Neurochemistry Laboratory, Department of Laboratory Medicine, Amsterdam Neuroscience, VU University Medical Center, Amsterdam UMC, Amsterdam, The Netherlands.
Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, Spain.
J Neuroinflammation. 2023 May 5;20(1):107. doi: 10.1186/s12974-023-02796-9.
There is a need for novel fluid biomarkers tracking neuroinflammatory responses in Alzheimer's disease (AD). Our recent cerebrospinal fluid (CSF) proteomics study revealed that migration inhibitory factor (MIF) and soluble triggering receptor expressed on myeloid cells 1 (sTREM1) increased along the AD continuum. We aimed to assess the potential use of these proteins, in addition to sTREM2, as CSF biomarkers to monitor inflammatory processes in AD.
We included cognitively unimpaired controls (n = 67, 63 ± 9 years, 24% females, all amyloid negative), patients with mild cognitive impairment (MCI; n = 92, 65 ± 7 years, 47% females, 65% amyloid positive), AD (n = 38, 67 ± 6 years, 8% females, all amyloid positive), and DLB (n = 50, 67 ± 6 years, 5% females, 54% amyloid positive). MIF, sTREM1, and sTREM2 levels were measured by validated immunoassays. Differences in protein levels between groups were tested with analysis of covariance (corrected for age and sex). Spearman correlation analysis was performed to evaluate the association between these neuroinflammatory markers with AD-CSF biomarkers (Aβ42, tTau, pTau) and mini-mental state examination (MMSE) scores.
MIF levels were increased in MCI (p < 0.01), AD (p < 0.05), and DLB (p > 0.05) compared to controls. Levels of sTREM1 were specifically increased in AD compared to controls (p < 0.01), MCI (p < 0.05), and DLB patients (p > 0.05), while sTREM2 levels were increased specifically in MCI compared to all other groups (all p < 0.001). Neuroinflammatory proteins were highly correlated with CSF pTau levels (MIF: all groups; sTREM1: MCI, AD and DLB; sTREM2: controls, MCI and DLB). Correlations with MMSE scores were observed in specific clinical groups (MIF in controls, sTREM1 in AD, and sTREM2 in DLB).
Inflammatory-related proteins show diverse expression profiles along different AD stages, with increased protein levels in the MCI stage (MIF and sTREM2) and AD stage (MIF and sTREM1). The associations of these inflammatory markers primarily with CSF pTau levels indicate an intertwined relationship between tau pathology and inflammation. These neuroinflammatory markers might be useful in clinical trials to capture dynamics in inflammatory responses or monitor drug-target engagement of inflammatory modulators.
需要新型的液体生物标志物来跟踪阿尔茨海默病（AD）中的神经炎症反应。我们最近的脑脊液（CSF）蛋白质组学研究表明，迁移抑制因子（MIF）和髓样细胞表达的可溶性触发受体 1（sTREM1）在 AD 连续体中增加。我们旨在评估这些蛋白（除 sTREM2 外）作为 CSF 生物标志物监测 AD 中炎症过程的潜力。
我们纳入了认知正常的对照组（n=67，63±9 岁，24%为女性，均为淀粉样蛋白阴性）、轻度认知障碍（MCI；n=92，65±7 岁，47%为女性，65%为淀粉样蛋白阳性）、AD（n=38，67±6 岁，8%为女性，均为淀粉样蛋白阳性）和路易体痴呆（DLB；n=50，67±6 岁，5%为女性，54%为淀粉样蛋白阳性）患者。通过验证的免疫测定法测量 MIF、sTREM1 和 sTREM2 水平。使用协方差分析（校正年龄和性别）检验组间蛋白水平的差异。采用 Spearman 相关分析评估这些神经炎症标志物与 AD-CSF 生物标志物（Aβ42、tTau、pTau）和简易精神状态检查（MMSE）评分之间的相关性。
与对照组相比，MCI（p<0.01）、AD（p<0.05）和 DLB（p>0.05）患者的 MIF 水平升高。与对照组相比，sTREM1 水平仅在 AD 中升高（p<0.01）、MCI（p<0.05）和 DLB 患者（p>0.05）中升高，而 sTREM2 水平仅在 MCI 中升高与所有其他组相比（均 p<0.001）。神经炎症蛋白与 CSF pTau 水平高度相关（MIF：所有组；sTREM1：MCI、AD 和 DLB；sTREM2：对照组、MCI 和 DLB）。在特定的临床组中观察到与 MMSE 评分的相关性（MIF 在对照组中，sTREM1 在 AD 中，sTREM2 在 DLB 中）。
炎症相关蛋白在不同的 AD 阶段表现出不同的表达谱，在 MCI 阶段（MIF 和 sTREM2）和 AD 阶段（MIF 和 sTREM1）中蛋白水平升高。这些炎症标志物主要与 CSF pTau 水平相关，表明 Tau 病理学与炎症之间存在交织关系。这些神经炎症标志物可能在临床试验中有用，以捕捉炎症反应的动态或监测炎症调节剂的药物靶向结合。
