Cognitive Disorders Unit, Clinical Neuroscience Research, Hospital Universitari Santa Maria, IRBLleida, Lleida, Spain.
Department of Experimental Medicine, University of Lleida, IRBLleida, Lleida, Spain.
Redox Biol. 2023 Aug;64:102772. doi: 10.1016/j.redox.2023.102772. Epub 2023 Jun 4.
Oxidative stress is considered to play an important role in the pathogenesis of Alzheimer's disease (AD). It has been observed that oxidative damage to specific protein targets affecting particular functional networks is one of the mechanisms by which oxidative stress contributes to neuronal failure and consequently loss of cognition and AD progression. Studies are lacking in which oxidative damage is measured at both systemic and central fluid levels and in the same cohort of patients. We aimed to determine the levels of both plasma and cerebrospinal fluid (CSF) nonenzymatic protein damage in patients in the continuum of AD and to evaluate the relation of this damage with clinical progression from mild cognitive impairment (MCI) to AD.
Different markers of nonenzymatic post-translational protein modification, mostly from oxidative processes, were detected and quantified in plasma and CSF by isotope dilution gas chromatography‒mass spectrometry using selected ion monitoring (SIM-GC/MS) for 289 subjects: 103 AD, 92 MCI, and 94 control subjects. Characteristics of the study population such as age, sex, Mini-mental state examination, CSF AD biomarkers, and APOE ϵ4, were also considered.
Forty-seven (52.8%) MCI patients progressed to AD during follow-up (58 ± 12.5 months). After controlling for age, sex, and APOE ϵ4 allele, plasma and CSF concentrations of protein damage markers were not associated with either diagnosis of AD or MCI. The CSF levels of nonenzymatic protein damage markers were associated with none of the CSF AD biomarkers. In addition, neither in CSF nor in plasma were the levels of protein damage associated with the MCI to AD progression.
The lack of association between both CSF and plasma concentrations of nonenzymatic protein damage markers and AD diagnosis and progression suggests that oxidative damage in AD is a pathogenic mechanism specifically expressed at the cell-tissue level, not in extracellular fluids.
氧化应激被认为在阿尔茨海默病（AD）的发病机制中发挥重要作用。已经观察到，特定蛋白质靶标的氧化损伤会影响特定的功能网络，这是氧化应激导致神经元衰竭以及认知能力下降和 AD 进展的机制之一。目前缺乏在同一批患者中测量系统和中枢液水平的氧化损伤的研究。我们旨在确定 AD 连续体患者的血浆和脑脊液（CSF）中非酶蛋白损伤的水平，并评估这种损伤与从轻度认知障碍（MCI）到 AD 的临床进展的关系。
使用同位素稀释气相色谱-质谱联用（SIM-GC/MS）通过选择离子监测（SIM-GC/MS）检测和定量 289 名受试者（103 名 AD、92 名 MCI 和 94 名对照）的血浆和 CSF 中的多种非酶蛋白翻译后修饰的标志物，这些标志物主要来自氧化过程。还考虑了研究人群的特征，如年龄、性别、简易精神状态检查、CSF AD 生物标志物和 APOE ϵ4。
在随访期间（58±12.5 个月），47 名（52.8%）MCI 患者进展为 AD。在控制年龄、性别和 APOE ϵ4 等位基因后，血浆和 CSF 中蛋白质损伤标志物的浓度与 AD 或 MCI 的诊断均无关。CSF 中非酶蛋白损伤标志物的水平与任何 CSF AD 生物标志物均无关。此外，CSF 和血浆中均未发现蛋白质损伤水平与 MCI 向 AD 进展有关。
CSF 和血浆中非酶蛋白损伤标志物的浓度与 AD 诊断和进展之间缺乏关联表明，AD 中的氧化损伤是一种特定在细胞-组织水平上表达的致病机制，而不是在细胞外液中表达。
