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1.
Glia ; 70(6): 1191-1209, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35266197

ABSTRACT

Oligodendrocyte progenitor cells (OPCs) are responsible for remyelination in the central nervous system (CNS) in health and disease. For patients with multiple sclerosis (MS), remyelination is not always successful, and the mechanisms differentiating successful from failed remyelination are not well-known. Growing evidence suggests an immune role for OPCs, in addition to their regenerative role; however, it is not clear if this helps or hinders the regenerative process. We studied the effect of cerebrospinal fluid (CSF) from relapsing MS (rMS) and progressive MS (pMS) patients on primary OPC differentiation and immune gene expression and function. We observed that CSF from either rMS or pMS patients has a differential effect on the ability of mice OPCs to differentiate into mature oligodendrocytes and to express immune functions. CSF of pMS patients impaired differentiation into mature oligodendrocytes. In addition, it led to decreased major histocompatibility complex class (MHC)-II expression, tumor necrosis factor (TNF)-α secretion, nuclear factor kappa-B (NFκB) activation, and less activation and proliferation of T cells. Our findings suggest that OPCs are not only responsible for remyelination, but they may also play an active role as innate immune cells in the CNS.


Subject(s)
Multiple Sclerosis , Oligodendrocyte Precursor Cells , Remyelination , Animals , Cell Differentiation/physiology , Humans , Immunity , Mice , Multiple Sclerosis/pathology , Myelin Sheath/metabolism , Oligodendrocyte Precursor Cells/metabolism , Oligodendroglia/metabolism , Remyelination/physiology
2.
Nat Commun ; 13(1): 2445, 2022 May 04.
Article in English | MEDLINE | ID: mdl-35508608

ABSTRACT

Remyelination failure in multiple sclerosis (MS) contributes to progression of disability. The deficient repair results from neuroinflammation and deposition of inhibitors including chondroitin sulfate proteoglycans (CSPGs). Which CSPG member is repair-inhibitory or alters local inflammation to exacerbate injury is unknown. Here, we correlate high versican-V1 expression in MS lesions with deficient premyelinating oligodendrocytes, and highlight its selective upregulation amongst CSPG members in experimental autoimmune encephalomyelitis (EAE) lesions modeling MS. In culture, purified versican-V1 inhibits oligodendrocyte precursor cells (OPCs) and promotes T helper 17 (Th17) polarization. Versican-V1-exposed Th17 cells are particularly toxic to OPCs. In NG2CreER:MAPTmGFP mice illuminating newly formed GFP+ oligodendrocytes/myelin, difluorosamine (peracetylated,4,4-difluoro-N-acetylglucosamine) treatment from peak EAE reduces lesional versican-V1 and Th17 frequency, while enhancing GFP+ profiles. We suggest that lesion-elevated versican-V1 directly impedes OPCs while it indirectly inhibits remyelination through elevating local Th17 cytotoxic neuroinflammation. We propose CSPG-lowering drugs as potential dual pronged repair and immunomodulatory therapeutics for MS.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , Oligodendrocyte Precursor Cells , Remyelination , Animals , Cell Differentiation , Encephalomyelitis, Autoimmune, Experimental/pathology , Inflammation/pathology , Mice , Mice, Inbred C57BL , Multiple Sclerosis/pathology , Oligodendrocyte Precursor Cells/metabolism , Oligodendroglia/metabolism , Remyelination/physiology , Versicans/metabolism
3.
Acta Neuropathol Commun ; 10(1): 67, 2022 May 02.
Article in English | MEDLINE | ID: mdl-35501931

ABSTRACT

Damage to long axons in white matter tracts is a major pathology in closed head traumatic brain injury (TBI). Acute TBI treatments are needed that protect against axon damage and promote recovery of axon function to prevent long term symptoms and neurodegeneration. Our prior characterization of axon damage and demyelination after TBI led us to examine repurposing of 4-aminopyridine (4-AP), an FDA-approved inhibitor of voltage-gated potassium (Kv) channels. 4-AP is currently indicated to provide symptomatic relief for patients with chronic stage multiple sclerosis, which involves axon damage and demyelination. We tested clinically relevant dosage of 4-AP as an acute treatment for experimental TBI and found multiple benefits in corpus callosum axons. This randomized, controlled pre-clinical study focused on the first week after TBI, when axons are particularly vulnerable. 4-AP treatment initiated one day post-injury dramatically reduced axon damage detected by intra-axonal fluorescence accumulations in Thy1-YFP mice of both sexes. Detailed electron microscopy in C57BL/6 mice showed that 4-AP reduced pathological features of mitochondrial swelling, cytoskeletal disruption, and demyelination at 7 days post-injury. Furthermore, 4-AP improved the molecular organization of axon nodal regions by restoring disrupted paranode domains and reducing Kv1.2 channel dispersion. 4-AP treatment did not resolve deficits in action potential conduction across the corpus callosum, based on ex vivo electrophysiological recordings at 7 days post-TBI. Thus, this first study of 4-AP effects on axon damage in the acute period demonstrates a significant decrease in multiple pathological hallmarks of axon damage after experimental TBI.


Subject(s)
Brain Injuries, Traumatic , Multiple Sclerosis , 4-Aminopyridine/pharmacology , 4-Aminopyridine/therapeutic use , Animals , Axons/pathology , Brain Injuries, Traumatic/pathology , Female , Humans , Male , Mice , Mice, Inbred C57BL , Multiple Sclerosis/pathology
4.
J Neuroinflammation ; 19(1): 103, 2022 Apr 29.
Article in English | MEDLINE | ID: mdl-35488271

ABSTRACT

OBJECTIVE: c-Met, a tyrosine kinase receptor, is the unique receptor for hepatocyte growth factor (HGF). The HGF/c-Met axis is reported to modulate cell migration, maturation, cytokine production, and antigen presentation. Here, we report that CD4+c-Met+ T cells are detected at increased levels in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). METHODS: c-Met expression by CD4+ T cells was analyzed mostly by flow cytometry and by immunohistochemistry from mice and human PBMCs. The in vivo role of CD4+c-Met+ T cells was assessed in EAE. RESULTS: CD4+c-Met+ T cells found in the CNS during EAE peak disease are characterized by a pro-inflammatory phenotype skewed towards a Th1 and Th17 polarization, with enhanced adhesion and transmigration capacities correlating with increased expression of integrin α4 (Itgα4). The adoptive transfer of Itgα4-expressing CD4+Vα3.2+c-Met+ T cells induces increased disease severity compared to CD4+Vα3.2+c-Met- T cells. Finally, CD4+c-Met+ T cells are detected in the brain of MS patients, as well as in the blood with a higher level of Itgα4. These results highlight c-Met as an immune marker of highly pathogenic pro-inflammatory and pro-migratory CD4+ T lymphocytes associated with neuroinflammation.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , Animals , Encephalomyelitis, Autoimmune, Experimental/pathology , Humans , Integrin alpha4 , Mice , Mice, Inbred C57BL , Multiple Sclerosis/pathology , Th17 Cells
5.
Neurol Neuroimmunol Neuroinflamm ; 9(4)2022 Jul.
Article in English | MEDLINE | ID: mdl-35473885

ABSTRACT

BACKGROUND AND OBJECTIVES: Pure relapsing short myelitis with clinical and paraclinical features suggesting multiple sclerosis (MS) has been described recently. Here, we evaluated the existence of this potential new form of MS by retrospectively searching for similar cases in the databases of the French tertiary MS centers. METHODS: Patients were included based on the present criteria: at least 2 short (<3 vertebral segments) myelitis episodes; minimum follow-up of 3 years; no MS-like brain lesion during all the follow-up; tested negative for both anti-myelin oligodendrocyte glycoprotein and anti-aquaporin 4 antibodies in serum; presence of oligoclonal bands in CSF; and comprehensive workup to exclude alternative diagnoses. RESULTS: Eighteen patients fulfilled all criteria. The sex ratio (females/males) was 5/1; the median (range) age at first relapse was 35.5 (25-54) years, the disease duration was 80.5 (50-308) months, and the annualized relapse rate was 0.36 (0.1-0.5). The median (range) number of relapses per patient was 2 (2-5), and the median (range) Expanded Disability Status Scale score at last follow-up was 1 (0-7.5). In CSF, the median (range) protein level was 0.34 g/L (0.18-0.77), and the median (range) number of mononuclear cells was 3 (0-28). Spinal cord MRI demonstrated a median (range) number of 2 (1-5) lesions per examination and 3 [1-7] on the last examination. Fifty-five percent of lesions involved the cervical levels. Secondary progressive evolution occurred in 3 of 18 (17%) patients. DISCUSSION: Pure spinal MS could be a rare entity in the MS disease spectrum. However, the existence of a distinct entity in the inflammatory CNS disorders cannot be excluded.


Subject(s)
Multiple Sclerosis , Myelitis , Female , Humans , Male , Multiple Sclerosis/diagnosis , Multiple Sclerosis/pathology , Myelin-Oligodendrocyte Glycoprotein , Myelitis/diagnosis , Recurrence , Retrospective Studies
6.
Biomolecules ; 12(4)2022 04 02.
Article in English | MEDLINE | ID: mdl-35454127

ABSTRACT

Over the past decade, multiple sclerosis (MS), a chronic neuroinflammatory disease with severe personal and social consequences, has undergone a steady increase in incidence and prevalence rates worldwide. Despite ongoing research and the development of several novel therapies, MS pathology remains incompletely understood, and the prospect for a curative treatment continues to be unpromising in the near future. A sustained research effort, however, should contribute to a deeper understanding of underlying disease mechanisms, which will undoubtedly yield improved results in drug development. In recent years, the blood-brain barrier (BBB) has increasingly become the focus of many studies as it appears to be involved in both MS disease onset and progression. More specifically, neurovascular unit damage is believed to be involved in the critical process of CNS immune cell penetration, which subsequently favors the development of a CNS-specific immune response, leading to the classical pathological and clinical hallmarks of MS. The aim of the current narrative review is to merge the relevant evidence on the role of the BBB in MS pathology in a comprehensive and succinct manner. Firstly, the physiological structure and functions of the BBB as a component of the more complex neurovascular unit are presented. Subsequently, the authors review the specific alteration of the BBB encountered in different stages of MS, focusing on both the modifications of BBB cells in neuroinflammation and the CNS penetration of immune cells. Finally, the currently accepted theories on neurodegeneration in MS are summarized.


Subject(s)
Blood-Brain Barrier , Multiple Sclerosis , Biological Transport , Humans , Multiple Sclerosis/pathology
7.
Front Immunol ; 13: 852563, 2022.
Article in English | MEDLINE | ID: mdl-35432382

ABSTRACT

Objective: This study aims to confirm the prognostic value of baseline serum neurofilament light chain (sNfL) for on-study disease activity and worsening in patients with relapsing MS (RMS). Background: Previous post-hoc studies suggested that sNfL could be a prognostic biomarker in RMS. In the phase 3 ASCLEPIOS I/II trials in which ofatumumab demonstrated better efficacy outcomes than teriflunomide, treatment with ofatumumab also led to significantly reduced sNfL levels compared to teriflunomide treatment. Design/Methods: In this study, we report protocol-planned analyses from the pooled ASCLEPIOS I/II trials (N=1882). Per protocol, patients were stratified by median baseline sNfL levels (9.3 pg/ml) into high (>median) and low (≤median) categories to prognosticate: annualized rate of new/enlarging T2 (neT2) lesions in year 1 and 2, annualized relapse rate, annual percentage change in whole brain (WB) and regional brain volume [thalamus, white matter (WM), cortical gray matter (cGM)], and disability outcomes. Similar analyses were performed for the recently diagnosed (within 3 years), treatment-naive patients (no prior disease-modifying therapy) subgroup. Results: High versus low sNfL at baseline was prognostic of increased on-study T2 lesion formation at year 1 (relative increase: ofatumumab +158%; teriflunomide +69%, both p<0.001), which persisted in year 2 (+65%, p=0.124; +46%, p=0.003); of higher annual percentage change of WB volume (ofatumumab, -0.32% vs. -0.24%, p=0.044, and teriflunomide, -0.43% vs. -0.29%, p=0.002), thalamic volume (-0.56% vs. -0.31%, p=0.047 and -0.94% vs. -0.49%, p<0.001), and WM volume (-0.30% vs. -0.19%, p=0.083 and -0.38% vs. -0.18%, p=0.003) but not of cGM volume (-0.39% vs. -0.32%, p=0.337 and -0.49% vs. -0.46%, p=0.563). A single sNfL assessment at baseline was not prognostic for on-study relapses or disability worsening. Results were similar in the subgroup of recently diagnosed, treatment-naive patients. Conclusion: This study confirms that baseline sNfL levels are prognostic of future on-study lesion formation and whole brain and regional atrophy in all RMS patients, including recently diagnosed, treatment-naive patients.


Subject(s)
Multiple Sclerosis , Gray Matter/pathology , Humans , Intermediate Filaments , Multiple Sclerosis/pathology , Prognosis , Recurrence
8.
Acta Neuropathol Commun ; 10(1): 51, 2022 04 11.
Article in English | MEDLINE | ID: mdl-35410629

ABSTRACT

Recent studies suggest that metabolic changes and oxygen deficiency in the central nervous system play an important role in the pathophysiology of multiple sclerosis (MS). In our present study, we investigated the changes in oxygenation and analyzed the vascular perfusion of the spinal cord in a rodent model of MS. We performed multispectral optoacoustic tomography of the lumbar spinal cord before and after an oxygen enhancement challenge in mice with experimental autoimmune encephalomyelitis (EAE), a model for MS. In addition, mice were transcardially perfused with lectin to label the vasculature and their spinal columns were optically cleared, followed by light sheet fluorescence microscopy. To analyze the angioarchitecture of the intact spine, we used VesSAP, a novel deep learning-based framework. In EAE mice, the spinal cord had lower oxygen saturation and hemoglobin concentration compared to healthy mice, indicating compromised perfusion of the spinal cord. Oxygen administration reversed hypoxia in the spinal cord of EAE mice, although the ventral region remained hypoxic. Additionally, despite the increased vascular density, we report a reduction in length and complexity of the perfused vascular network in EAE. Taken together, these findings highlight a new aspect of neuroinflammatory pathology, revealing a significant degree of hypoxia in EAE in vivo that is accompanied by changes in spinal vascular perfusion. The study also introduces optoacoustic imaging as a tractable technique with the potential to further decipher the role of hypoxia in EAE and to monitor it in MS patients.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , Animals , Humans , Hypoxia/metabolism , Mice , Mice, Inbred C57BL , Multiple Sclerosis/pathology , Oxygen/metabolism , Spinal Cord/metabolism
9.
Int J Mol Sci ; 23(7)2022 Mar 25.
Article in English | MEDLINE | ID: mdl-35408959

ABSTRACT

Trigeminal neuralgia (TN) is a complex orofacial pain syndrome characterized by the paroxysmal onset of pain attacks in the trigeminal distribution. The underlying mechanism for this debilitating condition is still not clearly understood. Decades of basic and clinical evidence support the demyelination hypothesis, where demyelination along the trigeminal afferent pathway is a major driver for TN pathogenesis and pathophysiology. Such pathological demyelination can be triggered by physical compression of the trigeminal ganglion or another primary demyelinating disease, such as multiple sclerosis. Further examination of TN patients and animal models has revealed significant molecular changes, channelopathies, and electrophysiological abnormalities in the affected trigeminal nerve. Interestingly, recent electrophysiological recordings and advanced functional neuroimaging data have shed new light on the global structural changes and the altered connectivity in the central pain-related circuits in TN patients. The current article aims to review the latest findings on the pathophysiology of TN and cross-examining them with the current surgical and pharmacologic management for TN patients. Understanding the underlying biology of TN could help scientists and clinicians to identify novel targets and improve treatments for this complex, debilitating disease.


Subject(s)
Multiple Sclerosis , Neuralgia , Trigeminal Neuralgia , Animals , Facial Pain/pathology , Humans , Multiple Sclerosis/pathology , Neuralgia/pathology , Trigeminal Nerve/metabolism , Trigeminal Neuralgia/metabolism
10.
Front Immunol ; 13: 842354, 2022.
Article in English | MEDLINE | ID: mdl-35386690

ABSTRACT

Objective: To ascertain the role of inflammation in the response to ocrelizumab in primary-progressive multiple sclerosis (PPMS). Methods: Multicenter prospective study including 69 patients with PPMS who initiated ocrelizumab treatment, classified according to baseline presence [Gd+, n=16] or absence [Gd-, n=53] of gadolinium-enhancing lesions in brain MRI. Ten Gd+ (62.5%) and 41 Gd- patients (77.4%) showed non-evidence of disease activity (NEDA) defined as no disability progression or new MRI lesions after 1 year of treatment. Blood immune cell subsets were characterized by flow cytometry, serum immunoglobulins by nephelometry, and serum neurofilament light-chains (sNfL) by SIMOA. Statistical analyses were corrected with the Bonferroni formula. Results: More than 60% of patients reached NEDA after a year of treatment, regardless of their baseline characteristics. In Gd+ patients, it associated with a low repopulation rate of inflammatory B cells accompanied by a reduction of sNfL values 6 months after their first ocrelizumab dose. Patients in Gd- group also had low B cell numbers and sNfL values 6 months after initiating treatment, independent of their treatment response. In these patients, NEDA status was associated with a tolerogenic remodeling of the T and innate immune cell compartments, and with a clear increase of serum IgA levels. Conclusion: Baseline inflammation influences which immunological pathways predominate in patients with PPMS. Inflammatory B cells played a pivotal role in the Gd+ group and inflammatory T and innate immune cells in Gd- patients. B cell depletion can modulate both mechanisms.


Subject(s)
Multiple Sclerosis, Chronic Progressive , Multiple Sclerosis , Humans , Inflammation , Magnetic Resonance Imaging , Multiple Sclerosis/drug therapy , Multiple Sclerosis/pathology , Multiple Sclerosis, Chronic Progressive/drug therapy , Prospective Studies
11.
Methods Cell Biol ; 168: 87-102, 2022.
Article in English | MEDLINE | ID: mdl-35366993

ABSTRACT

Multiple Sclerosis (MS) is characterized by the presence of demyelinating lesions in the Central Nervous System (CNS). The demyelination is accompanied by axonal degeneration and the activation of cells of the innate and adaptive immune systems that accumulate around the demyelinated plaques. Oligodendrocyte cell dysfunction and death are also evident. In the relapsing-remitting form of MS, this dysfunction is followed by periods of recovery, and newly mature oligodendrocytes have the ability to remyelinate the pathological axons. To specifically study the localized demyelination/remyelination processes, animal models involving specific demyelinating toxins or viruses have been generated. Through these models the pathological effects on oligodendrocytes can be analyzed, and pharmacological treatments that can restore oligodendrocyte myelination capabilities can be assessed. Here we describe the most commonly used models of toxic or viral demyelination, and provide protocols to induce and analyze them.


Subject(s)
Multiple Sclerosis , Animals , Axons , Central Nervous System/pathology , Disease Models, Animal , Multiple Sclerosis/pathology , Oligodendroglia
12.
Contrast Media Mol Imaging ; 2022: 1430380, 2022.
Article in English | MEDLINE | ID: mdl-35360267

ABSTRACT

This study was aimed to investigate the craniocerebral magnetic resonance imaging (MRI) measurement and clinical characteristics of patients with neuromyelitis optica (NMO) and multiple sclerosis (MS). 50 patients with NMO (NMO group) and 50 patients with MS (MS group) were studied. The clinical manifestations, brain injury morphology, MRI signal characteristics, brain distribution characteristics, and related laboratory tests (serum aquaporin 4 [AQP4] antibody) were statistically analyzed. The results showed that the analysis of clinical manifestations of patients revealed that optic neuritis (37 cases) was the most common disease in NMO patients, and myelitis (16 cases) was more common in MS patients than NMO patients. There were significant differences in gender ratio, abnormal expression of brain MR1, positive serum AQP4-IgG, and other immune diseases and symptoms between the two groups (P < 0.05). When the lesions measured by MRI were located in the white matter area of the cerebral hemisphere, the image showed blurred edges and a relatively symmetrical distribution. When the lesions measured by MRI were located around the medulla oblongata, the lesions mainly involved the central gray matter and white matter of the spinal cord, with patchy and line-like long T1 and long T2 signals. Moreover, in the late stage of recurrence of spinal cord disease, severe spinal cord atrophy may occur. In conclusion, craniocerebral MRI measurement in NMO patients can provide more basis for the diagnosis and differential diagnosis of the disease, so as to improve the diagnostic level of NMO.


Subject(s)
Multiple Sclerosis , Neuromyelitis Optica , Aquaporin 4/metabolism , Humans , Magnetic Resonance Imaging , Multiple Sclerosis/diagnosis , Multiple Sclerosis/pathology , Neuromyelitis Optica/diagnostic imaging , Spinal Cord
14.
Int J Mol Sci ; 23(6)2022 Mar 17.
Article in English | MEDLINE | ID: mdl-35328673

ABSTRACT

Multiple Sclerosis is a chronic neurological disease characterized by demyelination and axonal loss. This pathology, still largely of unknown etiology, carries within it a complex series of etiopathogenetic components of which it is difficult to trace the origin. An inflammatory state is likely to be the basis of the pathology. Crucial elements of the inflammatory process are the interactions between platelets and mast cells as well as the bacterial component of the intestinal microbiota. In addition, the involvement of mast cells in autoimmune demyelinating diseases has been shown. The present work tries to hang up on that Ariadne's thread which, in the molecular complexity of the interactions between mast cells, platelets, microbiota and inflammation, characterizes Multiple Sclerosis and attempts to bring the pathology back to the causal determinism of psychopathological phenomenology. Therefore, we consider the possibility that the original error of Multiple Sclerosis can be investigated in the genetic origin of the depressive pathology.


Subject(s)
Gastrointestinal Microbiome , Multiple Sclerosis , Blood Platelets/pathology , Humans , Inflammation , Mast Cells , Mood Disorders , Multiple Sclerosis/pathology , Stem Cells/pathology
15.
Radiologe ; 62(4): 322-326, 2022 Apr.
Article in German | MEDLINE | ID: mdl-35316355

ABSTRACT

BACKGROUND: To improve the efficient use of magnetic resonance imaging (MRI) in routine clinical practice, an expert panel has revised the guidelines for its use in the diagnosis and monitoring of multiple sclerosis (MS). OBJECTIVES: The revised guidelines now take into account new developments and relevant advances in knowledge, such as the ongoing debate about safety related to intravenous gadolinium-based contrast agents. The value of spinal cord MRI for diagnostic, prognostic, and surveillance purposes has been re-evaluated. Standardization of brain and spinal cord MRI protocols for diagnosis, assessment of prognosis, and monitoring of therapy, as well as the use of 3D-FLAIR (three-dimensional fluid-attenuated inversion recovery) as the most important sequence in the diagnosis of lesions in the brain have been included, as this allows better interpretation and comparability, e.g., in follow-up assessments.


Subject(s)
Multiple Sclerosis , Brain/diagnostic imaging , Brain/pathology , Contrast Media , Humans , Magnetic Resonance Imaging/methods , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/pathology , Spinal Cord
16.
Front Immunol ; 13: 761225, 2022.
Article in English | MEDLINE | ID: mdl-35309325

ABSTRACT

Multiple sclerosis (MS) is an inflammatory demyelinating and degenerative disease of the central nervous system (CNS). Although inflammatory responses are efficiently treated, therapies for progression are scarce and suboptimal, and biomarkers to predict the disease course are insufficient. Cure or preventive measures for MS require knowledge of core pathological events at the site of the tissue damage. Novelties in systems biology have emerged and paved the way for a more fine-grained understanding of key pathological pathways within the CNS, but they have also raised questions still without answers. Here, we systemically review the power of tissue and single-cell/nucleus CNS omics and discuss major gaps of integration into the clinical practice. Systemic search identified 49 transcriptome and 11 proteome studies of the CNS from 1997 till October 2021. Pioneering molecular discoveries indicate that MS affects the whole brain and all resident cell types. Despite inconsistency of results, studies imply increase in transcripts/proteins of semaphorins, heat shock proteins, myelin proteins, apolipoproteins and HLAs. Different lesions are characterized by distinct astrocytic and microglial polarization, altered oligodendrogenesis, and changes in specific neuronal subtypes. In all white matter lesion types, CXCL12, SCD, CD163 are highly expressed, and STAT6- and TGFß-signaling are increased. In the grey matter lesions, TNF-signaling seems to drive cell death, and especially CUX2-expressing neurons may be susceptible to neurodegeneration. The vast heterogeneity at both cellular and lesional levels may underlie the clinical heterogeneity of MS, and it may be more complex than the current disease phenotyping in the clinical practice. Systems biology has not solved the mystery of MS, but it has discovered multiple molecules and networks potentially contributing to the pathogenesis. However, these results are mostly descriptive; focused functional studies of the molecular changes may open up for a better interpretation. Guidelines for acceptable quality or awareness of results from low quality data, and standardized computational and biological pipelines may help to overcome limited tissue availability and the "snap shot" problem of omics. These may help in identifying core pathological events and point in directions for focus in clinical prevention.


Subject(s)
Multiple Sclerosis , White Matter , Brain/pathology , Humans , Multiple Sclerosis/genetics , Multiple Sclerosis/pathology , Proteome , Transcriptome , White Matter/pathology
17.
Sci Rep ; 12(1): 4411, 2022 03 15.
Article in English | MEDLINE | ID: mdl-35292734

ABSTRACT

Quantitative susceptibility mapping (QSM), an imaging technique sensitive to brain iron, has been used to detect paramagnetic rims of iron-laden active microglia and macrophages in a subset of multiple sclerosis (MS) lesions, known as rim+ lesions, that are consistent with chronic active lesions. Because of the potential impact of rim+ lesions on disease progression and tissue damage, investigating their influence on disability and neurodegeneration is critical to establish the impact of these lesions on the disease course. This study aimed to explore the relationship between chronic active rim+ lesions, identified as having a hyperintense rim on QSM, and both clinical disability and imaging measures of neurodegeneration in patients with MS. The patient cohort was composed of 159 relapsing-remitting multiple sclerosis patients. The Expanded Disability Status Scale (EDSS) and Brief International Cognitive Assessment for Multiple Sclerosis, which includes both the Symbol Digit Modalities Test and California Verbal Learning Test-II, were used to assess clinical disability. Cortical thickness and thalamic volume were evaluated as imaging measures of neurodegeneration. A total of 4469 MS lesions were identified, of which 171 QSM rim+ (3.8%) lesions were identified among 57 patients (35.8%). In a multivariate regression model, as the overall total lesion burden increased, patients with at least one rim+ lesion on QSM performed worse on both physical disability and cognitive assessments, specifically the Symbol Digit Modalities Test (p = 0.010), California Verbal Learning Test-II (p = 0.030), and EDSS (p = 0.001). In a separate univariate regression model, controlling for age (p < 0.001) and having at least one rim+ lesion was related to more cortical thinning (p = 0.03) in younger patients (< 45 years). Lower thalamic volume was associated with older patients (p = 0.038) and larger total lesion burden (p < 0.001); however, the association did not remain significant with rim+ lesions (p = 0.10). Our findings demonstrate a novel observation that chronic active lesions, as identified on QSM, modify the impact of lesion burden on clinical disability in MS patients. These results support further exploration of rim+ lesions for therapeutic targeting in MS to reduce disability and subsequent neurodegeneration.


Subject(s)
Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Brain/pathology , Disease Progression , Humans , Iron , Magnetic Resonance Imaging , Middle Aged , Multiple Sclerosis/pathology , Multiple Sclerosis, Relapsing-Remitting/pathology
18.
Oxid Med Cell Longev ; 2022: 9328160, 2022.
Article in English | MEDLINE | ID: mdl-35281467

ABSTRACT

Objective: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by chronic inflammation and demyelination. This study is aimed at identifying crucial genes and molecular pathways involved in MS pathogenesis. Methods: Raw data in GSE52139 were collected from the Gene Expression Omnibus. The top 50% expression variants were subjected to weighted gene coexpression network analysis (WGCNA), and the key module associated with MS occurrence was identified. A long noncoding RNA- (lncRNA-) associated competing endogenous RNA (ceRNA) network was constructed in the key module. The hub gene candidates were subsequently verified in an individual database. Results: Of the 18 modules obtained, the cyan module was designated as the key module. The established ceRNA network was composed of seven lncRNAs, 45 mRNAs, and 21 microRNAs (miRNAs), and the FAM13A-AS1 was the lncRNA with the highest centrality. Functional assessments indicated that the genes in the cyan module primarily gathered in ribosome-related functional terms. Interestingly, the targeted mRNAs of the ceRNA network enriched in diverse categories. Moreover, highly expressed CYBRD1, GNG12, and SMAD1, which were identified as hub genes, may be associated with "valine leucine and isoleucine degradation," "base excision repair," and "fatty acid metabolism," respectively, according to the results of single gene-based genomes and gene set enrichment analysis (GSEA). Conclusions: Combined with the WGCNA and ceRNA network, our findings provide novel insights into the pathogenesis of MS. The hub genes discovered herein might also serve as novel biomarkers that correlate with the development and management of MS.


Subject(s)
Computational Biology/methods , Gene Expression Profiling/methods , Multiple Sclerosis/genetics , RNA, Long Noncoding/genetics , Humans , Multiple Sclerosis/pathology
19.
Int J Mol Sci ; 23(5)2022 Feb 23.
Article in English | MEDLINE | ID: mdl-35269597

ABSTRACT

The pH-related metabolic paradigm has rapidly grown in cancer research and treatment. In this contribution, this recent oncological perspective has been laterally assessed for the first time in order to integrate neurodegeneration within the energetics of the cancer acid-base conceptual frame. At all levels of study (molecular, biochemical, metabolic, and clinical), the intimate nature of both processes appears to consist of opposite mechanisms occurring at the far ends of a physiopathological intracellular pH/extracellular pH (pHi/pHe) spectrum. This wide-ranging original approach now permits an increase in our understanding of these opposite processes, cancer and neurodegeneration, and, as a consequence, allows us to propose new avenues of treatment based upon the intracellular and microenvironmental hydrogen ion dynamics regulating and deregulating the biochemistry and metabolism of both cancer and neural cells. Under the same perspective, the etiopathogenesis and special characteristics of multiple sclerosis (MS) is an excellent model for the study of neurodegenerative diseases and, utilizing this pioneering approach, we find that MS appears to be a metabolic disease even before an autoimmune one. Furthermore, within this paradigm, several important aspects of MS, from mitochondrial failure to microbiota functional abnormalities, are analyzed in depth. Finally, and for the first time, a new and integrated model of treatment for MS can now be advanced.


Subject(s)
Multiple Sclerosis , Neoplasms , Neurodegenerative Diseases , Humans , Mitochondria/metabolism , Multiple Sclerosis/pathology , Neurodegenerative Diseases/metabolism , Protons
20.
J Neurol Sci ; 436: 120205, 2022 May 15.
Article in English | MEDLINE | ID: mdl-35259556

ABSTRACT

INTRODUCTION: Despite differences in the pathogenesis and treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), it remains difficult to distinguish them. In this study, we aimed to discriminate between MS and NMOSD using diffusion tensor imaging (DTI), free water (FW) imaging, and neurite orientation dispersion and density imaging (NODDI). METHODS: Thirty patients with relapsing-remitting (RR) MS, 18 NMOSD patients with positive anti-aquaporin-4 immunoglobulin G seroreactivity, and 20 age- and sex- matched currently healthy subjects underwent MRI. The differences in the DTI (fractional anisotropy [FA], axial diffusivity [AD], mean diffusivity [MD], and radial diffusivity [RD]), FW and FW-corrected DTI, and NODDI indices between the three groups were evaluated using tract-based spatial statistics (TBSS) and region-of-interest (ROI) analyses. RESULTS: The ROI analysis of lesions indicated that the RRMS group had significantly higher AD, MD, RD, ISO and FW-corrected AD, and MD; and lower intracellular volume fraction (ICVF) than the NMOSD group. TBSS analysis showed increased water content in RRMS patients compared to NMOSD patients. Compared with healthy controls (HCs) using TBSS and ROI analysis, the changes in FW imaging indices were more limited than those of in DTI in RRMS patients. CONCLUSION: FW imaging and NODDI were useful for identifying the etiology of neurodegeneration- and neuroinflammation-related microstructural changes in RRMS and NMOSD patients.


Subject(s)
Leukoaraiosis , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Neuromyelitis Optica , White Matter , Diffusion Tensor Imaging/methods , Humans , Multiple Sclerosis/pathology , Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging , Multiple Sclerosis, Relapsing-Remitting/pathology , Neuromyelitis Optica/diagnostic imaging , Neuromyelitis Optica/pathology , Water , White Matter/diagnostic imaging , White Matter/pathology
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