Abstract
Original language | English |
---|---|
Pages (from-to) | 1009-1022.e4 |
Journal | Neuron |
Volume | 110 |
Issue number | 6 |
DOIs | |
Publication status | Published - 16 Mar 2022 |
Keywords
- Alzheimer's disease
- TAM receptor
- biomarker
- neuroinflammation
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In: Neuron, Vol. 110, No. 6, 16.03.2022, p. 1009-1022.e4.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Soluble TAM receptors sAXL and sTyro3 predict structural and functional protection in Alzheimer's disease
AU - the DELCODE study group
AU - Brosseron, Frederic
AU - Maass, Anne
AU - Kleineidam, Luca
AU - Ravichandran, Kishore Aravind
AU - González, Pablo García
AU - McManus, R. isín M.
AU - Ising, Christina
AU - Santarelli, Francesco
AU - Kolbe, Carl-Christian
AU - Häsler, Lisa M.
AU - Wolfsgruber, Steffen
AU - Marquié, Marta
AU - Boada, Mercè
AU - Orellana, Adelina
AU - de Rojas, Itziar
AU - Röske, Sandra
AU - Peters, Oliver
AU - Cosma, Nicoleta-Carmen
AU - Cetindag, Arda
AU - Wang, Xiao
AU - Priller, Josef
AU - Spruth, Eike J.
AU - Altenstein, Slawek
AU - Schneider, Anja
AU - Fliessbach, Klaus
AU - Wiltfang, Jens
AU - Schott, Björn H.
AU - Bürger, Katharina
AU - Janowitz, Daniel
AU - Dichgans, Martin
AU - Perneczky, Robert
AU - Rauchmann, Boris-Stephan
AU - Teipel, Stefan
AU - Kilimann, Ingo
AU - Goerss, Doreen
AU - Laske, Christoph
AU - Munk, Matthias H.
AU - Düzel, Emrah
AU - Yakupov, Renat
AU - Dobisch, Laura
AU - Metzger, Coraline D.
AU - Glanz, Wenzel
AU - Ewers, Michael
AU - Dechent, Peter
AU - Haynes, John Dylan
AU - Scheffler, Klaus
AU - Roy, Nina
AU - Rostamzadeh, Ayda
AU - Teunissen, Charlotte E.
AU - Marchant, Natalie L.
N1 - Funding Information: A. Ramirez is supported by the PREADAPT project within the JPND PERSOMED ( German Federal Ministry of Education and Research [BMBF] grant number: 01ED1619A ). N.L.M. received support for this study from the project funded by the Medical Research Council within the JPND PERSOMED ( PREADAPT project grant number MR/T046171/1 ). Funding Information: This work was also supported by the JPND grant “ GENFI-prox ” (by DLR/BMBF to M.S.). B.H.S. holds two grants from the European Union and the State of Saxony-Anhalt (Research Alliance “Autonomy in Old Age”). Funding Information: This work was funded by the German Center for Neurodegenerative Diseases (DZNE e.V.) within the Helmholtz Association. F.B. C.-C.K. E.L. and M.T.H. are members of the Cluster of Excellence “Immunosensation.” Furthermore, this work was supported in the frame of the PREADAPT project (01ED2007B) within the EU Joint Programs for Neurodegenerative Diseases Research (JPND) PERSOMED. A. Ramirez is supported by the PREADAPT project within the JPND PERSOMED (German Federal Ministry of Education and Research [BMBF] grant number: 01ED1619A). N.L.M. received support for this study from the project funded by the Medical Research Council within the JPND PERSOMED (PREADAPT project grant number MR/T046171/1). I.d.R. is supported by a national grant from the Instituto de Salud Carlos III (ISCIII) FI20/00215. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria ‘La Caixa,’ Fundació ACE, and CIBERNED. A. Ruiz and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A. Ruiz are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240, and PI19/01301. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII–Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER–‘Una manera de hacer Europa’). A. Ruiz is also funded by JPco-fuND-2 “Multinational research projects on Personalised Medicine for Neurodegenerative Diseases,” PREADAPT project (ISCIII grant: AC19/00097), and EURONANOMED III Joint Transnational call for proposals (2017) for European Innovative Research & Technological Development Projects in Nanomedicine (ISCIII grant: AC17/00100). This work was also supported by the JPND grant “GENFI-prox” (by DLR/BMBF to M.S.). B.H.S. holds two grants from the European Union and the State of Saxony-Anhalt (Research Alliance “Autonomy in Old Age”). Conceptualization, generation, analysis, and interpretation of experiments and data for this manuscript were done by F.B. A.M. L.K. K.A.R. C.-C.K. R.M. C.I. L.M.H. F.S. E.L. M.J. C.E.T. N.L.M. A. Ramirez, A. Ruiz, and M.T.H. Braak ROI scores were generated from Freesurfer scores and analyzed by A.M. Data from neuropsychologic and neurocognitive assessments for PACC5 scoring were generated and analyzed by L.K. Overall design, implementation, and collection of data for the DELCODE study at the different study sites was provided by F.J. A. Rostamzadeh, A. Spottke, K.B. D.J. M.D. M.T.H. C.L. M.H.M. O.P. N.-C.C. A.C. X.W. J.P. E.J.S. S.A. A. Schneider, K.F. R.P. B.-S.R. S.T. I.K. D.G. J.W. B.H.S. M.W. J.D.H. P.D. M.E. K.S. E.D. S.R. L.D. R.Y. C.D.M. and W.G. Plasma Nf-L data for DELCODE were provided by D.M. and M.S. Furthermore, F.J. A. Spottke, N.R. F.B. M.T.H. O.P. A. Rostamzadeh, S.W. M.W. and E.D. were responsible for DELCODE methodological core central data management and data analyses. Data of F.ACE were provided by P.G.G. M.M. M.B. A.O. I.d.R. and A. Ruiz, within the framework of the EU-JPND project PREADAPT, coordinated by A. Ramirez, F.B. A.M. and L.K. contributed equally to data analysis strategy, conduction of statistics, and drafting of the manuscript. All authors read and approved the final version of this manuscript. The authors declare no competing interests. Funding Information: This work was funded by the German Center for Neurodegenerative Diseases (DZNE e.V.) within the Helmholtz Association. F.B., C.-C.K., E.L., and M.T.H. are members of the Cluster of Excellence “Immunosensation.” Furthermore, this work was supported in the frame of the PREADAPT project ( 01ED2007B ) within the EU Joint Programs for Neurodegenerative Diseases Research (JPND) PERSOMED. Funding Information: I.d.R. is supported by a national grant from the Instituto de Salud Carlos III (ISCIII) FI20/00215 . The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA , Fundación bancaria ‘La Caixa,’ Fundació ACE , and CIBERNED . A. Ruiz and M.B. receive support from the European Union / EFPIA Innovative Medicines Initiative joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985 , respectively). M.B. and A. Ruiz are also supported by national grants PI13/02434 , PI16/01861 , PI17/01474 , PI19/01240 , and PI19/01301 . Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII –Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER–‘Una manera de hacer Europa’). A. Ruiz is also funded by JPco-fuND-2 “Multinational research projects on Personalised Medicine for Neurodegenerative Diseases,” PREADAPT project ( ISCIII grant: AC19/00097 ), and EURONANOMED III Joint Transnational call for proposals (2017) for European Innovative Research & Technological Development Projects in Nanomedicine ( ISCIII grant: AC17/00100 ). Publisher Copyright: © 2021 Elsevier Inc.
PY - 2022/3/16
Y1 - 2022/3/16
N2 - There is an urgent need to improve the understanding of neuroinflammation in Alzheimer's disease (AD). We analyzed cerebrospinal fluid inflammatory biomarker correlations to brain structural volume and longitudinal cognitive outcomes in the DELCODE study and in a validation cohort of the F.ACE Alzheimer Center Barcelona. We investigated whether respective biomarker changes are evident before onset of cognitive impairment. YKL-40; sTREM2; sAXL; sTyro3; MIF; complement factors C1q, C4, and H; ferritin; and ApoE protein were elevated in pre-dementia subjects with pathological levels of tau or other neurodegeneration markers, demonstrating tight interactions between inflammation and accumulating neurodegeneration even before onset of symptoms. Intriguingly, higher levels of ApoE and soluble TAM receptors sAXL and sTyro3 were related to larger brain structure and stable cognitive outcome at follow-up. Our findings indicate a protective mechanism relevant for intervention strategies aiming to regulate neuroinflammation in subjects with no or subjective symptoms but underlying AD pathology profile.
AB - There is an urgent need to improve the understanding of neuroinflammation in Alzheimer's disease (AD). We analyzed cerebrospinal fluid inflammatory biomarker correlations to brain structural volume and longitudinal cognitive outcomes in the DELCODE study and in a validation cohort of the F.ACE Alzheimer Center Barcelona. We investigated whether respective biomarker changes are evident before onset of cognitive impairment. YKL-40; sTREM2; sAXL; sTyro3; MIF; complement factors C1q, C4, and H; ferritin; and ApoE protein were elevated in pre-dementia subjects with pathological levels of tau or other neurodegeneration markers, demonstrating tight interactions between inflammation and accumulating neurodegeneration even before onset of symptoms. Intriguingly, higher levels of ApoE and soluble TAM receptors sAXL and sTyro3 were related to larger brain structure and stable cognitive outcome at follow-up. Our findings indicate a protective mechanism relevant for intervention strategies aiming to regulate neuroinflammation in subjects with no or subjective symptoms but underlying AD pathology profile.
KW - Alzheimer's disease
KW - TAM receptor
KW - biomarker
KW - neuroinflammation
UR - http://www.scopus.com/inward/record.url?scp=85126306517&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.neuron.2021.12.016
DO - https://doi.org/10.1016/j.neuron.2021.12.016
M3 - Article
C2 - 34995486
SN - 0896-6273
VL - 110
SP - 1009-1022.e4
JO - Neuron
JF - Neuron
IS - 6
ER -