A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10451/53319 |
Resumo: | © 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.com |
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A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementiaBiomarkerDisease progression modelEvent-based modellingFrontotemporal dementiaNeurofilament light chain© 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.comSeveral 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.This 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.Oxford University PressRepositório da Universidade de Lisboavan der Ende, Emma L.Bron, Esther E.Poos, Jackie M.Jiskoot, Lize C.Panman, Jessica L.Papma, Janne M.Meeter, Lieke H.Dopper, Elise G. P.Wilke, CarloSynofzik, MatthisHeller, CarolinMiltenberger-Miltenyi, Gabrielvan Minkelen, RickMitchell, SaraMoore, KatrinaNacmias, BenedettaNicholas, JenniferÖijerstedt, LinnOlives, JaumeOurselin, SebastienPadovani, AlessandroSwift, Imogen J.Peakman, GeorgiaPievani, MichelaPijnenburg, YolandePolito, CristinaPremi, EnricoPrioni, SaraPrix, CatharinaRademakers, RosaRedaelli, VeronicaRittman, TimSogorb-Esteve, AitanaRogaeva, EkaterinaRosa-Neto, PedroRossi, GiacominaRosser, MartinSantiago, BeatrizScarpini, ElioSchönecker, SonjaSemler, ElisaShafei, RachelleShoesmith, ChristenBouzigues, ArabellaTábuas-Pereira, MiguelTainta, MikelTaipa, RicardoTang-Wai, DavidThomas, David L.Thompson, PaulThonberg, HakanTimberlake, CarolynTiraboschi, PietroTodd, EmilyBorroni, BarbaraVan Damme, PhilipVandenbulcke, MathieuVeldsman, MicheleVerdelho, AnaVillanua, JorgeWarren, JasonWoollacott, IoneWlasich, ElisabethZulaica, MirenSanchez-Valle, RaquelMoreno, FerminGraff, CarolineLaforce, RobertGalimberti, DanielaMasellis, MarioTartaglia, Maria CarmelaFinger, ElizabethVandenberghe, RikRowe, James B.De Mendonça, AlexandreTagliavini, FabrizioSantana, IsabelDucharme, SimonButler, Christopher R.Gerhard, AlexanderLevin, JohannesDanek, AdrianOtto, MarkusPijnenburg, Yolande A. L.Sorbi, SandroZetterberg, HenrikNiessen, Wiro J.Rohrer, Jonathan D.Klein, Stefanvan Swieten, John C.Venkatraghavan, VikramSeelaar, HarroAfonso, SóniaAlmeida, Maria RosarioAnderl-Straub, SarahAndersson, ChristinAntonell, AnnaArchetti, SilvanaArighi, AndreaBalasa, MirceaBarandiaran, MyriamBargalló, NuriaBartha, RobartBender, BenjaminBenussi, AlbertoBenussi, LuisaBessi, ValentinaBinetti, GiulianoBlack, SandraBocchetta, MartinaBorrego-Ecija, SergiBras, JoseBruffaerts, RoseCañada, MartaCantoni, ValentinaCaroppo, PaolaCash, DavidCastelo-Branco, MiguelConvery, RhianCope, ThomasDi Fede, GiuseppeDíez, AlinaDuro, DianaFenoglio, ChiaraFerrari, CamillaFerreira, Catarina B.Fox, NickFreedman, MorrisFumagalli, GiorgioGabilondo, AlazneGasparotti, RobertoGauthier, SergeGazzina, StefanoGiaccone, GiorgioGorostidi, AnaGreaves, CarolineGuerreiro, RitaHoegen, TobiasIndakoetxea, BegoñaJelic, VesnaKarnath, Hans-OttoKeren, RonLangheinrich, TobiasLeitão, Maria JoãoLladó, AlbertLombardi, GemmaLoosli, SandraMaruta, CarolinaMead, Simon2022-06-07T15:15:16Z20222022-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/53319engBrain. 2022 Jun 3;145(5):1805-18170006-895010.1093/brain/awab3821460-2156info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:59:01Zoai:repositorio.ul.pt:10451/53319Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:04:17.148705Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia |
title |
A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia |
spellingShingle |
A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia van der Ende, Emma L. Biomarker Disease progression model Event-based modelling Frontotemporal dementia Neurofilament light chain |
title_short |
A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia |
title_full |
A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia |
title_fullStr |
A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia |
title_full_unstemmed |
A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia |
title_sort |
A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia |
author |
van der Ende, Emma L. |
author_facet |
van der Ende, Emma L. Bron, Esther E. Poos, Jackie M. Jiskoot, Lize C. Panman, Jessica L. Papma, Janne M. Meeter, Lieke H. Dopper, Elise G. P. Wilke, Carlo Synofzik, Matthis Heller, Carolin Miltenberger-Miltenyi, Gabriel van Minkelen, Rick Mitchell, Sara Moore, Katrina Nacmias, Benedetta Nicholas, Jennifer Öijerstedt, Linn Olives, Jaume Ourselin, Sebastien Padovani, Alessandro Swift, Imogen J. Peakman, Georgia Pievani, Michela Pijnenburg, Yolande Polito, Cristina Premi, Enrico Prioni, Sara Prix, Catharina Rademakers, Rosa Redaelli, Veronica Rittman, Tim Sogorb-Esteve, Aitana Rogaeva, Ekaterina Rosa-Neto, Pedro Rossi, Giacomina Rosser, Martin Santiago, Beatriz Scarpini, Elio Schönecker, Sonja Semler, Elisa Shafei, Rachelle Shoesmith, Christen Bouzigues, Arabella Tábuas-Pereira, Miguel Tainta, Mikel Taipa, Ricardo Tang-Wai, David Thomas, David L. Thompson, Paul Thonberg, Hakan Timberlake, Carolyn Tiraboschi, Pietro Todd, Emily Borroni, Barbara Van Damme, Philip Vandenbulcke, Mathieu Veldsman, Michele Verdelho, Ana Villanua, Jorge Warren, Jason Woollacott, Ione Wlasich, Elisabeth Zulaica, Miren Sanchez-Valle, Raquel Moreno, Fermin Graff, Caroline Laforce, Robert Galimberti, Daniela Masellis, Mario Tartaglia, Maria Carmela Finger, Elizabeth Vandenberghe, Rik Rowe, James B. De Mendonça, Alexandre Tagliavini, Fabrizio Santana, Isabel Ducharme, Simon Butler, Christopher R. Gerhard, Alexander Levin, Johannes Danek, Adrian Otto, Markus Pijnenburg, Yolande A. L. Sorbi, Sandro Zetterberg, Henrik Niessen, Wiro J. Rohrer, Jonathan D. Klein, Stefan van Swieten, John C. Venkatraghavan, Vikram Seelaar, Harro Afonso, Sónia Almeida, Maria Rosario Anderl-Straub, Sarah Andersson, Christin Antonell, Anna Archetti, Silvana Arighi, Andrea Balasa, Mircea Barandiaran, Myriam Bargalló, Nuria Bartha, Robart Bender, Benjamin Benussi, Alberto Benussi, Luisa Bessi, Valentina Binetti, Giuliano Black, Sandra Bocchetta, Martina Borrego-Ecija, Sergi Bras, Jose Bruffaerts, Rose Cañada, Marta Cantoni, Valentina Caroppo, Paola Cash, David Castelo-Branco, Miguel Convery, Rhian Cope, Thomas Di Fede, Giuseppe Díez, Alina Duro, Diana Fenoglio, Chiara Ferrari, Camilla Ferreira, Catarina B. Fox, Nick Freedman, Morris Fumagalli, Giorgio Gabilondo, Alazne Gasparotti, Roberto Gauthier, Serge Gazzina, Stefano Giaccone, Giorgio Gorostidi, Ana Greaves, Caroline Guerreiro, Rita Hoegen, Tobias Indakoetxea, Begoña Jelic, Vesna Karnath, Hans-Otto Keren, Ron Langheinrich, Tobias Leitão, Maria João Lladó, Albert Lombardi, Gemma Loosli, Sandra Maruta, Carolina Mead, Simon |
author_role |
author |
author2 |
Bron, Esther E. Poos, Jackie M. Jiskoot, Lize C. Panman, Jessica L. Papma, Janne M. Meeter, Lieke H. Dopper, Elise G. P. Wilke, Carlo Synofzik, Matthis Heller, Carolin Miltenberger-Miltenyi, Gabriel van Minkelen, Rick Mitchell, Sara Moore, Katrina Nacmias, Benedetta Nicholas, Jennifer Öijerstedt, Linn Olives, Jaume Ourselin, Sebastien Padovani, Alessandro Swift, Imogen J. Peakman, Georgia Pievani, Michela Pijnenburg, Yolande Polito, Cristina Premi, Enrico Prioni, Sara Prix, Catharina Rademakers, Rosa Redaelli, Veronica Rittman, Tim Sogorb-Esteve, Aitana Rogaeva, Ekaterina Rosa-Neto, Pedro Rossi, Giacomina Rosser, Martin Santiago, Beatriz Scarpini, Elio Schönecker, Sonja Semler, Elisa Shafei, Rachelle Shoesmith, Christen Bouzigues, Arabella Tábuas-Pereira, Miguel Tainta, Mikel Taipa, Ricardo Tang-Wai, David Thomas, David L. Thompson, Paul Thonberg, Hakan Timberlake, Carolyn Tiraboschi, Pietro Todd, Emily Borroni, Barbara Van Damme, Philip Vandenbulcke, Mathieu Veldsman, Michele Verdelho, Ana Villanua, Jorge Warren, Jason Woollacott, Ione Wlasich, Elisabeth Zulaica, Miren Sanchez-Valle, Raquel Moreno, Fermin Graff, Caroline Laforce, Robert Galimberti, Daniela Masellis, Mario Tartaglia, Maria Carmela Finger, Elizabeth Vandenberghe, Rik Rowe, James B. De Mendonça, Alexandre Tagliavini, Fabrizio Santana, Isabel Ducharme, Simon Butler, Christopher R. Gerhard, Alexander Levin, Johannes Danek, Adrian Otto, Markus Pijnenburg, Yolande A. L. Sorbi, Sandro Zetterberg, Henrik Niessen, Wiro J. Rohrer, Jonathan D. Klein, Stefan van Swieten, John C. Venkatraghavan, Vikram Seelaar, Harro Afonso, Sónia Almeida, Maria Rosario Anderl-Straub, Sarah Andersson, Christin Antonell, Anna Archetti, Silvana Arighi, Andrea Balasa, Mircea Barandiaran, Myriam Bargalló, Nuria Bartha, Robart Bender, Benjamin Benussi, Alberto Benussi, Luisa Bessi, Valentina Binetti, Giuliano Black, Sandra Bocchetta, Martina Borrego-Ecija, Sergi Bras, Jose Bruffaerts, Rose Cañada, Marta Cantoni, Valentina Caroppo, Paola Cash, David Castelo-Branco, Miguel Convery, Rhian Cope, Thomas Di Fede, Giuseppe Díez, Alina Duro, Diana Fenoglio, Chiara Ferrari, Camilla Ferreira, Catarina B. Fox, Nick Freedman, Morris Fumagalli, Giorgio Gabilondo, Alazne Gasparotti, Roberto Gauthier, Serge Gazzina, Stefano Giaccone, Giorgio Gorostidi, Ana Greaves, Caroline Guerreiro, Rita Hoegen, Tobias Indakoetxea, Begoña Jelic, Vesna Karnath, Hans-Otto Keren, Ron Langheinrich, Tobias Leitão, Maria João Lladó, Albert Lombardi, Gemma Loosli, Sandra Maruta, Carolina Mead, Simon |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
dc.contributor.author.fl_str_mv |
van der Ende, Emma L. Bron, Esther E. Poos, Jackie M. Jiskoot, Lize C. Panman, Jessica L. Papma, Janne M. Meeter, Lieke H. Dopper, Elise G. P. Wilke, Carlo Synofzik, Matthis Heller, Carolin Miltenberger-Miltenyi, Gabriel van Minkelen, Rick Mitchell, Sara Moore, Katrina Nacmias, Benedetta Nicholas, Jennifer Öijerstedt, Linn Olives, Jaume Ourselin, Sebastien Padovani, Alessandro Swift, Imogen J. Peakman, Georgia Pievani, Michela Pijnenburg, Yolande Polito, Cristina Premi, Enrico Prioni, Sara Prix, Catharina Rademakers, Rosa Redaelli, Veronica Rittman, Tim Sogorb-Esteve, Aitana Rogaeva, Ekaterina Rosa-Neto, Pedro Rossi, Giacomina Rosser, Martin Santiago, Beatriz Scarpini, Elio Schönecker, Sonja Semler, Elisa Shafei, Rachelle Shoesmith, Christen Bouzigues, Arabella Tábuas-Pereira, Miguel Tainta, Mikel Taipa, Ricardo Tang-Wai, David Thomas, David L. Thompson, Paul Thonberg, Hakan Timberlake, Carolyn Tiraboschi, Pietro Todd, Emily Borroni, Barbara Van Damme, Philip Vandenbulcke, Mathieu Veldsman, Michele Verdelho, Ana Villanua, Jorge Warren, Jason Woollacott, Ione Wlasich, Elisabeth Zulaica, Miren Sanchez-Valle, Raquel Moreno, Fermin Graff, Caroline Laforce, Robert Galimberti, Daniela Masellis, Mario Tartaglia, Maria Carmela Finger, Elizabeth Vandenberghe, Rik Rowe, James B. De Mendonça, Alexandre Tagliavini, Fabrizio Santana, Isabel Ducharme, Simon Butler, Christopher R. Gerhard, Alexander Levin, Johannes Danek, Adrian Otto, Markus Pijnenburg, Yolande A. L. Sorbi, Sandro Zetterberg, Henrik Niessen, Wiro J. Rohrer, Jonathan D. Klein, Stefan van Swieten, John C. Venkatraghavan, Vikram Seelaar, Harro Afonso, Sónia Almeida, Maria Rosario Anderl-Straub, Sarah Andersson, Christin Antonell, Anna Archetti, Silvana Arighi, Andrea Balasa, Mircea Barandiaran, Myriam Bargalló, Nuria Bartha, Robart Bender, Benjamin Benussi, Alberto Benussi, Luisa Bessi, Valentina Binetti, Giuliano Black, Sandra Bocchetta, Martina Borrego-Ecija, Sergi Bras, Jose Bruffaerts, Rose Cañada, Marta Cantoni, Valentina Caroppo, Paola Cash, David Castelo-Branco, Miguel Convery, Rhian Cope, Thomas Di Fede, Giuseppe Díez, Alina Duro, Diana Fenoglio, Chiara Ferrari, Camilla Ferreira, Catarina B. Fox, Nick Freedman, Morris Fumagalli, Giorgio Gabilondo, Alazne Gasparotti, Roberto Gauthier, Serge Gazzina, Stefano Giaccone, Giorgio Gorostidi, Ana Greaves, Caroline Guerreiro, Rita Hoegen, Tobias Indakoetxea, Begoña Jelic, Vesna Karnath, Hans-Otto Keren, Ron Langheinrich, Tobias Leitão, Maria João Lladó, Albert Lombardi, Gemma Loosli, Sandra Maruta, Carolina Mead, Simon |
dc.subject.por.fl_str_mv |
Biomarker Disease progression model Event-based modelling Frontotemporal dementia Neurofilament light chain |
topic |
Biomarker Disease progression model Event-based modelling Frontotemporal dementia Neurofilament light chain |
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.com |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-06-07T15:15:16Z 2022 2022-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10451/53319 |
url |
http://hdl.handle.net/10451/53319 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Brain. 2022 Jun 3;145(5):1805-1817 0006-8950 10.1093/brain/awab382 1460-2156 |
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info:eu-repo/semantics/openAccess |
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openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Oxford University Press |
publisher.none.fl_str_mv |
Oxford University Press |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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