Modeling relationships between iron status, behavior, and brain electrophysiology: evidence from a randomized study involving a biofortified grain in Indian adolescents.

BACKGROUND: Iron deficiency (ID) and iron deficiency anemia (IDA) are highly-prevalent nutrient deficiencies and have been shown to have a range of negative effects on cognition and brain function. Human intervention studies including measures at three levels-blood, brain, and behavior-are rare and our objective was to model the relationships among measures at these three levels in school-going Indian adolescents. METHODS: Male and female adolescents in rural India were screened for ID/IDA. Subjects consumed 2 meals/day for 6 months; half were randomly assigned to consume meals made from a standard grain (pearl millet) and half consumed meals made from an iron biofortified pearl millet (BPM). Prior to and then at the conclusion of the feeding trial, they completed a set of cognitive tests with concurrent electroencephalography (EEG). RESULTS: Overall, serum ferritin (sFt) levels improved over the course of the study. Ten of 21 possible measures of cognition showed improvements from baseline (BL) to endline (EL) that were larger for those consuming BPM than for those consuming the comparison pearl millet (CPM). Critically, the best model for the relationship between change in iron status and change in cognition had change in brain measures as a mediating factor, with both change in serum ferritin as a primary predictor and change in hemoglobin as a moderator. CONCLUSIONS: A dietary intervention involving a biofortified staple grain was shown to be efficacious in improving blood iron biomarkers, behavioral measures of cognition, and EEG measures of brain function. Modeling the relationships among these variables strongly suggests multiple mechanisms by which blood iron level affects brain function and cognition. TRIAL REGISTRATION: Registered at ClinicalTrials.gov, NCT02152150 , 02 June 2014.

Changes in Iron Status Are Related to Changes in Brain Activity and Behavior in Rwandan Female University Students: Results from a Randomized Controlled Efficacy Trial Involving Iron-Biofortified Beans.

BACKGROUND: Evidence suggests that iron deficiency (ID) affects cognitive performance, as measured in behavior. Although such effects must be mediated by changes in the brain, very few studies have included measures of brain activity to assess this relation. OBJECTIVE: We tested the hypothesis that provision of iron-biofortified beans would result in improvements in measures of iron status, brain dynamics, and behavior. METHODS: A double-blind, randomized, intervention study was conducted in 55 women aged 18-27 y with low iron status (serum ferritin <20 µg/L). Women were randomly assigned to consume iron-biofortified (86.1 ppm iron) or comparison beans (50.1 ppm iron) daily for 18 wk. Iron status was assessed by hemoglobin, ferritin, transferrin receptor, and body iron; cognitive performance with 5 computerized tasks; and brain dynamics by concurrent electroencephalography (EEG). All measures were taken at baseline and endline. RESULTS: The groups did not differ on any measures at baseline. Intention-to-treat analyses revealed significant (all P < 0.05) improvements in hemoglobin (partial effect size attributable to the independent variable, η2 = 0.16), ferritin (η2 = 0.17), and body iron (η2 = 0.10), speed of responding in attentional and mnemonic tasks (η2 = 0.04-0.29), sensitivity and efficiency of memory retrieval (η2 = 0.12-0.55), and measures of EEG amplitude and spectral power (η2 = 0.08 to 0.49). Mediation models provided evidence in support of the hypothesis that changes in iron status produce changes in behavior by way of changes in brain activity. CONCLUSIONS: Behavioral performance and brain activity, as measured by EEG, are sensitive to iron status, and the consumption of iron-biofortified beans for 18 wk resulted in improvements in measures of both, relative to what was obtained with a comparison bean, in a sample of female university students. Furthermore, the results support the conclusion that changes in brain activity resulting from consumption of biofortified beans mediate the relations between changes in iron biomarkers and changes in cognition. Clinical trial registry: ClinicalTrials.gov Reg No. NCT01594359.

Cognitive Performance in Indian School-Going Adolescents Is Positively Affected by Consumption of Iron-Biofortified Pearl Millet: A 6-Month Randomized Controlled Efficacy Trial.

BACKGROUND: Iron deficiency remains the most prevalent micronutrient deficiency globally, but few studies have examined how iron status relates to cognition in adolescents. Iron biofortification of staple food crops is being scaled up, yet it is unknown whether consuming biofortified crops can benefit cognition. Objective: Our objective was to determine the efficacy of iron-biofortified pearl millet in improving attention and memory in Indian school-going adolescents. Methods: A double-blind, randomized, intervention study was conducted in 140 Indian boys and girls, aged 12-16 y, who were assigned to consume iron-biofortified [Fe = 86 parts per million (ppm)] or conventional (Fe = 21-52 ppm) pearl millet. Hemoglobin, ferritin, and transferrin receptor (TfR) were measured and body iron (BI) was calculated at baseline and after 4 and 6 mo. Five measures of cognitive function were obtained at baseline and 6 mo: simple reaction time (SRT), Go/No-Go (GNG) task, Attentional Network Task (ANT), Composite Face Effect (CFE) task, and Cued Recognition Task (CRT). Intention-to-treat analysis was used. Results: Daily iron intake from pearl millet was higher in those consuming biofortified compared with conventional pearl millet (19.6 compared with 4.8 mg/d). Effects on ferritin, TfR, and BI at 4 mo, and on TfR at 6 mo (all P < 0.05), indicated efficacy of biofortified pearl millet over conventional pearl millet in improving iron status. Compared with conventional pearl millet, the consumption of biofortified pearl millet resulted in greater improvement in attention (SRT, GNG, and ANT) and memory (CFE and CRT). Reaction time decreased twice as much from 0 to 6 mo in those consuming biofortified compared with conventional pearl millet on attention tasks (SRT: -123 compared with -63 ms; GNG: -67 compared with -30 ms; ANT double cue: -74 compared with -32 ms; all P < 0.01). Conclusion: Consuming iron-biofortified pearl millet improves iron status and some measures of cognitive performance in Indian adolescents. This trial was registered at http://www.clinicaltrials.gov as NCT02152150.

Consumption of Iron-Biofortified Beans Positively Affects Cognitive Performance in 18- to 27-Year-Old Rwandan Female College Students in an 18-Week Randomized Controlled Efficacy Trial.

Background: Evidence shows that iron deficiency in adulthood may affect cognitive performance, possibly by disrupting neurotransmitter regulation or brain energy metabolism. Women of reproductive age (WRA) are among those who are most vulnerable to iron deficiency; however, they have been largely ignored in the literature relating iron status to cognition.Objective: Our aim was to determine the efficacy of iron-biofortified beans in improving cognition in WRA compared with control beans.Methods: A double-blind, randomized intervention study was conducted in 150 women aged 18-27 y with low iron status (ferritin <20 µg/L). Women were randomly assigned to consume iron-biofortified beans (86.1 ppm iron) or control beans (50.1 ppm iron) daily for 18 wk. Iron status was assessed based on hemoglobin, ferritin, transferrin receptor, and body iron values and on cognitive performance on 5 computerized tasks at baseline and endline.Results: Groups did not differ on any variables at baseline. Per protocol analyses revealed that consumption of the biofortified beans resulted in a 17% larger improvement in the speed of spatial selective attention; a nearly 7-fold larger improvement in the speed, a 68% greater improvement in the efficiency, and a >2-fold greater improvement in the specificity of memory retrieval; and a >2-fold larger improvement in the speed and a >3-fold larger improvement in the efficiency of memory search-all of which are relative to consumption of the control beans (P < 0.01 for all comparisons).Conclusions: Cognitive performance is sensitive to iron status, and consumption of iron-biofortified beans for 18 wk improved cognitive performance, especially the efficiency of search and the speed of retrieval on memory tasks, in young adult women. This trial was registered at clinicaltrials.gov as NCT01594359.

The impact of anemia on child mortality: an updated review.

Iron deficiency anemia and child mortality are public health problems requiring urgent attention. However, the degree to which iron deficiency anemia contributes to child mortality is unknown. Here, we utilized an exhaustive article search and screening process to identify articles containing both anemia and mortality data for children aged 28 days to 12 years. We then estimated the reduction in risk of mortality associated with a 1-g/dL increase in hemoglobin (Hb). Our meta-analysis of nearly 12,000 children from six African countries revealed a combined odds ratio of 0.76 (0.62-0.93), indicating that for each 1-g/dL increase in Hb, the risk of death falls by 24%. The feasibility of a 1-g/dL increase in Hb has been demonstrated via simple iron supplementation strategies. Our finding suggests that ~1.8 million deaths in children aged 28 days to five years could be avoided each year by increasing Hb in these children by 1 g/dL.