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.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.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.doi http://dx.doi.org/10.1186/s13195-019-0478-z
• dc.identifier.issn 1758-9193
• dc.identifier.uri http://hdl.handle.net/10230/44630
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Alzheimers Res Ther. 2019; 11(1):27
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/752310
• 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.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• 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.title Centiloid cut-off values for optimal agreement between PET and CSF core AD biomarkers
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion