TY  - JOUR
AU  - Mravinacová, Sára
AU  - Bergström, Sofia
AU  - Olofsson, Jennie
AU  - de San José, Nerea Gómez
AU  - Anderl-Straub, Sarah
AU  - Diehl-Schmid, Janine
AU  - Fassbender, Klaus
AU  - Fliessbach, Klaus
AU  - Jahn, Holger
AU  - Kornhuber, Johannes
AU  - Landwehrmeyer, Georg Bernhard
AU  - Lauer, Martin
AU  - Levin, Johannes
AU  - Ludolph, Albert C
AU  - Prudlo, Johannes
AU  - Schneider, Anja
AU  - Schroeter, Matthias L
AU  - Wiltfang, Jens
AU  - Steinacker, Petra
AU  - Otto, Markus
AU  - Nilsson, Peter
AU  - Månberg, Anna
TI  - Addressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseases.
JO  - Scientific reports
VL  - 15
IS  - 1
SN  - 2045-2322
CY  - [London]
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DZNE-2025-00005
SP  - 668
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Neurodegenerative Diseases: cerebrospinal fluid
KW  - Neurodegenerative Diseases: diagnosis
KW  - Biomarkers: cerebrospinal fluid
KW  - Male
KW  - Female
KW  - Aged
KW  - Middle Aged
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Alzheimer Disease: cerebrospinal fluid
KW  - Alzheimer Disease: diagnosis
KW  - Cerebrospinal Fluid Proteins: analysis
KW  - Amyotrophic Lateral Sclerosis: cerebrospinal fluid
KW  - Amyotrophic Lateral Sclerosis: diagnosis
KW  - Affinity proteomics (Other)
KW  - Biomarker (Other)
KW  - Cerebrospinal fluid (Other)
KW  - Inter-individual variability (Other)
KW  - Multi-disease (Other)
KW  - Neurodegeneration (Other)
KW  - Biomarkers (NLM Chemicals)
KW  - Cerebrospinal Fluid Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39753643
C2  - pmc:PMC11698900
DO  - DOI:10.1038/s41598-024-83281-y
UR  - https://pub.dzne.de/record/274024
ER  -