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Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels in Down Syndrome and Sporadic Alzheimer´S Disease: A Cross-Sectional Study

2022; RELX Group (Netherlands); Linguagem: Inglês

10.2139/ssrn.4077901

1556-5068

Laia Montoliu‐Gaya, Daniel Alcolea, Nicholas J. Ashton, Jordi Pegueroles, Johannes Levin, María Carmona Iragui, Juan Lantero Rodrı́guez, Thomas K. Karikari, Isabel Barroeta, Przemysław R. Kac, Laura Videla, Fernándo González‐Ortiz, Bessy Benejam, Georg Nübling, Andréa Lessa Benedet, Rafael Blesa, Alberto Lleó, Kaj Blennow, Henrik Zetterberg, Juan Fortea,

Dementia and Cognitive Impairment Research

Background: A blood biomarker for clinical diagnosis of Alzheimer’s disease is of particular importance in Down syndrome, where a change in cognitive function is often difficult to delineate. The astrocytic Glial Fibrillary Acidic Protein (GFAP) is a marker of astrogliosis associated with amyloid pathology but its diagnostic performance in individuals with Down syndrome has not been established.Methods: We performed a dual centre cross-sectional study of adults with Down syndrome and euploid individuals enrolled in Barcelona (Spain) and Munich (Germany). Cerebrospinal fluid (CSF) and plasma concentrations of GFAP, neurofilament light (NfL), and phosphorylated-tau181 were quantified using Simoa. A subset of participants had PET18 F-fluorodeoxyglucose, amyloid tracers and MRI measurements. We used ANOVA to evaluate differences in the biomarker levels; AUC-ROC analysis to determine diagnostic performances; Spearman correlations to establish associations; linear mixed models to estimate changes with age; and Cox regression to study prognostic value.Findings: Between July 2009 and September 2021, we collected plasma from 502 with Down syndrome and 289 euploid individuals. Participants with Down syndrome were clinically classified as asymptomatic (330[65.7%]), prodromal Alzheimer´s disease (61[12.2%]) and Alzheimer´s disease dementia (111[22.1%]). Euploid individuals were grouped as cognitively unimpaired (196[67.8%]), prodromal Alzheimer´s disease (44[15.2%]) and Alzheimer´s disease dementia (49[17%]). Plasma GFAP levels were significantly increased in prodromal and Alzheimer´s disease dementia compared to asymptomatic individuals and showed higher AUC than CSF GFAP to discriminate symptomatic from asymptomatic (AUC=0.93 vs 0.85; 95% CI 0.91-0.96 and 0.80-0.91), superior to plasma NfL and p-tau181. Plasma GFAP levels were significantly different in progressors vs non-progressors to Alzheimer´s disease dementia (p<0.001), and were highly correlated with brain amyloidosis, hypometabolism and cortical thinning.Interpretation: Plasma GFAP is an accurate tool for prognosis, diagnosis, and reflecting Alzheimer´s disease pathology in Down syndrome. Our findings support the utility of plasma GFAP for medical application and clinical trials.Funding Information: This study was supported by the Fondo de Investigaciones Sanitario (FIS), Instituto de Salud Carlos III (PI14/01126, PI17/01019 and PI20/01473 to JF, PI18/00335 to MCI, PI18/00435 and INT19/00016 to DA, PI20/01330 and AC19/00103 to AL) and the CIBERNED programme (program 1, Alzheimer Disease to AL and SIGNAL study), partly jointly funded by Fondo Europeo de Desarrollo Regional, EU, Una manera de hacer Europa and the NANOSYN project funded through COEN Pathfinder IV) to AL. This work was also supported by the National Institutes of Health (NIA grants 1R01AG056850-01A1; R21AG056974; AG056850, 3RF1AG056850-01S1, NOT-OD-20-129 and R01AG061566 to JF), Departament de Salut de la Generalitat de Catalunya, Pla Estratègic de Recerca i Innovacio en Salut (SLT002/16/00408 to AL, SLT006/17/00119 to JF, and SLT006/17/00125 to DA), Fundació La Marató de TV3 (20141210 to JF and 044412 to RB). Fundación Tatiana Pérez de Guzmán el Bueno (grant IIBSP-DOW-2020-151) and Fundació Catalana Síndrome de Down partly supported this work. Horizon 21 Consortium is partly funded by Jérôme Lejeune Foundation (Clinical and trial outcome measures for dementia in individuals with Down syndrome). 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-930351, #AF-939721 and #AF-968270), Hjärnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986 and #ALFGBG965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG068398-01), and the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019- 0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003). TKK was funded by the Swedish Research Council (Vetenskåpradet; #2021-03244), the Alzheimer’s Association (#AARF-21-850325), the BrightFocus Foundation (#A2020812F), the International Society for Neurochemistry’s Career Development Grant, the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-930627), the Swedish Brain Foundation (Hjärnfonden; #FO2020- 0240), the Swedish Dementia Foundation (Demensförbundet), the Swedish Parkinson Foundation (Parkinsonfonden), Gamla Tjänarinnor Foundation, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Agneta Prytz-Folkes & Gösta Folkes Foundation (#2020-00124), the Gun and Bertil Stohnes Foundation, and the Anna Lisa and Brother Björnsson’s Foundation. JL was funded by the Verum foundation and 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).” Non-financial support was also provided through the European Reference Network for Rare Neurological Diseases (ERN-RND), one of 24 ERNs funded by the European Commission (ERNRND: 3HP 767231). Declaration of Interests: JF has served as a consultant for Novartis and Lundbeck, has received honoraria for lectures from Roche, NovoNordisk, Nestle, Esteve and Biogen and served at advisory boards for AC Immune, Zambon and Lundbeck. DA participated in advisory boards from Fujirebio-Europe and Roche 17 Diagnostics and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U. and Esteve Pharmaceuticals S.A. JF, DA and ALL declare a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. AL has served at scientific advisory boards from FujirebioEurope, Nutricia, Roche-Genentech, Biogen, Grifols and Roche Diagnostics and has filed a patent application of synaptic markers in neurodegenerative diseases (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). Ethics Approval Statement: The study was approved by the Sant Pau Ethics Committee and the ethics committee of Ludwig-Maximilians-University Munich, following the standards for medical research in humans recommended by the Declaration of Helsinki. All participants or their legally authorized representative gave written informed consent before enrolment.