Galgani Alessandro, Vergallo Andrea, Campese Nicole, Lombardo Francesco, Pavese Nicola, Petrozzi Lucia, LoGerfo Annalisa, Franzini Maria, Cecchetti Denise, Puglisi-Allegra Stefano, Busceti Carla L, Siciliano Gabriele, Tognoni Gloria, Baldacci Filippo, Lista Simone, Hampel Harald, Fornai Francesco, Giorgi Filippo S
Neurology Unit, Pisa University Hospital, Pisa, Italy.
Sorbonne University, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France.
J Neurochem. 2022 Oct;163(1):40-52. doi: 10.1111/jnc.15686. Epub 2022 Aug 22.
Converging translational and clinical research strongly indicates that altered immune and inflammatory homeostasis (neuroinflammation) plays a critical pathophysiological role in Alzheimer's disease (AD), across the clinical continuum. A dualistic role of neuroinflammation may account for a complex biological phenomenon, representing a potential pharmacological target. Emerging blood-based pathophysiological biomarkers, such as cytokines (Cyt) and interleukins (ILs), have been studied as indicators of neuroinflammation in AD. However, inconsistent results have been reported probably due to a lack of standardization of assays with methodological and analytical differences. We used machine-learning and a cross-validation-based statical workflow to explore and analyze the potential impact of key biological factors, such as age, sex, and apolipoprotein-E (APOE) genotype (the major genetic risk factor for late-onset AD) on Cyt. A set of Cyt was selected based on previous literature, and we investigated any potential association in a pooled cohort of cognitively healthy, mild cognitive impairment (MCI), and AD-like dementia patients. We also performed explorative analyses to extrapolate preliminary clinical insights. We found a robust sex effect on IL12 and an APOE-related difference in IL10, with the latter being also related to the presence of advanced cognitive decline. IL1β was the variable most significantly associated with MCI-to-dementia conversion over a 2.5 year-clinical follow-up. Although preliminary, our data support further clinical research to understand whether plasma Cyt may represent reliable and noninvasive tools serving the investigation of neuroimmune and inflammatory dynamics in AD and to foster biomarker-guided pathway-based therapeutic approaches, within the precision medicine development framework.
越来越多的转化研究和临床研究有力地表明，免疫和炎症稳态改变（神经炎症）在阿尔茨海默病（AD）整个临床过程中发挥着关键的病理生理作用。神经炎症的双重作用可能解释了一种复杂的生物学现象，这代表了一个潜在的药理学靶点。新兴的基于血液的病理生理生物标志物，如细胞因子（Cyt）和白细胞介素（ILs），已被作为AD中神经炎症的指标进行研究。然而，由于检测方法和分析存在差异，缺乏标准化，因此报告的结果并不一致。我们使用机器学习和基于交叉验证的统计工作流程，来探索和分析年龄、性别和载脂蛋白E（APOE）基因型（晚发性AD的主要遗传风险因素）等关键生物学因素对细胞因子的潜在影响。根据先前的文献选择了一组细胞因子，我们在认知健康、轻度认知障碍（MCI）和AD样痴呆患者的汇总队列中研究了任何潜在关联。我们还进行了探索性分析以推断初步的临床见解。我们发现IL12存在明显的性别效应，IL10存在与APOE相关的差异，后者也与严重认知衰退的存在有关。在2.5年的临床随访中，IL1β是与MCI向痴呆转化最显著相关的变量。尽管我们的数据尚属初步，但支持进一步的临床研究，以了解血浆细胞因子是否可作为可靠的非侵入性工具，用于研究AD中的神经免疫和炎症动态，并在精准医学发展框架内促进基于生物标志物引导的通路治疗方法。
