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Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer's continuum

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dc.contributor.author Vilor Tejedor, Natàlia, 1988-
dc.contributor.author Ciampa, Iacopo
dc.contributor.author Operto, Grégory
dc.contributor.author Falcón, Carles
dc.contributor.author Suárez-Calvet, Marc
dc.contributor.author Crous-Bou, Marta
dc.contributor.author Shekari, Mahnaz
dc.contributor.author Arenaza Urquijo, Eider M.
dc.contributor.author Milà Alomà, Marta
dc.contributor.author Grau-Rivera, Oriol
dc.contributor.author Minguillón, Carolina
dc.contributor.author Kollmorgen, Gwendlyn
dc.contributor.author Zetterberg, Henrik
dc.contributor.author Blennow, Kaj
dc.contributor.author Guigó Serra, Roderic
dc.contributor.author Molinuevo, José Luis
dc.contributor.author Gispert López, Juan Domingo
dc.contributor.author ALFA Study
dc.date.accessioned 2021-10-05T05:55:38Z
dc.date.available 2021-10-05T05:55:38Z
dc.date.issued 2021
dc.identifier.citation Vilor-Tejedor N, Ciampa I, Operto G, Falcón C, Suárez-Calvet M, Crous-Bou M, Shekari M, Arenaza-Urquijo EM, Milà-Alomà M, Grau-Rivera O, Minguillon C, Kollmorgen G, Zetterberg H, Blennow K, Guigo R, Molinuevo JL, Gispert JD; ALFA study. Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer's continuum. Alzheimers Res Ther. 2021;13(1):135. DOI: 10.1186/s13195-021-00878-5
dc.identifier.issn 1758-9193
dc.identifier.uri http://hdl.handle.net/10230/48559
dc.description.abstract Background: Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer's disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown. Objective: We aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors. Methods: The study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer's continuum. NeuroToolKit and Elecsys® immunoassays were used to measure CSF Aβ42, Aβ40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and α-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by Aβ status (positivity defined as Aβ42/40 < 0.071). Results: The degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of Aβ positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in Aβ negative participants. Conclusions: Our results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer's continuum.
dc.description.sponsorship The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004 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 Health Department of the Catalan Government (Health Research and Innovation Strategic Plan (PERIS) 2016–2020 grant# SLT002/16/00201) and the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2017-SGR-892. All CRG 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. NV-T is funded by a post-doctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministry of Science and Innovation– Spanish State Research Agency. MS-C received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action grant agreement No 752310, and currently receives funding from 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). EMAU is supported by the Spanish Ministry of Science, Innovation and Universities—Spanish State Research Agency (RYC2018-026053-I). OGR is supported by the Spanish Ministry of Science, Innovation and Universities (FJCI-2017–33437). JDG is supported by the Spanish Ministry of Science and Innovation (RYC-2013–13054). KB is supported by the Swedish Research Council (#2017–00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809–2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466–236). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018–02532), the European Research Council (#681712), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-720931), the ADDF, USA (#201809–2016862), and the UK Dementia Research Institute at UCL.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher BioMed Central
dc.relation.ispartof Alzheimers Res Ther. 2021;13(1):135
dc.rights © The Author(s) 2021. 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer's continuum
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1186/s13195-021-00878-5
dc.subject.keyword Alzheimer’s disease
dc.subject.keyword CSF biomarkers
dc.subject.keyword MRI
dc.subject.keyword Perivascular spaces
dc.subject.keyword Tau pathophysiology
dc.subject.keyword Virchow-Robin spaces
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/752310
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/681712
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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