阿尔茨海默病患者血清LncRNA MALAT1、LncRNA NEAT1的表达变化及临床意义

Serum levels and clinical significance of lncRNAs MALAT1 and NEAT1 in patients with Alzheimer's disease

摘要:

目的 分析阿尔茨海默病（AD）患者血清长链非编码RNA（LncRNA）转移相关的肺腺癌转录本1（MALAT1）、LncRNA核旁斑组装转录本1（NEAT1）的表达变化，探讨其是否参与AD炎症反应和认知功能损伤。方法 选取2018年1月—2021年1月青海大学附属医院收治的AD患者93例为AD组，选取同期该院54例体检健康者为对照组。采用实时荧光定量聚合酶链反应检测血清LncRNA MALAT1、LncRNA NEAT1的表达，酶联免疫吸附试验检测血清超敏C反应蛋白（hs-CRP）、白细胞介素-1β（IL-1β）、IL-6、肿瘤坏死因子α（TNF-α）水平，简易精神状态量表（MMSE）评估认知功能。Pearson或Spearman相关性分析AD患者血清LncRNA MALAT1、LncRNA NEAT1表达与病程、MMSE评分、炎症因子的相关性。ROC曲线分析血清炎症指标、LncRNA MALAT1、LncRNA NEAT1表达对AD的诊断价值。结果 AD组血清LncRNA MALAT1相对表达量和MMSE评分低于对照组，LncRNA NEAT1相对表达量高于对照组（P <0.05）。AD组hs-CRP、IL-1β、IL-6、TNF-α水平高于对照组（P <0.05）。Pearson或Spearman相关性分析显示，AD患者血清LncRNA MALAT1表达与MMSE评分呈正相关（r_s =0.587，P <0.05），与hs-CRP、IL-1β、IL-6、TNF-α水平均呈负相关（r_s =-0.522、-0.601、-0.574和-0.577，均P <0.05），LncRNA NEAT1表达与MMSE评分呈负相关（r_s =-0.593，P <0.05），与hs-CRP、IL-1β水平、IL-6、TNF-α均呈正相关（r =0.487、0.588、0.611和0.573，均P <0.05）。ROC曲线显示，血清LncRNA MALAT1诊断AD的AUC为0.915（95% CI：0.858，0.955），最佳临界值为0.98，其对应的敏感性为94.62%（95% CI：87.92，98.22），特异性为81.48%（95% CI：68.61，90.70）；血清LncRNA NEAT1诊断AD的AUC为0.858（95% CI：0.791，0.910），最佳临界值为2.37，其对应的敏感性为90.32%（95% CI：82.45，95.52），特异性为72.22%（95% CI：58.44，83.57）。结论 AD患者血清LncRNA MALAT1低表达、LncRNA NEAT1高表达可能参与AD炎症反应和认知功能损伤，可作为AD的诊断标志物。

Abstract:

Objective To analyze the serum levels of long non-coding RNAs (lncRNAs) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) and nuclear paraspeckle assembly transcript 1 (NEAT1) in patients with Alzheimer's disease (AD) and to explore whether they are involved in the inflammatory response and cognitive impairment in AD.Methods A total of 93 patients with AD admitted to our hospital from January 2018 to January 2021 were selected as the AD group, and another 54 healthy individuals undergoing physical examination during the same period were selected as the control group. Serum levels of lncRNAs MALAT1 and NEAT1 were measured by qRT-PCR, and serum levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) were measured by ELISA. The cognitive function of patients was assessed by the Mini-Mental State Examination (MMSE). Pearson or Spearman method was used to analyze the correlations between serum levels of lncRNAs MALAT1 and NEAT1 and the disease duration, MMSE scores and inflammatory factors in AD patients. ROC curves were used to analyze the diagnostic values of serum inflammatory indicators and expressions of lncRNAs MALAT1 and NEAT1 for AD.Results The serum expression of MALAT1 (Z = -8.381, P = 0.000) and MMSE score (Z = -9.904, P = 0.000) in AD group were lower than those in control group, while the serum expression of NEAT1 (t = 10.479, P = 0.000) in AD group was higher than that in the control group. The serum levels of hs-CRP (t = 14.575, P = 0.000), IL-1β (t = 8.503, P = 0.000), IL-6 (t = 10.739, P = 0.000), and TNF-α (t = 6.522, P = 0.000) in AD group were higher than those in control group (P < 0.05). Pearson or Spearman correlation analysis showed that the expression of serum MALAT1 was positively correlated with MMSE score (r_s = 0.587, P = 0.000), and negatively correlated with hs-CRP (r_s = -0.522, P = 0.000), IL-1β (r_s = -0.601, P = 0.000), IL-6 (r_s = -0.574, P = 0.000), and TNF-α levels (r_s = -0.577, P =0.000) in AD patients. The expression of NEAT1 was negatively correlated with MMSE score (r_s = -0.593, P = 0.000), and positively correlated with the levels of hs-CRP (r = 0.487, P = 0.000), IL-1β (r = 0.588, P = 0.000), IL-6 (r_s = 0.611, P = 0.000) and TNF-α (r = 0.573, P = 0.000). The ROC curve analysis showed that the AUC of serum MALAT1 for the diagnosis of AD was 0.915 (95% CI: 0.858, 0.955), and the optimal cut-off value was 0.98, with the corresponding sensitivity being 94.62% (95% CI: 87.92, 98.22) and the specificity being 81.48% (95% CI: 68.61, 90.70). The AUC of serum NEAT1 for the diagnosis of AD was 0.858 (95% CI: 0.791, 0.910), and the optimal cut-off value was 2.37, with the corresponding sensitivity being 90.32% (95% CI: 82.45, 95.52) and the specificity being 72.22% (95% CI: 58.44, 83.57).Conclusions The low expression of lncRNA MALAT1 and the high expression of lncRNA NEAT1 in the serum may be associated with the inflammatory response and cognitive impairment in AD patients. Thus, they can be established as potential diagnostic markers for AD.