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Centiloid cut-off values for optimal agreement between PET and CSF core AD biomarkers

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dc.contributor.author Salvadó, Gemma
dc.contributor.author Molinuevo, José Luis
dc.contributor.author Brugulat Serrat, Anna, 1986-
dc.contributor.author Falcón, Carles
dc.contributor.author Grau-Rivera, Oriol
dc.contributor.author Suárez-Calvet, Marc
dc.contributor.author Pavía Segura, Javier
dc.contributor.author Niñerola-Baizán, Aida
dc.contributor.author Perissinotti, Andrés
dc.contributor.author Lomeña, Francisco
dc.contributor.author Minguillón, Carolina
dc.contributor.author Fauria, Karine
dc.contributor.author Zetterberg, Henrik
dc.contributor.author Blennow, Kaj
dc.contributor.author Gispert López, Juan Domingo
dc.contributor.author Alzheimer’s Disease Neuroimaging Initiative
dc.date.accessioned 2020-05-21T07:03:03Z
dc.date.available 2020-05-21T07:03:03Z
dc.date.issued 2019
dc.identifier.citation Salvadó G, Molinuevo JL, Brugulat-Serrat A, Falcon C, Grau-Rivera O, Suárez-Calvet M, Pavia J, Niñerola-Baizán A, Perissinotti A, Lomeña F, Minguillon C, Fauria K, Zetterberg H, Blennow K, Gispert JD; Alzheimer’s Disease Neuroimaging Initiative. Centiloid cut-off values for optimal agreement between PET and CSF core AD biomarkers. Alzheimers Res Ther. 2019; 11(1):27. DOI: 10.1186/s13195-019-0478-z
dc.identifier.issn 1758-9193
dc.identifier.uri http://hdl.handle.net/10230/44630
dc.description.abstract Background: The Centiloid scale has been developed to standardize measurements of amyloid PET imaging. Reference cut-off values of this continuous measurement enable the consistent operationalization of decision-making for multicentre research studies and clinical trials. In this study, we aimed at deriving reference Centiloid thresholds that maximize the agreement against core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in two large independent cohorts. Methods: A total of 516 participants of the ALFA+ Study (N = 205) and ADNI (N = 311) underwent amyloid PET imaging ([18F]flutemetamol and [18F]florbetapir, respectively) and core AD CSF biomarker determination using Elecsys® tests. Tracer uptake was quantified in Centiloid units (CL). Optimal Centiloid cut-offs were sought that maximize the agreement between PET and dichotomous determinations based on CSF levels of Aβ42, tTau, pTau, and their ratios, using pre-established reference cut-off values. To this end, a receiver operating characteristic analysis (ROC) was conducted, and Centiloid cut-offs were calculated as those that maximized the Youden's J Index or the overall percentage agreement recorded. Results: All Centiloid cut-offs fell within the range of 25-35, except for CSF Aβ42 that rendered an optimal cut-off value of 12 CL. As expected, the agreement of tau/Aβ42 ratios was higher than that of CSF Aβ42. Centiloid cut-off robustness was confirmed even when established in an independent cohort and against variations of CSF cut-offs. Conclusions: A cut-off of 12 CL matches previously reported values derived against postmortem measures of AD neuropathology. Together with these previous findings, our results flag two relevant inflection points that would serve as boundary of different stages of amyloid pathology: one around 12 CL that marks the transition from the absence of pathology to subtle pathology and another one around 30 CL indicating the presence of established pathology. The derivation of robust and generalizable cut-offs for core AD biomarkers requires cohorts with adequate representation of intermediate levels.
dc.description.sponsorship 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 the TriBEKa Imaging Platform project. JDG holds a ‘Ramón y Cajal’ fellowship (RYC-2013-13054). MS-C receives funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie action grant agreement No 752310. CM is supported by the Spanish Ministry of Economy and Competitiveness (grant n° IEDI-2016-00690). KB holds the Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences, and is supported by the Swedish Research Council (#2017-00915), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), and a grant (#ALFGBG-715986) from the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher BioMed Central
dc.relation.ispartof Alzheimers Res Ther. 2019; 11(1):27
dc.rights © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 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.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Centiloid cut-off values for optimal agreement between PET and CSF core AD biomarkers
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1186/s13195-019-0478-z
dc.subject.keyword AD pathophysiology
dc.subject.keyword Biomarker categorization
dc.subject.keyword Biomarker concordance
dc.subject.keyword Early detection
dc.subject.keyword Phosphorylated tau
dc.subject.keyword Positivity
dc.subject.keyword Positron emission tomography
dc.subject.keyword Preclinical
dc.subject.keyword Threshold
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/752310
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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