Association between plasma levels of IL-6 and TNF-α and mild cognitive impairment in the elderly
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摘要:
目的 分析广东老年人(≥65岁)血浆白细胞介素-6(interleukin-6, IL-6)、肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)水平与轻度认知功能障碍(mild cognitive impairment, MCI)的关联。 方法 选取广东某社区卫生服务中心就诊的48例老年MCI患者作为病例组,96例无MCI的老年人作为对照组。采用logistic回归分析血浆IL-6、TNF-α水平与MCI的关联。绘制受试者工作特征(receiver operating characteristic, ROC)曲线评估血浆IL-6、TNF-α水平对MCI的诊断价值。 结果 共纳入144名老年人,其中48名MCI患者,63名男性(43.8%)。多因素logistic回归分析结果显示,血浆IL-6、TNF-α水平升高可使MCI患病风险增加,血浆IL-6、TNF-α水平每增高1个s,MCI患病风险分别增加53%和51%(OR=1.53, 95% CI: 1.02~2.29, P=0.040; OR=1.51, 95% CI: 1.04~2.20, P=0.029)。血浆IL-6、TNF-α的ROC曲线下面积分别为0.60、0.64。 结论 血浆IL-6和TNF-α水平升高可能与≥65岁老年人MCI患病风险的增加有关。 Abstract:Objective To analyze the association between plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and mild cognitive impairment (MCI) in elderly individuals aged 65 years and older in Guangdong. Methods A total of 48 MCI elderly patients who visited a community health service center in Guangdong were selected as the case group, while 96 non-MCI individuals served as controls. Logistic regression models were used to analyze the association between plasma levels of IL-6 and TNF-α and MCI. Receiver operating characteristic (ROC) curves were plotted to evaluate the diagnostic value of plasma levels of IL-6 and TNF-α for MCI. Results A total of 144 elderly individuals were enrolled, including 48 MCI patients and 63 males (43.8%). The results of the multivariate logistic regression models showed that increased plasma levels of IL-6 and TNF-α could lead to a higher risk of MCI. Specifically, the risk of MCI increased by 53% and 51% for each standard deviation increase in plasma levels of IL-6 and TNF-α, respectively (OR=1.53, 95% CI: 1.02-2.29, P=0.040; OR=1.51, 95% CI: 1.04-2.20, P=0.029). The areas under the ROC curves for IL-6 and TNF-α were 0.60 and 0.64, respectively. Conclusions The increased risk of MCI in individuals aged 65 years and older may be associated with elevated plasma levels of IL-6 and TNF-α. -
Key words:
- Elderly /
- Mild cognitive impairment /
- Interleukin-6 /
- Tumor necrosis factor-α /
- Case-control study
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轻度认知功能障碍(mild cognitive impairment, MCI)是阿尔茨海默病(Alzheimer′s disease, AD)的临床前期阶段,通过早期、有效地干预和治疗,可逆转并持续改善MCI患者记忆下降等认知功能损害[1]。因此,正确识别、诊断、治疗MCI,是延缓AD进程的关键环节[2-3]。
有研究表明炎症因子如白细胞介素-6(interleukin-6, IL-6)和肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)在AD和MCI的神经退行性病变中起着重要作用[4]。部分研究发现血浆IL-6、TNF-α水平与AD存在相关性,与健康对照组相比,AD组的血浆炎症因子水平更高,但也有研究未得出一致结果,有必要开展进一步研究[5-8]。血浆炎症因子具有易获取、易检测、相对无创的优点,且大多数研究集中探讨AD阶段的炎症反应,较少关注MCI与炎症因子的关联。因此,本研究拟分析广东≥65岁老年人血浆IL-6、TNF-α水平与MCI的关联,为早期识别、诊断、治疗MCI提供科学依据。
1. 对象与方法
1.1 研究对象
采用病例对照研究方法,选取2018―2022年在广东某社区卫生服务中心就诊的48例老年(年龄≥65岁)MCI患者作为病例组。本研究MCI组的诊断标准与《阿尔茨海默病源性轻度认知障碍诊疗中国专家共识2021》指出MCI临床诊断标准相符[9],依据简易精神状态检查量表(mini-mental state examination, MMSE)进行认知功能评估:MMSE评分文盲≤17分,受教育1~6年≤20分,受教育>6年≤24分。同期在该社区卫生服务中心按性别相同、年龄相差不超过3岁,选取96例无MCI的老年人作为对照组。所有研究对象均接受问卷调查、认知功能评估和血液样本采集。本研究经南方医科大学伦理委员会批准(伦理审批号:南医伦审[2023]第42号),所有研究对象或其家属已签署知情同意书。
1.2 变量定义
吸烟定义为在过去半年内每天至少吸1支烟;饮酒定义为在过去半年内喝过酒;锻炼定义为在过去半年内每周锻炼至少1次。
1.3 统计学方法
应用SPSS 25.0软件进行统计分析,年龄、IL-6、TNF-α等非正态分布计量资料采用M(P25,P75)表示,计数资料采用频数和频率表示,组间比较分别采用Mann-Whitney U检验或χ2检验。采用logistic回归分析IL-6、TNF-α水平与MCI的关联。采用受试者工作特征(receiver operating characteristic, ROC)曲线及曲线下面积(area under the curve, AUC)评估血浆IL-6、TNF-α水平对MCI的诊断价值。检验水准α=0.05。
2. 结果
2.1 研究对象基本特征
纳入144名年龄≥65岁老年人,其中MCI患者48名,男性63人(43.8%),年龄为72.0(69.0, 80.0)岁。与对照组相比,MCI组血浆IL-6、TNF-α水平较高,差异均有统计学意义(Z=-1.973, P=0.049; Z=-2.712, P=0.007)。见表 1。
表 1 研究对象基本特征Table 1. Basic characteristics of the study subjects变量Variable 总人数 ①Total ①(n=144) 对照组 ①Control group ①(n=96) MCI组 ①group ①(n=48) χ2/Z值value P值value 年龄/岁Age/years 72.0(69.0, 80.0) 72.5(69.0, 80.8) 71.5(69.0, 80.0) -0.117 0.907 性别Gender 0.001 0.999 男Male 63(43.8) 42(43.8) 21(43.8) 女Female 81(56.2) 54(56.2) 27(56.2) 婚姻状况Marital status 0.077 0.781 在婚Married 110(76.4) 74(77.1) 36(75.0) 其他Other 34(23.6) 22(22.9) 12(25.0) 吸烟Smoking 0.054 0.817 否No 134(93.1) 89(92.7) 45(93.8) 是Yes 10(6.9) 7(7.3) 3(6.2) 饮酒Drinking 0.030 0.862 否No 125(86.8) 83(86.5) 42(87.5) 是Yes 19(13.2) 13(13.5) 6(12.5) 锻炼情况Exercise status 0.286 0.593 是Yes 126(87.5) 85(88.5) 41(85.4) 否No 18(12.5) 11(11.5) 7(14.6) 高血压Hypertension 0.694 0.405 否No 62(43.1) 39(40.6) 23(47.9) 是Yes 82(56.9) 57(59.4) 25(52.1) 糖尿病Diabetes 0.758 0.384 否No 114(79.2) 74(77.1) 40(83.3) 是Yes 30(20.8) 22(22.9) 8(16.7) 冠状动脉粥样硬化Coronary heart disease 2.133 0.144 否No 135(93.8) 88(91.7) 47(97.9) 是Yes 9(6.2) 8(8.3) 1(2.1) 脑血管病Cerebrovascular disease 0.414 0.520 否No 139(96.5) 92(95.8) 47(97.9) 是Yes 5(3.5) 4(4.2) 1(2.1) 关节炎Arthritis 2.532 0.112 否No 130(90.3) 84(87.5) 46(95.8) 是Yes 14(9.7) 12(12.5) 2(4.2) IL-6/(ng·L-1) 13.87(11.05, 17.92) 13.41(9.80, 17.67) 14.93(11.96, 19.89) -1.973 0.049 TNF-α/(ng·L-1) 302.78(195.19, 393.37) 265.42(190.71, 374.09) 375.80(236.85, 432.99) -2.712 0.007 注:①以人数(占比/%)或M(P25,P75)表示。
Note: ① Number of people (proportion/%) or M(P25,P75).2.2 血浆IL-6、TNF-α水平与MCI的关联
logistic回归分析模型调整了相关混杂因素后,结果显示血浆IL-6、TNF-α水平每增高1个s,MCI患病风险分别增加53%和51%(OR=1.53, 95% CI: 1.02~2.29, P=0.040; OR=1.51, 95% CI: 1.04~2.20, P=0.029)。与第一水平组相比,第四水平组老年人IL-6和TNF-α的OR值(95% CI)分别为4.14(1.28~13.40)和3.13(1.09~8.97)。随着血浆IL-6、TNF-α水平升高,老年人MCI发生风险呈逐渐上升趋势(Ptrend<0.05)。见表 2。
表 2 血浆IL-6、TNF-α水平与MCI的关联Table 2. Association between IL-6, TNF-α and MCI变量Variable 人数Number of people 模型1 Model 1 模型2 Model 2 模型3 Model 3 OR值value(95% CI) P值value OR值value(95% CI) P值value OR值value(95% CI) P值value IL-6/(ng·L-1) 144 1.43(0.99~2.07) 0.054 1.50(1.02~2.18) 0.039 1.53(1.02~2.29) 0.040 <11.10 36 1.00 1.00 1.00 11.10~<13.90 36 3.24(1.07~9.83) 0.038 3.22(1.04~9.97) 0.042 3.53(1.11~11.21) 0.032 13.90~<17.90 36 3.30(1.07~10.14) 0.037 3.51(1.09~11.34) 0.036 3.37(1.02~11.17) 0.047 ≥17.90 36 3.24(1.07~9.83) 0.038 3.54(1.13~11.03) 0.030 4.14(1.28~13.40) 0.018 Ptrend 0.059 0.045 0.032 TNF-α/(ng·L-1) 144 1.43(1.01~2.04) 0.047 1.51(1.05~2.17) 0.025 1.51(1.04~2.20) 0.029 <194.20 36 1.00 1.00 1.00 194.20~<297.20 36 0.72(0.23~2.22) 0.566 0.75(0.24~2.36) 0.627 0.68(0.21~2.18) 0.519 297.20~<391.88 36 2.13(0.77~5.91) 0.145 2.45(0.85~7.03) 0.096 2.26(0.76~6.70) 0.142 ≥391.88 36 2.67(0.98~7.28) 0.055 2.99(1.07~8.34) 0.037 3.13(1.09~8.97) 0.034 Ptrend 0.013 0.008 0.008 注:模型1,调整年龄、性别;模型2,在模型1的基础上进一步调整婚姻状况、吸烟、饮酒、锻炼;模型3,在模型2的基础上进一步调整高血压、糖尿病、冠状动脉粥样硬化、脑血管病及关节炎患病情况。
Notes: Model 1, adjusting for age, gender; Model 2, on the basis of model 1, marital status, smoking, drinking, exercise were adjusted; Model 3, on the basis of model 2, hypertension, diabetes, coronary heart disease, cerebrovascular disease, arthritis were adjusted.2.3 血浆IL-6、TNF-α水平与MCI的ROC曲线分析
ROC曲线结果显示,血浆IL-6、TNF-α水平的AUC分别为0.60、0.64,诊断临界值分别为11.31 ng/L、353.86 ng/L。见表 3。
表 3 血浆IL-6、TNF-α水平对MCI的诊断价值Table 3. Diagnostic value of plasma levels of IL-6 and TNF-α for MCI变量Variable AUC 95% CI P值value 诊断临界值/(ng·L-1)Cut-off point/(ng·L-1) 约登指数Youden index 灵敏度/%Sensitivity/% 特异度/%Specificity/% IL-6/(ng·L-1) 0.60 0.51~0.69 0.049 11.31 0.24 87.50 36.50 TNF-α/(ng·L-1) 0.64 0.54~0.74 0.007 353.86 0.32 62.50 69.80 3. 讨论
本研究开展144名≥65岁老年人血浆IL-6、TNF-α水平与MCI的关联研究。结果显示,在调整混杂因素后,老年人MCI患病风险可能随着血浆IL-6、TNF-α水平升高而增大。此外,本研究探讨血浆IL-6、TNF-α水平对老年人MCI的诊断价值,研究所得的AUC分别为0.60、0.64,提示该模型具备一定的诊断能力。此前已有研究表明IL-6、TNF-α等炎症因子是认知功能受损的危险因素[10]。一项Meta分析纳入了170项测量外周血或脑脊液炎症因子的研究,结果显示与正常对照组相比,MCI组外周血IL-6水平较高[4]。
越来越多研究表明,炎症因子IL-6、TNF-α参与了MCI和AD的病理过程。外周炎症因子可引起血脑屏障(blood-brain barrier, BBB)功能损伤,导致BBB通透性提高,外周炎症因子通过BBB进入中枢神经系统,激活中枢免疫细胞如小胶质细胞等,造成神经元损伤或死亡,最终导致脑组织损伤[11-12]。小胶质细胞激活可能导致β-淀粉样蛋白(amyloid β-protein, Aβ)沉积增加,而Aβ也已被证明可诱导小胶质细胞和星形胶质细胞释放更多的炎症因子,激活氧化应激反应,从而加重脑神经损伤[4, 13]。由此可见,炎症因子在AD和MCI的神经退行性病变中起着重要作用。
本研究具有一定的局限性:一是本研究样本量较小且所有研究对象均来自广东,存在地域局限性,结果的外推仍待验证。二是仅分析了血浆IL-6、TNF-α水平与MCI的关联,未探究其他各类细胞因子与MCI的相关性,如干扰素、趋化因子等,需进一步探寻其他血浆炎症标志物。
综上所述,血浆IL-6、TNF-α水平升高可能与老年人MCI患病风险增高相关,对老年人MCI发生有一定的诊断价值。定期监测老年人群血浆IL-6、TNF-α水平,及时有效地治疗急性炎症,预防慢性炎症,可有效降低老年人MCI患病风险,延缓AD疾病进程,延长健康寿命年,减轻医疗负担,最终实现健康老龄化。
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表 1 研究对象基本特征
Table 1. Basic characteristics of the study subjects
变量Variable 总人数 ①Total ①(n=144) 对照组 ①Control group ①(n=96) MCI组 ①group ①(n=48) χ2/Z值value P值value 年龄/岁Age/years 72.0(69.0, 80.0) 72.5(69.0, 80.8) 71.5(69.0, 80.0) -0.117 0.907 性别Gender 0.001 0.999 男Male 63(43.8) 42(43.8) 21(43.8) 女Female 81(56.2) 54(56.2) 27(56.2) 婚姻状况Marital status 0.077 0.781 在婚Married 110(76.4) 74(77.1) 36(75.0) 其他Other 34(23.6) 22(22.9) 12(25.0) 吸烟Smoking 0.054 0.817 否No 134(93.1) 89(92.7) 45(93.8) 是Yes 10(6.9) 7(7.3) 3(6.2) 饮酒Drinking 0.030 0.862 否No 125(86.8) 83(86.5) 42(87.5) 是Yes 19(13.2) 13(13.5) 6(12.5) 锻炼情况Exercise status 0.286 0.593 是Yes 126(87.5) 85(88.5) 41(85.4) 否No 18(12.5) 11(11.5) 7(14.6) 高血压Hypertension 0.694 0.405 否No 62(43.1) 39(40.6) 23(47.9) 是Yes 82(56.9) 57(59.4) 25(52.1) 糖尿病Diabetes 0.758 0.384 否No 114(79.2) 74(77.1) 40(83.3) 是Yes 30(20.8) 22(22.9) 8(16.7) 冠状动脉粥样硬化Coronary heart disease 2.133 0.144 否No 135(93.8) 88(91.7) 47(97.9) 是Yes 9(6.2) 8(8.3) 1(2.1) 脑血管病Cerebrovascular disease 0.414 0.520 否No 139(96.5) 92(95.8) 47(97.9) 是Yes 5(3.5) 4(4.2) 1(2.1) 关节炎Arthritis 2.532 0.112 否No 130(90.3) 84(87.5) 46(95.8) 是Yes 14(9.7) 12(12.5) 2(4.2) IL-6/(ng·L-1) 13.87(11.05, 17.92) 13.41(9.80, 17.67) 14.93(11.96, 19.89) -1.973 0.049 TNF-α/(ng·L-1) 302.78(195.19, 393.37) 265.42(190.71, 374.09) 375.80(236.85, 432.99) -2.712 0.007 注:①以人数(占比/%)或M(P25,P75)表示。
Note: ① Number of people (proportion/%) or M(P25,P75).表 2 血浆IL-6、TNF-α水平与MCI的关联
Table 2. Association between IL-6, TNF-α and MCI
变量Variable 人数Number of people 模型1 Model 1 模型2 Model 2 模型3 Model 3 OR值value(95% CI) P值value OR值value(95% CI) P值value OR值value(95% CI) P值value IL-6/(ng·L-1) 144 1.43(0.99~2.07) 0.054 1.50(1.02~2.18) 0.039 1.53(1.02~2.29) 0.040 <11.10 36 1.00 1.00 1.00 11.10~<13.90 36 3.24(1.07~9.83) 0.038 3.22(1.04~9.97) 0.042 3.53(1.11~11.21) 0.032 13.90~<17.90 36 3.30(1.07~10.14) 0.037 3.51(1.09~11.34) 0.036 3.37(1.02~11.17) 0.047 ≥17.90 36 3.24(1.07~9.83) 0.038 3.54(1.13~11.03) 0.030 4.14(1.28~13.40) 0.018 Ptrend 0.059 0.045 0.032 TNF-α/(ng·L-1) 144 1.43(1.01~2.04) 0.047 1.51(1.05~2.17) 0.025 1.51(1.04~2.20) 0.029 <194.20 36 1.00 1.00 1.00 194.20~<297.20 36 0.72(0.23~2.22) 0.566 0.75(0.24~2.36) 0.627 0.68(0.21~2.18) 0.519 297.20~<391.88 36 2.13(0.77~5.91) 0.145 2.45(0.85~7.03) 0.096 2.26(0.76~6.70) 0.142 ≥391.88 36 2.67(0.98~7.28) 0.055 2.99(1.07~8.34) 0.037 3.13(1.09~8.97) 0.034 Ptrend 0.013 0.008 0.008 注:模型1,调整年龄、性别;模型2,在模型1的基础上进一步调整婚姻状况、吸烟、饮酒、锻炼;模型3,在模型2的基础上进一步调整高血压、糖尿病、冠状动脉粥样硬化、脑血管病及关节炎患病情况。
Notes: Model 1, adjusting for age, gender; Model 2, on the basis of model 1, marital status, smoking, drinking, exercise were adjusted; Model 3, on the basis of model 2, hypertension, diabetes, coronary heart disease, cerebrovascular disease, arthritis were adjusted.表 3 血浆IL-6、TNF-α水平对MCI的诊断价值
Table 3. Diagnostic value of plasma levels of IL-6 and TNF-α for MCI
变量Variable AUC 95% CI P值value 诊断临界值/(ng·L-1)Cut-off point/(ng·L-1) 约登指数Youden index 灵敏度/%Sensitivity/% 特异度/%Specificity/% IL-6/(ng·L-1) 0.60 0.51~0.69 0.049 11.31 0.24 87.50 36.50 TNF-α/(ng·L-1) 0.64 0.54~0.74 0.007 353.86 0.32 62.50 69.80 -
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