Plasma biomarkers associated with ALS and their relationship to iron homeostasis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with complicated pathogenesis with variable presentation and disease progression. There is a critical need for a panel of biomarkers to provide clinicians and researchers with additional information. In this study, multiplex immunoassays were used to screen a number of cytokines, growth factors, and iron-related proteins.

Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome.

Restless leg syndrome (RLS) is a sensorimotor disorder. Clinical studies have implicated the dopaminergic system in RLS, while others have suggested that it is associated with insufficient levels of brain iron. To date, alterations in brain iron status have been demonstrated but, despite suggestions from the clinical literature, there have been no consistent findings documenting a dopaminergic abnormality in RLS brain tissue.

Systems genetics analysis of iron regulation in the brain.

Iron imbalances in the brain, including excess accumulation and deficiency, are associated with neurological disease and dysfunction; yet, their origins are poorly understood. Using systems genetics analysis, we have learned that large individual differences exist in brain iron concentrations, even in the absence of neurological disease. Much of the individual differences can be tied to the genetic makeup of the individual.

Iron deficiency alters the day-night variation in monoamine levels in mice.

Monoamine metabolism in the central nervous system is altered by dietary iron deficiency, with a stronger effect seen during the active than rest span of the circadian cycle. In this report, we examined changes in intracellular and extracellular monoamine levels, synthetic enzymes, transporter and receptor densities, and responses to amphetamine-induced dopamine (DA) efflux in iron-deficient and iron-sufficient mice. Extracellular striatal DA levels were 15-20% higher in all groups during the active dark phase compared to the inactive light phase, with correspondingly lower dopamine transporter (DAT) and higher tyrosine hydroxylase levels.

Assessment of iron deficiency in US preschool children and nonpregnant females of childbearing age: National Health and Nutrition Examination Survey 2003-2006.

Background: A new index to determine body iron promises a simpler approach to monitoring iron deficiency (ID) prevalence.

Objective: Our objective was to compare ID defined as body iron <0 mg/kg and calculated from the log ratio of transferrin receptor to ferritin (the body iron model) to ID defined as >/=2 of 3 abnormal concentrations in ferritin, transferrin saturation, or erythrocyte protoporphyrin (the ferritin model).

Design: We used measures of iron status and inflammation from 486 children aged 1-2 y, 848 children aged 3-5 y, and 3742 nonpregnant females aged 12-49 y from the National Health and Nutrition Examination Survey 2003-2006.

A history of iron deficiency anemia during infancy alters brain monoamine activity later in juvenile monkeys.

Both during and after a period of iron deficiency (ID), iron-dependent neural processes are affected, which raises the potential concern that the anemia commonly experienced by many growing infants could have a protracted effect on the developing brain. To further investigate the effects of ID on the immature brain, 49 infant rhesus monkeys were evaluated across the first year of life. The mothers, and subsequently the infants after weaning, were maintained on a standardized diet containing 180 mg/kg of iron and were not provided other iron-rich foods as treats or supplements.

Iron deficiency and child and maternal health.

Background: Iron deficiency is most commonly found in women of reproductive age and infants worldwide, but the influence of maternal iron deficiency on infant development is underexplored.

Objective: The objective was to examine the relation between maternal iron status and mother-child interactions in a randomized, double-blind, intervention trial conducted in South Africa.

Design: Women were recruited into the study from a health clinic at 6-8 wk postpartum and were classified as either iron-deficient anemic (IDA) or iron-sufficient after blood analysis.

Nutrient adequacy and food group consumption of Filipino novices and religious sisters over a nine month period.

Rice is commonly consumed in the Philippines; however the contribution of other foods to the diet is not well defined. Our aim was to determine the nutrient intake and food group intake of Philippine nuns and compare their intakes to the current estimated average requirements (EAR), and food-based recommendations, respectively, and assess any differences in nutrient adequacy and energy intakes between body mass index (BMI) categories. Body weight was assessed at baseline and at nine months; three-day weighed food intakes were recorded once every fortnight (n=187).

Why iron deficiency is important in infant development.

Infants who experience iron deficiency during the first 6-12 mo of life are likely to experience persistent effects of the deficiency that alter functioning in adulthood. A lack of sufficient iron intake may significantly delay the development of the central nervous system as a result of alterations in morphology, neurochemistry, and bioenergetics. Depending on the stage of development at the time of iron deficiency, there may be an opportunity to reverse adverse effects, but the success of repletion efforts appear to be time dependent.

Dopamine D2 receptor expression is altered by changes in cellular iron levels in PC12 cells and rat brain tissue.

Iron deficiency anemia in early life alters the development and functioning of the dopamine neurotransmitter system, but data regarding the specific effects of brain iron loss on dopamine D(2) receptor regulation are lacking. Cell culture and animal models were employed in this study to determine whether D(2) receptor expression is altered when cellular iron levels are depleted. Endogenous D(2) receptor-expressing PC12 cells exposed to increasing concentrations of the iron chelator desferrioxamine (25-100 micromol/L) exhibited dose-dependent decreases in total D(2) receptor protein concentrations (20-65%), but there were minimal effects on D(2) receptor mRNA levels.

Diurnal cycle influences peripheral and brain iron levels in mice.

Iron movement between organ pools involves a dynamic equilibrium of iron efflux and uptake, and homeostatic mechanisms are likely involved in providing iron to cells and organs when required. Daily iron levels in the plasma pool fluctuate with the diurnal cycle, but clear explanations regarding the objectives and regulation of the flux are lacking. The association between diurnal cycle and iron flux is relevant in the disease of restless legs syndrome (RLS), where individuals display diurnal deficits in motor control, have impaired brain iron metabolism, and perhaps altered iron uptake from the plasma pool.

What matters most: an investigation of predictors of perceived stress among young mothers in Khayelitsha.

Our purpose in the present study was to examine how two different sets of stressors, one representing the physical environment and the other representing the social environment, related to perceived stress among new mothers served by a health clinic in Khayelitsha, South Africa. We found that among the chronic urban poverty-environmental stressors related to water, housing, transportation, toileting, and lack of food, that lack of drinkable water in the home had the strongest correlation with perceived stress. In terms of social stressors we found that 60% of new mothers had no partner, and 43% of those with a partner reported that they currently were not coresiding.

Altered iron metabolism in lymphocytes from subjects with restless legs syndrome.

Objective: Studies using cerebrospinal fluid, magnetic resonance imaging, and autopsy tissue have implicated a primary role for brain iron insufficiency in restless legs syndrome (RLS). If the abnormalities of brain iron regulation reflect a basic disturbance of iron metabolism, then this might be expressed at least partially in some peripheral systems. Thus the study aim was to determine whether patients with RLS and control subjects show differences in lymphocyte iron regulator proteins.

Iron deficiency alters dopamine uptake and response to L-DOPA injection in Sprague-Dawley rats.

Iron deficiency (ID) disrupts brain dopamine (DA) and norepinephrine (NE) metabolism including functioning of monoamine transporters and receptors. We employed caudate microdialysis and no net flux (NNF) in post-weaning rats to determine if ID decreased the extraction fraction (E(d)). Five micromolar quinpirole, a dopamine D(2) receptor agonist, resulted in 80% decrease in extracellular DA and 45% higher E(d) in control animals.

A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome.

Objective: The aim of this study was to ascertain whether high-dose intravenous (IV) iron sucrose could improve symptoms and change brain iron concentrations in idiopathic RLS.

Methods: The study was a randomized, parallel-group double-blind study of 1000mg iron sucrose given IV versus placebo. Primary measures of the clinical status were global rating scale (GRS) and periodic leg movements of sleep (PLMS).

Iron absorption: comparison of prediction equations and reality. Results from a feeding trial in the Philippines.

Background: A number of algorithms have been developed that seek to predict the bioavailability of iron from mixed meals and diets, but their direct validity in predicting change in iron status remains questionable. Throughout the course of conducting a large feeding trial in convents in Manila, we collected weighed food-intake data and have the opportunity to directly compare the performance of these prediction equations.

Aims: The specific aims of this particular analysis are as follows: (a) to determine habitual intakes of macro- and micronutrients in religious sisters in Manila, (b) to determine the predicted efficiency of iron absorption from each of the published bioavailability algorithms (Monsen, Hallberg, Reddy, Tseng, Barghava, and Du), and (c) to determine which of these equations best predicts the actual "gain" in iron in religious sisters over the duration of the trial.

Genetic analysis reveals polygenic influences on iron, copper, and zinc in mouse hippocampus with neurobiological implications.

Fe, Cu, and Zn are of widespread neurobiological importance, but must be regulated closely as too much or too little of these metals can have adverse effects on brain function. Recent evidence from nutritional models notes that the hippocampus is particularly vulnerable to Fe and Zn deficiencies. We recently performed a quantitative trait loci (QTL) analysis as a preliminary step in identifying genes that contribute to natural variation in hippocampal Fe, Cu, and Zn content.

CSF proteomic analysis reveals persistent iron deficiency-induced alterations in non-human primate infants.

Iron deficiency (ID) anemia during infancy results in long-term neurological consequences, yet the mediating mechanisms remain unclear. Infant monkeys often become naturally anemic during the first 6 months of life, presenting an opportunity to determine the effect of developmental iron deficiency. After weaning, animals were chosen randomly for supplementation with oral iron or, fed a standard commercial chow diet.

Iron absorption prediction equations lack agreement and underestimate iron absorption.

A number of algorithms have been developed to predict the bioavailability of iron from mixed meals and diets, but their direct validity in predicting change in iron status remains questionable. Throughout the course of conducting a large feeding trial in 10 convents in Manila, we collected weighed food intake data (n = 317) and directly compared the performance of these prediction equations to each other and to the change in serum ferritin (SF). Dietary weighed food intakes were measured on d 3 every 2 wk for each woman and iron status determined at baseline, 4.

Iron regulation in C57BLI6 and DBA/2 mice subjected to iron overload.

Many genes are likely involved in the control of iron metabolism in brain and in peripheral tissues, and genetically-defined murine strains present the opportunity to investigate genetic variations in iron metabolism. Weanling C57BL/6 (B6) and DBA/2 (D2) mice were divided into two treatment groups receiving distilled water with or without 5000 ppm ferric chloride ad libitum as their sole fluid source for 100 days. Iron overload increased liver, spleen and plasma iron levels in male and female B6 and female D2 mice.

Variation in the diets of Filipino women over 9 months of continuous observation.

Background: The variability in habitual intakes of most components in the Philippine diet is unknown.

Objective: To perform a quantitative evaluation of the traditional Philippine diet using data collected over an extended period of time. We sought to identify seasonal variations and within-subject components of variation in nutrient intake.

Systems genetic analysis of peripheral iron parameters in the mouse.

Iron homeostasis is one of the most critical functions in living systems. Too little iron can lead to anemia and tissue-specific disorders, such as splenomegaly. Excessive systemic iron is characteristic of hemochromatosis and is implicated in the brain in Parkinson's disease.

Early postnatal iron repletion overcomes lasting effects of gestational iron deficiency in rats.

Iron deficiency anemia in early childhood causes developmental delays and, very likely, irreversible alterations in neurological functioning. One primary goal for the present study was to determine whether the effects of late gestational iron deficiency on brain monoamine metabolism, iron content, and behavioral phenotypes could be repaired with iron intervention in early lactation. Young pregnant rats were provided iron-deficient or control diets from mid-gestation (G15).

Iron treatment normalizes cognitive functioning in young women.

Background: Evidence suggests that brain iron deficiency at any time in life may disrupt metabolic processes and subsequently change cognitive and behavioral functioning. Women of reproductive age are among those most vulnerable to iron deficiency and may be at high risk for cognitive alterations due to iron deficiency.

Objective: We aimed to examine the relation between iron status and cognitive abilities in young women.

Down-regulation of dopamine transporter by iron chelation in vitro is mediated by altered trafficking, not synthesis.

Neurological development and functioning of dopamine (DA) neurotransmission is adversely affected by iron deficiency in early life. Iron-deficient rats demonstrate significant elevations in extracellular DA and a reduction in dopamine transporter (DAT) densities in the caudate putamen and nucleus accumbens. To explore possible mechanisms by which cellular iron concentrations control DAT functioning, endogenous DAT-expressing PC12 cells were used to determine the effect of iron chelation on DAT protein and mRNA expression patterns.