Trupp Miles, Jonsson Pär, Öhrfelt Annika, Zetterberg Henrik, Obudulu Ogonna, Malm Linus, Wuolikainen Anna, Linder Jan, Moritz Thomas, Blennow Kaj, Antti Henrik, Forsgren Lars
Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
Department of Chemistry, Umeå University, Umeå, Sweden.
J Parkinsons Dis. 2014;4(3):549-560. doi: 10.3233/JPD-140389.
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.
To investigate the potential for a cluster of biomarkers visualized with multiple analytical platforms to provide a clinically useful tool.
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.
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 Aβ-38 and Aβ-42, and an increase in soluble APPα 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.
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.
帕金森病（PD）是一种进行性、多灶性神经退行性疾病，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强大且可重复的生物标志物，以便在临床前阶段识别PD。
研究通过多种分析平台可视化的一组生物标志物提供临床有用工具的潜力。
对瑞典北部诊断为PD的患者样本进行基于气相色谱 - 飞行时间质谱（GC - TOFMS）的代谢组学分析和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PD患者在诊断时（基线）血浆和脑脊液（CSF）中的低分子量化合物。
与对照组相比，患者血浆中几种氨基酸显著增加，C16 - C18饱和及不饱和脂肪酸减少。我们还观察到焦谷氨酸和2 - 氧代异己酸（酮亮氨酸）的血浆水平升高，这可能表明患者代谢应激增加。在脑脊液中，与对照组相比，PD患者的代谢物水平普遍较低，3 - 羟基异戊酸、色氨酸和肌酐有特异性降低。代谢物的多变量分析和建模表明，虽然PD样本可以与对照样本分开，但为了定义一个强大的预测模型，检测到的化合物列表需要扩展。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增加。此外，这些肽相互之间显示出显著相关性，并且与几种五碳和六碳糖的脑脊液水平呈正相关。然而，将这些代谢物和蛋白质/肽组合成一个单一模型并没有显著改善统计分析。
总之，这项代谢组学研究基于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、脂肪酸和糖类在血浆和脑脊液水平上的显著变化。
