补肾健脾化痰法治疗遗忘型轻度认知损害的临床效果
2019-10-19吴冬月魏明清田金洲时晶
吴冬月 魏明清 田金洲 时晶
[摘要] 目的 評价补肾健脾化痰法治疗遗忘型轻度认知损害(aMCI)临床效果。 方法 采用前瞻性、开放、空白对照的临床研究方法,将2014年1月~2017年1月就诊于北京中医药大学东直门医院脑病三区记忆门诊及周边社区具有认知功能下降主诉的患者进行初筛检查。筛选符合本研究诊断及纳入标准的aMCI患者共122例,根据随机数字表法将受试者分为两组:试验组(105例)口服补肾健脾化痰药物,对照组(17例)未使用任何改善认知水平药物或疗法。观察时间12周,记录治疗前后简易精神状态检查表(MMSE)评分及中医痴呆证候要素量表(PES-D/11)积分。 结果 总体认知评估方面,试验组治疗12周后MMSE总分高于治疗前,差异有统计学意义(P < 0.05)。试验组MMSE总分明显高于对照组,差异有统计学意义(P < 0.05)。中医证候方面,试验组治疗12周后肾虚、脾虚、痰浊积分低于治疗前,差异有统计学意义(P < 0.05)。试验组治疗12周后肾虚、脾虚、痰浊积分均低于对照组,差异有统计学意义(P < 0.05)。试验组不良反应共发生5例(6.4%),停药1周自行缓解,无严重不良事件。 结论 补肾健脾化痰法治疗aMCI 12周的疗效性及安全性较好,远期疗效需开展大样本、长疗程的临床试验进行验证。
[关键词] 遗忘型轻度认知功能损害;补肾健脾化痰法;中医证候;中药
[中图分类号] R749.1 [文献标识码] A [文章编号] 1673-7210(2019)10(a)-0122-04
The clinical efficacy of invigorating the kidney, strengthening spleen and eliminating phlegm in the treatment of amnestic mild cognitive impairment
WU Dongyue1 WEI Mingqing2 TIAN Jinzhou2 SHI Jing2
1.Department of Traditional Chinese Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; 2.Ward 3, Department of Neurology, Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing 100700, China
[Abstract] objective To evaluate the efficacy of invigorating the kidney, strengthening spleen and eliminating phlegm in the treatment of amnestic mild cognitive impairment(aMCI). Methods Using a prospective, open and blank-controlled clinical research method, patients admitted to Ward 3, the Department of Neurology of Dongzhimen Hospital of Beijing University of Chinese Medicine and surrounding communities with a cognitive decline function from January 2014 to January 2017 were screened. A total of 122 patients with aMCI were selected according to the diagnosis and inclusion criteria of this study. The subjects were divided into two groups by number table method: the experimental group (105 cases) received the drugs of invigorating the kidney, strengthening spleen and eliminating phlegm, while the control group (17 cases) was not used any medication or therapy to improves cognitive levels. The observation period was 12 weeks, while the mini mental state examination (MMSE) scores and the pattern element scale for dementia (PES-D/11) scores were recorded before and after treatment. Results In terms of overall cognitive assessment, the MMSE score after 12 weeks of treatment in the experimental group was higher than before treatment, and the difference was statistically significant (P < 0.05). The MMSE score in the experimental group was higher than that in the control group, and the difference was statistically significant (P < 0.05). In terms of Chinese medicine syndromes, the score of kidney deficiency, spleen deficiency and phlegm turbid syndrome in experimental group after 12 weeks of treatment were lower than before treatment, and the differences were statistically significant (P < 0.05). The score of kidney deficiency, spleen deficiency and phlegm turbid syndromes in the experimental group were lower than those in the control group, and the differences were statistically significant (P < 0.05). There were 5 cases (6.4%) of adverse reactions in experimental group, and the patients were relieved spontaneously for 1 week without serious adverse events. Conclusion The curative effect and safety of invigorating the kidney, strengthening spleen and eliminating phlegm for the treatment of aMCI for 12 weeks is good. The long-term curative effect can be verified by large-sample and long-course clinical trials.
[Key words] Amnestic mild cognitive impairment; Invigorating the kidney, strengthening spleen and eliminating phlegm; Traditional Chinese medicine syndromes; Chinese medicine
阿爾茨海默病(Alzheimer′s disease,AD)发病率日趋升高,国际AD协会2018年发布报告显示至2050年,AD患者将达1.52亿人,约每3秒就增加1例患者[1]。AD病程长,病情不可逆,应在疾病早期进行干预。遗忘型轻度认知损害(amnestic mild cognitive impairment,aMCI)在10年内向AD转化率达99%[2],是公认的AD早期阶段,但目前尚无指南推荐有效预防或延缓aMCI向AD发展的治疗方法[3]。因此,中药成为改善aMCI认知功能、逆转其向AD转化的崭新研究途径。aMCI以情节记忆损害为主,属中医“健忘”范畴,本团队早期有临床研究显示在aMCI阶段中医最主要证型为脾肾亏虚(67%)与痰浊蒙窍(40%)[4],在此基础上拟定补肾健脾化痰法治疗aMCI,并观察临床有效性及安全性。现将结果报道如下:
1 资料与方法
1.1 一般资料
所有病例来源于2014年1月~2017年1月北京中医药大学东直门医院(以下简称“我院”)脑病三区记忆门诊及周边社区。对受试者进行神经心理学初筛,并完善头部MRI及实验室检测指标,共筛选出122例aMCI患者符合本研究纳入标准。采用随机数字表法将受试者按试验组∶对照组约为6∶1的比例进行分组。试验组105例,对照组17例。在研究开始后,试验组剔除7例,脱落20例,共78例;对照组脱落2例,共15例。本研究已通过我院医学伦理委员会批准,所有患者均自愿签署知情同意书。
1.2 轻度认知损害(MCI)诊断标准
参照Petersen 2001年修订MCI诊断标准[6]。
1.3 中医证候分型诊断
釆用中医痴呆证候要素量表(The pattern element scale for dementia,PES-D/11)[6]。
1.4 纳入及排除标准
1.4.1 纳入标准 ①年龄50~85岁,体重45~90 kg。②符合MCI诊断标准。③简易精神状态量表(mini-mental state examination,MMSE)[7]:24~30分;汉密尔顿抑郁评定量表(Hamilton depression scale,HAMD)[8]:0~12分;海金斯基缺血量表(Hachinski ischemic scale,HIS)[9]:0~4分;日常生活活动量表(activities of daily living,ADL)[10]:0~<16分。④视、听力能配合完成测评。
1.4.2 排除标准 ①存在血管性痴呆或精神病或其他神经变性病;②合并严重全身性疾病,如心血管系统、消化系统、内分泌系统等;③有药物或酒精滥用史;④正在使用其他改善记忆的药物或疗法;⑤癫痫或严重头外伤;⑥头MRI扫描示脑梗(允许非关键部位的腔隙性脑梗)、颅腔感染。
1.5 方法
补肾健脾化痰颗粒(由北京康仁堂药业有限公司制作,东直门医院调配,9 g/袋),试验组9 g/次,口服,2次/d,连续服用12周;对照组为空白对照,即未使用改善认知的任何药物或非药物治疗。
1.6 观察指标
①认知功能评价:MMSE评分,得分与认知水平呈正比,即评分越高,认知功能越好;②中医证候:PES-D/11积分,得分与证候严重程度呈正比,积分越高,证候严重程度越高;③安全性指标:心电图,肝肾功能,血、尿、便常规,心电图。指标采集时间:基线、治疗12周后。
1.7 统计学方法
采用SPSS 21.0软件对数据进行统计分析。计数资料以例数或百分比表示,采用χ2检验。非正态分布计量资料以中位数(M)或四分位数(P25,P75)表示,采用秩和检验。以P < 0.05为差异有统计学意义。
2 结果
2.1 两组人口学特征比较
两组患者在性别、年龄、接受教育时间比较,差异无统计学意义(P > 0.05)。见表1。
2.2 两组治疗前后MMSE评分
两组治疗前MMSE评分比较,差异无统计学意义(P > 0.05)。与治疗前比较,试验组治疗12周后,MMSE评分明显高于治疗前,差异有统计学意义(P < 0.05);对照组治疗前后差异无统计学意义(P > 0.05)。试验组治疗12周后,MMSE评分显著高于对照组,差异有统计学意义(P < 0.05)。见表2。
注:与本组治疗前比较,*P < 0.05;与对照组同期比较,#P < 0.05。MMSE:简易精神状态检查表
2.3 两组治疗前后中医证候证候积分
两组治疗前,肾虚、脾虚、痰浊证候积分比较,差异无统计学意义(P > 0.05)。与治疗前比较,试验组治疗12周后,3种证候积分明显低于治疗前,差异有统计学意义(P < 0.05)。试验组治疗12周后,肾虚、脾虚、痰浊证候积分明显低于对照组,差异有统计学意义(P < 0.05)。见表3。
注:与本组治疗前比较,*P < 0.05;与对照组同期比较,#P < 0.05
2.4 安全性评价
在12周治疗中,试验组出现不良反应事件共5例(6.4%),分别为中药过敏、便秘、腹胀、牙龈肿痛及头痛,上述症状在停药1周左右缓解。两组受试者心电图、肝肾功能、血、尿、便常规未见异常。
3 讨论
AD是最常见的痴呆亚型,特征是认知功能合并身体综合状况下降,AD患者逐渐失去自我管理能力,随着病情加重往往需要长期护理,诊断后患者的平均生存期約为8~10年[11]。aMCI是AD的早期阶段,现有研究显示,aMCI阶段病情存在一定可逆性,AD病情发展呈不可逆性,因此应注重早期即aMCI阶段的治疗[12]。目前,针对aMCI的药物治疗尚无明确有效推荐,治疗方案主要参照AD。胆碱酯酶类药物是AD治疗推荐用药,但有研究证实,此类药物并未降低1~3年内aMCI进展为痴呆的风险[13]。此外,纳入2842名受试者的Meta分析显示,此类药物的副作用不容忽视[14]。因此,胆碱酯酶抑制剂不推荐用于治疗aMCI[15]。而非甾体类抗炎药、抗氧化和抗炎症、改善神经递质传递的药物,从理论上可以改善认知功能下降,延缓或阻止aMCI进展为AD,但临床疗效还需进一步考证[16]。因此,中药或是治疗aMCI的崭新研究领域,也是延缓aMCI向AD进展的新方法。
中医方面,aMCI属“健忘”“善忘”范畴。肾为先天之本,肾主藏精,精舍志;且肾主生髓,脑主藏髓,年事愈高,肾精愈亏,髓海不足,记忆善忘,故健忘治疗应注重补肾;陈士铎提出“痰气独盛,呆气最深”“治痰即治呆”,加之脾为生痰之源,故治痰应兼顾健脾,此为拟定补肾健脾化痰法治疗aMCI的理论基础。现代研究中,有临床试验证实aMCI阶段主要证候类型为肾精亏虚证和痰浊蒙窍证,痰浊是记忆力下降的主要因素,可加重认知功能衰退[17],为本研究运用补肾健脾化痰法治疗aMCI奠定了临床基础。中医证候改善评价方面,本研究选用PES-D/11,包括肾虚、脾虚、气虚、血虚、阴虚、阳虚、髓减、阳亢、内热、痰浊和血瘀共11个证候。若积分≥7分,表示该证候成立[18]。将复杂的中医证候进行积分量化,更有利于提高临床研究可信度。本研究中,补肾健脾化痰法方药主要包括熟地补肾,炒白术健脾,清半夏化痰。治疗12周后,试验组肾虚、脾虚、痰浊积分较对照组均有改善,从中医角度证明补肾健脾化痰法可以改善aMCI患者的临床症状。
近年有研究显示MCI进展为阿尔茨海默症的危险因素包括老龄、低教育水平、超重等,但其中更重要的是合并aMCI亚型[19-20]。而诊断及预测aMCI向AD转化程度的首选方法为综合认知评估,最常用量表为MMSE。有研究显示[21],神经心理学测评量表的组合使用虽然耗时较长,但仍是跟踪病情进展的最有效工具。其中MMSE操作简洁,成本效益合理,是aMCI向AD转化的有效纵向预测工具。本研究中,补肾健脾化痰法可以提高试验组患者MMSE评分,说明补肾健脾化痰法可改善aMCI的总体认知水平。试验组共出现不良反应5例(6.8%),无严重不良反应。
综上所述,补肾健脾化痰法可提高aMCI患者综合认知水平,改善了患者在肾虚、痰浊、脾虚方面的临床症状。因此,补肾健脾化痰法治疗aMCI 12周具有一定效果,安全性较好,可通过扩大样本量及延长随访时间更加深入探讨临床远期有效性及安全性。
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(收稿日期:2019-06-17 本文编辑:王晓晔)