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A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia

2022Artigo científico Acesso aberto
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dc.contributor.authorvan der Ende, Emma L.
dc.contributor.authorBron, Esther E.
dc.contributor.authorPoos, Jackie M.
dc.contributor.authorJiskoot, Lize C.
dc.contributor.authorPanman, Jessica L.
dc.contributor.authorPapma, Janne M.
dc.contributor.authorMeeter, Lieke H.
dc.contributor.authorDopper, Elise G. P.
dc.contributor.authorWilke, Carlo
dc.contributor.authorSynofzik, Matthis
dc.contributor.authorHeller, Carolin
dc.contributor.authorMiltenberger-Miltenyi, Gabriel
dc.contributor.authorvan Minkelen, Rick
dc.contributor.authorMitchell, Sara
dc.contributor.authorMoore, Katrina
dc.contributor.authorNacmias, Benedetta
dc.contributor.authorNicholas, Jennifer
dc.contributor.authorÖijerstedt, Linn
dc.contributor.authorOlives, Jaume
dc.contributor.authorOurselin, Sebastien
dc.contributor.authorPadovani, Alessandro
dc.contributor.authorSwift, Imogen J.
dc.contributor.authorPeakman, Georgia
dc.contributor.authorPievani, Michela
dc.contributor.authorPijnenburg, Yolande
dc.contributor.authorPolito, Cristina
dc.contributor.authorPremi, Enrico
dc.contributor.authorPrioni, Sara
dc.contributor.authorPrix, Catharina
dc.contributor.authorRademakers, Rosa
dc.contributor.authorRedaelli, Veronica
dc.contributor.authorRittman, Tim
dc.contributor.authorSogorb-Esteve, Aitana
dc.contributor.authorRogaeva, Ekaterina
dc.contributor.authorRosa-Neto, Pedro
dc.contributor.authorRossi, Giacomina
dc.contributor.authorRosser, Martin
dc.contributor.authorSantiago, Beatriz
dc.contributor.authorScarpini, Elio
dc.contributor.authorSchönecker, Sonja
dc.contributor.authorSemler, Elisa
dc.contributor.authorShafei, Rachelle
dc.contributor.authorShoesmith, Christen
dc.contributor.authorBouzigues, Arabella
dc.contributor.authorTábuas-Pereira, Miguel
dc.contributor.authorTainta, Mikel
dc.contributor.authorTaipa, Ricardo
dc.contributor.authorTang-Wai, David
dc.contributor.authorThomas, David L.
dc.contributor.authorThompson, Paul
dc.contributor.authorThonberg, Hakan
dc.contributor.authorTimberlake, Carolyn
dc.contributor.authorTiraboschi, Pietro
dc.contributor.authorTodd, Emily
dc.contributor.authorBorroni, Barbara
dc.contributor.authorVan Damme, Philip
dc.contributor.authorVandenbulcke, Mathieu
dc.contributor.authorVeldsman, Michele
dc.contributor.authorVerdelho, Ana
dc.contributor.authorVillanua, Jorge
dc.contributor.authorWarren, Jason
dc.contributor.authorWoollacott, Ione
dc.contributor.authorWlasich, Elisabeth
dc.contributor.authorZulaica, Miren
dc.contributor.authorSanchez-Valle, Raquel
dc.contributor.authorMoreno, Fermin
dc.contributor.authorGraff, Caroline
dc.contributor.authorLaforce, Robert
dc.contributor.authorGalimberti, Daniela
dc.contributor.authorMasellis, Mario
dc.contributor.authorTartaglia, Maria Carmela
dc.contributor.authorFinger, Elizabeth
dc.contributor.authorVandenberghe, Rik
dc.contributor.authorRowe, James B.
dc.contributor.authorDe Mendonça, Alexandre
dc.contributor.authorTagliavini, Fabrizio
dc.contributor.authorSantana, Isabel
dc.contributor.authorDucharme, Simon
dc.contributor.authorButler, Christopher R.
dc.contributor.authorGerhard, Alexander
dc.contributor.authorLevin, Johannes
dc.contributor.authorDanek, Adrian
dc.contributor.authorOtto, Markus
dc.contributor.authorPijnenburg, Yolande A. L.
dc.contributor.authorSorbi, Sandro
dc.contributor.authorZetterberg, Henrik
dc.contributor.authorNiessen, Wiro J.
dc.contributor.authorRohrer, Jonathan D.
dc.contributor.authorKlein, Stefan
dc.contributor.authorvan Swieten, John C.
dc.contributor.authorVenkatraghavan, Vikram
dc.contributor.authorSeelaar, Harro
dc.contributor.authorAfonso, Sónia
dc.contributor.authorAlmeida, Maria Rosario
dc.contributor.authorAnderl-Straub, Sarah
dc.contributor.authorAndersson, Christin
dc.contributor.authorAntonell, Anna
dc.contributor.authorArchetti, Silvana
dc.contributor.authorArighi, Andrea
dc.contributor.authorBalasa, Mircea
dc.contributor.authorBarandiaran, Myriam
dc.contributor.authorBargalló, Nuria
dc.contributor.authorBartha, Robart
dc.contributor.authorBender, Benjamin
dc.contributor.authorBenussi, Alberto
dc.contributor.authorBenussi, Luisa
dc.contributor.authorBessi, Valentina
dc.contributor.authorBinetti, Giuliano
dc.contributor.authorBlack, Sandra
dc.contributor.authorBocchetta, Martina
dc.contributor.authorBorrego-Ecija, Sergi
dc.contributor.authorBras, Jose
dc.contributor.authorBruffaerts, Rose
dc.contributor.authorCañada, Marta
dc.contributor.authorCantoni, Valentina
dc.contributor.authorCaroppo, Paola
dc.contributor.authorCash, David
dc.contributor.authorCastelo-Branco, Miguel
dc.contributor.authorConvery, Rhian
dc.contributor.authorCope, Thomas
dc.contributor.authorDi Fede, Giuseppe
dc.contributor.authorDíez, Alina
dc.contributor.authorDuro, Diana
dc.contributor.authorFenoglio, Chiara
dc.contributor.authorFerrari, Camilla
dc.contributor.authorFerreira, Catarina B.
dc.contributor.authorFox, Nick
dc.contributor.authorFreedman, Morris
dc.contributor.authorFumagalli, Giorgio
dc.contributor.authorGabilondo, Alazne
dc.contributor.authorGasparotti, Roberto
dc.contributor.authorGauthier, Serge
dc.contributor.authorGazzina, Stefano
dc.contributor.authorGiaccone, Giorgio
dc.contributor.authorGorostidi, Ana
dc.contributor.authorGreaves, Caroline
dc.contributor.authorGuerreiro, Rita
dc.contributor.authorHoegen, Tobias
dc.contributor.authorIndakoetxea, Begoña
dc.contributor.authorJelic, Vesna
dc.contributor.authorKarnath, Hans-Otto
dc.contributor.authorKeren, Ron
dc.contributor.authorLangheinrich, Tobias
dc.contributor.authorLeitão, Maria João
dc.contributor.authorLladó, Albert
dc.contributor.authorLombardi, Gemma
dc.contributor.authorLoosli, Sandra
dc.contributor.authorMaruta, Carolina
dc.contributor.authorMead, Simon
dc.date.accessioned2022-06-07T15:15:16Z
dc.date.available2022-06-07T15:15:16Z
dc.date.issued2022
dc.description© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.compt_PT
dc.description.abstractSeveral CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions.pt_PT
dc.description.sponsorshipThis study was supported in the Netherlands by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813,733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); V.V. and S.K. have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666992 (EuroPOND). E.B. was supported by the Hartstichting (PPP Allowance, 2018B011); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1); J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); I.J.S. is supported by the Alzheimer’s Association; J.B.R. is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to R.S.V.); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 ‘Solve-RD’ from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding and StratNeuro. H.Z. is a Wallenberg Scholar.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationBrain. 2022 Jun 3;145(5):1805-1817pt_PT
dc.identifier.doi10.1093/brain/awab382pt_PT
dc.identifier.eissn1460-2156
dc.identifier.issn0006-8950
dc.identifier.urihttp://hdl.handle.net/10451/53319
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherOxford University Presspt_PT
dc.relationData-driven models for Progression Of Neurological Disease
dc.relation.publisherversionhttps://academic.oup.com/brainpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectBiomarkerpt_PT
dc.subjectDisease progression modelpt_PT
dc.subjectEvent-based modellingpt_PT
dc.subjectFrontotemporal dementiapt_PT
dc.subjectNeurofilament light chainpt_PT
dc.titleA data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementiapt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumber666992
oaire.awardTitleData-driven models for Progression Of Neurological Disease
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/666992/EU
oaire.citation.endPage1817pt_PT
oaire.citation.issue5pt_PT
oaire.citation.startPage1805pt_PT
oaire.citation.titleBrainpt_PT
oaire.citation.volume145pt_PT
oaire.fundingStreamH2020
person.familyNameMiltenberger-Miltenyi
person.familyNameVerdelho
person.familyNamede Mendonça
person.familyNameCastelo-Branco
person.familyNameMaruta
person.givenNameGabriel
person.givenNameAna
person.givenNameAlexandre
person.givenNameMiguel
person.givenNameCarolina
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person.identifier.scopus-author-id35327513800
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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