【作者】 李梦月；

【导师】 黄国伟；

【作者基本信息】 天津医科大学 ， 营养与食品卫生学， 2021， 博士

【摘要】 目的轻度认知障碍(mild cognitive impairment,MCI)作为阿尔茨海默病(Alzheimer’s disease,AD)的前期可进一步发展为AD,改善MCI的认知功能是预防AD发生的重要手段。本研究旨在研究叶酸(folic acid,FA)、二十二碳六烯酸(docosahexaenoic acid,DHA)、端粒长度以及认知之间的相互关系,叶酸和DHA联合干预能否协同改善MCI老年人的认知功能以及二者是否是通过延缓端粒缩短来改善MCI老年人的认知功能。方法采用1:1匹配病例对照研究,分别招募280例MCI老年人和280例认知正常老年人,按照性别一致、年龄上下相差2岁、受教育年限上下相差1年进行1:1匹配。采用简易精神状况量表(minimum mental state examination,MMSE)得分估测研究对象的认知功能,检测血清叶酸、Hcy、血浆DHA、外周血白细胞端粒长度以及线粒体拷贝数。采用皮尔逊相关分析及Logistic回归分析,分析叶酸、Hcy、DHA、端粒长度以及线粒体拷贝数与认知功能及MCI的关系,以及它们之间的相互关系。采用结构方程模型进行中介效应分析,评价端粒长度是否在叶酸或DHA与认知功能关系中发挥中介作用。采用随机双盲对照试验,将招募的280例MCI老年人进行随机分组,分为FA+DHA组(800μg FA+800mg DHA/d),FA组(800μg FA/d),DHA组(800mg DHA/d)和安慰剂组,每组70例。干预期为12个月。分别在基线和干预12个月随访时,评价受试者的认知功能、外周血叶酸、Hcy、DHA、端粒长度、端粒相关蛋白的mRNA表达、氧化应激水平、线粒体功能以及p53蛋白水平和p53-mRNA的表达。采用混合线性模型分析各组受试者干预12个月后上述指标的变化情况。结果病例对照研究结果显示,MCI组的血清叶酸和血浆DHA水平较低、外周血白细胞端粒长度较短、线粒体拷贝数较少,而血清Hcy水平较高,与对照组相比差异具有统计学意义(P<0.05)。叶酸水平、DHA水平、端粒长度以及线粒体拷贝数与MMSE量表得分呈正相关,Hcy水平与MMSE量表得分呈负相关(P<0.05)。较高水平的叶酸、DHA、较长的端粒长度以及较大的线粒体拷贝数与较低的MCI患病风险相关,较高水平的Hcy与较高的MCI患病风险相关(P<0.05)。叶酸水平、端粒长度与Hcy水平呈负相关,端粒长度与DHA水平呈正相关(P<0.05)。端粒长度在Hcy水平与MMSE量表得分的关系以及DHA水平与MMSE量表得分的关系中发挥中介作用(P<0.05),其介导的中介效应分别占总效应的21.90%和12.10%。Hcy水平和端粒长度在叶酸水平与MMSE量表得分的关系中发挥串联中介作用(P<0.05)。随机双盲对照试验结果显示,经过12个月的干预,FA+DHA组总智商、言语智商、操作智商、知识、计算、相似性和木块图的得分高于安慰剂组;FA组和DHA组总智商、言语智商、知识、计算和相似性的得分高于安慰剂组;FA+DHA组总智商、操作智商及木块图得分高于FA组和DHA组,差异具有统计学意义(P<0.05)。FA+DHA组、FA组和DHA组的端粒长度大于安慰剂组,TRF2-mRNA表达量低于安慰剂组;FA+DHA组过氧化氢水平低于安慰剂组;FA+DHA组和FA组抑制超氧阴离子能力高于安慰剂组;FA+DHA组、FA组和DHA组基因组8-oxo G含量低于安慰剂组;FA+DHA组、FA组和DHA组线粒体拷贝数高于安慰剂组,FA+DHA组和FA组线粒体缺失少于安慰剂组;FA+DHA组、FA组和DHA组p53水平低于安慰剂组,差异具有统计学意义(P<0.05)。结论外周血叶酸、DHA、Hcy水平以及端粒长度与老年人的认知功能相关。叶酸、DHA及二者联合干预可以改善MCI老年人的认知功能,叶酸和DHA联合干预效果优于单独的叶酸和DHA干预,叶酸和DHA在改善MCI老年人认知功能方面可能发挥协同作用。叶酸和DHA可能是通过延缓端粒缩短来改善MCI老年人的认知功能。更多还原

【Abstract】 ObjectiveMild cognitive impairment(MCI)is the early status of Alzheimer’s disease,(AD).Delaying the decline of cognitive function in the elderly with MCI is an important means to prevent AD.The objective of this study was to discuss the mediating effect of telomere in the relationship between folic acid(FA)or docosahexaenoic acid(DHA)and cognitive function,whether the combined intervention of FA and DHA has a synergistic effect on the improvement of cognitive function in the elderly with MCI,and whether they can ameliorate the cognitive function of the elderly with MCI by delaying telomere shorting.MethodIn the case-control study,280 MCI elderly and 280 cognitively normal elderly were matched according to the same sex,two years in age and one year in education.The cognitive function was estimated by the scores of mini mental state examination(MMSE).Serum folate,Hcy,plasma DHA,leukocytes telomere length(LTL)and mitochondrial copy number were detected.The relationships between folate,Hcy,DHA,LTL,mitochondrial copy number and cognitive function were analyzed by Pearson correlation analysis and logistic regression.Structural equation models were used to analyze the mediating effect of LTL in the relationship between FA or DHA and cognitive function.In the randomized double-blind controlled trial,280 elderly patients with MCI were randomly divided into FA+DHA group(800 μg FA + 800 mg DHA/d),FA group(800 μg FA/d),DHA group(800 mg DHA/d)and Placebo group,with 70 subjects in each group.Cognitive function,peripheral folate,Hcy,DHA,LTL,telomere related protein mRNA expression,oxidative stress levels,mitochondrial function,p53 protein levels and p53-mRNA expression were measured at baseline and 12 months.Mixed linear models were used to analyze the changes of the above indexes after 12 months of intervention.ResultThe results of case-control study showed that,the serum folate and plasma DHA levels,LTL and mitochondrial copy numbers of MCI group were lower and the serum Hcy levels of MCI group was higher(P < 0.05),comparing with control group.The levels of folate,DHA,LTLs and numbers of mitochondrial copy number were positively correlated with MMSE scores,while the levels of Hcy was negatively correlated with LTL(P<0.05).Higher levels of folate,DHA,LTL and mitochondrial copy number were the protective factors of MCI,while higher levels of Hcy was a risk factor of MCI.The levels of folate,LTL and Hcy were negatively correlated,and the levels of LTL and DHA were positively correlated(P<0.05).LTL played mediating roles in the relationship of Hcy and cognitive function,and DHA and cognitive function(P<0.05),and the mediating effects were 21.90% and 12.10%.Hcy levels and LTL played a tandem mediating role in the relationship between folate levels and MMSE scores(P<0.05).The results of randomized double-blind controlled trial showed that,after a 12 months intervention,the full scale IQ(FIQ),verbal IQ(VIQ),performance IQ(PIQ),information,arithmetic,similar and block diagram scores in FA + DHA group,the FIQ,VIQ,information,arithmetic and similar scores in FA group and DHA group,were higher,comparing with placebo group(P<0.05).The FIQ,PIQ and block diagram scores in FA+DHA group were higher,comparing with FA group or DHA group(P<0.05).The LTL in FA + DHA group,FA group and DHA group were longer;the expression of TRF2-mRNA in FA + DHA group,FA group and DHA group were lower;the levels of hydrogen peroxide in FA+DHA group were lower;the ability of inhibiting superoxide anion in FA+DHA group and FA group were higher;the content of genomic 8-oxo G in FA+DHA group,FA group and DHA group were lower;the mitochondrial copy number in FA+DHA group,FA group and DHA group were higher;the mitochondrial deletion in FA+DHA group and FA group were less;the levels of p53 in FA+DHA group,FA group and DHA group were lower,comparing with placebo group(P < 0.05).ConclusionThe levels of folate,DHA,Hcy and LTL were related to cognitive function of the elderly.Folic acid,DHA can improve the cognitive function of MCI elderly.The effect of folic acid and DHA combined intervention is better than that of folic acid and DHA alone.Folic acid and DHA may play a synergistic role in improving the cognitive function of MCI elderly.Folic acid and DHA may improve cognitive function of MCI elderly by delaying telomere shortening.更多还原