摘要
背景:
老年人轻度认知功能障碍(mild cognitive impairment,MCI),现在已经被公认为是“痴呆临床前期状态”, MCI患者与早期AD患者存在着很多相同点,二者皆为以进行性认知功能减退为特征的中枢神经系统(Central nervous system,CNS)病变。流行病学调查显示,随着全球人口的老龄化提速,认知功能障碍和痴呆的发病率呈不断上升趋势,到2030年全球痴呆患病人数将达到6570万,到2050年将增至1亿1540万,迄今为止,认知功能障碍及痴呆发病机制尚不十分清楚,更缺乏有效的治疗药物及措施。祖国传统医学根据辨证论治的观点,充分发挥中药复方所特有的多环节、多途径、整体调节的作用特点,在防治MCI与早期AD方面具有一定的优势,基于中医“虚”、“瘀”、“浊”、“毒”病机理论组方的还脑益聪方,前期临床及基础研究现证实对MCI及AD有较好的防治作用,实验将还脑益聪方经现代工艺提取其组分,研究其对APP695V717I转基因痴呆小鼠模型的早期干预作用,并初步探讨其作用机制,为未来中医中药更为广泛地应用于临床MCI的预防及治疗提供依据。
目的:
基于胆碱能系统功能异常和自由基(Free radicals,FR)失衡理论导致认知功能减退的发病机制,以APP695V717I转基因小鼠为实验动物模型,应用以补肾益气、活血解毒功用为组方配伍依据的还脑益聪方对模型小鼠进行早期干预,观察动物的行为学改变,研究此中药复方对APP转基因小鼠脑组织Ap生成途径及胆碱能系统和氧化应激(Oxidative stress,OS)等相关指标的影响,探讨还脑益聪方提取物早期干预认知功能障碍的作用机制,为MCI患者与AD患者的中医药防治提供药理依据。
方法:
选用3月龄APP695V717I转基因小鼠,雌雄各半,随机分为模型组、阳性药物(盐酸多奈哌齐)对照组(按0.65mg/kg-d给药)、还脑益聪方提取物大剂量组(按2.8g/kg·d给药)及还脑益聪方提取物小剂量组(按1.4g/kg-d给药),并设立遗传背景相同的非转基因小鼠作为正常对照组(C57BL/6J小鼠),连续灌胃4个月(至7月龄)后进行相关指标检测。本实验共分为三个部分。实验一,采用Morris水迷宫观测APP转基因模型小鼠学习、记忆等认知相关能力,采用跳台实验(被动回避性条件反射)观测小鼠一次性被动回避反应记忆功能,研究还脑益聪方提取物对APP转基因模型小鼠行为学的影响;实验二,采用免疫组织化学方法检测APP、Aβ1-42在小鼠海马CA1区的表达,通过还脑益聪方提取物早期干预对APP695转基因小鼠脑组织Aβ生成途径的影响,探讨还脑益聪方防治的作用机制。实验三,采用酶联免疫吸附试验(ELISA)测定小鼠皮层及海马中乙酰胆碱(Acetylcholine,ACh)、乙酰胆碱酯酶(Acetylcholinesterase,AchE)、胆碱乙酰转移酶(Choline acetyltransferase,ChAT)的含量,研究还脑益聪方对APP转基因模型小鼠中枢胆碱能系统功能的影响;并采用比色法检测APP转基因小鼠血清超氧化物歧化酶(Superoxide Dismutase,SOD)的活性,硫代巴比妥酸法测定小鼠血清丙二醛(Malondialdehyde,MDA)的含量,观察还脑益聪方对APP转基因模型小鼠脑组织氧化应激损伤的影响。
结果:
实验一,还脑益聪方提取物早期干预对APP转基因模型小鼠行为学的影响。
Morris水迷宫实验结果表明:与正常对照组相比,7月龄模型组小鼠穿越原平台位置的次数、第四象限游泳时间及路程均显著缩短和减少(P<0.01或P<0.05);药物治疗后,小鼠在Morris水迷宫中穿越原平台位置次数、第四象限游泳时间及路程均较模型组显著提高(P<0.05或P<0.01)。
跳台实验结果表明:与正常对照组相比,模型组错误次数显著增高(P<0.05),潜伏期显著缩短(P<0.05);与模型组相比,还脑益聪方提取物大剂量组错误次数明显减少,有显著性差异(P<0.05),盐酸多奈哌齐组、还脑益聪方提取物小剂量组错误次数呈现减少趋势,但无显著性差异(P>0.05);还脑益聪方提取物大剂量组潜伏期显著延长(P<0.01),盐酸多奈哌齐组、小剂量组潜伏期亦有延长趋势,但无显著性差异(P>0.05)。
实验二,还脑益聪方提取物早期干预对APP转基因小鼠脑组织APP、Aβ蛋白表达的影响。
APP转基因小鼠海马CA1区均可见棕黄色阳性表达,分布于神经元胞浆和胞膜。与正常组比较,模型组APP阳性细胞数目和面积比例均显著增多(P<0.01)。各给药组治疗后,APP阳性细胞数目较模型组均显著减少(P<0.01);还脑益聪方提取物大、小剂量组APP阳性细胞面积比例均显著减少(P<0.05或P<0.01);盐酸多奈哌齐组有减小趋势,但无统计学差异(P>0.05)。
与正常组比较,模型组Aβ阳性细胞数目和面积比例均显著增多(P<0.01)。各给药组治疗后,Aβ阳性细胞数目和面积比例均较模型组显著减少(P<0.05或P<0.01)。
实验三,还脑益聪方提取物早期干预对APP转基因模型小鼠中枢胆碱能系统功能及氧化应激损伤指标的影响。
与正常对照组相比较,7月龄模型组小鼠海马区ACh及ChAT的含量均明显降低,AchE的含量明显增加,经统计学处理,有显著性差异(P<0.05);与模型组相比较,盐酸多奈哌齐组、还脑益聪方提取物大、小剂量组均能提高小鼠海马区ACh的含量,经统计学处理,有显著性差异(P<0.05,P<0.01);与模型组相比较,多奈哌齐组、还脑益聪方提取物大剂量组均能显著降低小鼠海马区AchE的含量(P<0.05);与模型组比较,盐酸多奈哌齐、还脑益聪方提取物大、小剂量组均能显著提高小鼠海马区ChAT的含量,经统计学处理,有显著性差异(P<0.05,P<0.01)。
与正常对照组比较,7月龄模型组小鼠脑皮层中ACh、ChAT的含量均明显降低,AchE含量明显增加,经统计学处理,差异有显著性(P<0.05);与模型组相比较,还脑益聪方提取物小剂量组能明显提高模型组小鼠脑皮层中ACh的含量,经统计学处理,差异有显著性(P<0.05);与模型组相比较,各组小鼠经给药治疗后测定脑皮层中AchE的含量,经统计学处理,无显著性差异(P<0.05);与模型组相比较,还脑益聪方提取物小剂量组能提高模型组小鼠脑皮层中ChAT的含量,经统计学处理,差异有显著性(P<0.05),而盐酸多奈哌齐组及还脑益聪方提取物大剂量组ChAT的含量无明显变化(P<0.05)。
与正常对照组比较,模型组小鼠血清SOD活性显著降低(P<0.01);与模型组比较,还脑益聪方提取物大、小剂量组的血清SOD活性有显著升高(P<0.05或P<0.01);与模型组比较,盐酸多奈哌齐组的血清SOD活性有显著升高(P<0.05);与正常对照组比较,模型组小鼠血清MDA含量显著升高(P<0.01);与模型组比较,各给药组血清MDA含量有减少的趋势,但无显著性差异(P>0.05)。
结论:
应用还脑益聪方提取物进行早期干预可以在一定程度上改善APP转基因模型小鼠空间学习、记忆等认知功能及一次性被动回避反应记忆功能,其机制可能与改善小鼠脑皮层及海马的中枢胆碱能系统功能及抑制脑组织的氧化应激损伤有关。
Background:
The mild cognitive impairment of old people, has now been recognized as the "Early clinical dementia status",patients with MCI and early AD have many similarities,both of them are central nervous system lesions characterized by Progressive cognitive decline. Epidemiological survey shows,with the accelerated aging of the global population,mild cognitive impairment and the incidence of dementia showed a continually rising trend,the number of Global prevalence of dementia by 2030 will reach 65.7 million,the year of 2050 will be increased to 100 million and 15.4 million,but so far, cognitive impairment and dementia as a worldwide medical problem, the pathogenesis is not very clear,In particular, the lack of effective treatments and measures. The treatment of Traditional Chinese Medicine (TCM), based on syndrome differentiation, has superiority and prospect at the prevention and treatment of MCI and AD which is beyond the reach of western medicine, especially by the role of Chinese herbal compound, which has many curative pathways and targets to MCI and AD. Huannao Yicong Fang (HNYCF) is a Chinese herbal compound based on"Deficiency-Blood Stasis-Turbidity-Toxin",the pathogenesis of MCI and AD in TCM.It has been confirmed by Early experiments and clinical research that HNYCF has good preventive and therapeutic effects to MCI and early AD,In this experiment, we use modern technology to extract the fractions of HNYCF, In-depth study its mechanism and effective channel to APP695V717I transgenic mouse model,so as to provide basis to the TCM is more widely used in clinical treatment of MCI and early Alzheimer's disease.
Objective:
Based on cognitive dysfunction in the pathogenesis of the Cholinergic system dysfunction and free radical imbalance theory, APP695V717I transgenic mice 3 month-old were used as models in this study,application of the extract of HNYCF (herbal extract) on the model of early intervention,observe the behavior of the model, generation of beta amyloid protein(Aβ),cholinergic system and oxidative stress-related index changes,discussion the mechanism of HNYCF in the treating of MCI and AD.
Methods:
APP695V717I transgenic mice 3 month-old were used as models in this study, which were randomly divided into model group, Donepezil group, the extract of HNYCF large dose group and the extract of HNYCF small dose group. Normal control adopted the same age and background C57BL/6J mice. The animals were administered intragastrically by the drug or water from 3 month-old to 7 month-old. This research was divided into three parts. PartⅠ: Morris water maze test was performed to measure the spatial learning、memory and other cognitive-related capacity.Step-down test (Passive avoidance conditioning) was performed to observe the learning and memory ability of single passive avoidance response, This part was to study HNYCF on the behavior of APP transgenic mice. PartⅡ:The expression ofβ-amyloid precursor protein (APP),β-site APP cleaving enzyme (BACE) and Aβin hippocampus CA1 region was detected by immunohistochemistry with image analysis. PartⅢ:Determination the content of ACh, AchE, ChAT by ELISA and Bradford method,This part was to study the extract of HNYCF on central cholinergic function of APP transgenic mice. The activity of superoxide dismutase (SOD) in serum was detected with colorimetry. The content of malondialdehyde (MDA) in serum was detected with Thibabituric Acid (TBA). This part was to study effects of HNYCF on free radical-induced oxidative stress in the brain of APP transgenic mice.
Results:
PartⅠ:The Early intervention with extract of HNYCF to improve the disorder of cognitive function in APP transgenic mice of the experimental observation of behavior.
Morris water maze test results show that:Compared with the control group, model mice through the security platform for the location of the original number, in the fourth quadrant swimming time and distance were significantly shortened and reduced (P<0.01 or P<0.05); after treatment, mice in the Morris water maze in the position of crossing the number of security platform, in the fourth quadrant swimming time and distance compared with model group was significantly increased (P<0.05 or P<0.01);
Step down test results show that:Compared with the control group, the number of errors of model group was significantly higher (P<0.05), latency was significantly shorter (P<0.05); Compared with model group, the extract of HNYCF large dose group had significantly fewer errors, there was significant difference (P<0.05), Donepezil hydrochloride group, the extract of HNYCF small dose group group showed a decreasing trend in the number of errors, but no significant difference (P>0.05);Compared with model group,the extract of HNYCF large dose group was significantly longer latency (P<0.01),Donepezil hydrochloride group, low dose group also extended incubation period of trend, but no significant difference (P>0.05).
PartⅡ:Effect of early intervention with extract of HNYCF on the pathway of APP transgenic mouse brain Aβgeneration
Comparing to the model group, the levels of expression of APP in hippocampus CA1 region of mice in the HNYCF group decreased obviously (P<0.01), including the number and area proportion of positive cells;the levels of expression of APP in hippocampus CA1 region of mice in the Donepezil group had the trend to reduce, but there was no statistical significant difference (P>0.05); The expression of Aβin hippocampus CA1 region of mice in all the treated groups decreased obviously (P<0.05 or P<0.01).
Part III:Effect of early intervention with extract of HNYCF fractions on the cholinergic system and related indicators of Free radical-induced oxidative stress of APP transgenic mice.
Comparing to the model group, model mice hippocampus ACh and ChAT levels were significantly reduced, AchE were significantly increased, through statistical analysis, the difference of the data was significant (P<0.05); Compared with model group, group of donepezil hydrochloride, the extract of HNYCF large and small dose group can effectively improve the content of ACh in hippocampus of mice, through statistical treatment, there was significant difference (P<0.05, P<0.01);Compared with model group, donepezil group and the extract of HNYCF large dose group could decrease the AchE consent of the hippocampus in mice, the difference was significant (P<0.05);Compared with model group, donepezil hydrochloride, the extract of HNYCF large and small dose group could significantly increase the content of ChAT in hippocampus of mice, through the statistical treatment, there was significant difference (P<0.05, P<0.01).
Compared with the control group, model group mice cortex ACh, ChAT levels were significantly reduced, AchE was significantly increased, the statistical difference was statistically significant (P<0.05); Compared with model group, the extract of HNYCF large and small dose group could significantly improve the model mice in the ACh content of cortex, the statistical difference was statistically significant (P<0.05); Compared with model group, the mice treated by the administration to determine the content of AchE cerebral cortex, the statistical treatment, no significant difference (P<0.05); Compared with model group, the extract of HNYCF small dose group can improve the model mice brain cortex ChAT levels, the statistical difference was statistically significant (P<0.05),the donepezil hydrochloride group and the extract of HNYCF large dose group have no significant change in ChAT levels (P<0.05).
Compared with the control group,serum SOD activity in model group were significantly different (P<0.01); Compared to the Serum SOD activity of the model group,the extract of HNYCF large and small dose group were significantly higher (P<0.05 or P<0.01); Compared to the Serum SOD activity of the model group,Donepezil hydrochloride group significantly increased (P<0.05); Compared with the control group, the Serum MDA levels of the model group,were significantly different (P<0.01); Compared to the Serum MDA levels of the model group,each treatment group of serum MDA content showed a decreasing trend, but no significant difference (P>0.05).
Conclusions:
Apply HNYCF effective fractions to early intervention, to a certain extent, improve the APP transgenic mouse model of spatial learning, memory and other cognitive function as well as the learning and memory ability of single passive, The mechanism may be related to the protective effect of the extract of HNYCF on the Cerebral cortex and hippocampus of the central cholinergic system function, and to improve the free radical induced oxidative stress in brain.
引文
[1]Petersen RC. Mild cognitive impairment as a diagnostic entity[J]. Intern Med,2004,256: 183.
[2]John C. Morris, Jeffrey Cummings. Mild cognitive impairment (MCI) represents early stage Alzheimer's disease[J]. Journal of Alzheimer's Disease,2005,7:235.
[3]Peterson RC. Mild cognitive impairment criteria[J]. Neurology,2001, (56):1133-1142.
[4]Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage Alzheimer's disease[J]. Arch Neurol.2001; 58:397-405.
[5]Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment [J]. Arch Neurol,2001, (58):1985-1992.
[6]Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage Alzheimer's disease[J]. Arch Neurol.2001; 58:397-405.
[7]Bennett DA, Schneider JA, Bienias JL, Evans DA, Wilson RS Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions[J]. J Neurology,2005, 64(5):834-841.
[8]田金洲,时晶,张新卿等.轻度认知损害临床研究指导原则(草案)[J].中西医结合学报,2008,6,(1):9-14.
[9]贾建平.临床痴呆病学[M].北京:北京大学医学出版社,2008:151-152.
[10]简文佳.语义记忆及其相关脑区机制[A];世界中联第三届中医、中西医结合老年医学学术大会论文集[C],2010:43-44.
[11]Kandel ER, Kupfermann L,Iversen S. Learning and Memory[M].In:Kandel ER, Schwartz JH, Jessell TM. Principles of neural.4th ed. Columbia:Mc Graw-Hill Comparies Inc,2000.1231-1233.
[12]RitchieK, Touchon J. Mild cognitive impairment:conceptual basis and current nosological status. Lancet.2000; 355:225-228.
[13]王荫华,白静,杨晓娜,陈晓红,周爱红.有关MCI的记忆、注意、语言等多方面神经心理学研究[A].2006年神经科学新进展国际研讨会会议日程和论文摘要[C],2006.
[14]Estevez-Gonzalez A, Garcia-Sanchez C, Boltes A, Otermin P, Pascual-Sedano B,& Gironell A, et al. (2004). Semantic knowledge of famous people in mild cognitive impairment and progression to Alzheimer's disease. Dementia and Geriatric Cognitive Disorders,17(3), 188-195.
[15]王鹏云,李娟.轻度认知损伤的语义记忆研究述评[J].心理科学进展,2009,17(5):931-937.
[16]陈福新.老年痴呆症早期有哪些表现[J].求医问药,2009,17(2):38-39.
[17]刘铁桥.老年精神病学[M].北京:人民卫生出版社,2009:60.
[18]张允岭,金香兰,陈志刚,郭蓉娟,侯小兵,陈宝鑫,高芳,白文,戴中,柳洪胜,谢颖祯,王麟 鹏,郭静.血管源性轻度认知障碍中医术语的临床初步验证[A];世界中医药学会联合会老年医学专业委员会成立大会暨第一届学术会议论文集[C].北京2008 31(3):158-161.
[19]香兰,张允岭,韩振蕴,等.痴呆前轻度认知障碍的相关中医术语探讨[J].北京中医药大学学报,2008,31(3):158-161.
[20]清·张琦.素问释义[M].北京:科学技术文献出版社,1998:212.
[21]灵枢[M].北京:人民卫生出版社,2000:23-152.
[22]隋·巢元方.诸病源候论[M].北京:人民卫生出版社,2000:863.
[23]陈永灿.陈言审因用方治疗健忘的学术特色[J].浙江中医杂志,2008,43(8):474-477.
[24]清·陈士铎.辨证录[M].北京:中国中医药出版社,2007:1-549.
[25]李浩,姚明江.浅谈中医“虚”、“瘀”、“浊”、“毒”轻度认知障碍发病的关系[J].中国中医药信息杂志,2006,13(11):4-5.
[26]苏莉娟,曹晓岚.轻度血管性认知功能损害的中医病机及治则初探[J].江西中医药,2010,41(334):12-13.
[27]何迎春,董陆.健脾填精方颗粒剂干预轻度认知障碍向痴呆转化的临床随机研究[J].中华中医药学刊,2008,26(12):2610-1611.
[28]陈克坚.加减薯蓣丸治疗轻度认知障碍(脾肾两虚型)的临床研究[D].湖北:湖北中医学院,2009:1-32.
[29]梁文慧,郭娜.血管性认知功能障碍中医诊疗思路[J].新中医,2008,40(9):12-13.
[30]郭仁真,周文泉,等.黄连温胆汤加味治疗老年轻度认知障碍痰浊阻窍证的临床研究[J].中国中西医结合杂志,2010,30(1):152-157.
[31]张艳萍,吴正治,钟琪,孙苏萍,李明,李映红,李耀芳,杨敏等.轻度认知障碍的中医证候分布规律研究[J].中医药导报,2010,16(5):1-3.
[32]Petersen RC. Mild cognitive impairment:transition between aging and Alzheimer's disease[J]. Neurologia,2000,15(3):93-101.
[33]Luis CA, Loewensteln DA, Acevedo A, et al. Mild cognitive impairment:directions for future research[J]. Neurology,2003,61:438-444.
[34]老膺荣,杨志敏,汤湘江.开展轻度认知障碍中医病因学研究的设想[J].上海中医药大学学报,2006,20(3):77-78.
[35]Tian J Z, Han MX, Wang YY, et al. Criteria for the diagnosis, the differentiation of syndrome and the evaluation of efficacy of vascular dementia for research studies[J]. Zhonggua Lao Nian Xue Za Zhi.2002; 22(5):329-331. Chinese with abstract in English.
[36]田金洲,韩明向,王永炎,等.血管性痴呆诊断、辨证及疗效评定标准(研究用)[J].中国老年学杂志.2002,22(5):329-331.
[37]Tian J Z. Vascular dementia. Beijing:People's Medical Publishing House.2003 586-590. Chinese田金洲.血管性痴呆.北京:人民卫生出版社.2003:586-590.
[38]Liu Y, Tian J Z. Research for the correlation between mild cognitive impairment and the syndrome defined by TCM[J]. Zhongguo Lao Nian Xue Za Zhi.2003; 24(6):602-604. Chinese.
[39]Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the t reatment of mild cognitive impairment[J]. N Engl J Med.2005; 352(23):2379-2388.
[40]Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment-beyond cont roversies, towards a consensus:report of the International Working Group on Mild Cognitive Impairment[J]. J Intern Med.2004; 256(3):240-246.
[41]Bennett DA, Wilson RS, Schneider JA, et al. Natural history of mild cognitive impairment in older persons[J]. Neurology.2002; 59 (2):198-205.
[42]Clinical trial:Rosiglitazone effects on cognition for adults in later life (RECALL). http://www.clinicaltrials.gov/ct/show/NCT00242593.[Accessed 2007-5-31].
[43]杨承芝,钟剑,朱爱华.老年人轻度认知损害的中医证候研究[J].北京中医药大学学报(中医临床版)2003,10(2):12-16.
[44]田金洲,杨承芝,盛彤等.可疑痴呆人群中阿尔茨海默氏病临床前的认识损害特征及其与中医证候的关系[J]湖北中医学院学报.1999,1(4):49-55.
[45]杨志敏,谢东平,陈淑慧,欧爱华,老膺荣.老年人轻度认知功能障碍的中医证候分布情况初步研究[J].世界中西医结合杂志,2007,2(4):219-221.
[46]郑筱萸.中药新药临床研究指导原则[S].北京:中国医药科技出版社,2002:91-99.
[47]Bennett DA, Schneider JA, Bienias JL, Evans DA, Wilson RS Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions [J]. J Neurology, 2005,64(5):834-841.
[48]陈可冀.老年性痴呆发病机理与诊治[M].北京:北京医科大学中国协和医科大学联合出版社,1998:268-281.
[49]赵振,赵立维.金匮肾气丸加味治疗老年轻度认知功能障碍临床观察[J].吉林中医药,2009,29(7):579-580.
[50]冯小燕,何亮,李爱民,彭永政.补肾益脑胶囊治疗轻度认知障碍的临床研究及其作用机理[J].中国新医学论坛,2007,7(4):172-175.
[51]戴忠卫,郑德勇.六味地黄汤加芳香开窍法治疗轻度认知障碍28例[J].中国民间疗法,2007,15(12):24.
[52]任仁安,等.中药鉴定学[M].上诲:上海科技出版社,1986:234.
[53]李卫民.中成药,1989,11(1):39.
[54]棣意波.党参提取物对中枢神经系统的影响[J].特产研究,1991,(1):49.
[55]王付荣,周洪雷.何首乌及夜交藤化学成份及药理作用的研究进展[J].江西中医学院学报,2007,10(19):9.
[56]曹凯,翘永平,李素婷.四种中药对小鼠脑组织谷胱甘肽过氧化物酶和脂质过氧化物的影响[J].中国中西医结合杂志,1993,13(特集):82.
[57]袁新初,张端莲.当归注射液对更年期大鼠超氧化物歧化酶和脂质过氧化物的影响[J].中草药,2001,32(9):822-823.
[58]张雪琴,汪伟民.白芍总甙对老年性疾病的治疗作用[J].国药理学通报,1987,3(5):314.
[59]饭冢进.远志的脑保护活性成分[J].国外医学,中医药分册,1995,17(5):29.
[60]谭子虎,朱明方.加减薯蓣丸对D-半乳糖致大鼠衰老作用的影响[J].中华老年医学杂志,1995,14(5):268-269.
[61]李浩,刘芳,徐立然,侯留法,崔玲,罗增刚.还脑益聪胶囊对老年轻度认知障碍的影响[J].中国中西医结合杂志,2004,24(8):689-693.
[62]李浩,徐立然,崔玲,侯留法.还脑益聪胶囊治疗老年轻度认知障碍的临床研究[A];第五次全国中西医结合养生学与康复医学学术研讨会论文集[C],2010:956-960.
[63]李浩,姚明江,赵文明,官杰,蔡琳琳,崔玲.还脑益聪胶囊治疗老年轻度认知损害的双盲随机对照研究[J].中西医结合学报,2008,6(1):25-31.
[64]药典委员会.中国药典(第一部).[M]北京:化学工业出版社,2000:69.
[65]刘厚淳,陈万生.何首乌水溶性成份2,3,5,4'-四羟基二苯乙烯-2-O-β-D-葡萄糖苷的体外抗氧化作用研究[J].药学实践杂,2000,18(4):232-233,237.
[66]朱晓莹,张树球,李朝敢,等.元首口服液的二苯乙烯苷含量与O2-·清除率关系的实验研究[J].现代中西医结合杂志,2003,12(27):685-686.
[67]Ryu G, Ju JH, Park YJ, et al. The radical scavenging effects of stilbene glucosides from Poygonum multiflorum[J]. Arch Pharm Res,2002,25(5):636-639.
[68]Chen Y, Wang M, Rosen RT, et al.2,2-Diphenyl-l-picrylhydrazyl radical-scavenging active components from Polygonum multiflorum thumb[J]. J Agric Food Chem,1999,47(6): 2226-2228.
[69]刘治军,李林,叶翠飞,等.二苯乙烯苷对脑缺血小鼠脑组织含水量及自由基代谢的影响[J].中国康复理论与实践,2003,9(11):641-642.
[70]楚晋,叶翠飞,李林.二苯乙烯苷对痴呆小鼠学习记忆及自由基代谢的影响[J].中国康复理论与实践,2003,9(11):643-645.
[71]刘丽,赵玲,李雅莉,等.四羟基二苯乙烯苷对慢性脑缺血致痴呆模型大鼠的保护作用[J].中国药学杂志,2006,41(5):354-358.
[72]Kimura Y, Okuda H, Arichi S. Effects of stilbenes on arachidonate metabolism in leukocytes[J]. Biochim Biophys Acta,1985,834(2):275-278.
[73]李雅莉,赵玲,徐艳玲,等.二苯乙烯苷对谷氨酸至原代培养大鼠海马神经原损伤的保护作用[J].中国康复理论与实践,2004,10(12):751-753.
[74]李雅莉,赵玲,李林.二苯乙烯苷对海马神经元细胞缺血性损伤模型大鼠的保护作用研究[J].中国药房,2006,17(1):12-14.
[75]楚晋,叶翠飞,李林.二苯乙烯苷对痴呆小鼠学习记忆及大脑炎性反应的影响[J].中国新药与临床药理,2004,15(4):235-237.
[76]楚晋,叶翠飞,李林,等.二苯乙烯苷对β-淀粉样肽至痴呆模型小鼠行为及胆碱能功能的影响[J].基础医学与临床,2006,26(2):197-198.
[77]楚晋,叶翠飞,李林,等.二苯乙烯苷对D-半乳糖致脑老化小鼠学习记忆及神经营养因子的影响[J].中国药房,2005,16(1):13-16.
[78]谢文杰,李林,魏海峰,等.二苯乙烯苷对D-半乳糖拟痴呆小鼠海马基因表达的影响[J].中国药理学与毒理学杂志,2005,19(1):24-28.
[79]张兰,叶翠飞,褚燕琦,等.二苯乙烯苷对鹅膏蕈氨酸致痴呆大鼠模型脑内胆碱能系统的影响[J].中国药学杂志,2005,40(10):749-752.
[80]张兰,邢颖,赵玲,等.不同时程APP转基因小鼠学习记忆改变及参乌胶囊、二苯乙烯苷的干预作用[J].中国行为医学科学,2006,15(3):193-196.
[81]楚世峰,张均田.人参抗老年痴呆的研究进展[A];2009全国抗衰老与老年痴呆学术会议论文汇编[C],2009:31-32.
[82]翁维良,房书亭主编.临床中药学.北京:河南科学技术出版社,1998:1201-1202.
[83]Weng WL, Fang ST, editors. Clinical science of Chinese materia medica. Beijing:Henan Science and Technology Publishing House,1998:1201-1202.
[84]蒋唯松,陈涛,等.人参治疗老年性痴呆的研究进展[J].解剖学研究,2007,29(6):463-464.
[85]方欣,杨吉平,赖红.人参皂苷Rb1对老年性痴采模型大鼠顶叶皮质β-分泌酶及早老蛋白-1表达的影响[J].解剖学杂志,2008,31(6):812-815.
[86]邬伟,马飞煜,杨景全,张昱.人参皂苷Rg1对痴呆模型大鼠行为学及酪氨酸蛋白激酶A表达的影响[J].中国老年学杂志,2007,27(1):41-43.
[87]Zang C, Yang T, Wang JA, et al. The chinese Traditional Medicine"Bushen Yinao Pian"increased the level of ageing-related gene LRPAP-1 expression in the cerebral tissue of accelerated senescence-prone mouse8/Ta[J]. Jo Ethnopharmacol,2005,98:61-65.
[88]顾健,胡锦官,谭睿,等.石菖蒲及其有效成分对小鼠学习记忆的作用α-细辛醚药物动力学研究[J].世界科学技术-中医药现代,2003,5(1):53-57.
[89]吴宾,方永奇.石菖蒲益智作用的物质基础及其机理研究[J].中医药学刊,2004,22(9):1635-1641.
[90]匡忠生,谢宇晖,李翎,等.石菖蒲提取液对脑缺血-再灌注诱导的神经细胞凋亡的保护作[J].广东医学,2002,23(5):60.
[91]柯雪梅,方永奇.石菖蒲挥发油对脑缺血-再灌注脑中氨基酸的影响[J].中国老年学杂志,2003,23(5):302.
[92]李成冲.石菖蒲活性成分p-细辛醚抗老年痴呆模型大鼠海马细胞凋亡作用及机制[D]黑龙江:佳木斯大学,2010:1-51.
[93]林慧光,等.石菖蒲挥发油香熏辅助治疗老年性痴呆大鼠的实验研究[J].福建中医学院学报,2007,17(4):25-27.
[94]余光.黄连素对CA诱导的tau蛋白过度磷酸化的保护作用及其机制[D].华中科技大学,2009.
[95]G. R. Schinella, et al. Antioxidant activity of anti-inflammatory plant extracts[J]. Life Science,2002,70:1023-1033.
[96]李琳琳,毛新民,王雪飞,等.胡芦巴总皂甙对小鼠学习记忆的促进作用及抗脑缺血作用初探.新疆医科大学学报2001;24(2):98-100.
[97]Zhang C,Wang SZ,Zuo PP,et al. Protective effect of tetramethylpyrazine on learning and memory function in Dgalactose-lesioned mice[J]. J Chin Med Sci,2004,19(3):754-760.
[98]赵琳,魏敏杰,何苗,等.川芎嗪对阿尔采末病模型小鼠学习记忆能力的影响及其机制 初探[J].中国药理学通报,2008,24(8):1088-1092.
[99]袁树民,曹兴水,高翔,张海涛,张连峰,秦川.川芎嗪对痴呆小鼠模型学习记忆能力的影响[J].中国比较医学杂志,2010,20(5):46-49.
[100]张妍.复方丹参对早老性痴呆动物的作用及机制研究[D].北京:北京中医药大学,2008:1-91.
[101]沈宝藩,赵永东,王晓峰,等.痰瘀互结内科常见病证的证候特点[J].新疆中医药,2001,19(4):3-5.
[102]刘莹.化痰脉通片治疗轻度认知功能障碍的临床研究[D].新疆:新疆医科大学.2008:1-56.
[103]阿提卡·吾布力哈斯木,胡晓灵.沈宝藩临床经验辑要[M].北京:中国医药科技出版社,2000:4.
[104]ADELMAN AM, DALY MP. Initial evaluation of the patient with suspected dementia [J].Am Fam Physician 2005,71(9):1745-1750.
[105]NYENHUIS DL, GORELICK PB, GEENEN EL el al The patter of neuropsychological deficits in Vascular Cognitive Inpairment No Dementia (Vascular CIND)[J]. Clinical Neuropsychology,2004.18(1):41-49.
[106]何任.上工治未病蕴含的预防思想[J].中国中医药报,2009-8-21(10).
[1]王永炎.阿尔茨海默病的诊断与治疗[M].北京:人民卫生出版社,2009:1-318.
[2]U.S. Department of Health and Human Services. Progression on Alzheimer's disease. Arch Neural,2001,58(3):397-405.
[3]丁萍,苗华栋,嵇鸣,魏文石.轻度认知功能障碍和轻度Alzheimer病的'H-MRS研究[J].上海医学影像,2008,17(1):5-8.
[4]Larrieu S, Letenneuer L, Orgogozo JM, et al. Incidence and outcome of mild cognitive impairment in a population based prospective cohort. Neurolog.2002; 59:1594-1599.
[5]Petersen RC. Mild cognitive impairment:transition between aging and Alzheimer's disease[J].Neurologia,2000,15(3):93-101.
[6]Hanninen T, Hallikainen M, Tuomainen S, et al. Prevalence of mild cognitive impairment: a population-based study in elderly subjects. Acta Neurol Scand,2002,106(3):148-154.
[7]Broich K. CONSENSUS CONFERENCE PAPER Outcome measures in clinical trials on medicinal products for the treatment of dementia:a European regulatory perspective. International Psychiogeriatrics,2007,19(3):509-524.
[8]Howard Chertkow, Fadi Massoud, Ziad Nasreddine, et al. Diagnosis and treatment of dementia:3. Mild cognitive impairment and cognitive impairment without dementia. CMAJ, 2008,178(10):1273-1285.
[9]Miao YC, Tian JZ, Shi J, et al. Correlation between cognitive functions and syndromes of traditional Chinese medicine in amnestic mild cognitive impairment. J Chin Integr Med,2009, (3):205-211.
[10]田金洲,时晶,张新卿等.轻度认知损害临床研究指导原则(草案)编制说明[J].中西医结合学报,2008,6(1):15-21.
[11]田金洲,时晶,张新卿等.轻度认知损害临床研究指导原则(草案)[J].中西医结合学报,2008,6(1):9-14.
[12]中国防治认知功能障碍专家共识专家组.中国防治认知功能障碍专家共识[J].中华内科杂志,2006,45(2):172.
[13]贾建平.神经病学新进展.北京:人民卫生出版社,2003.255-277.
[14]贾建平等.中国痴呆与认知障碍诊治指南[M].北京:人民卫生出版社,2010:154-155.
[15]Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment [J]. Arch Neurol,2001, (58):1985-1992.
[16]Busse A, Bischkopf J, Riedel-Heller SG, et al. Subclassifications for mild cognitive impairment:prevalence and predictive validity. Psychol Med,2003,33:1029-1038.
[17]贾建平.临床痴呆病学[M].北京:北京大学医学出版社,2008:1-498.
[18]Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med,2005,352(23):2379-2388.
[19]Petersen RC, Negash S. Mild cognitive impairment:an overview. CNS Spectr,2008, 13(1):45-53.
[20]Phillis JW. Acetylcholine release from the central nervous system:a 50-yearretrospective [J]. CritRevNeurobiol,2005,17(3-4):161-217.
[21]Weaver JD, Huang MH, Albert M, et al. Interleukin 6 and risk of cognitive decline: MacArthur studies of successful aging J. Neurology,2002,59(3):371.
[22]Tarkowski E, Liljeroth AM, Minthon L, et al. Cerebral pattern of pro-and anti-inflammatory cytokines in dementias[J]. Brain Res Bull,2003,61:255.
[23]Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics[J]. Science,2002,297(5580):353-356.
[24]DinizBS, Pinto JA J r, Forlenza OV. Do CSF total tau, phosphorylated tau, and beta-amyloid 42 help top redict progression of mild cognitive impairment to Alzheimerps disease? A systematic review and meta-analysis of the literature[J]. World J Biol Psychiatry,2008, 9(3):172-182.
[25]李强.轻度认知功能障碍与阿尔茨海默病临床综合性评价的对照研究[D].重庆:重庆医科大学,2008:1-128.
[26]Arendt T.Alzheimer's disease as a disorder of dynamic brain self-organization[J]. Prog Brain Res,2005,147:355-378.
[27]Spires TL,Hyman BT. Neuronal structure is altered by amyloid plaques[J]. Rev Neurosci, 2004,15(4):267-278.
[28]Masliah E, Crews L, Hansen L. Synaptic remodeling during aging and in Alzheimer's disease[J]. J Alzheimers Dis,2006,9(3 Suppl):91-99.
[29]Venkitaramani DV, Chin J, Netzer WJ, et al. Beta-amyloid modulation of synaptic transmission and plasticity[J]. J Neurosci,2007,27(44):11832-11837.
[30]Carulli D, Buffo A, Strata P. Reparative mechanisms in the cerebellar cortex[J]. ProgNeurobiol,2004,72(6):373-398.
[31]Mosevitsky MI, Konovalova ES, Bichevaya NK, et al.Enhanced level of site-specific proteolysis of GAP-43 protein during early stages of brain development[J]. Biochemistry (Mosc),2000,65(10):1153-1156.
[32]Hulo S, Alberis, Laux T, et al. A point mutant of GAP-43 induces enhanced short-term andlong-term hippocampal plasticity[J]. Eur J Neurosci,2002,15(12):1976-1982.
[33]Rekart JL, Quinn B, Mesulam MM, et al. Subfield-specific increase in brain growth-associated protein in postmortem hippocampus of Alzheimer's patients[J]. Neuroscience,2004, 126(3):579-584.
[34]Bogdanovic N, Davidsson P, Volkmann I, et al. Growth-associated protein GAP-43 in the frontal cortex and in the hippocampus in Alzheimer's disease:an immunohistochemical and quantitative study[J]. J Neural Transm,2000,107(4):463-478.
[35]Head E, Lott IT, Hof PR, et al. Parallel compensatory and pathological events associated with tau pathology in middle aged individuals with Down syndrome[J]. J Neuropathol Exp Neurol,2003,62(9):917-926.
[36]Sjogren M, Davidsson P, Gottfries J, et al. The cerebrospinal fluid levels of tau,growth-associated protein-43 and soluble amyloid precursor protein correlate in Alzheimer's disease,reflecting a common pathophysiological process[J]. Dement Geriatr Cogn Disord,2001,12(4):257-264.
[37]Sjogren M, Minthon L, Davidsson P, et al. CSF levels of tau,beta-amyloid(1-42)and GAP-43 in frontotemporal dementia,other types of dementia and normal aging[J]. J Neural Transm,2000,107(5):563-579.
[38]Sunderland T, Linker G, Mirza N, et al. Decreasedβ-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer's disease[J]. JAMA.2003,289:2094-2103.
[39]Andreasen N, Vanmechelen E, Vanderstichele H, et al. Cerebrospihal fluid levels of total-tau,phospho-tau and A beta 42 predicts development of Alzheimer's disease in patients with mild cognitive impairment[J]. Acta Neurol Scand Suppl,2003,179:47-51.
[40]Herukka SK, Helisalmi S, Hallikainen M, et al. CSF Abets42, Tau and phosphorylated Tau,APOE epsilon4 allele and MCI type in progressive MCI[J]. Neurobiol Aging,2007, 28(4):507-514.
[41]Reddy PH, Mani G, Park BS, et al. Differential loss of synaptic proteins in Alzheimer's disease:implications for synaptic dysfunction[J]. J Alzheimers Dis,2005,7(2):103-117.
[42]Mehta PD, Pirttila T, Mehta SP, et al. Plasma and cerebrospinal fluid levels of amyloidβproteins 1-40 and 1-42 in Alzheimer's disease[J]. Arch Neurol,2000,57:100-105.
[43]Otto M, Esselmann H, Schulz-Shaeffer W, et al. Decreasedp-amyloidl-42 in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease[J]. Neurology,2000,54:1099-1022.
[44]Sjogren M, Davidsson P, Wallin A, et al. Decreased CSF(3-amyloid42 in Alzheimer's disease and amyotrophic lateral sclerosis may reflect mismetabolism ofp-amyloid induced by separate mechanisms[J]. Dement Geriatr Cogn Disord,2002,13:112-118.
[45]Lane R, Feldman HH, Meyer J, et al. Synergistic effect of apolipoprotein Eepsilon4 and butyrylcholinest erase Kvariant on progression f rom mild cognitive impairment to Alzheimer's disease[J]. Pharmacogenet Genomics,2008,18(4):289-298.
[46]陈伟平,徐书雯,黄越冬.轻度认知障碍和阿尔茨海默病患者血脂及甲状腺激素水平的关系[J].中国老年学杂志.2008,28(23):2328-2330.
[47]刘铁桥.老年精神病学[M].北京:人民卫生出版社,2009:1-237.
[48]Whitwell JL, ShiungMM, Przybelski SA, et al. MRI patterns of atrophy associated with Progression to AD in amnestic mild cognitive imPairment [J]. Neurology,2008,70:512-520.
[49]McMahom PM, Araki SS, Neumann PJ, et al. Cost-effectiveness of functional imaging tests in the diagnosis of Alzheimer's disease[J]. Radiology,2000,217(1):58-68.
[50]Pakrasi S, O'Brien JT. Emission tomography in dementia[J]. Nucl Med Commun,2005, 26(3):189-196.
[51]Huang C, Wahlund LO, Almkvist O, et al. Voxel-and VOI-based analysis of SPECT CBF in relation to clinical and psychological heterogeneity of mild cognitive impairment[J]. Neuroimage, 2003,19(3):1137-1144.
[52]Okamura N, Shinkawa M, Anai H, et al. Prediction of progression in patients with mild cognitive impairment using IMP-SPECT[J]. Nippon Ronen Igakkai Zasshi,2000,37(12):974-978.
[53]Petersen RC, Mild cognitive impairment:transition between aging and Alzheimer's disease. Neurology[J].2001; 15(3):93-101.
[54]贾建平.重视轻度认知障碍与老年性痴呆关系的研究[J].中华神经科杂志.2002,35(6):324-326.
[55]安玉会,毛红利.老年痴呆病防治研究中假说,概念和理论的研究进展[J].河南医学研究,2008,17(3):262-265.
[56]于宝成,田京利,欧阳荔莎,等.部队老年人轻度认知功能损害的发生及向AD的转化情况[J].中华老年医学杂志,2006,25(1):61-63.
[57]Serge authier, Barry Reisberg, Michael Zaudig, et al. On behalf of the participants of the international Psychogeriatric Association Expert Conference on mild cognitive impairment, Mild cognitive impairment [J]. Lancet,2006,367:1267-1270.
[58]Bartus RT, Dean RT,3rd, Beer B, et al. The cholinergic hypothesis of geriatric memory dysfunction Science,1982,217(4558):408-414.
[59]Sims NR, Bowen DW, Davison AN. [14]acetylcholine synthesis and [14]carbon dioxide production from [U-14]glucose by tissue prisms human neocortex[J]. Biochem J,1981, 196(3):867-876.
[60]Greenwald BS, Davis KI. Experimental pharmachology of Alzheimer's disease[J]. Adv Neurol,1983,38(2):87-102.
[61]陈乔,侯吉华,谢斌,王智勇,汪建民.基于“胆碱能假说”中药抗老年性痴呆研究进展[J].江西中医学院学报,2010,22(5):95-97.
[62]Tomimoto H, Ohtani R, Shibata M, et al. Loss of eholinergic Pathways in vaseular dementia of the Binswanger type.Dementia and Geriatric Cogitive Disorders,2005,19(5-6): 282-288.
[63]Coyle JT, Priee DL, and DeLong MR. Alzheimer's disease:a disorder of cortical cholinergic innervation Science,1983,219(4589):1184-1190.
[64]Gibson GE, Peterson C, and Jenden DJ. Brain acetylcholine synthesis declines with Senescence.Science,1981,213(4508):674-676.
[65]Wurtman RJ. Choline metabolism as a basis for the selective vulnerability of cholinergic neurons. Trends in Neurosciences,1992,15(4):117-122.
[66]Terry AV Jr, Buclatusco JJ. The cholinergic hypothesis of age and Alzheimer's disease- related cognitive deficits:recent challenges and their implication for novel drug development[J]. J Pharmacol Exp T-her,2003,306(3):821-827.
[67]Bartus RT, Dean RT,3rd, Beer B, et al. The cholinergic hypothesis of geriatric memory dysfunction Science,1982,217(4558):408-414.
[68]Bartus RT. On neurodegenerative diseases, models, and treatment strategies:lessons learned and lessons forgotten a generation following the cholinergie hypothesis.Experimental Neurology,2000,163(2):495-529.
[69]海珊.老年人轻度认知功能障碍的研究新进展[J].实用老年医学,2009,23(1):72-74.
[70]许继取.莲房原花青素对老年认知障碍大鼠记忆功能的改善作用及其机制研究[D].武汉:华中科技大学,2010:1-137.
[71]Tomimoto H, Ohtani R, Shibata M, et al. Loss of cholinergic pathways in vascular dementia of the Binswanger type.Dementia and Geriatric Cognitive Disorders,2005,19(5-6): 282-288.
[72]Buccafusco JJ and Terry AV Jr.Multiple central nervous system targets for eliciting beneficial effects on memory and cognition Jounal of Pharmacology and Experimental Therapeutics,2000,295(2):438-446.
[73]Terry AV Jr. and Buccafusco JJ. The cholinergic hypothesis of age and Alzheimer's disease related cognitive deficits:recent challenges and their implications for novel drug development Journal of Pharmacology and Experimental Therapeutics,2003,306(3):821-827.
[74]Bonini JS, Da Silva WC, Bevilaqua LK, et al. On the participation of hippocampal PKC in acquisition, consolidation and reconsolidation of spatial memory[J]. Neurosci,2007,147(1): 37-45.
[75]Cahill JF, Baxter MG. Cholinergic and noncholinergic septal neurons modulate strategy selection in spatial learning[J]. Eur J Neurosci,2001,14(11):1856-1864
[76]Cuervo AM, Stefanis L, Fredenburg R, et al. Impaired degradation of mutant alphasynuclein by chaperonemediated auto phagy[J]. Science,2004,305(5688):1292-1295.
[77]Gron G, Brandenburg I, Wunderlich AP, et al. Inhibition of hippocampal function in mild cognitive impairment:targeting the cholinergic hypothesis[J]. Neurobiol Aging,2006, 27(1):78-87.
[78]Rideout H J, Stefanis L. Proteasomal inhibition induced inclusion format ion and death in cortical neurons require tr anscription and ubiquitination[J]. Mol Cell Neurosci,2002,21(2): 223-238.
[79]Pierce JP, Milner TA. Parallel increases in the synaptic and surface areas of mossy fiber terminals following seizure induction[J]. Synapse,2001,9(3):49-256.
[80]杨秀丽.脂欣康益智作用临床观察及干预ApoE基因敲除小鼠认知功能障碍的研究[D].山东:山东中医药大学,2007:1-132.
[81]Soreq H, Seidman S. Acetylcholinesterase-new roles for an old actor[J]. Nat RevNeurosci,2001,4(2):294-302.
[82]Arivazhagan P, Ayusawa D, and Panneerselvam C.Protective efficacy of alpha-lipoic acid on acetylcholinesterase activity in aged rat brain regions.Rejuvenation Researeh,2006, 9(2):198-201.
[83]Sharma D and Singh R. Centrophenoxine activates acetylcholinesterase activity in hippcampus of aged rats. Indian Journal of Experimental Biology,1995,33(5):365-368.
[84]Das A, Dikshit M, and Nath C.Profile of acetylcholinesterase in brain areas of male and female rats of adult and oldage. Life Sciences,2001,68(13):1545-1555.
[85]Blusz taji J K, Berse B. The cholincrgic neuronal phenotype in Alzheimer's Disease[J]. Metab Brain Dis,2000,15(1):45-64.
[86]Fas sbender K, Masters C, Bevreuther K. Alzheimer's Disease:molecular concepts and therapeutic targets [J]. Naturwissenschaften,2001,88(6):261-267.
[87]叶智文,娄艾琳,郑华等.老年大鼠的海马神经元对微量注射ACh的敏感性[J].生理科学进展,1988,8(4):257.
[88]Fong TG, Vogelsberg V, Neff NH, et al. GMI and NGF synergism on choline acetyltransferase and choline uptake in aged brain.Neurobiology of Aging,1995,16(6):917-923.
[89]Sherman KA and Friedman E.Pre-and Post-synaptic cholinergic dysfunction in aged rodent brain regions:new findings and an interpretative review.International Journal of Developmental Neuroscience,1990,8(6):689-708.
[90]Gallagher M, Burwell RD, Kodsi MH,et al.Markers for biogenic amines in the aged rat brain:relationship to decline in spatial leaning ability.Neurobiology of Aging,1990,11(5): 507-514.
[91]Dekosky ST, IkonomovicMD, Styren SD, et al. Up regulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjectswith mild cognitive impairment [J]. Ann Neurol,2002,51:145-155.
[92]IkonomovicMD, Mufson EJ, Wuu J, et al. Cholinergic plasticity in hippocampus of individuals with mild cognitive impairment:correlation with Alzheimer's neuropathology[J]. J Alzheimer's Dis,2003,5:39-48.
[93]Lopez OL, DeKosky ST.Neuropathology of Alzheimer's disease and mild cognitive impairment[J]. Rev Neurol,2003,37(2):155-163.
[94]汤颖,李绪领,王德生.复智散对阿尔茨海默病模型小鼠认知功能及脑内胆碱能系统的影响[J].中国老年学杂志,2008,28(1):1-3.
[95]Bierer LM, Haroutun ian V, Gabriel S, et al. Neu roch emical correlates of dementia severity in Alzheimer s'disease:relative importance of the cholinergic deficits[J]. JN eurochem,1995; 64:746-760.
[96]Paterson D, Nordberg A. Neuronal nicotinic receptors in the human brain[J]. Prog Neurobiol,2000,61(1):75-111.
[97]Perry E, Martin-Ruiz C, Lee M, et al. Nicotinic receptor subtypes in human brain ageing, Alzheimer and Lewy body diseases[J]. Eur J Pharmacol,2000,393(1-3):215-222.
[98]Anagnostaras SG, Murphy GG, Hamilton SE, et al. (2003)Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice[J]. Nat Neurosci,6(1):51-58.
[99]Ovsepian SV, Anwyl R, Rowan MJ.Endogenous acetylcholine lowers the threshold for long- term potentiation induction in the CA1 area through muscarinic receptor activation:in vivo study[J]. Eur J Neurosci,2004,20(5):1267-1275
[100]黎彬如.轻度认知障碍的临床研究[D].广西:广西医科大学,2006:1-48.
[101]Harman D. Free radical theory of aging.Mutation Research,1992,275(3-6):257-266.
[102]Siqueira IR, Fochesatto C, de Andrade A, et al. Total antioxidant capacity is impaired in different structures from aged rat brain.International Journal of Developmental Neuroscience, 2005,23(8):663-671.
[103]Polidori MC. Antioxidant micronutrients in the prevention of age-related diseases. Journal of Postgraduate Medicine,2003,49(3):229-235.
[104]Murali G and Panneerselvam C. Modulatory role of glutathione monoester in augmenting age-associated neuronal antioxidant system Experimental Aging Research,2008, 34(4):419-436.
[105]Navarro A and Boveris A.Rat brain and liver mitochondria develop oxidative stress and lose enzymatic activities on aging. American Journal of Physiology Regulatory Integrative and Comparative Physiology,2004,287(5):R1244-1249.
[106]Rodrigues Siqueiral I, Fochesatto C, da Silva Torres IL, et al. Aging affects oxidative state in hippocampus,hypofhalamus and adrenal glands of Wistar rats.Life Sciences,2005, 78(3):271-278.
[107]Calabrese V, Scapagnini G, Ravagna A, et al. Increased expression of heat shock Proteins in rat brain during aging:relationship with mitochondrial function and glutathione redox state. Mechanisms of Ageing and Development,2004,125(4):325-335.
[108]Murali G and Panneerselvam C. Modulatory role of glutathione monoester in augmenting age-associated neuronal antioxidant system Experimental Aging Research,2008, 34(4):419-436.
[109]Fukui K, Onodera K, Shinkai T, et al. Impairment of learning and memory in rats caused by oxidative stress and aging, and changes in antioxidative defense systems. Annals of the New York Academy of sciences,2001,928:168-175.
[110]Fukui K, Omoi NO, Hayasaka T, et al. Cognitive impairment of rats caused by oxidatives tress and aging, and its prevention by vitamin E. Annals of the New York Academy of Sciences,2002,959:275-284.
[111]富宏,王学美,刘庚信,等.轻度认知障碍与氧自由基代谢和胆碱酯酶相关性的研究[J].中国老年学杂志,2004,24(1):17-18.
[112]Radi R, Beckman JS, Bush KM, Freeman BA, Arch Biochem Biophys.288,481-7(1991)[113] Ceriello A, Mercuri F, Quagliaro L, Assaloni R, Motz E, Tonutti L, Taboga C, Diabetologia,44,834-8(2001).
[114]Barja G. Free radicals and aging. Trends In Neu-rosciences,2004,27(10):595-600.
[115]Poon HF, Calabrese V, Scapagnini G, et al. Free radicals and brain aging. Clinics In Geriatric Medicine,2004,20(2):329-359.
[116]Dringen R. Metabolism and functions of glutathione in brain Progress In Neurobiology, 2000,62(6):649-671.
[117]Gonenc S, Uysai N, Acikgoz O, et al. Effects of melatonin on oxidative stress and spatial memory impairment induced by acute ethanol treatment in rats. Physiological Research,2005,54(3):341-348.
[118]Liu R, Liu IY, Bi X, et al. Reversal of age-related learning deficits and brain oxidative stress in mice with superoxide dismutase/catalase mimetics. Proceedings of the National Academy of Sciences of the United States of America,2003,100(14):8526-8531.
[119]Migliore L, Fontana I, Trippi F, et al. Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients. Neurobiol Aging.2005 May,26(5):567-573.
[120]Butterfield DA, Poon HF, St Clair D, et al. Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment:Insights into the development of Alzheimer's disease. Neurobiol Dis.2006,22(2):223-132.
[121]Pulliam JF, Jennings CD, Kryscio RJ, et al. Association of HFE mutations with neurodegeneration and oxidative stress in Alzheimer's disease and correlation with APOE. Am J Med Genet B Neuropsychiatr Genet.2003 May 15,119(1):48-53.
[122]Rinaldi P, Polidori MC, Metastasio A, et al. Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer's disease. Neurobiol Aging.2003 Nov,24(7): 915-919.
[123]Michikawa M. The role of cholesterol in pathogenesis of Alzheimer's disease:dual metabolic interaction between amyloid beta-protein and cholesterol.Mol Neurobiol.2003 Feb, 27(1):1-12.
[124]Mecocci P. Oxidative stress in mild cognitive impairment and Alzheimer's disease:a continuum[J]. J Alzheimer's Dis,2004,6:159.
[125]Fukui K, Onodera K, Shinkai S. Impairment of learning and memory in rats caused by oxidative stress, and changes in andoxidative defense systems[J]. Ann NY Acad Sci,2001, 928:168.
[126]Farr SA, Poon HF, Dogrukol2AKD, et al. The antioxidants alphalipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice [J]. J Neurochem,2003,84:1173.
[127]李浩,吴敏,姚明江,赵文明,徐立然.老年轻度认知功能障碍与氧自由基代谢、乙酰胆碱酯酶、血脂及炎性介质的关系[J].临床神经病学杂志,2008,21(3):201-203.
[128]Frost D, Gorman PM, Yip CM, et al. Co-incorporation of A beta 40 and A beta 42 to form mixed pre- fibrillar aggregates[J]. Eur J Biochem,2003,270 (4):654-663.
[129]贾建军,王鲁宁,汤洪川,等.国人血清淀粉样p蛋白1-28的生理参考值[J].中国临床康复,2006,10(14):65-67.
[130]Friedlich AL, Butcher LL. Involvement of free oxygen radical in β-amyloidosis:an hypothesis. Neurobiol Aging.1994; 15:433-455.
[131]Multhaup G, Ruppert T, Schlichsupp A, et al. Biochem Pharmacol,1997,54(5):533.
[132]李求兵,梅荣.老年痴呆症的中西医诊断与治疗[M].北京:中国医药科技出版社,1999.
[133]张大鹏,王奇,陈云波.阿尔茨海默病发病中淀粉样β蛋白的神经毒性作用[J].中国临床康复,2005,9(25):174-175.
[134]富宏,王学美,刘庚信,等.加味五子衍宗颗粒对轻度认知障碍患者的影响[J].中国中西医结合急救杂志,2004,15(3):159-162.
[135]Tomimoto H, Ohtani R, ShibataM, et al. Loss of cholinergic pathways in vascular dementia of the Binswanger type[J]. Dement Geriatr Cogn Disord,2005,9:282.
[136]ADELMAN AM, DALY MP. Initial evaluation of the patient with suspected dementia [J].Am Fam Physician 2005,71(9):1745-1750.
[137]NYENHUIS DL, GORELICK PB, GEENEN EL, el al. The patter of neuropsychological deficits in Vascular Cognitive Inpairment No Dementia (Vascular CIND) [J]. Clinical Neuropsychology,2004.18(1):41-49.
[138]Weinstock M.The pharmacotherapy of Alzheimer's disease based on the cholinergic hypothesis:an update[J]. Neurodegeneration,1995,4(4):349-356.
[139]Freo U, Pizzolate G, Dam M, et al. A short review of cognitive and Functional neuroimaging studies of cholinergic drugs:implications for therapeutic potentials [J]. J Neural Transm,2002,109(5-6):857-870.
[140]王曙红,何国平.轻度认知功能障碍的临床研究进展[J].实用预防医学,2010,17(9):1916-1918.
[141]Sugimoto H, Yamanishi Y,Limura Y, et al. Donepezil hydrochloride(E22020) and other ACh Els[J]. Curr Med Chem,2000,7 (3):303-339.
[142]Alistair B, Roberto B, Roger B, et al. Safety and efficacy of galantamine (Reminyl) in severe Alzheimer's disease (the SERAD study):a randomised, placebo- controlled, double-blind trial [J]. Lancet Neurol,2009,8:39-47.
[143]Gracon SI, Knapp MJ, Berghoff WG, et al. Safety of tacrine:clinical trials, treatment IND, and postmarketing experience. Alzheimer's Disease and Associated Disorders,1998, 12(2):93-101.
[144]Hock FJ. Therapeutic approaches for memory impairments[J]. Behav Brain Res,1995, 66:143-150.
[145]Alpar A, Ueberham U, Bruckner MK, et al. Different dendrite and dendritic spine alterations in basal and apical arbors in mutant human amyloid precursor protein transgenic mice. Brain Res,2006,1099(1):189-198.
[146]Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration:lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol,2007,8(2):1010-112.
[147]Cleary JP, Walsh DM, Hofmeister JJ. Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci,2005,8(1):79-84.
[148]Townsend M, Shankar GM, Mehta T, et al. Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity:a potent role for trimers. J Physiol,2006, 572(2):477-492.
[149]Lambert MP, Velasco PT, Chang L, et al. Monoclonal antibodies that target pathological assemblies of Aβ.J Neurochem,2007,100(1):23-35.
[150]Lacor PN, Buniel MC, Chang L. Synaptic targeting by Alzheimer's-related amyloid beta oligomers. J Neurosci,2004,24(45):10191-10200.
[151]Lee EB, Leng LZ, Zhang B, et al. Targeting amyloid-β peptide (Aβ) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in Aβ precursor protein (APP) transgenic mice. J Biochem,2006,281(7):4292-4299.
[152]包福祥,何金生,曹贵方,尹凡,王鑫,庞思媛,张莹,洪涛.人源性天然抗体库的构建及淀粉样蛋白Aβ1-42寡聚体单链抗体的筛选和鉴定[J].生物工程学报,2009,25(8):1195-1203.
[153]Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment-beyond controversies, towards a consensus:report of the International Working Group on Mild Cognitive Impairment[J]. J Intern Med,2004,256(3):240-246.
[154]Petersen R. Mild cognitive impairment as a diagnostic entity[J]. Intern Med,2004, 256(3):240-246.
[155]王善钻.老年人轻度认知功能障碍的研究现状和进展[J].医学综述,2010,16(18):2772-2775.
[1]Mitchell SL, Teno JM, Miller SC, et al. A national study of the location of death for older Persons with dementia[J]. J Am Geriatr Soc,2005,53:299-305.
[2]张磊,杨苏蓓.老年痴呆症发病机制下的治疗药物研究[J].中国现代药物应用,2010,4(20):238-239.
[3]郑传东.AD病相关蛋白APP胞内功能域(AICD)基因调控功能的研究[D].广州:南方医科大学,2010:1.
[4]Ferri CP, PrinceM, Brayne C, et al. Global prevalence of dementia:a Delphi consensus study. Lancet,2005,366:2112-2117.
[5]Alzheimer's Disease International, alz. co. uk/research/statistics. Html accessed on 2007-5-16.
[6]王荫华.老年痴呆在世界流行及其预防干预对策[A];2010第二届中国老年保健(产业)高峰论坛文集[C].北京:中国学术期刊(光盘版)电子杂志社,2010:198-200.
[7]工文.二○一五年我国老年人数将达两亿[J].共产党员,2010,12(24):25.
[8]Zhang ZX, Zahner GE, Roman GC, et al. Dementia subtypes in China:pre-valence in Beijing, Xian, Shanghai, and Chengdu [J]. ArchNeurol,2005,62:447-453.
[9]Tian J. Dementia in Asian Context. In:The Cambridge Handbook of Age and Ageing, eds. Malcolm Johnson. Cambridge University Press,2005.261-274.
[10]贾建平.《中国痴呆与认知障碍诊治指南》简介[A];2009全国抗衰老与老年痴呆学术会议论文汇编[C].北京:中国学术期刊(光盘版)电子杂志社,2009:1-2.
[11]贾建平.临床痴呆病学[M].北京:北京大学医学出版社,2008:1-498.
[12]Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment. Arch Neurol.2001; 58(12):1985-1992.
[13]陈晓红,王荫华.轻度认知功能损害——AD的极早期阶段?[J].中华神经科杂志,2002,35(6):473.
[14]Petersen RC. Aging, mild cognitive impairment,and Alzheimer's disease[J]. Neural Clin.2000; 18(4):789-805.
[15]Pelersen RC, Stevens JC, Ganguli M, et al. Practice parameter:early detection of dementia; mild cognitive impairment (an evidence-based review). Neurology,2001; 56:1133-1142.
[16]Hanninen T, Hallikainen M, Tuomainen S, et al. Prevalence of mild cognitive impairment:a population based study in early subjects. Acta NeurolScand.2002; 106(3): 148-154.
[17]李浩,姚明江.浅谈中医“虚”、“瘀”、“浊”、“毒”轻度认知障碍发病的关系[J].中国中医药信息杂志,2006,13(11):4-5.
[18]李浩,徐立然,罗增刚,等.还脑益聪合灯盏花素治疗轻度认知障碍临床研究.中西医结 合心脑血管病杂志,2004,2(7):387-389.
[19]李浩,徐立然,等.还脑益聪胶囊治疗老年轻度认知障碍的临床研究[A];第五次全国中西医结合养生学与康复医学学术研讨会论文集[C];2006.
[20]李浩,等.还脑益聪胶囊治疗老年轻度认知损害的双盲随机对照研究[J].中西医结合学报,2008,6(1):25-31.
[21]姚明江,刘剑刚,李浩,等.还脑益聪方对早期认知功能障碍大鼠血浆P2选择素、血浆纤溶酶原激活物抑制剂和血液流变学指标的影响.中国微循环,2009,13(4):254-258.
[22]李浩,姚明江,徐立,等.还脑益聪方对认知功能障碍大鼠认知功能及海马bcl-2/bax蛋白表达的影响.中国中药杂志,2009,34(20):2622-2626.
[23]李浩,刘剑刚,赵文明,等.还脑益聪方对老龄认知障碍大鼠脂质代谢和海马内质网Aβ相关结合蛋白表达的影响.中国中医基础医学杂志,2009,15(5):354-357.
[24]Morris R. Developments of a Water-maze procedure for studying spatial learning in the rat. Journal of Neuroscience Methods,1984,11(1):47-60.
[25]O'Keefe J. A computational theory of the hippocampal cognitive map. Pro. Brain Res, 1990,83:301-312
[26]杨秀丽.脂欣康益智作用临床观察及干预ApoE基因敲除小鼠认知功能障碍的研究[D].山东:山东中医药大学,2007:1-132.
[27]Squrie LR, Zola-morgan S. Memory, brian system and behavior. Trends in Neuroscience, 1988,11:170.
[28]李国栋,王永奎,李欢娜等.不同月龄阿尔茨海默病模型小鼠行为学改变与胆碱酯酶活性的关系[J].第四军医大学学报,2009,30(9):819-822.
[29]唐康.黄皮酞胺对脑缺血损伤和APP转基因小鼠的保护作用及机制[D].北京:中国协和医科大学研究生院,1999:1-104.
[30]秦川等.阿尔茨海默症转基因动物模型脑组织病理学及免疫组化研究[J].中国实验动物学报,2000,8(4):213-217.
[31]黄澜等.不同月龄人App老年痴呆病转基因小鼠行为学观察比较[J].中国老年学杂志2,2004,24(12):1185-1186.
[32]Hermans RH, Hunter DE, McGivern RF, et al. Behavioral sequelae in young rats of acute intermittent antenatal hypoxia Neurotoxieology and Teratology,1992,14(2):119-129.
[33]Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics[J]. Science,2002,297(5580):353-356.
[34]White AM, Mattews DB, Best PJ. Ethanol, memory, and hippocampal function:a review of recent findings[J]. Hippocampus,2002,10(1):88-93.
[35]Sberna G, Saez2valero J, Li QX, et al. Acetylcholinesterase is increased in the brains of transgenic mice exp ressing the C2terminal fragment (CT100) of the beta2amyloid p rotein p recursor of Alzheimerps disease[J]. J Neurochem,1998,71 (2):723-731.
[36]Mufson EJ, Ginsberg SD. Human cholinergicbasal forebrain:chemoanatomy and neurologic dysfunction. JChem Neuroanat,2003,26 (4):233-242.
[37]李前,朱振霞,孙曼雯.乙酰胆碱酯酶与老年性痴呆关系的研究进展[J].中国老年医学杂志,2002(22):325-326.
[38]TUPPO EE, FORMAN LJ. Free radical oxidative damage and Alzheimer's Disease[J]. J Am Osteopath Assoc,2001,101 (12 Suppl Pt 1):S11-S5.
[39]Moreira PI, Santos MS, Oliveira CR, et al. Alzheimer's Disease and the Role of Free Radicals in the Pathogenesis of the Disease[J]. CNS & Neurological Disorders-Drug Targets, 2008,7(1):3-10.
[40]Pratico D. Alzheimer's disease and oxygen radicals:New insights[J]. Biochem Pharm, 2002; 63:563-567.
[41]Cahill JF, Baxter MG. Cholinergic and noncholinergic septal neurons modulate strategy selection in spatial learning[J]. Eur J Neurosci,2001,14(11):1856-1864.
[42]C Gotti, F Clementi. Neuronalnicotinic receptors:from structure to pathology[J]. Nrobiology,2004,74:363.
[43]Fas sbender K, Masters C, Bevreuther K. Alzheimer's Disease:molecular concepts and therapeutic targets [J]. Naturwissenschaften,2001,88(6):261-267.
[44]KASA P, RAKONCZAY Z, GLUYA K. The cholinergic system in Alzheimer's Disease[J]. Prog Neurobiol,1997,52(6):511-535.
[45]谢明,成志.丹参酮对阿尔茨海默病样大鼠海马内诱导型一氧化氮合酶mRNA和乙酰胆碱酯酶表达的影响[J].中国现代医学杂志,2008,18(8):1005-1012.
[46]王德生.复智散对阿尔茨海默病模型大鼠治疗作用的研究[J].中国实验方剂学杂志,2008,14(10):28-30.
[47]Ulrich J, Meier Ruge, W, Meier E, Ipsen, S, Senile plaque:staining for acetylcholine sterase and A4 protein:a comparative study in the hippocampus and entorhinal cortex[J]. Aeta neuropathologiea,1990,80:624-628.
[48]李梅,林来祥,徐淑梅.H102对APP转基因小鼠胆碱能系统及自由基的影响[J].中国新药与临床杂志,2009,28(2):106-109.
[49]黎彬如.轻度认知障碍的临床研究[D].广西:广西医科大学,2006:1-48.
[50]梅峥嵘等.隐丹参酮对APP/PS1双转基因模型小鼠学习记忆和抗氧化能力的影响[J].中国现代应用药学,2010,27(12):1072-1076.
[51]林茂,万章,王春梅.白藜芦醇对阿尔茨海默病小鼠记忆和抗氧化能力的影响[J].现代中西医结合杂志,2009,18(5):484-486.
[52]李守民.三七总皂昔对D-半乳糖联合Aβ(1-40)致老年痴呆大鼠模型治疗作用的研究[D].云南:昆明医学院,2009:1-69.
[53]朱晓莹,张树球,李朝敢,等.元首口服液的二苯乙烯苷含量与O2-·清除率关系的实验研究[J].现代中西医结合杂志,2003,12(27):685-686.
[54]Ryu G, Ju JH, Park YJ, et al. The radical scavenging effects of stilbene glucosides from Poygonum multiflorum.Arch Pharm Res,2002,25(5):636-639.
[55]刘丽,赵玲,李雅莉,等.四羟基二苯乙烯苷对慢性脑缺血致痴呆模型大鼠的保护作用[J]. 中国药学杂志,2006,41(5):354-358.
[56]Zang C, Yang T, Wang JA, et al. The chinese Traditional Medicine"Bushen Yinao Pian"increased the level of ageing-related gene LRPAP-1 expression in the cerebral tissue of accelerated senescence-prone mouse8/Ta[J]. Jo Ethnopharmacol,2005,98:61-65.
[57]吴宾,方永奇.石菖蒲益智作用的物质基础及其机理研究[J].中医药学刊,2004,22(9):1635-1641.
[58]林慧光,等.石菖蒲挥发油香熏辅助治疗老年性痴呆大鼠的实验研究[J].福建中医学院学报,2007,17(4):25-27.
[59]余光.黄连素对CA诱导的tau蛋白过度磷酸化的保护作用及其机制[D].华中科技大学,2009.
[60]李彩虹,周克元.黄连活性成分的作用及机制研究进展[J].时珍国医国药,2010,21(2):466-468.
[61]G. R. Schinella, et al. Antioxidant activity of anti-inflammatory plant extracts [J]. Life Science,2002,70:1023-1033.
[62]Zhang C, Wang SZ, Zuo PP, et al. Protective effect of tetramethylpyrazine on learning and memory function in Dgalactose-lesioned mice [J]. J Chin Med Sci,2004,19(3):754-760.
[63]赵琳,魏敏杰,何苗,等.川芎嗪对阿尔采末病模型小鼠学习记忆能力的影响及其机制初探[J].中国药理学通报,2008,24(8):1088-1092.