Metabolomics Unit, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
Department of Psychiatry, University of Geneva, Geneva, Switzerland.
Alzheimers Res Ther. 2019 Nov 28;11(1):93. doi: 10.1186/s13195-019-0551-7.
Metabolic alterations, related to cerebral glucose metabolism, brain insulin resistance, and age-induced mitochondrial dysfunction, play an important role in Alzheimer's disease (AD) on both the systemic and central nervous system level. To study the extent and significance of these alterations in AD, quantitative metabolomics was applied to plasma and cerebrospinal fluid (CSF) from clinically well-characterized AD patients and cognitively healthy control subjects. The observed metabolic alterations were associated with core pathological processes of AD to investigate their relation with amyloid pathology and tau-related neurodegeneration.
In a case-control study of clinical and biomarker-confirmed AD patients (n = 40) and cognitively healthy controls without cerebral AD pathology (n = 34) with paired plasma and CSF samples, we performed metabolic profiling, i.e., untargeted metabolomics and targeted quantification. Targeted quantification focused on identified deregulated pathways highlighted in the untargeted assay, i.e. the TCA cycle, and its anaplerotic pathways, as well as the neuroactive tryptophan and kynurenine pathway.
Concentrations of several TCA cycle and beta-oxidation intermediates were higher in plasma of AD patients, whilst amino acid concentrations were significantly lower. Similar alterations in these energy metabolism intermediates were observed in CSF, together with higher concentrations of creatinine, which were strongly correlated with blood-brain barrier permeability. Alterations of several amino acids were associated with CSF Amyloidβ1-42. The tryptophan catabolites, kynurenic acid and quinolinic acid, showed significantly higher concentrations in CSF of AD patients, which, together with other tryptophan pathway intermediates, were correlated with either CSF Amyloidβ1-42, or tau and phosphorylated Tau-181.
This study revealed AD-associated systemic dysregulation of nutrient sensing and oxidation and CNS-specific alterations in the neuroactive tryptophan pathway and (phospho)creatine degradation. The specific association of amino acids and tryptophan catabolites with AD CSF biomarkers suggests a close relationship with core AD pathology. Our findings warrant validation in independent, larger cohort studies as well as further investigation of factors such as gender and APOE genotype, as well as of other groups, such as preclinical AD, to identify metabolic alterations as potential intervention targets.
与脑葡萄糖代谢、脑胰岛素抵抗和年龄相关的线粒体功能障碍相关的代谢改变，在全身性和中枢神经系统水平上，在阿尔茨海默病（AD）中都起着重要作用。为了研究这些改变在 AD 中的程度和意义，我们应用定量代谢组学方法对来自临床特征明确的 AD 患者和认知健康对照者的血浆和脑脊液（CSF）进行了研究。观察到的代谢改变与 AD 的核心病理过程相关，以研究它们与淀粉样蛋白病理学和 tau 相关神经退行性变的关系。
在一项临床和生物标志物确诊的 AD 患者（n=40）和无大脑 AD 病理学的认知健康对照者（n=34）的病例对照研究中，我们进行了代谢谱分析，即非靶向代谢组学和靶向定量。靶向定量侧重于非靶向测定中突出显示的失调途径，即三羧酸（TCA）循环及其补料途径，以及神经活性色氨酸和犬尿氨酸途径。
AD 患者的血浆中 TCA 循环和β-氧化中间产物的浓度较高，而氨基酸浓度显著降低。在 CSF 中观察到这些能量代谢中间产物的类似改变，同时还观察到肌酸浓度升高，肌酸与血脑屏障通透性密切相关。几种氨基酸的改变与 CSF 中的淀粉样β1-42（Aβ1-42）有关。AD 患者 CSF 中的色氨酸分解产物犬尿酸和喹啉酸浓度明显升高，与 CSF 中的 Aβ1-42，或 tau 和磷酸化 tau-181 相关的还有其他色氨酸途径中间产物。
本研究揭示了 AD 相关的系统性营养感应和氧化失调，以及中枢神经系统中神经活性色氨酸途径和（磷酸）肌酸降解的特异性改变。氨基酸和色氨酸分解产物与 AD CSF 生物标志物的特异性关联表明，它们与 AD 的核心病理密切相关。我们的发现需要在独立的更大队列研究中进行验证，并进一步研究性别和 APOE 基因型等因素，以及其他群体，如临床前 AD，以确定代谢改变是否可作为潜在的干预靶点。
