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WIREs Mechanisms of Disease Jan 2023Axonal loss in multiple sclerosis (MS) is a key component of disease progression and permanent neurologic disability. MS is a heterogeneous demyelinating and... (Review)
Review
Axonal loss in multiple sclerosis (MS) is a key component of disease progression and permanent neurologic disability. MS is a heterogeneous demyelinating and neurodegenerative disease of the central nervous system (CNS) with varying presentation, disease courses, and prognosis. Immunomodulatory therapies reduce the frequency and severity of inflammatory demyelinating events that are a hallmark of MS, but there is minimal therapy to treat progressive disease and there is no cure. Data from patients with MS, post-mortem histological analysis, and animal models of demyelinating disease have elucidated patterns of MS pathogenesis and underlying mechanisms of neurodegeneration. MRI and molecular biomarkers have been proposed to identify predictors of neurodegeneration and risk factors for disease progression. Early signs of axonal dysfunction have come to light including impaired mitochondrial trafficking, structural axonal changes, and synaptic alterations. With sustained inflammation as well as impaired remyelination, axons succumb to degeneration contributing to CNS atrophy and worsening of disease. These studies highlight the role of chronic demyelination in the CNS in perpetuating axonal loss, and the difficulty in promoting remyelination and repair amidst persistent inflammatory insult. Regenerative and neuroprotective strategies are essential to overcome this barrier, with early intervention being critical to rescue axonal integrity and function. The clinical and basic research studies discussed in this review have set the stage for identifying key propagators of neurodegeneration in MS, leading the way for neuroprotective therapeutic development. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology.
Topics: Animals; Multiple Sclerosis; Neurodegenerative Diseases; Central Nervous System; Axons; Disease Progression
PubMed: 35948371
DOI: 10.1002/wsbm.1583 -
Brain : a Journal of Neurology Aug 2023The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in...
The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the CNS within individuals lacking symptoms typical of multiple sclerosis (MS). The RIS criteria have been validated and predict the transition to symptomatic MS reliably. The performance of RIS criteria that require fewer MRI lesions is unknown. 2009-RIS subjects, by definition, fulfil three to four of four criteria for 2005 dissemination in space (DIS) and subjects fulfilling only one or two lesions in at least one 2017 DIS location were identified within 37 prospective databases. Univariate and multivariate Cox regression models were used to identify predictors of a first clinical event. Performances of different groups were calculated. Seven hundred and forty-seven subjects (72.2% female, mean age 37.7 ± 12.3 years at the index MRI) were included. The mean clinical follow-up time was 46.8 ± 45.4 months. All subjects had focal T2 hyperintensities suggestive of inflammatory demyelination on MRI; 251 (33.6%) fulfilled one or two 2017 DIS criteria (designated as Groups 1 and 2, respectively), and 496 (66.4%) fulfilled three or four 2005 DIS criteria representing 2009-RIS subjects. Group 1 and 2 subjects were younger than the 2009-RIS group and were more likely to develop new T2 lesions over time (P < 0.001). Groups 1 and 2 were similar regarding survival distribution and risk factors for transition to MS. At 5 years, the cumulative probability for a clinical event was 29.0% for Groups 1 and 2 compared to 38.7% for 2009-RIS (P = 0.0241). The presence of spinal cord lesions on the index scan and CSF-restricted oligoclonal bands in Groups 1-2 increased the risk of symptomatic MS evolution at 5 years to 38%, comparable to the risk of development in the 2009-RIS group. The presence of new T2 or gadolinium-enhancing lesions on follow-up scans independently increased the risk of presenting with a clinical event (P < 0.001). The 2009-RIS subjects or Groups 1 and 2 with at least two of the risk factors for a clinical event demonstrated better sensitivity (86.0%), negative predictive value (73.1%), accuracy (59.8%) and area under the curve (60.7%) compared to other criteria studied. This large prospective cohort brings Class I evidence that subjects with fewer lesions than required in the 2009 RIS criteria evolve directly to a first clinical event at a similar rate when additional risk factors are present. Our results provide a rationale for revisions to existing RIS diagnostic criteria.
Topics: Humans; Female; Adult; Middle Aged; Male; Disease Progression; Demyelinating Diseases; Multiple Sclerosis; Magnetic Resonance Imaging; Risk Factors
PubMed: 36864688
DOI: 10.1093/brain/awad073 -
Der Radiologe Apr 2022Acute disseminated encephalomyelitis (ADEM) is a rare demyelinating disease that occurs predominantly in children. According to the guidelines, ADEM belongs to the... (Review)
Review
BACKGROUND
Acute disseminated encephalomyelitis (ADEM) is a rare demyelinating disease that occurs predominantly in children. According to the guidelines, ADEM belongs to the myelin oligodendrocyte glycoprotein (MOG)-associated diseases and usually manifests after febrile infections (also after SARS-CoV-2) or postvaccinally.
OBJECTIVES
Incidence, course and clinical, and as well, as radiological features and new developments and treatment of ADEM.
METHODS
Analysis and review of the literature on ADEM and of notable cases and guidelines.
RESULTS
The first signs of ADEM include fever, nausea and vomiting, headache and meningism as well as, by definition, encephalopathy, which usually manifests as drowsiness and confusion. The radiological diagnosis is made by magnetic resonance imaging (MRI). Here, the asymmetrically distributed, diffuse and tumefactive lesions can be located supra- and infratentorially. In the acute phase, the lesions usually show contrast enhancement and restricted diffusion. Spinal involvement of the gray matter with the typical H‑pattern with myelitis transversa is not uncommon. ADEM has mostly a monophasic course, with a recurrent form ("relapsing ADEM") in 1-20% of cases. For treatment, steroids and in severe cases immunosuppressive drugs are used.
CONCLUSIONS
ADEM is generally a monophasic disease whose symptoms usually last for a few weeks or months. It is crucial to differentiate ADEM from other demyelinating diseases, like for example multiple sclerosis, in order not to delay the proper treatment.
Topics: Encephalomyelitis, Acute Disseminated; Humans; Magnetic Resonance Imaging; Myelin-Oligodendrocyte Glycoprotein
PubMed: 35290492
DOI: 10.1007/s00117-022-00982-z -
Cell Reports Aug 2022Oligodendrocyte dysfunction has been implicated in the pathogenesis of neurodegenerative diseases, so understanding oligodendrocyte activation states would shed light on... (Meta-Analysis)
Meta-Analysis
Oligodendrocyte dysfunction has been implicated in the pathogenesis of neurodegenerative diseases, so understanding oligodendrocyte activation states would shed light on disease processes. We identify three distinct activation states of oligodendrocytes from single-cell RNA sequencing (RNA-seq) of mouse models of Alzheimer's disease (AD) and multiple sclerosis (MS): DA1 (disease-associated1, associated with immunogenic genes), DA2 (disease-associated2, associated with genes influencing survival), and IFN (associated with interferon response genes). Spatial analysis of disease-associated oligodendrocytes (DAOs) in the cuprizone model reveals that DA1 and DA2 are established outside of the lesion area during demyelination and that DA1 repopulates the lesion during remyelination. Independent meta-analysis of human single-nucleus RNA-seq datasets reveals that the transcriptional responses of MS oligodendrocytes share features with mouse models. In contrast, the oligodendrocyte activation signature observed in human AD is largely distinct from those observed in mice. This catalog of oligodendrocyte activation states (http://research-pub.gene.com/OligoLandscape/) will be important to understand disease progression and develop therapeutic interventions.
Topics: Animals; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Neurodegenerative Diseases; Oligodendroglia
PubMed: 36001972
DOI: 10.1016/j.celrep.2022.111189 -
Neurologia 2020Experimental animal models constitute a useful tool to deepen our knowledge of central nervous system disorders. In the case of multiple sclerosis, however, there is no... (Review)
Review
INTRODUCTION
Experimental animal models constitute a useful tool to deepen our knowledge of central nervous system disorders. In the case of multiple sclerosis, however, there is no such specific model able to provide an overview of the disease; multiple models covering the different pathophysiological features of the disease are therefore necessary.
DEVELOPMENT
We reviewed the different in vitro and in vivo experimental models used in multiple sclerosis research. Concerning in vitro models, we analysed cell cultures and slice models. As for in vivo models, we examined such models of autoimmunity and inflammation as experimental allergic encephalitis in different animals and virus-induced demyelinating diseases. Furthermore, we analysed models of demyelination and remyelination, including chemical lesions caused by cuprizone, lysolecithin, and ethidium bromide; zebrafish; and transgenic models.
CONCLUSIONS
Experimental models provide a deeper understanding of the different pathogenic mechanisms involved in multiple sclerosis. Choosing one model or another depends on the specific aims of the study.
Topics: Animals; Cuprizone; Demyelinating Diseases; Humans; In Vitro Techniques; Multiple Sclerosis; Myelin Sheath; Remyelination
PubMed: 28863829
DOI: 10.1016/j.nrl.2017.07.002 -
Frontiers in Immunology 2020Microglia originate from myeloid progenitors in the embryonic yolk sac and play an integral role in central nervous system (CNS) development, immune surveillance and... (Review)
Review
Microglia originate from myeloid progenitors in the embryonic yolk sac and play an integral role in central nervous system (CNS) development, immune surveillance and repair. The role of microglia in multiple sclerosis (MS) has been complex and controversial, with evidence suggesting that these cells play key roles in both active inflammation and remyelination. Here we will review the most recent histological classification of MS lesions as well as the evidence supporting both inflammatory and reparative functions of these cells. We will also review how microglia may yield new biomarkers for MS activity and serve as a potential target for therapy.
Topics: Antirheumatic Agents; Biomarkers; Demyelinating Diseases; Genetic Diseases, Inborn; Humans; Immunologic Surveillance; Macrophages; Microglia; Multiple Sclerosis; Neurodegenerative Diseases; Neuroimaging; T-Lymphocyte Subsets
PubMed: 32265902
DOI: 10.3389/fimmu.2020.00374 -
Cell Reports Apr 2023Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is...
Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAFB microglia, as well as astrocytes and vascular cells with signatures of altered metabolism, oxidative stress, and interferon response. Furthermore, snRNA-seq provides insights into how brain cell types connect and interact, defining complex circuitries that impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency indirectly impairs the induction of DOLs. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelinating diseases.
Topics: Animals; Mice; Demyelinating Diseases; Transcriptome; Remyelination; Brain; Oligodendroglia; Microglia; Cuprizone; Disease Models, Animal; Mice, Inbred C57BL; Myelin Sheath
PubMed: 36952346
DOI: 10.1016/j.celrep.2023.112293 -
The Journal of Clinical Investigation Apr 2022Proper myelination of axons is crucial for normal sensory, motor, and cognitive function. Abnormal myelination is seen in brain disorders such as major depressive...
Proper myelination of axons is crucial for normal sensory, motor, and cognitive function. Abnormal myelination is seen in brain disorders such as major depressive disorder (MDD), but the molecular mechanisms connecting demyelination with the pathobiology remain largely unknown. We observed demyelination and synaptic deficits in mice exposed to either chronic, unpredictable mild stress (CUMS) or LPS, 2 paradigms for inducing depression-like states. Pharmacological restoration of myelination normalized both synaptic deficits and depression-related behaviors. Furthermore, we found increased ephrin A4 receptor (EphA4) expression in the excitatory neurons of mice subjected to CUMS, and shRNA knockdown of EphA4 prevented demyelination and depression-like behaviors. These animal data are consistent with the decrease in myelin basic protein and the increase in EphA4 levels we observed in postmortem brain samples from patients with MDD. Our results provide insights into the etiology of depressive symptoms in some patients and suggest that inhibition of EphA4 or the promotion of myelination could be a promising strategy for treating depression.
Topics: Animals; Axons; Behavior, Animal; Demyelinating Diseases; Depression; Depressive Disorder, Major; Disease Models, Animal; Hippocampus; Humans; Mice; Receptor, EphA4; Stress, Psychological
PubMed: 35271507
DOI: 10.1172/JCI152187 -
Journal of Neuroimmune Pharmacology :... Dec 2021Autoimmune neurological disorders are commonly treated with immunosuppressive therapy. In patients with refractory conditions, standard immunosuppression is often... (Review)
Review
Autoimmune neurological disorders are commonly treated with immunosuppressive therapy. In patients with refractory conditions, standard immunosuppression is often insufficient for complete recovery or to prevent relapses. These patients rely on other treatments to manage their disease. While treatment of refractory cases differs between diseases, intravenous immunoglobulin, plasma exchange (PLEX), and immune-modulating treatments are commonly used. In this review, we focus on five autoimmune neurological disorders that were the themes of the 2018 Midlands Neurological Society meeting on PLEX in refractory neurology: Autoimmune Encephalitis (AE), Multiple Sclerosis (MS), Neuromyelitis Optica Spectrum disorders (NMOSD), Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) and Myasthenia Gravis (MG). The diagnosis of inflammatory neuropathies is often challenging, and while PLEX can be very effective in refractory autoimmune diseases, its ineffectiveness can be confounded by misdiagnosis. One example is POEMS syndrome (characterized by Polyneuropathy Organomegaly, Endocrinopathy, Myeloma protein, Skin changes), which is often wrongly diagnosed as CIDP; and while CIDP responds well to PLEX, POEMS does not. Accurate diagnosis is therefore essential. Success rates can also differ within 'one' disease: e.g. response rates to PLEX are considerably higher in refractory relapsing remitting MS compared to primary or secondary progressive MS. When sufficient efforts are made to correctly pinpoint the diagnosis along with the type and subtype of refractory autoimmune disease, PLEX and other immunotherapies can play a valuable role in the patient management.
Topics: Humans; Immunoglobulins, Intravenous; Multiple Sclerosis; Neuromyelitis Optica; Plasma Exchange; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating
PubMed: 34599742
DOI: 10.1007/s11481-021-10004-9 -
Neurology Jul 2020Myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) associated disorder (MOGAD) often manifests with recurrent CNS demyelinating attacks. The optimal...
OBJECTIVE
Myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) associated disorder (MOGAD) often manifests with recurrent CNS demyelinating attacks. The optimal treatment for reducing relapses is unknown. To help determine the efficacy of long-term immunotherapy in preventing relapse in patients with MOGAD, we conducted a multicenter retrospective study to determine the rate of relapses on various treatments.
METHODS
We determined the frequency of relapses in patients receiving various forms of long-term immunotherapy for MOGAD. Inclusion criteria were history of ≥1 CNS demyelinating attacks, MOG-IgG seropositivity, and immunotherapy for ≥6 months. Patients were reviewed for CNS demyelinating attacks before and during long-term immunotherapy.
RESULTS
Seventy patients were included. The median age at initial CNS demyelinating attack was 29 years (range 3-61 years; 33% <18 years), and 59% were female. The median annualized relapse rate (ARR) before treatment was 1.6. On maintenance immunotherapy, the proportion of patients with relapse was as follows: mycophenolate mofetil 74% (14 of 19; ARR 0.67), rituximab 61% (22 of 36; ARR 0.59), azathioprine 59% (13 of 22; ARR 0.2), and IV immunoglobulin (IVIG) 20% (2 of 10; ARR 0). The overall median ARR on these 4 treatments was 0.3. All 9 patients treated with multiple sclerosis (MS) disease-modifying agents had a breakthrough relapse on treatment (ARR 1.5).
CONCLUSION
This large retrospective multicenter study of patients with MOGAD suggests that maintenance immunotherapy reduces recurrent CNS demyelinating attacks, with the lowest ARR being associated with maintenance IVIG therapy. Traditional MS disease-modifying agents appear to be ineffective. Prospective randomized controlled studies are required to validate these conclusions.
Topics: Adolescent; Adult; Age of Onset; Antirheumatic Agents; Child; Child, Preschool; Demyelinating Diseases; Female; Humans; Immunization, Passive; Immunosuppressive Agents; Immunotherapy; Male; Middle Aged; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Recurrence; Retrospective Studies; Steroids; Young Adult
PubMed: 32554760
DOI: 10.1212/WNL.0000000000009758