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Abstract：
Understanding the exact pathophysiological mechanisms underlying the involvement of triggering receptor expressed on myeloid cells 2 (TREM2) related microglia activation is crucial for the development of clinical trials targeting microglia activation at different stages of Alzheimer\'s disease (AD). Given the contradictory findings in the literature, it is imperative to investigate the longitudinal alterations in cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) levels as a marker for microglia activation, and its potential association with AD biomarkers, in order to address the current knowledge gap. In this study, we aimed to assess the longitudinal changes in CSF sTREM2 levels within the framework of the A/T/N classification system for AD biomarkers and to explore potential associations with AD pathological features, including the presence of amyloid-beta (Aβ) plaques and tau aggregates. The baseline and longitudinal (any available follow-up visit) CSF sTREM2 levels and processed tau-PET and Aβ-PET data of 1001 subjects were recruited from the ADNI database. The participants were classified into four groups based on the A/T/N framework: A+ /TN+ , A+ /TN- , A- /TN+ , and A- /TN- . Linear regression analyses were conducted to assess the relationship between CSF sTREM2 with cognitive performance, tau and Aβ-PET adjusting for age, gender, education, and APOE ε4 status. Based on our analysis there was a significant difference in baseline and rate of change of CSF sTREM2 between ATN groups. While there was no association between baseline CSF sTREM2 and cognitive performance (ADNI-mem), we found that the rate of change of CSF sTREM2 is significantly associated with cognitive performance in the entire cohort but not the ATN groups. We found that the baseline CSF sTREM2 is significantly associated with baseline tau-PET and Aβ-PET rate of change only in the A+ /TN+ group. A significant association was found between the rate of change of CSF sTREM2 and the tau- and Aβ-PET rate of change only in the A+ /TN- group. Our study suggests that the TREM2-related microglia activation and their relations with AD markers and cognitive performance vary the in presence or absence of Aβ and tau pathology. Furthermore, our findings revealed that a faster increase in the level of CSF sTREM2 might attenuate future Aβ plaque formation and tau aggregate accumulation only in the presence of Aβ pathology.
摘要：
了解与髓样细胞2（TREM2）相关的小胶质细胞活化相关的触发受体参与的确切病理生理机制对于在阿尔茨海默病（AD）的不同阶段开展针对小胶质细胞活化的临床试验至关重要。鉴于文献中矛盾的发现，必须研究脑脊液（CSF）可溶性TREM2（sTREM2）水平的纵向变化作为小胶质细胞活化的标志物，以及它与AD生物标志物的潜在关联，以解决当前的知识差距。在这项研究中,我们旨在评估AD生物标志物A/T/N分类系统框架内CSFsTREM2水平的纵向变化，并探索与AD病理特征的潜在关联，包括β淀粉样蛋白(Aβ)斑块和tau聚集体的存在。从ADNI数据库中招募1001名受试者的基线和纵向（任何可用的随访访问）CSFsTREM2水平以及处理的tau-PET和Aβ-PET数据。根据A/T/N框架将参与者分为四组：A/TN，A+/TN-,A-/TN+,和A-/TN-。进行线性回归分析以评估CSFsTREM2与认知表现之间的关系，tau和Aβ-PET适应年龄，性别,教育,和APOEε4状态。根据我们的分析，ATN组之间的CSFsTREM2的基线和变化率存在显着差异。虽然基线CSFsTREM2和认知表现(ADNI-mem)之间没有关联，我们发现,在整个队列中,CSFsTREM2的变化率与认知能力显著相关,但与ATN组无关.我们发现，仅在A/TN组中，基线CSFsTREM2与基线tau-PET和Aβ-PET变化率显着相关。仅在A/TN-组中，CSFsTREM2的变化率与tau-和Aβ-PET的变化率之间存在显着关联。我们的研究表明，TREM2相关的小胶质细胞激活及其与AD标志物和认知表现的关系在存在或不存在Aβ和tau病理时有所不同。此外，我们的研究结果表明,只有在存在Aβ病理的情况下,CSFsTREM2水平的更快增加可能会减弱未来Aβ斑块形成和tau聚集体积累.
