Zinc intake, status and indices of cognitive function in adults and children: a systematic review and meta-analysis

Abstract

In developing countries, deficiencies of micronutrients are thought to have a major impact on child development; however, a consensus on the specific relationship between dietary zinc intake and cognitive function remains elusive. The aim of this systematic review was to examine the relationship between zinc intake, status and indices of cognitive function in children and adults. A systematic literature search was conducted using EMBASE, MEDLINE and Cochrane Library databases from inception to March 2014. Included studies were those that supplied zinc as supplements or measured dietary zinc intake. A meta-analysis of the extracted data was performed where sufficient data were available. Of all of the potentially relevant papers, 18 studies met the inclusion criteria, 12 of which were randomised controlled trials (RCTs; 11 in children and 1 in adults) and 6 were observational studies (2 in children and 4 in adults). Nine of the 18 studies reported a positive association between zinc intake or status with one or more measure of cognitive function. Meta-analysis of data from the adult’s studies was not possible because of limited number of studies. A meta-analysis of data from the six RCTs conducted in children revealed that there was no significant overall effect of zinc intake on any indices of cognitive function: intelligence, standard mean difference of <0.001 (95% confidence interval (CI) –0.12, 0.13) P=0.95; executive function, standard mean difference of 0.08 (95% CI, –0.06, 022) P=0.26; and motor skills standard mean difference of 0.11 (95% CI –0.17, 0.39) P=0.43. Heterogeneity in the study designs was a major limitation, hence only a small number (n=6) of studies could be included in the meta-analyses. Meta-analysis failed to show a significant effect of zinc supplementation on cognitive functioning in children though, taken as a whole, there were some small indicators of improvement on aspects of executive function and motor development following supplementation but high-quality RCTs are necessary to investigate this further.

Introduction

Brain growth and development are critically dependent on several micronutrients.1, 2, 3 Zinc is a key modulator of intracellular and intercellular neuronal signalling4 that is found in high levels in the brain particularly the hippocampus, considered as the area involved in learning and memory,5, 6, 7 and in the amygdala, striatum and neocortex.7, 8, 9 Zinc is essential for the activity of a large number of metalloenzymes, cellular functions including RNA and DNA synthesis,10 cellular growth, differentiation and metabolism. During early development, cellular activity may be particularly sensitive to zinc deficiency, which has been shown to compromise cognitive development.11, 12 Experimental studies in animals have shown that, during the early stages of brain development, deficiency of zinc caused brain defects,13 reducing the cerebellum size14 and altering zinc homeostasis,15 whereas zinc deficiency during the latter stages of brain development impaired function.16 Zinc-deficient rats experienced diminished learning and some working memory deficit17, 18, 19, 20 and pups whose dams have suffered prenatal zinc deficiency tend to be more aggressive than pups whose dams suffered prenatal undernutrition.21 Evidence in humans, however, is less clear and the exact role of zinc on brain function and cognitive development remain poorly understood.11, 22, 23, 24, 25

It has been estimated that 20% of the world population are zinc deficient26 and countries with a prevalence of poor dietary zinc intake of >25% are considered at high risk of zinc deficiency.27 Zinc deficiency occurs in individuals and populations whose diets are low in sources of readily bioavailable zinc (such as red meat and seafood) and high in unrefined cereals (rich in phytate and dietary fibre).28, 29, 30 These dietary patterns are characteristics that are common in many developing countries where zinc deficiency has a major impact on child development.12, 31, 32 The precise role of zinc in cognitive function is still unclear, however, zinc is present in relatively high concentrations in the hippocampal and neocortical regions of the brain. Much of the evidence for the role of zinc in the function of the central nervous system has come from animal studies, which have shown that zinc deficiency results in reduced activity, poor memory and attention,33 also in offspring rats, zinc deficiency during the last trimester of pregnancy and during lactation impaired spatial learning and memory and had a negative effect on motor activity.18 Although studies in humans, the observational studies have suggested a relationship between zinc deficiency and poor cognition, but the evidence from randomised controlled trials (RCTs) during infancy, pregnancy and lactation has shown little effect.34 The essential role of zinc in the central nervous systems is marked during brain growth, particularly between 24 and 40 weeks after conception,3 which is the period where the brain goes through extraordinary structural changes, and it is during this critical time that the brain is most sensitive of zinc deficiency and its deficiency will affect the involvement of zinc in various enzymes and neurochemical processes such as synaptic transmission and the release of neurotransmitters.35

The specific question we sought to address in this systematic review was 'what is the evidence for an association between zinc intake, through diet or supplement, zinc status (plasma zinc concentration), and indices of cognitive function in adults and children?'. A narrative review is presented in this article, along with a meta-analysis of the data was undertaken where studies were sufficiently homogenous in terms of their design and the outcomes measured. This review was part of a wider systematic review process to identify studies assessing the relationships between zinc intake, status and various health outcomes in health populations within the EURRECA (European Micronutrient Recommendations Aligned) framework.36

Materials and methods

Search strategy

The databases Ovid MEDLINE, Ovid Embase and the Cochrane Library were used to search for relevant papers from inception, initially to February 2010, and then updated to March 2014. Both indexing and text terms were used and languages included were restricted to those spoken in the EURRECA network (English, Dutch, French, German, Hungarian, Italian, Norwegian, Polish, Spanish, Greek or Serbian).

The search and paper selection procedures were conducted according to EURRECA protocols.37, 38 The full Ovid MEDLINE search strategy can be found in Table 1. Reference lists of retrieved articles and published literature reviews were also checked for relevant studies. Authors were contacted to request missing data or clarify methods or results, some replied to our request and data values were used in the analysis, if no reply from the author, the study was excluded or additional conversion of data was performed, for example, transforming interquartile ranges (IQRs) to s.d. The search process is illustrated in Figure 1. It should be noted that these search strategies were part of the wider zinc systematic review that investigated a range of intake–status–health relationships, which refers to the study of the relationship between zinc intake and status, zinc intake and health, and zinc status and health outcomes that were considered within EURRECA.39 The search was therefore intentionally broad in order to capture a range of health outcomes, which is the reason for the high number of identified studies and the relatively low proportion of relevant cognitive studies. The updated search followed the same search strategy. Details of the search, selection, data extraction and statistical methods developed and used by the EURRECA consortium can be access at www.eurreca.org.

Table 1 Search strategy: EMBASE, MEDLINE March 2014
Figure 1
figure1

Study selection process for the systematic review.

Inclusion/exclusion criteria

The titles and abstracts were screened and sorted on the basis of predefined inclusion criteria: relevant to the research question, human study, zinc intake–plasma/serum zinc status–cognition relationship, reviews, RCTs, cohort studies, cohort nested case–control studies and cross-sectional studies. Included studies were those conducted in apparently healthy human populations that supplied zinc supplementation either as zinc gluconate, zinc sulphate, zinc acetate, zinc picolinate or zinc oxide or measured dietary zinc intake with either a validated food frequency questionnaire, a dietary history method, a 24-h recall method for at least 3 days or a food record/diary for at least 3 days (observational studies), which are established best practise methods.36, 40 For studies to be included in this review, both zinc intake/status measurement had to occur either in adults or children. Thus, intervention and observational studies reporting zinc intake/status and cognitive domains in adults and children were included. Studies were excluded if they were non-RCT, a group RCT (community trial), case–control studies, or uncontrolled trials (an intervention without a control group) or were commentaries, reviews or duplicate publications from the same study. Of all studies included in the strategic review, only those RCTs in children reporting sufficient data on zinc intake/status and cognitive domains were included in the subsequent meta-analysis.

This review focused on studies conducted in children (aged 1 to <18 years), and adults (≥ 18 years). Studies relating to infants (aged 0–12 months) were excluded from this review because the systematic review and meta-analyses in infants were conducted by the research team at ULPGC and reported elsewhere.41

Data extraction

For each of the studies, data were extracted independently by two reviewers and input into a standardised database. Extracted data included population characteristics, dose of zinc in intervention studies, duration of the study, dietary intake of zinc, mean concentration of zinc in plasma or serum for observational studies and measures of cognitive function. Unit conversions to μmol/l were performed for the observational studies, which reported μg/dl for serum/plasma zinc concentrations. Variances that were provided as IQRs were converted to s.d., using the following formula: s.d.=IQR/1.35 where IQR=75th percentile–25th percentile. The characteristics of these studies are presented in Tables 2a and 2b. A database of the references found in the systematic search can be found on the EURRECA website.42

Table 2a Characteristics of identified studies assessing zinc intake/status and cognitive function. Randomised controlled trials (n=12) reporting the effect of dietary zinc intake/serum or plasma zinc status on cognitive function in adults and children
Table 2b Characteristics of identified studies assessing zinc intake/status and cognitive function. Observational studies (n=6) reporting the effect of dietary zinc intake/serum or plasma zinc status on cognitive function

Assessment of risk of bias in included studies

The criteria for assessing risk of bias of the included RCTs were adapted from the Cochrane Handbook for Systematic Reviews.43 Studies were not included or excluded on the basis of their quality assessment. Rather the assessment of study quality provides a context for interpreting the reported effect sizes. The criteria for the RCTs and observational studies are presented in Tables 4a and 4b, respectively. Based on these indicators, two reviewers decided on the overall risk of bias. Disagreements were resolved by discussion.

Meta-analysis

Meta-analysis of data extracted from six RCTs conducted in children was undertaken using Review Manager (v5.2, Copenhagen, Denmark). RCT studies that were included for meta-analysis were those which measured one of the following cognitive domains: intelligence, executive function and motor development. These outcomes are described in Table 3 with corresponding studies, the test used and the function assessed. All data input for meta-analysis were cross-checked (NML and VHM). All RCTs were grouped per population. Of the RCTs in children, those that measured the same cognitive outcome were subgrouped, and those which provided sufficient outcome data (mean and s.d.) were included in the meta-analysis. Owing to the different scales used by the cognitive tests, the standardised mean difference was used in the random effects meta-analysis. For the quantification of heterogeneity between studies the (I)2 value was used.44 Studies were also sorted by effect size, defined as the measurement of the magnitude of the phenomenon.45 The limited data available from observational studies meant that it was not possible to combine these studies in a meta-analysis.

Table 3 Categorisation of cognitive function tests

Results

Selection of articles

A diagram illustrating results of the systematic search and selection process is presented in Figure 1. A total of 5635 articles were identified as potentially relevant for inclusion in the wider search on zinc intake, status and health outcomes in all populations. Of these, 3447 were excluded based upon screening abstracts. Two independent reviewers screened 10% of the abstracts in duplicate and any discrepancies were discussed before screening the remaining references. A further update to the search in March 2014 found 13 further relevant articles. The full texts of the remaining 2188 manuscripts were assessed to determine inclusion and exclusion by two independent reviewers and disagreements rectified through discussion. A total of 1640 studies were excluded because they did not meet the inclusion criteria. In all, 174 studies relating to zinc intake–status relationships have been reported elsewhere,46, 47, 48 and 356 infants studies were also passed to another team within the EURRECA network for a separate review.49 The final selection included 12 RCTs (11 in children) and 6 observational studies, all of which were published between 1985 and 2009.

Reasons for exclusion

A total of 3447 abstracts were excluded, for the following reasons: no zinc data, no baseline data, no measurement of the relationship of zinc intake/status with cognition, ineligible study design, ineligible dietary zinc measurement (that is, neither validated food frequency questionnaire, dietary history method nor a 24-h recall for at least 3 days), or ineligible biomarker of zinc (that is, neither plasma/serum, urine nor hair zinc concentrations). For the purpose of this review, studies with infant were not included (n=356) as this has been reported elsewhere.41 A further 1814 studies were excluded because they did not assess cognitive function outcomes or they provided insufficient data to be considered for a comparative analysis, were not conducted on healthy participants, provided zinc as a multi-micronutrient supplement or were published in a language outside the scope of this study.

Studies included

A total of 18 studies that reported zinc intake or plasma/serum zinc and its association with cognitive function met the inclusion criteria. Twelve were RCTs and six were observational studies. A summary of the key characteristics of these studies are given in Tables 2a and 2b. Studies were conducted in Europe (n=3), North America (n=3), Asia (n=8), Africa (n=2), Central America (n=1) and South America (n=1) and age of participants ranged from 23 to 94 years for adults (including pregnant women), and 3–16 years for children. In the majority of studies included in this article, children were under 10 years old; only two studies included older children.50, 51

Adults and pregnant women

A small number of studies included in this review (5 of 18) addressed the relationship between zinc intake and/or status on cognitive function in adults, four of which were observational cross-sectional studies52, 53, 54, 55 and one was an RCT.56 The search identified only one observational study conducted in pregnant women.55 Meta-analyses of adults or pregnant women could not be performed because of the variability in the presentation of the data and the lack of comparable studies.

Children

Eleven RCTs51, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 and two observational studies50, 67 were conducted with children. In five studies, supplements were given before cognitive testing; either prenatally to pregnant women between 10 and 19 weeks of gestation with children assessed for cognitive skills at age 4–9 years60, 61, 65 or postnatal supplementation for up to 2 years (4–35 months old), with cognitive skills assessed in a follow-up at age 7- to 9-year old57 or mean age of 9.3-year old.58 For these studies, supplements were given in the form of a caplet,60 tablet57, 61, 65 or in a form of syrup.58 The remaining six RCT studies assessed cognitive function immediately after supplementation51, 59, 62, 63, 64, 66 in children aged on average 81.5 months66 and 7.6-year old59 and age ranging from 5- to 7-year old,64 6- to 9-year old62, 63 and 10- to 16-year old.51 Participants were given zinc supplements, either in the form of a zinc sulphate solution64 as a tablet51, 62, 63, 66 or as a meat supplement.59 The two observational studies compared plasma zinc concentrations with cognitive function in children aged 3- to 5-year67 and 6- to 11-year old.50

Indices of cognitive function

The indices of cognitive development and function used in the studies included in this review are summarised in Table 3. They included measures of motor skills, executive function (memory, attention, language and global cognitive function) and intelligence. Of the 18 studies described in Tables 2a and 2b, nine reported a positive association between zinc intake or status with one or more measure of cognitive function.50, 51, 53, 55, 56, 59, 62, 63, 67 Negative associations or no significant effect were reported for the remaining nine studies.52, 54, 57, 58, 60, 61, 64, 65, 66

Meta-analysis of data from studies with children

A random effects model was used to investigate the impact of zinc intake on indices of cognitive function including intelligence (six data sets from five publications),57, 58, 61, 65, 66 executive function (six data sets from four publications)57, 61, 64, 65 and motor development (four data sets from three publications).57, 61, 65

The analysis yielded a pooled standard mean difference for the impact of zinc supplementation on intelligence of <0.001 (95% confidence interval (CI) −0.12, 0.13) P=0.95; executive function, 0.08 (95% CI, −0.06, 022) P=0.26 and motor skills, 0.11 (95% CI −0.17, 0.39) P=0.43. These results revealed no significant overall effect of zinc supplementation on these cognitive function domains (Figures 2a–c respectively). Stratifying the data by subgroups based on whether the child was given the supplements or given prenatally to the mother, revealed that maternal supplementation during pregnancy did not have a significant impact on these cognitive domains in children assessed during childhood. For trials in which the supplements were given directly to the child, there was a significant effect of supplementation on executive function (mean difference=0.21, 95% CI 0.06, 0.36, P=0.006) and motor skills (mean difference=0.34, 95% CI 0.19, 0.50, P<0.0001; Figures 2b and c). However, this must be interpreted with caution because of the limited number of data sets contributing to these analyses, two of which come from the same study.57

Figure 2
figure2figure2

Forest plots of RCTs of intelligence, executive function and motor outcome in children. (a) The effect of zinc supplementation on intelligence in children. (b) The effect of zinc supplementation on executive function in children. (c) The effect of zinc supplementation on motor outcome in children.

Risk of bias

The risk of bias for each study identified was assessed. Twelve RCTs studies were assessed and a high risk of bias was found for most of the studies, except for three,57, 58, 60 which had moderate-to-low risk of bias (Table 4a). Six observational studies were assessed, and a moderate risk of bias was found for most of the studies, except for two,50, 67 which had high risk of bias and one,55 which had low risk of bias (Table 4b). The sources of bias included inadequate information about sources of funding, unclear adequacy of sequence generation (randomisation procedure) and inadequate blinding.

Table 4a Assessment of risk of bias of included randomised controlled trials reporting zinc intake and serum/plasma zinc in children and adults (adapted from the Cochrane handbook)
Table 4b Assessment of risk of bias of included observational studies reporting zinc intake and serum/plasma zinc in children and adults (adapted from the Cochrane handbook)

Discussion

The purpose of this review was to present the evidence for the relationship between zinc intake and/or zinc status (plasma/serum zinc concentration), and indices of cognitive function in adults (18 years) and children (aged 1 to <18 years). This review differs from other reviews in that it includes both intervention and observational studies that investigated the association between zinc intake, through diet or supplement, zinc status (plasma/serum zinc concentration), and indices of cognitive function in adults and children and a short meta-analyses of studies in the child group.

Narrative overview

Adult and pregnant women

Of the five studies identified,52, 53, 54, 55, 56 three suggested a positive association between zinc intake and measures of cognitive function.53, 55, 56 Ortega et al.53 indicated a small but significant correlation (r=0.135, P<0.05), between increased zinc intake and mini-mental state examination test. Stoecker et al.55 reported a positive correlation between plasma zinc concentration and Raven’s coloured progressive matrices test scores, a test of non-verbal intelligence, in women in their third trimester of pregnancy (r=0.27, P<0.008). Results revealed a weak, positive association between the test score and plasma zinc concentration. The study by Maylor et al.56 indicated both a positive significant effect of zinc supplementation on memory (P=0.030) and a negative significant effect on indices of attention (matching to sample visual search; P=−0.015). Two studies examined the association between plasma zinc concentration and cognitive score.52, 54 One of these revealed that lower plasma zinc was significantly correlated with poor cognitive performance in women (P=0.008) but not in men,52 whereas the other study54 failed to find any association in men or women.

Children—executive function

The studies included in this review reported contrasting outcomes of the relationship between zinc intake/status on indices of executive function, including attention, inhibitory control, memory and language. Gibson et al.64 reported that zinc supplementation had no significant effect on attention span in boys aged 5−7 years, which was consistent to the findings reported by Tamura et al.65 in a group of girls and boys of a similar age. In contrast, a positive association was reported between zinc intake and the digit span scores test, which measures verbal working memory ability, in children59 and adolescent girls.51 In the studies where the supplements were given prenatally, no effect was reported on working memory or inhibitory control57, 60 or language development.61

Children—intelligence

Intelligence was measured using a variety of tests detailed in Table 3. Cavan et al.66 reported that zinc supplementation in children had no significant effect on the total cognitive score of the Detroit tests of learning aptitude, which tests general mental abilities,68 although children did responded to zinc supplementation with significant changes in cognitive scores.66 This concurs with the results of the study by Gewa et al.59 conducted in children in Kenya in which children’s diets were supplemented with meat in order to increase their overall zinc intake. After 2 years, there were no significant differences in Raven test scores between the children consuming additional meat, compared with those consuming the control diets. Furthermore, prenatal zinc supplementation did not have a significant effect on any indices of intelligence measured in children aged 4–9 years.60, 61, 65

A follow-up study in which zinc supplements were given to children from 12 to 35 months, indicated that there were significant improvements in intellectual function scores in the zinc supplemented group compared with the placebo control group when children were followed up at 7–9 years of age. However, when adjustments were made for co-variants, the difference was not significant.57 A study of similar design also reported no long-term effects of zinc supplementation given from 4 to 6 months, on indices of intelligence at age 9.3 s.d. (0.3) years.58

Children—motor skills

Penland et al.62 undertook a study in Chinese children of the impact of 10 weeks supplementation with zinc alone or zinc plus miconutrients or micronutrients alone, on indices of motor function. The test used was the cognition-psychomotor assessment-revised (CPAS-R) battery, which revealed that zinc, and zinc with micronutrients, significantly improved performance in all subtests of the CPAS-R battery. In addition, Sandstead et al.63 showed that zinc plus micronutrients significantly improved neuropsychologic performance including the tasks of tapping, circular tracking (motor) and oddity (concept formation) compared with micronutrients or zinc alone. Hubbs-Tait et al.67 reported a negative association between plasma zinc concentration and motor scores from the motor subset within the McCarthy scales of children’s ability test. Prenatal zinc supplementation did not have a significant effect on motor score in a follow-up study of children aged 5.3 (s.d. 0.3) year.65

Meta-analysis

One of the challenges researchers encounter when comparing studies in this field is the broad variety of study designs and outcome measures used. For the meta-analysis part of this review, only RCTs conducted in children were included, with outcome measures clustered into three main cognitive domains: intelligence, executive function and motor outcome. Reasons for excluding studies from meta-analyses included: only percentage change in measurements reported,51 lack of control group,62, 63 test scores reported as differences rather than the mean and s.d. data for both intervention and placebo group to enable analytical comparison.59

Results from the meta-analyses of the impact of zinc supplementation on cognitive domains in children indicated that supplements given prenatally did not have a long-term impact on offspring during childhood but supplements given directly to children may have a positive impact on executive function and motor skills. Despite the small number of studies that were eligible for the meta-analysis, it could be argued that the usefulness of this meta-analysis lies in the analyses per cognitive domain and in the categorisation of prenatal supplementation and supplements given to children that add an insight into the effect of zinc supplementation in both situations. Irrespective of the instrument used (UNIT, WISC), it was considered a logical process to combine studies that measured intelligence and similarly this was done for executive function and motor outcome. Well-designed RCT studies,69 which follow standardised measurement techniques to facilitate direct comparison of outcome data with other studies, are required to measure zinc intake and/or status and cognitive function relationships

Comparisons with findings from other studies

The narrative review in this article highlights the limited number of studies looking at the association between zinc intake/status and cognitive function, particularly in the adult and children populations. The main findings of this review are the evaluation of the range of cognitive aspects that were assessed in the included studies in the narrative review (memory, attention, cognitive score, performance, motor skills, intelligence, language and inhibitory response) and its association with zinc intake and/or plasma zinc status, where 9 studies out of 18 reported a positive association. In addition, evidence from the six RCTs conducted in children that examined the effect of zinc supplementation either pre or post-nataly, revealed that the overall pooled standard mean difference of the impact of zinc supplementation on intelligence, executive function and motor outcome was not significant. The strength of this systematic review is in the unique methodology of the defined criteria of identifying zinc intake, biomarker of zinc status and the health outcome cognitive function identified, following a thorough systematic review process following EURRECA best practises and guidelines.

Recent reviews of children and zinc supplementation for mental and motor development have found no convincing evidence that zinc supplementation has a beneficial effect on motor or mental development. A recent Cochrane review70 used a different meta-analytical approach to the one used in the present review, including both infants and children together, and reported no effect of zinc on intelligence, executive function or motor development in children from birth up to 5 years of age. This review, however, focussed on neonates, infants and toddlers up to 5 years of age, rather than older children.70 Similarly, Brown et al.71 conducted a review on zinc supplementation of children up to 30 months of age and reported no significant overall impact on mental and motor development.

Other reviews have examined the effect of multi-micronutrient supplementation on cognition rather than zinc alone.72, 73 Best et al.72 concluded that four of six included studies reported a significant (P<0.05) beneficial effect of multi-micronutrient food fortification on memory and Eilander et al.73 reported a significant overall effect of micronutrient supplementation on academic performance (P=0.044), but not for crystallised intelligence (the acquiring of knowledge and learning that considers short-term memory, visual perception, retrieval ability, cognitive processing speed and sustained attention).73 A recent review by Nyaradi et al.74 examined the role of nutrition on children’s neurocognitive development from pregnancy through childhood and reported that evidence from observational studies suggests that multiple micronutrients may have an important role in children’s cognitive development, with the results of intervention trials using single micronutrients remaining inconclusive. It is difficult to determine a specific effect of zinc intake or status on indices of cognition, partly because of the methodological challenges of assessing long-term cognition effects, but also because the identification of 'at risk populations' (identified vulnerable population exposed to zinc deficiency) seems to be a key factor in disentangling the impact of supplementation on cognitive outcomes.75

The major limitation in the interpretation of the meta-analysis is the paucity of data that could be included because of the difference of the study design and the type of cognitive test administered per cognitive domain. In addition, many of the studies included in our meta-analysis were assessed as having moderate-to-high risk of bias, which may have impacted on the reported pooled effect sizes. Limits on the number of studies eligible for meta-analysis, however, meant that we were unable to restrict meta-analyses to studies at low (or lower) risk of bias, or to stratify studies according to risk of bias. Furthermore, a reliable and specific biomarker of zinc status has not yet been identified.76 However, our previously published systematic review of biomarkers of zinc status have confirmed that, in healthy individuals, plasma zinc concentration does respond to changes in dietary intake.77 All the studies included in this review were conducted in healthy individuals, therefore we are confident that plasma zinc concentration (although not perfect) is a reasonable biomarker for zinc status, and is widely used as such in the studies reported in this review despite poor sensitivity and specificity.78, 79

Conclusions

Although some studies report a positive effect of zinc intake/status on cognitive function,50, 51, 53, 55, 56, 59, 62, 63, 67 others reported mixed results.52, 54, 57, 58, 60, 61, 64, 65, 66 Therefore, to date, the evidence regarding the effect of zinc intake or status on cognitive function is lacking and inconsistent. Therefore, although the meta-analysis of a subset of the studies conducted in children showed no significant overall effect of zinc supplementation on any of the identified cognitive domains, a positive effect of zinc supplementation on cognitive function cannot be ruled out. However, there remains a paucity of well-designed carefully controlled long-term trials investigating the relationship between zinc intake, status and cognitive function in humans. Studies should be reported in a consistent and standardised manner or in comparable units of measurement to facilitate future comparisons and more readily contribute to the body of scientific evidence.

References

  1. 1

    Huskisson E, Maggini S, Ruf M . The influence of micronutrients on cognitive function and performance. J Int Med Res 2007; 35: 1–19.

    CAS  Article  Google Scholar 

  2. 2

    Dauncey MJ . New insights into nutrition and cognitive neuroscience. Proc Nutr Soc 2009; 68: 408–415.

    CAS  Article  Google Scholar 

  3. 3

    Georgieff MK . Nutrition and the developing brain: nutrient priorities and measurement. Am J Clin Nutr 2007; 85: 614S–620S.

    CAS  PubMed  Google Scholar 

  4. 4

    Sensi SL, Paoletti P, Koh JY, Aizenman E, Bush AI, Hershfinkel M . The neurophysiology and pathology of brain zinc. J Neurosci 2011; 31: 16076–16085.

    CAS  Article  Google Scholar 

  5. 5

    Black MM . Zinc deficiency and child development. Am J Clin Nutr 1998; 68: 464–469.

    Article  Google Scholar 

  6. 6

    Levenson CW . Regulation of the NMDA receptor: implications for neuropsychological development. Nutr Rev 2006; 64: 428–432.

    Article  Google Scholar 

  7. 7

    Takeda A . Movement of zinc and its functional significance in the brain. Brain Res Rev 2000; 34: 137–148.

    CAS  Article  Google Scholar 

  8. 8

    Flinn JM, Hunter D, Linkous DH, Lanzirotti A, Smith LN, Brightwell J et al. Enhanced zinc consumption causes memory deficits and increased brain levels of zinc. Physiol Behav 2005; 83: 793–803.

    CAS  Article  Google Scholar 

  9. 9

    Bitanihirwe BKY, Cunningham MG . Zinc: the brain's dark horse. Synapse 2009; 63: 1029–1049.

    CAS  Article  Google Scholar 

  10. 10

    Terhune MW, Sandstead HH . Decreased RNA polymerase activity in mammalian zinc deficiency. Science 1972; 177: 68–69.

    CAS  Article  Google Scholar 

  11. 11

    Black MM . The evidence linking zinc deficiency with children's cognitive and motor functioning. J Nutr 2003; 133: 1473S–1476S.

    CAS  Article  Google Scholar 

  12. 12

    Black MM . Micronutrient deficiencies and cognitive functioning. J Nutr 2003; 133: 3927S–3931S.

    CAS  Article  Google Scholar 

  13. 13

    Hurley LS, Swenert'on H . Congenital malformations resulting from zinc deficiency in rats. Exp Biol Med 1966; 123: 692–696.

    CAS  Article  Google Scholar 

  14. 14

    Dvergsten CL, Fosmire GJ, Ollerich DA, Sandstead HH . Alterations in the postnatal development of the cerebellar cortex due to zinc deficiency. I. Impaired acquisition of granule cells. Brain Res 1983; 271: 217–226.

    CAS  Article  Google Scholar 

  15. 15

    Takeda A . Zinc homeostasis and functions of zinc in the brain. Biometals 2001; 14: 343–351.

    CAS  Article  Google Scholar 

  16. 16

    Sandstead HH, Frederickson CJ, Penland JG . History of zinc as related to brain function. J Nutr 2000; 130: 496.

    Article  Google Scholar 

  17. 17

    Massaro TF, Mohs M, Fosmire G . Effects of moderate zinc deficiency on cognitive performance in young adult rats. Physiol Behav 1982; 29: 117–121.

    CAS  Article  Google Scholar 

  18. 18

    Boroujeni ST, Naghdi N, Shahbazi M, Farrokhi A, Bagherzadeh F, Kazemnejad A et al. The effect of severe zinc deficiency and zinc supplement on spatial learning and memory. Biol Trace Elem Res 2009; 130: 48–61.

    Article  Google Scholar 

  19. 19

    Halas E, Eberhardt M, Diers M, Sandstead H . Learning and memory impairment in adult rats due to severe zinc deficiency during lactation. Physiol Behav 1983; 30: 371–381.

    CAS  Article  Google Scholar 

  20. 20

    Takeda A, Tamano H, Tochigi M, Oku N . Zinc homeostasis in the hippocampus of zinc-deficient young adult rats. Neurochem Int 2005; 46: 221–225.

    CAS  Article  Google Scholar 

  21. 21

    Halas ES, Reynolds GM, Sandstead HH . Intra-uterine nutrition and its effects on aggression. Physiol Behav 1977; 19: 653–661.

    CAS  Article  Google Scholar 

  22. 22

    Bhatnagar S, Taneja S . Zinc and cognitive development. Br J Nutr 2001; 85: S139–S145.

    CAS  Article  Google Scholar 

  23. 23

    Benton D . Micronutrient status, cognition and behavioral problems in childhood. Eur J Nutr 2008; 47: 38–50.

    CAS  Article  Google Scholar 

  24. 24

    Sandstead HH . Zinc is essential for brain development and function. J Trace Elem Exp Med 2003; 16: 165–173.

    CAS  Article  Google Scholar 

  25. 25

    Black JL, Piñero DJ, Parekh N . Zinc and cognitive development in children: perspectives from international studies. Topics Clin Nutr 2009; 24: 130–138.

    Article  Google Scholar 

  26. 26

    Maret W, Sandstead HH . Possible roles of zinc nutriture in the fetal origins of disease. Exp Gerontol 2008; 43: 378–381.

    CAS  Article  Google Scholar 

  27. 27

    Black RE, Allen LH, Bhutta ZA, Caulfield LE, De Onis M, Ezzati M et al. Maternal and child undernutrition: global and regional exposures and health consequences. Lancet 2008; 371: 243–260.

    Article  Google Scholar 

  28. 28

    Sandstrom B, Sandberg AS . Inhibitory effects of isolated inositol phosphates on zinc-absorption in humans. J Trace Elem Electrolytes Health Dis 1992; 6: 99–103.

    CAS  PubMed  Google Scholar 

  29. 29

    Grantham-McGregor SM, Fernald LC, Sethuraman K . Effects of health and nutrition on cognitive and behavioural development in children in the first three years of life. Part 2: infections and micronutrient deficiencies: iodine, iron, and zinc http://archive.unu.edu/unupress/food/V201e/ch08.htm. Food Nutr Bull 1999; 20: 76–99.

    Article  Google Scholar 

  30. 30

    Sandstead HH . Causes of iron and zinc deficiencies and their effects on brain. J Nutr 2000; 130: 347S–349S.

    CAS  Article  Google Scholar 

  31. 31

    Grantham-McGregor SM, Ani CC . The role of micronutrients in psychomotor sad cognitive development. Br Med Bull 1999; 55: 511–527.

    CAS  Article  Google Scholar 

  32. 32

    Walker SP, Wachs TD, Gardner JM, Lozoff B, Wasserman GA, Pollitt E et al. Child development in developing countries 2 - Child development: risk factors for adverse outcomes in developing countries. Lancet 2007; 369: 145–157.

    Article  Google Scholar 

  33. 33

    Golub M, Takeuchi P, Keen C, Gershwin M, Hendrickx A, Lonnerdal B . Modulation of behavioral performance of prepubertal monkeys by moderate dietary zinc deprivation. Am J Clin Nutr 1994; 60: 238–243.

    CAS  Article  Google Scholar 

  34. 34

    Black MM . Zinc deficiency and cognitive development. In: Benton D editor. Lifetime Nutritional Influences on Cognition, Behaviour and Psychiatric Illness Woodhead Publishing in Food Science Technology and Nutrition. Woodhead Publ Ltd: Cambridge, 2011, pp 79–93.

    Google Scholar 

  35. 35

    Dreosti I . Zinc in brain development and function. In: Tomita H editor. Trace Elements in Clinical Medicine. Springer: Japan, 1990, pp 47–52.

    Google Scholar 

  36. 36

    Dhonukshe-Rutten RAM, Bouwman J, Brown KA, AEJM Cavelaars, Collings R, Grammatikaki E et al. EURRECA—evidence-based methodology for deriving micronutrient recommendations. Crit Rev Food Sci Nutr 2013; 53: 999–1040.

    CAS  Article  Google Scholar 

  37. 37

    EURRECA Systematic reviews: methods and main results. Available at http://www.eurreca.org/everyone/8567/7/0/32 (accessed 8 January 2015).

  38. 38

    EURRECA Best practice guidelines: nutrient intake assessment. Available at http://www.eurreca.org/everyone/8632/5/0/32 (accessed 8 January 2015).

  39. 39

    Matthys, van 't Veer P, de Groot L, Hooper L, Cavelaars AE, Collings R et al. EURRECA's approach for estimating micronutrient requirements. Int J Vitam Nutr Res 2011; 81: 256–263.

    CAS  Article  Google Scholar 

  40. 40

    Serra-Majem L, Pfrimer K, Doreste-Alonso J, Ribas-Barba L, Sanchez-Villegas A, Ortiz-Andrellucchi A et al. Dietary assessment methods for intakes of iron, calcium, selenium, zinc and iodine. Br J Nutr 2009; 102: S38–S55.

    CAS  Article  Google Scholar 

  41. 41

    Nissensohn M, Sánchez-Villegas A, Fuentes Lugo D, Henríquez Sánchez P, Doreste Alonso J, Skinner AL et al. Effect of zinc intake on mental and motor development in infants: a meta-analysis. Int J Vitamin Nutr Res 2013; 83: 203–215.

    CAS  Article  Google Scholar 

  42. 42

    EURRECA Databases and search strategies for zinc. Available at http://www.eurreca.org/everyone/8414/5/0/32 (accessed 8 January 2015).

  43. 43

    Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from (www.cochrane-handbook.org (accessed 9 April 2015).

  44. 44

    Higgins J, Thompson SG . Quantifying heterogeneity in a meta‐analysis. Stat Med 2002; 21: 1539–1558.

    Article  Google Scholar 

  45. 45

    Kelley K, Preacher KJ . On effect size. Psychol Methods 2012; 17: 137.

    Article  Google Scholar 

  46. 46

    Moran VH, Skinner A-L, Medina MW, Patel S, Dykes F, Souverein OW et al. The relationship between zinc intake and serum/plasma zinc concentration in pregnant and lactating women: a systematic review with dose-response meta-analyses. J Trace Elem Med Biol 2012; 26: 74–79.

    CAS  Article  Google Scholar 

  47. 47

    Moran VH, Stammers A-L, Medina MW, Patel S, Dykes F, Souverein OW et al. The relationship between zinc intake and serum/plasma zinc concentration in children: a systematic review and dose-response meta-analysis. Nutrients 2012; 4: 841–858.

    CAS  Article  Google Scholar 

  48. 48

    Lowe NM, Medina MW, Stammers A-L, Patel S, Souverein OW, Dullemeijer C et al. The relationship between zinc intake and serum/plasma zinc concentration in adults: a systematic review and dose–response meta-analysis by the EURRECA Network. Br J Nutr 2012; 108: 1962–1971.

    CAS  Article  Google Scholar 

  49. 49

    Nissensohn M, Sanchez Villegas A, Fuentes Lugo D, Henriquez Sanchez P, Doreste Alonso J, Lowe NM et al. Effect of zinc intake on serum/plasma zinc status in infants: a meta-analysis. Maternal Child Nutr 2013; 9: 285–298.

    Article  Google Scholar 

  50. 50

    Umamaheswari K, Bhaskaran M, Krishnamurthy G, Hemamalini, Vasudevan K . Effect of iron and zinc deficiency on short term memory in children. Indian Pediatr 2011; 48: 289–293.

    CAS  Article  Google Scholar 

  51. 51

    Tupe RP, Chiplonkar SA . Zinc supplementation improved cognitive performance and taste acuity in Indian adolescent girls. J Am Coll Nutr 2009; 28: 388–396.

    CAS  Article  Google Scholar 

  52. 52

    Lam PK, Kritz-Silverstein D, Barrett-Connor E, Milne D, Nielsen F, Gamst A et al. Plasma trace elements and cognitive function in older men and women: the Rancho Bernardo study. J Nutr Health Aging 2008; 12: 22–27.

    CAS  Article  Google Scholar 

  53. 53

    Ortega RM, Requejo AM, Andres P, LopezSobaler AM, Quintas ME, Redondo MR et al. Dietary intake and cognitive function in a group of elderly people. Am J Clin Nutr 1997; 66: 803–809.

    CAS  Article  Google Scholar 

  54. 54

    Gao S, Jin Y, Unverzagt FW, Ma F, Hall KS, Murrell JR et al. Trace element levels and cognitive function in rural elderly Chinese. J Gerontol A Biol Sci Med Sci 2008; 63: 635–641.

    Article  Google Scholar 

  55. 55

    Stoecker BJ, Abebe Y, Hubbs-Tait L, Kennedy TS, Gibson RS, Arbide I et al. Zinc status and cognitive function of pregnant women in Southern Ethiopia. Eur J Clin Nutr 2009; 63: 916–918.

    CAS  Article  Google Scholar 

  56. 56

    Maylor EA, Simpson EEA, Secker DL, Meunier N, Andriollo-Sanchez M, Polito A et al. Effects of zinc supplementation on cognitive function in healthy middle-aged and older adults: the ZENITH study. Br J Nutr 2006; 96: 752–760.

    CAS  Google Scholar 

  57. 57

    Murray-Kolb LE, Khatry SK, Katz J, Schaefer BA, Cole PM, Le Clerq SC et al. Preschool micronutrient supplementation effects on intellectual and motor function in school-aged nepalese children. Arch Pediatr Adolesc Med 2012; 166: 404–410.

    Article  Google Scholar 

  58. 58

    Pongcharoen T, Ramakrishnan U, Di Girolamo AM, Winichagoon P, Flores R, Singkhornard J et al. Influence of prenatal and postnatal growth on intellectual functioning in school-aged children. Arch Pediatr Adolesc Med 2012; 166: 411–416.

    Article  Google Scholar 

  59. 59

    Gewa CA, Weiss RE, Bwibo NO, Whaley S, Sigman M, Murphy SP et al. Dietary micronutrients are associated with higher cognitive function gains among primary school children in rural Kenya. Br J Nutr 2009; 101: 1378–1387.

    CAS  Article  Google Scholar 

  60. 60

    Christian P, Murray-Kolb LE, Khatry SK, Katz J, Schaefer BA, Cole PM et al. Prenatal micronutrient supplementation and intellectual and motor function in early school-aged children in Nepal. JAMA 2010; 304: 2716–2723.

    CAS  Article  Google Scholar 

  61. 61

    Caulfield LE, Putnick DL, Zavaleta N, Lazarte F, Albornoz C, Chen P et al. Maternal gestational zinc supplementation does not influence multiple aspects of child development at 54 mo of age in Peru. Am J Clin Nutr 2010; 92: 130–136.

    CAS  Article  Google Scholar 

  62. 62

    Penland JG, Sandstead HH, Alcock NW, Dayal HH, Chen XC, Li JS et al. A preliminary report: effects of zinc and micronutrient repletion on growth and neuropsychological function of urban Chinese children. J Am Coll Nutr 1997; 16: 268–272.

    CAS  Article  Google Scholar 

  63. 63

    Sandstead HH, Penland JG, Alcock NW, Hari H, Xue D, Chen C et al. Effects of repletion with zinc and other micronutrients on neuropsychologic performance and growth of Chinese children. Am J Clin Nutr 1998; 68: 470S–475S.

    CAS  Article  Google Scholar 

  64. 64

    Gibson RS, Smit Vanderkooy PD, MacDonald AC, Goldman A, Ryan BA, Berry M . A growth-limiting, mild zinc-deficiency syndrome in some southern Ontario boys with low height percentiles. Am J Clin Nutr 1989; 49: 1266–1273.

    CAS  Article  Google Scholar 

  65. 65

    Tamura T, Goldenberg RL, Ramey SL, Nelson KG, Chapman VR . Effect of zinc supplementation of pregnant women on the mental and psychomotor development of their children at 5 y of age. Am J Clin Nutr 2003; 77: 1512–1516.

    CAS  Article  Google Scholar 

  66. 66

    Cavan KR, Gibson RS, Grazioso CF, Isalgue AM, Ruz M, Solomons NW . Growth and body composition of periurban Guatemalan children in relation to zinc status: a longitudinal zinc intervention trial. Am J Clin Nutr 1993; 57: 344–352.

    CAS  Article  Google Scholar 

  67. 67

    Hubbs-Tait L, Kennedy TS, Droke EA, Belanger DM, Parker JR . Zinc, iron, and lead: relations to head start children's cognitive scores and teachers' ratings of behavior. J Am Diet Assoc 2007; 107: 128–133.

    CAS  Article  Google Scholar 

  68. 68

    Kaye DB, Baron MB . The validity of the Detroit test of learning aptitude. J Psychoeduc Assess 1984; 2: 117–124.

    Article  Google Scholar 

  69. 69

    Stanley K . Evaluation of randomized controlled trials. Circulation 2007; 115: 1819–1822.

    Article  Google Scholar 

  70. 70

    Gogia S, Sachdev HS . Zinc supplementation for mental and motor development in children. Cochrane Database Syst Rev 2012; 12: CD007991-CD.

    Google Scholar 

  71. 71

    Brown KH, Peerson JM, Baker SK, Hess SY . Preventive zinc supplementation among infants, preschoolers, and older prepubertal children. Food Nutr Bull 2009; 30: S12–S40.

    Article  Google Scholar 

  72. 72

    Best C, Neufingerl N, Del Rosso JM, Transler C, van den Briel T, Osendarp S . Can multi-micronutrient food fortification improve the micronutrient status, growth, health, and cognition of schoolchildren? A systematic review. Nutr Rev 2011; 69: 186–204.

    Article  Google Scholar 

  73. 73

    Eilander A, Gera T, Sachdev HS, Transler C, van der Knaap HCM, Kok FJ et al. Multiple micronutrient supplementation for improving cognitive performance in children: systematic review of randomized controlled trials. Am J Clin Nutr 2010; 91: 115–130.

    CAS  Article  Google Scholar 

  74. 74

    Nyaradi A, Li J, Hickling S, Foster J, Oddy WH . The role of nutrition in children's neurocognitive development, from pregnancy through childhood. Front Hum Neurosci 2013; 7.

  75. 75

    Schmitt JA . Nutrition and cognition: meeting the challenge to obtain credible and evidence-based facts. Nutr Rev 2010; 68: S2–S5.

    Article  Google Scholar 

  76. 76

    Wood RJ . Assessment of marginal zinc status in humans. J Nutr 2000; 130: 1350S–1354S.

    CAS  Article  Google Scholar 

  77. 77

    Lowe NM, Fekete K, Decsi T . Methods of assessment of zinc status in humans: a systematic review. Am J Clin Nutr 2009; 89: 2040S–2051S.

    CAS  Article  Google Scholar 

  78. 78

    Hambidge M . Biomarkers of trace mineral intake and status. J Nutr 2003; 133: 948S–955S.

    CAS  Article  Google Scholar 

  79. 79

    Sandstead HH, Prasad AS, Penland JG, Beck FW, Kaplan J, Egger NG et al. Zinc deficiency in Mexican American children: influence of zinc and other micronutrients on T cells, cytokines, and antiinflammatory plasma proteins. Am J Clin Nutr [Internet] 2008 13.02.09 [cited MN 88: 1067–1073. Available from: http://www.mrw.interscience.wiley.com/cochrane/clcentral/articles/360/CN-00651360/frame.html.

    CAS  Article  Google Scholar 

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Acknowledgements

The original conception of the systematic review was undertaken by the EURRECA network and coordinated by partners based at Wageningen University (WU), the Netherlands and the University of East Anglia (UEA), United Kingdom, Susan Fairweather-Tait (UEA), Lisette de Groot (WU), Pieter van’t Veer (WU), Kate Ashton (UEA), Amélie Casgrain (UEA), Adriënne Cavelaars (WU), Rachel Collings (UEA), Rosalie Dhonukshe-Rutten (WU), Esmée Doets (WU), Linda Harvey (UEA) and Lee Hooper (UEA) designed and developed the review protocol and search strategy. We thank the EURRECA Network of Excellence and to Sujata Patel, Joseph Saavedra, Nick Kenworthy, Sarah Richardson-Owen and Christine Cockburn for assistance with screening, data extraction of studies and Fiona Dykes for helpful discussions. NML, MW-M, A-LS, VHM, PQ and SD collected and analysed the data. LS-M and MN were also involved in the screening process. All authors were involved in writing the manuscript. We like to acknowledge networking support by Zn-Net COST Action TD1304, The Network for the Biology of Zinc, (http://www.cost.eu/COST_Actions/fa/Actions/TD1304). Names for PubMed indexing: Warthon-Medina, Hall Moran, Stammers, Dillon, Qualter, Nissenhohn, Serra-Majem, Lowe. This study has been supported by the EURRECA Network of Excellence (http://www.eurreca.org), which was funded by the Commission of the European Communities, specific Research, Technology and Development (RTD) Programme Quality of Life and Management of Living Resources, within the Sixth Framework Programme, contract no. 036196. Member of the Zinc-Net COST Action TD1304, http://www.cost.eu/domains_actions/fa/Actions/TD1304. This report does not necessarily reflect the Commission’s views or its future policy in this area.

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Warthon-Medina, M., Moran, V., Stammers, A. et al. Zinc intake, status and indices of cognitive function in adults and children: a systematic review and meta-analysis. Eur J Clin Nutr 69, 649–661 (2015). https://doi.org/10.1038/ejcn.2015.60

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