重复经颅磁刺激联合多奈哌齐对阿尔茨海默病患者认知功能和血清炎症因子的影响.pdf

2023,43(6)http:/J Clin Pathol Res 临床与病理杂志重复经颅磁刺激联合多奈哌齐对阿尔茨海默病患者认知功能和血清炎症因子的影响王爱花，徐锐，林荫（海南省安宁医院精神康复科，海口 570206）摘要 目的：探究重复经颅磁刺激(repetitive transcranial magnetic stimulation，rTMS)联合多奈哌齐对阿尔茨海默病(Alzheimer s disease，AD)患者认知功能和血清炎症因子的影响。方法：选取2019年3月至2021年10月海南省安宁医院收治的100例AD患者，按随机数字表法随机分为对照组和观察组，每组50例。对照组予以伪刺激+多奈哌齐治疗，观察组予以rTMS+多奈哌齐治疗。比较2组临床疗效及治疗前后简易精神状态检查量表(Mini-Mental State Examination Scale，MMSE)、AD 认知评定量表(AD Cognitive Assessment Scale，ADAS-Cog)、行为记忆量表(Behavioral Memory Scale，BRMT)、神经精神问卷(Neuropsychiatric Inventory，NPI)、日常生活能力量表(Activity of Daily Living Scale，ADL)、社会功能活动问卷(Social Function Activity Questionnaire，FAQ)及血清白细胞介素-6(interleukin-6，IL-6)、肿瘤坏死因子-(tumor necrosis factor-，TNF-)、淀粉样蛋白1-42(amyloid protein 1-42，A1-42)水平。结果：观察组临床总有效率明显高于对照组(P0.05)。与对照组相比，观察组治疗后MMSE、BRMT评分均明显更高，ADAS-Cog、NPI、ADL、FAQ评分则明显更低(均P0.05)。观察组血清IL-6、TNF-、A1-42水平均明显低于对照组(均P0.05)。结论：rTMS联合多奈哌齐治疗AD疗效显著，可有效提高患者认知功能，缓解精神行为症状，改善日常生活能力，抑制炎症反应。关键词 重复经颅磁刺激；多奈哌齐；阿尔茨海默病；认知功能；炎症因子Effect of repetitive transcranial magnetic stimulation combined with donepezil on cognitive function and serum inflammatory factors in patients with Alzheimer s diseaseWANG Aihua,XU Rui,LIN Yin(Department of Mental Rehabilitation,Hainan Anning Hospital,Haikou 570206,China)DOI：10.11817/j.issn.2095-6959.2023.222593收稿日期(Date of reception)：2022-12-03第一作者(First author)：王爱花，Email:,ORCID:0000-0001-8683-373X通信作者(Corresponding author)：林荫，Email:,ORCID:0000-0002-1243-7846基金项目(Foundation item)：海南省卫生健康行业科研项目(21A200382)。This work was supported by the Hainan Provincial Health Industry Scientific Research Project,China(21A200382).1199临床与病理杂志,2023,43(6)http:/ABSTRACT Objective:To investigate the effect of repetitive transcranial magnetic stimulation(rTMS)combined with donepezil on cognitive function and serum inflammatory factors in patients with Alzheimer s disease(AD).Methods:A total of 100 AD patients admitted to Hainan Anning Hospital from March 2019 to October 2021 were selected as research subjects and randomly divided into a control group and an observation group according to the random number table method,with 50 cases in each group.The control group was treated with pseudostimulation and donepezil,and the observation group was treated with rTMS and donepezil.The clinical efficacy and the levels of Mini-Mental State Examination Scale(MMSE),AD Cognitive Assessment Scale(ADAS-Cog),Behavioral Memory Scale(BRMT),Neuropsychiatric Questionnaire(NPI),Activity of Daily Living Scale(ADL),Social Function Activity Questionnaire(FAQ),serum interleukin-6(IL-6),tumor necrosis factor-(TNF-),and amyloid protein 1-42(A1-42)before and after treatment were compared between the 2 groups.Results:The total effective rate of the observation group was significantly higher than that of the control group(P0.05).Compared with the control group,the scores of MMSE and BRMT in the observation group were significantly higher after the treatment(both P0.05).The scores of ADAS-Cog,NPI,ADL,FAQ were significantly lower(all P0.05).The serum levels of IL-6,TNF-,and A1-42 in the observation group were significantly lower than those in the control group(all P6个月；3)年龄5580岁；4)临床痴呆评定量表(clinical dementia rating，CDR)8评分为12分；5)无严重肝、肾、心、肺等脏器病变；6)无1200重复经颅磁刺激联合多奈哌齐对阿尔茨海默病患者认知功能和血清炎症因子的影响 王爱花，等严重听力、语言等障碍，可配合完成相关测试；7)患者及家属知情同意参与研究，且治疗配合度高。排除标准：1)有明确的老年精神分裂症、血管性痴呆、路易体痴呆、帕金森病及其他精神疾病者；2)合并出血性疾病、恶性肿瘤等严重内科疾病者；3)有rTMS、多奈哌齐治疗禁忌证者；4)有偏瘫、失语、感觉障碍等神经系统体征者；5)近3个月内有抗精神病、镇静类药及 rTMS 治疗史者；6)有脑外伤、脑血管病史者。将入组患者按随机数字表法随机分为对照组和观察组，每组50例。1.2 治疗方法观察组予以rTMS+多奈哌齐治疗，治疗仪为丹麦 Tonica Elektvonik A/s MagPro R30 型 rTMS 治疗仪及“8”字型线圈，患者呈卧位，保持平静，选取左、右 侧 前 额 叶 背 外 侧 皮 质 区(dorsolateral prefrontal cortex，DLPFC)为刺激部位，先检测患者静息运动阈值(resting motor threshold，RMT)，治疗时调节刺激频率为 10 Hz、刺激强度为 80%RMT，左、右侧DLPFC均刺激30个序列，每序列行20个脉冲，每刺激 2 s 后间歇 28 s，先左后右，各刺激15 min，1次/d，每周5次；盐酸多奈哌齐片(5 mg，陕西方舟制药有限公司，国药准字：H20030583)，5 mg/次，1 次/d，口服。对照组予以伪刺激+多奈哌齐治疗，伪刺激治疗时，将线圈放置与头皮呈90，其他设置与观察组相同；多奈哌齐用法、用量同观察组。2组均连续治疗4周。1.3 观察指标于治疗前后检测 2 组下述指标：1)认知功能。使 用 简 易 精 神 状 态 检 查 量 表(Mini-Mental State Examination Scale，MMSE)9、AD 认知评定量表(AD Cognitive Assessment Scale，ADAS-Cog)10、行为记忆量表(Behavioral Memory Scale，BRMT)11评估2组认知功能。2)精神行为症状。使用神经精神问卷(Neuropsychiatric Questionnaire，NPI)12评估精神行为症状。3)日常生活能力。使用日常生活能力量表(Daily Living Ability Scale，ADL)13、社会功能活动问卷(Social Function Activity Questionnaire，FAQ)14评估日常生活能力。4)血清炎症因子使用酶联免疫吸附法检测2组血清白细胞介素-6(interleukin-6，IL-6)、肿瘤坏死因子-(tumor necrosis factor-，TNF-)、淀粉样 蛋白 1-42(amyloid protein 1-42，A1-42)水平。1.4 疗效评价根据治疗前后MMSE评分对疗效进行3级评价。显效：MMSE 改善率20%；有效：10%MMSE 改善率20%；无效：MMSE 改善率10%。MMSE 改善率=(MMSE 评分治疗前MMSE 评分治疗后)/MMSE 评分治疗前100%。临床总有效率=(显效例数+有效例数)/总例数100%。1.5 统计学处理使用统计学软件 SPSS 24.0 处理研究数据。计量资料均符合正态分布且方差齐，描述为均数标准差(xs)，比较行独立样本 t 检验或配对 t 检验；计数资料描述为例(%)，比较行 2检验。均以 P0.05，表1)。2.2 临床疗效观察组临床总有效率为88.00%(44/50)，对照组临床总有效率为70.00%(35/50)，组间比较差异有统计学意义(P0.05)。治疗后，2组MMSE、BRMT评分均较治疗前明显增高，ADAS-Cog评分则较治疗前明显降低(均P0.05)；且与对照组相比，观察组 MMSE、BRMT 评分均明显更高，ADAS-Cog评分则明显更低(均P0.05)。治 疗 后，2 组 NPI、ADL、FAQ 评分均较治疗前明显降低(均 P0.05)；且观察组NPI、ADL、FAQ评分均明显低于对照组(均P0.05)。治疗后，2组血清IL-6、TNF-、A1-42水平均较治疗前明显降低(均P0.05)；且观察组血清IL-6、TNF-、A1-42水平均明1201临床与病理杂志,2023,43(6)http:/显低于对照组(均P0.05，表5)。2.6 不良反应治疗期间，观察组发生恶心3例、腹泻1例、失眠2例，总不良反应发生率为12.00%(6/50)；对照组发生恶心4例、呕吐1例、失眠3例、肌肉痉挛1例，总不良反应发生率为18.00%(9/50)，组间比较差异无统计学意义(2=0.706，P=0.401)。2组不良反应均较轻微且短暂，无需特殊干预。表1 2组一般资料比较(n=50)Table 1 Comparison of general data between the 2 groups(n=50)组别观察组对照组t/2P男/女27/2325/250.1600.689年龄/岁55.787.6955.948.210.1010.902BMI/(kgm2)23.073.4522.923.550.2140.831病程/年2.680.742.650.810.1930.847受教育年限/年9.323.039.172.960.2500.803CDR评分1.900.581.880.610.1680.867计量资料以均数标准差(xs)表示；计数资料以例表示。BMI：身高体重指数；CDR：临床痴呆评定量表。表2 2组临床疗效比较(n=50)Table 2 Comparison of clinical efficacy between the 2 groups(n=50)组别观察组对照组2P显效/例(%)15(30.00)8(16.00)有效/例(%)29(58.00)27(54.00)无效/例(%)6(12.00)15(30.00)总有效率/%88.0070.004.8820.027表3 2组MMSE、ADAS-Cog、BRMT评分比较(n=50，xs)Table 3 Comparison of MMSE,ADAS-Cog,and BRMT scores between the 2 groups(n=50,xs)组别观察组对照组tPMMSE评分治疗前16.123.8915.974.020.1900.850治疗后23.824.74*19.464.59*4.6720.001ADAS-Cog评分治疗前39.339.6539.229.320.0580.954治疗后30.426.84*34.167.07*2.6880.008BRMT评分治疗前12.203.5112.013.460.2730.786治疗后17.123.02*15.583.49*2.3590.020与同组治疗前相比，*P0.05。MMSE：简易精神状态检查量表；ADAS-Cog：AD认知评定量表；BRMT：行为记忆量表。表4 2组NPI、ADL、FAQ评分比较(n=50，xs)Table 4 Comparison of NPI,ADL,and FAQ scores between the 2 groups(n=50,xs)组别观察组对照组tPNPI评分治疗前69.088.6368.949.120.0790.937治疗后54.188.06*58.418.57*2.5420.013ADL评分治疗前30.357.5629.947.880.2650.791治疗后22.297.04*26.277.15*2.8050.006FAQ评分治疗前11.863.2711.733.450.1930.847治疗后7.341.97*9.692.16*5.6840.001与同组治疗前相比，*P0.05。NPI：神经精神问卷；ADL：日常生活能力量表；FAQ：社会功能活动问卷。1202重复经颅磁刺激联合多奈哌齐对阿尔茨海默病患者认知功能和血清炎症因子的影响 王爱花，等3 讨 论 AD 在中国 65 岁以上人群中患病率达 3%7%，且随人口老龄化发展，患病率将不断上升，给个人、家庭及社会均造成了一定的经济负担15。AD病因、病理机制尚不完全明晰，现普遍认为是因A沉积损伤中枢神经元及突触导致患者记忆、学习能力受损16。多奈哌齐为乙酰胆碱酯酶(acetylcholinesterase，AChE)I类药物，可通过抑制AChE活性来提高ACh浓度，进而改善AD症状，是各指南首荐药物。但AD多为老年人，其排泄和代谢能力随躯体衰老、脑器质性病变等因素而逐渐减弱，药物蓄积风险相对更高；且患者功能完整的ACh神经元也将随AD病情进展而减少，多奈哌齐的疗效也将随之减弱。因此，探寻疗效和安全性俱佳的AD综合治疗方案临床意义重大。rTMS为新型神经电生理技术，近年来在神经精神科中应用逐渐广泛，研究17证实rTMS在改善多种精神疾病精神症状的同时，对受损的认知功能的恢复也有积极作用。本研究结果显示：观察组临床总有效率明显高于对照组，且与对照组相比，观察组治疗后BRMT评分更高、ADAS-Cog评分更低，表明rTMS联合多奈哌齐可明显提高对AD的临床疗效，改善患者认知功能，这可能得益于二者的协同作用。多奈哌齐可增加神经突触中ACh含量，可为认知功能的恢复提供物质基础18；对双侧 DLPFC 区进行rTMS治疗也可有效增加脑血流量、促进脑活性物质的新陈代谢、调节皮质兴奋性来平衡大脑功能、促进神经网络及神经通路的重塑和修复等多种途径加速脑区损伤的修复，改善认知功能19-20。Karton等21研究也发现：刺激 DLPFC 区域可有效改善个体的P300波幅和潜伏期，提高脑内神经兴奋性，提高个体信息加工、思维逻辑、注意力、记忆力等，进而改善认知功能。精神行为症状也是AD患者的常见伴随症状，但多奈哌齐由于作用机制单一，对精神行为异常的缓解作用较弱。rTMS对患者大脑局部的高频次及不仅可提高局部皮质兴奋性来改善大脑局部的代谢状态、脑血流量等，还可影响脑内多种神经递质5-羟色胺等的产生及传递、相关神经元兴奋性及受体的基因表达22。本研究结果显示：观察组治疗后NPI评分明显高于对照组，表明增加rTMS治疗可有效改善AD患者的精神行为症状，与吴越等23研究结果相一致。另外，本研究还发现：观察组治疗后ADL、FAQ评分均明显高于对照组，表明rTMS联合多奈哌齐还可明显提高AD患者日常生活能力，这与rTMS对患者认知功能、精神行为症状的积极作用密不可分。近年来，炎症机制在 AD 相关研究中备受重视24。A 可过度激活小胶质细胞(microglia，MG)，使其大量合成并释放过氧化物、炎症因子，加重炎症程度，扩大AD病变程度及范围25。梁春荣等26研究发现：AD患者外周血中IL-6、TNF-等炎症因子水平较正常人群明显更高，且炎症因子水平与整体人群认知功能密切相关。本研究结果显示：观察组治疗后血清IL-6、TNF-、A1-42水平均明显低于对照组，表明rTMS联合多奈哌齐可有效减轻AD患者炎症反应程度。基础研究27发现：rTMS可抑制AD模型大鼠脑内MG的过度激活，提高突触传递和重组效能，并抑制MG释放IL-6、TNF-等促炎因子，避免A沉积损伤周围神经元。随燕芳等28也认为rTMS也可通过增加患者脑部血流量来加速炎症因子的转运，降低其水平。综上所述，在多奈哌齐治疗 AD 基础上增加rTMS可明显提高临床疗效，改善精神行为症状，促进患者认知功能、日常生活能力的恢复，减轻炎症反应可能是其疗效的作用机制。但本研究仍存在一定不足：由于本院收治病例数及纳入排除标准的限制，最终进入统计学分析的样本量较少，结果可能表5 2组血清炎症因子水平比较(n=50，xs)Table 5 Comparison of serum inflammatory factors between the 2 groups(n=50,xs)组别观察组对照组tPIL-6/(ngL1)治疗前39.124.6238.864.580.2830.778治疗后24.663.58*30.494.19*7.4800.001TNF-/(ngL1)治疗前146.2418.65146.0819.380.0420.966治疗后109.1013.56*128.4214.83*6.7980.000A1-42/(pgmL1)治疗前128.6923.64127.3525.060.2750.784治疗后90.4218.67*105.1420.35*3.7690.001与同组治疗前相比，*P0.05。IL-6：白细胞介素-6；TNF-：肿瘤坏死因子-；A1-42：淀粉样蛋白1-42。1203临床与病理杂志,2023,43(6)http:/存在一定偏倚，此外，未对患者进行长期随访。未来仍需前瞻性、大样本研究验证和完善结论。利益冲突声明：作者声称无任何利益冲突。参考文献1GBD 2016 Dementia Collaborators.Global,regional,and national burden of Alzheimer s disease and other dementias,1990 2016:a systematic analysis for the Global Burden of Disease Study 2016J.Lancet Neurol,2019,18(1):88-106.https:/doi.org/10.1016/S1474-4422(18)30403-4.2李涛,王华丽.多奈哌齐治疗阿尔茨海默病的临床额外获益J.中华老年医学杂志,2020,39(9):1091-1093.https:/doi.org/10.3760/cma.j.issn.0254-9026.2020.09.024.LI Tao,WANG Huali.The additional clinical benefits of Donepezil for Alzheimers diseaseJ.Chinese Journal of Geriatrics,2020,39(9):1091-1093.https:/doi.org/10.3760/cma.j.issn.0254-9026.2020.09.024.3Atri 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