阿尔茨海默病患者血浆和脑组织中靶向代谢组学分析。
Targeted Metabolomic Analysis in Alzheimer's Disease Plasma and Brain Tissue in Non-Hispanic Whites.
机构信息
Institute of Biomedical Studies, Baylor University, Waco, TX, USA.
Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, USA.
出版信息
J Alzheimers Dis. 2022;86(4):1875-1895. doi: 10.3233/JAD-215448.
BACKGROUND
Metabolites are biological compounds reflecting the functional activity of organs and tissues. Understanding metabolic changes in Alzheimer's disease (AD) can provide insight into potential risk factors in this multifactorial disease and suggest new intervention strategies or improve non-invasive diagnosis.
OBJECTIVE
In this study, we searched for changes in AD metabolism in plasma and frontal brain cortex tissue samples and evaluated the performance of plasma measurements as biomarkers.
METHODS
This is a case-control study with two tissue cohorts: 158 plasma samples (94 AD, 64 controls; Texas Alzheimer's Research and Care Consortium - TARCC) and 71 postmortem cortex samples (35 AD, 36 controls; Banner Sun Health Research Institute brain bank). We performed targeted mass spectrometry analysis of 630 compounds (106 small molecules: UHPLC-MS/MS, 524 lipids: FIA-MS/MS) and 232 calculated metabolic indicators with a metabolomic kit (Biocrates MxP® Quant 500).
RESULTS
We discovered disturbances (FDR≤0.05) in multiple metabolic pathways in AD in both cohorts including microbiome-related metabolites with pro-toxic changes, methylhistidine metabolism, polyamines, corticosteroids, omega-3 fatty acids, acylcarnitines, ceramides, and diglycerides. In AD, plasma reveals elevated triglycerides, and cortex shows altered amino acid metabolism. A cross-validated diagnostic prediction model from plasma achieves AUC = 82% (CI95 = 75-88%); for females specifically, AUC = 88% (CI95 = 80-95%). A reduced model using 20 features achieves AUC = 79% (CI95 = 71-85%); for females AUC = 84% (CI95 = 74-92%).
CONCLUSION
Our findings support the involvement of gut environment in AD and encourage targeting multiple metabolic areas in the design of intervention strategies, including microbiome composition, hormonal balance, nutrients, and muscle homeostasis.
背景
代谢物是反映器官和组织功能活动的生物化合物。了解阿尔茨海默病（AD）中的代谢变化可以深入了解这种多因素疾病的潜在风险因素，并为新的干预策略提供思路或改善非侵入性诊断。
目的
本研究旨在寻找 AD 患者血浆和额叶脑皮质组织样本中的代谢变化，并评估血浆检测作为生物标志物的性能。
方法
这是一项病例对照研究，包含两个组织队列：158 份血浆样本（94 例 AD，64 例对照；德克萨斯州阿尔茨海默病研究与护理联合会 - TARCC）和 71 份死后皮质样本（35 例 AD，36 例对照；班纳太阳健康研究协会脑库）。我们使用代谢组学试剂盒（Biocrates MxP® Quant 500）对 630 种化合物（106 种小分子：UHPLC-MS/MS，524 种脂质：FIA-MS/MS）和 232 种计算代谢指标进行了靶向质谱分析。
结果
我们在两个队列的 AD 中均发现了多种代谢途径的紊乱（FDR≤0.05），包括与促毒性变化相关的微生物组代谢物、甲基组氨酸代谢、多胺、皮质类固醇、ω-3 脂肪酸、酰基辅酶 A、神经酰胺和双甘油酯。在 AD 中，血浆中发现甘油三酯升高，皮质中发现氨基酸代谢改变。来自血浆的经过交叉验证的诊断预测模型的 AUC 为 82%（95%CI95%=75-88%）；对于女性，AUC 为 88%（95%CI95%=80-95%）。使用 20 个特征的简化模型的 AUC 为 79%（95%CI95%=71-85%）；对于女性，AUC 为 84%（95%CI95%=74-92%）。
结论
我们的研究结果支持肠道环境在 AD 中的作用，并鼓励在干预策略的设计中靶向多个代谢区域，包括微生物组组成、激素平衡、营养物质和肌肉稳态。
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