老年健忘肾虚痰阻证的流行病学和血浆代谢组学研究
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摘要
目的
随着我国社会老龄化日益加重，老年性认知功能障碍患者日益增多，成为迫切需要解决的社会问题。西医所言的遗忘型轻度认知功能障碍（aMCI）及老年性痴呆（AD）与中医老年健忘和呆病相似。由于目前缺乏根本上扭转AD的治疗方法，因此AD的防治重心前移，MCI成为有效的时间窗。中医推崇上工治未病，对老年健忘的相关认识历史悠久，积淀深厚，掌握和运用老年健忘的中医药防治规律对解决老年认知功能障碍这一社会难题大有裨益。中医临床辨证论治是从证候入手的，证候也是评价治疗方案或新药疗效的重要依据之一。前期研究中补肾化痰法被证实是治疗老年认知功能障碍的有效治法，从证治的对应关系看该疗法针对的证候类型是肾虚痰阻证，肾虚痰阻证的临床证候规律如何？如何客观量度肾虚痰阻证？本研究试图从历史文献、临床流行病学和代谢组学三个层面揭示肾虚痰阻证的证候规律。
方法
1.文献研究：分析整理有关老年健忘的古今文献，从病因病机、治疗方药、辨证证型等多个角度归纳总结老年健忘的证治规律，梳理补肾化痰益智法的历史源流和现实依据。
2.流行病学调查：在前期老年健忘痰证患者的流行病学调查的基础上，依据肾虚证和痰证的证候对315例入选患者的症状，运用SPSS16.0软件进行聚类分型、频数统计等数据分析。
3.在武汉市中西结合医院和湖北省中医院分别筛选出32例aMCI肾气虚痰阻证患者和30例健康老年志愿者，空腹抽取血样，采用美国WatersSYNAPT G2-S Q-TOF液相色谱-质谱联用仪进行代谢组学分析。
结果
1.文献研究结果
（1）自《黄帝内经》开始，肾虚痰阻即是健忘的主要病机之一，明清时期医家主要采用补肾化痰类治法治疗健忘和痴呆。
（2）古代医籍中并未系统记载肾虚痰阻证的证候表现，但对肾虚证和痰证有较多记录，二者紧密相关；现代医家分别对肾虚证和痰证证候表现做过规范化的探索。
2.流行病学调查结果
（1）315患者的症状聚类分析并结合症状频次分布，发现可以分为三类，第一类症状见：神疲乏力、少气懒言、齿痕舌、食少纳呆、脉虚无力、自汗、苔腻、健忘、腰酸痛、腰膝酸软、肢体困重、齿发脱落、神情呆滞、头重如裹；第二类主要症状有：舌苔白滑、脉象沉迟、畏寒肢冷、面足虚浮、便溏、小便清长、夜尿频多、脉弦、嗜睡、舌胖大、尿失禁、体态臃肿、腐苔、酣睡痰鸣；第三类症状主要有：五心烦热、脉细数、口干咽燥、舌红少苔、小便短赤、盗汗、大便干结、失眠、咳痰、面色秽浊。从中医辨证理论分析，第一类证候归属于肾气虚痰阻；第二类证候为肾阳虚痰阻；第三类证候为肾阴虚痰阻。
（2）315患者各类证型比例：肾气虚痰阻38.41%，肾阳虚痰阻30.03%，肾阴虚痰阻35.56%
（3）用单因素方差分析患者年龄差异显示，肾气虚痰阻与肾阳虚及肾阴虚痰阻相比，P<0.05，具有显著性差异；肾阳虚痰阻组与肾阴虚痰阻组比较，P>0.05，无明显差异。这表明，随着年龄的增长或病情的加重，肾气虚痰阻证可能转化为肾阳虚痰阻，也可能转化为肾阴虚痰阻，或者出现兼夹情况。
2.血浆代谢组学发现：与健康人群比较，肾气虚痰阻健忘患者人群较正常老年人群溶血磷脂LysoPC(16:0)、戊糖Pentosidine、11,18,21β-三羟基-4-烯-3,20-二酮18-Hydroxycorticosterone均显著升高p<0.05，0.01)；磷脂酰乙醇胺PE(22:2(13Z,16Z)/15:0)、胱硫醚L-Cystathionine、甘油磷脂PE(O-18:1(1Z)/20:4(5Z,8Z,11Z,14Z)、3a-羟基-5β-孕烷-20-酮、磷脂酰胆碱PC(20:1(11Z)/14:1(9Z)有明显降低趋势(p<0.05，0.01)。与健康对照人群比较，证候人群多个代谢途径发生变化，证候人群肾上腺皮质激素分泌改变，在脂代谢、糖代谢等方面发生了紊乱。
结论
一、老年健忘的复合证候肾虚痰阻证更符合临床实际，文献研究、流行病学调查和代谢组学分析有助于揭示证候的规律和实质。
二、肾虚与痰浊在老年健忘这一特定疾病中的相互作用和紧密联系，明清医家对老年健忘与痴呆的辨治最为成熟，补肾化痰是明清以来医家的主要治法。
三、肾虚痰阻证证候可以进一步分化为肾气虚痰阻、肾阳虚痰阻和肾阴虚痰阻。
四、老年健忘患者中肾气虚痰阻所占比重最大，且三种证型与年龄有一定关联。元气亏虚致病论在老年认知功能障碍等疾病中的防治方面具有重要应用价值。
五、老年健忘肾气虚痰阻证与健康老人的血浆代谢组学存在差异，健忘组肾功能下降，脂代谢、糖代谢紊乱，证候组存在潜在标志物。
Objectives:
Senile cognitive dysfunction is becoming a major issue that needs resolutionunder the condition of the increasing ageing population. It is of great benefitfor this tough issue using methods under traditional Chinese medical theory onprevention for senescent forgetfulness, because of the similarity of mildcognitive impairment (MCI) and dementia to senescent forgetfulness andidiocy, as the famous saying goes,“superior doctors treat disease before itsonset”. Traditional Chinese Medicine (TCM) treats diseases with theframework of Bian Zheng Lun Zhi (diagnosis and treatment according to thesyndrome differentiation), thus the syndromes are the one of the importantbasis for evaluating the treatment scheme or the therapeutic effect of newdrugs. The method of tonifying kidney and removing phlegm to benefitintelligence is considered effective in treating senile cognitive impairment,whcih aims at the syndrome of kidney deficiency and phlegm stasis. Thisstudy was conducted for revealing the law of the syndrome of kidneydeficiency and phlegm stasis, such as the law of clinical manifestation andquantitative assessment, via searching literatures, means of clinicalepidemiology and metabonomics.
Methods:
1Theoretical exploration.Working out the origin and realistic basis of the method of tonifying kidneyand removing phlegm to benefit intelligence to summarize through literaturereview the etiology and pathology of senescent forgetfulness, its treatmentformulae and syndrome differentiation for the law of senescent forgetfulness.
2Epidemiological investigation.
315cases matching the syndrome of kidney deficiency and phlegm syndromefrom the epidemiological investigation on senescent forgetfulness patientswith phlegm syndrome were involved for clustering analysis and frequencystatistics, using SPSS16.0software.
3Empty-stomach blood sample from32cases of senescent forgetfulnesspatients with the syndrome of kidney deficiency and phlegm stasis and30healthy elderly volunteers selected from Wuhan Chinese and WesternMedicine Hospital and Hubei Hospital of Traditional Chinese Medicine weredetected using Waters SYNAPT G2-S QTOF liquid chromatograph-massspectrometer (US) for metabonomical analysis.
Results:
1Epidemiology
1.1The clustering analysis together with the frequency distribution on the datafrom the315patients indicated the following3types of symptoms. Type onecontains fatigue, lack of energy, teeth-printed tongue, dyspepsia, weak pulse,spontaneous sweating, greasy coating on the tongue, forgetfulness, sore waist,lumbar and knee strengthlessness, heaviness of limbs, alopecia, gomphiasis,sluggish looking, heaviness of head. Major symptoms in type two includes:white and smooth tongue coating, deep and slow pulse, cold sensation oflimbs and chillness, edema in face and feet, loose stool, clear abundant urine,frequent nocturia, taut pulse, drowsiness, enlarged tongue, uroclepsia, fat body, curdy fur, snooze and gurgling with sputum. The third type symptoms aredysphoria in chestpalms-soles, thready and rapid pulse, thirsty and dry throat,red tongue with little coating, scanty dark urine, night sweat, dry stool,insomnia, expectoration and dirty looking face. Type one in TCM refers tokidney qi deficiency and phlegm stasis. Type two refers to kidney yangdeficiency and phlegm stasis. Type three refers to kidney ying deficiency andphlegm stasis.
1.2Proportion of syndrome of315patients. Kidney qi deficiency and phlegmstasis syndrome took up38.41%, and the kidney yang deficiency and phlegmstasis syndrome30.03%, the kidney ying deficiency and phlegm stasissyndrome35.56%.
1.3The one-way analysis of variance showed that group of kidney qideficiency and phlegm stasis syndrome was significantly different with kidneyyang deficiency and phlegm stasis syndrome group and the kidney yingdeficiency and phlegm stasis syndrome group, P<0.05. The group of kidneyyang deficiency and phlegm stasis syndrome was observed insignificantlydifference with the group of kidney ying deficiency and phlegm stasissyndrome, P>0.05. This outcome indicates that type one may be transformedinto type two or three with the increase of age or the aggravation of disease.The coexistence of the three types is also possible.
2Plasma metabonomics outcomes showed obvious elevated (P<0.05, P<0.01)in the following indices, as compared with healthy elderly contrast:lysophosphatide (16:0), pentaglucose,11,18,21β-trihydroxy-4-olefince-3,20-diketone18-Hydroxycorticosterone. And the following were seenobviously declined (P<0.05, P<0.01): phosphatidyl ethanolaminePE(22:2(13Z,16Z)/15:0), cystathionine L-Cystathionine, glyceryl phosphatidePE(O-18:1(1Z)/20:4(5Z,8Z,11Z,14Z),phosphatidylcholinePC(20:1(11Z)/14:1(9Z). The above results indicate that, when compared with healthy elderly contrast,patient groups underwent multiple changes to their metabolic pathways.Disorder occurred in lipid and energy metabolism.
Conclusions:
1Kidney deficiency and phlegm turbid interact with and closely related toeach other in senescent forgetfulness. Doctors in Ming and Qing dynasties arethe most skilled practitioners on the treatment for this disease. Tonifyingkidney and removing phlegm are their major treatment method.
2The kidney deficiency and phlegm stasis syndrome can be further dividedinto three syndromes: kidney qi deficiency and phlegm stasis, kidney yangdeficiency and phlegm stasis, kidney ying deficiency and phlegm stasis.
3This study indicates that the kidney qi deficiency and phlegm stasissyndrome takes the major proportion and is relevant to the three subtypes:patients of kidney qi deficiency and phlegm stasis syndrome are relativelyyoung olds. Theory of deficiency of primordial qi is of great theoretical valuein the exploration of senile cognitive impairment.
4Kidney qi deficiency and phlegm stasis syndrome senescent forgetfulnesspatients were different from healthy contrast in plasma metabonomics. Kidneyfunction declined in the group of forgetfulness, together with lipid metabolicdisorder. Markers were observed in syndrome groups.
5It is closer to the real clinical condition of the compound syndromes ofsenescent forgetfulness. The literature, epidemiological investigation andmetabonomical analysis facilitate revealing the law and essence of thesyndromes.
随着我国社会老龄化日益加重，老年性认知功能障碍患者日益增多，成为迫切需要解决的社会问题。西医所言的遗忘型轻度认知功能障碍（aMCI）及老年性痴呆（AD）与中医老年健忘和呆病相似。由于目前缺乏根本上扭转AD的治疗方法，因此AD的防治重心前移，MCI成为有效的时间窗。中医推崇上工治未病，对老年健忘的相关认识历史悠久，积淀深厚，掌握和运用老年健忘的中医药防治规律对解决老年认知功能障碍这一社会难题大有裨益。中医临床辨证论治是从证候入手的，证候也是评价治疗方案或新药疗效的重要依据之一。前期研究中补肾化痰法被证实是治疗老年认知功能障碍的有效治法，从证治的对应关系看该疗法针对的证候类型是肾虚痰阻证，肾虚痰阻证的临床证候规律如何？如何客观量度肾虚痰阻证？本研究试图从历史文献、临床流行病学和代谢组学三个层面揭示肾虚痰阻证的证候规律。
方法
1.文献研究：分析整理有关老年健忘的古今文献，从病因病机、治疗方药、辨证证型等多个角度归纳总结老年健忘的证治规律，梳理补肾化痰益智法的历史源流和现实依据。
2.流行病学调查：在前期老年健忘痰证患者的流行病学调查的基础上，依据肾虚证和痰证的证候对315例入选患者的症状，运用SPSS16.0软件进行聚类分型、频数统计等数据分析。
3.在武汉市中西结合医院和湖北省中医院分别筛选出32例aMCI肾气虚痰阻证患者和30例健康老年志愿者，空腹抽取血样，采用美国WatersSYNAPT G2-S Q-TOF液相色谱-质谱联用仪进行代谢组学分析。
结果
1.文献研究结果
（1）自《黄帝内经》开始，肾虚痰阻即是健忘的主要病机之一，明清时期医家主要采用补肾化痰类治法治疗健忘和痴呆。
（2）古代医籍中并未系统记载肾虚痰阻证的证候表现，但对肾虚证和痰证有较多记录，二者紧密相关；现代医家分别对肾虚证和痰证证候表现做过规范化的探索。
2.流行病学调查结果
（1）315患者的症状聚类分析并结合症状频次分布，发现可以分为三类，第一类症状见：神疲乏力、少气懒言、齿痕舌、食少纳呆、脉虚无力、自汗、苔腻、健忘、腰酸痛、腰膝酸软、肢体困重、齿发脱落、神情呆滞、头重如裹；第二类主要症状有：舌苔白滑、脉象沉迟、畏寒肢冷、面足虚浮、便溏、小便清长、夜尿频多、脉弦、嗜睡、舌胖大、尿失禁、体态臃肿、腐苔、酣睡痰鸣；第三类症状主要有：五心烦热、脉细数、口干咽燥、舌红少苔、小便短赤、盗汗、大便干结、失眠、咳痰、面色秽浊。从中医辨证理论分析，第一类证候归属于肾气虚痰阻；第二类证候为肾阳虚痰阻；第三类证候为肾阴虚痰阻。
（2）315患者各类证型比例：肾气虚痰阻38.41%，肾阳虚痰阻30.03%，肾阴虚痰阻35.56%
（3）用单因素方差分析患者年龄差异显示，肾气虚痰阻与肾阳虚及肾阴虚痰阻相比，P<0.05，具有显著性差异；肾阳虚痰阻组与肾阴虚痰阻组比较，P>0.05，无明显差异。这表明，随着年龄的增长或病情的加重，肾气虚痰阻证可能转化为肾阳虚痰阻，也可能转化为肾阴虚痰阻，或者出现兼夹情况。
2.血浆代谢组学发现：与健康人群比较，肾气虚痰阻健忘患者人群较正常老年人群溶血磷脂LysoPC(16:0)、戊糖Pentosidine、11,18,21β-三羟基-4-烯-3,20-二酮18-Hydroxycorticosterone均显著升高p<0.05，0.01)；磷脂酰乙醇胺PE(22:2(13Z,16Z)/15:0)、胱硫醚L-Cystathionine、甘油磷脂PE(O-18:1(1Z)/20:4(5Z,8Z,11Z,14Z)、3a-羟基-5β-孕烷-20-酮、磷脂酰胆碱PC(20:1(11Z)/14:1(9Z)有明显降低趋势(p<0.05，0.01)。与健康对照人群比较，证候人群多个代谢途径发生变化，证候人群肾上腺皮质激素分泌改变，在脂代谢、糖代谢等方面发生了紊乱。
结论
一、老年健忘的复合证候肾虚痰阻证更符合临床实际，文献研究、流行病学调查和代谢组学分析有助于揭示证候的规律和实质。
二、肾虚与痰浊在老年健忘这一特定疾病中的相互作用和紧密联系，明清医家对老年健忘与痴呆的辨治最为成熟，补肾化痰是明清以来医家的主要治法。
三、肾虚痰阻证证候可以进一步分化为肾气虚痰阻、肾阳虚痰阻和肾阴虚痰阻。
四、老年健忘患者中肾气虚痰阻所占比重最大，且三种证型与年龄有一定关联。元气亏虚致病论在老年认知功能障碍等疾病中的防治方面具有重要应用价值。
五、老年健忘肾气虚痰阻证与健康老人的血浆代谢组学存在差异，健忘组肾功能下降，脂代谢、糖代谢紊乱，证候组存在潜在标志物。
Objectives:
Senile cognitive dysfunction is becoming a major issue that needs resolutionunder the condition of the increasing ageing population. It is of great benefitfor this tough issue using methods under traditional Chinese medical theory onprevention for senescent forgetfulness, because of the similarity of mildcognitive impairment (MCI) and dementia to senescent forgetfulness andidiocy, as the famous saying goes,“superior doctors treat disease before itsonset”. Traditional Chinese Medicine (TCM) treats diseases with theframework of Bian Zheng Lun Zhi (diagnosis and treatment according to thesyndrome differentiation), thus the syndromes are the one of the importantbasis for evaluating the treatment scheme or the therapeutic effect of newdrugs. The method of tonifying kidney and removing phlegm to benefitintelligence is considered effective in treating senile cognitive impairment,whcih aims at the syndrome of kidney deficiency and phlegm stasis. Thisstudy was conducted for revealing the law of the syndrome of kidneydeficiency and phlegm stasis, such as the law of clinical manifestation andquantitative assessment, via searching literatures, means of clinicalepidemiology and metabonomics.
Methods:
1Theoretical exploration.Working out the origin and realistic basis of the method of tonifying kidneyand removing phlegm to benefit intelligence to summarize through literaturereview the etiology and pathology of senescent forgetfulness, its treatmentformulae and syndrome differentiation for the law of senescent forgetfulness.
2Epidemiological investigation.
315cases matching the syndrome of kidney deficiency and phlegm syndromefrom the epidemiological investigation on senescent forgetfulness patientswith phlegm syndrome were involved for clustering analysis and frequencystatistics, using SPSS16.0software.
3Empty-stomach blood sample from32cases of senescent forgetfulnesspatients with the syndrome of kidney deficiency and phlegm stasis and30healthy elderly volunteers selected from Wuhan Chinese and WesternMedicine Hospital and Hubei Hospital of Traditional Chinese Medicine weredetected using Waters SYNAPT G2-S QTOF liquid chromatograph-massspectrometer (US) for metabonomical analysis.
Results:
1Epidemiology
1.1The clustering analysis together with the frequency distribution on the datafrom the315patients indicated the following3types of symptoms. Type onecontains fatigue, lack of energy, teeth-printed tongue, dyspepsia, weak pulse,spontaneous sweating, greasy coating on the tongue, forgetfulness, sore waist,lumbar and knee strengthlessness, heaviness of limbs, alopecia, gomphiasis,sluggish looking, heaviness of head. Major symptoms in type two includes:white and smooth tongue coating, deep and slow pulse, cold sensation oflimbs and chillness, edema in face and feet, loose stool, clear abundant urine,frequent nocturia, taut pulse, drowsiness, enlarged tongue, uroclepsia, fat body, curdy fur, snooze and gurgling with sputum. The third type symptoms aredysphoria in chestpalms-soles, thready and rapid pulse, thirsty and dry throat,red tongue with little coating, scanty dark urine, night sweat, dry stool,insomnia, expectoration and dirty looking face. Type one in TCM refers tokidney qi deficiency and phlegm stasis. Type two refers to kidney yangdeficiency and phlegm stasis. Type three refers to kidney ying deficiency andphlegm stasis.
1.2Proportion of syndrome of315patients. Kidney qi deficiency and phlegmstasis syndrome took up38.41%, and the kidney yang deficiency and phlegmstasis syndrome30.03%, the kidney ying deficiency and phlegm stasissyndrome35.56%.
1.3The one-way analysis of variance showed that group of kidney qideficiency and phlegm stasis syndrome was significantly different with kidneyyang deficiency and phlegm stasis syndrome group and the kidney yingdeficiency and phlegm stasis syndrome group, P<0.05. The group of kidneyyang deficiency and phlegm stasis syndrome was observed insignificantlydifference with the group of kidney ying deficiency and phlegm stasissyndrome, P>0.05. This outcome indicates that type one may be transformedinto type two or three with the increase of age or the aggravation of disease.The coexistence of the three types is also possible.
2Plasma metabonomics outcomes showed obvious elevated (P<0.05, P<0.01)in the following indices, as compared with healthy elderly contrast:lysophosphatide (16:0), pentaglucose,11,18,21β-trihydroxy-4-olefince-3,20-diketone18-Hydroxycorticosterone. And the following were seenobviously declined (P<0.05, P<0.01): phosphatidyl ethanolaminePE(22:2(13Z,16Z)/15:0), cystathionine L-Cystathionine, glyceryl phosphatidePE(O-18:1(1Z)/20:4(5Z,8Z,11Z,14Z),phosphatidylcholinePC(20:1(11Z)/14:1(9Z). The above results indicate that, when compared with healthy elderly contrast,patient groups underwent multiple changes to their metabolic pathways.Disorder occurred in lipid and energy metabolism.
Conclusions:
1Kidney deficiency and phlegm turbid interact with and closely related toeach other in senescent forgetfulness. Doctors in Ming and Qing dynasties arethe most skilled practitioners on the treatment for this disease. Tonifyingkidney and removing phlegm are their major treatment method.
2The kidney deficiency and phlegm stasis syndrome can be further dividedinto three syndromes: kidney qi deficiency and phlegm stasis, kidney yangdeficiency and phlegm stasis, kidney ying deficiency and phlegm stasis.
3This study indicates that the kidney qi deficiency and phlegm stasissyndrome takes the major proportion and is relevant to the three subtypes:patients of kidney qi deficiency and phlegm stasis syndrome are relativelyyoung olds. Theory of deficiency of primordial qi is of great theoretical valuein the exploration of senile cognitive impairment.
4Kidney qi deficiency and phlegm stasis syndrome senescent forgetfulnesspatients were different from healthy contrast in plasma metabonomics. Kidneyfunction declined in the group of forgetfulness, together with lipid metabolicdisorder. Markers were observed in syndrome groups.
5It is closer to the real clinical condition of the compound syndromes ofsenescent forgetfulness. The literature, epidemiological investigation andmetabonomical analysis facilitate revealing the law and essence of thesyndromes.
引文
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