Iron is essential in various physiological processes, but its accumulation leads to oxidative stress and cell damage, thus iron homeostasis has to be tightly regulated. Ferroptosis is an iron-dependent non-apoptotic regulated cell death characterized by iron overload and reactive oxygen species accumulation. Mitochondria are organelles playing a crucial role in iron metabolism and involved in ferroptosis. MitoNEET, a protein of mitochondrial outer membrane, is a key element in this process. Ferroptosis, altering iron levels in several metabolically active organs, is linked to several non-communicable diseases. For example, iron overload in the liver leads to hepatic fibrosis and cirrhosis, accelerating non-alcholic fatty liver diseases progression, in the muscle cells contributes to oxidative damage leading to sarcopenia, and in the brain is associated to neurodegeneration. The aim of this review is to investigate the intricate balance of iron regulation focusing on the role of mitochondria and oxidative stress, and analyzing the ferroptosis implications in health and disease.

The literature on the relationships among blood iron levels, cognitive performance, and brain iron levels specific to women at the menopausal transition is ambiguous at best. The need to better understand these potential relationships in women for whom monthly blood loss (and thus iron loss) is ceasing is highlighted by iron's accumulation in brain tissue over time, thought to be a factor in the development of neurodegenerative disease.

Non-anemic women who were either low in iron or had normal iron levels for their age and race/ethnicity provided blood samples, underwent MRI scans to estimate brain iron levels, and performed a set of cognitive tasks with concurrent EEG.

Cognitive performance and brain dynamics were positively related to iron levels, including measures associated with oxygen transport. There were no relationships between any of the blood measures of iron and brain iron.

Higher iron status was associated with better cognitive performance in a sample of women who were neither iron deficient nor anemic, without there being any indication that higher levels of systemic iron were related to higher levels of brain iron. Consequently, addressing low iron levels at the menopausal transition may be a candidate approach for alleviating the "brain fog" commonly experienced at menopause.

Iron deficiency (ID) is the most prevalent nutrient deficiency in the world, with a growing literature documenting the negative effects of ID on perception, attention, and memory. Animal models of ID suggest that dysregulation of dopamine is responsible for the deficits in memory. However, evidence that ID affects dopamine in humans is extremely limited. We report the results of a study involving college-aged women with and without ID learning two different category structures - a rule-based and an information-integration structure - selected based on the putative differential role of dopamine in learning these two structures. ID non-anemic (IDNA) and iron-sufficient (IS) women completed 1200 learning trials for each structure. EEG was collected to assess the effects of ID on features affected by dopaminergic state: error-related negativity (ERN) and positivity (Pe), feedback-related negativity (FRN), and task-related blink rate. In addition, we examined the EEG data for dynamics distinguishing IDNA from IS women, including a measure of neural efficiency. Both groups of women were able to learn both structures. However, IDNA women were initially slower and less accurate than IS women, specifically for the rule-based structure. There were large and persistent group differences in brain dynamics and neural efficiency measures. The results are discussed with respect to the selective impact of ID on initial rule-based learning and the persistent effect of ID on dopamine signaling and energetic efficiency.

Iron in the brain is essential to neurodevelopmental processes, as it supports neural functions, including processes of oxygen delivery, electron transport, and enzymatic activity. However, the development of brain iron before birth is scarcely understood. By estimating R2* (1/T2*) relaxometry from a sizable sample of fetal multiecho echo-planar imaging (EPI) scans, which is the standard sequence for functional magnetic resonance imaging (fMRI), across gestation, this study investigates age and sex-related changes in iron, across regions and tissue segments. Our findings reveal that brain R2* levels significantly increase throughout gestation spanning many different regions, except the frontal lobe. Furthermore, females exhibit a faster rate of R2* increase compared to males, in both gray matter and white matter. This sex effect is particularly notable within the left insula. This work represents the first MRI examination of iron accumulation and sex differences in developing fetal brains. This is also the first study to establish R2* estimation methodology in fetal multiecho functional MRI.

The literature on the relationships among blood iron levels, cognitive performance, and brain iron levels specific to women at the menopausal transition is ambiguous at best. The need to better to understand these potential relationships in women for whom monthly blood loss (and thus iron loss) is ceasing is highlighted by the fact that iron accumulates in brain tissue over time and that accumulation is thought to be a factor in the development of neurodegenerative disease.

Non-anemic women who were either low in iron or had normal iron levels for their age and race/ethnicity provided blood samples, underwent MRI scans to estimate brain iron levels, and performed a set of cognitive tasks with concurrent EEG. Results: Cognitive performance as well as brain dynamics were positively related to iron levels, including measures associated with oxygen transport. There were no relationships between any of the blood measures of iron and brain iron.

Higher iron status was associated with better cognitive performance in a sample of women who were neither iron deficient nor anemic, without there being any indication that higher levels of systemic iron were related to higher levels of brain. Consequently, addressing low iron levels at the menopausal transition may be a candidate approach for alleviating the "brain fog" commonly experienced at menopause.

Deferoxamine mesylate (DFX) is a microorganism-derived iron chelator used in hematology to treat acute iron intoxication and chronic iron overload. Many studies have reported adverse neurological events from DFX exposure, but it is challenging to distinguish these from the effects of iron intoxication. This study aimed to evaluate whether DFX exposure alone can directly impair neurological functions and to elucidate its toxicological mechanisms. Our findings from in vivo and in vitro experiments indicate that DFX exposure can directly cause emotional and cognitive dysfunction in mice. Neuronal apoptosis, resulting from chaperone-mediated autophagy (CMS) dysfunction, was identified as a key toxicological mechanism underlying DFX-induced neuronal impairment. This study provides evidence for the comprehensive monitoring and timely management of neurotoxic adverse events associated with DFX exposure, as well as a foundation for developing medications to prevent and treat these events to enhance patient quality of life.

Iron overload has been shown to have deleterious effects in the brain through the formation of reactive oxygen species, which ultimately may contribute to neurodegenerative disorders. Accordingly, rodent studies have indicated that systemic administration of iron produces excess iron in the brain and results in behavioral and cognitive deficits. To what extent cognitive abilities are affected and which neurobiological mechanisms underlie those deficits remain to be more fully characterized. In the present study, we looked at the effects of a 30 mg/kg iron sub-chronic treatment on cognitive abilities in two hippocampal-dependent spatial tasks (place navigation, spatial/non-spatial object recognition), in relation with iron content and oxidative stress biomarkers (MDA, SOD, CAT) in the cerebellum, hippocampus, prefrontal cortex and striatum, four brain areas known to be involved in the processing of spatial information. Iron-treated rats were impaired in acquisition and retention of the platform location in the navigation task and in the spatial/non-spatial object recognition task. Iron content and MDA were found to be increased in the four brain regions of interest, but activity of the antioxidant enzymes was not modified. The results indicate that the ability of rats to process spatial information whether in place navigation or spontaneous object spatial/non-spatial recognition is disrupted following a 30 mg/kg sub-chronic treatment. The deficits are hypothesized to result from iron excess-induced oxidative stress in the network of brain areas involved in the processing of spatial information.

Early environments can have significant and lasting effects on brain, body, and behavior across the lifecourse. Here, we address current research efforts to understand how experiences impact neurodevelopment with a new perspective integrating two well-known conceptual frameworks - the Developmental Origins of Health and Disease (DOHaD) and sensitive/critical period frameworks. Specifically, we consider how prenatal experiences characterized in the DOHaD model impact two key neurobiological mechanisms of sensitive/critical periods for adapting to and learning from the postnatal environment. We draw from both animal and human research to summarize the current state of knowledge on how particular prenatal substance exposures (psychoactive substances and heavy metals) and nutritional profiles (protein-energy malnutrition and iron deficiency) each differentially impact brain circuits' excitation/GABAergic inhibition balance and myelination. Finally, we highlight new research directions that emerge from this integrated framework, including testing how prenatal environments alter sensitive/critical period timing and learning and identifying potential promotional/buffering prenatal exposures to impact postnatal sensitive/critical periods. We hope this integrative framework considering prenatal influences on postnatal neuroplasticity will stimulate new research to understand how early environments have lasting consequences on our brains, behavior, and health.

A large number of clinical studies demonstrate that the ketogenic diet (KD) may be an effective approach to the reduction of epileptic seizures in children and adults. Such dietary therapy could also help pregnant women with epilepsy, especially since most antiseizure drugs have teratogenic action. However, there is a lack of medical data, considering the safety of using KD during gestation for the progeny. Therefore, we examined the influence of KD used prenatally in rats on the elemental composition of the selected brain regions in their offspring. For this purpose, synchrotron radiation-induced X-ray fluorescence (SR-XRF) microscopy was utilized, and elements such as P, S, K, Ca, Fe, and Zn were determined. Moreover, to verify whether the possible effects of KD are temporary or long-term, different stages of animal postnatal development were taken into account in our experiment. The obtained results confirmed the great applicability of SR-XRF microscopy to track the element changes occurring in the brain during postnatal development as well as those induced by prenatal exposure to the high-fat diet. The topographic analysis of the brains taken from offspring of mothers fed with KD during pregnancy and appropriate control individuals showed a potential influence of such dietary treatment on the brain levels of elements such as P and S. In the oldest progeny, a significant reduction of the surface of brain areas characterized by an increased P and S content, which histologically/morphologically correspond to white matter structures, was noticed. In turn, quantitative elemental analysis showed significantly decreased levels of Fe in the striatum and white matter of 30-day-old rats exposed prenatally to KD. This effect was temporary and was not noticed in adult animals. The observed abnormalities may be related to the changes in the accumulation of sphingomyelin and sulfatides and may testify about disturbances in the structure and integrity of the myelin, present in the white matter.

Maternal nutrition during the perinatal stage is critical to offspring brain development. Egg yolks are a balanced and nutrient-dense food that is rich in bioactive components crucial to optimal neurodevelopment early in life. Egg consumption is often recommended to pregnant women to enhance both maternal and fetal health. We hypothesized that maternal intake of egg yolk from late gestation and throughout lactation would enhance functional organization and cognitive developmental outcomes in offspring using a pig model. Sows were fed a control diet (n = 6) or a diet containing egg yolks (n = 5, 350 mg egg yolk powder/kg BW/day, equivalent to ∼3 eggs/day for humans) from late gestation through lactation. At weaning, piglet offspring (n = 2/sow, total n = 22) underwent structural magnetic resonance imaging (MRI) and resting-state-functional MRI. Piglets underwent novel object recognition testing to assess hippocampal-dependent learning and memory. Functional MRI results demonstrated that egg yolk significantly increased functional activation in the executive network (p = 0.0343) and cerebellar network (p = 0.0253) in piglets when compared to control. Diffusion tensor imaging analysis showed that perinatal intake of egg yolks significantly increased white matter fiber length in the hippocampus (p = 0.0363) and cerebellum (p = 0.0287) in piglet offspring compared to control piglets. Furthermore, piglets from egg yolk-fed sows spent significantly more proportional frequency exploring the novel object than the familiar object in novel object recognition testing (p = 0.0370). The findings from this study support egg yolk-altered activation of specific brain networks may be associated with functional cognitive outcomes in weaning piglets.

Introduction Febrile seizures are the most common type of seizure in neurologically healthy children under six years of age. Iron deficiency is a prevalent micronutrient deficiency worldwide, though it is medically preventable and treatable. In many developing countries, anaemia remains a significant concern in young children. Iron plays a crucial role in neurodevelopment and overall bodily growth, and low levels of serum ferritin may lower the seizure threshold. Methods The study aimed to determine the correlation of iron profiles between patients with their first episode of febrile seizures and patients with only febrile illnesses. This case-control study enrolled children between 6 and 60 months of age. The case group comprised children who experienced their first episode of febrile seizure, while the control group included children presenting with febrile illness without seizures. The cost of the iron profile was waived for patients enrolled in the study. The study was conducted at a tertiary care centre and charitable hospital. Total blood counts and iron profiles were analyzed to find the association between the risk of febrile seizures and anaemia. Results The study included 150 children, with 50 febrile seizure cases and 100 controls with only febrile illness. The mean age of cases was 2.15 years, while that of the controls was 1.73 years. Males were more prevalent in the febrile seizure group, with 31 (62%) compared to 19 (38%) females. The mean serum transferrin value in cases was 22.46, compared to 28.42 in controls, indicating lower levels in cases (p=0.029). The mean TIBC in cases was 434.84, higher than the control group's 334.46 (p<0.001). The mean serum iron level in cases was 77.64, lower than that of controls at 86.63, though the difference was not significant (p=0.195). RDW >15% was observed in 46 (92%) cases compared to 57 (57%) controls (p<0.001). Conclusion Iron deficiency anaemia is a correctable risk factor for children with febrile seizures between 6 and 60 months of age. Timely diagnosis and correction of anaemia may help prevent febrile seizures in these children. Further research is needed to evaluate effective prevention strategies.

Brain iron homeostasis plays a vital role in maintaining brain development and controlling neuronal function under physiological conditions. Many studies have shown that the imbalance of brain iron homeostasis is closely related to the pathogenesis of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD). Recent advances have revealed the importance of iron transporters and regulatory molecules in the pathogenesis and treatment of NDs. This review summarizes the research progress on brain iron overload and the aberrant expression of several key iron transporters and regulators in AD and PD, emphasizes the pathological roles of these molecules in the pathogenesis of AD and PD, and highlights the therapeutic prospects of targeting these iron transporters and regulators to restore brain iron homeostasis in the treatment of AD and PD. A comprehensive understanding of the pathophysiological roles of iron, iron transporters and regulators, and their regulations in NDs may provide new therapeutic avenues for more targeted neurotherapeutic strategies for treating these diseases.

Animal studies have suggested that dietary iron deficiency (ID) negatively affects dopamine (DA) synthesis and re-uptake, which in turn negatively affects memory and cognition. This study was intended to assess whether the pattern electroretinogram (pattern ERG) could be used as an indirect measure of DA in college-age women with and without ID by determining the extent to which features of the ERG were sensitive to iron status and were related to other indirect measures of DA.

The pattern ERG was measured in 21 iron deficient non-anemic (IDNA) and 21 iron sufficient (IS) women, who also performed a contrast detection and probabilistic selection task, both with concurrent electroencephalography (EEG). Both spontaneous and task-related blink rates were also measured.

The implicit times of the A- and B-waves were significantly longer for the IDNA than for the IS women. Both the amplitudes and implicit times of the A- and B-waves were significantly correlated with levels of serum ferritin (sFt). Only the amplitude of the A-wave was correlated with spontaneous blink rate. It was possible to accurately identify a woman's iron status solely on the basis of the implicit time of the B-wave. Finally, the implicit times of the ERG features mediated the relationship between iron levels and accuracy in the probabilistic selection task.

Results suggest the utility of the pattern ERG in testing the hypothesis that iron deficiency affects DA levels in humans and that this may be one of the mechanisms by which iron deficiency negatively affects cognition.

Postpartum depression (PPD) represents a significant challenge to maternal and child health. Early screening for PPD is essential to ensure appropriate treatment and support. The present study aimed to assess whether maternal prepartum anaemia influences the likelihood of developing PPD within 3 days after delivery.

In collaboration with the Department of Psychiatry, a prospective observational study was carried out at the Gynaecology and Obstetrics Department of the University of Campania "Luigi Vanvitelli" in Naples. A total of 211 full-term pregnant women were enrolled, and their predelivery haemoglobin value was recorded. Women with gestational diabetes, hypertension, pre-eclampsia, intrauterine growth restriction, intellectual disability, or pre-existing diagnosis of psychotic spectrum disorder were excluded. Participants provided written informed consent to fill out the Edinburgh Postnatal Depression Scale (EPDS) 3 days after delivery. EPDS cut-off score of ≥ 10 was used to identify women at risk of developing PPD. Statistical analysis was performed using Student's t test, the Wilcoxon Rank Sum test, and linear regression.

The participants were categorized into 2 groups based on EPDS scores: EPDS < 10 (176 patients) or EPDS ≥ 10 (35 patients). The two groups showed homogeneity in terms of socio-demographic and clinical characteristics. The mean haemoglobin values of anaemic pregnant women in the EPDS ≤ 10 group (11.78 ± 1.39 g/dl) and the EPDS > 10 group (11.62 ± 1.27 g/dl) were not significantly different (p = 0.52). There was no significant correlation between the predelivery haemoglobin value and the EPDS postpartum score of < 10 or ≥ 10. The Wilcoxon Rank Sum test and the estimated coefficients of the linear regression model did not show any statistical relationship between continuous and binary haemoglobin values.

Our study found that maternal prepartum anaemia did not negatively impact the likelihood of developing postpartum depressive symptoms, in the first 3 days after delivery.

Parkinson's disease (PD) ranks as the second most prevalent neurodegenerative disorder globally, marked by a complex pathogenesis. Lipocalin-2 (LCN2) emerges as a crucial factor during the progression of PD. Belonging to the lipocalin family, LCN2 is integral to several biological functions, including glial cell activation, iron homeostasis regulation, immune response, inflammatory reactions, and oxidative stress mitigation. Substantial research has highlighted marked increases in LCN2 expression within the substantia nigra (SN), cerebrospinal fluid (CSF), and blood of individuals with PD. This review focuses on the pathological roles of LCN2 in neuroinflammation, aging, neuronal damage, and iron dysregulation in PD. It aims to explore the underlying mechanisms of LCN2 in the disease and potential therapeutic targets that could inform future treatment strategies.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder of the blood vessels that leads to the formation of telangiectasias and arteriovenous malformations (AVMs). HHT affects ∼1/5,000 people, but this varies significantly by geography and ancestry. The Curaçao criteria for HHT consist of four diagnostic criteria: spontaneous epistaxis, first-degree relative with HHT, AVMs in characteristic location (liver, lung, brain), and telangiectasias. Sequelae and major symptomology include recurrent epistaxis, dyspnea, heart failure, and stroke from paradoxical emboli among others. HHT patients are best cared for by a multidisciplinary team, ideally all with HHT-specific experience, but in this review, we will discuss the major aspects of the disease including etiology, diagnosis, and treatment recommendations.

Aim: To evaluate using different iron preparations for iron deficiency and/or iron deficiency anemia prophylaxis in infants and their iron status. Methods: In this study, we retrospectively evaluated the electronic patient records of 651 healthy children aged 9 to 13 months who met the inclusion criteria and who were followed up in pediatric follow-up outpatient clinics between January 2023 and June 2023. Results: A total of 651 children with a mean age of 11.2 ± 1.4 months, 54.7% of whom were boys, who met the inclusion criteria were included in the study; 56.5% of the children were using Fe + 3 salt and the others were using Fe + 2 salt, microencapsulated iron, or sucrosomial iron drops. After the fifth month of prophylaxis, when the effects of the iron preparations used on the mean laboratory values were evaluated, it was found that hemoglobin, serum iron, and ferritin levels were lower in sucrosomial iron and microencapsulated iron users compared to other preparations (p = 0.001). When statistically pairwise comparisons were made between the groups, hemoglobin and serum iron values were found to be lower in the group using sucrosomial iron compared to the groups using Fe + 2 and Fe + 3 salts (p < 0.0001). Hemoglobin and ferritin levels were higher in the group using Fe + 2 salt compared to both sucrosomial iron and microencapsulated iron groups (p < 0.0001). When the infants were evaluated according to iron status, it was found that 208 (31.9%) had iron deficiency. Iron deficiency was found to be less in infants of families who defined their economic status as rich and in infants who used iron regularly (p-values 0.044 and 0.001, respectively). Iron deficiency/iron deficiency anemia was observed at a higher rate in the group using sucrosomial iron and microencapsulated iron prophylaxis (p = 0.001). Conclusions: To prevent iron deficiency, it is very important to use appropriate iron preparations for prophylaxis and to feed foods with high iron content. Although we found that families were willing to use different iron preparations other than iron salts for their infants, the results presented herein indicate that the rate of iron deficiency was lower in patients using iron salts. However, randomized controlled studies are needed to determine whether these preparations are effective in iron prophylaxis in infants.

Restless legs syndrome (RLS) is a prevalent sensorimotor nervous system disorder in patients accompanied with insomnia, blood pressure fluctuation, and sympathetic dysfunction. These symptoms may disrupt cerebral hemodynamics. Dynamic cerebral autoregulation (dCA) describes the temporary response of cerebrovascular system to abrupt fluctuations in blood pressure, which keep cerebral blood flow stable and serve as a marker of cerebrovascular system ability.

This research aimed to assess dCA in RLS patients.

In this study, RLS patients were recruited and subsequently classified into four groups (mild, moderate, severe, and very severe) based on the International RLS Rating Scale (IRLS). Healthy controls matched for age and sex were enrolled. All participants were evaluated dCA by assessing phase difference (PD). A portion of patients with RLS was reassessed for dCA after one month of medication therapy (pramipexole [0.125 mg/day] and gabapentin [300 mg/day]).

There were altogether 120 patients with RLS and 30 controls completed the polysomnography and dCA assessment. PD was lower in the moderate, severe, and very severe RLS groups than that in the controls and mild RLS groups. Periodic limb movement index (PLMI), arousal index, and IRLS all showed a linear correlation with PD in RLS patients. Additionally, PD increased in RLS patients after therapy.

The dCA was compromised in moderate, severe, and very severe RLS patients and was negatively correlated with the IRLS, arousal index, and PLMI. After 1 month of therapy, dCA improved in RLS patients.

Observational studies had investigated the association of iron metabolism with anxiety disorders. The conclusions were inconsistent and not available to reveal the causal or reverse-causal association due to the confounding. In this study we estimated the potential causal effect of iron homeostasis markers on anxiety disorders using two-sample Mendelian randomization (MR) analysis.

Summary data of single nucleotide polymorphisms (SNPs) associated with four iron-related biomarkers were extracted from a recent report about analysis of three genome-wide association study (GWAS), the sample size of which ranged from 131471 to 246139 individuals. The corresponding data for anxiety disorders were from Finngen database (20992 cases and 197800 controls). The analyses were mainly based on inverse variance weighted (IVW) method. In addition, the heterogeneity and pleiotropy of the results were assessed by Cochran's Q test and MR-Egger regression.

Basing on IVW method, genetically predicted serum iron level, ferritin and transferrin had negative effects on anxiety disorders. The odd ratios (OR) of anxiety disorders per 1 standard deviation (SD) unit increment in iron status biomarkers were 0.922 (95% confidence interval (CI) 0.862-0.986; p = 0.018) for serum iron level, 0.873 (95% CI 0.790-0.964; p = 0.008) for log-transformed ferritin and 0.917 (95% CI 0.867-0.969; p = 0.002) for transferrin saturation. But no statical significance was found in the association of 1 SD unit increased total iron-binding capacity (TIBC) with anxiety disorders (OR 1.080; 95% CI 0.988-1.180; p = 0.091). The analyses were supported by pleiotropy test which suggested no pleiotropic bias.

Our results indicated that genetically determined iron status biomarkers causally linked to the risk of anxiety disorders, providing valuable insights into the genetic research and clinical intervention of anxiety disorders.

Delayed cord clamping has significant beneficial effects on the neonate and its transition to extrauterine life and, therefore, is common practice at vaginal births in the Netherlands. In 2015, 16% of neonates were born via cesarean delivery; moreover, in 81% of these cases, the umbilical cord was clamped and cut immediately. Neonatal benefits of delayed cord clamping are an increased circulating volume of 25 to 30 mL/kg, leading to a higher preload of both the right and left ventricles during the transition from umbilical circulation to pulmonary circulation, thus maintaining a stable left ventricle output, and to higher neonatal hemoglobin and hematocrit levels 24 to 48 hours after birth. Currently, little is known about whether the abovementioned neonatal benefits of delayed cord clamping could apply to neonates delivered by cesarean delivery. In these cases, possible negative effects on neonatal outcomes (ie, neonatal hypothermia, lower Apgar scores, and hyperbilirubinemia) and maternal outcomes (ie, increased maternal blood loss and higher postoperative infection rate) should also be taken into consideration.

This study aimed to determine whether clamping the umbilical cord after 2 minutes is superior to cord milking during elective cesarean deliveries at term, taking both short- and long-term neonatal and maternal outcomes into consideration, and to determine whether cord milking could be an appropriate alternative to delayed cord clamping.

A randomized controlled trial was conducted in a large secondary care center in the Netherlands (Amphia Hospital in Breda) from October 2020 to April 2022. A total of 115 patients who underwent an elective cesarean delivery between 37 0/7 and 41 6/7 weeks of gestation were included. The primary outcomes were neonatal hemoglobin and hematocrit levels at 48 hours after birth. The secondary outcomes were divided into neonatal and maternal outcomes.

After randomization, 58 participants were treated with cord milking, and 57 participants were treated with delayed cord clamping. There was no significant difference in demographic characteristics between both groups. There was no significant difference in the primary outcomes, with a mean hemoglobin level 48 hours after birth of 12.1 mmol/L in the delayed cord clamping group and 12.2 mmol/L in the cord milking group (P=.80). Regarding our secondary outcomes, there was no significant difference regarding Apgar score, neonatal body temperature, maternal blood loss, and postoperative infection rate between our intervention groups.

Hemoglobin and hematocrit levels at 48 hours after birth showed no significant difference when comparing delayed cord clamping with cord milking. Delayed cord clamping did not lead to increased maternal blood loss or postoperative infections compared with a method with a much shorter timeframe between delivery and clamping of the umbilical cord, namely, cord milking. In addition, delayed cord clamping did not lead to a lower Apgar score or neonatal temperature compared with cord milking. Our research suggests that delayed cord clamping can be safely performed during elective cesarean deliveries at term. If intraoperative circumstances do not allow for delayed cord clamping, cord milking can be an appropriate alternative for the neonate at term.

This article provides an overview of the background knowledge of ferroptosis in the nervous system, as well as the key role of nuclear factor E2-related factor 2 (Nrf2) in regulating ferroptosis. The article takes Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) as the starting point to explore the close association between Nrf2 and ferroptosis, which is of clear and significant importance for understanding the mechanism of neurodegenerative diseases (NDs) based on oxidative stress (OS). Accumulating evidence links ferroptosis to the pathogenesis of NDs. As the disease progresses, damage to the antioxidant system, excessive OS, and altered Nrf2 expression levels, especially the inhibition of ferroptosis by lipid peroxidation inhibitors and adaptive enhancement of Nrf2 signaling, demonstrate the potential clinical significance of Nrf2 in detecting and identifying ferroptosis, as well as targeted therapy for neuronal loss and mitochondrial dysfunction. These findings provide new insights and possibilities for the treatment and prevention of NDs.

Introduction. The pneumonia pattern in young children may vary across different catchment areas. Therefore, this study aims to analyze the predictive factors for toddlers with an Acute Respiratory Infection (ARI) developing into pneumonia in the catchment area of Banjar Regency, Indonesia. Methods. A case-control design, with 300 respondents, consisting of 106 cases and 194 controls. A questionnaire of interviews with mothers/caregivers of toddlers. Forty-one indicators data were analyzed using multiple logistic regression with backward stepwise regression to arrive at the final model. Results. The predictive factors for toddlers with pneumonia were the child's age (P-value .070), child development (P-value .007), breastfeeding (P-value .051), family income (P-value .026), and location of houses along the river (P-value .025). Conclusion. A prediction index for toddler pneumonia has been compiled, which can be applied to improve the health of lower middle-class toddlers requiring more government attention.

The prevalence of autism spectrum disorder (ASD), a neurodevelopmental disorder with a predominance of social behavioral disorders, has increased dramatically in various countries in recent decades. The interplay between genetic and environmental factors is believed to underlie ASD pathogenesis. Recent analyses have shown that abnormal vitamin levels in early life are associated with an increased risk of autism. As essential substances for growth and development, vitamins have been shown to have significant benefits for the nervous and immune systems. However, it is unknown whether certain vitamin types influence the emergence or manifestation of ASD symptoms. Several studies have focused on vitamin levels in children with autism, and neurotypical children have provided different insights into the types of vitamins and their intake. Here, we review the mechanisms and significance of several vitamins (A, B, C, D, E, and K) that are closely associated with the development of ASD in order to prevent, mitigate, and treat ASD. Efforts have been made to discover and develop new indicators for nutritional assessment of children with ASD to play a greater role in the early detection of ASD and therapeutic remission after diagnosis.

Iron is an essential mineral whose deficiency results in cognitive alteration, impaired emotional behaviors, and altered myelination and neurotransmission. In animal models, it has been shown that vitamin A (VA) could affect cognition.

The study aimed to evaluate the effectiveness of intermittent iron and VA supplementation on cognitive development of schoolchildren, and to assess the interaction between these supplementations.

Considering a 2 × 2 factorial design, 504 children were randomly assigned to 1 of the 4 arms: placebo VA and placebo iron supplement; high-dose vitamin VA and placebo iron supplement; iron supplement and placebo VA; and iron and high-dose vitamin VA supplements. Cognitive development was assessed using Raven's Coloured Progressive Matrices, digit span, Tower of London, and visual search tasks.

The mean [± standard deviation (SD)] age of the enrolled children was 9.6 (±1.6) y. One-fifth of the children had iron deficiency or anemia, whereas 2.9%, 3.9%, and 12.1% of children had low iron stores, iron deficiency anemia, and VA deficiency, respectively. Intermittent iron supplementation did not result in any significant improvement of children's cognitive development and had a negative effect on the performance index of the visual search task compared with placebo (-0.17 SD, 95% confidence interval: -0.32, -0.02). Effects were evident among children with stunting, thinness, or children coming from understimulating home environments. High-dose VA supplementation resulted in a significant improvement of digit span z-score with a mean difference of 0.30 SD (95% confidence interval: 0.14, 0.46) compared with placebo VA. VA had a more beneficial impact for girls, children infected with helminths, and those from food secure households.

In a population where the prevalence of iron deficiency is low, intermittent iron supplementation did not have any or negative effect on the child's cognitive development outcomes. Conversely, VA supplementation improved the child's working memory.

The study is registered at clinicaltrials.gov as NCT04137354 (https://clinicaltrials.gov/study/NCT04137354).

Iron physiology is regulated by a complex interplay of extracellular transport systems, coordinated transcriptional responses, and iron efflux mechanisms. Dysregulation of iron metabolism can result in defects in myelination, neurotransmitter synthesis, and neuronal maturation. In neonates, germinal matrix-intraventricular hemorrhage (GMH-IVH) causes iron overload as a result of blood breakdown in the ventricles and brain parenchyma which can lead to post-hemorrhagic hydrocephalus (PHH). However, the precise mechanisms by which GMH-IVH results in PHH remain elusive. Understanding the molecular determinants of iron homeostasis in the developing brain may lead to improved therapies. This manuscript reviews the various roles iron has in brain development, characterizes our understanding of iron transport in the developing brain, and describes potential mechanisms by which iron overload may cause PHH and brain injury. We also review novel preclinical treatments for IVH that specifically target iron. Understanding iron handling within the brain and central nervous system may provide a basis for preventative, targeted treatments for iron-mediated pathogenesis of GMH-IVH and PHH.

In accordance with the developmental origins of health and disease, early-life environmental exposures, such as maternal diet, can enhance the probability and gravity of health concerns in their offspring in the future. Over the past few years, compelling evidence has emerged suggesting that prenatal exposure to a maternal high-fat diet (HFD) could trigger neuropsychiatric disorders in the offspring, such as depression. The majority of brain development takes place before birth and during lactation. Nevertheless, our understanding of the impact of HFD on myelination in the offspring's brain during both gestation and lactation remains limited. In the present study, we investigated the effects of maternal HFD (60% energy from fat) on depressive-like and myelin-related changes in adolescent and adult rat offspring. Maternal HFD increased immobility time during the forced swimming test in both adolescent and adult offspring. Correspondingly, the depressive-like phenotype in offspring correlated with dysregulation of several genes and proteins in the prefrontal cortex, especially of myelin-oligodendrocyte glycoprotein (MOG), myelin and lymphocyte protein (MAL), 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase), kallikrein 6, and transferrin in male offspring, as well as of MOG and kallikrein 6 in female offspring, which persist even into adulthood. Maternal HFD also induced long-lasting adaptations manifested by the reduction of immature and mature oligodendrocytes in the prefrontal cortex in adult offspring. In summary, maternal HFD-induced changes in myelin-related genes are correlated with depressive-like behavior in adolescent offspring, which persists even to adulthood.

Iron is one of the essential metals that functions as a cofactor in various biological cascades in the brain. However, excessive iron accumulation in the brain may lead to neurodegeneration and may show toxic effects. Quercetin, a pigment flavonoid compound, has been proven to be a potent antioxidant and anti-inflammatory that can inhibit lipid peroxidation during metal-induced neurotoxicity. Although iron-induced neuroinflammation and neurodegeneration have been reported in many studies, but the proof for its exact mechanisms needs to be explored.

The key target of the study was to explore the neuroprotective effect of quercetin after oral exposure of iron in rats and explore its underlying molecular mechanisms.

The outcomes of the study have shown that oral exposure to ferrous sulfate may modulate behavioral paradigms such as locomotor activity, neuromuscular coordination, and increased anxiety level. The pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), apoptotic protein (caspase 3), beta-amyloid and phosphorylated tau were found to be increased on iron exposure. Also, the expressions of ferritin heavy and light chain, BACE-1 and GFAP expressions were altered. These behavioral, structural, and biochemical alterations in the brain were significantly and dose-dependently reversed by treatment with quercetin.

The current study provides a fundamental understanding of molecular signaling pathways, and structural proteins implicated in iron-induced neurotoxicity along with the ameliorative effects of quercetin.

Adequate and timely delivery of iron is essential for brain development. The uptake of transferrin-bound (Tf) iron into the brain peaks at the time of myelination, whereas the recently discovered H-ferritin (FTH1) transport of iron into the brain continues to increase beyond the peak in myelination. Here, we interrogate the impact of dietary iron deficiency (ID) on the uptake of FTH1- and Tf-bound iron. In the present study, we used C57BL/6J male and female mice at a developing (post-natal day (PND) 15) and adult age (PND 85). In developing mice, ID results in increased iron delivery from both FTH1 and Tf for both males and females. The amount of iron uptake from FTH1 was higher than the Tf and this difference between the iron delivery was much greater in females. In contrast, in the adult model, ID was associated with increased brain iron uptake by both FTH1 and Tf but only in the males. There was no increased uptake from either protein in the females. Moreover, transferrin receptor expression on the microvasculature as well as whole brain iron, and H and L ferritin levels revealed the male brains became iron deficient but not the female brains. Last, under normal dietary conditions, 55 Fe uptake was higher in the developing group from both delivery proteins than in the adult group. These results indicate that there are differences in iron acquisition between the developing and adult brain for FTH1 and Tf during nutritional ID and demonstrate a level of regulation of brain iron uptake that is age and sex-dependent.

Sleep problems are highly prevalent in those with neurodevelopmental disorders (NDDs). We propose this is secondary to multiple factors that directly and indirectly negatively impact sleep and circadian processes in those with NDDs, which in turn, further perturbs development, resulting in a "developmental and sleep/circadian-related encephalopathy." In this review, we discuss select NDDs with known or suspected sleep and circadian phenotypes. We also highlight important considerations when evaluating and treating sleep and circadian disorders in these populations.

Iron plays an essential role in various physiological processes. A disruption in iron homeostasis can lead to severe consequences, including impaired neurodevelopment, neurodegenerative disorders, stroke, and cancer. Interestingly, the link between mental health disorders and iron homeostasis has not received significant attention. Therefore, our understanding of iron metabolism in the context of psychological diseases is incomplete. In this review, we aim to discuss the pathologies and potential mechanisms that relate to iron homeostasis in associated mental disorders. We propose the hypothesis that maintaining brain iron homeostasis can support neuronal physiological functions by impacting key enzymatic activities during neurotransmission, redox balance, and myelination. In conclusion, our review highlights the importance of investigating the relationship between trace element nutrition and the pathological process of mental disorders, focusing on iron. This nutritional perspective can offer valuable insights for the clinical treatment of mental disorders.

Proprioception is essential to several conscious and unconscious sensations and automatic control of movement in daily life activities. Iron deficiency anemia (IDA) may alter proprioception as it could induce fatigue, and affect neural processes such as myelination, and neurotransmitters synthesis and degradation. This study aimed to explore the effect of IDA on proprioception in adult women. Thirty adult women with IDA and 30 controls participated in this study. The weight discrimination test was performed to assess proprioceptive acuity. Attentional capacity and fatigue were evaluated, too. Women with IDA had a significantly (P < 0.001) lower ability to discriminate weights compared to controls in the two difficult increments, and for the second easy weight (P < 0.01). For the heaviest weight, no significant difference was found. Attentional capacity and fatigue values were significantly (P < 0.001) higher in patients with IDA compared to controls. Moreover, moderate positive correlations between the representative proprioceptive acuity values and Hb (r = 0.68) and ferritin (r = 0.69) concentrations were found. Moderate negative correlations were found between the proprioceptive acuity values and general (r =  - 0.52), physical (r =  - 0.65) and mental (r =  - 0.46) fatigue scores, and attentional capacity (r =  - 0.52). Women with IDA had impaired proprioception compared to their healthy peers. This impairment may be related to neurological deficits due to the disruption of iron bioavailability in IDA. In addition, fatigue resulting from IDA due to the poor muscle oxygenation could also explain the proprioceptive acuity decrease in women suffering from IDA.

Impaired iron homeostasis has been proven to be one of the critical contributors to the pathology of Parkinson's disease (PD). Ferritin is considered an intracellular protein responsible for storing cytosolic iron. Recent studies have found that ferritin can be secreted from cells independent of the classical endoplasmic reticulum-Golgi system. However, the precise mechanisms underlying the secretion of ferritin in the brain were not elucidated. In the present study, we demonstrated that the primary cultured astrocytes do have the ability to secrete ferritin, which is enhanced by iron treatment. Increased ferritin secretion was accompanied by increased protein expression of ferritin response to iron stimulation. Further study showed that iron-induced expression and secretion of ferritin could be inhibited by CQ or 3-MA pretreatment. In addition, the knockdown of transient receptor potential mucolipin 1 (TRPML1) antagonized iron-induced ferritin secretion, accompanied by further increased intracellular protein levels of ferritin. Further study demonstrated that ferritin colocalized with LAMP1 in iron-treated astrocytes. On the contrary, ras-associated protein 27a (Rab27a) knockdown further enhanced iron-induced ferritin secretion and decreased intracellular protein levels of ferritin. Furthermore, we also showed that the secretory autophagy protein tripartite motif containing 16 (TRIM16) and sec22b decreased in iron-treated astrocytes. These results suggested that astrocytes might secrete ferritin via TRPML1-mediated exocytosis. This provides new evidence for the mechanisms underlying the secretion of ferritin in primary cultured astrocytes under a high iron environment.

Iron plays a crucial role in the biochemistry and development of nearly all living organisms. Iron starvation of pathogens during infection is a striking feature utilized by a host to quell infection. In mammals and some other animals, iron is essentially obtained from diet and recycled from erythrocytes. Free iron is cytotoxic and is readily available to invading pathogens. During infection, most pathogens utilize host iron for their survival. Therefore, to ensure limited free iron, the host's natural system denies this metal in a process termed nutritional immunity. In this fierce battle for iron, hosts win over some pathogens, but others have evolved mechanisms to overdrive the host barriers. Production of siderophores, heme iron thievery, and direct binding of transferrin and lactoferrin to bacterial receptors are some of the pathogens' successful strategies which are highlighted in this review. The intricate interplay between hosts and pathogens in iron alteration systems is crucial for understanding host defense mechanisms and pathogen virulence. This review aims to elucidate the current understanding of host and pathogen iron alteration systems and propose future research directions to enhance our knowledge in this field.

The multifactorial etiology of major depressive disorder (MDD) includes biological, environmental, genetic, and psychological aspects. Recently, there has been an increasing interest in metallomic studies in psychiatry, aiming to evaluate the role of chosen trace elements in the MDD etiology as well as the progression of symptoms. This narrative review aims to summarize the available literature on the relationship between the concentration of chosen elements in the serum of patients with MDD and the onset and progression of this psychiatric condition. The authors reviewed PubMed, Web of Science, and Scopus databases searching for elements that had been investigated so far and further evaluated them in this paper. Ultimately, 15 elements were evaluated, namely, zinc, magnesium, selenium, iron, copper, aluminium, cadmium, lead, mercury, arsenic, calcium, manganese, chromium, nickel, and phosphorus. The association between metallomic studies and psychiatry has been developing dynamically recently. According to the results of current research, metallomics might act as a potential screening tool for patients with MDD while at the same time providing an assessment of the severity of symptoms. Either deficiencies or excessive amounts of chosen elements might be associated with the progression of depressive symptoms or even the onset of the disease among people predisposed to MDD.

Exposure to early-life adversity (ELA) and iron deficiency early in life are known risk factors for suboptimal brain and socioemotional development. Iron deficiency may arise from and co-occur with ELA, which could negatively affect development. In the present study, we investigated whether ELA is associated with iron deficiency in infants receiving no iron supplementation. This study is a secondary analysis of extant data collected in the 1990s; participants were healthy infants from working-class communities in Santiago, Chile (N = 534, 45.5% female). We measured stressful life events, maternal depression, and low home support for child development during infancy and assessed iron status when the infant was 12 months old. Slightly more than half of the infants were iron-deficient (51%), and 25.8% were iron-deficient anemic at 12 months. Results indicated that ELA was associated with lower iron levels and iron deficiency at 12 months. The findings are consistent with animal and human prenatal models of stress and iron status and provide evidence of the association between postnatal ELA and iron status in humans. The findings also highlight a nutritional pathway by which ELA may impact development and present a nutritionally-focused avenue for future research on ELA and psychopathology.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric movement disorder with reported abnormalities in various neurotransmitter systems. Considering the integral role of iron in neurotransmitter synthesis and transport, it is hypothesized that iron exhibits a role in GTS pathophysiology. As a surrogate measure of brain iron, quantitative susceptibility mapping (QSM) was performed in 28 patients with GTS and 26 matched controls. Significant susceptibility reductions in the patients, consistent with reduced local iron content, were obtained in subcortical regions known to be implicated in GTS. Regression analysis revealed a significant negative association of tic scores and striatal susceptibility. To interrogate genetic mechanisms that may drive these reductions, spatially specific relationships between susceptibility and gene-expression patterns from the Allen Human Brain Atlas were assessed. Correlations in the striatum were enriched for excitatory, inhibitory, and modulatory neurochemical signaling mechanisms in the motor regions, mitochondrial processes driving ATP production and iron‑sulfur cluster biogenesis in the executive subdivision, and phosphorylation-related mechanisms affecting receptor expression and long-term potentiation in the limbic subdivision. This link between susceptibility reductions and normative transcriptional profiles suggests that disruptions in iron regulatory mechanisms are involved in GTS pathophysiology and may lead to pervasive abnormalities in mechanisms regulated by iron-containing enzymes.

This review presents evidence from animal and human studies demonstrating the possible connection and significant impact of poor iron status and psychological distress on neurocognitive development during pregnancy and the neonatal period, with implications for long-term cognition. Stress and iron deficiency are independently prevalent and thus are frequently comorbid. While iron deficiency and early-life stress independently contribute to long-term neurodevelopmental alterations, their combined effects remain underexplored. Psychological stress responses may engage similar pathways as infectious stress, which alters fundamental iron metabolism processes and cause functional tissue-level iron deficiency. Psychological stress, analogous to but to a lesser degree than infectious stress, activates the hypothalamic-pituitary-adrenocortical (HPA) axis and increases proinflammatory cytokines. Chronic or severe stress is associated with dysregulated HPA axis functioning and a proinflammatory state. This dysregulation may disrupt iron absorption and utilization, likely mediated by the IL-6 activation of hepcidin, a molecule that impedes iron absorption and redistributes total body iron. This narrative review highlights suggestive studies investigating the relationship between psychological stress and iron status and outlines hypothesized mechanistic pathways connecting psychological stress exposure and iron metabolism. We examine findings regarding the overlapping impacts of early stress exposure to iron deficiency and children's neurocognitive development. We propose that studying the influence of psychological stress on iron metabolism is crucial for comprehending neurocognitive development in children exposed to prenatal and early postnatal stressors and for children at risk of early iron insufficiency. We recommend future directions for dual-exposure studies exploring iron as a potential mediating pathway between early stress and offspring neurodevelopment, offering opportunities for targeted interventions.

Children in foster care are classified as a highly vulnerable population and struggle with both physical and mental health problems. Medical conditions, like poor nutritional status, remain understudied in children in foster care. To our knowledge, few studies in children in U.S. foster care have quantified the prevalence of anemia, and no studies have examined the association between anemia status and relevant developmental and behavioral outcomes.

(1) To determine the prevalence of anemia among children in or adopted from Pennsylvania foster care, between the ages of six months to ten years and (2) To examine if a child's anemia status is associated with greater odds of relevant developmental and behavioral diagnoses.

We conducted a secondary data analysis utilizing the Medicaid Analytic eXtract database between 2010-2015. Children six months-ten years were included in the analysis if they were in or had been adopted from Pennsylvania foster care. Logistic regression was used to calculate adjusted odds ratios (AOR) with 95% confidence intervals for the association between iron status and health outcomes.

A total of 50,311 children were included in our sample, of which 1,365 children (2.7%) were diagnosed with anemia. Children diagnosed with anemia had greater odds of delayed milestones (AOR: 2.38 [1.64-3.45]), specific delays in development (AOR: 1.59 [1.23-2.07]), adjustment disorder (AOR: 1.59 [1.06-2.39]), and irritability (AOR: 10.57 [3.36-33.25]), than children not diagnosed with anemia.

The prevalence of anemia among children between six months-ten years in or adopted from the Pennsylvania foster care system is within the national rate of U.S. childhood anemia. Odds of several relevant developmental and behavioral diagnoses were greater among children diagnosed with anemia than children who were not.

Previous studies have revealed structural, functional, and metabolic changes in brain regions inside the cortico-striatal-thalamo-cortical (CSTC) loop in patients with paroxysmal kinesigenic dyskinesia (PKD), whereas no quantitative susceptibility mapping (QSM)-related studies have explored brain iron deposition in these areas.

A total of eight familial PKD patients and 10 of their healthy family members (normal controls) were recruited and underwent QSM on a 3T magnetic resonance imaging system. Magnetic susceptibility maps were reconstructed using a multi-scale dipole inversion algorithm. Thereafter, we specifically analyzed changes in local mean susceptibility values in cortical regions and subcortical nuclei inside the motor CSTC loop.

Compared with normal controls, PKD patients had altered brain iron levels. In the cortical gray matter area involved with the motor CSTC loop, susceptibility values were generally elevated, especially in the bilateral M1 and PMv regions. In the subcortical nuclei regions involved with the motor CSTC loop, susceptibility values were generally lower, especially in the bilateral substantia nigra regions.

Our results provide new evidence for the neuropathogenesis of PKD and suggest that an imbalance in brain iron levels may play a role in PKD.

The incidence of neurological diseases, such as Parkinson's disease, Alzheimer's disease and stroke, is increasing. An increasing number of studies have correlated these diseases with brain iron overload and the resulting oxidative damage. Brain iron deficiency has also been closely linked to neurodevelopment. These neurological disorders seriously affect the physical and mental health of patients and bring heavy economic burdens to families and society. Therefore, it is important to maintain brain iron homeostasis and to understand the mechanism of brain iron disorders affecting reactive oxygen species (ROS) balance, resulting in neural damage, cell death and, ultimately, leading to the development of disease. Evidence has shown that many therapies targeting brain iron and ROS imbalances have good preventive and therapeutic effects on neurological diseases. This review highlights the molecular mechanisms, pathogenesis and treatment strategies of brain iron metabolism disorders in neurological diseases.

Parkinson's disease (PD) is the most common neurodegenerative disorder with motor symptoms. The neuropathological alterations characterizing the brain of patients with PD include the loss of dopaminergic neurons of the nigrostriatal system and the presence of Lewy bodies (LB), intraneuronal inclusions that are mainly composed of alpha-synuclein (α-Syn) fibrils. The accumulation of α-Syn in insoluble aggregates is a main neuropathological feature in PD and in other neurodegenerative diseases, including LB dementia (LBD) and multiple system atrophy (MSA), which are therefore defined as synucleinopathies. Compelling evidence supports that α-Syn post translational modifications (PTMs) such as phosphorylation, nitration, acetylation, O-GlcNAcylation, glycation, SUMOylation, ubiquitination and C-terminal cleavage, play important roles in the modulation α-Syn aggregation, solubility, turnover and membrane binding. In particular, PTMs can impact on α-Syn conformational state, thus supporting that their modulation can in turn affect α-Syn aggregation and its ability to seed further soluble α-Syn fibrillation. This review focuses on the importance of α-Syn PTMs in PD pathophysiology but also aims at highlighting their general relevance as possible biomarkers and, more importantly, as innovative therapeutic targets for synucleinopathies. In addition, we call attention to the multiple challenges that we still need to face to enable the development of novel therapeutic approaches modulating α-Syn PTMs.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric movement disorder with reported abnormalities in various neurotransmitter systems. Considering the integral role of iron in neurotransmitter synthesis and transport, it is hypothesized that iron exhibits a role in GTS pathophysiology. As a surrogate measure of brain iron, quantitative susceptibility mapping (QSM) was performed in 28 patients with GTS and 26 matched controls. Significant susceptibility reductions in the patient cohort, consistent with reduced local iron content, were obtained in subcortical regions known to be implicated in GTS. Regression analysis revealed a significant negative association of tic scores and striatal susceptibility. To interrogate genetic mechanisms that may drive these reductions, spatially specific relationships between susceptibility and gene-expression patterns extracted from the Allen Human Brain Atlas were assessed. Correlations in the striatum were enriched for excitatory, inhibitory, and modulatory neurochemical signaling mechanisms in the motor regions, mitochondrial processes driving ATP production and iron-sulfur cluster biogenesis in the executive subdivision, and phosphorylation-related mechanisms that affect receptor expression and long-term potentiation. This link between susceptibility reductions and normative transcriptional profiles suggests that disruptions in iron regulatory mechanisms are involved in GTS pathophysiology and may lead to pervasive abnormalities in mechanisms regulated by iron-containing enzymes.

Iron plays a key role in a broad set of metabolic processes. Iron deficiency is the most common nutritional deficiency in the world, but its neuropsychiatric implications in adolescents have not been examined.

Twelve- to 17-year-old unmedicated females with major depressive or anxiety disorders or with no psychopathology underwent a comprehensive psychiatric assessment for this pilot study. A T1-weighted magnetic resonance imaging scan was obtained, segmented using Freesurfer. Serum ferritin concentration (sF) was measured. Correlational analyses examined the association between body iron stores, psychiatric symptom severity, and basal ganglia volumes, accounting for confounding variables.

Forty females were enrolled, 73% having a major depressive and/or anxiety disorder, 35% with sF < 15 ng/mL, and 50% with sF < 20 ng/mL. Serum ferritin was inversely correlated with both anxiety and depressive symptom severity (r = -0.34, p < 0.04 and r = -0.30, p < 0.06, respectively). Participants with sF < 15 ng/mL exhibited more severe depressive and anxiety symptoms as did those with sF < 20 ng/mL. Moreover, after adjusting for age and total intracranial volume, sF was inversely associated with left caudate (Spearman's r = -0.46, p < 0.04), left putamen (r = -0.58, p < 0.005), and right putamen (r = -0.53, p < 0.01) volume.

Brain iron may become depleted at a sF concentration higher than the established threshold to diagnose iron deficiency (i.e. 15 ng/mL), potentially disrupting brain maturation and contributing to the emergence of internalizing disorders in adolescents.