路易体痴呆新型脑脊液生物标志物候选物的鉴定：蛋白质组学方法
Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach.
作者信息
van Steenoven Inger, Koel-Simmelink Marleen J A, Vergouw Leonie J M, Tijms Betty M, Piersma Sander R, Pham Thang V, Bridel Claire, Ferri Gian-Luca, Cocco Cristina, Noli Barbara, Worley Paul F, Xiao Mei-Fang, Xu Desheng, Oeckl Patrick, Otto Markus, van der Flier Wiesje M, de Jong Frank Jan, Jimenez Connie R, Lemstra Afina W, Teunissen Charlotte E
机构信息
Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, De Boelelaan 1118, 1081 HV, Amsterdam, The Netherlands.
Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
出版信息
Mol Neurodegener. 2020 Jun 18;15(1):36. doi: 10.1186/s13024-020-00388-2.
BACKGROUND
Diagnosis of dementia with Lewy bodies (DLB) is challenging, largely due to a lack of diagnostic tools. Cerebrospinal fluid (CSF) biomarkers have been proven useful in Alzheimer's disease (AD) diagnosis. Here, we aimed to identify novel CSF biomarkers for DLB using a high-throughput proteomic approach.
METHODS
We applied liquid chromatography/tandem mass spectrometry with label-free quantification to identify biomarker candidates to individual CSF samples from a well-characterized cohort comprising patients with DLB (n = 20) and controls (n = 20). Validation was performed using (1) the identical proteomic workflow in an independent cohort (n = 30), (2) proteomic data from patients with related neurodegenerative diseases (n = 149) and (3) orthogonal techniques in an extended cohort consisting of DLB patients and controls (n = 76). Additionally, we utilized random forest analysis to identify the subset of candidate markers that best distinguished DLB from all other groups.
RESULTS
In total, we identified 1995 proteins. In the discovery cohort, 69 proteins were differentially expressed in DLB compared to controls (p < 0.05). Independent cohort replication confirmed VGF, SCG2, NPTX2, NPTXR, PDYN and PCSK1N as candidate biomarkers for DLB. The downregulation of the candidate biomarkers was somewhat more pronounced in DLB in comparison with related neurodegenerative diseases. Using random forest analysis, we identified a panel of VGF, SCG2 and PDYN to best differentiate between DLB and other clinical groups (accuracy: 0.82 (95%CI: 0.75-0.89)). Moreover, we confirmed the decrease of VGF and NPTX2 in DLB by ELISA and SRM methods. Low CSF levels of all biomarker candidates, except PCSK1N, were associated with more pronounced cognitive decline (0.37 < r < 0.56, all p < 0.01).
CONCLUSION
We identified and validated six novel CSF biomarkers for DLB. These biomarkers, particularly when used as a panel, show promise to improve diagnostic accuracy and strengthen the importance of synaptic dysfunction in the pathophysiology of DLB.
背景
路易体痴呆（DLB）的诊断具有挑战性，主要原因是缺乏诊断工具。脑脊液（CSF）生物标志物已被证明在阿尔茨海默病（AD）诊断中有用。在此，我们旨在使用高通量蛋白质组学方法鉴定DLB的新型CSF生物标志物。
方法
我们应用液相色谱/串联质谱结合无标记定量来鉴定生物标志物候选物，这些候选物来自一个特征明确的队列中的个体脑脊液样本，该队列包括DLB患者（n = 20）和对照组（n = 20）。使用（1）在独立队列（n = 30）中相同的蛋白质组学工作流程、（2）来自相关神经退行性疾病患者（n = 149）的蛋白质组学数据以及（3）在由DLB患者和对照组组成的扩展队列（n = 76）中的正交技术进行验证。此外，我们利用随机森林分析来鉴定最能将DLB与所有其他组区分开来的候选标志物子集。
结果
我们总共鉴定出1995种蛋白质。在发现队列中，与对照组相比，DLB中有69种蛋白质差异表达（p < 0.05）。独立队列复制证实VGF、SCG2、NPTX2、NPTXR、PDYN和PCSK1N是DLB的候选生物标志物。与相关神经退行性疾病相比，DLB中候选生物标志物的下调更为明显。使用随机森林分析，我们鉴定出一组VGF、SCG2和PDYN，它们最能区分DLB和其他临床组（准确率：0.82（95%CI：0.75 - 0.89））。此外，我们通过ELISA和SRM方法证实了DLB中VGF和NPTX2的降低。除PCSK1N外，所有生物标志物候选物的脑脊液水平低与更明显的认知下降相关（0.37 < r < 0.56，所有p < 0.01）。
结论
我们鉴定并验证了六种DLB的新型CSF生物标志物。这些生物标志物，特别是当作为一组使用时，有望提高诊断准确性，并强化突触功能障碍在DLB病理生理学中的重要性。
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