阿尔茨海默病患者睡眠障碍与血清β-淀粉样蛋白1-42、磷酸化tau蛋白181的相关性研究

Correlation of sleep disorders with serum Aβ_(1-42)and P-Tau_(181)in patients with Alzheimer's disease

目的:探讨阿尔茨海默病(AD)患者睡眠障碍(SD)的临床特征及其与血清β-淀粉样蛋白1-42(Aβ_(1-42))、磷酸化tau蛋白181(P-Tau_(181))的相关性。方法:选择2017年2月至2020年1月在长江大学附属江汉油田总医院记忆门诊、睡眠门诊和老年医学科符合入组条件的126例轻、中度AD患者,运用匹兹堡睡眠质量指数量表(PSQI)评估患者的睡眠质量,将PSQI评分≥7分列入AD伴发睡眠障碍组(AD-SD组),PSQI评分<7分列入AD无睡眠障碍组(AD-NSD组)。采用蒙特利尔认知评估量表(MoCA)、总体衰退量表(GDS)、临床痴呆评估量表(CDR)、汉密尔顿抑郁量表(HRSD)、汉密尔顿焦虑量表(HAMA)等评估患者的认知和精神行为症状,同时采用酶联免疫法检测患者血清Aβ_(1-42)、Aβ_(1-40)、P-Tau_(181)等生物学标志物。两组患者在运用多奈哌齐进行抗痴呆治疗的同时,对AD-SD组患者进行针对性的睡眠干预和治疗。所有患者在入组时和第6个月末进行神经心理评估和生化检测,并在基线和第6个月末对各项指标进行比较。然后在治疗第6个月末,根据AD-SD组患者睡眠改善情况,细分为AD-SD康复组和AD-SD未康复组。结果:(1)126例AD患者中有93例(73.8%)伴发SD。两组患者入组时在性别、年龄、发病年龄、文化程度、病程及CDR、GDS、MoCA、Aβ_(1-40)、Aβ_(1-42)/Aβ_(1-40)等方面评分比较差异无统计学意义(均P>0.05)。与AD-NSD组相比,AD-SD组PSQI、HRSD、HAMA评分及Aβ_(1-42)、P-Tau_(181)差异有统计学意义(P<0.05或P<0.01)。(2)第6个月末,与AD-NSD组相比,AD-SD组PSQI、GDS、HRSD、HAMA评分及Aβ_(1-42)、Aβ_(1-40)、P-Tau_(181)差异有统计学意义(P<0.05或P<0.01),其他指标比较差异无统计学意义(均P>0.05)。(3)AD-SD组在基线时PSQI评分与其他指标进行Spearman相关性分析,结果显示PSQI与HRSD(r=0.271,P=0.009)、HAMA(r=0.479,P=0.000)、Aβ_(1-42)(r=0.470,P=0.000)、Aβ_(1-42)/Aβ_(1-40)(r=0.479,P=0.000)、P-Tau_(181)(r=0.371,P=0.000)相关。(4)多因素Logistic回归模型显示Aβ_(1-42)、P-Tau_(181)、HRSD的评分对AD患者的睡眠质量变化具有预测作用(OR=1.897、1.269、1.889;P=0.000、0.003、0.000)。Aβ_(1-42)、P-Tau_(181)、HRSD的评分绘制ROC曲线,曲线下面积分别为0.926(95%CI:0.860~0.991)、0.837(95%CI:0.746~0.927)和0.854(95%CI:0.776~0.932)。结论:AD患者睡眠质量与血清Aβ_(1-42)、P-Tau_(181)具有相关性,高Aβ_(1-42)、P-Tau_(181)值和高HRSD的评分是AD患者SD的重要预测因素,可作为临床疗效判定指标。

Objective To investigate the correlation of sleep disorders(SD)with serum levels of amyloidβ-proteins(Aβ_(1-42))and tau phosphorylated at threonine(P-Tau_(181))in patients with Alzheimer's disease(AD).Methods A total of 126 patients with mild and moderate AD who met the inclusion criteria in the memory clinic,sleep clinic and geriatrics department of Jianghan Oilfield General Hospital affiliated to Yangtze University from February 2017 to January 2020 were included.The Pittsburgh Sleep Quality Index(PSQI)was used to evaluate sleep quality.Patients with PSQI scores≥7 were included in the AD group with sleep disorders(AD-SD group),and patients with PSQI scores<7 were included in the AD group without sleep disorders(AD-NSD group).The Montreal Cognitive Assessment(MoCA),Global Deterioration Scale(GDS),Clinical Dementia Rating(CDR),Hamilton Rating Scale for Depression(HRSD)and Hamilton Anxiety Rating Scale(HAM-A)were used to evaluate cognitive and psychosocial symptoms.During the same time,biological markers such as serum Aβ_(1-42),Aβ_(1-40) and P-Tau_(181) were detected by using enzyme-linked immunosorbent assays.Patients in the two groups received donepezil as an anti-dementia therapy,while the AD-SD group was treated additionally with a targeted sleep intervention.All patients underwent neuropsychological assessment and biochemical tests at enrollment and at the end of the 6th month,and results from all parameters at baseline and at the end of the 6th month were compared.At the end of the six-month treatment,patients in the AD-SD group were further divided into the recovery AD-SD sub-group and the no-recovery AD-SD sub-group based on the extent of sleep improvement.Results Of the 126 AD patients,93(73.8%)had sleep disorders.There was no statistically significant difference between the two groups in gender,age,onset age,educational level,course of disease,CDR,GDS,MoCA,Aβ_(1-40) or Aβ_(1-42)/Aβ_(1-40)(all P>0.05).The scores of PSQI,HRSD and HAM-A and serum levels of Aβ_(1-42)and p-Tau_(181) showed statistically significant differences between the AD-ND and AD-NSD groups(P<0.05 or P<0.01).At the end of the 6th month,the scores of PSQI,GDS,HRSD and HAM-A and levels of Aβ_(1-42),Aβ_(1-40),and P-Tau_(181) also showed statistically significant differences between the AD-ND and AD-NSD groups(P<0.05 or P<0.01).There was no statistically significant difference in results from other parameters(P>0.05).Spearman correlation analysis showed that PSQI was correlated with HRSD(r=0.271,P=0.009),HAM-A(r=0.479,P=0.000),Aβ_(1-42)(r=0.470,P=0.000),Aβ_(1-42)/Aβ_(1-40)(r=0.479,P=0.000)and P-Tau_(181)(r=0.371,P=0.000)in the AD-SD group at baseline.Multivariate Logistic regression model showed that serum Aβ_(1-42)and P-Tau_(181) levels and HRSD had predictive effects on changes in sleep quality in AD patients(OR=1.897,1.269 and 1.889,P=0.000,0.003 and 0.000).The areas under the receiver operating characteristic(ROC)curves for Aβ_(1-42),P-Tau_(181) and HRSD were 0.926(95%CI:0.860-0.991),0.837(95%CI:0.746-0.927)and 0.854(95%CI:0.776-0.932),respectively.Conclusions Sleep quality is correlated with serum Aβ_(1-42)and P-Tau_(181) levels in AD patients.Elevated serum levels of Aβ_(1-42)and P-Tau_(181) and high HRSD scores are important predictors of SD in AD patients and may be used as indexes for clinical treatment efficacy.