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.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.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.doi http://dx.doi.org/10.1186/s13195-021-00878-5
• dc.identifier.issn 1758-9193
• dc.identifier.uri http://hdl.handle.net/10230/48559
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Alzheimers Res Ther. 2021;13(1):135
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/752310
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/681712
• 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.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• 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.title Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer's continuum
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion