Demyelination In Multiple Sclerosis Research Articles

Characterization of cortico-meningeal translocator protein expression in multiple sclerosis.

Compartmentalized meningeal inflammation is thought to represent one of the key players in the pathogenesis of cortical demyelination in multiple sclerosis. PET targeting the 18 kDa mitochondrial translocator protein (TSPO) is a molecular-specific approach to quantifying immune cell-mediated density in the cortico-meningeal tissue compartment in vivo. This study aimed to characterize cortical and meningeal TSPO expression in a heterogeneous cohort of multiple sclerosis cases using in vivo simultaneous MR-PET with 11C-PBR28, a second-generation TSPO radioligand, and ex vivo immunohistochemistry. Forty-nine multiple sclerosis patients (21 with secondary progressive and 28 with relapsing-remitting multiple sclerosis) with mixed or high affinity binding for 11C-PBR28 underwent 90-min 11C-PBR28 simultaneous MR-PET. Tracer binding was measured using 60-90 min normalized standardized uptake value ratios sampled at mid-cortical depth and ∼3 mm above the pial surface. Data in multiple sclerosis patients were compared to 21 age-matched healthy controls. To characterize the nature of 11C-PBR28 PET uptake, the meningeal and cortical lesion cellular expression of TSPO was further described in post-mortem brain tissue from 20 cases with secondary progressive multiple sclerosis and five age-matched healthy donors. Relative to healthy controls, patients with multiple sclerosis exhibited abnormally increased TSPO signal in the cortex and meningeal tissue, diffusively in progressive disease and more localized in relapsing-remitting multiple sclerosis. In multiple sclerosis, increased meningeal TSPO levels were associated with increased Expanded Disability Status Scale scores (P = 0.007, by linear regression). Immunohistochemistry, validated using in situ sequencing analysis, revealed increased TSPO expression in the meninges and adjacent subpial cortical lesions of post-mortem secondary progressive multiple sclerosis cases relative to control tissue. In these cases, increased TSPO expression was related to meningeal inflammation. Translocator protein immunostaining was detected on meningeal MHC-class II+ macrophages and cortical-activated MHC-class II+ TMEM119+ microglia. In vivo arterial blood data and neuropathology showed that endothelial binding did not significantly account for increased TSPO cortico-meningeal expression in multiple sclerosis. Our findings support the use of TSPO-PET in multiple sclerosis for imaging in vivo inflammation in the cortico-meningeal brain tissue compartment and provide in vivo evidence implicating meningeal inflammation in the pathogenesis of the disease.

Follicular CD8+ T cells promote immunoglobulin production and demyelination in multiple sclerosis and a murine model

Emerging evidence underscores the importance of CD8+ T cells in the pathogenesis of multiple sclerosis (MS), but the precise mechanisms remain ambiguous. This study intends to elucidate the involvement of a novel subset of follicular CD8+ T cells (CD8+CXCR5+ T) in MS and an experimental autoimmune encephalomyelitis (EAE) murine model. The expansion of CD8+CXCR5+ T cells was observed in both MS patients and EAE mice during the acute phase. In relapsing MS patients, higher frequencies of circulating CD8+CXCR5+ T cells were positively correlated with new gadolinium-enhancement lesions in the central nervous system (CNS). In EAE mice, frequencies of CD8+CXCR5+ T cells were also positively correlated with clinical scores. These cells were found to infiltrate into ectopic lymphoid-like structures in the spinal cords during the peak of the disease. Furthermore, CD8+CXCR5+ T cells, exhibiting high expression levels of ICOS, CD40L, IL-21, and IL-6, were shown to facilitate B cell activation and differentiation through a synergistic interaction between CD40L and IL-21. Transferring CD8+CXCR5+ T cells into naïve mice confirmed their ability to enhance the production of anti-MOG35–55 antibodies and contribute to the disease progression. Consequently, CD8+CXCR5+ T cells may play a role in CNS demyelination through heightening humoral immune responses.

Neurodegeneration and demyelination in multiple sclerosis.

Progressive multiple sclerosis (PMS) is an immune-initiated neurodegenerative condition that lacks effective therapies. Although peripheral immune infiltration is a hallmark of relapsing-remitting MS (RRMS), PMS is associated with chronic, tissue-restricted inflammation and disease-associated reactive glial states. The effector functions of disease-associated microglia, astrocytes, and oligodendrocyte lineage cells are beginning to be defined, and recent studies have made significant progress in uncovering their pathologic implications. In this review, we discuss the immune-glia interactions that underlie demyelination, failed remyelination, and neurodegeneration with a focus on PMS. We highlight the common and divergent immune mechanisms by which glial cells acquire disease-associated phenotypes. Finally, we discuss recent advances that have revealed promising novel therapeutic targets for the treatment of PMS and other neurodegenerative diseases.

The possible role of oxidative stress marker glutathione in the assessment of cognitive impairment in multiple sclerosis.

Oxidative stress markers have a distinct role in the process of demyelination in multiple sclerosis. This study investigated the potential correlation of markers of oxidative stress (glutathione [GSH], catalase) with the number of demyelinating lesions and the degree of disability, cognitive deficit, and depression in patients with relapsing-remitting multiple sclerosis (RRMS). Sixty subjects meeting the criteria for RRMS (19 men and 41 women), and 66 healthy controls (24 men, 42 women) were included. In this study, GSH significantly negatively correlated with the degree of cognitive impairment. This is the first study of subjects with RRMS that performed the mentioned research of serum GSH levels on the degree of cognitive damage examined by the Montreal Scale of Cognitive Assessment (MoCA) test. The development of cognitive changes, verified by the MoCA test, was statistically significantly influenced by the positive number of magnetic resonance lesions, degree of depression, expanded disability status scale (EDSS), age, and GSH values. Based on these results, it can be concluded that it is necessary to monitor cognitive status early in RRMS patients, especially in those with a larger number of demyelinating lesions and a higher EDSS level and in older subjects. Also, the serum level of GSH is a potential biomarker of disease progression, which could be used more widely in RRMS.

The prevalence and topography of spinal cord demyelination in multiple sclerosis: a retrospective study

Spinal cord pathology is a major determinant of irreversible disability in progressive multiple sclerosis. The demyelinated lesion is a cardinal feature. The well-characterised anatomy of the spinal cord and new analytic approaches allows the systematic study of lesion topography and its extent of inflammatory activity unveiling new insights into disease pathogenesis. We studied cervical, thoracic, and lumbar spinal cord tissue from 119 pathologically confirmed multiple sclerosis cases. Immunohistochemistry was used to detect demyelination (PLP) and classify lesional inflammatory activity (CD68). Prevalence and distribution of demyelination, staged by lesion activity, was determined and topographical maps were created to identify patterns of lesion prevalence and distribution using mixed models and permutation-based voxelwise analysis. 460 lesions were observed throughout the spinal cord with 76.5% of cases demonstrating at least 1 lesion. The cervical level was preferentially affected by lesions. 58.3% of lesions were inflammatory with 87.9% of cases harbouring at least 1 inflammatory lesion. Topographically, lesions consistently affected the dorsal and lateral columns with relative sparing of subpial areas in a distribution mirroring the vascular network. The presence of spinal cord lesions and the proportion of active lesions related strongly with clinical disease milestones, including time from onset to wheelchair and onset to death. We demonstrate that spinal cord demyelination is common, highly inflammatory, has a predilection for the cervical level, and relates to clinical disability. The topography of lesions in the dorsal and lateral columns and relative sparing of subpial areas points to a role of the vasculature in lesion pathogenesis, suggesting short-range cell infiltration from the blood and signaling molecules circulating in the perivascular space incite lesion development. These findings challenge the notion that end-stage progressive multiple sclerosis is ‘burnt out’ and an outside-in lesional gradient predominates in the spinal cord. Taken together, this study provides support for long-term targeting of inflammatory demyelination in the spinal cord and nominates vascular dysfunction as a potential target for new therapeutic approaches to limit irreversible disability.

Application of a computer vision algorithm to identify foci of demyelination in multiple sclerosis on MRI images

The research was aimed at analyzing modern algorithms for diagnosing lesions in multiple sclerosis on MRI images. Multiple sclerosis is a severe disease of the central nervous system and ranks first among the causes of disability in patients of young working age. In connection with the development of computer vision and machine learning technologies, the relevance of using these technologies for medical diagnostics is growing. Such approaches are necessary for the effective development and implementation of diagnostic systems using artificial intelligence. Modern algorithms and models for lesion segmentation were selected and implemented. Material and methods. The paper presents CV features of diagnosing multiple sclerosis on MRI images, existing data sets: ISBI-2015, MSSEG-2016, MSSEG-2021; existing algorithms and models for lesion segmentation: U-Net, nnU-Net, TransUnet, TransBTS, UNETR, Swin UNETR. Results and discussion. The architectures and models of nnU-Net, UNETR, Swin UNETR were trained and compared at ISBI2015 with various parameters and loss functions. Four MRI sequences were used: T2-WI, T2-FLAIR, PD, MPRAGE. Lesion segmentation was approved by certified experienced neuroradiologists. Conclusions. The approaches described in the paper including data processing, model training, and results analysis, focused on the selection and development of high-quality computer vision algorithms for identifying multiple sclerosis lesions in MRI images. Identification and segmentation of demyelination foci is a necessary step for diagnosing the disease, as well as for calculating and interpreting more meaningful indicators of disease severity and progression.

In-silico studies of phytoconstituents of Bacopa monnieri and Centella asiatica with Crystal structure of Myelin Oligodendrocyte Glycoprotein against primary demyelination in Multiple Sclerosis

In-silico studies of phytoconstituents of Bacopa monnieri and Centella asiatica with Crystal structure of Myelin Oligodendrocyte Glycoprotein against primary demyelination in Multiple Sclerosis

The Fulcrum of Demyelination in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disorder that affects the central nervous system (CNS), including the brain, spinal cord, and optic nerves. The symptoms can vary from muscle weakness to vision loss. In the case of MS, the immune system attacks the myelin sheath, which protects the nerve fiber and causes inflammation resulting in demyelination. The myelin sheath has the composition of various proteins including membrane proteins and glycoproteins. The four main proteins namely Myelin Basic Protein (MBP), Myelin associated Oligodendrocyte Basic protein (MOBP), Myelin Proteolipid Protein (PLP) and Myelin Associated Glycoprotein (MAG) are known to be critical auto-antigens in causing demyelination in CNS leading to MS. Three out of these four proteins are intrinsically disordered proteins and in this review, we attempted to understand how these proteins play a crucial role in maintaining the integrity of myelin, by exploring its structural and functional aspects and also their auto-antigenicity leading to multiple sclerosis.

Pseudocystic demyelination in multiple sclerosis.

Pseudocystic demyelination in multiple sclerosis.

Roles of Adenosine Receptor (subtypes A1 and A2A) in Cuprizone-Induced Hippocampal Demyelination.

Hippocampal demyelination in multiple sclerosis (MS) has been linked with cognitive deficits, however, patients could benefit from treatment that induces oligodendroglial cell function and promotes remyelination. We investigated the role of A1 and A2A adenosine receptors (AR) in regulating oligodendrocyte precursor cells (OPCs) and myelinating oligodendrocyte (OL) in the demyelinated hippocampus using the cuprizone model of MS. Spatial learning and memory were assessed in wild type C57BL/6 mice (WT) or C57BL/6 mice with global deletion of A1 (A1AR-/-) or A2A AR (A2AAR-/-) fed standard or cuprizone diet (CD) for four weeks. Histology, immunofluorescence, Western blot and TUNEL assays were performed to evaluate the extent of demyelination and apoptosis in the hippocampus. Deletion of A1 and A2A AR alters spatial learning and memory. In A1AR-/- mice, cuprizone feeding led to severe hippocampal demyelination, A2AAR-/- mice had a significant increase in myelin whereas WT mice had intermediate demyelination. The A1AR-/- CD-fed mice displayed significant astrocytosis and decreased expression of NeuN and MBP, whereas these proteins were increased in the A2AAR-/- CD mice. Furthermore, Olig2 was upregulated in A1AR-/- CD-fed mice compared to WT mice fed the standard diet. TUNEL staining of brain sections revealed a fivefold increase in the hippocampus of A1AR-/- CD-fed mice. Also, WT mice fed CD showed a significant decrease expression of A1 AR. A1 and A2A AR are involved in OPC/OL functions with opposing roles in myelin regulation in the hippocampus. Thus, the neuropathological findings seen in MS may be connected to the depletion of A1 AR.

Chelation Therapy Associated with Antioxidant Supplementation Can Decrease Oxidative Stress and Inflammation in Multiple Sclerosis: Preliminary Results.

An imbalance of oxy-inflammation status has been involved in axonal damage and demyelination in multiple sclerosis (MS). The aim of this study was to investigate the efficacy of an antioxidant treatment (calcium disodium ethylenediaminetetracetic acid-EDTA) chelation therapy associated with a micronutrient complex in MS patients. A total of 20 MS patients and 20 healthy subjects, enrolled as a control group (CTR), were recruited. We measured the plasma ROS production and total antioxidant capacity (TAC) by a direct assessment using Electron Paramagnetic Resonance; activities of the antioxidant system (thiols' redox status and enzymes); and the urinary presence of biomarkers of oxidative stress by immunoenzymatic assays. We also evaluated the levels of inflammation by plasmatic cytokines (TNFα, IL-1β, and IL-6) and assessed the sICAM levels, as well as the nitric oxide (NO) catabolism and transthyretin (TTR) concentration. Comparing CTR and MS, in the latter ROS production, oxidative damage, inflammatory biomarkers, and NO metabolite concentrations results were significantly higher, while TAC was significantly lower. Treatment in MS induced significant (p < 0.05) down-regulating of pro-inflammatory sICAM1, TNF-α, IL6, as well as biomarkers of lipid peroxidation and DNA damage production. The protective effect exhibited may occur by decreasing ROS production and increasing antioxidant capacity, turning into a more reduced thiols' status.

AXL-Induced Autophagy mitigates experimental autoimmune encephalomyelitis by suppressing microglial inflammation via the PI3K/AKT/mTOR signaling pathway

Microglia, being the primary immune cells of the central nervous system (CNS), are responsible for pathological inflammatory demyelination in multiple sclerosis (MS). It has been demonstrated that AXL, one of the receptor tyrosine kinases, could alleviate the inflammatory response of microglia. However, the specific mechanism remains unclear. Herein, we explored the role of AXL in the autophagy of microglia and its effect on the experimental autoimmune encephalomyelitis (EAE) model. We revealed that knockout of AXL in BV2 microglia significantly promoted the expression of phosphorylated-PI3K/p-AKT/p-mTOR while significantly inhibiting LC3-Ⅱ/Beclin1. Similarly, autophagy was significantly inhibited in the AXL-/- mice. Knockout of AXL induced serious symptoms, infiltration of inflammatory cells, and demyelination changes, manifesting as the upregulation of pro-inflammatory factors TNF-α and IL-6 and downregulation of anti-inflammatory factors TGF-β and IL-10. In conclusion, this study substantiated that autophagy induced by AXL inhibited the inflammatory response of microglia and alleviated symptoms of EAE. Autophagy activation was mediated by the PI3K/AKT/mTOR signaling pathway.

In vivo MRI is sensitive to remyelination in a nonhuman primate model of multiple sclerosis.

Remyelination is crucial to recover from inflammatory demyelination in multiple sclerosis (MS). Investigating remyelination in vivo using magnetic resonance imaging (MRI) is difficult in MS, where collecting serial short-interval scans is challenging. Using experimental autoimmune encephalomyelitis (EAE) in common marmosets, a model of MS that recapitulates focal cerebral inflammatory demyelinating lesions, we investigated whether MRI is sensitive to, and can characterize, remyelination. In six animals followed with multisequence 7 T MRI, 31 focal lesions, predicted to be demyelinated or remyelinated based on signal intensity on proton density-weighted images, were subsequently assessed with histopathology. Remyelination occurred in four of six marmosets and 45% of lesions. Radiological-pathological comparison showed that MRI had high statistical sensitivity (100%) and specificity (90%) for detecting remyelination. This study demonstrates the prevalence of spontaneous remyelination in marmoset EAE and the ability of in vivo MRI to detect it, with implications for preclinical testing of pro-remyelinating agents.

In vivo characterization of microglia and myelin relation in multiple sclerosis by combined 11C-PBR28 PET and synthetic MRI.

The in vivo relation between microglia activation and demyelination in multiple sclerosis is still unclear. We combined 11C-PBR28 positron emission tomography and rapid estimation of myelin for diagnostic imaging (REMyDI) to characterize the relation between these pathological processes in a heterogeneous MS cohort. 11C-PBR28 standardized uptake values normalized by a pseudo-reference region (SUVR) were used to measure activated microglia. A voxelwise analysis compared 11C-PBR28 SUVR in the white matter of 38 MS patients and 16 matched healthy controls. The relative difference in SUVR served as a threshold to classify patients' lesioned, perilesional and normal-appearing white matter as active or inactive. REMyDI was acquired in 27 MS patients for assessing myelin content in active and inactive white matter and its relationship with SUVR. Finally, we investigated the contribution of radiological metrics to clinical outcomes. 11C-PBR28 SUVR were abnormally higher in several white matter areas in MS. Myelin content was lower in active compared to inactive corresponding white matter regions. An inverse correlation between SUVR and myelin content was found. Radiological metrics correlated with both neurological and cognitive impairment. our data suggest an inverse relation of microglia activation and myelination, particularly in perilesional white matter tissue.

Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis.

Astrocyte activation is associated with progressive inflammatory demyelination in multiple sclerosis (MS). The molecular mechanisms underlying astrocyte activation remain incompletely understood. Recent studies have suggested that classical neurotransmitter receptors are implicated in the modulation of brain innate immunity. We investigated the role of dopamine signaling in the process of astrocyte activation. Here, we show the upregulation of dopamine D2 receptor (DRD2) in reactive astrocytes in MS brain and noncanonical role of astrocytic DRD2 in MS pathogenesis. Mice deficient in astrocytic Drd2 exhibit a remarkable suppression of reactive astrocytes and amelioration of experimental autoimmune encephalomyelitis (EAE). Mechanistically, DRD2 regulates the expression of 6-pyruvoyl-tetrahydropterin synthase, which modulates NF-κB activity through protein kinase C-δ. Pharmacological blockade of astrocytic DRD2 with a DRD2 antagonist dehydrocorybulbine remarkably inhibits the inflammatory response in mice lacking neuronal Drd2. Together, our findings reveal previously an uncharted role for DRD2 in astrocyte activation during EAE-associated CNS inflammation. Its therapeutic inhibition may provide a potent lever to alleviate autoimmune diseases.

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis

T1/T2-weighted ratio is a surrogate marker of demyelination in multiple sclerosis – Commentary

T1/T2-weighted ratio is a surrogate marker of demyelination in multiple sclerosis – Commentary

T1/T2-weighted ratio is a surrogate marker of demyelination in multiple sclerosis—yes

T1/T2-weighted ratio is a surrogate marker of demyelination in multiple sclerosis—yes

T1/T2-weighted ratio is a surrogate marker of demyelination in multiple sclerosis: No

T1/T2-weighted ratio is a surrogate marker of demyelination in multiple sclerosis: No

Dietary restriction in multiple sclerosis: evidence from preclinical and clinical studies

Dietary restriction (DR) interventions, which encompass both chronic and intermittent reductions in energy intake, are emerging as potential therapeutic approaches for dampening neuroinflammation and demyelination in multiple sclerosis (MS). Mechanisms mediating the beneficial effects of DR include the regulation of pro- and anti-inflammatory signalling molecules and gut microbiome remodelling. This article summarises the preclinical evidence supporting the role of DR in attenuating disease in animal models of MS and the developing clinical evidence indicating the safety and feasibility of such DR interventions in people with MS (pwMS).