Rutjes Anne Ws, Denton David A, Di Nisio Marcello, Chong Lee-Yee, Abraham Rajesh P, Al-Assaf Aalya S, Anderson John L, Malik Muzaffar A, Vernooij Robin Wm, Martínez Gabriel, Tabet Naji, McCleery Jenny
Centre for Systematic Reviews, Fondazione "Università G. D'Annunzio", Via dei Vestini 31, Chieti, Chieti, Italy, 66100.
Cochrane Database Syst Rev. 2018 Dec 17;12(12):CD011906. doi: 10.1002/14651858.CD011906.pub2.
Vitamins and minerals play multiple functions within the central nervous system which may help to maintain brain health and optimal cognitive functioning. Supplementation of the diet with various vitamins and minerals has been suggested as a means of maintaining cognitive function, or even of preventing dementia, in later life.
To evaluate the effects of vitamin and mineral supplementation on cognitive function in cognitively healthy people aged 40 years or more.
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's (CDCIG) specialised register, as well as MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov and the WHO Portal/ICTRP from inception to 26th January 2018.
We included randomised controlled trials that evaluated the cognitive effects on people aged 40 years or more of any vitamin or mineral supplements taken by mouth for at least three months.
Study selection, data extraction, and quality assessments were done in duplicate. Vitamins were considered broadly in the categories of B vitamins, antioxidant vitamins, and combinations of both. Minerals were considered separately, where possible. If interventions and outcomes were considered sufficiently similar, then data were pooled. In order to separate short-term cognitive effects from possible longer-term effects on the trajectory of cognitive decline, data were pooled for various treatment durations from 3 months to 12 months and up to 10 years or more.
In total, we included 28 studies with more than 83,000 participants. There were some general limitations of the evidence. Most participants were enrolled in studies which were not designed primarily to assess cognition. These studies often had no baseline cognitive assessment and used only brief cognitive assessments at follow-up. Very few studies assessed the incidence of dementia. Most study reports did not mention adverse events or made only very general statements about them. Only 10 studies had a mean follow-up > 5 years. Only two studies had participants whose mean age was < 60 years at baseline. The risk of bias in the included studies was generally low, other than a risk of attrition bias for longer-term outcomes. We considered the certainty of the evidence behind almost all results to be moderate or low.We included 14 studies with 27,882 participants which compared folic acid, vitamin B12, vitamin B6, or a combination of these to placebo. The majority of participants were aged over 60 years and had a history of cardio- or cerebrovascular disease. We found that giving B vitamin supplements to cognitively healthy adults, mainly in their 60s and 70s, probably has little or no effect on global cognitive function at any time point up to 5 years (SMD values from -0.03 to 0.06) and may also have no effect at 5-10 years (SMD -0.01). There were very sparse data on adverse effects or on incidence of cognitive impairment or dementia.We included 8 studies with 47,840 participants in which the active intervention was one or more of the antioxidant vitamins: ß-carotene, vitamin C or vitamin E. Results were mixed. For overall cognitive function, there was low-certainty evidence of benefit associated with ß-carotene after a mean of 18 years of treatment (MD 0.18 TICS points, 95% CI 0.01 to 0.35) and of vitamin C after 5 years to 10 years (MD 0.46 TICS points, 95% CI 0.14 to 0.78), but not at earlier time points. From two studies which reported on dementia incidence, there was low-certainty evidence of no effect of an antioxidant vitamin combination or of vitamin E, either alone or combined with selenium. One of the included studies had been designed to look for effects on the incidence of prostate cancer; it found a statistically significant increase in prostate cancer diagnoses among men taking vitamin E.One trial with 4143 participants compared vitamin D3 (400 IU/day) and calcium supplements to placebo. We found low- to moderate-certainty evidence of no effect of vitamin D3 and calcium supplements at any time-point up to 10 years on overall cognitive function (MD after a mean of 7.8 years -0.1 MMSE points, 95% CI -0.81 to 0.61) or the incidence of dementia (HR 0.94, 95% CI 0.72 to 1.24). A pilot study with 60 participants used a higher dose of vitamin D3 (4000 IU on alternate days) and found preliminary evidence that this dose probably has no effect on cognitive function over six months.We included data from one trial of zinc and copper supplementation with 1072 participants. There was moderate-certainty evidence of little or no effect on overall cognitive function (MD 0.6 MMSE points, 95% CI -0.19 to 1.39) or on the incidence of cognitive impairment after 5 years to 10 years. A second smaller trial provided no usable data, but reported no cognitive effects of six months of supplementation with zinc gluconate.From one study with 3711 participants, there was low-certainty evidence of no effect of approximately five years of selenium supplementation on the incidence of dementia (HR 0.83, 95% CI 0.61 to 1.13).Finally, we included three trials of complex supplements (combinations of B vitamins, antioxidant vitamins, and minerals) with 6306 participants. From the one trial which assessed overall cognitive function, there was low-certainty evidence of little or no effect on the TICS (MD after a mean of 8.5 years 0.12, 95% CI -0.14 to 0.38).
AUTHORS' CONCLUSIONS: We did not find evidence that any vitamin or mineral supplementation strategy for cognitively healthy adults in mid or late life has a meaningful effect on cognitive decline or dementia, although the evidence does not permit definitive conclusions. There were very few data on supplementation starting in midlife (< 60 years); studies designed to assess cognitive outcomes tended to be too short to assess maintenance of cognitive function; longer studies often had other primary outcomes and used cognitive measures which may have lacked sensitivity. The only positive signals of effect came from studies of long-term supplementation with antioxidant vitamins. These may be the most promising for further research.
维生素和矿物质在中枢神经系统中发挥多种功能，可能有助于维持大脑健康和最佳认知功能。有人建议通过在饮食中补充各种维生素和矿物质来维持认知功能，甚至预防晚年痴呆症。
评估补充维生素和矿物质对40岁及以上认知健康人群认知功能的影响。
我们检索了Cochrane痴呆与认知改善小组（CDCIG）的专业注册库ALOIS，以及MEDLINE、Embase、PsycINFO、CINAHL、ClinicalTrials.gov和世界卫生组织门户网站/国际临床试验注册平台（ICTRP），检索时间从各数据库建库至2018年1月26日。
我们纳入了随机对照试验，这些试验评估了口服任何维生素或矿物质补充剂至少三个月对40岁及以上人群认知功能的影响。
研究选择、数据提取和质量评估均由两人独立进行。维生素大致分为B族维生素、抗氧化维生素以及两者的组合。矿物质尽可能单独考虑。如果干预措施和结果被认为足够相似，则合并数据。为了区分短期认知效应与对认知衰退轨迹可能的长期效应，我们合并了3个月至12个月以及长达10年或更长时间的不同治疗时长的数据。
我们总共纳入了28项研究，参与者超过83,000人。证据存在一些普遍局限性。大多数参与者参与的研究并非主要为评估认知而设计。这些研究通常没有基线认知评估，仅在随访时使用简短的认知评估。很少有研究评估痴呆症的发病率。大多数研究报告未提及不良事件，或仅对其进行了非常笼统的说明。只有10项研究的平均随访时间>5年。只有两项研究的参与者基线平均年龄<60岁。纳入研究中的偏倚风险总体较低，但长期结果存在失访偏倚风险。我们认为几乎所有结果背后证据的确定性为中等或低等。我们纳入了14项研究，共27,882名参与者，这些研究比较了叶酸、维生素B12、维生素B6或它们的组合与安慰剂。大多数参与者年龄超过60岁，有心血管或脑血管疾病史。我们发现，给主要为60多岁和70多岁的认知健康成年人补充B族维生素，在长达5年的任何时间点对整体认知功能可能几乎没有影响（标准化均数差值[SMD]值为-0.03至0.06），在5至10年时可能也没有影响（SMD -0.01）。关于不良反应或认知障碍或痴呆症发病率的数据非常稀少。我们纳入了8项研究，共47,840名参与者，其中积极干预措施为一种或多种抗氧化维生素：β-胡萝卜素、维生素C或维生素E。结果不一。对于总体认知功能，有低确定性证据表明，治疗18年后补充β-胡萝卜素有益（平均差[MD]为0.18个TICS评分点，95%置信区间[CI]为0.01至0.35），5至10年后补充维生素C有益（MD为0.46个TICS评分点，95%CI为0.14至0.78），但在更早时间点没有益处。从两项报告痴呆症发病率的研究来看，有低确定性证据表明，抗氧化维生素组合或维生素E单独使用或与硒联合使用均无效果。其中一项纳入研究旨在寻找对前列腺癌发病率的影响；该研究发现服用维生素E的男性前列腺癌诊断有统计学显著增加。一项有4143名参与者的试验比较了维生素D3（400国际单位/天）和钙补充剂与安慰剂。我们发现，有低至中等确定性证据表明，在长达10年的任何时间点，维生素D3和钙补充剂对总体认知功能（平均7.8年后的MD为-0.1个简易精神状态检查表[MMSE]评分点；95%CI为-0.81至0.61）或痴呆症发病率（风险比[HR]为0.94；95%CI为0.72至1.24）没有影响。一项有60名参与者的试点研究使用了更高剂量的维生素D3（隔日4000国际单位），并发现初步证据表明该剂量在六个月内可能对认知功能没有影响。我们纳入了一项锌和铜补充剂试验的数据，共1072名参与者。有中等确定性证据表明，在5至10年后，对总体认知功能（MD为0.6个MMSE评分点；95%CI为-0.19至1.39）或认知障碍发病率几乎没有影响。另一项较小的试验没有提供可用数据，但报告称补充葡萄糖酸锌六个月没有认知方面的影响。从一项有3711名参与者的研究来看，有低确定性证据表明，补充约五年的硒对痴呆症发病率没有影响（HR为0.83；95%CI为0.61至1.13）。最后，我们纳入了三项复合补充剂（B族维生素、抗氧化维生素和矿物质的组合）试验，共6306名参与者。从一项评估总体认知功能的试验来看，有低确定性证据表明，对TICS几乎没有影响（平均8.5年后的MD为0.12；95%CI为-0.14至0.38）。
我们没有发现证据表明，中年或老年认知健康成年人的任何维生素或矿物质补充策略对认知衰退或痴呆症有有意义的影响，尽管证据不允许得出明确结论。关于中年（<60岁）开始补充的数据非常少；旨在评估认知结果的研究往往太短，无法评估认知功能的维持情况；较长时间的研究通常有其他主要结果，并使用可能缺乏敏感性的认知测量方法。唯一的积极效应信号来自抗氧化维生素长期补充的研究。这些可能是最有希望进行进一步研究的。
