衰老性认知功能下降(专业版)
随着年龄的增长、老化,大脑将在认知能力上出现不同程度地下降,包括记性变差、难于集中精神,以及思维、解决问题能力下降等。如果不及时治疗和控制,将可能出现更严重的症状和疾病,
其他名称:年龄相关性认知功能障碍
英文名称:Age-related Cognitive Decline,Age-related Cognitive Disorders
导致年龄相关性的认知衰退,原因包括如下:
综合选项可以包括如下:
调整饮食与生活方式
在人类研究中,南非醉茄可以改善记忆和认知功能。在一项双盲安慰剂对照研究中,50名成年人被随机分配接受南非醉茄根提取物(300mg,每天两次)或安慰剂治疗八周。南非醉茄与短期和一般记忆、执行功能、持续注意力和信息处理速度的统计学显著改善有关171。此外,在一项针对53名双相情感障碍患者的随机对照试验中,每天补充500mg 南非醉茄提取物可改善听觉-言语工作记忆、反应时间和社会认知172。
以及参阅本网如下专文的有关内容:
医疗干预
常规药物治疗包括如下:
参考文献:
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美国老年痴呆症协会
http://www.alz.org
美国神经研究学会
http://www.aan.com
美国国立公众健康网
www.medlineplus.gov
加拿大老年痴呆协会
http://www.alzheimer.ca
多伦多痴呆网
http://www.dementiatoronto.org
免责声明和安全信息
英文名称:Age-related Cognitive Decline,Age-related Cognitive Disorders
定义
随着年龄的增长、老化,大脑将在认知能力上出现不同程度地下降,包括记性变差、难于集中精神,以及思维、解决问题能力下降等。如果不及时治疗和控制,将可能出现更严重的症状和疾病,如痴呆、抑郁症和老年痴呆等。病因
年龄老化过程深刻地影响着大脑,如神经元和线粒体膜的退化,引起脑细胞完整性的丧失和神经元功能受损;神经递质合成和信号传导显著性下降,神经突触密度和可塑性的降低等,使大脑功能随着年龄的增长而功能衰退、效率降低。导致年龄相关性的认知衰退,原因包括如下:
- 氧化应激损伤神经细胞和组织
- 慢性低度炎症,影响微循环
- 激素水平下降,如雌激素、睾丸、DHEA和孕烯醇酮等
- 动脉内膜(内皮)功能障碍
- 胰岛素抵抗
- 过多体重
- 营养素不足
- 孤独,缺乏社交网络
- 长期精神压力
风险因素
许多因素都可能影响到认知功能下降:- 生物学因素包括:
- 氧化应激:大脑耗氧约占据全身的20%,及脑皮层所含的大量磷脂,年龄的老化使得大脑极易处于氧化应激之中。
- 慢性低度炎症:因吸烟、睡眠紊乱和饮食差等不良饮食与生活习惯引起的血液循环中的炎性因子,突破脑屏障而引起脑损伤。
- 激素失衡:大脑遍布类固醇激素受体,调节和参与认知等行为,激素失衡都将引起脑功能变化,主要激素是雌激素、睾酮激素、DHEA和孕烯醇酮以及甲状腺激素等。
- 脑源性神经营养因子(BDNF),有助于现有神经元的存活和突触适应,并刺激新神经元形成,参与大脑区域的学习、记忆和高阶思维等。年龄老化、痴呆症等BDNF含量较低。
- 脑血管因素包括如下:
- 低的“好”胆固醇(HDL),影响移除脑血管中的脂蛋白,导致血凝块和脑血栓。
- 高同型半胱氨酸血症,脑卒中的独立发病因素,可致血管性痴呆。
- 高血压,脑中的微细血管特别容易受到高血压的损伤,引起脑功能下降。
- 高血糖,葡萄糖是大脑的唯一能源,血糖波动大可严重影响脑功能。
- 精神心理因素包括如下:
- 焦虑
- 抑郁
- 长期精神压力
- 心理活动,大脑的可塑性和认知储备。
- 其他因素如:
- 体力活动:经常锻炼有助于产生脑源性神经营养因子(BDNF), 维持大脑认知功能。
- 社会交际与个人关系
症状
衰老性认知功能下降的主要症状,包括如下:- 记忆紊乱,能记忆的东西越来越少
- 难于集中和维持精力
- 思维能力受损,抽象概括过程障碍、联想过程障碍、思维逻辑障碍等
- 解决问题的能力下降等
疗法
治疗旨在支持脑功能健康、延缓认知退化并预防痴呆症发生。综合选项可以包括如下:
调整饮食与生活方式
- 健康饮食,富含优质蛋白、深海鱼和坚果,及新鲜蔬菜、水果
- 限制热量摄入,并须满足维生素和矿素物质等营养素
- 适度饮酒
- 不抽烟,或戒烟
- 定期运动锻炼,尤其是各种有氧运动
营养与草本综合干预
以下是基于循证医学和营养学有关文献综合的结果。有助于防控年龄相关性认知下降的营养和草本主要包括如下:
- 银杏叶:可能是研究最广泛、最常用的支持认知功能的综合疗法。银杏提取物已被证明可以减少氧化应激、减少神经炎症、改善微循环、调节神经递质活性和促进神经可塑性1。动物研究表明,银杏可能刺激神经干细胞增殖和活性2。
大量随机对照试验、系统综述和荟萃分析得出结论,标准化银杏叶提取物通常每天120-240mg剂量,可以减缓轻度认知障碍和痴呆患者的认知能力下降并减少神经精神症状(如妄想、抑郁或焦虑情绪)1,3。2019年的一篇专家共识论文发现,有效性和安全性证据足以推荐标准化银杏提取物,单独或与传统疗法联合使用,用于治疗轻度认知障碍和痴呆4。
- 假马齿苋:一种在印度具有宗教、文化和医学重要性的植物,在阿育吠陀医学中已经使用了数百年5。在临床前研究中,假马齿苋提取物已被证明具有降低大脑氧化应激、调节神经递质活性、减少β-淀粉样蛋白沉积、加强神经元连接以及增加脑血流量等6。人类研究表明,假马齿苋也可能改善应激反应7。此外,在小鼠中,假马齿苋提取物增加了大脑中脑源性神经营养因子(BDNF)的水平和新神经元的产生8。
一项荟萃分析包括了9项随机对照试验中518名受试者的数据,表明假马齿苋有可能改善认知的某些方面9。在一项针对54名65岁及以上参与者的随机对照试验,与安慰剂相比,每天服用300mg假马齿苋提取物12周的患者认知能力更好,12周后焦虑和抑郁症状减轻10。两项使用假马齿苋不同草药营养组合的临床试验报告称,这些补充剂对患有轻度认知障碍的老年人的具有认知益处11,12。
- 石杉碱甲:已被证明能抑制乙酰胆碱酯酶。乙酰胆碱是自主神经系统中的一种主要神经递质,其被乙酰胆碱酯酶加速分解会导致与年龄相关的认知能力下降和痴呆13。一些抗痴呆药物如多奈哌齐,也通过抑制乙酰胆碱酯酶发挥作用。此外,临床前证据表明,石杉碱甲可以减少氧化应激,防止β-淀粉样蛋白和磷酸化tau积累,支持线粒体功能,并增加大脑中神经生长因子的产生14。
大量临床试验表明,石杉碱甲可以改善痴呆症患者的认知功能。一项荟萃分析包括10项随机对照试验,评估石杉碱甲在825名阿尔茨海默病或血管性痴呆患者中的疗效,剂量从每天100-400mcg不等。分析结果表明,石杉碱甲可以改善痴呆症患者的认知功能,长期使用可能会带来更大的益处15。另一项对阿尔茨海默病患者进行的20项随机对照试验的荟萃分析也指出,石杉碱甲可能对认知功能有好处16。在一项初步试验中,含有石杉碱甲和姜黄素的补充剂在痴呆症患者和轻度认知障碍患者的6-12周和22-28周后改善了认知表现17。
需要注意的是,服用石杉碱甲可能存在轻微的副作用,如消化不良和便秘、头晕、心率减慢和口干15。
- 乙酰L肉碱:在线粒体中产生并参与细胞能量生产,而且是乙酰胆碱形成的前体分子18。一项研究报告称,从没有认知问题到主观记忆障碍,再到轻度认知功能障碍,再到痴呆,受试者的血清乙酰L肉碱水平逐渐降低19。临床前研究表明,乙酰L肉碱可以保护脑线粒体功能,减少氧化应激,通过小胶质细胞抑制炎症活性,并改善神经系统中的多巴胺信号传导20。
一项随机对照试验的荟萃分析包括来自21项研究的数据,这些研究涉及1200多名受试者。该荟萃分析发现,在轻度认知障碍和早期阿尔茨海默病患者中,补充乙酰L肉碱三个月或更长时间与临床改善相关21。一项针对老年人的临床试验发现,用乙酰L肉碱治疗可以减少身心疲劳,改善认知和身体功能22。一项比较试验发现,乙酰L肉碱作用略快于氟西汀(百忧解),在改善老年人轻度抑郁症状方面疗效相似,一种可能与更好的认知功能有关的效果23。服用六个月的含有乙酰L肉碱加维生素B族、维生素E和其他氨基酸衍生物的联合补充剂,与安慰剂相比,改善了轻度认知障碍参与者的认知功能24。
- 多酚类:多酚是一类在植物中发现的强氧化应激降低化合物。在652名65岁及以上无痴呆症的受试者中,尿液中多酚含量较高,表明多酚摄入量较高,三年监测表明认知功能下降少25。此外,在认知功能的某些方面测试中,摄入特定的富含多酚的食物(橄榄油、咖啡、核桃和葡萄酒)与更好的认知表现独立相关26。
有证据表明,多酚可以减少大脑氧化应激和神经炎症,改善脑血管功能27。除了抑制过量的自由基外,多酚还可以影响与衰老相关的信号传导,保护神经干细胞活性,促进神经可塑性,减少蛋白质积累,诱导突触可塑性相关基因的表观遗传学变化,并支持健康的肠道微生物群27,28。
浆果类多酚:蓝莓及其多酚,尤其是赋予其颜色的花青素,可能对包括认知障碍在内的慢性疾病具有预防作用29。对老年人的研究表明,蓝莓可以增强大脑血流量,并增加与年龄相关的认知障碍相关区域的大脑活动30。在一项针对37名60-75岁人群的随机对照试验中,与安慰剂相比,每天24g冷冻干燥蓝莓(相当于一杯新鲜蓝莓)持续90天可提高认知能力31。
葡萄多酚:常见如葡萄籽、白藜芦醇等花青素32。一项针对111名健康老年受试者的随机对照试验发现,每天250mg葡萄籽提取物可在12周后改善认知测试得分33。在小型对照试验中,认知能力下降和轻度认知障碍的老年人在每天饮用450-600ml(取决于体重)的Concord葡萄汁,12-16周后认知能力有所改善34。一项针对215名健康老年人的随机对照试验发现,高多酚葡萄籽加蓝莓提取物对那些认知测试得分最低的人有显著影响,每天服用600mg,持续六个月35。
白藜芦醇:白藜芦醇似乎通过调节与年龄相关的信号传导、改善脑血流量和增加神经可塑性来减缓认知能力下降36。不过,临床试验的结果喜忧参半。包括10项临床对照试验的荟萃分析发现,白藜芦醇可以改善老年人认知功能和情绪的某些方面37。
在一项针对46名50-75岁健康人的随机安慰剂对照试验中,每天服用200mg白藜芦醇26周的治疗可以改善记忆任务,改善葡萄糖代谢(表现为血红蛋白HbA1c降低),增强神经元连接,并减少身体脂肪38。另一项针对40名轻度认知障碍患者的试验发现,每天服用200mg白藜芦醇治疗26周,可以改善葡萄糖代谢和大脑结构,但与安慰剂相比,认知功能没有差异39。在一项对绝经后妇女的对照试验中,每天150mg白藜芦醇补充14周后,改善了脑血管功能和认知能力;研究者提出,白藜芦醇在该人群中的一些作用可能是由于其植物雌激素效应40。
绿茶:其活性成分绿茶多酚(EGCG)可通过调节神经生长因子、调节参与炎症和神经元存活的细胞信号传导以及减少异常蛋白质的积累来减缓大脑衰老41。一项对21项研究的综述发现,绿茶可以减少焦虑,有益于记忆和注意力,并增强大脑功能42。
绿原酸:绿原酸是咖啡中发现的多酚,尤其在生咖啡豆中含量高。许多研究将摄入绿原酸与更好的认知功能和情绪联系起来43。在38名50-69岁有主观记忆问题的健康成年人中,睡前喝一种提供300mg绿原酸的饮料16周,可以改善认知能力,并改善血液中被认为是早期阿尔茨海默病标志的蛋白质水平44。一般烘焙咖啡几乎不含绿原酸,因为高温加工使其受到破坏。不过,绿咖啡豆提取物富含绿原酸。
褪黑素:昼夜节律和夜间褪黑激素的产生随着年龄的增长而减少,导致睡眠不足和随之而来的神经退行性变45。在老年人中,夜间褪黑激素水平较低与轻度认知障碍和痴呆相关46。在阿尔茨海默病和血管性痴呆的动物模型中也发现了褪黑激素减少神经炎症和神经退行性变的潜力47,48。
在对轻度认知障碍患者的回顾性分析中,报告了褪黑素对睡眠、情绪和几种认知功能测试的影响。该分析比较了睡前添加或不添加褪黑素对96名门诊患者的影响,剂量为3-24mg。参与者被监测了15-60个月,结果显示褪黑素治疗组改善了睡眠、情绪,在所有认知功能测试中表现更好49。在这些研究人员之前进行的一项类似设计的回顾性分析中,轻度认知障碍患者每晚服用3–9mg褪黑素治疗9–18个月后,除一项认知测试外,其他所有认知测试的表现都有所改善50。
一项针对139名接受髋关节手术的老年参与者的随机对照试验发现,从手术前一天开始,睡前服用1mg褪黑素,持续六天,可以防止术后认知能力下降;与安慰剂相比,睡眠质量、疲劳和总体健康状况也有所改善51。阿尔茨海默病患者的临床试验表明,褪黑素可以改善睡眠,减轻行为症状,并增强认知功能的某些方面52。
- 欧米伽3脂肪酸:DHA(二十二碳六烯酸)是大脑健康的关键营养素,缺乏DHA会导致情绪不佳和认知功能障碍等症状;它在神经元细胞膜中的浓度很高,在维持膜流动性方面发挥着重要的结构作用53。临床前研究表明,DHA加上EPA可以预防淀粉样斑块和神经原纤维缠结54,以及防止脑内小血管堵塞和改善血液流动55。大脑中B族维生素的正确使用也可能需要充足的ω-3脂肪酸状态56。此外,DHA具有抗炎作用,是神经保护素D1的前体,D1是一种参与神经元生长和存活的信号分子53。
许多研究指出,血液或饮食中ω-3脂肪酸水平越高,与认知功能越好之间存在着密切的联系57。一项针对2,622名老年人的研究发现,在13年的时间里,血液中长链-3脂肪酸(包括EPA和DHA)含量最高的人患不健康衰老的风险降低了18%,不健康衰老的定义是慢性疾病、身体或认知功能障碍,或因任何原因死亡58。其他研究的结果表明,ω-6与ω-3脂肪酸的比例可能是影响大脑结构和认知功能的重要因素59。
对六项随机对照试验的荟萃分析发现,补充ω-3脂肪酸可减缓老年人认知能力下降的速度。该试验使用每天400至1800mg的ω-3脂肪酸,持续3-40个月60。同样,一项对24项研究的大型综述发现,有证据表明摄入ω-3脂肪酸对认知能力产生有益影响61。
不过,有的研究结果并不一致。例如,在390名健康老年受试者中,连续18个月每天1720mg DHA和600mg EPA对认知能力下降没有影响62。
可能影响临床试验结果的一个因素是载脂蛋白E4(ApoE4)基因变体的存在,这与DHA代谢紊乱有关63。ApoE4变体与认知障碍患者患痴呆症的风险增加有关64。一项针对915名老年参与者的研究,仅注意到ApoE4携带者食用更多海鲜与认知能力下降减少之间的联系65。在另一项研究中,观察到食用海鲜对淀粉样蛋白斑块和神经原纤维缠结的保护作用仅仅是由于ApoE4携带者的作用54。由于这些发现,有人认为补充DHA在ApoE4载体中可能更重要66。
- 维生素B族:同型半胱氨酸代谢需要B族维生素,而B族维生素水平较低,特别是叶酸、维生素B12和维生素B6,与高血同水平和老年人更大的认知能力下降有关。虽然B族维生素可降低高血同,不过,临床试验结果在认知益处方面参差不齐67,68。
研究人员一直在调查那些最有可能从B族维生素治疗中受益的因素,如ω -3脂肪酸状态、同型半胱氨酸水平或认知障碍程度。一项随机试验发现,补充B族维生素对认知功能的积极作用依赖于充足的omega-3脂肪酸状态69。一项为期2年的随机对照试验发现,补充B6、B12和叶酸仅对基线同型半胱氨酸水平为11.3 mmol/L或更高的患者可减缓认知能力下降70。在对轻度认知障碍的老年人进行的5年监测中,补充叶酸和B12与降低痴呆风险有关71。在诊断为轻度认知障碍的老年人中,每天服用400 mcg叶酸可在6个月和1年后降低认知能力下降和血液中炎症细胞因子水平72。在一项轻度认知障碍参与者的试验中,即使在仅仅12周后,补充B6、叶酸和B12降低了同型半胱氨酸水平,改善了认知功能和抑郁73。
另一个潜在的重要因素是亚甲基四氢叶酸还原酶(MTHFR)基因的作用;特定MTHFR变体的携带者具有异常的叶酸代谢,需要更高的叶酸摄入量以避免叶酸缺乏74。他们也可能从普通叶酸补充剂中获益较少。为了克服这一障碍,一项初步研究在同型半胱氨酸水平高的患者中使用了L-甲基叶酸(叶酸的活性形式)和B12(甲钴胺)补充剂,发现这种治疗可以减少认知能力下降,对轻度认知功能障碍的患者更有效,而非重度认知障碍患者75。
- 甘磷酰胆碱(α-GPC):它是磷脂酰胆碱的半合成衍生物,也是神经递质乙酰胆碱的前体。乙酰胆碱是自主神经系统中的一种主要神经递质,其加速分解可能导致与年龄相关的认知能力下降和痴呆76。事实上,在“超级老年人”(即具有异常年轻认知功能的老年人)的大脑中,已经观察到乙酰胆碱代谢酶(乙酰胆碱酯酶)的浓度降低77。
单独或与乙酰胆碱酯酶抑制剂联合使用的乙酰胆碱前体是治疗痴呆症的一种很有前途的方法76,78。一项随机对照试验在261名轻度至中度阿尔茨海默病患者中比较了每天1200 mg α-GPC、连续180天与安慰剂的效果。接受α-GPC治疗的患者认知功能和行为评估有所改善,而接受安慰剂治疗的患者临床测量没有变化或恶化79。在一项针对50名轻度认知障碍受试者的初步试验中,每天1200 mg α-GPC,持续三个月,可改善认知功能。治疗结束后7至9个月进行的随访评估发现,认知功能仍高于治疗前80。
一项正在进行的随机对照试验的报告显示,乙酰胆碱酯酶抑制剂多奈哌齐加α-GPC联合治疗,在维持阿尔茨海默病和脑血管损伤患者的认知和行为功能方面比多奈哌齐加安慰剂更有效,3年后可减少与进行性痴呆相关的冷漠和动力丧失。该试验的最新报告显示,这两种药物联合治疗可减少阿尔茨海默病相关的行为和情绪障碍81。
- 丝氨酸磷脂:大脑中含有高浓度的磷脂酰丝氨酸,构成细胞膜和髓鞘的一部分。磷脂酰丝氨酸对认知功能的各个方面以及神经系统对运动功能的控制都是必要的。衰老与大脑结构和化学物质的恶化有关,而脑结构和化学成分的恶化可能受到磷脂酰丝氨酸补充的影响82。
使用从牛脑组织中提取的磷脂酰丝氨酸的早期临床试验显示,对老年人的认知有益83;然而,与这种磷脂酰丝氨酸来源有关的安全问题导致其从市场上退出。磷脂酰丝氨酸也可以从大豆中提取。非对照试验表明,每天300mg的大豆磷脂酰丝氨酸可以改善一些有记忆障碍的老年人的认知能力84。
海洋来源的磷脂酰丝氨酸与ω-3脂肪酸EPA和DHA复合物已被证明是安全的,并可能对老年人的认知产生积极影响85。在一项随机对照试验中,157名有主观记忆问题的参与者比较了每天服用300mg海洋磷脂酰丝氨酸和安慰剂的效果。在15周结束时,那些接受丝氨酸磷脂治疗的参与者在短期记忆测试中表现更好,那些基线认知功能最好的参与者身上效果最强86。试验继续了另外15周,所有参与者每天接受100mg丝氨酸磷脂。那些已经服用补充剂的人保持了认知能力的提高,而那些服用安慰剂的人则表现出认知能力改善87。
- 苏糖酸镁:它被发现在提高脑镁水平方面尤其有效88。脑镁水平的升高增强了研究动物的神经可塑性和改善了认知功能89。补充苏糖酸镁已被证明可以防止特定神经递质受体(NMDA受体亚基NR2B)与年龄相关的减少,在衰老和阿尔茨海默病的动物模型中,可抑制炎症信号传导、减少淀粉样斑块的形成,保护神经连接和防止记忆丧失90。其他动物研究表明,苏糖酸镁可能会增强阿尔茨海默病样脑病小鼠的精神和身体刺激活动的认知增强作用91。
- 吡咯喹啉醌(PQQ):一种支持生长和发育的重要化合物,在氧化还原生物化学反应中发挥着关键作用92。临床前研究表明,提高PQQ水平可以改善线粒体数量和功能,减少全身和大脑炎症,延长细胞寿命,防止神经毒素,并可能改善神经和心血管健康93,94。多项研究还表明,PQQ可以防止β-淀粉样蛋白的积累95。此外,已经发现PQQ可以刺激一种名为神经生长因子的蛋白质产生96,促进神经细胞的再生97,并保持实验动物的认知功能98。
研究结果表明,PQQ可以通过增加局部脑血流量和氧气使用来改善认知功能。在一项针对41名健康老年受试者的对照试验中,与安慰剂相比,每天20mg PQQ、持续12周可导致脑血流量增加,认知能力下降较慢。此外,试验开始时认知功能最低的参与者在试验结束时表现出认知功能的一个方面的改善99。另一项研究同样指出,在12周内每天服用20mg PQQ可以增加健康受试者的局部脑血流量和氧气利用率100。
- 辅酶Q10:辅酶q10已证明其神经保护作用可能是通过增强线粒体功能和调节小胶质细胞(介导神经炎症的大脑免疫细胞)介导的101。低血清辅酶Q10与老年人致残性痴呆的风险增加和心力衰竭患者认知功能恶化有关102,103。临床前证据表明辅酶Q10可以减缓神经退行性疾病如亨廷顿、帕金森和阿尔茨海默病患者的认知能力下降104。长期(1至2年)每天摄入100-150mg辅酶Q10泛醇已被证明可以改善日本各年龄段人群的认知表现105。
- 类胡萝卜素:包括叶黄素和玉米黄质、β胡萝卜素、番茄红素和虾青素等。在人类食用的水果和蔬菜中发现了大约50种不同类型的类胡萝卜素,在人体组织和血液中发现了约20种类胡萝卜素106。血清和视网膜中叶黄素和玉米黄质浓度较高与炎症的几种生物标志物以及认知和神经传递测量的改善有关;类胡萝卜素保护细胞免受氧化应激,从而可能通过防止神经元细胞损伤来减缓认知能力下降;类胡萝卜素还被证明可以通过降低细胞因子和其他促炎分子的循环水平来减少炎症信号106。神经成像研究表明,叶黄素和玉米黄质浓度较高的老年人脑白质完整性增加107。
有大量证据支持类胡萝卜素在认知表现中的作用。根据2011-2014年美国国家健康和营养调查(NHANES)结果,在60岁及以上的参与者中,叶黄素和玉米黄质的饮食摄入量越高,在所有学习和记忆测试中的得分越高,这表明叶黄素和玉米黄质可能有助于预防或减缓与年龄相关的认知能力下降108。相反,胡萝卜素摄入量低与老年人认知能力下降的风险增加显著相关109。
另一项观察性研究对7000多名基线年龄至少为45岁的参与者进行了平均16年的随访。基线时血清总叶黄素和玉米黄质浓度与患全因性痴呆的风险降低有关—叶黄素和玉米黄质每增加15.4μg/dL,65岁或以上人群的风险就会降低7%。在两个年龄组(45+和65+)中,基线时血清β-隐黄质每增加8.6μg/dL,患痴呆症的风险就会降低14%110。
此外,血清和视网膜中叶黄素和玉米黄质浓度的升高与视觉空间处理和决策的改善有关。在处理和决策任务期间,功能性核磁共振成像(fMRI)显示,在任务表现更好、叶黄素和玉米黄素水平较高的参与者中,神经效率有所提高111。最后,对近5万名女护士的饮食类胡萝卜素效果进行了评估,2012年至2014年评估的自我报告的主观认知功能与前三十年(1984年至2006年)的饮食类胡萝卜素消耗显著相关。摄入类胡萝卜素最少的护士患认知功能差的风险比摄入最多的护士高33%112。
在一项随机对照试验中,80名65至92岁的成年人接受了12 mg叶黄素和玉米黄质或安慰剂治疗12个月。与低水平的参与者相比,叶黄素和玉米黄质水平较高的参与者大脑皮层的神经元对视觉刺激的反应明显更强,这表明视觉记忆和处理速度得到了改善113。此外,在一项对91名黄斑色素(大脑中类胡萝卜素水平的生物标志物)水平较低的参与者(平均年龄45岁)进行的安慰剂对照试验中,每天补充10mg叶黄素、10mg消旋玉米黄质和2mg玉米黄质持续12个月,显著改善了记忆力114。
- 维生素D:尽管维生素D一般与骨骼和免疫健康有关,但它在中枢神经系统中也发挥着重要作用。影响细胞功能和基因表达的维生素D受体几乎存在于身体的每一个细胞上,包括中枢神经系统的细胞(如神经元、星形胶质细胞和小胶质细胞)。其中一些细胞可以合成生物活性形式的维生素D(1,25-二羟基维生素D),这表明活性形式在中枢神经系统中很重要115。
2022年发表的一项观察性研究评估了1865名平均年龄为52岁受试者的维生素D水平和大脑衰老数据。获得全脑体积、灰质体积和海马体积的结构MRI数据。在本研究中的男性中,维生素D缺乏症(定义为25-羟基维生素D<16.08 ng/mL)与晚期大脑衰老的神经影像学模式显著相关。此外,维生素D水平与大脑总体积和灰质体积呈正相关116。
2023年发表的一项前瞻性队列研究评估了12388名无痴呆症患者的维生素D暴露和痴呆症发生率。与不暴露维生素D相比,暴露于维生素D可显著延长无痴呆症生存期,并使痴呆症发病率降低40%。经年龄、性别、教育、种族、认知诊断、抑郁症和载脂蛋白E4(APOE4)状态调整后,各组的痴呆症发病率仍显著降低117。
在一项随机对照试验中,183名65岁及以上患有轻度认知障碍的参与者每天接受20mcg(800IU)维生素D或安慰剂治疗,为期12个月。结果表明,维生素D组的整体认知功能有了更大的改善,这是通过评估记忆、注意力和处理能力的各种测试来衡量的,且端粒长度增加,与安慰剂组相比,减少了氧化应激118。
- 维生素K2:“维生素K2”是指一组至少15种相关的化合物,称为甲萘醌(MKs)。在甲萘醌中,MK-4和MK-7与年龄相关的认知功能变化有关119。例如,在一项对365名老年参与者进行的研究中,大脑中MK-4浓度越高,患MCI的风险可低达17-20%120。
几项体外和动物模型研究已经调查了甲萘醌支持大脑健康和认知功能的机制。这些研究表明,甲萘醌参与鞘脂(神经细胞膜脂质)的合成,有助于促进细胞信号传导、突触可塑性和髓鞘形成121。甲萘醌还可能有助于保护酪氨酸羟化酶的表达,后者参与多巴胺、去甲肾上腺素和肾上腺素的生产122。MK-4和MK-7已被证明特异性抑制促炎细胞因子的上调,如白细胞介素-6(IL-6)和肿瘤坏死因子-α(TNF-α),并保护免受氧化应激123,124。
在一项研究MK-7对认知衰老影响的临床前研究中,3个月大的大鼠在17个月内服用高剂量维生素K2(MK-7)。它们的认知功能与服用安慰剂的对照大鼠进行了比较。维生素K2的服用改善了记忆力,减少了社交焦虑和抑郁样行为,并减少了炎症,这表明大脑中与年龄相关的变化有所减弱125。
尽管维生素K2水平低与神经退行性疾病(如帕金森病)的进展有关,但需要进行临床研究来检查维生素K2与认知能力下降之间的关系126。
- 芒果叶提取物:已在传统医学实践中用于一般健康和治疗疲劳127。在临床前研究中,芒果叶提取物已被证明具有抗炎和神经保护特性,这些积极作用主要归因于芒果苷(Mangiferin),其所含的一种多酚128。芒果苷似乎是儿茶酚-O-甲基转移酶(COMT)的抑制剂,COMT负责分解神经递质如多巴胺、肾上腺素和去甲肾上腺素127。动物研究表明,芒果苷改善了认知的几个方面,包括空间识别和短期和长期记忆129。
在两项小型、随机、双盲、安慰剂对照的交叉试验中,单次500 mg剂量的芒果叶提取物(标准化为60%芒果苷),与安慰剂相比,反应时间缩短了近5%,与基线相比,疲劳减轻了近50%127。在另一项针对70名健康成年人的RCT交叉临床试验中,与安慰剂相比,单次300mg剂量的相同芒果叶提取物在几个小时内显著提高了表现准确性(2.4%)、情景记忆(2.8%)和视觉信息处理得分128。
- 长春西汀:长春西汀已证明具有神经保护作用,如改变炎症信号、减少氧化应激、改善细胞能量产生、抑制血管壁增厚、扩张脑血管,并可能防止动脉粥样硬化斑块形成130,131。在一项针对26名经历过多次中风的患者的安慰剂对照试验中,在三个月后的一次认知功能测试中,长春西汀防止了认知功能恶化132。其他使用口服长春西汀的研究表明,它能够改善轻度认知障碍和脑血管功能不全患者的认知能力133。注意:怀孕或可能怀孕的妇女不宜服用长春西汀。
- 锂:锂是一种在临床上高剂量用于情绪稳定剂的矿物,主要针对双相情感障碍患者134,135。有些地区的饮用水中天然存在微量锂,在人群研究中,饮用水中锂的含量较高与痴呆和精神疾病的发病率较低有关136。越来越多的临床前证据表明,锂可能通过其预防氧化和炎症神经元损伤、增强神经可塑性、调节蛋白质代谢、控制生理节律和下丘脑-垂体-肾上腺(HPA)轴活性134,137。此外,动物和实验室研究表明,长期低剂量锂治疗可以增加BDNF的神经元产生138。在易患阿尔茨海默病的大鼠中显示出小剂量锂可以减少氧化应激、神经炎症和异常蛋白质积累,以及促进神经元再生和防止记忆丧失139。
对三项临床试验(包括222名受试者)的荟萃分析得出结论,锂疗法可能对轻度认知障碍和阿尔茨海默病患者有益140。由于锂在高剂量下具有巨大的毒性潜力135,微剂量锂疗法尤其有吸引力。在一项试验中,接受每天300mcg微量锂治疗的阿尔茨海默病患者的认知能力下降幅度低于未接受治疗的患者。认知功能的差异在三个月后是显著的,并在15个月的试验过程中逐渐扩大141。临床前研究表明,用于膳食补充剂的锂形式乳清酸锂具有很高的安全性142。
- 可可:含有高浓度的多酚/黄烷醇抗氧化剂。可可及其黄烷醇可以改善血管功能,促进脑血液循环和改善认知功能143。实验研究表明,可可能抑制β-定粉样蛋白的聚集144。此外,可可的咖啡因、儿茶素和其他成分可能有助于其对大脑健康的益处145。黑色巧克力富含可可多酚。
研究了2056名西班牙老年人营养和心血管风险研究参与者的数据,研究人员指出,与不吃黑巧克力相比,前一年每天食用10g(0.35盎司,约1英寸见方)或更多的黑巧克力与更好的认知能力和更低的轻度认知障碍风险有关146。另一项对531名年龄在65岁及以上的受试者进行的研究发现,在大约4年的监测中,巧克力摄入与认知能力下降的风险降低有关,这些受试者咖啡因摄入量低(每天少于75mg,大约相当于一杯180ml咖啡)147。
在一项针对40名健康老年人的随机对照试验中,连续12周每天服用一次提供494mg黄烷醇的可可饮料,可提高血液BDNF水平并改善认知功能148。在一项针对健康老年人的为期三个月的随机对照试验中,高可可饮食改善了区域大脑功能和认知能力149。
- 野燕麦:野生绿燕麦(Avena sativa)的提取物可抑制一种名为单胺氧化酶-B(MAO-B)的酶150。代谢多巴胺的MAO-B活性随着年龄的增长而增加,降低多巴胺水平,可能导致氧化应激和线粒体功能障碍,加速组织老化151。阻断MAO-B有助于使多巴胺水平正常化,并可以减少氧化应激,改善认知和记忆152。野燕麦提取物还能扩张脑血管,抑制磷酸二酯酶-4153,这种作用可以减缓与年龄相关的认知能力下降154。
在健康成年人中,1500 mg野燕麦提取物与安慰剂相比,使动脉血流量增加了40%155。在健康的中年人中,单次800mg野燕麦提取物改善了注意力、延迟回忆、记忆和执行功能测试的表现156。在轻度年龄相关认知问题的患者中,1600mg野燕麦提取物在一项测试中提高了注意力、集中思考和专注能力157。
- 猴头菇:又称狮鬃菇,一种历史悠久的药用菇。其提取物已被证明具有抗炎、降低氧化应激作用,据报道,食用猴头菇与神经保护、促认知、抗衰老和抗抑郁等健康益处有关158。在一项针对30名患有轻度认知障碍的老年人的随机对照试验中,与安慰剂相比,每天服用3000 mg狮鬃菇粉治疗16周可改善认知功能159。在动物研究中,狮鬃菇增强了健康野生型小鼠的神经元功能并改善了记忆能力160。还发现狮鬃菇提取物可刺激神经元生长因子和新神经元的形成,以及在阿尔茨海默病小鼠模型中减少β-淀粉样蛋白斑块和淀粉样蛋白诱导的炎症161。
- 鼠尾草:自古以来就因其药食同源特性而闻名。近年来,鼠尾草增强认知能力而引起关注162。在阿尔茨海默病动物模型中,鼠尾草提取物已显示出抑制乙酰胆碱酯酶活性和防止外周BDNF水平下降的作用,在阿尔茨海默病或轻度认知障碍患者中BDNF往往会减少163,164。鼠尾草的提取物和生物活性化合物被证明具有一些抗炎作用162。
在一项针对轻度至中度阿尔茨海默病患者的安慰剂对照试验中,接受鼠尾草提取物治疗16周的患者在两种不同的认知功能标准化评估中的得分高于接受安慰剂治疗的患者165。在另一项随机安慰剂对照试验中,给20名年龄在65岁及以上的参与者服用剂量范围为167mg至1332mg的标准化鼠尾草提取物。受试者服用了单次剂量,间隔7天的冲洗期。与安慰剂相比,333mg剂量提高了治疗后长达6小时的注意力准确性和某些记忆方面166。在一项针对18-25岁健康年轻人的急性、双盲、安慰剂对照研究中,150mg和300 mg商业鼠尾草提取物与安慰剂相比提高了记忆性能167。
干燥的鼠尾草叶也被证明可以改善健康年轻志愿者的情绪和认知能力。一项系统综述得出结论,鼠尾草制剂可能有助于提高健康受试者和痴呆症患者的认知能力,然而,还需要进一步严格的试验168。
- 南非醉茄:阿育吠陀医学重要的草药之一。它含有抗氧化、抗炎和免疫刺激特性的生物活性化合物169。细胞和动物模型研究表明,南非醉茄提取物和相关化合物通过多种信号通路拯救神经元细胞免受化学损伤和炎症,保护神经元免受阿尔茨海默病、帕金森病和亨廷顿舞蹈症等典型疾病的神经退行性过程的影响170。
在人类研究中,南非醉茄可以改善记忆和认知功能。在一项双盲安慰剂对照研究中,50名成年人被随机分配接受南非醉茄根提取物(300mg,每天两次)或安慰剂治疗八周。南非醉茄与短期和一般记忆、执行功能、持续注意力和信息处理速度的统计学显著改善有关171。此外,在一项针对53名双相情感障碍患者的随机对照试验中,每天补充500mg 南非醉茄提取物可改善听觉-言语工作记忆、反应时间和社会认知172。
在南非醉茄提取物中发现的活性化合物之一是Withanone。大鼠服用Withanone三周后,炎症分子水平显著降低,从而显著提高认知能力。在同一项研究中,Withanone被证明可以抑制β-淀粉样蛋白,一种与阿尔茨海默病发展有关的蛋白质173。
- 孕烯醇酮:一种类固醇激素,在肾上腺、大脑和其他器官中由胆固醇合成。孕烯醇酮既可以自身调节信号通路,也可以进一步代谢形成其他类固醇激素,包括孕酮、醛固酮、皮质醇和睾酮。在大脑中,孕烯醇酮已被证明可以调节NMDA受体介导的神经传递,从而支持学习和记忆174。此外,孕烯醇酮具有抗炎特性175。
在出现学习和记忆挑战的大鼠中,鼻内注射孕烯醇酮可改善学习、长期记忆和对记忆消失的抵抗力176。在一项初步研究中,衰老大鼠的海马和其他大脑区域的孕烯醇酮水平显著降低,记忆问题较少的动物孕烯醇酮浓度较高。注射孕烯醇酮暂时纠正了这些动物的记忆缺陷177。
在人类研究中,大多数关于孕烯醇酮对认知能力下降影响都是在精神疾病的背景下进行的,如精神分裂症和双相情感障碍。在一项针对近期发作的精神分裂症或相关疾病患者的为期8周的随机安慰剂对照试验中,每天50mg口服孕烯醇酮可以显著改善执行功能以及视觉和持续注意力178。另一项针对精神分裂症患者的安慰剂对照研究发现,每天30mg的孕烯醇酮可以改善注意力和工作记忆179。
- 雷公根(积雪草):含有高浓度的几种有益营养物质,包括三萜、类胡萝卜素、维生素B和C、矿物质和其他植物营养素等。其所含的关键活性成分之一是积雪草酸(Asiatic acid),临床前研究表明,它可以预防某些药物引起的认知能力下降,还可以调节神经传递,以及其他有益的认知和神经作用180。许多积雪草制剂被标准化为积雪草苷,积雪草苷在体内代谢为积雪草酸181。
临床前研究表明,雷公根可以降低氧化应激标志物,进而改善神经元健康182。此外,雷公根可以降低大鼠海马和大脑皮层的乙酰胆碱酯酶水平,其降低速度与药物乙酰胆碱酯酶抑制剂多奈哌齐相当183。
在阿尔茨海默病的小鼠模型中,雷公根水提取物显示出以剂量依赖的方式改善记忆。此外,影响信息处理的大脑区域(即海马体和前额叶皮层)的神经密度标志物增加182。在老年小鼠中,雷公根水提取物在测量空间学习和记忆的测试中被证明可以提高表现184。
在一项对28名健康的老年志愿者进行的研究中,连续两个月每天服用250-750mg的雷公根提取物可以改善工作记忆和自我评价的情绪185。在一项随机对照试验的系统回顾和荟萃分析中,与安慰剂相比,积雪草产品并没有显著改善认知功能领域;然而,积雪草确实改善了情绪和警觉性,没有不良事件报告186。
- 碧萝芷:一种法国海松皮提取物,具有强大的抗炎和抗氧化特性,支持认知功能和精神表现。碧萝芷已被证明可以对抗氧化应激、促进持续注意力和改善记忆力187。临床前和临床研究都支持使用碧萝芷进行认知支持188,189。例如,碧萝芷被证明可以减轻帕金森病患者认知障碍的进展190。此外,在阿尔茨海默病的小鼠模型中,补充碧萝芷可以减少β-淀粉样蛋白斑块的数量,并改善记忆的某些方面191。
一项为期12个月的临床试验招募了44名55-70岁的高氧化应激健康受试者,发现每天100 mg碧萝芷似乎可以改善认知功能192。一项为期一周的单独试验涉及30名35-55岁的健康受试人和29名匹配的对照组,发现每天补充150mg碧萝芷可促进认知功能并减少氧化应激193。截至2021年年中,澳大利亚正在进行一项随机对照试验,研究每天150mg碧萝芷在改善60-75岁老年参与者的认知能力和减少认知能力下降方面的疗效194。
- 提升NAD+:NAD+是一种通用的辅因子,在氧化还原生物化学反应中发挥关键作用,通过氧化还原反应转化为还原形式NADH。此外,NAD+似乎参与调节酶,这些酶控制一系列细胞功能,包括基因表达、代谢、DNA修复、细胞凋亡和衰老195,196。
衰老与NAD+产生减少有关,NAD+/NADH比率的降低与线粒体功能障碍和年龄相关的代谢紊乱有关,如认知能力下降和痴呆、糖尿病、肥胖、非酒精性脂肪肝、心血管疾病,以及一些癌症197,198。研究认为,提高NAD+的可用性可能有助于减缓衰老过程和预防与年龄相关的疾病199,200。在一项使用小胶质细胞系的体外研究中,NAD+对炎症、线粒体损伤和活性氧产生具有保护作用。此外,Sirt1过表达模拟了NAD+的保护作用201。
在健康的老年志愿者中,每天250mg或500mg的NAD+前体烟酰胺核糖(NR)安全且剂量依赖性地提高了四周后的血液NAD+水平201。在小鼠中,口服烟酰胺核糖被发现可以增加大脑NAD+水平并改善认知功能202,增强神经可塑性,并减少tau蛋白诱导的神经元损伤203。在血管性痴呆大鼠模型中,腹膜内注射NAD+可通过保护线粒体免受损伤和减少活性氧的产生来改善认知缺陷和抑制神经炎症204。PPAR-γ共激活剂1α(PGC-1α)的基因表达降低,除了其上游转录因子Sirt1外,还被认为是导致这种认知障碍的原因,NAD+给药逆转了这种下降。来自动物研究的进一步证据表明,NAD+疗法可能刺激线粒体活性,保持干细胞的再生潜力,并延长寿命205,206。
目前,NMN(β-烟酰胺单核苷酸,烟酰胺单核苷酸)和烟酰胺核糖苷(NR)是提高NAD+的营养补充剂。
更多的营养和草本,可点击有关的综合干预方案:
- 脑功能管理:
- 脑力支持:
以及参阅本网如下专文的有关内容:
医疗干预
常规药物治疗包括如下:
- 吡拉西坦:可能调节多种神经递质受体的信号转导,并改善神经元膜的流动性。
- 喜得镇(双氢麦角胺):增强脑葡萄糖利用率,增加乙酰胆碱信号。
- 丙炔苯丙胺/司来吉兰:改善认知障碍。
- 氯酯醒:增加乙酰胆碱能突触信号传导,改善健记忆和智力警觉等。
预防
有助于预防大脑衰老的方法主要包括如下:- 健康饮食,如地中海饮食法
- 多吃深海鱼
- 饮食忌过饱
- 适度饮酒
- 不抽烟,或戒烟
- 经常运动锻炼、户外活动
- 参与智力游戏,如下棋等
- 积极加入社会活动、人际交流等。
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参考来源:
美国老年痴呆症协会
http://www.alz.org
美国神经研究学会
http://www.aan.com
美国国立公众健康网
www.medlineplus.gov
加拿大老年痴呆协会
http://www.alzheimer.ca
多伦多痴呆网
http://www.dementiatoronto.org
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