【作者】 张书；

【导师】 王平；

【作者基本信息】 湖北中医药大学 ， 中医基础理论， 2014， 博士

【摘要】 目的基于数据挖掘技术，对导师辨证论治认知功能障碍患者的临床经验进行研究，以探寻导师治疗MCI的辨证经验、用药特点和组方规律；同时观察导师经验方益智温胆汤对48例MCI患者进行临床验证研究，为中医药治疗MCI的有效性和安全性提供参考依据。方法对导师2008年6月至2010年6月期间诊治的MCI临床病案进行原始资料的整理，建立数据库。对符合纳入标准的301次病案运用SPSS17.0软件对症状、体征、证候要素、方剂、药物等进行频数分析，总结和归纳MCI的常见症状、主要证候特征、常用方剂以及核心治疗药物等；采用聚类方法对纳入病例中使用频率在5%次以上的药物进行聚类分析，寻求治疗MCI关系密切的药物组合体；采用Apriori法对症状与方剂，症状与中药，中药与症状之间的关联规则进行分析，设最小支持度为10%，最小置信度为60%，总结导师治疗MCI的临床辨证用药规律。临床研究收集2011年3月至2013年9月期间96例老年MCI患者，采用随机对照的方法分为治疗组和对照组，治疗组给予益智温胆汤，一日一剂，口服，2次/天；对照组给予多奈派齐5mg，口服，1次/天。12周为一个疗程，观察两组治疗前后认知能力(MMSE)、记忆水平(DSR)、日常生活活动能力(ADL)及中医证候疗效，并进行血脂（TG、H-LDL及L-LDL）、Aβ(Aβ1-40、Aβ1-42)、炎性因子（IL-1β、IL-6及TNF-α）及相关安全性指标检测。另设健康对照组，比较老年MCI患者MMSE评分，血脂、Aβ及炎性因子的水平的变化。结果1.数据挖掘结果:（1）症状频数分析结果:老年认知功能障碍临床症状除主诉“健忘”以外，出现频率最高的是“失眠”，达到76.74%，其它出现频率在20%以上的症状从高到低依次为：倦怠乏力、头晕耳鸣、头晕而重、畏寒肢冷、夜尿频多、面色少华、腰膝酸软、少气懒言、体胖、口唇淡白、食少纳呆、小便清长、动作迟缓、口臭、面浮肢肿、便秘、情绪抑郁、痰多、肢体麻木、肢体困重、胁胀、口干咽燥、大便稀溏、口苦、脘痞；常见病位要素以肾(70.43%)、心(59.47%)为主，病性要素则主要为痰证(56.81%)、气虚证(52.49%)和血瘀证(36.54%)。（2）药物频数分析结果：对收集到的117例301次病案的处方进行频数分析，得出总频数为6469次，得出其核心药物依次为：半夏、茯苓、竹茹、熟地、白术、黄芪、何首乌、杜仲、石菖蒲、益智仁、酸枣仁、当归、合欢皮、白芍、山茱萸、川芎、山药、泽泻、知母、神曲、柴胡、陈皮、升麻，共23味，使用频数均在90次以上；对核心药物进行归类，主要药类有补虚药、化痰药和安神药三类。其中补虚药的药物频次为1759次，频率为46.52%，其次为化痰药和安神药，频率分别为13.54%和7.14%。按照药物四气、五味、归经对使用频率在5%以上的67味中药进行统计分析，温性药使用频率最高，占39.52%，其次为寒性药及平性药，频率分别为32.73%和22.15%。药性分析表明，治疗MCI主要使用的药性依次为甘味、苦味和辛味，使用频率分别为40.50%、25.50%和17.95%。而归经分析显示治疗认知功能障碍药物多选用足厥阴肝经、足太阴脾经、手少阴心经、足少阴肾经4条经脉，使用频率合计为64.14%。（3）聚类分析结果：对使用频率在5%以上的67味中药进行聚类分析，得出治疗老年认知功能障碍的6个多味药物组合体及10个常用药对，其中B2、B3、B6是补益药对；B1、B5是化痰药对；B8是活血药对；B7是清热药对；B9是养心安神药对；B4是滋阴药对；B10是解表药对，它们分别从不同角度体现了导师临证组方特点。（4）关联规则分析结果:根据症状与方剂进行关联规则分析，得到以下结果：以健忘、失眠、头晕、苔腻、脉滑为主症者，用益智温胆汤加减治疗；以失眠、健忘、脉细为主症时，常予酸枣仁汤；以倦怠乏力、少气懒言为主症时，常用补中益气汤；以腰膝酸软、头晕耳鸣为主症时，喜用六味地黄汤；以肢体困重、痰多、脉滑为主症时善用二陈汤祛湿化痰；当患者出现失眠、心悸、倦怠乏力、舌质红，常用天王补心丹加减治疗；以心悸、自汗、苔白时，予玉屏风散益气固表。根据症状与中药、中药与症状的关联规则分析：健忘者，多用半夏、竹茹、石菖蒲、益智仁、何首乌；失眠者，常用枣仁、柏子仁、茯苓、竹茹、石菖蒲、合欢皮、杜仲；倦怠乏力者，常用黄芪、山药、柴胡、升麻；头晕耳鸣者，多用熟地、白芍、山茱萸；头晕而重者，多用半夏、石菖蒲、泽泻；畏寒肢冷者，常予杜仲、益智仁、山药、山茱萸；夜尿频多者多用杜仲、山茱萸、益智仁、山药；面色少华者，宜选黄芪、当归、白芍、山茱萸；腰膝酸软者，多用熟地、山药、山茱萸、何首乌、益智仁；少气懒言者，选黄芪、白术、山药、柴胡、升麻、陈皮；食少纳呆者，宜用黄芪、白术、石菖蒲、山药、神曲、柴胡、陈皮；面浮肢肿者，加茯苓、白术、黄芪、泽泻；情绪抑郁者，宜合欢皮、白芍、当归、川芎、柴胡、陈皮；肢体麻木者加川芎、当归；胁胀者，用合欢皮、白芍、川芎、柴胡；脘痞者用神曲、陈皮、半夏、竹茹；心悸者，用茯苓、熟地、何首乌、酸枣仁。总之，导师临床用药平和，既避免大苦大寒伤脾败胃，又避免大辛大热伤津耗液，务以临床实效为是。2.临床研究结果：（1）认知功能疗效比较：与健康组比较，MCI患者综合认知能力、地点定向能力、时间定向能力、即刻记忆能力、计算能力、短程记忆能力及语言理解能力均显著降低（P<0.01）；治疗前，两组各项指标比较无统计学差异(P>0.05)；与治疗前比较，治疗后治疗组综合认知能力、定向能力、即刻记忆能力、计算能力、短程记忆能力有显著提高(P<0.05，P<0.01)，对照组综合认知能力、即刻记忆能力、计算能力、短程记忆能力及语言理解能各项指标比较有显著提高(P<0.05，P<0.01)；治疗后比较，治疗组定向能力改善优于对照组(P<0.05)，对照组语言理解能改善优于治疗组(P<0.05)。（2）记忆水平疗效比较：治疗组和对照组治疗前后DSR评分比较表明，治疗组和对照组治疗后DSR评分较治疗前均明显提高(P<0.05，P<0.01），两组组间比较无统计差异(P>0.05)。提示益智温胆汤治疗老年MCI患者后，DSR积分均较治疗前明显提高(P<0.01)；与多奈派齐对照组比较疗效无差异(P>0.05)。（3）日常活动能力的比较：治疗前，两组DSR评分比较无统计学差异(P>0.05)；与治疗前比较，治疗后两组DSR评分较治疗前均明显提高(P<0.01)，组间比较无统计学差异(P>0.05)。结果提示：益智温胆汤治疗老年MCI的临床疗效与多奈派齐比较无统计学差异(P>0.05)。（4）证候疗效比较：治疗前，两组证候积分比较无统计学差异(P>0.05)；与治疗前比较，治疗后治疗组脾肾亏虚、气血不足和痰浊蒙窍型证候积分均较治疗前明显降低（P<0.01），阴虚阳亢型证候积分均较治疗前降低（P<0.05），对照组各证型证候积分均无明显改善(P＞0.05)；治疗后比较，治疗组优于对照组（P<0.01）。结果提示：益智温胆汤治疗老年MCI，在改善证候积分方面，疗效优于对照组（P<0.01）。（5）两组治疗前后血脂水平的比较：与健康组比较，治疗组和对照组HDL-C水平降低(P<0.05)，TG和LDL-C水平较健康组比较无统计学差异(P>0.05)；治疗组治疗后较治疗前比较HDL-C显著升高(P<0.01)，TG下降(P<0.05)；对照组治疗后较治疗前比较，HDL-C升高(P<0.05)，TG及LDL-C比较无统计学差异。两组治疗后比较，治疗组较对照组HDL-C升高明显（P<0.05），TG及LDL-C比较无统计学差异。提示益智温胆汤治疗老年MCI患者后，患者血清HDL-C含量均较治疗前明显提高，且作用优于多奈派齐对照组。（6）两组治疗前后血清Aβ1-40、Aβ1-42的比较：与健康组比较，两组患者血浆Aβ1-42浓度明显升高（P＜0.01），而血浆Aβ1-40浓度及Aβ1-40/Aβ1-42无统计学差异（P＞0.05）。与治疗前比较，治疗后治疗组Aβ1-42的血浆浓度显著降低（P＜0.01），对照组Aβ1-42的血浆浓度降低（P＜0.05）。组间比较，治疗组和对照组患者血浆Aβ1-42浓度较治疗前相比无统计学差异（P＞0.05）。结果提示：两组均能有效降低血浆Aβ1-42浓度，无统计学差异（P＞0.05）。（7）两组治疗前后血清炎性因子的比较：与健康组比较，两组血清IL-1β、IL-6和TNF-α浓度均明显升高（P＜0.01）；与治疗前比较，治疗后治疗组血清IL-1β、IL-6和TNF-α的表达均显著降低（P＜0.01），对照组血清IL-1β、IL-6和TNF-α的表达均降低（P＜0.05）；组间比较，治疗后治疗组抑制IL-1β表达的疗效优于对照组（P＜0.05），抑制IL-6表达的作用劣于对照组（P＜0.05），对于TNF-α表达的影响，两组无统计学差异（P＞0.05）。结果提示：益智温胆汤治疗老年MCI的作用机制可能与调节血清IL-1β、IL-6和TNF-α水平有关。结论1.数据挖掘是总结中医经验的有效途径，可以归纳提炼导师临证用药规律及治疗法则。治疗MCI患者辨证病位当以心、脾、肾为主，临床表现为失眠、倦怠乏力、头晕耳鸣、头晕而重、畏寒肢冷、夜尿频多等症状。病性以正虚为本，邪实为标。正虚以肾之精气虚损为主，邪实则以痰浊为患。利用频数分析，可得补益、化痰是MCI的主要治法；利用关联规则可以总结出MCI的药物配伍规律；利用聚类分析方法可得出治疗MCI的常用药物组合体。运用数据挖掘技术分析海量的中医诊疗信息，有助于发现中医辨证施治、处方用药等环节中隐含的关联和规律，有助于促进中医的发展和创新。2.益智温胆汤在改善老年MCI患者的中医证候疗效、提高HDL-C表达、抑制IL-1β表达方面优于多奈派齐；在改善患者记忆水平、日常生活活动能力、降低Aβ1-42的血浆浓度方面与多奈派齐疗效近似。因此，益智温胆汤的作用机制可能是通过减少在MCI中潜在神经毒性的IL-1β、IL-6、TNF-α等炎性因子分泌，降低β类淀粉蛋白Aβ1-42的的表达，减少神经细胞的损害，从而延缓MCI的的发生发展。更多还原

【Abstract】 OBJECTIVEIn order to find out the rule of differentiation and treatment of MCI，weinvestigated the clinical experience of tutor and aided Based on data miningtechnology and modern epidemiology statistical methods. In addition，with theherbal formula extracting from the Data Mining of the research，a clinicalresearch was performed in MCI patients， aiming at supporting theeffectiveness and safety of the treatment of MCI with Chinese TraditionalMedicine.METHODWe Collect the clinical MCI cases of tutor in recent years，First of all，theinformation of the clinical cases that met the inclusion criteria should to besaved. then the information is preprocessed and database was established withExcel software. By the use of statistical methods such as frequency analysiswas applied to find the commonly used medicines，symptom frequency，Differentiation type frequency， Prescription frequency and Thepharmacologic properties of frequency；Association rules was applied tosummarize the law of Clinical drug law of the tutor and the Close relationshipDrug combinations that treated the MCI were learned from clustering.A clinical research is performed with the herbal formula extracting from the Data Mining of the research，96patients with MCI were dividedinto treatment group and control group，the treatment group received YizhiWendantang； control group was given Donepezil.12weeks for a course.observing of the clinical efficacy (MMSE、DSR、ADL)，lipids (TG，H-LDLand L-LDL)，Aβ (Aβ1-40，Aβ1-42) and inflammatory factors (IL-1β，IL-6andTNF-α) and adverse reactions of Western medicine.RESULT1.Data mining results:（1）Symptom frequency analysis: cognitive dysfunction in the elderlycomplained of clinical symptoms in addition to " forgetfulness " other than themost frequent symptom is " Insomnia"，reached76.74%，the frequency ofother symptoms in more than20%in the order of: Burnout fatigue，dizziness，tinnitus，dizziness and heavy，chills，Nocturia，looking Shaohua，waistand knees，less gas lazy words，body fat，pale lips，poor appetite，nocturiaclear long，slow movement，bad breath，face limb edema，constipation，depression，phlegm，numbness，body weight difficulties，threateningswelling，dry mouth and throat，loose stool，mouth pain，abdominalswelling； common position elements in the kidney (70.43[difference apercent sign]%)，heart (59.47%) mainly，disease resistance elements aremainly phlegm (56.81%)，qi (52.49%) and blood stasis syndrome(36.54%).（2）Drug frequency analysis: The collected117cases diagnosed301times prescription frequency analysis，the total frequency of6，469times，come to the core of the drug were: Pinellia，Poria，Zhuru，foxglove，Atractylodes，Astragalus，Polygonum，Eucommia，Shichangpu，treatingdiabetes，Semen，Angelica，Albizia，white peony root，dogwood root，Chinese yam，Alisma，Anemarrhena，Divine Comedy，Bupleurum， Citrus，cohosh，a total of [number to the number only23，and later a poorlicorice]23flavor，use frequency were more than90times；Core drugs areclassified，the main drug class has tonic medicine，phlegm drugs and sedativedrug categories. Tonic medicine which is1759times the frequency of drug，frequency of46.52%，followed by phlegm drugs，and sedative drugs，frequency of13.54%and7.14%respectively. Four gas in accordance withdrugs，flavors，owned by the frequency of the use of more than5%of the67herbs for statistical analysis，the temperature of the drugs most frequentlyused，accounting for39.52%，followed by cold medicine and levelingagents，the frequency is32.73%，respectively，，22.15%.Potency analysisshowed the potency of the treatment were mainly used MCI sweet taste，bitter and pungent，the frequency is40.50%，25.50%and17.95%，respectively. The analysis showed that the treatment of MCI owned by multi-choice drugs Foot Jue Yin Liver Meridian，full moon spleen，hand Shao YinHeart Sutra，kidney meridian four meridians，the total frequency of64.14%.（3）Cluster analysis: the use of a frequency of more than5%of the67herbs clustering analysis，the treatment of MCI multi-drug combinationsflavor and body6to10commonly used drugs，including B2，B3，B6is atonic for； B1，B5is phlegm drugs on； B8is the blood of the drug； B7is antipyretic for； B9is uneasiness of mind on drugs； B4is yin drugson； B10is relieving drugs on， they are reflected from differentperspectives clinical tutor group Fang Siwei feature set of square principles.（4）association rules analysis: according to symptoms with prescriptionassociation rules analysis， the following results: the forgetfulness，insomnia，dizziness，moss greasy main symptoms，with the addition andsubtraction Yizhi Wendantang treatment； when insomnia，forgetfulness，pulse-based disease，often to Suanzaorentang； when fatigue，less gas lazy words based disease，commonly Buzhongyiqitang； in waist and knees，dizziness，tinnitus based disease when，like to use Liuweidihuang soup；utilize Erchen dampness and phlegm when body weight difficulties，phlegm，slippery pulse-based disease；With palpitations，spontaneous，white fur when I Yupingfengsan Qi solid form. According to the symptomswith medicine， Chinese medicine with symptom association rules，forgetfulness multi Breit， Zhuru， Shichangpu， treating diabetes，Polygonum； insomnia commonly Zaoren， Bozi， Poria， Zhuru，Shichangpu， Acacia leather， gutta； lassitude commonly used byastragalus，Chinese yam，Bupleurum，Cimicifuga； dizziness，tinnitus andmore with Rehmannia，white peony root，dogwood； dizziness and severemulti Breit，Shichangpu，Alisma； chills are often subject to Eucommia，treating diabetes，yam，dogwood； nocturia were more with gutta，dogwood，treating diabetes，yams；Looking Shaohua advised to chooseastragalus，angelica，white peony root，dogwood； Yaoxisuanruan multiRehmannia，Chinese yam，dogwood，Polygonum，treating diabetes；less gas lazy speaker election Astragalus，Atractylodes，yam，Bupleurum，Cimicifuga，Citrus； poor appetite suitably Astragalus，Atractylodes，Shichangpu，yams，Divine Comedy，Bupleurum，Citrus； surface limbedema plus Poria，Atractylodes，Astragalus，Alisma；depression advisedAlbizia，white peony root，angelica，Chuanxiong，Radix，Citrus；numbness plus Chuanxiong，Angelica；Threat of inflation by using Albizia，white peony root，Bupleurum；abdominal swelling by using Divine Comedy，Citrus，Pinellia，Zhuru palpitations with Poria，Radix，Polygonum，Semen.In short，the instructor of clinical medicine peace，not only to avoid defeatbitter Big Chill injured spleen stomach，and avoid injury Jin Xin consumptionof hot liquid，the clinical effectiveness of services to Yes.2.Clinical study results: （1）Comparison of efficacy of cognitive function:MCI patientscomprehensive cognitive ability，the ability to place orientation，timeorientation capabilities，immediate memory capacity，computing power，short-term memory capacity and language comprehension were significantlylower than the normal group. The treatment group and the control groupshowed no significant difference (P>0.05) in front of the indicators； Aftertreatment of cognitive ability，directional capabilities，immediate memorycapacity，computing power，short-term memory capacity has improvedsignificantly (P <0.05，P <0.01)；The control group before and after treatmentof cognitive ability，immediate memory capacity，computing power，short-term memory and language comprehension ability can compare theindicators have improved significantly (P <0.05，P <0.01)； compare the twogroups，the treatment group targeting capabilities improvement than thecontrol group (P <0.05)，language understanding can improve the controlgroup than the treatment group (P <0.05).（2）Memory level (DSR) compare the efficacy: treatment group andcontrol group DSR scores before and after treatment showed significantlyimproved (P <0.01) after treatment before DSR score than the treatmentgroup； former DSR score in the control group were significantly improvedcompared to treatment There was no statistical difference between the twogroups(P>0.05). Tip Yizhi Wendantang treatment of elderly patients with mildcognitive impairment，the two groups of patients before treatment than DSRintegration significantly improved (P <0.05)； with donepezil send its efficacywas no difference in the control group (P>0.05).（3）Comparison of activities of daily living: the treatment group and thecontrol group before and after treatment ADL comparison， significantimprovement in ADL scores than before treatment after treatment (P <0.01)，after treatment ADL scores than the control group before treatment improved significantly (P <0.01). The treatment group compared with the control groupsignificantly improved ADL，statistical analysis was no difference (P>0.05).Tip Yizhi Wendantang treatment of elderly patients with mild cognitiveimpairment after two groups of patients ADL points than before treatmentsignificantly improved； donepezil send compare the efficacy and nodifferences (P>0.05) in control groups.（4）Compare syndromes: syndrome score before and after treatmentshowed no significant difference； before and after treatment，spleen andkidney deficiency， blood deficiency， phlegm Mongolia awakened，hyperactivity symptom scores compared with four card before treatmentreduced (P <0.05)，each syndrome symptoms improved compared with beforetreatment，including spleen and kidney deficiency，blood deficiency andphlegm syndrome improve Mongolia awakened three most significant (P<0.01)；Each treatment group before and after treatment were not improvedsymptom scores (P>0.05)； symptom scores after treatment comparisonshowed that the treatment group spleen deficiency，lack of blood and phlegmMongolia awakened three syndromes compared with the control group asignificant improvement (P <0.01)， there is a certain improvement inhyperactivity syndrome (P <0.05). Yizhi Wendantang treatment of elderlypatients with mild cognitive impairment after，syndromes than the controlgroup.（5）Lipid levels were compared before and after treatment: the threegroups before treatment lipids compared with the treatment group and thecontrol group compared with cognitively normal HDL-C were lower (P<0.05)，TG and LDL-C showed no statistical difference. Treatment groupsignificantly increased HDL-C compared with pre-treatment (P <0.01)，compared with pre-treatment also decreased TG (P <0.05)； the control groupbefore and after treatment，compared with pre-treatment HDL-C increased (P <0.05)，TG and no significant difference in LDL-C after treatment. Aftertreatment，the treatment group compared with the control group HDL-Cincreased significantly (P <0.05)，TG and LDL-C was no significant difference(P>0.05).（6）Compared with the normal group，before treatment significantlyincreased plasma concentrations of Aβ1-42treatment group and the controlgroup (P <0.01)，while plasma concentrations of Aβ1-40and Aβ1-42: serumAβ1-40， Aβ1-42for comparison before and after treatment Aβ1-40/42comparison，there was no significant difference (P>0.05). After treatmentthan before treatment plasma concentrations of Aβ1-42is reduced，and thereis a significant difference (P <0.01)；after treatment than before treatmentcontrol group comparison，a significant difference (P <0.05). Treatment groupand control group， Aβ1-42was no significant difference in plasmaconcentration decreased (P>0.05). Prompt treatment and control groups caneffectively reduce serum Aβ1-42levels，and no significant difference (P>0.05)effect.（7）Comparison of serum inflammatory factors before and aftertreatment: Compared with the normal group，the treatment group and thecontrol group before treatment serum IL-1β，IL-6，TNF-α concentrations weresignificantly elevated compared with normal group with a statisticallysignificant difference (P <0.01). Treatment group after treatment than beforetreatment IL-1β，IL-6，expressing TNF-α were reduced，and there was asignificant difference (P <0.01)； than before treatment IL-1β in the controlgroup，IL-6，TNF expression-α were significantly decreased，and there wassignificant difference (P <0.05). Treatment group and control group，to moreeffectively inhibit the expression of IL-1β (P <0.05)； but at a reducedexpression of IL-6，the effect is better than the control group (P <0.05)； theexpression of TNF-α，the no significant difference (P>0.05). CONCLUSION1.Data mining is a summary of the heritage of Chinese medicinepractitioners experience an effective way，instructors can be summarizedrefining and treatment of drug law rules. MCI syndrome treatment whenpatients with heart disease，spleen，kidney main clinical manifestations ofinsomnia，fatigue，dizziness，tinnitus，dizziness and heavy，chills，nocturiaand other symptoms.Disease resistance to positive imaginary oriented，realevil is standard. Positive imaginary to kidney essence deficiency mainly withphlegm actually evil infestation. The use of frequency analysis，we havetonic， expectorant and sedative is MCI ’s main treatment method；association rules can be summed up drug compatibility rule of MCI； usingcluster analysis can be drawn from the treatment of MCI ’s commonly useddrugs combination.Analysis using data mining techniques massive Chinesemedical information to help find and laws associated with TCM therapy，prescription medication and other aspects implied，help to promote thedevelopment and innovation of traditional Chinese medicine.2.Yizhi Wendantang older MCI patients in improving the efficacy ofTCM symptoms and improve HDL-C levels，inhibit IL-1β expression interms of efficacy than donepezil send it； improve memory levels in patientswith activities of daily living，reduce Aβ1-42the plasma concentrations ofdonepezil sent his respects with similar efficacy. Therefore， YizhiWendantang MCI possible by reducing the potential neurotoxicity IL-1β，IL-6，TNF-α and other inflammatory cytokine secretion，reduced β amyloidprotein Aβ1-42’s， reducing nerve cells damage， thus delaying thedevelopment of MCI.更多还原