Mravinacová Sára, Bergström Sofia, Olofsson Jennie, de San José Nerea Gómez, Anderl-Straub Sarah, Diehl-Schmid Janine, Fassbender Klaus, Fliessbach Klaus, Jahn Holger, Kornhuber Johannes, Landwehrmeyer G Bernhard, Lauer Martin, Levin Johannes, Ludolph Albert C, Prudlo Johannes, Schneider Anja, Schroeter Matthias L, Wiltfang Jens, Steinacker Petra, Otto Markus, Nilsson Peter, Månberg Anna
Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden.
Department of Neurology, University Hospital Ulm (UKU), Ulm, Germany.
Sci Rep. 2025 Jan 3;15(1):668. doi: 10.1038/s41598-024-83281-y.
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.
神经退行性疾病的准确诊断和监测需要可靠的生物标志物。脑脊液（CSF）蛋白有望反映脑病理学特征；然而，个体间的自然变异性可能会影响其诊断效用，削弱它们与疾病的关联。在此，我们使用基于抗体的悬浮微珠阵列技术，在一个包含499名神经退行性疾病患者（包括阿尔茨海默病（AD）、行为变异型额颞叶痴呆、原发性进行性失语症、肌萎缩侧索硬化症（ALS）、皮质基底节综合征、原发性核上性麻痹）以及健康对照的多病种队列中，测量了脑脊液中69种预先选定蛋白的水平。我们发现脑源性蛋白的总体脑脊液水平存在显著的个体间差异，且这种差异不能归因于特定的疾病关联。通过线性建模，我们表明调整脑源性蛋白的脑脊液中位数水平可提高先前在神经退行性疾病背景下被确定为脑脊液中发生改变的蛋白的诊断准确性。我们进一步展示了一种使用疾病中具有相反变化的成对相关蛋白进行调整的简化方法。通过这种方法，这些蛋白相互调整，并通过累加效应进一步提高生物标志物的性能。在比较这些疾病时，与其他疾病相比，神经丝中型和髓鞘碱性蛋白这两种蛋白在ALS中的水平升高，而神经颗粒蛋白在AD中呈现特异性升高。其他几种蛋白在所有研究疾病中都呈现出类似趋势，表明这些蛋白可能反映了与神经退行性变相关的共同过程。总体而言，我们的研究结果表明，在未来研究中考虑个体间差异对于提高相关生物标志物的识别和性能至关重要。重要的是，我们强调需要进行多病种研究以识别疾病特异性生物标志物。
