Morató Xavier, Puerta Raquel, Cano Amanda, Orellana Adelina, de Rojas Itziar, Capdevila María, Montrreal Laura, Rosende-Roca Maitée, García-González Pablo, Olivé Claudia, García-Gutiérrez Fernando, Blázquez Josep, Miguel Andrea, Núñez-Llaves Raúl, Pytel Vanesa, Alegret Montserrat, Fernández María Victoria, Marquié Marta, Valero Sergi, Cavazos Jose Enrique, Mañes Santos, Boada Mercè, Cabrera-Socorro Alfredo, Ruiz Agustín
Ace Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, Spain.
Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
Brain Behav Immun Health. 2024 Nov 16;42:100899. doi: 10.1016/j.bbih.2024.100899. eCollection 2024 Dec.
Despite the central role attributed to neuroinflammation in the etiology and pathobiology of Alzheimer's disease (AD), the direct link between levels of inflammatory mediators in blood and cerebrospinal fluid (CSF) compartments, as well as their potential implications for AD diagnosis and progression, remains inconclusive. Moreover, there is debate on whether inflammation has a protective or detrimental effect on disease onset and progression. Indeed, distinct immunological mechanisms may govern protective and damaging effects at early and late stages, respectively. This study aims to (i) identify inflammatory mediators demonstrating robust correlations between peripheral and central nervous system (CNS) compartments by means of plasma and CSF analysis, respectively, and (ii) assess their potential significance in the context of AD and disease progression from mild cognitive impairment (MCI) to dementia. To achieve this, we have examined the inflammatory profile of a well-defined subcohort comprising 485 individuals from the Ace Alzheimer Center Barcelona (ACE). Employing a hierarchical clustering approach, we thoroughly evaluated the intercompartmental correlations of 63 distinct inflammation mediators, quantified in paired CSF and plasma samples, using advanced SOMAscan technology. Of the array of mediators investigated, only six mediators (CRP, IL1RAP, ILRL1, IL6RA, PDGFRB, and YKL-40) exhibited robust correlations between the central and peripheral compartments (proximity scores <400). To strengthen the validity of our findings, these identified mediators were subsequently validated in a second subcohort of individuals from ACE (n = 873). The observed plasma correlations across the entire cohort consistently have a Spearman rho value above 0.51 (n = 1,360, p < 1.77E-93). Of the high CSF-plasma correlated proteins, only soluble IL6RA (sIL6RA) displayed a statistically significant association with the conversion from MCI to dementia. This association remained robust even after applying a stringent Bonferroni correction (Cox proportional hazard ratio [HR] = 1.936 per standard deviation; p = 0.0018). This association retained its significance when accounting for various factors, including CSF amyloid (Aβ42) and Thr181-phosphorylated tau (p-tau) levels, age, sex, baseline Mini-Mental State Examination (MMSE) score, and potential sampling biases identified through principal component analysis (PCA) modeling. Furthermore, our study confirmed the association of both plasma and CSF levels of SPARC-related modular calcium-binding protein 1 (SMOC1) with amyloid and tau accumulation, indicating their role as early surrogate biomarkers for AD pathology. Despite the lack of a statistically significant correlation between SMOC1 levels in CSF and plasma, both acted as independent biomarkers of disease progression (HR > 1.3, p < 0.002). In conclusion, our study unveils that sIL6RA and SMOC1 are associated with MCI progression. The absence of correlations among inflammatory mediators between the central and peripheral compartments appears to be a common pattern, with only a few intriguing exceptions.
尽管神经炎症在阿尔茨海默病（AD）的病因和病理生物学中被认为起着核心作用，但血液和脑脊液（CSF）隔室中炎症介质水平之间的直接联系，以及它们对AD诊断和病情进展的潜在影响，仍尚无定论。此外，关于炎症对疾病的发生和进展是具有保护作用还是有害作用也存在争议。事实上，不同的免疫机制可能分别在疾病的早期和晚期阶段发挥保护和损害作用。本研究旨在：（i）通过分别对血浆和脑脊液进行分析，确定在外周和中枢神经系统（CNS）隔室之间表现出强相关性的炎症介质；（ii）评估它们在AD以及从轻度认知障碍（MCI）到痴呆的疾病进展中的潜在意义。为实现这一目标，我们研究了来自巴塞罗那阿兹海默中心（ACE）的485名个体组成的明确亚组的炎症特征。采用分层聚类方法，我们使用先进的SOMAscan技术，对配对的脑脊液和血浆样本中定量的63种不同炎症介质的隔室间相关性进行了全面评估。在所研究的一系列介质中，只有六种介质（CRP、IL1RAP、ILRL1、IL6RA、PDGFRB和YKL - 40）在中枢和外周隔室之间表现出强相关性（接近分数<400）。为加强我们研究结果的有效性，随后在ACE的第二个个体亚组（n = 873）中对这些已确定的介质进行了验证。在整个队列中观察到的血浆相关性的Spearman rho值始终高于0.51（n = 1,360，p < 1.77E - 93）。在脑脊液与血浆高度相关的蛋白质中，只有可溶性IL6RA（sIL6RA）与从MCI向痴呆的转化存在统计学上的显著关联。即使应用严格的Bonferroni校正后，这种关联仍然很强（Cox比例风险比[HR] = 每标准差1.936；p = 0.0018）。当考虑各种因素时，这种关联仍然具有显著性，这些因素包括脑脊液淀粉样蛋白（Aβ42）和苏氨酸181磷酸化tau（p - tau）水平、年龄、性别、基线简易精神状态检查表（MMSE）评分以及通过主成分分析（PCA）模型确定的潜在采样偏差。此外，我们的研究证实了与淀粉样蛋白和tau积累相关的血浆和脑脊液中SPARC相关模块化钙结合蛋白1（SMOC1）水平，表明它们作为AD病理学早期替代生物标志物的作用。尽管脑脊液和血浆中SMOC1水平之间缺乏统计学上的显著相关性，但两者均作为疾病进展的独立生物标志物（HR > 1.3，p < 0.002）。总之，我们的研究揭示sIL6RA和SMOC1与MCI进展相关。中枢和外周隔室之间炎症介质缺乏相关性似乎是一种常见模式，只有少数有趣的例外情况。
