Childs Ryan, Karamacoska Diana, Lim Chai K, Steiner-Lim Genevieve Z
NICM Health Research Institute, Western Sydney University, Penrith, NSW, 2751, Australia.
Faculty of Medicine, Health, and Human Sciences, Macquarie University, Macquarie Park NSW, 2190, Australia.
Brain Behav Immun Health. 2024 Jul 20;40:100819. doi: 10.1016/j.bbih.2024.100819. eCollection 2024 Oct.
Chronic inflammation is recognised as an important component of Alzheimer's disease (AD), yet its relationship with cognitive decline, sex-differences, and age is not well understood. This study investigated the relationship between inflammatory markers, cognition, sex, and age in individuals with mild cognitive impairment (MCI) and AD.
A systematic review was performed to identify case-control studies which measured cognitive function and inflammatory markers in serum, plasma, and cerebrospinal fluid in individuals with MCI or AD compared with healthy control (HC) participants. Meta-analysis was performed with Hedges' calculated in a random effects model. Meta-regression was conducted using age, sex, and mini-mental status exam (MMSE) values.
A total of 106 studies without a high risk of bias were included in the meta-analysis including 18,145 individuals: 5625 AD participants, 3907 MCI participants, and 8613 HC participants. Combined serum and plasma meta-analysis found that IL1β, IL6, IL8, IL18, CRP, and hsCRP were significantly raised in individuals with AD compared to HC. In CSF, YKL40, and MCP-1 were raised in AD compared to HC. YKL40 was also raised in MCI compared to HC. Meta-regression analysis highlighted several novel findings: MMSE was negatively correlated with IL6 and positively correlated with IL1α in AD, while in MCI studies, MMSE was negatively correlated with IL8 and TNFα. Meta-regression also revealed sex-specific differences in levels of IL1α, IL4, IL6, IL18, hsCRP, MCP-1, and YKL-40 across AD and MCI studies, and age was found to account for heterogeneity of CRP, MCP-1, and IL4 in MCI and AD.
Elevated levels of IL6 and YKL40 may reflect microglial inflammatory activity in both MCI and AD. Systemic inflammation may interact with the central nervous system, as poor cognitive function in individuals with AD and MCI was associated with higher levels of serum and plasma proinflammatory cytokines IL6 and TNFα. Moreover, variations of systemic inflammation between males and females may be modulated by sex-specific hormonal changes, such as declining oestrogen levels in females throughout the menopause transition. Longitudinal studies sampling a range of biospecimen types are needed to elucidate the nuances of the relationship between inflammation and cognition in individuals with MCI and AD, and understand how systemic and central inflammation differentially impact cognitive function.
慢性炎症被认为是阿尔茨海默病（AD）的一个重要组成部分，但其与认知衰退、性别差异和年龄的关系尚未完全明确。本研究调查了轻度认知障碍（MCI）和AD患者炎症标志物、认知、性别和年龄之间的关系。
进行了一项系统综述，以确定病例对照研究，这些研究测量了MCI或AD患者与健康对照（HC）参与者血清、血浆和脑脊液中的认知功能和炎症标志物。采用随机效应模型计算的Hedges'进行荟萃分析。使用年龄、性别和简易精神状态检查（MMSE）值进行荟萃回归分析。
荟萃分析共纳入106项无高偏倚风险的研究，包括18145名个体：5625名AD参与者、3907名MCI参与者和8613名HC参与者。血清和血浆联合荟萃分析发现，与HC相比，AD患者的IL1β、IL6、IL8、IL18、CRP和hsCRP显著升高。在脑脊液中，与HC相比，AD患者的YKL40和MCP-1升高。与HC相比，MCI患者的YKL40也升高。荟萃回归分析突出了几个新发现：在AD中，MMSE与IL6呈负相关，与IL1α呈正相关，而在MCI研究中，MMSE与IL8和TNFα呈负相关。荟萃回归还揭示了AD和MCI研究中IL1α、IL4、IL6、IL18、hsCRP、MCP-1和YKL-40水平的性别特异性差异，并且发现年龄是MCI和AD中CRP、MCP-1和IL4异质性的原因。
IL6和YKL40水平升高可能反映了MCI和AD中的小胶质细胞炎症活动。全身炎症可能与中枢神经系统相互作用，因为AD和MCI患者的认知功能较差与血清和血浆促炎细胞因子IL6和TNFα水平较高有关。此外，男性和女性之间全身炎症的差异可能受性别特异性激素变化的调节，例如女性在整个绝经过渡期间雌激素水平下降。需要对一系列生物样本类型进行纵向研究，以阐明MCI和AD患者炎症与认知之间关系的细微差别，并了解全身炎症和中枢炎症如何不同地影响认知功能。
