Ferroptosis in ischemic stroke: Animal models and mechanisms.

Stroke is a major cause of death and disability worldwide, with the majority of cases resulting from ischemic events due to arterial occlusion. Current therapeutic approaches focus on rapid reperfusion through intravenous thrombolysis and intravascular thrombectomy. Although these interventions can mitigate long-term disability, reperfusion itself may induce neuronal injury. The exact mechanisms underlying neuronal damage following cerebral ischemia have yet to be reported. Recent research suggests that ferroptosis may play a significant role in post-ischemic neuronal death, which can be targeted to prevent neuronal loss. This review explores the three essential hallmarks of ferroptosis: the presence of redox-active iron, the peroxidation of polyunsaturated fatty acid-containing phospholipids, and the loss of lipid peroxide repair capacity. The involvement of ferroptosis in neuronal injury following ischemic stroke is also explored, along with an overview of ferroptosis-associated changes in different ischemic stroke animal models. Furthermore, recent therapeutic interventions targeting the ferroptosis pathway, as well as the opportunities, difficulties, and future directions of ferroptosis-targeted therapies in ischemic stroke, are discussed.

Iron Deposition and Functional Connectivity Differences in Females With Migraine Without Aura: A Comparative Study of Headache Sides.

BACKGROUND: The pathophysiological mechanisms underlying migraine without aura (MwoA) in females remain incompletely elucidated. Currently, the association between headache laterality and iron deposition (ID), and functional connectivity (FC) in female MwoA patients has not been fully studied. METHODS: We prospectively recruited 63 female patients with MwoA and 31 matched healthy controls (HC) from the hospital. ID and FC among the four groups were analyzed using two-sample t-tests (with cluster-wise family-wise error [FWE] correction). Pearson correlation analysis was used to evaluate the relationships between clinical variables and both ID and FC values. Significance level: p < 0.05. RESULTS: Compared to HC, left-sided MwoA exhibited differences in ID in various brain regions, including the cerebellum, left orbital inferior frontal gyrus, left calcarine gyrus, right putamen, and left caudate nucleus, as well as exhibited enhanced FC between the left lobule III of the cerebellum and the right superior temporal gyrus. Compared to bilateral MwoA, left-sided MwoA showed significantly enhanced in FC values in the left calcarine gyrus, the right precentral gyrus, the right postcentral gyrus, and the right lingual gyrus. Additionally, significant differences were observed in the Pearson correlations between clinical variables and both ID and FC in the female MwoA subgroups. CONCLUSION: Our study provided preliminary evidence indicating significant differences in ID, FC, and correlations among subgroups of female MwoA. This provides neuroimaging references for further subclassifying MwoA patients. This offers valuable insights into potential pathophysiological mechanisms linked to the brain functional impairment in female MwoA.

Iron overload regulates cognitive function in rats with minimal hepatic encephalopathy by inducing an increase in frontal butyrylcholinesterase activity.

Background and aims: This study aimed to investigate the effect of iron overload on acetylcholinesterase activity in the frontal lobe tissue of rats with minimal hepatic encephalopathy (MHE) and its relation to cognitive ability. By elucidating the potential mechanisms of cognitive impairment, this study may offer insights into novel therapeutic targets for MHE. Materials and methods: Twelve Sprague-Dawley rats were purchased and randomly assigned to either the experimental or control group with six rats in each group. Following the induction of MHE, the Morris Water Maze (MWM) was utilized to assess spatial orientation and memory capacity. Subsequently, Magnetic Resonance Imaging (MRI) scans were performed to capture Quantitative Susceptibility Mapping (QSM) images of all rats' heads. Results: Compared to the control group rats, the MHE model rats showed significantly reduced learning and memory capabilities as well as spatial orientation abilities (P < 0.05). Furthermore, the susceptibility values in the frontal lobe tissue of MHE model rats was significantly higher than that of the control group rats (P < 0.05), and the corresponding BuChE activity in the frontal lobe extract of model rats was significantly increased while BuChE activity in the peripheral blood serum was significantly decreased compared to the control group rats (P < 0.05). Meanwhile, our findings indicate a significant positive correlation between latency period and BuChE activity with susceptibility values in the MHE group. Conclusion: The changes in BuChE activity in frontal lobe extract may be related to changes in spatial orientation and behavioral changes in MHE, and iron overload in the frontal lobe tissue may regulate changes in BuChE activity, BuChE levels appear to be iron-dependent.

Levodopa-induced dyskinesia: brain iron deposition as a new hypothesis.

Parkinson's disease (PD) is a common neurodegenerative disease in the older adults. The main pathological change in PD is the degenerative death of dopamine (DA) neurons in the midbrain substantia nigra, which causes a significant decrease in the DA content of the striatum. However, the exact etiology of this pathological change remains unclear. Genetic factors, environmental factors, aging, and oxidative stress may be involved in the degenerative death of dopaminergic neurons in PD. Pharmacological treatment using levodopa (L-DOPA) remains the main treatment for PD. Most patients with PD consuming L-DOPA for a long time usually develop levodopa-induced dyskinesia (LID) after 6.5 years of use, and LID seriously affects the quality of life and increases the risk of disability. Recently, studies have revealed that cerebral iron deposition may be involved in LID development and that iron deposition has neurotoxic effects and accelerates disease onset. However, the relationship between cerebral iron deposition and LID remains unclear. Herein, we reviewed the mechanisms by which iron deposition may be associated with LID development, which are mainly related to oxidative stress, neuroinflammation, and mitochondrial and lysosomal dysfunction. Using iron as an important target, the search and development of safe and effective brain iron scavengers, and thus the alleviation and treatment of LID, has a very important scientific and clinical value, as well as a good application prospect.

TMEM106B Knockdown Exhibits a Neuroprotective Effect in Parkinson's Disease via Decreasing Inflammation and Iron Deposition.

Parkinson's disease (PD) is closely related to iron accumulation and inflammation. Emerging evidence indicates that TMEM106B plays an essential role in PD. But whether TMEM106B could act on neuroinflammation and iron metabolism in PD has not yet been investigated. The aim of this study was to investigate the pathological mechanisms of inflammation and iron metabolism of TMEM106B in PD. 1-methyl-4-phenylpyridinium (MPP+)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced SH-SY5Y cells and mice were treated with LV-shTMEM106B and AAV-shTMEM106B to construct PD cellular and mouse models. Pole tests and open-field test (OFT) were performed to evaluate the locomotion of the mice. Immunohistochemistry and iron staining were used to detect TH expression and iron deposition in the SN. Iron staining was used to measure the levels of iron. Western blotting was used to detect the expression of inflammatory factors (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6)), NOD-like receptor protein 3 (NLRP3) inflammasome, divalent metal transporter 1 (DMT1), and Ferroportin1 (FPN1)). Knockdown of TMEM106B improved motor ability and rescued dopaminergic (DA) neuron loss. TMEM106B knockdown attenuated the increases of TNF-α, IL-6, NLRP3 inflammasome, and DMT1 expression in the MPP+ and MPTP-induced PD models. Furthermore, TMEM106B knockdown also increases the expression of FPN1. This study provides the first evidence that knockdown of TMEM106B prevents dopaminergic neurodegeneration by modulating neuroinflammation and iron metabolism.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Potential of ferroptosis and ferritinophagy in migraine pathogenesis.

Objective: To assess the potential of ferroptosis and ferritinophagy in migraine pathogenesis. Background: Ferroptosis and ferritinophagy are related to increased cellular iron concentration and have been associated with the pathogenesis of several neurological disorders, but their potential in migraine pathogenesis has not been explored. Increased iron deposits in some deep brain areas, mainly periaqueductal gray (PAG), are reported in migraine and they have been associated with the disease severity and chronification as well as poor response to antimigraine drugs. Results: Iron deposits may interfere with antinociceptive signaling in the neuronal network in the brain areas affected by migraine, but their mechanistic role is unclear. Independently of the location, increased iron concentration may be related to ferroptosis and ferritinophagy in the cell. Therefore, both phenomena may be related to increased iron deposits in migraine. It is unclear whether these deposits are the reason, consequence, or just a correlate of migraine. Still, due to migraine-related elevated levels of iron, which is a prerequisite of ferroptosis and ferritinophagy, the potential of both phenomena in migraine should be explored. If the iron deposits matter in migraine pathogenesis, they should be mechanically linked with the clinical picture of the disease. As iron is an exogenous essential trace element, it is provided to the human body solely with diet or supplements. Therefore, exploring the role of iron in migraine pathogenesis may help to determine the potential role of iron-rich/poor dietary products as migraine triggers or relievers. Conclusion: Ferroptosis and ferritinophagy may be related to migraine pathogenesis through iron deposits in the deep areas of the brain.

Flexible, Stable, and Efficient Counter Electrode for Quantum-Dot-Sensitized Solar Cells Based on Carbon Nanotube Films.

With the rapid development in information, communication, energy, medical care, and other fields, the demand for light, strong, flexible, and stable materials continues to grow. Carbon nanotube (CNT) films possess outstanding properties, such as flexibility, good tensile properties, low density, and high electrical conductivity, making them promising materials for a wide range of applications. This paper reports an effective strategy that combines stretching treatment, laser etching, and electron beam deposition to fabricate an iron-deposited CNT film, which can serve as a counter electrode (CE) of quantum-dot-sensitized solar cells. The study also investigates the influences of processing parameters, such as stretching ratio and iron-depositing thickness on the film's stacking structure, electrical conductivity, and catalytic activity. Under optimized stretching ratios and depositing thicknesses, the catalytic activity of the reacted deposited layer and the high electrical conductivity of the flexible film basis can be fully utilized, allowing the photoelectric conversion efficiency (PCE) of the solar cells to reach approximately 4.58%. Additionally, the CE exhibits flexibility, light transmission, and good stability, with its primary properties remaining above 97% after nearly 50 days. Thus, this research provides innovative material options and development strategies for the development of electrode materials.

Reactive oxygen species regulation by NCF1 governs ferroptosis susceptibility of Kupffer cells to MASH.

Impaired self-renewal of Kupffer cells (KCs) leads to inflammation in metabolic dysfunction-associated steatohepatitis (MASH). Here, we identify neutrophil cytosolic factor 1 (NCF1) as a critical regulator of iron homeostasis in KCs. NCF1 is upregulated in liver macrophages and dendritic cells in humans with metabolic dysfunction-associated steatotic liver disease and in MASH mice. Macrophage NCF1, but not dendritic cell NCF1, triggers KC iron overload, ferroptosis, and monocyte-derived macrophage infiltration, thus aggravating MASH progression. Mechanistically, elevated oxidized phospholipids induced by macrophage NCF1 promote Toll-like receptor (TLR4)-dependent hepatocyte hepcidin production, leading to increased KC iron deposition and subsequent KC ferroptosis. Importantly, the human low-functional polymorphic variant NCF190H alleviates KC ferroptosis and MASH in mice. In conclusion, macrophage NCF1 impairs iron homeostasis in KCs by oxidizing phospholipids, triggering hepatocyte hepcidin release and KC ferroptosis in MASH, highlighting NCF1 as a therapeutic target for improving KC fate and limiting MASH progression.

Abnormal mitochondrial iron metabolism damages alveolar type II epithelial cells involved in bleomycin-induced pulmonary fibrosis.

Rationale: Pulmonary fibrosis is a chronic progressive lung disease with limited therapeutic options. We previously revealed that there is iron deposition in alveolar epithelial type II cell (AECII) in pulmonary fibrosis, which can be prevented by the iron chelator deferoxamine. However, iron in the cytoplasm and the mitochondria has two relatively independent roles and regulatory systems. In this study, we aimed to investigate the role of mitochondrial iron deposition in AECII injury and pulmonary fibrosis, and to find potential therapeutic strategies. Methods: BLM-treated mice, MLE-12 cells, and primary AECII were employed to establish the mouse pulmonary fibrosis model and epithelial cells injury model, respectively. Mitochondrial transplantation, siRNA and plasmid transfection, western blotting (WB), quantitative real-time polymerase chain reaction (RT-qPCR), polymerase chain reaction (PCR), immunofluorescence, immunoprecipitation (IP), MitoSOX staining, JC-1 staining, oxygen consumption rate (OCR) measurement, and Cell Counting Kit-8 (CCK8) assay were utilized to elucidate the role of mitochondrial iron deposition in cell and lung fibrosis and determine its mechanism. Results: This study showed that prominent mitochondrial iron deposition occurs within AECII in bleomycin (BLM)-induced pulmonary fibrosis mouse model and in BLM-treated MLE-12 epithelial cells. Further, the study revealed that healthy mitochondria rescue BLM-damaged AECII mitochondrial iron deposition and cell damage loss. Mitoferrin-2 (MFRN2) is the main transporter that regulates mitochondrial iron metabolism by transferring cytosolic iron into mitochondria, which is upregulated in BLM-treated MLE-12 epithelial cells. Direct overexpression of MFRN2 causes mitochondrial iron deposition and cell damage. In this study, decreased ubiquitination of the ubiquitin ligase F-box/LRR-repeat protein 5 (FBXL5) degraded iron-reactive element-binding protein 2 (IREB2) and promoted MFRN2 expression as well as mitochondrial iron deposition in damaged AECII. Activation of the prostaglandin E2 receptor EP4 subtype (EP4) receptor signaling pathway counteracted mitochondrial iron deposition by downregulating IREB2-MFRN2 signaling through upregulation of FBXL5. This intervention not only reduced mitochondrial iron content but also preserved mitochondrial function and protected against AECII damage after BLM treatment. Conclusion: Our findings highlight the unexplored roles, mechanisms, and regulatory approaches of abnormal mitochondrial iron metabolism of AECII in pulmonary fibrosis. Therefore, this study deepens the understanding of the mechanisms underlying pulmonary fibrosis and offers a promising strategy for developing effective therapeutic interventions using the EP4 receptor activator.

Clinical findings of hyperechoic substantia nigra in patients with Parkinson's disease.

This study aims to analyse hyperechoic substantia nigra (HSN) characteristics and the correlation of HSN with clinical features and blood biomarkers in patients with Parkinson's disease (PD). Transcranial sonography (TCS) evaluations of the substantia nigra (SN) were performed in 40 healthy controls and 71 patients with PD, including patients with SN hyperechogenicity (SN+) and those with normal SN echogenicity (SN-). Evaluation of motor and non-motor symptoms was assessed by a series of rating scales. The uricase method was used to determine serum uric acid (UA) levels, and enzyme-linked immunosorbent assay (ELISA) was used to measure plasma interleukin (IL)-1ß levels. TCS showed 92.50% specificity and 61.97% sensitivity in differentiating PD patients from controls. The area of SN+ contralateral to the side of initial motor symptoms (SNcontra) was larger than that ipsilateral to the side of initial motor symptoms (SNipsi). The PDSN+ group had lower Argentine Hyposmia Rating Scale (AHRS) scores and UA levels than the PDSN- group. Binary logistic regression analysis revealed that AHRS scores and UA levels could be independent predictors for HSN. The larger SN echogenic area (SNL) sizes positively correlated with plasma IL-1ß levels in PD patients with SN+. The present study provides further evidence of the potential of SN echogenicity as an imaging biomarker for PD diagnosis. PD patients with HSN have more severe non-motor symptoms of hyposmia. HSN in PD patients is related to the mechanism of abnormal iron metabolism and microglial activation.

Indoleamine 2,3-dioxygenase 1-mediated iron metabolism in macrophages contributes to lipid deposition in nonalcoholic steatohepatitis.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a rapidly progressing chronic liver disease of global significance. However, the underlying mechanisms responsible for NASH remain unknown. Indoleamine 2,3-dioxygenase 1 (IDO1) has been recognized as essential factor in immune response and metabolic regulation. Here we aimed to investigate the functions and mechanisms of the IDO1 in macrophages on hepatic lipid deposition and iron metabolism in NASH. METHODS: The effect of IDO1 in NASH was evaluated by WT and IDO1-/- mice model fed with methionine/choline-deficient (MCD) diet in vivo. Macrophages scavenger clodronate liposomes (CL) and overexpressing of IDO1 in macrophages by virus were employed as well. Lipid deposition was assessed through pathological examination and lipid droplet staining, while iron levels were measured using an iron assay kit and western blotting. Primary hepatocytes and bone marrow-derived macrophages were treated with oleic acid/palmitic acid (OA/PA) to assess IDO1 expression via Oil Red O staining and immunofluorescence staining in vitro. RESULTS: Pathological images demonstrated that the increase of IDO1 exacerbated lipid accumulation in the livers of mice with MCD diet, while reduction of iron accumulation was observed in the liver and the serum of MCD-fed mice. Scavenging of macrophages effectively mitigated both lipid and iron accumulation. In addition, the deficiency of IDO1 in macrophages significantly mitigated lipid accumulation and iron overload in hepatic parenchymal cells. Finally, lentivirus-mediated overexpression of IDO1 in liver macrophages exacerbated hepatic steatosis and iron deposition in NASH. CONCLUSIONS: Our results demonstrated that effective inhibition of IDO1 expression in macrophages in NASH alleviated hepatic parenchymal cell lipid accumulation and iron deposition, which provided new insights for the future treatment of NASH.

Iron Deposition in Parkinson's Disease: A Mini-Review.

Iron deposition is crucial pathological changes observed in patients with Parkinson's disease (PD). Recently, scientists have actively explored therapeutic approaches targeting iron deposition in PD. However, several clinical studies have failed to yield consistent results. In this review, we provide an overview of iron deposition in PD, from both basic research and clinical perspectives. PD patients exhibit abnormalities in various iron metabolism-related proteins, leading to disruptions in iron distribution, transport, storage, and circulation, ultimately resulting in iron deposition. Excess iron can induce oxidative stress and iron-related cell death, and exacerbate mitochondrial dysfunction, contributing to the progression of PD pathology. Magnetic resonance imaging studies have indicated that the characteristics of iron deposition in the brains of PD patients vary. Iron deposition correlates with the clinical symptoms of PD, and patients with different disease courses and clinical presentations display distinct patterns of iron deposition. These iron deposition patterns may contribute to PD diagnosis. Iron deposition is a promising target for PD treatment. However, further research is required to elucidate the underlying mechanisms and their impacts on PD.

Kidney R2* Mapping for Noninvasive Evaluation of Iron Overload in Paroxysmal Nocturnal Hemoglobinuria.

PURPOSE: The kidney iron deposition can cause kidney damage and renal insufficiency in paroxysmal nocturnal hemoglobinuria (PNH) patients. Assessment of iron deposition in the kidney is essential for the early diagnosis of renal damage in PNH patients. The purpose of this study was to evaluate kidney R2* (T2* reciprocals) values in PNH patients using the iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL-IQ). METHODS: Two radiologists measured the R2* values of the renal cortex in 14 PNH patients and 13 healthy volunteers using IDEAL-IQ. Lactate dehydrogenase (LDH), a reliable marker of intravascular hemolysis, was also measured in all participants. RESULTS: The kidney R2* values were significantly higher in PNH patients compared with those in healthy volunteers (P < 0.001). High inter-operator reproducibility of the measurements was also acquired using IDEAL-IQ. LDH levels were also significantly higher in PNH patients compared with those in healthy volunteers (P < 0.001). Kidney R2* values strongly correlated with LDH levels in PNH patients. CONCLUSION: IDEAL-IQ has a possibility of becoming a useful method for the noninvasive evaluation of renal iron overload in PNH patients.

Increased plasma lipocalin-2 levels are associated with nonmotor symptoms and neuroimaging features in patients with Parkinson's disease.

Lipocalin-2 (LCN2) is essential for the regulation of neuroinflammation and cellular uptake of iron. This study aimed to evaluate plasma LCN2 levels and explore their correlation with clinical and neuroimaging features in Parkinson's disease (PD) patients. Enzyme-linked immunosorbent assay (ELISA) was used to measure plasma LCN2 levels in 120 subjects. Evaluation of motor symptoms and nonmotor symptoms in PD patients was assessed by the associated scales. Voxel-based morphometry (VBM) was used to evaluate brain volume alterations, and quantitative susceptibility mapping (QSM) was used to quantitatively analyze brain iron deposition in 46 PD patients. Plasma LCN2 levels were significantly higher in PD patients than those in healthy controls. LCN2 levels were negatively correlated with Montreal Cognitive Assessment (MoCA) scores, total brain gray matter volume (GMV), and GMV/total intracranial volume (TIV) ratio, but positively correlated with Hamilton Anxiety Rating Scale (HAMD) scores and mean QSM values of the bilateral substantial nigra (SN). Receiver operating characteristic (ROC) curves confirmed that plasma LCN2 levels had good predictive accuracy for PD. The results suggest that plasma LCN2 levels have potential as a biomarker for the diagnosis of PD. LCN2 may be a therapeutic target for neuroinflammation and brain iron deposition.

Research on the clinical factors of cardiac iron deposition in children with beta-thalassemia major.

Magnetic resonance imaging (MRI) T2* is the gold standard for detecting iron deposition in cardiac tissue, but the technique has limitations and cannot be fully performed in paediatric thalassemia patients. The aim of this study was to analyse clinical data to identify other predictors of cardiac iron deposition. A retrospective analysis was performed on 370 children with ß-TM. According to the cardiac MRI results, patients were allocated to a cardiac deposition group and noncardiac deposition group. Multivariate analysis revealed that genotype and corrected QT interval were associated with cardiac iron deposition, indicating that the-ß0/ß0 genotype conferred greater susceptibility to cardiac iron deposition. Receiver operating characteristic curve (ROC) analysis was performed, and the area under the curve (AUC) of genotype was 0.651. The AUC for the corrected QT interval was 0.711, at a cut-off value of 418.5 ms. ROC analysis of the combined genotype and corrected QT interval showed an AUC of 0.762 with 81.3% sensitivity and 64.7% specificity. Compared to patients with the ß+/ß+ and ß0ß+ genotypes, ß0ß0 children with ß-TM were more likely to have cardiac iron deposition.  Conclusion: The genotype and QTc interval can be used to predict cardiac iron deposition in children with ß-TM who are unable to undergo MRI T2 testing.

Increased Brain Iron Deposition in Episodic Migraine: A Pilot Voxel-based Quantitative Susceptibility Mapping

INTRODUCTION: Although iron deposition has been identified as a significant migraine trigger, the key structures in episodic migraine (EM) remain unknown. OBJECTIVE: The aim of this study is to investigate cerebral iron deposition in EM using an advanced voxel-based quantitative susceptibility mapping (QSM). METHODS: A multi-echo gradient echo sequence MR was performed in 15 episodic migraine patients (EMs) and 27 normal control subjects (NCs). The reconstructed quantitative susceptibility mapping images and voxel-based analysis were performed over the entire brain. The susceptibility value of all brain regions with altered iron deposition was extracted, and the correlations between susceptibility value and clinical variables (including HAMA, HAMD, MoCA, VAS, MIDAS score, diseased duration, and headache frequency) were calculated. RESULTS: EM patients presented increased susceptibility value in the left putamen and bilateral substantia nigra (SN) compared with NC. There was no correlation between susceptibility value and the clinical variables. CONCLUSION: Increased brain iron deposition in the extrapyramidal system may be a biomarker for migraine, and abnormal iron metabolism may be involved in the extrapyramidal mechanism. The QSM technique would be an optimal and simple tool for clinical practice and research in iron measurement.

[Brain iron deposition increases in the bilateral substantia nigra of patients with medication-overuse headache: a quantitative susceptibility mapping analysis].

OBJECTIVE: To investigate iron accumulation level over the whole brain and explore the possible neuromechanism of medication-overuse headache (MOH) using quantitative susceptibility mapping (QSM). METHODS: Thirty-seven MOH patients and 27 normal control subjects were enrolled in the study for examinations with both a multiecho gradient echo magnetic resonance (MR) sequence and brain high resolution structural imaging. A voxel-based analysis was performed to detect the brain regions with altered iron deposition, and the quantitative susceptibility mapping values of the positive brain regions were extracted. Correlation analysis was performed between the susceptibility values and the clinical variables of the patients. RESULTS: In patients with MOH, increased susceptibility values were found mainly in the bilateral substantia nigra (SN) (MNI coordinate: 8, -18, -14; -6, -16, -14) as compared with the normal control subjects (P < 0.001), but these alterations in iron deposition were not significantly correlated with the clinical variables of the patients (P > 0.05). The susceptibility value in the left SN had an area under curve (AUC) of 0.734, and at the cut-off value of 0.077, its diagnostic sensitivity was 72.97% and its specificity was 70.37% for distinguishing MOH from normal controls; The susceptibility value in the right SN had an AUC of 0.699 with a diagnostic sensitivity of 72.97% and a specificity of 62.96% at the cut-off value of 0.084. CONCLUSION: Increased iron deposition occurs in the bilateral SN of MOH patients, which provides a new insight into the mechanism of mesocorticolimbic dopamine system dysfunction in MOH. QSM technique can be used as a non-invasive means for quantitative analysis of brain iron deposition in migraine neuroimaging.