CSF synaptic biomarkers in the preclinical stage of Alzheimer disease and their association with MRI and PET: a cross-sectional study
Background and objectives: To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer continuum and associated with Alzheimer disease (AD) risk factors, primary pathology, and neurodegeneration markers. Methods: This cross-sectional study was performed i...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universitat Pompeu Fabra |
| Repositorio: | Repositorio Digital de la UPF |
| OAI Identifier: | oai:repositori.upf.edu:10230/52318 |
| Acceso en línea: | http://hdl.handle.net/10230/52318 http://dx.doi.org/10.1212/WNL.0000000000012853 |
| Access Level: | acceso abierto |
| Palabra clave: | Alzheimer, Malaltia d |
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CSF synaptic biomarkers in the preclinical stage of Alzheimer disease and their association with MRI and PET: a cross-sectional study |
| title |
CSF synaptic biomarkers in the preclinical stage of Alzheimer disease and their association with MRI and PET: a cross-sectional study |
| spellingShingle |
CSF synaptic biomarkers in the preclinical stage of Alzheimer disease and their association with MRI and PET: a cross-sectional study Milà Alomà, Marta Alzheimer, Malaltia d |
| title_short |
CSF synaptic biomarkers in the preclinical stage of Alzheimer disease and their association with MRI and PET: a cross-sectional study |
| title_full |
CSF synaptic biomarkers in the preclinical stage of Alzheimer disease and their association with MRI and PET: a cross-sectional study |
| title_fullStr |
CSF synaptic biomarkers in the preclinical stage of Alzheimer disease and their association with MRI and PET: a cross-sectional study |
| title_full_unstemmed |
CSF synaptic biomarkers in the preclinical stage of Alzheimer disease and their association with MRI and PET: a cross-sectional study |
| title_sort |
CSF synaptic biomarkers in the preclinical stage of Alzheimer disease and their association with MRI and PET: a cross-sectional study |
| dc.creator.none.fl_str_mv |
Milà Alomà, Marta Brinkmalm, Ann Ashton, Nicholas J. Kvartsberg, Hlin Shekari, Mahnaz Operto, Grégory Salvadó, Gemma Falcon, Carles Gispert, Juan Domingo Vilor Tejedor, Natàlia, 1988- Arenaza Urquijo, Eider M. Grau, Oriol (Grau Rivera) Sala Vila, Aleix Sánchez Benavides, Gonzalo González de Echávarri, José Maria Minguillón, Carolina Fauria, Karine Niñerola-Baizán, Aida Perissinotti, Andrés Kollmorgen, Gwendlyn Suridjan, Ivonne Zetterberg, Henrik Molinuevo, José Luis Blennow, Kaj Suárez-Calvet, Marc ALFA Study |
| author |
Milà Alomà, Marta |
| author_facet |
Milà Alomà, Marta Brinkmalm, Ann Ashton, Nicholas J. Kvartsberg, Hlin Shekari, Mahnaz Operto, Grégory Salvadó, Gemma Falcon, Carles Gispert, Juan Domingo Vilor Tejedor, Natàlia, 1988- Arenaza Urquijo, Eider M. Grau, Oriol (Grau Rivera) Sala Vila, Aleix Sánchez Benavides, Gonzalo González de Echávarri, José Maria Minguillón, Carolina Fauria, Karine Niñerola-Baizán, Aida Perissinotti, Andrés Kollmorgen, Gwendlyn Suridjan, Ivonne Zetterberg, Henrik Molinuevo, José Luis Blennow, Kaj Suárez-Calvet, Marc ALFA Study |
| author_role |
author |
| author2 |
Brinkmalm, Ann Ashton, Nicholas J. Kvartsberg, Hlin Shekari, Mahnaz Operto, Grégory Salvadó, Gemma Falcon, Carles Gispert, Juan Domingo Vilor Tejedor, Natàlia, 1988- Arenaza Urquijo, Eider M. Grau, Oriol (Grau Rivera) Sala Vila, Aleix Sánchez Benavides, Gonzalo González de Echávarri, José Maria Minguillón, Carolina Fauria, Karine Niñerola-Baizán, Aida Perissinotti, Andrés Kollmorgen, Gwendlyn Suridjan, Ivonne Zetterberg, Henrik Molinuevo, José Luis Blennow, Kaj Suárez-Calvet, Marc ALFA Study |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Alzheimer, Malaltia d |
| topic |
Alzheimer, Malaltia d |
| description |
Background and objectives: To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer continuum and associated with Alzheimer disease (AD) risk factors, primary pathology, and neurodegeneration markers. Methods: This cross-sectional study was performed in the Alzheimer's and Families (ALFA+) cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and growth-associated protein-43 (GAP-43) were measured with immunoassays, and synaptosomal-associated protein-25 (SNAP-25) and synaptotagmin-1 were measured with immunoprecipitation mass spectrometry. AD CSF biomarkers β-amyloid (Aβ)42/40, phosphorylated tau (p-tau), and total tau and the neurodegeneration biomarker neurofilament light chain (NfL) were also measured. Participants underwent structural MRI and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers. Results: All CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE ε4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ42/40 and Aβ PET Centiloid values), and it is important to note that the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism but lower cortical thickness in AD-related brain regions. Discussion: CSF synaptic biomarkers increase in the early preclinical stages of the Alzheimer continuum even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, APOE ε4, and markers of neurodegeneration. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 2022 2022 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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http://hdl.handle.net/10230/52318 http://dx.doi.org/10.1212/WNL.0000000000012853 |
| url |
http://hdl.handle.net/10230/52318 http://dx.doi.org/10.1212/WNL.0000000000012853 |
| dc.language.none.fl_str_mv |
Inglés |
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Inglés |
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info:eu-repo/grantAgreement/EC/H2020/948677 info:eu-repo/grantAgreement/EC/H2020/681712 info:eu-repo/grantAgreement/ES/2PE/FJCI-2017-33437 |
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https://creativecommons.org/licenses/by-nc-nd/4.0/deed.ca info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf application/pdf |
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Lippincott Williams & Wilkins |
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Lippincott Williams & Wilkins |
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reponame:Repositorio Digital de la UPF instname:Universitat Pompeu Fabra |
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Universitat Pompeu Fabra |
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Repositorio Digital de la UPF |
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Repositorio Digital de la UPF |
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1869420027675934720 |
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CSF synaptic biomarkers in the preclinical stage of Alzheimer disease and their association with MRI and PET: a cross-sectional studyMilà Alomà, MartaBrinkmalm, AnnAshton, Nicholas J.Kvartsberg, HlinShekari, MahnazOperto, GrégorySalvadó, GemmaFalcon, CarlesGispert, Juan DomingoVilor Tejedor, Natàlia, 1988-Arenaza Urquijo, Eider M.Grau, Oriol (Grau Rivera)Sala Vila, AleixSánchez Benavides, GonzaloGonzález de Echávarri, José MariaMinguillón, CarolinaFauria, KarineNiñerola-Baizán, AidaPerissinotti, AndrésKollmorgen, GwendlynSuridjan, IvonneZetterberg, HenrikMolinuevo, José LuisBlennow, KajSuárez-Calvet, MarcALFA StudyAlzheimer, Malaltia dBackground and objectives: To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer continuum and associated with Alzheimer disease (AD) risk factors, primary pathology, and neurodegeneration markers. Methods: This cross-sectional study was performed in the Alzheimer's and Families (ALFA+) cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and growth-associated protein-43 (GAP-43) were measured with immunoassays, and synaptosomal-associated protein-25 (SNAP-25) and synaptotagmin-1 were measured with immunoprecipitation mass spectrometry. AD CSF biomarkers β-amyloid (Aβ)42/40, phosphorylated tau (p-tau), and total tau and the neurodegeneration biomarker neurofilament light chain (NfL) were also measured. Participants underwent structural MRI and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers. Results: All CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE ε4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ42/40 and Aβ PET Centiloid values), and it is important to note that the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism but lower cortical thickness in AD-related brain regions. Discussion: CSF synaptic biomarkers increase in the early preclinical stages of the Alzheimer continuum even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, APOE ε4, and markers of neurodegeneration.The research leading to these results has received funding from “la Caixa” Foundation (LCF/PR/GN17/10300004) and the Alzheimer's Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17-519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under grant 2017-SGR-892. J.D.G. holds a “Ramón y Cajal” fellowship (RYC-2013-13054). E. Arenaza-Urquijo is supported by the Spanish Ministry of Science, Innovation and Universities–Spanish State Research Agency (RYC2018-026053-I). N. Vilor-Tejedor is funded by a postdoctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministry of Science and Innovation– Spanish State Research Agency. Her research has received additional support of “la Caixa” Foundation (LCF/PR/GN17/10300004) and the Health Department of the Catalan Government (Health Research and Innovation Strategic Plan 2016–2020 grant SLT002/16/00201). All Centre for Genomic Regulation authors acknowledge the support of the Spanish Ministry of Science, Innovation and Universities to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya. O. Grau-Rivera is supported by the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-33437) and receives funding from the Alzheimer's Association Research Fellowship Program (2019-AARF-644568). A. Sala-Vila is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship (CP II 17/00029). H. Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (No. 2018-02532), European Research Council (No. 681712), Swedish State Support for Clinical Research (No. ALFGBG-720931), Alzheimer Drug Discovery Foundation (No. 201809-2016862), and the UK Dementia Research Institute at UCL. K. Blennow is supported by the Swedish Research Council (No. 2017-00915), Alzheimer Drug Discovery Foundation (No. RDAPB-201809-2016615), Swedish Alzheimer Foundation (No. AF-742881), Hjärnfonden, Sweden (No. FO2017-0243), the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (No. ALFGBG-715986), European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), and NIH (No. 1R01AG068398-01). M. Suárez-Calvet receives funding from the European Research Council under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement 948677). M. Suárez-Calvet also receives funding from the Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I)Lippincott Williams & Wilkins202220222021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/52318http://dx.doi.org/10.1212/WNL.0000000000012853reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésinfo:eu-repo/grantAgreement/EC/H2020/948677info:eu-repo/grantAgreement/EC/H2020/681712info:eu-repo/grantAgreement/ES/2PE/FJCI-2017-33437© 2021 Marta Milà-Alomà et al. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journalhttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.cainfo:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/523182026-06-12T07:21:37Z |
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15,812429 |