背景:需要生物标志物来支持帕金森病(PD)的准确诊断。脑脊液(CSF)已成功发现神经退行性生物标志物的生物流体,和现代高度敏感的多路复用方法提供了进行发现研究的可能性。使用大规模多重邻近延伸测定(PEA)方法,我们旨在发现新的诊断性蛋白质生物标志物,从而能够准确区分PD与对照和非典型帕金森病(APD).
方法:来自PD患者的CSF,皮质基底综合征(CBS),进行性核上性麻痹(PSP),多系统萎缩和控制,用OlinkPEA小组进行了分析。在这项研究中使用了三个队列,包括192、88和36例,分别。所有样本都在心血管II上运行,肿瘤学II和代谢PEA小组。
结果:我们的分析显示,在测试和验证PD队列的CSF中,有26和39种蛋白质差异表达,分别,与对照组相比。其中,6种蛋白质在两个队列中都发生了变化。中期因子(MK)在PD中增加,作用大小最强,结果用ELISA验证。PD中另一个增加最多的蛋白质,多巴脱羧酶(DDC),催化DOPA(L-3,4-二羟基苯丙氨酸)脱羧为多巴胺,与多巴胺能治疗密切相关。此外,与PD和对照相比,激肽释放酶10在APD中特别变化,但PD和对照组之间没有变化。在两个独立的队列中,CBS和PSP患者的Wnt抑制因子1持续下调。
结论:使用大规模PEA方法,我们已经确定了潜在的新型PD诊断生物标志物,最著名的是MK和DDC,在PD患者的CSF中。
There is a need for biomarkers to support an accurate diagnosis of Parkinson\'s disease (PD). Cerebrospinal fluid (CSF) has been a successful biofluid for finding neurodegenerative biomarkers, and modern highly sensitive multiplexing methods offer the possibility to perform discovery studies. Using a large-scale multiplex proximity extension assay (PEA) approach, we aimed to discover novel diagnostic protein biomarkers allowing accurate discrimination of PD from both controls and atypical Parkinsonian disorders (APD).
CSF from patients with PD, corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), multiple system atrophy and controls, were analysed with Olink PEA panels. Three cohorts were used in this study, comprising 192, 88 and 36 cases, respectively. All samples were run on the Cardiovascular II, Oncology II and Metabolism PEA panels.
Our analysis revealed that 26 and 39 proteins were differentially expressed in the CSF of test and validation PD cohorts, respectively, compared to controls. Among them, 6 proteins were changed in both cohorts. Midkine (MK) was increased in PD with the strongest effect size and results were validated with ELISA. Another most increased protein in PD, DOPA decarboxylase (DDC), which catalyses the decarboxylation of DOPA (L-3,4-dihydroxyphenylalanine) to dopamine, was strongly correlated with dopaminergic treatment. Moreover, Kallikrein 10 was specifically changed in APD compared with both PD and controls, but unchanged between PD and controls. Wnt inhibitory factor 1 was consistently downregulated in CBS and PSP patients in two independent cohorts.
Using the large-scale PEA approach, we have identified potential novel PD diagnostic biomarkers, most notably MK and DDC, in the CSF of PD patients.