Metabolite and Peptide Levels in Plasma and CSF Differentiating Healthy Controls from Patients with Newly Diagnosed Parkinson's Disease
Metabolite and Peptide Levels in Plasma and CSF Differentiating Healthy Controls from Patients with Newly Diagnosed Parkinson's Disease
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DOI：
10.3233/jpd-140389
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发表时间：
2014-01-01
影响因子：
5.2
通讯作者：
Forsgren, Lars
中科院分区：
文献类型：
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作者：
Trupp, Miles;Jonsson, Par;Forsgren, Lars
背景：帕金森病（PD）是一种进行性、多病灶的神经退行性疾病，目前尚无有效的疾病修饰治疗方法。设计成功的临床试验的一个关键要求是开发出可靠且可重复的生物标志物，以便在临床前阶段识别帕金森病。
目的：研究通过多种分析平台可视化的一组生物标志物作为一种临床有用工具的潜力。
方法：对瑞典北部确诊的帕金森病患者的样本进行基于气相色谱 - 飞行时间质谱（GC - TOFMS）的代谢组学以及基于免疫测定的蛋白质/肽分析。分析了20名健康受试者（对照组）和20名确诊时（基线）的帕金森病患者的血浆和脑脊液（CSF）中的低分子量化合物。
结果：在血浆中，我们发现与对照组相比，患者的几种氨基酸显著增加，C16 - C18饱和及不饱和脂肪酸减少。我们还观察到血浆中焦谷氨酸和2 - 氧代异己酸（酮亮氨酸）水平升高，这可能表明患者的代谢应激增加。在脑脊液中，与对照组相比，帕金森病患者的代谢物水平普遍较低，其中3 - 羟基异戊酸、色氨酸和肌酐显著降低。代谢物的多变量分析和建模表明，虽然帕金森病样本可与对照样本区分开，但为了定义一个可靠的预测模型，需要扩大检测到的化合物清单。对候选肽/蛋白质生物标志物的脑脊液生物标志物免疫测定显示，患者脑脊液中Aβ - 38和Aβ - 42水平显著降低，可溶性APPα水平升高。此外，这些肽彼此之间存在显著相关性，并且与几种5碳和6碳糖的脑脊液水平呈正相关。然而，将这些代谢物以及蛋白质/肽组合到一个单一模型中并没有显著改善统计分析。
结论：总体而言，这项代谢组学研究根据临床诊断以及已知蛋白质和肽生物标志物的水平，检测到一组氨基酸、脂肪酸和糖在血浆和脑脊液水平上的显著变化。
Background: Parkinson's disease (PD) is a progressive, multi-focal neurodegenerative disease for which there is no effective disease modifying treatment. A critical requirement for designing successful clinical trials is the development of robust and reproducible biomarkers identifying PD in preclinical stages.Objective: To investigate the potential for a cluster of biomarkers visualized with multiple analytical platforms to provide a clinically useful tool.Methods: Gas Chromatography-Mass Spectrometry (GC-TOFMS) based metabolomics and immunoassay-based protein/peptide analyses on samples from patients with PD diagnosed in Northern Sweden. Low molecular weight compounds from both plasma and cerebrospinal fluid (CSF) from 20 healthy subjects (controls) and 20 PD patients at the time of diagnosis (baseline) were analyzed.Results: In plasma, we found a significant increase in several amino acids and a decrease in C16-C18 saturated and unsaturated fatty acids in patients as compared to control subjects. We also observed an increase in plasma levels of pyroglutamate and 2-oxoisocaproate (ketoleucine) that may be indicative of increased metabolic stress in patients. In CSF, there was a generally lower level of metabolites in PD as compared to controls, with a specific decrease in 3-hydroxyisovaleric acid, tryptophan and creatinine. Multivariate analysis and modeling of metabolites indicates that while the PD samples can be separated from control samples, the list of detected compounds will need to be expanded in order to define a robust predictive model. CSF biomarker immunoassays of candidate peptide/protein biomarkers revealed a significant decrease in the levels of A beta-38 and A beta-42, and an increase in soluble APP alpha in CSF of patients. Furthermore, these peptides showed significant correlations to each other, and positive correlations to the CSF levels of several 5- and 6-carbon sugars. However, combining these metabolites and proteins/peptides into a single model did not significantly improve the statistical analysis.Conclusions: Together, this metabolomics study has detected significant alterations in plasma and CSF levels of a cluster of amino acids, fatty acids and sugars based on clinical diagnosis and levels of known protein and peptide biomarkers.