Biomarkers; Amyloid beta-Peptides; tau Proteins; Humans; Male; Female; Aged; Middle Aged; Longitudinal Studies; Gray Matter/pathology; Cohort Studies; Biomarkers/cerebrospinal fluid; Alzheimer Disease/cerebrospinal fluid; Alzheimer Disease/pathology; Brain/pathology; Amyloid beta-Peptides/cerebrospinal fluid; Cognition/physiology; Inflammation/cerebrospinal fluid; Magnetic Resonance Imaging/methods; Cognitive Dysfunction/cerebrospinal fluid; White Matter/pathology; tau Proteins/cerebrospinal fluid; Alzheimer Disease; Brain; Cognition; Cognitive Dysfunction; Gray Matter; Inflammation; Magnetic Resonance Imaging; White Matter; Molecular Biology; Psychiatry and Mental Health; Cellular and Molecular Neuroscience
Abstract :
[en] Neuroinflammation is a hallmark of Alzheimer's disease (AD) and both positive and negative associations of individual inflammation-related markers with brain structure and cognitive function have been described. We aimed to identify inflammatory signatures of CSF immune-related markers that relate to changes of brain structure and cognition across the clinical spectrum ranging from normal aging to AD. A panel of 16 inflammatory markers, Aβ42/40 and p-tau181 were measured in CSF at baseline in the DZNE DELCODE cohort (n = 295); a longitudinal observational study focusing on at-risk stages of AD. Volumetric maps of gray and white matter (GM/WM; n = 261) and white matter hyperintensities (WMHs, n = 249) were derived from baseline MRIs. Cognitive decline (n = 204) and the rate of change in GM volume was measured in subjects with at least 3 visits (n = 175). A principal component analysis on the CSF markers revealed four inflammatory components (PCs). Of these, the first component PC1 (highly loading on sTyro3, sAXL, sTREM2, YKL-40, and C1q) was associated with older age and higher p-tau levels, but with less pathological Aβ when controlling for p-tau. PC2 (highly loading on CRP, IL-18, complement factor F/H and C4) was related to male gender, higher body mass index and greater vascular risk. PC1 levels, adjusted for AD markers, were related to higher GM and WM volumes, less WMHs, better baseline memory, and to slower atrophy rates in AD-related areas and less cognitive decline. In contrast, PC2 related to less GM and WM volumes and worse memory at baseline. Similar inflammatory signatures and associations were identified in the independent F.ACE cohort. Our data suggest that there are beneficial and detrimental signatures of inflammatory CSF biomarkers. While higher levels of TAM receptors (sTyro/sAXL) or sTREM2 might reflect a protective glia response to degeneration related to phagocytic clearance, other markers might rather reflect proinflammatory states that have detrimental impact on brain integrity.
Disciplines :
Neurology
Author, co-author :
Hayek, Dayana; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, Magdeburg, 39120, Germany ; Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany
Ziegler, Gabriel; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, Magdeburg, 39120, Germany ; Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany
Kleineidam, Luca; Department of Neurodegenerative Disease and Geriatric Psychiatry/Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
Brosseron, Frederic; German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry/Neurology, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany
Nemali, Aditya; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, Magdeburg, 39120, Germany ; Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany
Vockert, Niklas ; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, Magdeburg, 39120, Germany
Ravichandran, Kishore A; German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry/Neurology, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany
Betts, Matthew J; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, Magdeburg, 39120, Germany ; Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany
Peters, Oliver; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institute of Psychiatry and Neuroscience, Hindenburgdamm 30, 12203, Berlin, Germany ; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
Schneider, Luisa-Sophie ; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institute of Psychiatry and Neuroscience, Hindenburgdamm 30, 12203, Berlin, Germany
Wang, Xiao; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institute of Psychiatry and Neuroscience, Hindenburgdamm 30, 12203, Berlin, Germany
Priller, Josef; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, 10117, Berlin, Germany ; School of Medicine, Technical University of Munich, Department of Psychiatry and Psychotherapy, Munich, Germany ; University of Edinburgh and UK DRI, Edinburgh, UK
Altenstein, Slawek; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, 10117, Berlin, Germany
Schneider, Anja; Department of Neurodegenerative Disease and Geriatric Psychiatry/Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
Fliessbach, Klaus; Department of Neurodegenerative Disease and Geriatric Psychiatry/Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
Wiltfang, Jens ; German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, Göttingen, 37075, Germany ; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, University of Göttingen, Von-Siebold-Str. 5, 37075, Göttingen, Germany ; Neurosciences and Signaling Group, Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Aveiro, Portugal
Bartels, Claudia; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, University of Göttingen, Von-Siebold-Str. 5, 37075, Göttingen, Germany
Rostamzadeh, Ayda; Department of Psychiatry, University of Cologne, Medical Faculty, Kerpener Strasse 62, 50924, Cologne, Germany
Glanz, Wenzel; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, Magdeburg, 39120, Germany
Buerger, Katharina; German Center for Neurodegenerative Diseases (DZNE, Munich), Feodor-Lynen-Strasse 17, 81377, Munich, Germany ; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Feodor-Lynen-Strasse 17, 81377, Munich, Germany
Janowitz, Daniel; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Feodor-Lynen-Strasse 17, 81377, Munich, Germany
Perneczky, Robert ; German Center for Neurodegenerative Diseases (DZNE, Munich), Feodor-Lynen-Strasse 17, 81377, Munich, Germany ; Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy) Munich, Munich, Germany ; Ageing Epidemiology Research Unit (AGE), School of Public Health, Imperial College London, London, UK
Rauchmann, Boris-Stephan; Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany ; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK ; Department of Neuroradiology, University Hospital LMU, Munich, Germany
Teipel, Stefan; German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany ; Department of Psychosomatic Medicine, Rostock University Medical Center, Gehlsheimer Str. 20, 18147, Rostock, Germany
Kilimann, Ingo; German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany ; Department of Psychosomatic Medicine, Rostock University Medical Center, Gehlsheimer Str. 20, 18147, Rostock, Germany
Laske, Christoph; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany ; Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
Mengel, David; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany ; Division Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany
Synofzik, Matthis ; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany ; Division Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany
Munk, Matthias H; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany ; Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
Spottke, Annika; German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Neurology, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
Roy, Nina; German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
Roeske, Sandra; German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
Kuhn, Elizabeth ; Department of Neurodegenerative Disease and Geriatric Psychiatry/Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
Ramirez, Alfredo ; Department of Neurodegenerative Disease and Geriatric Psychiatry/Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany ; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931, Köln, Germany ; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany ; Department of Psychiatry & Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, TX, USA
Dobisch, Laura; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, Magdeburg, 39120, Germany
Schmid, Matthias; German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany ; Institute for Medical Biometry, University Hospital Bonn, Venusberg-Campus 1, D-53127, Bonn, Germany
Berger, Moritz; Institute for Medical Biometry, University Hospital Bonn, Venusberg-Campus 1, D-53127, Bonn, Germany
Wolfsgruber, Steffen; German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
Yakupov, Renat ; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, Magdeburg, 39120, Germany ; Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany
Hetzer, Stefan; Berlin Center for Advanced Neuroimaging, Charité - Universitätsmedizin Berlin, Berlin, Germany
Dechent, Peter; MR-Research in Neurosciences, Department of Cognitive Neurology, Georg-August-University Goettingen, Goettingen, Germany
Ewers, Michael ; German Center for Neurodegenerative Diseases (DZNE, Munich), Feodor-Lynen-Strasse 17, 81377, Munich, Germany
Scheffler, Klaus; Department for Biomedical Magnetic Resonance, University of Tübingen, 72076, Tübingen, Germany
Schott, Björn H; German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, Göttingen, 37075, Germany ; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, University of Göttingen, Von-Siebold-Str. 5, 37075, Göttingen, Germany ; Leibniz Institute for Neurobiology, Brenneckestr. 6, 39118, Magdeburg, Germany ; Center for Behavioral Brain Sciences, Magdeburg, Germany
Schreiber, Stefanie; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, Magdeburg, 39120, Germany ; Center for Behavioral Brain Sciences, Magdeburg, Germany ; Department of Neurology, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, 39120, Magdeburg, Germany
Orellana, Adelina; Research Center and Memory Clinic. Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain ; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
de Rojas, Itziar ; Research Center and Memory Clinic. Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain ; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
Marquié, Marta ; Research Center and Memory Clinic. Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain ; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
Boada, Mercè ; Research Center and Memory Clinic. Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain ; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
Sotolongo, Oscar ; Research Center and Memory Clinic. Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain ; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
González, Pablo García ; Research Center and Memory Clinic. Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain
Puerta, Raquel ; Research Center and Memory Clinic. Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain
Düzel, Emrah; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, Magdeburg, 39120, Germany ; Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany ; Center for Behavioral Brain Sciences, Magdeburg, Germany
Jessen, Frank; German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Psychiatry, University of Cologne, Medical Faculty, Kerpener Strasse 62, 50924, Cologne, Germany ; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931, Köln, Germany
Wagner, Michael; Department of Neurodegenerative Disease and Geriatric Psychiatry/Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
Ruiz, Augustín; Research Center and Memory Clinic. Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain ; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
HENEKA, Michael ; University of Luxembourg ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry/Neurology, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, 55 Lake Avenue, North Worcester, MA, 01655, USA
Maass, Anne ; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, Magdeburg, 39120, Germany. anne.maass@dzne.de ; Center for Behavioral Brain Sciences, Magdeburg, Germany. anne.maass@dzne.de
Deutsche Forschungsgemeinschaft Deutsche Forschungsgemeinschaft Deutsche Forschungsgemeinschaft
Funding text :
The Genome Research @ Fundaci\u00F3 ACE project (GR@ACE) is supported by Fundaci\u00F3n bancaria \u201CLa Caixa,\u201D Grifols SA, Fundaci\u00F3 ACE, and ISCIII (Ministry of Health, Spain). We want to thank the private sponsors who support the basic and clinical projects of our institution (Piramal AG, Laboratorios Echevarne, Araclon Biotech S.A., and Fundaci\u00F3 ACE) and the patients who participated in this study. We are indebted to the Trinitat Port-Carb\u00F3 legacy and her family for their support of Fundaci\u00F3 ACE research programs. MB, AR, and MM are supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240, PI19/01301, PI19/00335 and PI22/011403 and CIBERNED grant 2019/08. PG-G is supported by CIBERNED employment plan CNV-304-PRF-866. AR is supported by ISCIII national grant PMP22/00022, funded by the European Union (NextGenerationEU). Acci\u00F3n Estrat\u00E9gica en Salud is integrated into the Spanish National R\u2009+\u2009D\u2009+\u2009I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdirecci\u00F3n General de Evaluaci\u00F3n and the Fondo Europeo de Desarrollo Regional (FEDER- \u201CUna manera de Hacer Europa\u201D). AR is also funded by JPco-fuND-2 \u201CMultinational research projects on Personalised Medicine for Neurodegenerative Diseases,\u201D 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). AR, MTH and MW are also funded by JPco-fuND-2 \u201CMultinational research projects on Personalised Medicine for Neurodegenerative Diseases,\u201D PREADAPT project (BMBF grants 01ED2007A, 01ED2007B). DH, ED, MJB, AM, BS, and SS are funded by German Research Foundation (DFG, Project-ID 425899996 SFB 1436). MJB is also supported by the German Federal Ministry of Education and Research (BMBF, funding code 01ED2102B) under the aegis of the EU Joint Programme\u2014Neurodegenerative Disease Research (JPND).The Genome Research @ Fundaci\u00F3 ACE project (GR@ACE) is supported by Fundaci\u00F3n bancaria \u201CLa Caixa,\u201D Grifols SA, Fundaci\u00F3 ACE, and ISCIII (Ministry of Health, Spain). We want to thank the private sponsors who support the basic and clinical projects of our institution (Piramal AG, Laboratorios Echevarne, Araclon Biotech S.A., and Fundaci\u00F3 ACE) and the patients who participated in this study. We are indebted to the Trinitat Port-Carb\u00F3 legacy and her family for their support of Fundaci\u00F3 ACE research programs. MB, AR, and MM are supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240, PI19/01301, PI19/00335 and PI22/011403 and CIBERNED grant 2019/08. PG-G is supported by CIBERNED employment plan CNV-304-PRF-866. AR is supported by ISCIII national grant PMP22/00022, funded by the European Union (NextGenerationEU). Acci\u00F3n Estrat\u00E9gica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdirecci\u00F3n General de Evaluaci\u00F3n and the Fondo Europeo de Desarrollo Regional (FEDER- \u201CUna manera de Hacer Europa\u201D). AR is also funded by JPco-fuND-2 \u201CMultinational research projects on Personalised Medicine for Neurodegenerative Diseases,\u201D 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). AR, MTH and MW are also funded by JPco-fuND-2 \u201CMultinational research projects on Personalised Medicine for Neurodegenerative Diseases,\u201D PREADAPT project (BMBF grants 01ED2007A, 01ED2007B). DH, ED, MJB, AM, BS, and SS are funded by German Research Foundation (DFG, Project-ID 425899996 SFB 1436). MJB is also supported by the German Federal Ministry of Education and Research (BMBF, funding code 01ED2102B) under the aegis of the EU Joint Programme\u2014Neurodegenerative Disease Research (JPND).
M.T. Heneka M.J. Carson J.E. Khoury G.E. Landreth F. Brosseron D.L. Feinstein et al. Neuroinflammation in Alzheimer’s disease Lancet Neurol 2015 14 388 405 1:CAS:528:DC%2BC2MXkvVSksrw%3D 25792098 5909703 10.1016/S1474-4422(15)70016-5
Q. Li B.A. Barres Microglia and macrophages in brain homeostasis and disease Nat Rev Immunol 2018 18 225 42 1:CAS:528:DC%2BC2sXhvVaksrvN 29151590 10.1038/nri.2017.125
B.M. Bettcher M.G. Tansey G. Dorothée M.T. Heneka Peripheral and central immune system crosstalk in Alzheimer disease - a research prospectus Nat Rev Neurol 2021 17 689 701 34522039 8439173 10.1038/s41582-021-00549-x
B. De Strooper E. Karran The cellular phase of Alzheimer’s disease Cell 2016 164 603 15 26871627 10.1016/j.cell.2015.12.056
G. Krabbe A. Halle V. Matyash J.L. Rinnenthal G.D. Eom U. Bernhardt et al. Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology PLoS One 2013 8 e60921 1:CAS:528:DC%2BC3sXmtlSmtr8%3D 23577177 3620049 10.1371/journal.pone.0060921
J.D. Gispert M. Suárez-Calvet G.C. Monté A. Tucholka C. Falcon S. Rojas et al. Cerebrospinal fluid sTREM2 levels are associated with gray matter volume increases and reduced diffusivity in early Alzheimer’s disease Alzheimers Dement 2016 12 1259 72 27423963 10.1016/j.jalz.2016.06.005
M. Ewers N. Franzmeier M. Suárez-Calvet E. Morenas-Rodriguez M.A.A. Caballero G. Kleinberger et al. Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease Sci Transl Med 2019 11 eaav6221 31462511 7050285 10.1126/scitranslmed.aav6221
F. Brosseron A. Maass L. Kleineidam K.A. Ravichandran P.G. González R.M. McManus et al. Soluble TAM receptors sAXL and sTyro3 predict structural and functional protection in Alzheimer’s disease Neuron 2022 110 1009.e4 1:CAS:528:DC%2BB38XltlWmtA%3D%3D 34995486 10.1016/j.neuron.2021.12.016
J.D. Gispert G.C. Monté C. Falcon A. Tucholka S. Rojas R. Sánchez-Valle et al. CSF YKL-40 and pTau181 are related to different cerebral morphometric patterns in early AD Neurobiol Aging 2016 38 47 55 1:CAS:528:DC%2BC2MXhvVCqs73F 26827642 10.1016/j.neurobiolaging.2015.10.022
F. Brosseron A. Traschütz C.N. Widmann M.P. Kummer P. Tacik F. Santarelli et al. Characterization and clinical use of inflammatory cerebrospinal fluid protein markers in Alzheimer’s disease Alzheimers Res Ther 2018 10 25 29482610 5828084 10.1186/s13195-018-0353-3
N.D. Prins P. Scheltens White matter hyperintensities, cognitive impairment and dementia: an update Nat Rev Neurol 2015 11 157 65 25686760 10.1038/nrneurol.2015.10
J. Alber S. Alladi H.-J. Bae D.A. Barton L.A. Beckett J.M. Bell et al. White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities Alzheimers Dement 2019 5 107 17 10.1016/j.trci.2019.02.001
C.L. Satizabal Y.C. Zhu B. Mazoyer C. Dufouil C. Tzourio Circulating IL-6 and CRP are associated with MRI findings in the elderly: the 3C-Dijon Study Neurology 2012 78 720 7 1:CAS:528:DC%2BC38Xjt1Gnsrc%3D 22357713 10.1212/WNL.0b013e318248e50f
S. Hilal M.A. Ikram M.M. Verbeek O.H. Franco E. Stoops H. Vanderstichele et al. C-reactive protein, plasma amyloid-β levels, and their interaction with magnetic resonance imaging markers Stroke 2018 49 2692 8 1:CAS:528:DC%2BC1cXhvF2mtb3N 30355213 10.1161/STROKEAHA.118.022317
Y. Gu R. Vorburger N. Scarmeas J.A. Luchsinger J.J. Manly N. Schupf et al. Circulating inflammatory biomarkers in relation to brain structural measurements in a non-demented elderly population Brain Behav Immun 2017 65 150 60 1:CAS:528:DC%2BC2sXnt1Cru7g%3D 28457809 5537030 10.1016/j.bbi.2017.04.022
A.L. Marsland P.J. Gianaros D.C.-H. Kuan L.K. Sheu K. Krajina S.B. Manuck Brain morphology links systemic inflammation to cognitive function in midlife adults Brain Behav Immun 2015 48 195 204 1:CAS:528:DC%2BC2MXms1Wkurc%3D 25882911 4508197 10.1016/j.bbi.2015.03.015
B.S. Aribisala S. Wiseman Z. Morris M.C. Valdés-Hernández N.A. Royle S.M. Maniega et al. Circulating inflammatory markers are associated with magnetic resonance imaging-visible perivascular spaces but not directly with white matter hyperintensities Stroke 2014 45 605 7 1:CAS:528:DC%2BC2cXitFynu78%3D 24399375 3906539 10.1161/STROKEAHA.113.004059
G. Salvadó M. Shekari C. Falcon G. Operto M. Milà-Alomà G. Sánchez-Benavides et al. Brain alterations in the early Alzheimer’s continuum with amyloid-β, tau, glial and neurodegeneration CSF markers Brain Commun 2022 4 fcac134 35702732 9185381 10.1093/braincomms/fcac134
F. Jessen A. Spottke H. Boecker F. Brosseron K. Buerger C. Catak et al. Design and first baseline data of the DZNE multicenter observational study on predementia Alzheimer’s disease (DELCODE) Alzheimers Res Ther 2018 10 15 29415768 5802096 10.1186/s13195-017-0314-2
M. Boada L. Tárraga I. Hernández S. Valero M. Alegret A. Ruiz et al. Design of a comprehensive Alzheimer’s disease clinic and research center in Spain to meet critical patient and family needs Alzheimers Dement 2014 10 409 15 24035148 10.1016/j.jalz.2013.03.006
F. Jessen R.E. Amariglio M. Boxtel M. van, Breteler M. Ceccaldi G. Chételat et al. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer’s disease Alzheimer’s Dement: J Alzheimer’s Assoc 2014 10 844 10.1016/j.jalz.2014.01.001
G.M. McKhann D.S. Knopman H. Chertkow B.T. Hyman C.R. Jack C.H. Kawas et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease Alzheimers Dement 2011 7 263 9 21514250 10.1016/j.jalz.2011.03.005
C.R. Jack H.J. Wiste S.D. Weigand T.M. Therneau V.J. Lowe D.S. Knopman et al. Defining imaging biomarker cut points for brain aging and Alzheimer’s disease Alzheimers Dement 2017 13 205 16 27697430 10.1016/j.jalz.2016.08.005
D. Bertens B.M. Tijms P. Scheltens C.E. Teunissen P.J. Visser Unbiased estimates of cerebrospinal fluid β-amyloid 1-42 cutoffs in a large memory clinic population Alzheimers Res Ther 2017 9 8 28193256 5307885 10.1186/s13195-016-0233-7
F. Brosseron C.C. Kolbe F. Santarelli S. Carvalho A. Antonell S. Castro-Gomez et al. Multicenter Alzheimer’s and Parkinson’s disease immune biomarker verification study Alzheimers Dement 2020 16 292 304 31630996 10.1016/j.jalz.2019.07.018
F. Brosseron M. Krauthausen M. Kummer M.T. Heneka Body fluid cytokine levels in mild cognitive impairment and Alzheimer’s disease: a comparative overview Mol Neurobiol 2014 50 534 44 1:CAS:528:DC%2BC2cXjt1Srtr8%3D 24567119 4182618 10.1007/s12035-014-8657-1
J. Ashburner G.R. Ridgway Symmetric diffeomorphic modeling of longitudinal structural MRI Front Neurosci 2012 6 197 23386806
P. Schmidt C. Gaser M. Arsic D. Buck A. Förschler A. Berthele et al. An automated tool for detection of FLAIR-hyperintense white-matter lesions in Multiple Sclerosis Neuroimage 2012 59 3774 83 22119648 10.1016/j.neuroimage.2011.11.032
F. Ribaldi D. Altomare J. Jovicich C. Ferrari A. Picco F.B. Pizzini et al. Accuracy and reproducibility of automated white matter hyperintensities segmentation with lesion segmentation tool: a European multi-site 3T study Magn Reson Imaging 2021 76 108 15 33220450 10.1016/j.mri.2020.11.008
A. de Sitter M.D. Steenwijk A. Ruet A. Versteeg Y. Liu R.A. van Schijndel et al. Performance of five research-domain automated WM lesion segmentation methods in a multi-center MS study Neuroimage 2017 163 106 14 28899746 10.1016/j.neuroimage.2017.09.011
P.W. Wilson R.B. D’Agostino D. Levy A.M. Belanger H. Silbershatz W.B. Kannel Prediction of coronary heart disease using risk factor categories Circulation 1998 97 1837 47 1:STN:280:DyaK1c3msVOjsA%3D%3D 9603539 10.1161/01.CIR.97.18.1837
S. Wolfsgruber L. Kleineidam J. Guski A. Polcher I. Frommann S. Roeske et al. Minor neuropsychological deficits in patients with subjective cognitive decline Neurology 2020 95 e1134 e1143 1:CAS:528:DC%2BB3cXhslKhs7bM 32636322 10.1212/WNL.0000000000010142
K.V. Papp D.M. Rentz I. Orlovsky R.A. Sperling E.C. Mormino Optimizing the preclinical Alzheimer’s cognitive composite with semantic processing: The PACC5 Alzheimers Dement 2017 3 668 77 10.1016/j.trci.2017.10.004
Karlsson L, Vogel J, Arvidsson I, Åström K, Janelidze S, Blennow K, et al. Cerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases. bioRxiv 2023:2023.06.08.544222. https://doi.org/10.1101/2023.06.08.544222.
V.A. Korshunov A.M. Mohan M.A. Georger B.C. Berk Axl, a receptor tyrosine kinase, mediates flow-induced vascular remodeling Circ Res 2006 98 1446 52 1:CAS:528:DC%2BD28XltFWqsL0%3D 16627783 10.1161/01.RES.0000223322.16149.9a
G. Tondo D. Perani C. Comi TAM receptor pathways at the crossroads of neuroinflammation and neurodegeneration Dis Markers 2019 2019 2387614 31636733 6766163 10.1155/2019/2387614
J.H.M. van der Meer T. van der Poll C. van ’t Veer TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis Blood 2014 123 2460 9 24596417 10.1182/blood-2013-09-528752
L. Fourgeaud P.G. Través Y. Tufail H. Leal-Bailey E.D. Lew P.G. Burrola et al. TAM receptors regulate multiple features of microglial physiology Nature 2016 532 240 4 1:CAS:528:DC%2BC28Xlsl2gsr0%3D 27049947 5358512 10.1038/nature17630
Y. Huang K.E. Happonen P.G. Burrola C. O’Connor N. Hah L. Huang et al. Microglia use TAM receptors to detect and engulf amyloid β plaques Nat Immunol 2021 22 586 94 1:CAS:528:DC%2BB3MXovVOru7k%3D 33859405 8102389 10.1038/s41590-021-00913-5
Y. Zheng Q. Wang B. Xiao Q. Lu Y. Wang X. Wang Involvement of receptor tyrosine kinase Tyro3 in amyloidogenic APP processing and β-amyloid deposition in Alzheimer’s disease models PLoS One 2012 7 e39035 1:CAS:528:DC%2BC38XovFWjur4%3D 22701746 3372537 10.1371/journal.pone.0039035
H. Jung S.Y. Lee S. Lim H.R. Choi Y. Choi M. Kim et al. Anti-inflammatory clearance of amyloid-β by a chimeric Gas6 fusion protein Nat Med 2022 28 1802 12 1:CAS:528:DC%2BB38XitVOhtr%2FK 35927581 10.1038/s41591-022-01926-9
J.B. Pereira S. Janelidze O. Strandberg C.D. Whelan H. Zetterberg K. Blennow et al. Microglial activation protects against accumulation of tau aggregates in nondemented individuals with underlying Alzheimer’s disease pathology Nat Aging 2022 2 1138 44 1:CAS:528:DC%2BB3sXmtFSlurs%3D 37118533 10154192 10.1038/s43587-022-00310-z
A. Deczkowska A. Weiner I. Amit The physiology, pathology, and potential therapeutic applications of the TREM2 signaling pathway Cell 2020 181 1207 17 1:CAS:528:DC%2BB3cXhtFOis73P 32531244 10.1016/j.cell.2020.05.003
S.-H. Lee W.J. Meilandt L. Xie V.D. Gandham H. Ngu K.H. Barck et al. Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology Neuron 2021 109 1283.e6 1:CAS:528:DC%2BB3MXmtFWnurw%3D 33675684 10.1016/j.neuron.2021.02.010
A. Deczkowska H. Keren-Shaul A. Weiner M. Colonna M. Schwartz I. Amit Disease-associated microglia: a universal immune sensor of neurodegeneration Cell 2018 173 1073 81 1:CAS:528:DC%2BC1cXpvVemuro%3D 29775591 10.1016/j.cell.2018.05.003
H. Keren-Shaul A. Spinrad A. Weiner O. Matcovitch-Natan R. Dvir-Szternfeld T.K. Ulland et al. A unique microglia type associated with restricting development of Alzheimer’s disease Cell 2017 169 1276.e17 1:CAS:528:DC%2BC2sXpslCqtbY%3D 28602351 10.1016/j.cell.2017.05.018
M. Ewers G. Biechele M. Suárez-Calvet C. Sacher T. Blume E. Morenas-Rodriguez et al. Higher CSF sTREM2 and microglia activation are associated with slower rates of beta-amyloid accumulation EMBO Mol Med 2020 12 e12308 1:CAS:528:DC%2BB3cXhsFCitL%2FK 32790063 7507349 10.15252/emmm.202012308
E. Morenas-Rodríguez Y. Li B. Nuscher N. Franzmeier C. Xiong M. Suárez-Calvet et al. Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer’s disease: a longitudinal observational study Lancet Neurol 2022 21 329 41 35305339 8926925 10.1016/S1474-4422(22)00027-8
S.H. Krance C.-Y. Wu Y. Zou H. Mao S. Toufighi X. He et al. The complement cascade in Alzheimer’s disease: a systematic review and meta-analysis Mol Psychiatry 2021 26 5532 41 31628417 10.1038/s41380-019-0536-8
D. Bonneh-Barkay G. Wang A. Starkey R.L. Hamilton C.A. Wiley In vivo CHI3L1 (YKL-40) expression in astrocytes in acute and chronic neurological diseases J Neuroinflammation 2010 7 20540736 2892443 10.1186/1742-2094-7-34
D. Alcolea E. Vilaplana J. Pegueroles V. Montal P. Sánchez-Juan A. González-Suárez et al. Relationship between cortical thickness and cerebrospinal fluid YKL-40 in predementia stages of Alzheimer’s disease Neurobiol Aging 2015 36 2018 23 1:CAS:528:DC%2BC2MXlsVKlu7k%3D 25865441 10.1016/j.neurobiolaging.2015.03.001
M. Herrera-Rivero F. Santarelli F. Brosseron M.P. Kummer M.T. Heneka Dysregulation of TLR5 and TAM Ligands in the Alzheimer’s Brain as Contributors to Disease Progression Mol Neurobiol 2019 56 6539 50 1:CAS:528:DC%2BC1MXmsV2hsb0%3D 30852796 10.1007/s12035-019-1540-3
Q. Qin Z. Teng C. Liu Q. Li Y. Yin Y. Tang TREM2, microglia, and Alzheimer’s disease Mech Ageing Dev 2021 195 111438 1:CAS:528:DC%2BB3MXktlWlurg%3D 33516818 10.1016/j.mad.2021.111438
S.A. Liddelow K.A. Guttenplan L.E. Clarke F.C. Bennett C.J. Bohlen L. Schirmer et al. Neurotoxic reactive astrocytes are induced by activated microglia Nature 2017 541 481 7 1:CAS:528:DC%2BC2sXht1Olt74%3D 28099414 5404890 10.1038/nature21029
K. Haapasalo S. Meri Regulation of the complement system by pentraxins Front Immunol 2019 10 1750 1:CAS:528:DC%2BB3cXksFSqur4%3D 31428091 6688104 10.3389/fimmu.2019.01750
S.R. Moore S.S. Menon C. Cortes V.P. Ferreira Hijacking factor H for complement immune evasion Front Immunol 2021 12 602277 1:CAS:528:DC%2BB3MXhtVSlt7%2FI 33717083 7947212 10.3389/fimmu.2021.602277
M.C. Dalakas H. Alexopoulos P.J. Spaeth Complement in neurological disorders and emerging complement-targeted therapeutics Nat Rev Neurol 2020 16 601 17 33005040 7528717 10.1038/s41582-020-0400-0
S.A. Ihim S.D. Abubakar Z. Zian T. Sasaki M. Saffarioun S. Maleknia et al. Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment Front Immunol 2022 13 919973 36032110 9410767 10.3389/fimmu.2022.919973
M.J. Engelhart M.I. Geerlings J. Meijer A. Kiliaan A. Ruitenberg J.C. van Swieten et al. Inflammatory proteins in plasma and the risk of dementia: the rotterdam study Arch Neurol 2004 61 668 72 15148142 10.1001/archneur.61.5.668
A.W. Kranjac D. Kranjac O. Lounsbury Deconstructing sex differences in C-reactive protein trends over time Am J Hum Biol 2022 34 e23705 1:CAS:528:DC%2BB38XitlCltrbI 34792252 10.1002/ajhb.23705
T.A. Pascoal A.L. Benedet N.J. Ashton M.S. Kang J. Therriault M. Chamoun et al. Microglial activation and tau propagate jointly across Braak stages Nat Med 2021 27 1592 9 1:CAS:528:DC%2BB3MXhvVygur%2FE 34446931 10.1038/s41591-021-01456-w
