Journal Article

DZNE-2025-00005

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Addressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseases.

Mravinacová, S. ; Bergström, S. ; Olofsson, J. ; de San José, N. G. ; Anderl-Straub, S. ; Diehl-Schmid, J. ; Fassbender, K. ; Fliessbach, K.DZNE* ; Jahn, H. ; Kornhuber, J. ; Landwehrmeyer, G. B.Extern* ; Lauer, M. ; Levin, J.DZNE* ; Ludolph, A. C.DZNE* ; Prudlo, J.DZNE* ; Schneider, A.DZNE* ; Schroeter, M. L. ; Wiltfang, J.DZNE* ; Steinacker, P. ; Consortium, F. (Collaboration Author) ; Otto, M. ; Nilsson, P. ; Månberg, A.

2025
Macmillan Publishers Limited, part of Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41598-024-83281-y

Abstract: Accurate diagnosis and monitoring of neurodegenerative diseases require reliable biomarkers. Cerebrospinal fluid (CSF) proteins are promising candidates for reflecting brain pathology; however, their diagnostic utility may be compromised by natural variability between individuals, weakening their association with disease. Here, we measured the levels of 69 pre-selected proteins in cerebrospinal fluid using antibody-based suspension bead array technology in a multi-disease cohort of 499 individuals with neurodegenerative disorders including Alzheimer's disease (AD), behavioral variant frontotemporal dementia, primary progressive aphasias, amyotrophic lateral sclerosis (ALS), corticobasal syndrome, primary supranuclear palsy, along with healthy controls. We identify significant inter-individual variability in overall CSF levels of brain-derived proteins, which could not be attributed to specific disease associations. Using linear modelling, we show that adjusting for median CSF levels of brain-derived proteins increases the diagnostic accuracy of proteins previously identified as altered in CSF in the context of neurodegenerative disorders. We further demonstrate a simplified approach for the adjustment using pairs of correlated proteins with opposite alteration in the diseases. With this approach, the proteins adjust for each other and further increase the biomarker performance through additive effect. When comparing the diseases, two proteins-neurofilament medium and myelin basic protein-showed increased levels in ALS compared to other diseases, and neurogranin showed a specific increase in AD. Several other proteins showed similar trends across the studied diseases, indicating that these proteins likely reflect shared processes related to neurodegeneration. Overall, our findings suggest that accounting for inter-individual variability is crucial in future studies to improve the identification and performance of relevant biomarkers. Importantly, we highlight the need for multi-disease studies to identify disease-specific biomarkers.

Keyword(s): Humans (MeSH) ; Neurodegenerative Diseases: cerebrospinal fluid (MeSH) ; Neurodegenerative Diseases: diagnosis (MeSH) ; Biomarkers: cerebrospinal fluid (MeSH) ; Male (MeSH) ; Female (MeSH) ; Aged (MeSH) ; Middle Aged (MeSH) ; Brain: metabolism (MeSH) ; Brain: pathology (MeSH) ; Alzheimer Disease: cerebrospinal fluid (MeSH) ; Alzheimer Disease: diagnosis (MeSH) ; Cerebrospinal Fluid Proteins: analysis (MeSH) ; Amyotrophic Lateral Sclerosis: cerebrospinal fluid (MeSH) ; Amyotrophic Lateral Sclerosis: diagnosis (MeSH) ; Affinity proteomics ; Biomarker ; Cerebrospinal fluid ; Inter-individual variability ; Multi-disease ; Neurodegeneration ; Biomarkers ; Cerebrospinal Fluid Proteins

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Contributing Institute(s):

1. Patient Studies (Bonn) (Patient Studies (Bonn))
2. Molecular biomarkers for predictive diagnostics of neurodegenerative diseases (AG Wiltfang)
3. Clinical Research (Munich) (Clinical Research (Munich))
4. Clinical Study Center (Ulm) (Clinical Study Center (Ulm))
5. Clinical Dementia Research (Rostock /Greifswald) (AG Teipel)
6. Translational Dementia Research (Bonn) (AG Schneider)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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