Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, Ohio, 44195.
Neurological Institute, Cleveland Clinic, Cleveland, Ohio, 44195.
Ann Clin Transl Neurol. 2019 Jul;6(7):1248-1262. doi: 10.1002/acn3.50827. Epub 2019 Jul 4.
To determine the key inflammatory pathways that are activated in the peripheral and CNS compartments at the mild cognitive impairment (MCI) stage of Alzheimer's disease (AD).
A cross-sectional study of patients with clinical and biomarker characteristics consistent with MCI-AD in a discovery cohort, with replication in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Inflammatory analytes were measured in the CSF and plasma with the same validated multiplex analyte platform in both cohorts and correlated with AD biomarkers (CSF Aβ42, total tau (t-tau), phosphorylated tau (p-tau) to identify key inflammatory pathway activations. The pathways were additionally validated by evaluating genes related to all analytes in coexpression networks of brain tissue transcriptome from an autopsy confirmed AD cohort to interrogate if the same pathway activations were conserved in the brain tissue gene modules.
Analytes of the tumor necrosis factor (TNF) signaling pathway (KEGG ID:4668) in the CSF and plasma best correlated with CSF t-tau and p-tau levels, and analytes of the complement and coagulation pathway (KEGG ID:4610) best correlated with CSF Aβ42 levels. The top inflammatory signaling pathways of significance were conserved in the peripheral and the CNS compartments. They were also confirmed to be enriched in AD brain transcriptome gene clusters.
A cell-protective rather than a proinflammatory analyte profile predominates in the CSF in relation to neurodegeneration markers among MCI-AD patients. Analytes from the TNF signaling and the complement and coagulation pathways are relevant in evaluating disease severity at the MCI stage of AD.
确定在阿尔茨海默病（AD）轻度认知障碍（MCI）阶段，外周和中枢神经系统中被激活的关键炎症途径。
在发现队列中对具有临床和生物标志物特征与 MCI-AD 一致的患者进行横断面研究，在阿尔茨海默病神经影像学倡议（ADNI）队列中进行复制。在两个队列中使用相同的经过验证的多重分析物平台测量 CSF 和血浆中的炎症分析物，并与 AD 生物标志物（CSF Aβ42、总tau（t-tau）、磷酸化 tau（p-tau））相关，以确定关键的炎症途径激活。通过评估与脑组织转录组中所有分析物相关的基因在尸检证实的 AD 队列的共表达网络中的关系，进一步验证这些途径，以探讨在脑组织基因模块中是否存在相同的途径激活。
CSF 和血浆中的肿瘤坏死因子（TNF）信号通路（KEGG ID：4668）分析物与 CSF t-tau 和 p-tau 水平相关性最好，补体和凝血途径（KEGG ID：4610）分析物与 CSF Aβ42 水平相关性最好。重要的外周和中枢神经系统炎症信号通路具有保守性。它们在 AD 脑组织转录组基因簇中也被证实是丰富的。
与 MCI-AD 患者的神经退行性变标志物相比，CSF 中以细胞保护而非促炎分析物为主。TNF 信号和补体及凝血途径中的分析物在评估 AD MCI 阶段的疾病严重程度方面具有重要意义。
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