血浆磷酸化tau217在牙周炎与轻度认知功能障碍间的中介效应

doi:10.7518/hxkq.2025.2025078

华西口腔医学杂志 ›› 2025, Vol. 43 ›› Issue (6): 845-859.doi: 10.7518/hxkq.2025.2025078

• 临床研究 • 上一篇

血浆磷酸化tau217在牙周炎与轻度认知功能障碍间的中介效应

张彦表¹(), 魏美荣², 赵雪娟², 齐小蕾³, 左姗姗³, 毛淑梅⁴, 王军¹(), 丁刚¹()

^1.山东第二医科大学口腔医学院，潍坊 261053
^2.山东第二医科大学第一附属医院牙周病科，潍坊 261042
^3.山东第二医科大学第一附属医院神经内科，潍坊 261042
^4.山东第二医科大学药学院，潍坊 261053

收稿日期:2025-03-01 修回日期:2025-07-03 出版日期:2025-12-01 发布日期:2025-11-27
通讯作者: 王军,丁刚 E-mail:zhangyb@sdsmu.edu.cn;wangjun28@sdsmu.edu.cn;dinggang@sdsmu.edu.cn
作者简介:张彦表，硕士，E-mail：zhangyb@sdsmu.edu.cn
基金资助:
山东省自然科学基金面上项目(ZR2024MH147);山东省自然科学基金面上项目(ZR-2020MH381);潍坊市鸢都学者项目(ydxz2023002);山东省中医药发展计划项目(20190436)

Mediation analysis of plasma phosphorylated tau217 in the association between periodontitis and mild cognitive impairment

Zhang Yanbiao¹(), Wei Meirong², Zhao Xuejuan², Qi Xiaolei³, Zuo Shanshan³, Mao Shumei⁴, Wang Jun¹(), Ding Gang¹()

^1.School of Stomatology, Shandong Second Medical University, Weifang 261053, China
^2.Dept. of Periodontology, The First Affiliated Hospital of Shandong Second Medical University, Weifang 261042, China
^3.Dept. of Neurology, The First Affiliated Hospital of Shandong Second Medical University, Weifang 261042, China
^4.School of Pharmacy, Shandong Second Medical University, Weifang 261053, China

Received:2025-03-01 Revised:2025-07-03 Online:2025-12-01 Published:2025-11-27
Contact: Wang Jun,Ding Gang E-mail:zhangyb@sdsmu.edu.cn;wangjun28@sdsmu.edu.cn;dinggang@sdsmu.edu.cn
Supported by:
Natural Science Foundation of Shandong Province(ZR2024MH147);Weifang City “Yuan Du” Scholar Program(ydxz2023002);Traditional Chinese Medicine Science and Technology Development Program of Shandong Province(20190436)

摘要/Abstract

摘要：

目的探讨血浆磷酸化tau217（p-tau217）在牙周炎与轻度认知功能障碍（MCI）间的中介效应。方法病例对照研究设计，选取2023年11月—2024年5月在山东第二医科大学第一附属医院神经内科确诊为MCI的患者为病例组（MCI组），以同期在体检中心招募的年龄及受教育水平相匹配的认知功能正常（CN）的志愿者为对照组（CN组）。收集研究参与者的一般人口学资料。采用北京版蒙特利尔认知评估量表（MoCA）、临床痴呆评定量表（CDR）和日常生活能力评估量表（ADL）评估神经心理学功能。完成临床牙周检查，计算牙周感染表面积（PISA），以2018年分类法进行牙周炎分期。抽取晨起空腹肘静脉血，检测血液生化指标，酶联免疫吸附试验（ELISA）检测血浆p-tau217水平。采用独立样本t检验、Mann-Whitney U检验、χ²检验、偏相关分析、多因素Logistic回归分析、多元线性回归分析、限制性立方样条（RCS）回归分析、中介效应分析进行统计学分析。结果研究共纳入192例参与者，MCI组和CN组各96例，均完成所有试验检查项目。MCI组牙周炎患病率（63.5%）显著高于CN组（43.8%）（χ²=7.561，P=0.006）。MCI组血浆p-tau217水平［7.00（4.27-9.65）ng/mL］显著高于CN组［2.02（0.80-3.81）ng/mL］（Z=-8.108，P<0.001）。偏相关分析显示，血浆p-tau217与各临床牙周指标均呈正相关（均P<0.001）。校正基线协变量后，多因素Logistic回归分析显示，牙周炎是MCI的独立危险因素，牙周炎患者的MCI患病风险是非牙周炎的1.977倍（OR=1.977，95%CI：1.088~3.594，P=0.025）；Ⅰ/Ⅱ期牙周炎、Ⅲ/Ⅳ期牙周炎的MCI患病风险分别是非牙周炎的1.878倍（OR=1.878，95%CI：1.029~3.425，P=0.040）和2.625倍（OR=2.625，95%CI：1.073~6.246，P=0.035）。趋势检验显示，MCI患病风险随牙周炎分期数增大而增加（P_trend=0.016）。校正基线协变量后，多元线性回归分析显示，牙周炎是血浆p-tau217水平升高的独立危险因素（β=3.309，95%CI：2.363~4.254，P<0.001）；与非牙周炎相比，Ⅰ/Ⅱ期牙周炎（β=1.838，95%CI：0.869~2.806，P<0.001）和Ⅲ/Ⅳ期牙周炎（β=5.539，95%CI：4.442~6.636，P<0.001）的血浆p-tau217水平均升高。趋势检验显示，血浆p-tau217水平随牙周炎分期数增大而升高（P_trend<0.001）。RCS分析显示，校正基线协变量后，PISA与MIC患病风险（P_overall=0.002，P_nonlinear=0.344）及血浆p-tau217水平（P_overall<0.001，P_nonlinear=0.140）均呈正向线性剂量-反应关系。校正基线协变量后，中介效应分析显示，血浆p-tau217在牙周炎与MCI关联中存在中介效应，中介占比为13.99%（95% Bootstrap CI：0.38%~49.39%，P=0.038）。结论牙周炎是MCI患病风险增加和血浆p-tau217水平升高的危险因素，血浆p-tau217负荷加重在牙周炎与MCI患病风险增加的关联中起中介效应。

关键词: 牙周炎, 轻度认知功能障碍, 磷酸化tau217, 中介效应

Abstract:

Objective This study aimed to investigate the potential mediating role of plasma phosphorylated tau217 (p-tau217) in the association between periodontitis and mild cognitive impairment (MCI). Methods In this case-control study, patients diagnosed with MCI in the Neurology Department of the First Affiliated Hospital of Shandong Second Medical University from November 2023 to May 2024 were selected as the case group (MCI group). Cognitively normal (CN) volunteers, matched for age and education level and recruited from the physical examination center during the same period, served as the control group (CN group). The general demographic data of the study participants were collected. The Beijing versions of the Montreal Cognitive Assessment (MoCA), clinical dementia rating (CDR), and activities of daily living scale (ADL) were used to assess neuropsychological functions. Clinical periodontal examinations were conducted, the periodontal inflamed surface area (PISA) was calculated, and the periodontitis stage was determined in accordance with the 2018 classification. Fasting elbow venous blood samples were collected in the morning, and blood biochemical indicators were measured. Plasma p-tau217 levels were detected using enzyme-linked immunosorbent assay (ELISA). Statistical analyses were performed using t-test, Mann-Whitney U test, chi-square test, partial correlation analysis, multivariate Logistic regression analysis, multiple linear regression analysis, restricted cubic spline (RCS) regression analysis, and mediation effect analysis. Results Among the 192 participants, 96 belong to the MCI group and 96 to the CN group. The prevalence of periodontitis was 63.5% in the MCI group and 43.8% in the CN group, with a statistically significant difference (χ²=7.561, P=0.006). The plasma p-tau217 levels in the MCI group were significantly higher than those in the CN group [7.00 (4.27-9.65) ng/mL versus 2.02 (0.80-3.81) ng/mL, Z=-8.108, P<0.001]. Partial correlation analysis revealed that plasma p-tau217 levels were positively correlated with all the clinical periodontal indices (all P<0.001). After adjustments for baseline covariates, multivariate Logistic regression indicated that periodontitis was an independent risk factor for MCI. Patients with periodontitis had a 1.977-fold higher MCI risk than those without periodontitis (OR=1.977, 95%CI: 1.088-3.594, P=0.025). Moreover, the MCI risk for stage Ⅰ/Ⅱ periodontitis and stage Ⅲ/Ⅳ periodontitis was 1.878 times (OR=1.878, 95%CI: 1.029-3.425, P=0.040) and 2.625 times (OR=2.625, 95%CI: 1.073-6.246, P=0.035) higher than that for patients without periodontitis, respectively. Trend test showed that the MCI risk increased with periodontitis severity (P_trend=0.016). After adjustments for baseline covariates, multiple linear regression analysis showed that periodontitis was an independent risk factor for increased plasma p-tau217 levels (β=3.309, 95%CI: 2.363-4.254, P<0.001). Compared with patients without periodontitis, those with stage Ⅰ/Ⅱ periodontitis (β=1.838, 95%CI: 0.869-2.806, P<0.001) and stage Ⅲ/Ⅳ periodontitis (β=5.539, 95%CI: 4.442-6.636, P<0.001) had significantly higher plasma p-tau217 levels. In addition, trend test indicated that plasma p-tau217 levels increased with periodontitis severity (P_trend<0.001). After adjustments for baseline covariates, RCS regression analysis further revealed that PISA had a positive linear dose-response relationship with MCI risk (P_overall=0.002, P_nonlinear=0.344) and plasma p-tau217 levels (P_overall<0.001, P_nonlinear=0.140). After adjustments for baseline covariates, mediation analysis showed that plasma p-tau217 mediated the association between periodontitis and MCI, with a mediation proportion of 13.99% (95% Bootstrap CI: 0.38%-49.39%, P=0.038). Conclusion Periodontitis was independently positively associated with MCI risk, and plasma p-tau217 plays a mediating role in this association.

Key words: periodontitis, mild cognitive impairment, phosphorylated tau217, mediation analysis

张彦表, 魏美荣, 赵雪娟, 齐小蕾, 左姗姗, 毛淑梅, 王军, 丁刚. 血浆磷酸化tau217在牙周炎与轻度认知功能障碍间的中介效应[J]. 华西口腔医学杂志, 2025, 43(6): 845-859.

Zhang Yanbiao, Wei Meirong, Zhao Xuejuan, Qi Xiaolei, Zuo Shanshan, Mao Shumei, Wang Jun, Ding Gang. Mediation analysis of plasma phosphorylated tau217 in the association between periodontitis and mild cognitive impairment[J]. West China Journal of Stomatology, 2025, 43(6): 845-859.

图/表 8

表 1

MCI组和CN组基线特征的比较

项目	MCI组（n=96）	CN组（n=96）	χ²/t/Z值	P值
一般资料
性别			0.534^a	0.465
女	43（44.8%）	38（39.6%）
男	53（55.2%）	58（60.4%）
年龄^*/岁	55（52-58）	54（52-60）	-0.898^c	0.369
受教育水平^*/年	10（8-12）	9（8-12）	-1.641^a	0.101
吸烟	24（25.0%）	13（13.5%）	4.051^a	0.044
饮酒	29（30.2%）	22（22.9%）	1.308^a	0.253
体育锻炼	37（38.5%）	59（61.5%）	10.083^a	0.001
高血压	30（31.3%）	17（17.7%）	4.761^a	0.029
BMI/（kg/m²）	23.27±3.75	22.06±4.21	2.105^b	0.037
收缩压^*/mmHg	129（123-140）	129（124-136）	-0.603^c	0.546
舒张压^*/mmHg	83（81-86）	83（80-86）	-0.853^c	0.394
血液检验
GHbA_1c^*/%	5.3（5.2-5.7）	5.2（5.1-5.4）	-2.514^c	0.012
空腹血糖^*/（mol/mL）	5.5（4.9-6.1）	5.3（4.8-5.6）	-2.917^c	0.004
总胆固醇^*/（mol/mL）	4.5（4.2-5.1）	4.6（4.2-5.0）	-0.269^c	0.788
甘油三酯/（mol/mL）	1.16±0.50	1.17±0.52	0.136^b	0.892
HDL-C^*/（mol/mL）	1.3（1.2-1.5）	1.4（1.1-1.5）	-0.251^c	0.802
LDL-C^*/（mol/mL）	3.0（2.7-3.4）	2.8（2.2-3.1）	-3.008^c	0.003
肌酐^*/（mol/mL）	86（82-91）	87（82-92）	-0.844^c	0.399
eGFR^*/［mL/min/（1.73 m²）］	104（97-110）	107（99-112）	-1.285^c	0.199
神经心理学评估
MoCA^*/分	22（20-24）	29（28-30）	-11.743^c	<0.001
ADL^*/分	19（17-21）	15（14-15）	-12.195^c	<0.001
CDR/分	0.5	0	－	－
牙周炎	61（63.5%）	42（43.8%）	7.561^a	0.006
牙周炎分期			-3.054^c	0.002
Ⅰ期	11（11.5%）	12（12.5%）
Ⅱ期	24（25.0%）	15（15.6%）
Ⅲ期	17（17.7%）	9（9.4%）
Ⅳ期	9（9.4%）	6（6.3%）
临床牙周指标^*
PD/mm	3.31（2.47-3.79）	2.49（2.28-3.10）	-3.490^c	<0.001
CAL/mm	2.98（1.63-3.54）	1.60（1.39-3.10）	-3.965^c	<0.001
BOP/%	27.74（21.36-48.17）	22.44（17.47-43.03）	-2.600^c	0.009
GI（0~3）	1.36（0.92-1.88）	1.07（0.73-1.52）	-2.723^c	0.006
PLI（0~3）	1.60（1.23-2.25）	1.37（0.99-1.82）	-2.325^c	0.020
PISA/mm²	477.26（27.57-803.55）	69.61（22.98-451.68）	-3.270^c	0.001
p-tau217/（ng/mL）	7.00（4.27-9.65）	2.02（0.80-3.81）	-8.108^c	<0.001

表 1

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表 4

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图 4

表 5

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变量	单因素线性回归分析		共线性诊断
变量	β值	P值	容差	方差膨胀因子
性别	0.198	0.731
受教育水平	0.068	0.540
年龄	0.235	<0.001	0.836	1.196
高血压	2.499	<0.001	0.398	2.511
吸烟	2.678	<0.001	0.719	1.392
饮酒	1.344	0.036	0.755	1.325
体育锻炼	-1.394	0.014	0.923	1.084
BMI	0.274	<0.001	0.830	1.205
收缩压	0.106	<0.001	0.422	2.368
舒张压	0.108	0.040	0.832	1.202
GHbA_1c	2.109	0.001	0.873	1.146
空腹血糖	0.210	0.625
总胆固醇	0.217	0.611
甘油三酯	0.696	0.219
HDL-C	0.249	0.826
LDL-C	1.879	<0.001	0.854	1.171
肌酐	0.026	0.533
eGFR	-0.133	0.001	0.900	1.111
MoCA	-0.767	<0.001	0.263	3.807
ADL	0.654	<0.001	0.322	3.106
CDR	9.024	<0.001	0.154	6.490

自变量	例数		模型1		模型2		模型3		模型4
自变量	MCI组	CN组	OR（95%CI）	P值	OR（95%CI）	P值	OR（95%CI）	P值	OR（95%CI）	P值
是否牙周炎
非牙周炎	35	54	1（参照）		1（参照）		1（参照）		1（参照）
牙周炎	61	42	2.241（1.256~3.998）	0.006	2.153（1.158~4.003）	0.015	2.024（1.074~3.814）	0.029	1.977（1.088~3.594）	0.025
牙周炎分期
非牙周炎	35	54	1（参照）		1（参照）		1（参照）		1（参照）
Ⅰ/Ⅱ期	35	27	2.000（1.036~3.862）	0.039	2.082（1.061~4.087）	0.039	1.919（1.055~3.419）	0.033	1.878（1.029~3.425）	0.040
Ⅲ/Ⅳ期	26	15	2.674（1.245~5.745）	0.012	2.845（1.308~6.188）	0.008	2.747（1.042~7.244）	0.041	2.625（1.073~6.246）	0.035
P_trend值				0.006		0.009		0.013		0.016
PISA per 10 mm²	96	96	1.021（1.011~1.031）	<0.001	1.018（1.009~1.027）	<0.001	1.020（1.010~1.030）	<0.001	1.017（1.008~1.026）	<0.001

自变量	例数	p-tau217^*/（ng/mL）	模型1		模型2		模型3		模型4
自变量	例数	p-tau217^*/（ng/mL）	β（95%CI）	P值	β（95%CI）	P值	β（95%CI）	P值	β（95%CI）	P值
是否牙周炎
非牙周炎	89	1.70（0.80-3.88）	0（参照）		0（参照）		0（参照）		0（参照）
牙周炎	103	6.11（3.81-9.22）	3.753（2.765~4.742）	<0.001	3.692（2.722~4.662）	<0.001	3.431（2.437~4.425）	<0.001	3.309（2.363~4.254）	<0.001
牙周炎分期
非牙周炎	89	1.70（0.80-3.88）	0（参照）		0（参照）		0（参照）		0（参照）
Ⅰ/Ⅱ期	62	4.63（2.27-7.85）	2.527（1.454~3.600）	<0.001	2.364（1.323~3.404）	<0.001	2.121（1.049~3.192）	<0.001	1.838（0.869~2.806）	<0.001
Ⅲ/Ⅳ期	41	8.71（5.28-11.15）	5.607（4.383~6.831）	<0.001	5.651（4.475~6.827）	<0.001	5.333（4.131~6.536）	<0.001	5.539（4.442~6.636）	<0.001
P_trend值				<0.001		<0.001		<0.001		<0.001
PISA per 10 mm²	192	4.04（1.22-7.48）	0.056（0.043~0.069）	<0.001	0.055（0.041~0.068）	<0.001	0.055（0.043~0.067）	<0.001	0.053（0.041~0.066）	<0.001

模型	总效应		直接效应		间接效应		中介占比
模型	效应量（95% Bootstrap CI）	P值	效应量（95% Bootstrap CI）	P值	效应量（95% Bootstrap CI）	P值	效应量（95% Bootstrap CI）	P值
模型1	0.180（0.038~0.308）	0.020	0.150（0.003~0.282）	0.044	0.031（0.002~0.076）	0.028	17.04%（0.51%~78.31%）	0.044
模型2	0.195（0.054~0.339）	0.012	0.159（0.013~0.304）	0.034	0.036（0.004~0.086）	0.014	18.57%（1.68%~70.59%）	0.026
模型3	0.202（0.068~0.332）	0.004	0.169（0.026~0.302）	0.020	0.033（0.005~0.076）	0.016	16.41%（2.39%~61.93%）	0.020
模型4	0.197（0.057~0.332）	0.012	0.169（0.032~0.307）	0.024	0.028（0.001~0.067）	0.026	13.99%（0.38%~49.39%）	0.038

血浆磷酸化tau217在牙周炎与轻度认知功能障碍间的中介效应

Mediation analysis of plasma phosphorylated tau217 in the association between periodontitis and mild cognitive impairment

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