Vitamin D insufficiency is common in the United States; the elderly and African-Americans are at particularly high risk of deficiency. This review, written for a broad scientific readership, presents a critical overview of scientific evidence relevant to a possible causal relationship between vitamin D deficiency and adverse cognitive or behavioral effects. Topics discussed are 1) biological functions of vitamin D relevant to cognition and behavior; 2) studies in humans and rodents that directly examine effects of vitamin D inadequacy on cognition or behavior; and 3) immunomodulatory activity of vitamin D relative to the proinflammatory cytokine theory of cognitive/behavioral dysfunction. We conclude there is ample biological evidence to suggest an important role for vitamin D in brain development and function. However, direct effects of vitamin D inadequacy on cognition/behavior in human or rodent systems appear to be subtle, and in our opinion, the current experimental evidence base does not yet fully satisfy causal criteria. Possible explanations for the apparent inconsistency between results of biological and cognitive/behavioral experiments, as well as suggested areas for further research are discussed. Despite residual uncertainty, recommendations for vitamin D supplementation of at-risk groups, including nursing infants, the elderly, and African-Americans appear warranted to ensure adequacy.

This review, intended for a broad scientific readership, summarizes evidence relevant to whether a causal relation exists between dietary iron deficiency with (ID+A) or without (ID-A) anemia during development and deficits in subsequent cognitive or behavioral performance. An overview of expert opinion and major evidence in humans and animals is provided. Cognitive and behavioral effects observed in humans with ID-A and in animals with ID+/-A are provided in tables. The degree to which 5 conditions of causality are satisfied and whether deleterious effects of ID-A might be expected to occur are discussed. On the basis of the existing literature, our major conclusions are as follows. Although most of the 5 conditions of causality (association, plausible biological mechanisms, dose response, ability to manipulate the effect, and specificity of cause and effect) are partially satisfied in humans, animals, or both, a causal connection has not been clearly established. In animals, deficits in motor activity are consistently associated with severe ID+A, but adverse effects on performance in tests that target cognitive function have not been clearly shown. Resistance to iron treatment was observed in most trials of children <2 y of age with ID+A, but not in older children. Similar observations were made in rodents when ID+A occurred before rather than after weaning. In children >2 y of age and in adolescents with ID-A, evidence suggests cognitive or behavioral deficits; however, the surprisingly small number of studies conducted in either humans or animals prevents a thorough assessment.

This review is part of a series intended for nonspecialists that will summarize evidence relevant to the question of whether causal relations exist between micronutrient deficiencies and brain function. Here, we focus on experiments that used cognitive or behavioral tests as outcome measures in experimental designs that were known to or were likely to result in altered brain concentrations of the n-3 fatty acid docosahexaenoic acid (DHA) during the perinatal period of "brain growth spurt." Experimental designs reviewed include observational breastfeeding studies and randomized controlled trials in humans and studies in rodents and nonhuman primates. This review is based on a large number of expert reviews and commentaries and on some 50 recent studies in humans and animals that have not yet been included in published reviews. Expert opinion regarding the strengths and weaknesses of the major experimental systems and uncertainties associated with interpreting results is summarized. On the basis of our reading of this literature, we conclude that evidence from several types of studies, particularly studies in animals, suggests that, within the context of specific experimental designs, changes in brain concentrations of DHA are positively associated with changes in cognitive or behavioral performance. Additional experimental information required to conclude that a causal association exists is discussed, as are uncertainties associated with applying results from specific experimental designs to the question of whether infant formula should be supplemented with DHA.

The triage theory posits that some functions of micronutrients (the approximately 40 essential vitamins, minerals, fatty acids, and amino acids) are restricted during shortage and that functions required for short-term survival take precedence over those that are less essential. Insidious changes accumulate as a consequence of restriction, which increases the risk of diseases of aging. For 16 known vitamin K-dependent (VKD) proteins, we evaluated the relative lethality of 11 known mouse knockout mutants to categorize essentiality. Results indicate that 5 VKD proteins that are required for coagulation had critical functions (knockouts were embryonic lethal), whereas the knockouts of 5 less critical VKD proteins [osteocalcin, matrix Gla protein (Mgp), growth arrest specific protein 6, transforming growth factor beta-inducible protein (Tgfbi or betaig-h3), and periostin] survived at least through weaning. The VKD gamma-carboxylation of the 5 essential VKD proteins in the liver and the 5 nonessential proteins in nonhepatic tissues sets up a dichotomy that takes advantage of the preferential distribution of dietary vitamin K1 to the liver to preserve coagulation function when vitamin K1 is limiting. Genetic loss of less critical VKD proteins, dietary vitamin K inadequacy, human polymorphisms or mutations, and vitamin K deficiency induced by chronic anticoagulant (warfarin/coumadin) therapy are all linked to age-associated conditions: bone fragility after estrogen loss (osteocalcin) and arterial calcification linked to cardiovascular disease (Mgp). There is increased spontaneous cancer in Tgfbi mouse knockouts, and knockdown of Tgfbi causes mitotic spindle abnormalities. A triage perspective reinforces recommendations of some experts that much of the population and warfarin/coumadin patients may not receive sufficient vitamin K for optimal function of VKD proteins that are important to maintain long-term health.

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