[en] [en] 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.
Disciplines :
Neurology
Author, co-author :
Brosseron, Frederic; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Traschütz, Andreas; Department of Neurodegenerative Diseases & Geropsychiatry/Neurology, University of Bonn Medical Center, Bonn, Germany
Widmann, Catherine N; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Neurodegenerative Diseases & Geropsychiatry/Neurology, University of Bonn Medical Center, Bonn, Germany
Kummer, Markus P; Department of Neurodegenerative Diseases & Geropsychiatry/Neurology, University of Bonn Medical Center, Bonn, Germany
Tacik, Pawel; Department of Neurodegenerative Diseases & Geropsychiatry/Neurology, University of Bonn Medical Center, Bonn, Germany
Santarelli, Francesco; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Jessen, Frank; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Psychiatry, University of Cologne, Medical Faculty, Kerpener Strasse 62, 50924, Cologne, Germany
HENEKA, Michael ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. michael.heneka@ukbonn.de ; Department of Neurodegenerative Diseases & Geropsychiatry/Neurology, University of Bonn Medical Center, Bonn, Germany. michael.heneka@ukbonn.de
External co-authors :
yes
Language :
English
Title :
Characterization and clinical use of inflammatory cerebrospinal fluid protein markers in Alzheimer's disease.
EU/EFPIA/(Associated Partner) Innovative Medicines Initiative (2) Joint Undertaking European Union’s Seventh Framework Programme INMiND Deutsche Forschungsgemeinschaft
Funding text :
This work was funded by the German Center for Neurodegenerative Diseases (DZNE e.V.) within the Helmholtz Association, by the German Research Council (DFG; Deutsche Forschungsgemeinschaft KFO177, TP4), the European Union (EU) Seventh Framework Programme (FP7/2007–2013) Imaging of Neuroinflammation in Neurodegenerative Diseases (INMiND) program (grant agreement number HEALTH-F2–2011-278850 TP21), and the EU/European Federation of Pharmaceutical Industries and Associations (EFPIA)/(Associated Partner) Innovative Medicines Initiative (2) Joint Undertaking (AETIONOMY) (grant number 115568). MTH is a member of the Cluster of Excellence “ImmunoSensation.”
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