Brain Iron Deposition Research Articles

Gut microbiota-induced CXCL1 elevation triggers early neuroinflammation in the substantia nigra of Parkinsonian mice.

Gut microbiota disturbance and systemic inflammation have been implicated in the degeneration of dopaminergic neurons in Parkinson's disease (PD). How the alteration of gut microbiota results in neuropathological events in PD remains elusive. In this study, we explored whether and how environmental insults caused early neuropathological events in the substantia nigra (SN) of a PD mouse model. Aged (12-month-old) mice were orally administered rotenone (6.25 mg·kg-1·d-1) 5 days per week for 2 months. We demonstrated that oral administration of rotenone to ageing mice was sufficient to establish a PD mouse model and that microglial activation and iron deposition selectively appeared in the SN of the mice prior to loss of motor coordination and dopaminergic neurons, and these events could be fully blocked by microglial elimination with a PLX5622-formulated diet. 16 S rDNA sequencing analysis showed that the gut microbiota in rotenone-treated mice was altered, and mice receiving faecal microbial transplantation (FMT) from ageing mice treated with rotenone for 2 months exhibited the same pathology in the SN. We demonstrated that C-X-C motif chemokine ligand-1 (CXCL1) was an essential molecule, as intravenous injection of CXCL1 mimicked almost all the pathology in serum and SN induced by oral rotenone and FMT. Using metabolomics and transcriptomics analyses, we identified the PPAR pathway as a key pathway involved in rotenone-induced neuronal damage. Inhibition of the PPARγ pathway was consistent in the above models, whereas its activation by linoleic acid (60mg·kg-1·d-1, i.g. for 1 week) could block these pathological events in mice intravenously injected with CXCL1. Altogether, these results reveal that the altered gut microbiota resulted in neuroinflammation and iron deposition occurring early in the SN of ageing mice with oral administration of rotenone, much earlier than motor symptoms and dopaminergic neuron loss. We found that CXCL1 plays a crucial role in this process, possibly via PPARγ signalling inhibition. This study may pave the way for understanding the "brain-gut-microbiota" molecular regulatory networks in PD pathogenesis. The aged C57BL/6 male mice with rotenone intragastric administration showed altered gut microbiota, which caused systemic inflammation, PPARγ signalling inhibition and neuroinflammation, brain iron deposition and ferroptosis, and eventually dopaminergic neurodegeneration in PD.

Relationship between brain iron dynamics and blood-brain barrier function during childhood: a quantitative magnetic resonance imaging study

BackgroundMounting evidence suggests that the blood-brain barrier (BBB) plays an important role in the regulation of brain iron homeostasis in normal brain development, but these imaging profiles remain to be elucidated. We aimed to establish a relationship between brain iron dynamics and BBB function during childhood using a combined quantitative magnetic resonance imaging (MRI) to depict both physiological systems along developmental trajectories.MethodsIn this single-center prospective study, consecutive outpatients, 2–180 months of age, who underwent brain MRI (3.0-T scanner; Ingenia; Philips) between January 2020 and January 2021, were included. Children with histories of preterm birth or birth defects, abnormalities on MRI, and diagnoses that included neurological diseases during follow-up examinations through December 2022 were excluded. In addition to clinical MRI, quantitative susceptibility mapping (QSM; iron deposition measure) and diffusion-prepared pseudo-continuous arterial spin labeling (DP-pCASL; BBB function measure) were acquired. Atlas-based analyses for QSM and DP-pCASL were performed to investigate developmental trajectories of regional brain iron deposition and BBB function and their relationships.ResultsA total of 78 children (mean age, 73.8 months ± 61.5 [SD]; 43 boys) were evaluated. Rapid magnetic susceptibility progression in the brain (Δsusceptibility value) was observed during the first two years (globus pallidus, 1.26 ± 0.18 [× 10− 3 ppm/month]; substantia nigra, 0.68 ± 0.16; thalamus, 0.15 ± 0.04). The scattergram between the Δsusceptibility value and the water exchange rate across the BBB (kw) divided by the cerebral blood flow was well fitted to the sigmoidal curve model, whose inflection point differed among each deep gray-matter nucleus (globus pallidus, 2.96–3.03 [mL/100 g]−1; substantia nigra, 3.12–3.15; thalamus, 3.64–3.67) in accordance with the regional heterogeneity of brain iron accumulation.ConclusionsThe combined quantitative MRI study of QSM and DP-pCASL for pediatric brains demonstrated the relationship between brain iron dynamics and BBB function during childhood.Trial registrationUMIN Clinical Trials Registry identifier: UMIN000039047, registered January 6, 2020.

Quantification of Iron Deposition in the Brain of Hypertensive Patients Using 3D-enhanced Susceptibility-weighted Angiography (ESWAN).

Cerebral microbleeds (CMBs) are commonly present in patients with hypertension, producing iron-containing metabolites. A small amount of regional iron deposition is hardly discernible on conventional magnetic resonance imaging (MRI). Three-dimensional enhanced susceptibility-weighted angiography (ESWAN) provides tissue images with high spatial resolution and signal-noise ratio, and has been widely used to measure brain iron deposition in neurodegenerative diseases and intracranial hemorrhage. The study aimed to demonstrate iron deposition in the brain of hypertensive patients using ESWAN. Twenty-seven hypertension patients, with or without CMBs, and 16 matched healthy controls (HCs) were enrolled. From the post-processed ESWAN images, phase and magnitude values of the regions of interest (ROIs) were calculated. Two-sample t-test and one-way variance analysis were applied to compare groups. The relationship between ESWAN parameters and clinical variables was assessed using Pearson's correlation coefficient. Compared to HCs, the phase value of the hippocampus, head of caudate nucleus (HCN), and substantia nigra (SN) was decreased in hypertension with the CMBs subgroup, while that of HCN and SN was decreased in hypertension without CMBs subgroup. Similarly, the magnitude value of the hippocampus, HCN, thalamus red nucleus, and SN was significantly lower in the hypertension group than HCs. In addition, the phase and magnitude values showed a correlation with clinical variables, including disease duration and blood pressure. Deep grey matter nuclei displayed greater iron content in hypertension patients. Iron deposition may precede the appearance of CMBs on MRI, serving as a potential marker of microvascular damage.

Artificial light at night, MRI-based measures of brain iron deposition and incidence of multiple mental disorders

BackgroundEpidemiologic evidence on whether iron accumulation in brain modified the association between artificial light at night (ALAN) and incident mental disorders is lacking. The authors aims to investigate modification of brain iron deposition on the associations of ALAN with multiple mental disorders in the middle-aged and older adults. MethodsThis prospective study used data from the UK Biobank. ALAN was drawn from satellite datasets. Susceptibility-weighted magnetic resonance imaging was used to ascertain iron content of each brain region. T2* signal loss was used as indices of iron deposition. The main outcomes are impacts of ALAN exposure on onset of wide spectrum of physician-diagnosed mental disorders, which was estimated by time-varying Cox proportional hazard model. The authors further conducted stratified analyses by levels of iron brain deposition to examine the potential modifying effects. ResultsAmong 298,283 participants followed for a median of 10.91 years, higher ALAN exposure was associated with increased risk of mental disorders. An IQR (11.37 nW/cm2/sr) increase in annual levels of ALAN was associated with an HR of 1.050 (95 % CI: 1.034,1.066) for any mental disorder, 1.076 (95 % CI: 1.053,1.099) for substance use disorder, and 1.036 (95 % CI: 1.004,1.069) for depression disorder in fully adjusted models. The exposure-response curves showed steeper trends at lower ALAN levels and a plateau at higher exposures. The associations were stronger in participants with high iron deposition in left hippocampus, left accumbens and left pallidum. ConclusionsALAN was associated with multiple mental disorders in the middle-aged and older adults, and the findings indicated stricter standards of ALAN is needed and targeted preventive measures are warranted, especially with high brain iron deposition.

Evaluation of iron deposition in the motor CSTC loop of a Chinese family with paroxysmal kinesigenic dyskinesia using quantitative susceptibility mapping.

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.

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

Although iron deposition has been identified as a significant migraine trigger, the key structures in episodic migraine (EM) remain unknown. The aim of this study is to investigate cerebral iron deposition in EM using an advanced voxel-based quantitative susceptibility mapping (QSM). 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. 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. 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.

Pantothenate Kinase Deficiency Related Neurodegeneration (PKAN) – An Ultra Rare Inherited Metabolic Disorder

Abstract: Pantothenate Kinase-related Neurodegeneration (PKAN) is an Autosomal Recessive (AR) inherited disease identified by focal iron accumulation in the basal ganglia. Formerly recognized as Hallervorden-Spatz disease. PKAN is now considered to be one of several diseases that clinically presents with Neurodegeneration due to deposition of iron in brain (NBIA). Here, we describe an eleven-year-old boy identified as typical PKAN.

Atypical forms of Alzheimer's disease: patients not to forget.

The aim of this paper is to summarize the latest work on neuroimaging in atypical Alzheimer's disease (AD) patients and to emphasize innovative aspects in the clinic and research. The paper will mostly cover language (logopenic variant of primary progressive aphasia; lvPPA), visual (posterior cortical atrophy; PCA), behavioral (bvAD) and dysexecutive (dAD) variants of AD. MRI and PET can detect and differentiate typical and atypical AD variants, and novel imaging markers like brain iron deposition, white matter hyperintensities (WMH), cortical mean diffusivity, and brain total creatine can also contribute. Together, these approaches have helped to characterize variant-specific distinct imaging profiles. Even within each variant, various subtypes that capture the heterogeneity of cases have been revealed. Finally, in-vivo pathology markers have led to significant advances in the atypical AD neuroimaging field. Overall, the recent neuroimaging literature on atypical AD variants contribute to increase knowledge of these lesser-known AD variants and are key to generate atypical variant-specific clinical trial endpoints, which are required for inclusion of these patients in clinical trials assessing treatments. In return, studying these patients can inform the neurobiology of various cognitive functions, such as language, executive, memory, and visuospatial abilities.

Ketogenic diet alleviates brain iron deposition and cognitive dysfunction via Nrf2-mediated ferroptosis pathway in APP/PS1 mouse

Progressive cognitive decline and increased brain iron deposition with age are important features of Alzheimer’s disease. Previous studies have found that the short-term ketogenic diet has neuroprotective effects in a variety of neurodegenerative diseases, but the effects of an early and long-term ketogenic diet on brain iron content and cognition of Alzheimer's disease have not been reported. In our study, 8-week-old APP/PS1 mice were given a 12-month ketogenic or standard diet, while C57BL/6 mice matched with the age and genetic background of APP/PS1 mice were used as normal controls to be given a standard diet for the same length of time. We found that 12 months of an early ketogenic diet improved the impaired learning and memory ability of APP/PS1 mice. The improvement of cognitive function may be related to the reduction of amyloid-beta deposition and neuronal ferroptosis. The mechanism was achieved by the regulation of ferroptosis-related pathways after activation of nuclear factor erythroid 2-related factor 2 by ketogenic diet-induced elevated β-hydroxybutyrate. In addition, blood biochemical results showed that compared with the standard diet group of the disease, although the early and long-term ketogenic diet increased blood lipids to some extent, it seemed to reduce liver, renal, and myocardial damage caused by genetic differences. This will provide a piece of positive evidence for the early and long-term use of ketogenic diets in people at risk of Alzheimer’s disease.

A Case of Pantothenate Kinase-Associated Neurodegeneration (PKAN) in a Patient with One Known Pathologic Variant and One Variant of Unknown Significance (P11-4.006)

<h3>Objective:</h3> Raise interest in the possibility of an unidentified PANK2 gene mutation in the pathogenesis of PKAN <h3>Background:</h3> Pantothenate kinase-associated neurodegeneration (PKAN), previously known as Hallervorden-Spatz Disease, is a neurodegenerative disorder associated with brain iron deposition. PKAN follows an autosomal recessive inheritance pattern and presents in childhood (classical) or around the second decade of life (atypical). Individuals with PKAN typically present with dysarthria, dystonia, speech difficulties, and extrapyramidal symptoms. PKAN has a characteristic “eye of the tiger” sign on MRI with hypointensity of the globus pallidus surrounded by an area of hyperintensity. Pantothenate kinase 2 (PANK2) gene sequencing changes have been identified as markers of PKAN. <h3>Case Description:</h3> The patient discussed is a 27-year-old woman who presented in 2013 for abnormal posturing and cramping of her hands and feet since she was four. Based on the patient’s physical exam, it was believed she was suffering from young-onset Parkinson’s disease or dystonia. However, a trial of Levodopa resulted in no improvement, genetic testing for dystonia was negative, and her brain MRI was read as normal. Due to worsening symptoms, her MRI was reassessed, and the subtle “eye of the tiger” sign was recognized. Further genetic testing showed she was a carrier for two heterozygous PANK2 mutations, one known pathologic variant and one unknown. The patient elected to join a clinical trial as her symptoms progressed. Nine years since presenting, she has completed two clinical trials and is currently on Deferiprone (an iron chelator), Artane, and Baclofen for symptom management. <h3>Design/Methods:</h3> NA <h3>Results:</h3> NA <h3>Conclusions:</h3> This report discusses a patient with PKAN who has one PANK2 mutation of known significance and one unknown variant. Considering PKAN is an autosomal recessive disease, this report suggests a novel PANK2 pathogenic variant. This study also demonstrates how the diagnosis of PKAN can be easily missed due to subtle MRI changes. <b>Disclosure:</b> Dr. Cevallos has nothing to disclose. Miss Rubin has nothing to disclose. Miss Rhinehart has nothing to disclose. Dr. Houghton has nothing to disclose.

Nox4-and Tf/TfR-mediated peroxidation and iron overload exacerbate neuronal ferroptosis after intracerebral hemorrhage: Involvement of EAAT3 dysfunction.

Intracerebral hemorrhage (ICH) induces high mortality and disability. Neuronal death is the principal factor to unfavourable prognosis in ICH. However, the mechanisms underlying this association remain unclear. In this study, we investigated the molecular mechanisms by which neuronal ferroptosis occurs after ICH and whether the use of corresponding modulators can inhibit neuronal death and improve early outcomes in a rat ICH model. Our findings indicated that Nox4 and TF/TfR were upregulated in the perihematomal tissues of ICH rats. Oxidative stress and iron overload induced by Nox4 and TF/TfR promoted neuronal ferroptosis post-ICH. In contrast, application of Nox4-siRNA and the deferoxamine (DFO) attenuated peroxidation and iron deposition in the hemorrhagic brain, alleviated neuronal ferroptosis, and improved sensorimotor function in ICH rats. Additionally, our findings indicated that the post-ICH neuronal reduced glutathione (GSH) depletion were not related to dysfunctional glutamine delivery in astrocytes but rather to downregulation of EAAT3 due to lipid peroxidation-induced dysfunction in the neuronal membrane. These findings indicate that ferroptosis is involved in neuronal death in model rats with collagenase-induced ICH. Oxidative stress and iron overload induced by Nox4 and TF/TfR exacerbate ferroptosis after ICH, while Nox4 downregulation and iron chelation exert neuroprotective effects. The present results highlight the cysteine importer EAAT3 as a potential biomarker of ferroptosis and provide insight into the neuronal death process that occurs following ICH, which may aid in the development of translational treatment strategies for ICH.

Comparison between Dual-Energy CT and Quantitative Susceptibility Mapping in Assessing Brain Iron Deposition in Parkinson Disease.

Both dual-energy CT and quantitative susceptibility mapping can evaluate iron depositions in the brain. The purpose of this study was to compare these 2 techniques in evaluating brain iron depositions in Parkinson disease. Forty-one patients with Parkinson disease (Parkinson disease group) and 31 age- and sex-matched healthy controls (healthy control group) were included. All participants underwent brain dual-energy CT and quantitative susceptibility mapping. ROIs were set bilaterally in the globus pallidus, substantia nigra, red nucleus, caudate nucleus, and putamen. CT values and magnetic susceptibility values were obtained in each ROI. Differences in CT values and magnetic susceptibility values between the Parkinson disease and healthy control groups were compared, followed by analysis of receiver operating characteristic curves. Correlations between CT values and magnetic susceptibility values were then evaluated. The CT values of the bilateral globus pallidus, substantia nigra, and red nucleus were higher in the Parkinson disease group (P < .05). The magnetic susceptibility values of the bilateral globus pallidus and substantia nigra were higher in the Parkinson disease group (P < .05). The CT value of the right globus pallidus in linear fusion images had the highest diagnostic performance (0.912). Magnetic susceptibility values of the bilateral globus pallidus in the Parkinson disease group were positively correlated with CT values at the level of 80 kV(peak), linear fusion images, and SN150 kV(p) (r = 0.466∼0.617; all, P < .05). Both dual-energy CT and quantitative susceptibility mapping could assess excessive brain iron depositions in Parkinson disease, and we found a positive correlation between CT values and magnetic susceptibility values in the bilateral globus pallidus.

Brain iron deposition is positively correlated with cognitive impairment in patients with chronic cerebral hypoperfusion: a MRI susceptibility mapping study

To investigate the relationship of brain iron deposition with cognitive impairment in patients with chronic cerebral hypoperfusion (CHP). Brain iron deposition was detected using quantitative susceptibility mapping (QSM), and cognitive function by neuropsychological tests including the Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Activities of Daily Living (ADLs), and verbal fluency tests in a total of 40 participants, 23 with CHP and 17 age- and sex-matched healthy participants without CHP (controls). The neuropsychological tests revealed that cognitive impairment (p<0.05) and susceptibility values (p<0.05) of the bilateral hippocampus (HP) and substantia nigra (SN) in CHP patients were significantly higher than those of the controls. The susceptibility values of bilateral HP and left putamen correlated closely with the scores of neuropsychological tests in the CHP patients (p<0.05, r2>0.1). The susceptibility values in the left putamen and bilateral HP were significantly higher in CHP patients with mild cognitive impairment (MCI; n=8) than those of CHP patients without MCI (n=15; p<0.05). The present findings indicated that brain iron deposition in specific areas may be responsible for the cognitive impairment in CHP patients, and that QSM is a useful tool to determine brain iron, predicting cognitive impairment in CHP patients.

The impact of iron deposition on the fear circuit of the brain in patients with Parkinson's disease and anxiety.

Anxiety is one of the most common psychiatric symptoms of Parkinson's disease (PD), and brain iron deposition is considered to be one of the pathological mechanisms of PD. The objective of this study was to explore alterations in brain iron deposition in PD patients with anxiety compared to PD patients without anxiety, especially in the fear circuit. Sixteen PD patients with anxiety, 23 PD patients without anxiety, and 26 healthy elderly controls were enrolled prospectively. All subjects underwent neuropsychological assessments and brain magnetic resonance imaging (MRI) examinations. Voxel-based morphometry (VBM) was used to study morphological brain differences between the groups. Quantitative susceptibility mapping (QSM), an MRI technique capable of quantifying susceptibility changes in brain tissue, was used to compare susceptibility changes in the whole brain among the three groups. The correlations between brain susceptibility changes and anxiety scores quantified using the Hamilton Anxiety Rating Scale (HAMA) were compared and analyzed. PD patients with anxiety had a longer duration of PD and higher HAMA scores than PD patients without anxiety. No morphological brain differences were observed between the groups. In contrast, voxel-based and ROI-based QSM analyses showed that PD patients with anxiety had significantly increased QSM values in the medial prefrontal cortex, anterior cingulate cortex, hippocampus, precuneus, and angular cortex. Furthermore, the QSM values of some of these brain regions were positively correlated with the HAMA scores (medial prefrontal cortex: r = 0.255, p = 0.04; anterior cingulate cortex: r = 0.381, p < 0.01; hippocampus: r = 0.496, p < 0.01). Our findings support the idea that anxiety in PD is associated with iron burden in the brain fear circuit, providing a possible new approach to explaining the potential neural mechanism of anxiety in PD.

Age-dependent changes in brain iron deposition and volume in deep gray matter nuclei using quantitative susceptibility mapping

BackgroundMicrostructural changes in deep gray matter (DGM) nuclei are related to physiological behavior, cognition, and memory. Therefore, it is critical to study age-dependent trajectories of biomarkers in DGM nuclei for understanding brain development and aging, as well as predicting cognitive or neurodegenerative diseases. ObjectivesWe aimed to (1) characterize age-dependent trajectories of mean susceptibility, adjusted volume, and total iron content simultaneously in DGM nuclei using quantitative susceptibility mapping (QSM); (2) examine potential contributions of sex related effects to the different age-dependence trajectories of volume and iron deposition; and (3) evaluate the ability of brain age prediction by combining mean magnetic susceptibility and volume of DGM nuclei. MethodsMagnetic susceptibilities and volumetric values of DGM nuclei were obtained from 220 healthy participants (aged 10–70 years) scanned on a 3T MRI system. Regions of interest (ROIs) were drawn manually on the QSM images. Univariate regression analysis between age and each of the MRI measurements in a single ROI was performed. Pearson correlation coefficients were calculated between magnetic susceptibility and adjusted volume in a single ROI. The statistical significance of sex differences in age-dependent trajectories of magnetic susceptibilities and adjusted volumes were determined using one-way ANCOVA. Multiple regression analysis was used to evaluate the ability to estimate brain age using a combination of the mean susceptibilities and adjusted volumes in multiple DGM nuclei. ResultsMean susceptibility and total iron content increased linearly, quadratically, or exponentially with age in all six DGM nuclei. Negative linear correlation was observed between adjusted volume and age in the head of the caudate nucleus (CN; R2 = 0.196, p < 0.001). Quadratic relationships were found between adjusted volume and age in the putamen (PUT; R2 = 0.335, p < 0.001), globus pallidus (GP; R2 = 0.062, p = 0.001), and dentate nucleus (DN; R2 = 0.077, p < 0.001). Males had higher mean magnetic susceptibility than females in the PUT (p = 0.001), red nucleus (RN; p = 0.002), and substantia nigra (SN; p < 0.001). Adjusted volumes of the CN (p < 0.001), PUT (p = 0.030), GP (p = 0.007), SN (p = 0.021), and DN (p < 0.001) were higher in females than those in males throughout the entire age range (10–70 years old). The total iron content of females was higher than that of males in the CN (p < 0.001), but lower than that of males in the PUT (p = 0.014) and RN (p = 0.043) throughout the entire age range (10–70 years old). Multiple regression analyses revealed that the combination of the mean susceptibility value of the PUT, and the volumes of the CN and PUT had the strongest associations with brain age (R2 = 0.586). ConclusionsQSM can be used to simultaneously investigate age- and sex- dependent changes in magnetic susceptibility and volume of DGM nuclei, thus enabling a comprehensive understanding of the developmental trajectories of iron accumulation and volume in DGM nuclei during brain development and aging.

Brain iron imaging markers in the presence of white matter hyperintensities

PurposeTo investigate the relationship between pathological brain iron deposition and white matter hyperintensities (WMHs) in cerebral small vessel disease (CSVD), via Monte Carlo simulations of magnetic susceptibility imaging and the development of a novel imaging marker called the Expected Iron Coefficient (EIC). MethodsA synthetic pathological model of a different number of impenetrable spheres at random locations was employed to represent pathological iron deposition. The diffusion process was simulated with a Monte Carlo method with adjustable parameters to manipulate sphere size, distribution, and extracellular properties. Quantitative susceptibility mapping (QSM) was performed in a clinical dataset to study CSVD to derive and evaluate QSM, R2*, the iron microenvironment coefficient (IMC), and the EIC in the presence of WMHs. ResultsThe simulations show that QSM signals increase in the presence of increased tissue iron, confirming that the EIC increases with pathology. Clinical results demonstrate that while QSM, R2*, and the IMC do not show significant differences in brain iron, the EIC does in the context of CSVD. ConclusionThe EIC is more sensitive to subtle changes in brain iron deposition caused by pathology, even when QSM, R2*, and the IMC fail.

Association between Beta Oscillations from Subthalamic Nucleus and Quantitative Susceptibility Mapping in Deep Gray Matter Structures in Parkinson's Disease.

This study aimed to investigate the association between beta oscillations and brain iron deposition. Beta oscillations were filtered from the microelectrode recordings of local field potentials (LFP) in the subthalamic nucleus (STN), and the ratio of the power spectral density of beta oscillations (PSDXb) to that of the LFP signals was calculated. Iron deposition in the deep gray matter (DGM) structures was indirectly assessed using quantitative susceptibility mapping (QSM). The Unified Parkinson's Disease Rating Scale (UPDRS), part III, was used to assess the severity of symptoms. Spearman correlation coefficients were applied to assess the associations of PSDXb with QSM values in the DGM structures and the severity of symptoms. PSDXb showed a significant positive correlation with the average QSM values in DGM structures, including caudate and substantia nigra (SN) (p = 0.008 and 0.044). Similarly, the PSDXb showed significant negative correlations with the severity of symptoms, including axial symptoms and the gait in the medicine-off state (p = 0.006 for both). The abnormal iron metabolism in the SN and striatum pathways may be one of the underlying mechanisms for the occurrence of abnormal beta oscillations in the STN, and beta oscillations may serve as important pathophysiological biomarkers of PD.

Withaferin A inhibits ferroptosis and protects against intracerebral hemorrhage.

Recent studies have indicated that suppressing oxidative stress and ferroptosis can considerably improve the prognosis of intracerebral hemorrhage (ICH). Withaferin A (WFA), a natural compound, exhibits a positive effect on a number of neurological diseases. However, the effects of WFA on oxidative stress and ferroptosis-mediated signaling pathways to ICH remain unknown. In this study, we investigated the neuroprotective effects and underlying mechanism for WFA in the regulation of ICH-induced oxidative stress and ferroptosis. We established a mouse model of ICH by injection of autologous tail artery blood into the caudate nucleus and an in vitro cell model of hemin-induced ICH. WFA was injected intracerebroventricularly at 0.1, 1 or 5 µg/kg once daily for 7 days, starting immediately after ICH operation. WFA markedly reduced brain tissue injury and iron deposition and improved neurological function in a dose-dependent manner 7 days after cerebral hemorrhage. Through in vitro experiments, cell viability test showed that WFA protected SH-SY5Y neuronal cells against hemin-induced cell injury. Enzyme-linked immunosorbent assays in vitro and in vivo showed that WFA markedly decreased the level of malondialdehyde, an oxidative stress marker, and increased the activities of anti-oxidative stress markers superoxide dismutase and glutathione peroxidase after ICH. Western blot assay, quantitative polymerase chain reaction and immunofluorescence results demonstrated that WFA activated the nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling axis, promoted translocation of Nrf2 from the cytoplasm to nucleus, and increased HO-1 expression. Silencing Nrf2 with siRNA completely reversed HO-1 expression, oxidative stress and protective effects of WFA. Furthermore, WFA reduced hemin-induced ferroptosis. However, after treatment with an HO-1 inhibitor, the neuroprotective effects of WFA against hemin-induced ferroptosis were weakened. MTT test results showed that WFA combined with ferrostatin-1 reduced hemin-induced SH-SY5Y neuronal cell injury. Our findings reveal that WFA treatment alleviated ICH injury-induced ferroptosis and oxidative stress through activating the Nrf2/HO-1 pathway, which may highlight a potential role of WFA for the treatment of ICH.

Associations between brain iron deposition and structural Alzheimer’s disease signature in cognitively unimpaired adults

AbstractBackgroundIron dyshomeostasis appears to be an early event in the Alzheimer’s continuum. However, little is known how incipient cerebral iron deposition affects brain structure and function in cognitively unimpaired (CU) individuals. Here, we assessed the relationship between mean intensities in subcortical nuclei, a proxy measure for iron content, and regional cortical thickness as well as brain metabolism in middle‐aged CU individuals and sought for interactions with biomarkers of Alzheimer’s pathology.MethodWe included 288 CU adults from the ALFA+ cohort (Table 1). Mean intensities were quantified from T2‐weighted magnetic resonance images in 18 a priori defined subcortical nuclei. Due to the high correlations among regional intensities, we performed a principal component analysis to obtain a single measurement of cerebral iron load (Table 2). Cortical thickness (CT) of the “Alzheimer’s disease (AD) signature” composite region of interest (ROI) was assessed using FreeSurfer v6.0. [18F]fluorodeoxyglucose (FDG) PET scans were used to calculate the standardized uptake value ratio (SUVr) within a meta ROI. We created separate general linear models where cortical thickness and PET meta‐ROIs were the dependent variables, while the first principal component (PC1), age, sex, APOE‐ε4 status, and education level were entered as predictors. In additional models, CSF levels of amyloid‐beta ratio (Aβ42/40) and phosphorylated tau (p‐tau) were entered as covariates. We also tested the interaction between PC1 and CSF Aβ42/40 and pTau status. Statistical significance was set at p&lt;0.05.ResultPC1 explained 47.64% of the variance of mean intensities in subcortical regions with lower values denoting higher iron concentration. Lower PC1 values were negatively associated with AD‐signature thickness (p=0.004), but not with brain glucose metabolism in the meta ROI (p=0.936). (Table 3. Figure 1). These results remained unchanged once AD core CSF biomarkers were entered into the model. No significant interactions with abnormal levels of CSF Aβ or p‐Tau were revealed with AD‐signature thickness or brain metabolism.ConclusionIn CU individuals, higher content of iron deposition is associated with reduced thickness, but not glucose metabolism, in cortical areas that typically show atrophy early in the Alzheimer’s continuum. This association was not modified by the presence of altered biomarkers of AD pathology.

Associations between brain iron deposition and structural Alzheimer’s disease signature in cognitively unimpaired adults

AbstractBackgroundIron dyshomeostasis appears to be an early event in the Alzheimer’s continuum. However, little is known how incipient cerebral iron deposition affects brain structure and function in cognitively unimpaired (CU) individuals. Here, we assessed the relationship between mean intensities in subcortical nuclei, a proxy measure for iron content, and regional cortical thickness as well as brain metabolism in middle‐aged CU individuals and sought for interactions with biomarkers of Alzheimer’s pathology.MethodWe included 288 CU adults from the ALFA+ cohort (Table 1). Mean intensities were quantified from T2‐weighted magnetic resonance images in 18 a priori defined subcortical nuclei. Due to the high correlations among regional intensities, we performed a principal component analysis to obtain a single measurement of cerebral iron load (Table 2). Cortical thickness (CT) of the “Alzheimer’s disease (AD) signature” composite region of interest (ROI) was assessed using FreeSurfer v6.0. [18F]fluorodeoxyglucose (FDG) PET scans were used to calculate the standardized uptake value ratio (SUVr) within a meta ROI. We created separate general linear models where cortical thickness and PET meta‐ROIs were the dependent variables, while the first principal component (PC1), age, sex, APOE‐ε4 status, and education level were entered as predictors. In additional models, CSF levels of amyloid‐beta ratio (Aβ42/40) and phosphorylated tau (p‐tau) were entered as covariates. We also tested the interaction between PC1 and CSF Aβ42/40 and p‐Tau status. Statistical significance was set at p&lt;0.05.ResultPC1 explained 47.64% of the variance of mean intensities in subcortical regions with lower values denoting higher iron concentration. Lower PC1 values were negatively associated with AD‐signature thickness (p=0.004), but not with brain glucose metabolism in the meta ROI (p=0.936). (Table 3. Figure 1). These results remained unchanged once AD core CSF biomarkers were entered into the model. No significant interactions with abnormal levels of CSF Aβ or p‐Tau were revealed with AD‐signature thickness or brain metabolism.ConclusionIn CU individuals, higher content of iron deposition is associated with reduced thickness, but not glucose metabolism, in cortical areas that typically show atrophy early in the Alzheimer’s continuum. This association was not modified by the presence of altered biomarkers of AD pathology.