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Cited by 113Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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Characterization and clinical use of inflammatory cerebrospinal fluid protein markers in Alzheimer’s disease

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Brosseron, Frederic, Traschütz, Andreas, Widmann, Catherine N., Kummer, Markus P., Tacik, Pawel, Santarelli, Francesco, Jessen, Frank, Heneka, Michael T.·2018·Alzheimer's Research & Therapy
DOI 10.1186/s13195-018-0353-3PMC PMC5828084
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Abstract

BACKGROUND: Neuroinflammation has gained increasing attention as a potential contributing factor in Alzheimer's disease (AD) pathology. A clinical cerebrospinal fluid biomarker capable of monitoring this process during the course of the disease has yet to emerge, chiefly owing to contradictory research findings. In this study, we sought to clarify the utility of inflammatory biomarkers in diagnostic procedures of AD in three steps: (1) to screen for proteins that are robustly detectable in cerebrospinal fluid; (2) based on this analysis, to explore any associations between the analytically robust markers and salient pathological features of AD; and (3) to determine the discriminative power of these markers in the clinical diagnosis of AD. METHODS: From a total of 46 proteins, 15 that were robustly detectable in cerebrospinal fluid were identified. A subsequent analysis of these markers in a cohort of 399 patients (nondemented subjects, patients with mild cognitive impairment [MCI], and patients with AD, supplemented by smaller cohorts of other diseases) was conducted. Fluid biomarker data were related to AD pathology and neuropsychological markers and adjusted for confounders such as age, sex, apolipoprotein E genotype, and biobank storage time. RESULTS: Cerebrospinal fluid levels of C-reactive protein and soluble TREM2 differed between nondemented subjects, patients with MCI, or patients with AD and were associated with amyloid and tau pathology. Several markers were associated with tau pathology only or with other neurodegenerative diseases. Correlations between neuropsychological performance and inflammatory markers were weak, but they were most prominent in AD and for the most challenging cognitive tests. All investigated covariates had significant influence, with varying effects across the markers. Still, none of the markers achieved discriminative power of more than 70% to distinguish between patient groups defined by clinical or neuropathological categories. CONCLUSIONS: Basic analytical considerations proved indispensable for this type of study because only one-third of the tested markers were robustly detectable in cerebrospinal fluid. Detectable inflammatory protein markers were associated in multiple ways with AD pathology. Yet, even significantly associated markers were not powerful enough in terms of effect strength, sensitivity, and specificity, and hence they were not suited for direct use in clinical diagnostic practice. Targets other than those most commonly considered in this field of research might provide results with better clinical applicability.

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Fig. 1 Biomarker distribution in the main cohorts. a Principal component analysis of cerebrospinal fluid levels of standard Alzheimer’s disease (AD) biomarkers and inflammatory proteins in nondemented subjects (ND), patients with mild cognitive impairment (MCI), and patients with AD. The first two dimensions account for approximately 24% and 15% of the variance in the dataset, respectively. CIs were set at 0.7. The standard amyloid and tau markers and their ratios were the main separators of the clinical cohorts. In contrast, inflammatory markers did not achieve comparable discriminatory strength. b, c In direct comparisons, only soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and C-reactive protein (CRP) differed significantly between the nondemented cohort on the one hand and patients with MCI as well as patients with AD on the other. Box plots represent median and IQR, 5% and 95% percentile whiskers, and all data points outside that range. Aβ40 β-Amyloid 1–40, Aβ42 β-Amyloid 1–42, IP-10 Interferon-γ-induced protein 10, MCP-1 Monocyte chemoattractant protein 1, MIF Macrophage migration inhibitory factor, p-tau-181 Tau phosphorylated at position 181, SAA Serum amyloid A protein, sICAM-1 Soluble intercellular adhesion molecule 1, sIL-1RAcP Soluble inhibition of soluble interleukin-1 receptor accessory protein, sVCAM-1 Soluble vascular cell adhesion molecule 1, t-tau Total tau, VEGF Vascular endothelial growth factor, VEGFR Vascular endothelial growth factor receptor
Fig. 1 Biomarker distribution in the main cohorts. a Principal component analysis of cerebrospinal fluid levels of standard Alzheimer’s disease (AD) biomarkers and inflammatory proteins in nondemented subjects (ND), patients with mild cognitive impairment (MCI), and patients with AD. The first two dimensions account for approximately 24% and 15% of the variance in the dataset, respectively. CIs were set at 0.7. The standard amyloid and tau markers and their ratios were the main separators of the clinical cohorts. In contrast, inflammatory markers did not achieve comparable discriminatory strength. b, c In direct comparisons, only soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and C-reactive protein (CRP) differed significantly between the nondemented cohort on the one hand and patients with MCI as well as patients with AD on the other. Box plots represent median and IQR, 5% and 95% percentile whiskers, and all data points outside that range. Aβ40 β-Amyloid 1–40, Aβ42 β-Amyloid 1–42, IP-10 Interferon-γ-induced protein 10, MCP-1 Monocyte chemoattractant protein 1, MIF Macrophage migration inhibitory factor, p-tau-181 Tau phosphorylated at position 181, SAA Serum amyloid A protein, sICAM-1 Soluble intercellular adhesion molecule 1, sIL-1RAcP Soluble inhibition of soluble interleukin-1 receptor accessory protein, sVCAM-1 Soluble vascular cell adhesion molecule 1, t-tau Total tau, VEGF Vascular endothelial growth factor, VEGFR Vascular endothelial growth factor receptorCC BY · PubMed Central
Fig. 2 Association of inflammatory markers with amyloid and tau levels. The figure shows the ten strongest associations when dichotomizing the main cohorts by pathological (+) and nonpathological (−) levels of the β-amyloid 1–42 (Aβ42)/β-amyloid 1–40 (Aβ40) ratio or total tau (t-tau) (Mann-Whitney U test). See Additional file 2 for weaker or redundant associations. C-reactive protein (CRP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were associated with both amyloid and tau pathology (a–d). Other markers were predominantly associated with pathological tau levels, including (e) soluble vascular endothelial growth factor receptor (sVEGFR), (f) macrophage migration inhibitory factor (MIF), (g) C1q, (h) soluble vascular cell adhesion molecule 1 (sVCAM-1), (i) soluble intercellular adhesion molecule 1 (sICAM-1), and (j) monocyte chemoattractant protein 1 (MCP-1). Box plots represent median and IQR, 5% and 95% percentile whiskers, and all data points outside that range
Fig. 2 Association of inflammatory markers with amyloid and tau levels. The figure shows the ten strongest associations when dichotomizing the main cohorts by pathological (+) and nonpathological (−) levels of the β-amyloid 1–42 (Aβ42)/β-amyloid 1–40 (Aβ40) ratio or total tau (t-tau) (Mann-Whitney U test). See Additional file 2 for weaker or redundant associations. C-reactive protein (CRP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were associated with both amyloid and tau pathology (a–d). Other markers were predominantly associated with pathological tau levels, including (e) soluble vascular endothelial growth factor receptor (sVEGFR), (f) macrophage migration inhibitory factor (MIF), (g) C1q, (h) soluble vascular cell adhesion molecule 1 (sVCAM-1), (i) soluble intercellular adhesion molecule 1 (sICAM-1), and (j) monocyte chemoattractant protein 1 (MCP-1). Box plots represent median and IQR, 5% and 95% percentile whiskers, and all data points outside that rangeCC BY · PubMed Central
Fig. 3 Correlation matrix of the main cohorts depicting results of nonparametric Spearman’s correlations, visualized by plotting significance values (p, lower left) against strength of correlation (r, upper right) as a heat map. In general, there were a large number of highly significant correlations of weak or moderate strength: (1) correlation of standard Alzheimer’s disease (AD) markers with each other, (2) cerebrospinal fluid (CSF) total protein and inflammatory markers against each other, (3) neuropsychiatric tests (NPTs) against each other, (4) AD markers against inflammatory markers, (5) AD markers against NPT results, (6) inflammatory markers against NPT results, and (7) and (8) influence of patient age and biobank storage time. Aβ40 β-Amyloid 1–40, Aβ42 β-Amyloid 1–42, CRP C-reactive protein, FCSRT Free and Cued Selective Reminding Test, IgG Immunoglobulin G, IL Interleukin, IP-10 Interferon-γ-induced protein 10, MCP-1 Monocyte chemoattractant protein 1, MIF Macrophage migration inhibitory factor, MMSE Mini Mental State Examination, p-tau-181 Tau phosphorylated at position 181, SAA Serum amyloid A protein, sICAM-1 Soluble intercellular adhesion molecule 1, sIL-1RAcP Soluble inhibition of soluble interleukin-1 receptor accessory protein, sTREM2 Soluble triggering receptor expressed on myeloid cells 2, sVCAM-1 Soluble vascular cell adhesion molecule 1, TMT Trail Making Test, t-tau Total tau, VEGF Vascular endothelial growth factor, VEGFR Vascular endothelial growth factor receptor
Fig. 3 Correlation matrix of the main cohorts depicting results of nonparametric Spearman’s correlations, visualized by plotting significance values (p, lower left) against strength of correlation (r, upper right) as a heat map. In general, there were a large number of highly significant correlations of weak or moderate strength: (1) correlation of standard Alzheimer’s disease (AD) markers with each other, (2) cerebrospinal fluid (CSF) total protein and inflammatory markers against each other, (3) neuropsychiatric tests (NPTs) against each other, (4) AD markers against inflammatory markers, (5) AD markers against NPT results, (6) inflammatory markers against NPT results, and (7) and (8) influence of patient age and biobank storage time. Aβ40 β-Amyloid 1–40, Aβ42 β-Amyloid 1–42, CRP C-reactive protein, FCSRT Free and Cued Selective Reminding Test, IgG Immunoglobulin G, IL Interleukin, IP-10 Interferon-γ-induced protein 10, MCP-1 Monocyte chemoattractant protein 1, MIF Macrophage migration inhibitory factor, MMSE Mini Mental State Examination, p-tau-181 Tau phosphorylated at position 181, SAA Serum amyloid A protein, sICAM-1 Soluble intercellular adhesion molecule 1, sIL-1RAcP Soluble inhibition of soluble interleukin-1 receptor accessory protein, sTREM2 Soluble triggering receptor expressed on myeloid cells 2, sVCAM-1 Soluble vascular cell adhesion molecule 1, TMT Trail Making Test, t-tau Total tau, VEGF Vascular endothelial growth factor, VEGFR Vascular endothelial growth factor receptorCC BY · PubMed Central
Fig. 4 Association between inflammatory markers and cognitive performance in Alzheimer’s disease (AD). Six significant correlations were robust in multivariable linear regression analysis adjusting for age, sex, and education (see Additional file 2). Correlations (a) between the total sum of the Free and Cued Selective Reminding Test (FCSRT sum) and macrophage migration inhibitory factor (MIF), (b) between semantic fluency and vascular endothelial growth factor (VEGF), and between (c) phonetic fluency and VEGF, (d) C-reactive protein (CRP), (e) soluble intercellular adhesion molecule 1 (sICAM-1), and (f) C3aDesArg. Phonetic fluency was the most prominent cognitive correlate. In all cases, higher levels of inflammatory markers in the cerebrospinal fluid were associated with lower cognitive performance
Fig. 4 Association between inflammatory markers and cognitive performance in Alzheimer’s disease (AD). Six significant correlations were robust in multivariable linear regression analysis adjusting for age, sex, and education (see Additional file 2). Correlations (a) between the total sum of the Free and Cued Selective Reminding Test (FCSRT sum) and macrophage migration inhibitory factor (MIF), (b) between semantic fluency and vascular endothelial growth factor (VEGF), and between (c) phonetic fluency and VEGF, (d) C-reactive protein (CRP), (e) soluble intercellular adhesion molecule 1 (sICAM-1), and (f) C3aDesArg. Phonetic fluency was the most prominent cognitive correlate. In all cases, higher levels of inflammatory markers in the cerebrospinal fluid were associated with lower cognitive performanceCC BY · PubMed Central
Fig. 5 Inflammatory biomarkers in nondemented (ND) subjects and patients with mild cognitive impairment (MCI), Alzheimer’s disease (AD), and other neurodegenerative diseases. The figure shows results for inflammatory markers with significant differences in intercohort comparisons (p values derived by Kruskal-Wallis test; see Additional file 2 for all pairwise comparisons). Clustered cohorts with significant differences are colored blue and red; gray indicates indiscriminate cohorts. Effects observed for C-reactive protein (CRP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the main cohorts remained significant after inclusion of supplemental cohorts in the Kruskal-Wallis test (a, b). Furthermore, significant differences between cohorts were observed for sVEGFR (c), IP-10 (d), sIl-1RAcP (e), sICAM-1 (f), MIF (g) and Il-6 (h). Box plots represent median and IQR, 5% and 95% percentile whiskers, and all data points outside that range. ALS Amyotrophic lateral sclerosis, DLB Dementia with Lewy bodies, FTD Frontotemporal dementia, Ig Immunoglobulin, IL Interleukin, IP-10 Interferon-γ-induced protein 10, MCI Mild cognitive impairment, MCP-1 Monocyte chemoattractant protein 1, MIF Macrophage migration inhibitory factor, PD Parkinson’s disease, sICAM-1 Soluble intercellular adhesion molecule 1, sIL-1RAcP Soluble inhibition of soluble interleukin-1 receptor accessory protein, sTREM2 Soluble triggering receptor expressed on myeloid cells 2, sVEGFR Soluble vascular endothelial growth factor receptor
Fig. 5 Inflammatory biomarkers in nondemented (ND) subjects and patients with mild cognitive impairment (MCI), Alzheimer’s disease (AD), and other neurodegenerative diseases. The figure shows results for inflammatory markers with significant differences in intercohort comparisons (p values derived by Kruskal-Wallis test; see Additional file 2 for all pairwise comparisons). Clustered cohorts with significant differences are colored blue and red; gray indicates indiscriminate cohorts. Effects observed for C-reactive protein (CRP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the main cohorts remained significant after inclusion of supplemental cohorts in the Kruskal-Wallis test (a, b). Furthermore, significant differences between cohorts were observed for sVEGFR (c), IP-10 (d), sIl-1RAcP (e), sICAM-1 (f), MIF (g) and Il-6 (h). Box plots represent median and IQR, 5% and 95% percentile whiskers, and all data points outside that range. ALS Amyotrophic lateral sclerosis, DLB Dementia with Lewy bodies, FTD Frontotemporal dementia, Ig Immunoglobulin, IL Interleukin, IP-10 Interferon-γ-induced protein 10, MCI Mild cognitive impairment, MCP-1 Monocyte chemoattractant protein 1, MIF Macrophage migration inhibitory factor, PD Parkinson’s disease, sICAM-1 Soluble intercellular adhesion molecule 1, sIL-1RAcP Soluble inhibition of soluble interleukin-1 receptor accessory protein, sTREM2 Soluble triggering receptor expressed on myeloid cells 2, sVEGFR Soluble vascular endothelial growth factor receptorCC BY · PubMed Central
Fig. 6 Diagnostic power of inflammatory biomarkers. ROC based on nonparametric data distribution to calculate cutoff values with equally weighted sensitivity and specificity (discriminative power). The figure shows the results for proteins associated with clinical cohorts or amyloid and tau levels based on the ratio Aβ42/Aβ40 and t-tau. In general, markers reached a discriminative power between 50% and 70%. For use as biomarkers, a power of at least 80–90% (indicated by red and green dashed lines) would be necessary. Values in that range are achieved using Alzheimer’s disease core biomarkers, which are shown for comparison purposes based on the internal laboratory-specific cutoff values. Aβ40 β-Amyloid 1–40, Aβ42 β-Amyloid 1–42, AD Alzheimer’s disease, ALS Amyotrophic lateral sclerosis, CRP C-reactive protein, IP-10 Interferon-γ-induced protein 10, MCI Mild cognitive impairment, MCP-1 Monocyte chemoattractant protein 1, MIF Macrophage migration inhibitory factor, ND Nondemented, p-tau-181 Tau phosphorylated at position 181, sICAM-1 Soluble intercellular adhesion molecule 1, sIL-1RAcP Soluble inhibition of soluble interleukin-1 receptor accessory protein, sTREM2 Soluble triggering receptor expressed on myeloid cells 2, sVCAM-1 Soluble vascular cell adhesion molecule 1, sVEGFR Soluble vascular endothelial growth factor receptor, t-tau Total tau, VEGF Vascular endothelial growth factor
Fig. 6 Diagnostic power of inflammatory biomarkers. ROC based on nonparametric data distribution to calculate cutoff values with equally weighted sensitivity and specificity (discriminative power). The figure shows the results for proteins associated with clinical cohorts or amyloid and tau levels based on the ratio Aβ42/Aβ40 and t-tau. In general, markers reached a discriminative power between 50% and 70%. For use as biomarkers, a power of at least 80–90% (indicated by red and green dashed lines) would be necessary. Values in that range are achieved using Alzheimer’s disease core biomarkers, which are shown for comparison purposes based on the internal laboratory-specific cutoff values. Aβ40 β-Amyloid 1–40, Aβ42 β-Amyloid 1–42, AD Alzheimer’s disease, ALS Amyotrophic lateral sclerosis, CRP C-reactive protein, IP-10 Interferon-γ-induced protein 10, MCI Mild cognitive impairment, MCP-1 Monocyte chemoattractant protein 1, MIF Macrophage migration inhibitory factor, ND Nondemented, p-tau-181 Tau phosphorylated at position 181, sICAM-1 Soluble intercellular adhesion molecule 1, sIL-1RAcP Soluble inhibition of soluble interleukin-1 receptor accessory protein, sTREM2 Soluble triggering receptor expressed on myeloid cells 2, sVCAM-1 Soluble vascular cell adhesion molecule 1, sVEGFR Soluble vascular endothelial growth factor receptor, t-tau Total tau, VEGF Vascular endothelial growth factorCC BY · PubMed Central

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Metadata

Authors
Brosseron, F., Traschütz, A., Widmann, C. N., Kummer, M. P., Tacik, P., Santarelli, F., Jessen, F., & Heneka, M. T.
Affiliations
  • German Center for Neurodegenerative Diseases (DE)
  • University of Bonn (DE)
  • University of Cologne (DE)
Corresponding author
Heneka, Michael T.
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2018-02-26
Volume
10
Issue
1
Pages
25-25
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-018-0353-3
PMC
PMC5828084
OpenAlex
W2796088161
Cited by
113
References
51
Citations by year
2026: 6 · 2025: 9 · 2024: 16 · 2023: 10 · 2022: 12 · 2021: 16 · 2020: 29 · 2019: 10 · 2018: 5
FWCI
11.72
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DZNE Pub (submittedVersion, cc-by)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
Funders
  • EU/EFPIA/(Associated Partner) Innovative Medicines Initiative (2) Joint Undertaking (115568)
  • European Union’s Seventh Framework Programme (FP7/2007-2013)
  • INMiND (HEALTH-F2-2011-278850 TP21)
  • Deutsche Forschungsgemeinschaft (KFO177, TP4)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, cerebrospinal fluid biomarkers, neuroinflammation, inflammatory proteins, C-reactive protein, soluble TREM2, amyloid pathology, tau pathology, mild cognitive impairment, diagnostic accuracy, apolipoprotein E
MeSH terms
Adult, Aged, Aged, 80 and over, Alzheimer Disease, C-Reactive Protein, Cerebrospinal Fluid Proteins, Female, Humans, Male, Membrane Glycoproteins, Middle Aged, Receptors, Immunologic, Cohort Studies, Cytokines, Amyloid beta-Peptides, tau Proteins, Statistics, Nonparametric, Vascular Endothelial Growth Factor A

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