Differences between plasma and cerebrospinal fluid glial fibrillary acidic protein levels across the alzheimer disease continuum

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• dc.contributor.author Benedet, Andrea L.
• dc.contributor.author Milà Alomà, Marta
• dc.contributor.author Salvadó, Gemma
• dc.contributor.author Shekari, Mahnaz
• dc.contributor.author Operto, Grégory
• dc.contributor.author Gispert López, Juan Domingo
• dc.contributor.author Minguillón, Carolina
• dc.contributor.author Molinuevo, José Luis
• dc.contributor.author Suárez-Calvet, Marc
• dc.contributor.author Translational Biomarkers in Aging and Dementia (TRIAD) study
• dc.contributor.author ALFA Study
• dc.contributor.author BioCogBank Paris Lariboisière cohort
• dc.date.accessioned 2022-06-17T06:36:24Z
• dc.date.available 2022-06-17T06:36:24Z
• dc.date.issued 2021
• dc.description.abstract Importance: Glial fibrillary acidic protein (GFAP) is a marker of reactive astrogliosis that increases in the cerebrospinal fluid (CSF) and blood of individuals with Alzheimer disease (AD). However, it is not known whether there are differences in blood GFAP levels across the entire AD continuum and whether its performance is similar to that of CSF GFAP. Objective: To evaluate plasma GFAP levels throughout the entire AD continuum, from preclinical AD to AD dementia, compared with CSF GFAP. Design, setting, and participants: This observational, cross-sectional study collected data from July 29, 2014, to January 31, 2020, from 3 centers. The Translational Biomarkers in Aging and Dementia (TRIAD) cohort (Montreal, Canada) included individuals in the entire AD continuum. Results were confirmed in the Alzheimer's and Families (ALFA+) study (Barcelona, Spain), which included individuals with preclinical AD, and the BioCogBank Paris Lariboisière cohort (Paris, France), which included individuals with symptomatic AD. Main outcomes and measures: Plasma and CSF GFAP levels measured with a Simoa assay were the main outcome. Other measurements included levels of CSF amyloid-β 42/40 (Aβ42/40), phosphorylated tau181 (p-tau181), neurofilament light (NfL), Chitinase-3-like protein 1 (YKL40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and levels of plasma p-tau181 and NfL. Results of amyloid positron emission tomography (PET) were available in TRIAD and ALFA+, and results of tau PET were available in TRIAD. Results: A total of 300 TRIAD participants (177 women [59.0%]; mean [SD] age, 64.6 [17.6] years), 384 ALFA+ participants (234 women [60.9%]; mean [SD] age, 61.1 [4.7] years), and 187 BioCogBank Paris Lariboisière participants (116 women [62.0%]; mean [SD] age, 69.9 [9.2] years) were included. Plasma GFAP levels were significantly higher in individuals with preclinical AD in comparison with cognitively unimpaired (CU) Aβ-negative individuals (TRIAD: Aβ-negative mean [SD], 185.1 [93.5] pg/mL, Aβ-positive mean [SD], 285.0 [142.6] pg/mL; ALFA+: Aβ-negative mean [SD], 121.9 [42.4] pg/mL, Aβ-positive mean [SD], 169.9 [78.5] pg/mL). Plasma GFAP levels were also higher among individuals in symptomatic stages of the AD continuum (TRIAD: CU Aβ-positive mean [SD], 285.0 [142.6] pg/mL, mild cognitive impairment [MCI] Aβ-positive mean [SD], 332.5 [153.6] pg/mL; AD mean [SD], 388.1 [152.8] pg/mL vs CU Aβ-negative mean [SD], 185.1 [93.5] pg/mL; Paris: MCI Aβ-positive, mean [SD], 368.6 [158.5] pg/mL; AD dementia, mean [SD], 376.4 [179.6] pg/mL vs CU Aβ-negative mean [SD], 161.2 [67.1] pg/mL). Plasma GFAP magnitude changes were consistently higher than those of CSF GFAP. Plasma GFAP more accurately discriminated Aβ-positive from Aβ-negative individuals than CSF GFAP (area under the curve for plasma GFAP, 0.69-0.86; area under the curve for CSF GFAP, 0.59-0.76). Moreover, plasma GFAP levels were positively associated with tau pathology only among individuals with concomitant Aβ pathology. Conclusions and relevance: This study suggests that plasma GFAP is a sensitive biomarker for detecting and tracking reactive astrogliosis and Aβ pathology even among individuals in the early stages of AD.
• dc.description.sponsorship The Translational Biomarkers in Aging and Dementia (TRIAD) is supported by the Canadian Institutes of Health Research (MOP-11-51-31; RFN 152985, 159815, 162303); Canadian Consortium of Neurodegeneration and Aging (MOP-11-51-31 -team 1); Weston Brain Institute, Brain Canada Foundation (Canadian Foundation for Innovation Project 34874; 33397), and the Fonds de Recherche du Québec–Santé (Chercheur Boursier, 2020-VICO-279314). The Alzheimer’s and Families (ALFA) study receives 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). Dr Benedet is supported by the Swedish Alzheimer Foundation, Stiftelsen för Gamla Tjänarinnor, and Stohne Stiftelsen. Dr Vrillon is supported by Fondation Adolphe de Rotschild, Fondation Philippe Chatrier, Association des Anciens Internes des Hôpitaux de Paris, Fondation Vaincre Alzheimer, Stiftelsen för Gamla Tjänarinnor, Demensfundet, and Stohne Stiftelsen. Dr Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (grant 2018-02532), the European Research Council (grant 681712), Swedish State Support for Clinical Research (grant ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF) (grant 201809-2016862), the Alzheimer Disease (AD) Strategic Fund and the Alzheimer’s Association (grants ADSF-21-831376-C, ADSF-21-831381-C, and ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (grant FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at University College London. Dr Blennow is supported by the Swedish Research Council (grant 2017-00915), the ADDF (grant RDAPB-201809-2016615), the Swedish Alzheimer Foundation (grant AF-742881), Hjärnfonden, Sweden (grant FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the Avtal om Läkarutbildning och Forskining agreement (grant ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (grant JPND2019-466-236), and the National Institutes of Health (grant 1R01AG068398-01). Dr Suárez-Calvet receives funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant 948677), the Instituto de Salud Carlos III (grant PI19/00155), and the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I).
• dc.format.mimetype application/pdf
• dc.identifier.citation Benedet AL, Milà-Alomà M, Vrillon A, Ashton NJ, Pascoal TA, Lussier F, Karikari TK, et al. Differences between plasma and cerebrospinal fluid glial fibrillary acidic protein levels across the alzheimer disease contínuum. JAMA Neurol. 2021 Dec 1; 78(12): 1471-83. DOI: 10.1001/jamaneurol.2021.3671
• dc.identifier.doi http://dx.doi.org/10.1001/jamaneurol.2021.3671
• dc.identifier.issn 2168-6149
• dc.identifier.uri http://hdl.handle.net/10230/53516
• dc.language.iso eng
• dc.publisher American Medical Association
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/948677
• dc.rights This is an open access article distributed under the terms of the CC-BY License. http://creativecommons.org/licenses/by/4.0/ © 2021 Benedet AL et al. JAMA Neurology.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.other Alzheimer, Malaltia d'
• dc.subject.other Marcadors bioquímics
• dc.subject.other Plasma sanguini
• dc.subject.other Demència
• dc.title Differences between plasma and cerebrospinal fluid glial fibrillary acidic protein levels across the alzheimer disease continuum
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion