC Canada
                [4 ]GRID grid.414449.8, ISNI 0000 0001 0125 3761, ADHD Outpatient Program & Development Psychiatry Program, Hospital de Clínicas de Porto Alegre, ; Porto Alegre, RS Brazil
                [5 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Department of Psychiatry and Neurochemistry, , The Sahlgrenska Academy at the University of Gothenburg, ; Mölndal, Sweden
                [6 ]GRID grid.1649.a, ISNI 000000009445082X, Clinical Neurochemistry Laboratory, , Sahlgrenska University Hospital, ; Gothenburg, Sweden
                [7 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Wallenberg Centre for Molecular and Translational Medicine, , University of Gothenburg, ; Gothenburg, Sweden
                [8 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Department of Old Age Psychiatry, , Institute of Psychiatry, Psychology & Neuroscience, King’s College London, ; London, UK
                [9 ]GRID grid.83440.3b, ISNI 0000000121901201, Department of Neurodegenerative Disease, , UCL Queen Square Institute of Neurology, ; London, UK
                [10 ]GRID grid.83440.3b, ISNI 0000000121901201, UK Dementia Research Institute at UCL, ; London, UK
                [11 ]GRID grid.24515.37, ISNI 0000 0004 1937 1450, Hong Kong Center for Neurodegenerative Diseases, ; Hong Kong, China
                [12 ]GRID grid.8532.c, ISNI 0000 0001 2200 7498, Department of Pharmacology, , Universidade Federal do Rio Grande do Sul, ; Porto Alegre, RS Brazil
                [13 ]GRID grid.8532.c, ISNI 0000 0001 2200 7498, Graduate Program in Biological Sciences: Pharmacology and Therapeuctis, , Universidade Federal do Rio Grande do Sul, ; Porto Alegre, RS Brazil
                Author information
                http://orcid.org/0000-0003-2711-3833
                http://orcid.org/0000-0003-3924-5278
                http://orcid.org/0000-0003-1567-3374
                http://orcid.org/0000-0002-7826-4781
                http://orcid.org/0000-0002-6877-4825
                http://orcid.org/0000-0002-1890-4193
                http://orcid.org/0000-0003-3930-4354
                http://orcid.org/0000-0003-1422-4358
                http://orcid.org/0000-0001-9116-1376
                http://orcid.org/0000-0001-9057-8014
                Article
                1716
                10.1038/s41380-022-01716-2
                9734046
                35948658
                fccdeefe-e4d7-437d-8b6f-51ca3d4ff96d
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 9 February 2022
                : 15 July 2022
                : 20 July 2022
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);
                Award ID: R01AG075336
                Award ID: R01AG073267
                Award Recipient :
                Funded by: U.S. Department of Health & Human Services | National Institutes of Health (NIH)
                Funded by: FundRef https://doi.org/10.13039/100000957, Alzheimer's Association;
                Award ID: AACSF-20-648075
                Award ID: NIRG-12-92090
                Award ID: NIRP-12-259245
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100002322, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brazilian Federal Agency for the Support and Evaluation of Graduate Education);
                Award ID: 88887.627297/2021-00
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100003593, Ministry of Science, Technology and Innovation | Conselho Nacional de Desenvolvimento Científico e Tecnológico (National Council for Scientific and Technological Development);
                Award ID: 435642/2018-9
                Award ID: 312410/2018- 2
                Award Recipient :
                Funded by: Instituto Serrapilheira (#Serra-1912-31365), Brazilian National Institute of Science and Technology in Excitotoxicity and Neuroprotection (#465671/2014-4), FAPERGS/MS/CNPq/SESRS–PPSUS (#30786.434.24734.231120170), and ARD/FAPERGS (#54392.632.30451.05032021).
                Funded by: FundRef https://doi.org/10.13039/501100000024, Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada);
                Award ID: MOP-11-51-31
                Award Recipient :
                Funded by: Alzheimer's Association
                Funded by: Alzheimer's Association
                Funded by: FundRef https://doi.org/10.13039/100009408, Fondation Brain Canada (Fondation Neuro Canada);
                Award ID: 33397
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000156, Fonds de Recherche du Québec - Santé (Fonds de la recherche en sante du Quebec);
                Award ID: 2020-VICO-279314
                Award Recipient :
                Funded by: Canadian Consortium of Neurodegeneration and Aging (MOP-11-51-31 - team 1)
                Categories
                Article
                Custom metadata
                © The Author(s), under exclusive licence to Springer Nature Limited 2022

                Molecular medicine
                biomarkers,diseases,neuroscience
                Molecular medicine
                biomarkers, diseases, neuroscience

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