Addressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseases
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...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41598-024-83281-y |
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| author | Sára Mravinacová Sofia Bergström Jennie Olofsson Nerea Gómez de San José Sarah Anderl-Straub Janine Diehl-Schmid Klaus Fassbender Klaus Fliessbach Holger Jahn Johannes Kornhuber G. Bernhard Landwehrmeyer Martin Lauer Johannes Levin Albert C. Ludolph Johannes Prudlo Anja Schneider Matthias L. Schroeter Jens Wiltfang Petra Steinacker FTLD Consortium Markus Otto Peter Nilsson Anna Månberg |
| author_facet | Sára Mravinacová Sofia Bergström Jennie Olofsson Nerea Gómez de San José Sarah Anderl-Straub Janine Diehl-Schmid Klaus Fassbender Klaus Fliessbach Holger Jahn Johannes Kornhuber G. Bernhard Landwehrmeyer Martin Lauer Johannes Levin Albert C. Ludolph Johannes Prudlo Anja Schneider Matthias L. Schroeter Jens Wiltfang Petra Steinacker FTLD Consortium Markus Otto Peter Nilsson Anna Månberg |
| author_sort | Sára Mravinacová |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2775738ef12047ad88ce45d17d261488 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-2775738ef12047ad88ce45d17d2614882025-01-05T12:18:44ZengNature PortfolioScientific Reports2045-23222025-01-0115111510.1038/s41598-024-83281-yAddressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseasesSára Mravinacová0Sofia Bergström1Jennie Olofsson2Nerea Gómez de San José3Sarah Anderl-Straub4Janine Diehl-Schmid5Klaus Fassbender6Klaus Fliessbach7Holger Jahn8Johannes Kornhuber9G. Bernhard Landwehrmeyer10Martin Lauer11Johannes Levin12Albert C. Ludolph13Johannes Prudlo14Anja Schneider15Matthias L. Schroeter16Jens Wiltfang17Petra Steinacker18FTLD ConsortiumMarkus Otto19Peter Nilsson20Anna Månberg21Department of Protein Science, SciLifeLab, KTH Royal Institute of TechnologyDepartment of Protein Science, SciLifeLab, KTH Royal Institute of TechnologyDepartment of Protein Science, SciLifeLab, KTH Royal Institute of TechnologyDepartment of Neurology, University Hospital Ulm (UKU)Department of Neurology, University Hospital Ulm (UKU)Department of Psychiatry, Technical University of MunichDepartment of Neurology, Saarland UniversityDepartment of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn and DZNE BonnDepartment of Psychiatry, University HospitalDepartment of Psychiatry, Friedrich-Alexander University Erlangen-NurembergDepartment of Neurology, University Hospital Ulm (UKU)Center for Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital WürzburgDepartment of Neurology, LMU University Hospital, LMU MunichDepartment of Neurology, University Hospital Ulm (UKU)Rostock University Medical Center and German Center for Neurodegenerative Diseases (DZNE)Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn and DZNE BonnClinic for Cognitive Neurology, University Clinic Leipzig, and Max Planck Institute for Human Cognitive and Brain SciencesDepartment of Psychiatry and Psychotherapy, University Medical Center Goettingen, and DZNEDepartment of Neurology, Martin-Luther-University Halle-WittenbergDepartment of Neurology, University Hospital Ulm (UKU)Department of Protein Science, SciLifeLab, KTH Royal Institute of TechnologyDepartment of Protein Science, SciLifeLab, KTH Royal Institute of TechnologyAbstract 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.https://doi.org/10.1038/s41598-024-83281-yInter-individual variabilityAffinity proteomicsBiomarkerCerebrospinal fluidMulti-diseaseNeurodegeneration |
| spellingShingle | Sára Mravinacová Sofia Bergström Jennie Olofsson Nerea Gómez de San José Sarah Anderl-Straub Janine Diehl-Schmid Klaus Fassbender Klaus Fliessbach Holger Jahn Johannes Kornhuber G. Bernhard Landwehrmeyer Martin Lauer Johannes Levin Albert C. Ludolph Johannes Prudlo Anja Schneider Matthias L. Schroeter Jens Wiltfang Petra Steinacker FTLD Consortium Markus Otto Peter Nilsson Anna Månberg Addressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseases Scientific Reports Inter-individual variability Affinity proteomics Biomarker Cerebrospinal fluid Multi-disease Neurodegeneration |
| title | Addressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseases |
| title_full | Addressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseases |
| title_fullStr | Addressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseases |
| title_full_unstemmed | Addressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseases |
| title_short | Addressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseases |
| title_sort | addressing inter individual variability in csf levels of brain derived proteins across neurodegenerative diseases |
| topic | Inter-individual variability Affinity proteomics Biomarker Cerebrospinal fluid Multi-disease Neurodegeneration |
| url | https://doi.org/10.1038/s41598-024-83281-y |
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