Brain Iron Distribution Research Articles

Differently Distributed Iron Deposition in Mild and Moderate Stroke with Small Artery Occlusion: A Pilot Voxel-Based Susceptibility Mapping Study.

Small artery occlusion (SAO) is a common ischemic stroke subtype. However, its clinical outcome can be more severe than commonly understood. The severity of SAO can vary, ranging from mild to moderate. Iron deposition has been associated with the development and progression of stroke. However, its specific distribution and relationship with stroke severity in SAO remain unclear. The study's purpose is to investigate the differences in iron deposition between mild stroke with SAO (SAO-MiS) and moderate stroke with SAO (SAO-MoS) through quantitative susceptibility mapping (QSM) and its association with neurological deficits. Sixty-eight SAO participants within 24 hours of first onset were enrolled and separated into SAO-MiS and SAO-MoS according to the National Institutes of Health Stroke Scale (NIHSS) scores. QSM helped calculate the susceptibility maps, reflecting the iron content within the brain. The susceptibility maps were analyzed using voxel-wise statistical analysis to compare the iron deposition between SAO-MiS and SAO-MoS. Then, differentially distributed iron deposition helped differentiate between mild and moderate stroke using support vector machine (SVM) methods. Compared with SAO-MiS, SAO-MoS depicted elevated iron deposition in the left pallidum, parahippocampal gyrus, and superior frontal gyrus medial region, and is lower in the right superior/middle frontal gyrus and bilateral supplementary motor area. Based on iron deposition, the SVM classifier's analysis revealed a high power to discriminate SAO-MoS from SAO-MiS. In addition, fibrinogen, triglyceride (TG), and total cholesterol (TC) were linked with QSM values in specific brain regions. Our study first revealed the brain iron distribution after SAO and differently distributed iron deposition in SAO-MiS and SAO-MoS. The results indicate that iron deposition could play a role in the pathophysiology of SAO and its correlation with stroke severity.

Regional iron distribution and soluble ferroprotein profiles in the healthy human brain

Iron is essential for brain development and health where its redox properties are used for a number of neurological processes. However, iron is also a major driver of oxidative stress if not properly controlled. Brain iron distribution is highly compartmentalised and regulated by a number of proteins and small biomolecules. Here, we examine heterogeneity in regional iron levels in 10 anatomical structures from seven post-mortem human brains with no apparent neuropathology. Putamen contained the highest levels, and most case-to-case variability, of iron compared with the other regions examined. Partitioning of iron between cytosolic and membrane-bound iron was generally consistent in each region, with a slightly higher proportion (55 %) in the ‘insoluble’ phase. We expand on this using the Allen Human Brain Atlas to examine patterns between iron levels and transcriptomic expression of iron regulatory proteins and using quantitative size exclusion chromatography-inductively coupled plasma-mass spectrometry to assess regional differences in the molecular masses to which cytosolic iron predominantly binds. Approximately 60 % was associated with ferritin, equating to approximately 25 % of total tissue iron essentially in storage. This study is the first of its kind in human brain tissue, providing a valuable resource and new insight for iron biologists and neuroscientists, alike.

Gender-related differences in the regional distribution of brain iron in A53T transgenic mice

Gender-related differences in the regional distribution of brain iron in A53T transgenic mice

Ferroportin-mediated iron export from vascular endothelial cells in retina and brain

Retinal iron accumulation has been implicated in the pathogenesis of age-related macular degeneration (AMD) and other neurodegenerative diseases. The retina and the brain are protected from the systemic circulation by the blood retinal barrier (BRB) and blood brain barrier (BBB), respectively. Iron levels within the retina and brain need to be tightly regulated to prevent oxidative injury. The method of iron entry through the retina and brain vascular endothelial cells (r&bVECs), an essential component of the BRB and BBB, is not fully understood. However, localization of the cellular iron exporter, ferroportin (Fpn), to the abluminal membrane of these cells, leads to the hypothesis that Fpn may play an important role in the import of iron across the BRB and BBB. To test this hypothesis, a mouse model with deletion of Fpn within the VECs in both the retina and the brain was developed through tail vein injection of AAV9-Ple261(CLDN5)-icre to both experimental Fpnf/f, and control Fpn+/+ mice at P21. Mice were aged to 9 mo and changes in retinal and brain iron distribution were observed. In vivo fundus imaging and quantitative serum iron detection were used for model validation. Eyes and brains were collected for immunofluorescence. Deletion of Fpn from the retinal and brain VECs leads to ferritin-L accumulation, an indicator of elevated iron levels, in the retinal and brain VECs. This occurred despite lower serum iron levels in the experimental mice. This result suggests that Fpn normally transfers iron from retinal and brain VECs into the retina and brain. These results help to better define the method of retina and brain iron import and will increase understanding of neurodegenerative diseases involving iron accumulation.

T2*-weighted MRI values correlate with motor and cognitive dysfunction in Parkinson's disease

Brain iron load is one of the main neuropathologic hallmarks of Parkinson's disease (PD). Previous studies indicated that iron in the substantia nigra (SN) is related to disease duration and motor impairment. We explore, through a cross-sectional study, the association between brain iron distribution, evaluated by T2*-weighted magnetic resonance imaging (T2*), and clinical features in a cohort of patients with PD. Thirty-two patients with PD, compared with 10 control subjects, were evaluated for motor and cognitive features (attention and working memory, executive functions, language, memory, and visuospatial function). They underwent a magnetic resonance imaging protocol including T2* analysis of specific brain regions of interest to measure iron load compared with healthy control subjects. We found that iron content of the SN correlated positively with both disease duration and Unified Parkinson's Disease Rating Scale III off score. Montreal Cognitive Assessment, Spatial Span, and Graded Naming Test scores were inversely associated with iron load of the SN, whereas Wechsler Adult Intelligence Scale-IV Similarities score showed an inverse relationship with iron content in all the regions of interest examined. Our findings suggest a relationship between topographic brain iron distribution and cognitive domain impairment.

Synchrotron XRF imaging of Alzheimer’s disease basal ganglia reveals linear dependence of high-field magnetic resonance microscopy on tissue iron concentration

BackgroundChemical imaging of the human brain has great potential for diagnostic and monitoring purposes. The heterogeneity of human brain iron distribution, and alterations to this distribution in Alzheimer’s disease, indicate iron as a potential endogenous marker. The influence of iron on certain magnetic resonance imaging (MRI) parameters increases with magnetic field, but is under-explored in human brain tissues above 7 T. New MethodMagnetic resonance microscopy at 9.4 T is used to calculate parametric images of chemically-unfixed post-mortem tissue from Alzheimer’s cases (n = 3) and healthy controls (n = 2). Iron-rich regions including caudate nucleus, putamen, globus pallidus and substantia nigra are analysed prior to imaging of total iron distribution with synchrotron X-ray fluorescence mapping. Iron fluorescence calibration is achieved with adjacent tissue blocks, analysed by inductively coupled plasma mass spectrometry or graphite furnace atomic absorption spectroscopy. ResultsCorrelated MR images and fluorescence maps indicate linear dependence of R2, R2* and R2’ on iron at 9.4 T, for both disease and control, as follows: [R2(s−1) = 0.072[Fe] + 20]; [R2*(s−1) = 0.34[Fe] + 37]; [R2’(s−1) = 0.26[Fe] + 16] for Fe in μg/g tissue (wet weight). Comparison with Existing MethodsThis method permits simultaneous non-destructive imaging of most bioavailable elements. Iron is the focus of the present study as it offers strong scope for clinical evaluation; the approach may be used more widely to evaluate the impact of chemical elements on clinical imaging parameters. ConclusionThe results at 9.4 T are in excellent quantitative agreement with predictions from experiments performed at lower magnetic fields.

234. Susceptibility-weighted MRI values correlate with motor and cognitive dysfunction in Parkinson’s disease

Introduction Brain iron load is an important neuropathological mark in Parkinson’s disease (PD) and it can be quantified by MR susceptibility-weighted imaging (SWI). We estimated the correlation between cerebral iron distribution evaluated by SWI and cognitive pattern in a group of PD patients. Materials and methods 32 patients and 10 healthy subjects comparable for age and gender were enrolled. Patients were examined for motor and cognitive assessment. Cognitive outline was assessed with MoCA for global cognitive abilities and with a battery of neuropsychological tests. Functional daily abilities were tested using ADL and IADL scales. Patients and controls underwent MRI acquisition on a 3.0 T Philips Achieva system. For each emisphere seven ROIs were considered: putamen, globus pallidus, caudate nucleus, red nucleus, substantia nigra, dentate nucleus and frontal white matter. We measured SWI-intensity values for each ROI: lower values correspond to higher iron content. All the collected data were expressed as mean value and standard deviation. Chi-square test was used to verify associations between categorical variables. Results Higher iron deposits were detected in all the ROIs in patients compared to controls. SWI-intensity values of substantia nigra correlates negatively with disease duration and UPDRS-III off and positively with ADL and IADL scores. A positive and significant relationship between MoCA ( Conclusions According to literature [1] , brain iron distribution estimated by SWI seems to be a useful tool for cognitive decline in PD.

The Role of Presenilin in Protein Trafficking and Degradation—Implications for Metal Homeostasis

An imbalance in metal homeostasis is a prominent feature of Alzheimer's disease (AD). A wealth of evidence from independent studies over the past two and half decades has found changes to the distribution of brain iron, zinc, and copper in AD patients and animal models of the disease. Early research focused on the association of these metals with amyloid beta (Aβ), particularly extraneuronal Aβ plaque pathology. In contrast, there are numerous studies that have demonstrated a loss of iron-, zinc-, or copper-dependent cellular functions in AD animal and cell models, highlighting the importance of metal homeostasis in maintaining healthy brain function. Characterizing the molecular pathways that are impacted by iron, zinc, or copper will shed light on how these metals affect neuoroprotection, and conversely, neurodegeneration. Of particular interest is the role that the AD-associated presenilins have on protein trafficking and degradation, as metal homeostasis is dependent on the efficient trafficking and recycling of specific metal transporters. This review summarizes what is currently known about presenilin-dependent protein trafficking and the role of presenilin in protein turnover, particularly via the autophagy-lysosomal system.

The role of iron accumulation in postoperative cognitive dysfunction

Background Postoperative cognitive dysfunction (POCD) is a common neurological complication after anesthesia and surgery,especially prevalent in the elderly.Iron accumulation in the brain is an initial cause of neurodegeneration,it gives rise to neuronal degeneration and necrosis by arousing oxidative stress.Objective This review aims to investigate the role of iron accumulation in POCD.Content The distribution of brain iron,iron metabolism protein function,the relationship of excessive iron levels in the brain and neurodegeneration,as well as the progress of iron accumulation in POCD are described in the article.Trend Iron accumulation may be an important mechanism of POCD,the neuroprotection of iron chelator is expected to provide new target for the management of POCD. Key words: Iron accumulation; Neurodegeneration; Postoperative cognitive dysfunction

Measurement of brain iron distribution in Hallevorden‐Spatz syndrome

To investigate spatial distribution of iron accumulation in the globus pallidus (GP) in patients with Hallevorden-Spatz syndrome (HSS) using phase imaging. We compared sensitivity of a phase imaging technique to relaxation rate measurement methods (R1,R2,R2*) for iron quantification. R1, R2, and R2* were measured in GP structure of the brain of eight pantothenate kinase-associated neurodegeneration (PKAN) patients and a healthy volunteer using a 3T magnetic resonance imaging (MRI) scanner. The phase of gradient-echo images was preprocessed to eliminate phase 2pi wrapping and filtered to remove phase background variations. Phase gap across GP structure was used as a metric for iron effects quantification. Among the relaxation rates the most sensitive to iron accumulation was the R2* rate. The R1 and R2 rates demonstrated only small variations in this group of subjects. Up to an order of magnitude phase gap changes were measured between one PKAN patient and an age-matched healthy volunteer. Assuming that phase gap differences scale linearly with iron concentration we estimate that up to 2 mg Fe/g ww accumulates in GP of these patients. Our results demonstrate significantly higher sensitivity of the phase measurements for quantitative assessment of iron concentration compared to the relaxation rate measurements. Phase measurements could potentially be used for monitoring a progression and a response to therapy in PKAN.

A comparison of rapid-scanning X-ray fluorescence mapping and magnetic resonance imaging to localize brain iron distribution

The clinical diagnosis of many neurodegenerative disorders relies primarily or exclusively on observed behaviors rather than measurable physical tests. One of the hallmarks of Alzheimer disease (AD) is the presence of amyloid-containing plaques associated with deposits of iron, copper and/or zinc. Work in other laboratories has shown that iron-rich plaques can be seen in the mouse brain in vivo with magnetic resonance imaging (MRI) using a high-field strength magnet but this iron cannot be visualized in humans using clinical magnets. To improve the interpretation of MRI, we correlated iron accumulation visualized by X-ray fluorescence spectroscopy, an element-specific technique with T1, T2, and susceptibility weighted MR (SWI) in a mouse model of AD. We show that SWI best shows areas of increased iron accumulation when compared to standard sequences.

HFE gene mutations in a population of Italian Parkinson's disease patients

An abnormal accumulation and distribution of brain iron are common to different neurodegenerative disorders, including Parkinson's disease (PD), and alteration of genes involved in iron metabolism cause neurodegeneration with brain iron accumulation. HFE participates in the regulation of iron metabolism, its mutations are primary cause of hereditary hemochromatosis and appear to be more frequent in neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis. However, conflicting results were obtained in previous studies aimed to verify if nucleotide variations in HFE gene act as risk modifiers for PD. We used denaturing HPLC for scanning DNA sequence variations in exon 2 and 4 of HFE gene in a cohort of 475 Italian PD patients. We identified the most common H63D, C282Y and S65C, and also other 4 rare mutation types (R66H, R224W, E277K, and T281M). The allele frequency of H63D and C282Y was not statistically different from that of 2 control groups with similar mean age or of a large cohort of the same geographical area. In addition we could not find statistical differences in the clinical phenotypes of patients carrying at least one mutated HFE allele from those with the normal allele. We conclude that in the Italian population, the most common HFE mutations, H63D and C282Y are not associated with the individual risk to develop PD, nor have specific influence on the clinical features of the disease.

Quiescence induced by iron challenge protects neuroblastoma cells from oxidative stress

The brain uses massive amounts of oxygen, generating large quantities of reactive oxygen species (ROS). Because of its lipid composition, rich in unsaturated fatty acids, the brain is especially vulnerable to ROS. Furthermore, oxidative damage in the brain is often associated with iron, which has pro-oxidative properties. Iron-mediated oxidative damage in the brain is compounded by the fact that brain iron distribution is non-uniform, being particularly high in areas sensitive to neurodegeneration. This work was aimed to further our understanding of the cellular mechanisms by which SHSY5Y neuroblastoma cells adapt to, and survive increasing iron loads. Using an iron accumulation protocol that kills about 50% of the cell population, we found by cell sorting analysis that the SHSY5Y sub-population that survived the iron loading arrested in the G(0) phase of the cell cycle. These cells expressed neuronal markers, while their electrical properties remained largely unaltered. These results suggest that upon iron challenge, neuroblastoma cells respond by entering the G(0) phase, somehow rendering them resistant to oxidative stress. A similar physiological condition might be involved in neuronal survival in tissues known to accumulate iron with age, such as the hippocampus and the substantia nigra pars compacta.

Regulation of the profile of iron-management proteins in brain microvasculature.

The distribution of brain iron is heterogeneous, but the mechanism by which these regional differences are achieved and maintained is unknown. In this study, the authors test two hypotheses related to brain iron transport. The first is that there is regional variability in the profile of proteins associated with iron transport and storage in the brain microvasculature. The second hypothesis is that the iron status of the brain will dictate the response of the protein profile in the microvasculature to changes in systemic iron status. The profile analysis consists of transferrin (iron transport), ferritin (iron storage), transferrin receptor (iron uptake), and divalent metal transporter 1 (release of iron from endosomes). An additional protein involved in cellular iron efflux, ferroportin, was not detected in brain microvasculature. The results show that there are significantly higher levels of these proteins in the microvasculature from each area of the brain compared to a whole brain homogenate, but no regional differences within the microvasculature. The levels of ferritin observed in the microvasculature indicate that the microvascular endothelial cells have significant iron storage capacity. There are no significant changes in the regional protein profiles in response to systemic iron manipulation when brain iron status was normal. In contrast, in Belgrade rats, whose brain is iron deficient, the expression of both divalent metal transporter 1 and transferrin receptor was increased compared with control in almost all brain regions examined, but not transferrin or ferritin. These findings indicate that regional brain iron heterogeneity is not maintained by differences in microvascular iron-management protein levels. The results also indicate that brain iron status dictates the response of the microvascular protein profile to systemic iron manipulation.

Iron deficiency alters iron regulatory protein and iron transport protein expression in the perinatal rat brain.

Iron plays an important role in numerous vital enzyme systems in the perinatal brain. The membrane proteins that mediate iron transport [transferrin receptor (TfR) and divalent metal transporter 1 (DMT-1)] and the iron regulatory proteins (IRP-1 and IRP-2) that stabilize their mRNAs undergo regional developmental changes in the iron-sufficient rat brain between postnatal day (P) 5 and 15. Perinatal iron deficiency (ID) affects developing brain regions nonhomogeneously, suggesting potential differences in regional iron transporter and regulatory protein expression. The objective of the study was to determine the effect of perinatal ID on regional expression of IRP-1, IRP-2, TfR, and DMT-1 in the developing rat brain. Gestationally iron-deficient Sprague Dawley rat pups were compared with iron-sufficient control pups at P10. Serial 12-mu coronal sections of fixed frozen brain from pups on P10 were assessed by light microscopy for IRP-1, IRP-2, DMT-1, and TfR localization. ID did not change the percentage of cells with positive staining for the four proteins in the choroid epithelium, ependyma, vascular endothelium, or neurons of the striatum. ID increased the percentage of neurons expressing the four proteins in the hippocampus and the cerebral cortex. Increased numbers of TfR- and DMT-1-positive cells were always associated with increased IRP-positive cells. The P10 rat responds to perinatal ID by selectively increasing the number of neurons expressing IRP-regulated transporters in brain regions that are rapidly developing, without any change at transport surfaces or in regions that are quiescent. Brain iron distribution during ID seems to be locally rather than globally regulated.

Cord serum ferritin levels, fetal iron status, and neurodevelopmental outcomes: Correlations and confounding variables

Cord serum ferritin levels, fetal iron status, and neurodevelopmental outcomes: Correlations and confounding variables

Distribution of brain iron, ferritin, and transferrin in the 28-day-old piglet

This study sought to gain understanding of the effect of iron deficiency anemia on regional brain iron, ferritin, and transferrin concentrations in the growing piglet. We wanted to use an animal whose development is more similar to human development than rodent models. Fourteen 1-month-old piglets were used for this study. One group (n = 7) received supplemental iron (100 mg iron dextran injected intramuscularly) at postnatal day 2; the second group (n = 7) received no iron injection and became iron deficient anemic. Anemia was verified in the iron deficient group [hemoglobin of 41 g/L, compared with 112 g/L in controls and hematocrit (15%, compared with 34% in controls)] when piglets were 28 days old. Brain iron concentrations were significantly lower due to iron deficiency ( P = 0.02). The H-chain to L-chain (H:L chain) ferritin ratio was decreased in response to iron deficiency with the exception of substantia nigra and deep cerebellar nuclei, which were significantly higher than controls ( P < 0.05). Compared with adult levels, brain iron concentrations were much lower and transferrin much higher in the piglets, suggesting a very active iron uptake system even in control piglets. A much lower H:L chain ferritin ratio ( P < 0.05) in adult brain regions indicates a shift in the ferritin isoform expression in brain either as a function of increasing iron concentration or development. These data indicate that the brain of the 28-day-old piglet is actively acquiring iron regardless of the administration of exogenous iron.

Implication of iron in seizure syndrome of mutant chicks ( Gallus domesticus)

1. 1. An investigation was made of systemic iron in paroxysmal ( px) chicks. 2. 2. Serum transferrin levels in px chicks are greatly increased ( P < 0.05) over control levels, but iron-binding capacity is decreased ( P < 0.05). 3. 3. The delayed (by 10 days) increase in px hemoglobin ( P < 0.01) may be due to the general debilitation seen in px syndrome. 4. 4. An attempt to determine brain iron showed no deposits comparable to mammalian brain iron distribution, but this was consistent with inability of others to locate iron in adult chicken brain tissue.