Alzheimer’s disease; Biomarker; Blood-based; Cognition; Inflammation; Structural MRI; Amyloid beta-Peptides; Biomarkers; Chitinase-3-Like Protein 1; Interleukin-6; tau Proteins; AXL protein, human; Humans; Amyloid beta-Peptides/cerebrospinal fluid; Biomarkers/blood; Brain/pathology; tau Proteins/cerebrospinal fluid; Alzheimer Disease/blood; Alzheimer Disease/pathology; Chitinase-3-Like Protein 1/blood; Cognitive Dysfunction/blood; Cognitive Dysfunction/diagnosis; Interleukin-6/blood; Brain; Cognitive Dysfunction; Neurology; Neurology (clinical); Cognitive Neuroscience
Abstract :
[en] [en] BACKGROUND: Neuroinflammation constitutes a pathological hallmark of Alzheimer's disease (AD). Still, it remains unresolved if peripheral inflammatory markers can be utilized for research purposes similar to blood-based beta-amyloid and neurodegeneration measures. We investigated experimental inflammation markers in serum and analyzed interrelations towards AD pathology features in a cohort with a focus on at-risk stages of AD.
METHODS: Data of 74 healthy controls (HC), 99 subjective cognitive decline (SCD), 75 mild cognitive impairment (MCI), 23 AD relatives, and 38 AD subjects were obtained from the DELCODE cohort. A panel of 20 serum biomarkers was determined using immunoassays. Analyses were adjusted for age, sex, APOE status, and body mass index and included correlations between serum and CSF marker levels and AD biomarker levels. Group-wise comparisons were based on screening diagnosis and routine AD biomarker-based schematics. Structural imaging data were combined into composite scores representing Braak stage regions and related to serum biomarker levels. The Preclinical Alzheimer's Cognitive Composite (PACC5) score was used to test for associations between the biomarkers and cognitive performance.
RESULTS: Each experimental marker displayed an individual profile of interrelations to AD biomarkers, imaging, or cognition features. Serum-soluble AXL (sAXL), IL-6, and YKL-40 showed the most striking associations. Soluble AXL was significantly elevated in AD subjects with pathological CSF beta-amyloid/tau profile and negatively related to structural imaging and cognitive function. Serum IL-6 was negatively correlated to structural measures of Braak regions, without associations to corresponding IL-6 CSF levels or other AD features. Serum YKL-40 correlated most consistently to CSF AD biomarker profiles and showed the strongest negative relations to structure, but none to cognitive outcomes.
CONCLUSIONS: Serum sAXL, IL-6, and YKL-40 relate to different AD features, including the degree of neuropathology and cognitive functioning. This may suggest that peripheral blood signatures correspond to specific stages of the disease. As serum markers did not reflect the corresponding CSF protein levels, our data highlight the need to interpret serum inflammatory markers depending on the respective protein's specific biology and cellular origin. These marker-specific differences will have to be considered to further define and interpret blood-based inflammatory profiles for AD research.
Disciplines :
Life sciences: Multidisciplinary, general & others Neurology
Author, co-author :
Brosseron, Frederic; German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany
Maass, Anne; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, 39120, Magdeburg, Germany
Kleineidam, Luca; German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany
Ravichandran, Kishore Aravind; German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany
Kolbe, Carl-Christian; Institute of Innate Immunity, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany ; Bayer AG, Alfred-Nobel-Straße 50, 40789, Monheim am Rhein, Germany
Wolfsgruber, Steffen; German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany
Santarelli, Francesco; German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany
Häsler, Lisa M; Hertie Institute for Clinical Brain Research, Department Cellular Neurology, University of Tübingen, Otfried-Müller-Strasse 27, 72076, Tübingen, Germany ; German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Straße 27, 72076, Tübingen, Germany
McManus, Róisín; German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany
Ising, Christina; German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, 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
Röske, Sandra; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany
Peters, Oliver; German Center for Neurodegenerative Diseases (DZNE), Charitéplatz 1, 10117, Berlin, Germany ; Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, 10117, Berlin, Germany
Cosma, Nicoleta-Carmen; Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany
Schneider, Luisa-Sophie; German Center for Neurodegenerative Diseases (DZNE), Charitéplatz 1, 10117, Berlin, Germany ; Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, 10117, Berlin, Germany
Wang, Xiao; Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, 10117, Berlin, Germany
Priller, Josef; German Center for Neurodegenerative Diseases (DZNE), Charitéplatz 1, 10117, Berlin, Germany ; Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, 10117, Berlin, Germany ; Department of Psychiatry and Psychotherapy, Technical University Munich, 81675, Munich, Germany
Spruth, Eike J; German Center for Neurodegenerative Diseases (DZNE), Charitéplatz 1, 10117, Berlin, Germany ; Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, 10117, Berlin, Germany
Altenstein, Slawek; German Center for Neurodegenerative Diseases (DZNE), Charitéplatz 1, 10117, Berlin, Germany ; Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, 10117, Berlin, Germany
Schneider, Anja; German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany
Fliessbach, Klaus; German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany
Wiltfang, Jens; German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075, Göttingen, 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
Schott, Björn H; German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075, Göttingen, 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
Buerger, Katharina; German Center for Neurodegenerative Diseases (DZNE), 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
Dichgans, Martin; German Center for Neurodegenerative Diseases (DZNE), 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
Perneczky, Robert; German Center for Neurodegenerative Diseases (DZNE), 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 ; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK
Rauchmann, Boris-Stephan; Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
Teipel, Stefan; German Center for Neurodegenerative Diseases (DZNE), Gehlsheimer Str. 20, 18147, Rostock, Germany ; Department of Psychosomatic Medicine, Rostock University Medical Center, Gehlsheimer Str. 20, 18147, Rostock, Germany
Kilimann, Ingo; German Center for Neurodegenerative Diseases (DZNE), Gehlsheimer Str. 20, 18147, Rostock, Germany ; Department of Psychosomatic Medicine, Rostock University Medical Center, Gehlsheimer Str. 20, 18147, Rostock, Germany
Görß, Doreen; Department of Psychosomatic Medicine, Rostock University Medical Center, Gehlsheimer Str. 20, 18147, Rostock, Germany
Laske, Christoph; German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Straße 27, 72076, Tübingen, Germany ; Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
Munk, Matthias H; German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Straße 27, 72076, Tübingen, Germany ; Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
Düzel, Emrah; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, 39120, Magdeburg, Germany ; Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany
Yakupow, Renat; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, 39120, Magdeburg, Germany
Dobisch, Laura; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, 39120, Magdeburg, Germany
Metzger, Coraline D; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, 39120, Magdeburg, Germany ; Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany ; Department of Psychiatry and Psychotherapy, Otto-von-Guericke University, Magdeburg, Germany
Glanz, Wenzel; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, 39120, Magdeburg, Germany
Ewers, Michael; German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377, Munich, Germany
Dechent, Peter; MR-Research in Neurosciences, Department of Cognitive Neurology, Georg-August-University, Goettingen, Germany
Haynes, John Dylan; Bernstein Center for Computational Neurosciences, Charité - Universitätsmedizin, Berlin, Germany
Scheffler, Klaus; Department for Biomedical Magnetic Resonance, University of Tübingen, 72076, Tübingen, Germany
Roy, Nina; German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127, Bonn, Germany
Rostamzadeh, Ayda; Department of Psychiatry, University of Cologne, Medical Faculty, Kerpener Strasse 62, 50924, Cologne, Germany
Spottke, Annika; German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Neurology, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
Ramirez, Alfredo; German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, 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
Mengel, David; German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Straße 27, 72076, Tübingen, Germany ; Division Translational Genomics of Neurodegenerative Diseases, Center for Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller-Strasse 27, 72076, Tübingen, Germany
Synofzik, Matthis; German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Straße 27, 72076, Tübingen, Germany ; Division Translational Genomics of Neurodegenerative Diseases, Center for Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller-Strasse 27, 72076, Tübingen, Germany
Jucker, Mathias; Hertie Institute for Clinical Brain Research, Department Cellular Neurology, University of Tübingen, Otfried-Müller-Strasse 27, 72076, Tübingen, Germany ; German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Straße 27, 72076, Tübingen, Germany
Latz, Eicke; German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127, Bonn, Germany ; Institute of Innate Immunity, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany
Jessen, Frank; German Center for Neurodegenerative Diseases (DZNE), 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 ; Department of Psychiatry, University of Cologne, Medical Faculty, Kerpener Strasse 62, 50924, Cologne, Germany
Wagner, Michael; German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127, Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany
HENEKA, Michael ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) ; German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127, Bonn, Germany. michael.heneka@uni.lu ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany. michael.heneka@uni.lu
This work was funded by the German Center for Neurodegenerative Diseases (DZNE e.V.) within the Helmholtz Association. FB, CCK, EL, and MTH are members of the Cluster of Excellence “Immunosensation.”
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