Multiple sclerosis and iron

The accumulation of focal white matter and cortical inflammatory demyelinating lesions represents the pathologic hallmark of multiple sclerosis (MS).1 Typically, acute white matter lesions are characterized by an increased blood-brain barrier (BBB) permeability, an inflammatory infiltrate, and ongoing demyelination and axonal transection.2 In the chronic phase, a substantial proportion of white matter lesions, known as chronic active lesions, exhibit a hypocellular core with a rim of iron-laden activated microglia/macrophages, with no abnormal BBB permeability...

BACKGROUND AND OBJECTIVES: A subgroup of patients with multiple sclerosis (MS) presents focal paramagnetic rims at the border between cortex and white matter (juxtacortical paramagnetic rims [JPRs]). We investigated the presence of this finding in our in vivo MS cohort and explored its potential clinical relevance. Moreover, we exploited postmortem MRI of fixed whole MS brains to (1) detect those rims and (2) investigate their histologic correlation. METHODS: Quantitative susceptibility mapping (QSM) and magnetization-prepared 2 rapid acquisition gradient-echo (MP2RAGE) images at 3T-MRI of 165 patients with MS from the in vivo cohort were screened for JPRs and the presence of cortical lesions...

Intrathecal IgM production in multiple sclerosis (MS) is associated with a worse disease course. To investigate pathogenic relevance of autoreactive IgM in MS, CSF from two independent cohorts, including MS patients and controls, were screened for antibody binding to induced pluripotent stem cell-derived neurons and astrocytes, and a panel of CNS- related cell lines. IgM binding to a primitive neuro-ectodermal tumour cell line discriminated 10% of MS donors from controls. Transcriptomes of single IgM producing CSF B cells from patients with cell-binding IgM were sequenced and used to produce recombinant monoclonal antibodies for characterisation and antigen identification...

Prediction of disease progression is challenging in multiple sclerosis as the sequence of lesion development and retention of inflammation within a subset of chronic lesions is heterogeneous among patients. We investigated the sequence of lesion-related regional structural disconnectivity across the spectrum of disability and cognitive impairment in multiple sclerosis. In a full cohort of 482 multiple sclerosis patients (age: 41.83 ± 11.63 years, 71.57% females), the Expanded Disability Status Scale was used to classify patients into (i) no or mild (Expanded Disability Status Scale <3) versus (ii) moderate or severe disability groups (Expanded Disability Status Scale ≥3)...

The causes of neurodegenerative diseases remain largely elusive, increasing their personal and societal impacts. To reveal the causal effects of iron load on Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis and multiple sclerosis, we used Mendelian randomisation and brain imaging data from a UK Biobank genome-wide association study of 39,691 brain imaging samples (predominantly of European origin). Using susceptibility-weighted images, which reflect iron load, we analysed genetically significant brain regions...

The inability of disease-modifying therapies to stop the progression of multiple sclerosis (MS), has led to the development of a new therapeutic strategy focussing on myelin repair. While conventional MRI lacks sensitivity for quantifying myelin damage, advanced MRI techniques are proving effective. The development of targeted therapeutics requires histological validation of myelin imaging results, alongside the crucial task of establishing correlations between myelin imaging results and clinical assessments, so that the effectiveness of therapeutic interventions can be evaluated...

The transcription factor Nrf2 is the master regulator of cellular stress response, facilitating the expression of cytoprotective genes, including those responsible for drug detoxification, immunomodulation, and iron metabolism. FDA-approved Nrf2 activators, Tecfidera and Skyclarys for patients with multiple sclerosis and Friedreich's ataxia, respectively, are non-specific alkylating agents exerting side effects. Nrf2 is under feedback regulation through its target gene, transcriptional repressor Bach1. Specifically, in Parkinson's disease and other neurodegenerative diseases with Bach1 dysregulation, excessive Bach1 accumulation interferes with Nrf2 activation...

Quantitative Susceptibility Mapping has the potential to provide additional insights into neurological diseases but is typically based on a quite long (5-10 min) 3D gradient-echo scan which is highly sensitive to motion. We propose an ultra-fast acquisition based on three orthogonal (sagittal, coronal and axial) 2D simultaneous multi-slice EPI scans with 1 mm in-plane resolution and 3 mm thick slices. Images in each orientation are corrected for susceptibility-related distortions and co-registered with an iterative non-linear Minimum Deformation Averaging (Volgenmodel) approach to generate a high SNR, super-resolution data set with an isotropic resolution of close to 1 mm...

Extracellular vesicles (EVs) are involved in diverse cellular functions, playing a significant role in cell-to-cell communication in both physiological conditions and pathological scenarios. Therefore, EVs represent a promising therapeutic strategy. Oligodendrocytes (OLs) are myelinating glial cells developed from oligodendrocyte progenitor cells (OPCs) and damaged in chronic demyelinating diseases such as multiple sclerosis (MS). Glycoprotein transferrin (Tf) plays a critical role in iron homeostasis and has pro-differentiating effects on OLs in vivo and in vitro...

OBJECTIVE: To investigate the metabolic pattern of different types of iron accumulation in multiple sclerosis (MS) lesions, and compare metabolic alterations within and at the periphery of lesions and newly emerging lesions in vivo according to iron deposition. METHODS: 7 T MR spectroscopic imaging and susceptibility-weighted imaging was performed in 31 patients with relapsing-remitting MS (16 female/15 male; mean age, 36.9 ± 10.3 years)...

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease involving immune-mediated damage. Iron deposition in deep gray matter (DGM) structures like the thalamus and basal ganglia have been suggested to play a role in MS pathogenesis. Magnetic Resonance Imaging (MRI) imaging methods like T2 and T2* imaging, susceptibility-weighted imaging, and quantitative susceptibility mapping can track iron deposition storage in the brain primarily from ferritin and hemosiderin (paramagnetic iron storage proteins) with varying levels of tissue contrast and sensitivity...

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterised by the loss of motor control. Current understanding of ALS pathology is largely based on post-mortem investigations at advanced disease stages. A systematic in-vivo description of the microstructural changes that characterise early-stage ALS, and their subsequent development, is so far lacking. Recent advances in ultra-high field (7 T) MRI data modelling allow us to investigate cortical layers in-vivo...

UNLABELLED: Quantification of the myelin content of the white matter is important for studying demyelination in neurodegenerative diseases such as Multiple Sclerosis (MS), particularly for longitudinal monitoring. A novel noninvasive MRI method, called Microstructure-Informed Myelin Mapping (MIMM), is developed to quantify the myelin volume fraction (MVF) by utilizing a multi gradient echo sequence (mGRE) and a detailed biophysical model of tissue microstructure. Myelin is modeled as anisotropic negative susceptibility source based on the Hollow Cylindrical Fiber Model (HCFM), and iron as isotropic positive susceptibility source in the extracellular region...

BACKGROUND: Though most patients with multiple sclerosis (MS) presented earlier on as a relapsing-remitting (RR) disease, disability progression eventually occurred. Uncovering the mechanisms underlying progression may facilitate the unmet need for developing therapies to prevent progression. Benign MS (BMS), a rare form of MS, is the opposite from secondary progressive MS (SPMS) in that it lacks disease progression defined as Expanded Disability Status Scale (EDSS) ≤3 after at least 15 years of disease onset...

Multiple Sclerosis (MS) is an autoimmune demyelinating disease characterised by changes in iron and myelin content. These biomarkers are detectable by Quantitative Susceptibility Mapping (QSM), an advanced Magnetic Resonance Imaging technique detecting magnetic properties. When analysed with radiomic techniques that exploit its intrinsic quantitative nature, QSM may furnish biomarkers to facilitate early diagnosis of MS and timely assessment of progression. In this work, we explore the robustness of QSM radiomic features by varying the number of grey levels (GLs) and echo times (TEs), in a sample of healthy controls and patients with MS...

BACKGROUND: Musculoskeletal disorders were commonly reported in patients with multiple sclerosis. However, the underlying etiology linking Multiple Sclerosis (MS) and musculoskeletal disorders is not well studied. With large-scale Genome-Wide Association Studies (GWAS) publicly available, we conducted genetic correlation analysis to identify shared pleiotropic genetic effects between MS and musculoskeletal traits. We also conducted Mendelian Randomization (MR) to estimate the causal relation between MS and increased risks of musculoskeletal disorders...

BACKGROUND: Recent developments in iron-sensitive MRI techniques have enabled visualization of chronic active lesions as paramagnetic rim lesions (PRLs) in vivo. Although PRLs have potential as a diagnostic and prognostic tool for multiple sclerosis (MS), limited studies have reported the reliability of PRL assessment. Further evaluation of PRL reliability, through original investigations and review of PRL literature, are warranted. METHODS: A single-center cohort study was conducted to evaluate the inter-rater reliability of PRL identification on quantitative susceptibiltiy mapping (QSM) in 10 people with MS, 5 people with clinically isolated syndrome, and 5 healthy controls...

In multiple sclerosis (MS), sustained inflammatory activity can be visualized by iron-sensitive magnetic resonance imaging (MRI) at the edges of chronic lesions. These paramagnetic rim lesions (PRLs) are associated with clinical worsening, although the cell type-specific and molecular pathways of iron uptake and metabolism are not well known. We studied two postmortem cohorts: an exploratory formalin-fixed paraffin-embedded (FFPE) tissue cohort of 18 controls and 24 MS cases and a confirmatory snap-frozen cohort of 6 controls and 14 MS cases...

BACKGROUND: Paramagnetic rim lesions (PRLs) are an imaging biomarker in multiple sclerosis (MS), associated with a more severe disease. OBJECTIVES: To determine quantitative magnetic resonance imaging (MRI) metrics of PRLs, lesions with diffuse susceptibility-weighted imaging (SWI)-hypointense signal (DSHLs) and SWI-isointense lesions (SILs), their surrounding periplaque area (PPA) and the normal-appearing white matter (NAWM). METHODS: In a cross-sectional study, quantitative MRI metrics were measured in people with multiple sclerosis (pwMS) using the multi-dynamic multi-echo (MDME) sequence post-processing software "SyMRI...

Mitochondrial dysfunction is reiteratively involved in the pathogenesis of diverse neurodegenerative diseases. Current in vitro and in vivo approaches support that mitochondrial dysfunction is branded by several molecular and cellular defects, whose impact at different levels including the calcium and iron homeostasis, energetic balance and/or oxidative stress, makes it difficult to resolve them collectively given their multifactorial nature. Mitochondrial transfer offers an overall solution since it contains the replacement of damage mitochondria by healthy units...