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International Journal of Molecular... Sep 2022Multiple Sclerosis (MS) is a neuroinflammatory disorder, which is histopathologically characterized by multifocal inflammatory demyelinating lesions affecting both the... (Review)
Review
Multiple Sclerosis (MS) is a neuroinflammatory disorder, which is histopathologically characterized by multifocal inflammatory demyelinating lesions affecting both the central nervous system's white and grey matter. Especially during the progressive phases of the disease, immunomodulatory treatment strategies lose their effectiveness. To develop novel progressive MS treatment options, pre-clinical animal models are indispensable. Among the various different models, the cuprizone de- and remyelination model is frequently used. While most studies determine tissue damage and repair at the histological and ultrastructural level, functional readouts are less commonly applied. Among the various overt functional deficits, gait and coordination abnormalities are commonly observed in MS patients. Motor behavior is mediated by a complex neural network that originates in the cortex and terminates in the skeletal muscles. Several methods exist to determine gait abnormalities in small rodents, including the rotarod testing paradigm. In this review article, we provide an overview of the validity and characteristics of the rotarod test in cuprizone-intoxicated mice.
Topics: Animals; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Sheath; Remyelination; Rotarod Performance Test
PubMed: 36232643
DOI: 10.3390/ijms231911342 -
The Lancet. Neurology Feb 2021The field of acquired CNS neuroimmune demyelination in children is transforming. Progress in assay development, refinement of diagnostic criteria, increased biological... (Review)
Review
The field of acquired CNS neuroimmune demyelination in children is transforming. Progress in assay development, refinement of diagnostic criteria, increased biological insights provided by advanced neuroimaging techniques, and high-level evidence for the therapeutic efficacy of biological agents are redefining diagnosis and care. Three distinct neuroimmune conditions-multiple sclerosis, myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder (AQP4-NMOSD)-can now be distinguished, with evidence from humans and animal models supporting distinct pathobiological disease mechanisms. The development of highly effective therapies for adult-onset multiple sclerosis and AQP4-NMOSD that suppress relapse rate by more than 90% has motivated advocacy for trials in children. However, doing clinical trials is challenging because of the rarity of these conditions in the paediatric age group, necessitating new approaches to trial design, including age-based trajectory modelling based on phase 3 studies in adults. Despite these limitations, the future for children and adolescents living with multiple sclerosis, MOGAD, or AQP4-NMOSD is far brighter than in years past, and will be brighter still if successful therapies to promote remyelination, enhance neuroprotection, and remediate cognitive deficits can be further accelerated.
Topics: Adolescent; Child; Demyelinating Diseases; Humans; Multiple Sclerosis; Neuroimaging; Young Adult
PubMed: 33484648
DOI: 10.1016/S1474-4422(20)30432-4 -
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 -
Glia Jul 2022In human demyelinating diseases such as multiple sclerosis (MS), an imbalance between demyelination and remyelination can trigger progressive degenerative processes. The... (Review)
Review
In human demyelinating diseases such as multiple sclerosis (MS), an imbalance between demyelination and remyelination can trigger progressive degenerative processes. The clearance of myelin debris (phagocytosis) from the site of demyelination by microglia is critically important to achieve adequate remyelination and to slow the progression of the disease. However, how microglia phagocytose the myelin debris, and why clearance is impaired in MS, is not fully known; likewise, the role of the microglia in remyelination remains unclear. Recent studies using cuprizone (CPZ) as an animal model of central nervous system demyelination revealed that the up-regulation of signaling proteins in microglia facilitates effective phagocytosis of myelin debris. Moreover, during demyelination, protective mediators are released from activated microglia, resulting in the acceleration of remyelination in the CPZ model. In contrast, inadequate microglial activation or recruitment to the site of demyelination, and the production of toxic mediators, impairs remyelination resulting in progressive demyelination. In addition to the microglia-mediated phagocytosis, astrocytes play an important role in the phagocytic process by recruiting microglia to the site of demyelination and producing regenerative mediators. The current review is an update of these emerging findings from the CPZ animal model, discussing the roles of microglia and astrocytes in phagocytosis and myelination.
Topics: Animals; Astrocytes; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Mice; Mice, Inbred C57BL; Microglia; Multiple Sclerosis; Myelin Sheath; Phagocytosis
PubMed: 35107839
DOI: 10.1002/glia.24148 -
The Journal of Clinical Investigation Jan 2021Oligodendrocytes express low-density lipoprotein receptor (LDLR) to endocytose cholesterol for the maintenance of adulthood myelination. However, the potential role of...
Oligodendrocytes express low-density lipoprotein receptor (LDLR) to endocytose cholesterol for the maintenance of adulthood myelination. However, the potential role of LDLR in chronic cerebral ischemia-related demyelination remains unclear. We used bilateral carotid artery stenosis (BCAS) to induce sustained cerebral ischemia in mice. This hypoxic-ischemic injury caused a remarkable decrease in oligodendroglial LDLR, with impaired oligodendroglial differentiation and survival. Oligodendroglial cholesterol levels, however, remained unchanged. Mouse miR-344e-3p and the human homolog miR-410-3p, 2 miRNAs directly targeting Ldlr, were identified in experimental and clinical leukoaraiosis and were thus implicated in the LDLR reduction. Lentiviral delivery of LDLR ameliorated demyelination following chronic cerebral ischemia. By contrast, Ldlr-/- mice displayed inadequate myelination in the corpus callosum. Ldlr-/- oligodendrocyte progenitor cells (OPCs) exhibited reduced ability to differentiate and myelinate axons in vitro. Transplantation with Ldlr-/- OPCs could not rescue the BCAS-induced demyelination. Such LDLR-dependent myelin restoration might involve a physical interaction of the Asn-Pro-Val-Tyr (NPVY) motif with the phosphotyrosine binding domain of Shc, which subsequently activated the MEK/ERK pathway. Together, our findings demonstrate that the aberrant oligodendroglial LDLR in chronic cerebral ischemia impairs myelination through intracellular signal transduction. Preservation of oligodendroglial LDLR may provide a promising approach to treat ischemic demyelination.
Topics: Animals; Brain Ischemia; Chronic Disease; Corpus Callosum; Demyelinating Diseases; Male; Mice; Mice, Knockout; Oligodendroglia; Receptors, LDL
PubMed: 33141760
DOI: 10.1172/JCI128114 -
Brain and Nerve = Shinkei Kenkyu No... Apr 2020The diagnosis of multiple sclerosis (MS) relies on the demonstration of disease dissemination in space and time, and the exclusion of other neurological disorders....
The diagnosis of multiple sclerosis (MS) relies on the demonstration of disease dissemination in space and time, and the exclusion of other neurological disorders. However, it is often difficult to exclude alternative diagnoses with a single MRI examination or during a short clinical course. "Red flags" are recommended as clinical and paraclinical indicators that could help suggest alternative diagnoses to MS, and may improve diagnostic accuracy.
Topics: Demyelinating Diseases; Diagnosis, Differential; Humans; Magnetic Resonance Imaging; Multiple Sclerosis; Nervous System Diseases
PubMed: 32284460
DOI: 10.11477/mf.1416201534 -
Molecular Neurodegeneration May 2022The dietary consumption of cuprizone - a copper chelator - has long been known to induce demyelination of specific brain structures and is widely used as model of... (Review)
Review
The dietary consumption of cuprizone - a copper chelator - has long been known to induce demyelination of specific brain structures and is widely used as model of multiple sclerosis. Despite the extensive use of cuprizone, the mechanism by which it induces demyelination are still unknown. With this review we provide an updated understanding of this model, by showcasing two distinct yet overlapping modes of action for cuprizone-induced demyelination; 1) damage originating from within the oligodendrocyte, caused by mitochondrial dysfunction or reduced myelin protein synthesis. We term this mode of action 'intrinsic cell damage'. And 2) damage to the oligodendrocyte exerted by inflammatory molecules, brain resident cells, such as oligodendrocytes, astrocytes, and microglia or peripheral immune cells - neutrophils or T-cells. We term this mode of action 'extrinsic cellular damage'. Lastly, we summarize recent developments in research on different forms of cell death induced by cuprizone, which could add valuable insights into the mechanisms of cuprizone toxicity. With this review we hope to provide a modern understanding of cuprizone-induced demyelination to understand the causes behind the demyelination in MS.
Topics: Animals; Astrocytes; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Mice; Mice, Inbred C57BL; Microglia; Myelin Sheath; Oligodendroglia
PubMed: 35526004
DOI: 10.1186/s13024-022-00538-8 -
Continuum (Minneapolis, Minn.) Feb 2023This article summarizes neuroimaging findings in demyelinating disease, the most common being multiple sclerosis. Revisions to criteria and treatment options have been... (Review)
Review
OBJECTIVE
This article summarizes neuroimaging findings in demyelinating disease, the most common being multiple sclerosis. Revisions to criteria and treatment options have been ongoing, and MRI plays a pivotal role in diagnosis and disease monitoring. The common antibody-mediated demyelinating disorders with their respective classic imaging features are reviewed, as well as the differential diagnostic considerations on imaging.
LATEST DEVELOPMENTS
The clinical criteria of demyelinating disease rely heavily on imaging with MRI. With novel antibody detection, the range of clinical demyelinating syndromes has expanded, most recently with myelin oligodendrocyte glycoprotein-IgG antibodies. Imaging has improved our understanding of the pathophysiology of multiple sclerosis and disease progression, and further research is underway. The importance of increased detection of pathology outside of the classic lesions will have an important role as therapeutic options are expanding.
ESSENTIAL POINTS
MRI has a crucial role in the diagnostic criteria and differentiation among common demyelinating disorders and syndromes. This article reviews the typical imaging features and clinical scenarios that assist in accurate diagnosis, differentiation between demyelinating diseases and other white matter diseases, the importance of standardized MRI protocols in clinical practice, and novel imaging techniques.
Topics: Humans; Myelin-Oligodendrocyte Glycoprotein; Syndrome; Multiple Sclerosis; Central Nervous System Diseases; Central Nervous System; Autoantibodies
PubMed: 36795881
DOI: 10.1212/CON.0000000000001246 -
Seminars in Neurology Oct 2019Neuromuscular ultrasound (NMUS) is a diagnostic technique that is now commonly used to complement electrodiagnostic studies when evaluating for suspected peripheral... (Review)
Review
Neuromuscular ultrasound (NMUS) is a diagnostic technique that is now commonly used to complement electrodiagnostic studies when evaluating for suspected peripheral nerve pathology. The use of NMUS has been described in focal mononeuropathies, polyneuropathies, and motor neuron disease. This article provides a general overview of NMUS for the evaluation of peripheral neuropathies based on clinical practice guidelines, primary literature, and expert opinion. The characteristic changes detected by NMUS are described in focal mononeuropathies (including entrapment and other causes), polyneuropathies (including demyelinating and axonal processes), and motor neuron disease.
Topics: Amyotrophic Lateral Sclerosis; Demyelinating Diseases; Humans; Motor Neuron Disease; Peripheral Nervous System Diseases; Polyneuropathies; Ultrasonography
PubMed: 31639837
DOI: 10.1055/s-0039-1688987 -
BMJ Case Reports Mar 2020Young man with acute onset nausea, vomiting, joint pain, abdominal pain, fever and weight loss was found to have gait ataxia and positive titres. He deteriorated...
Young man with acute onset nausea, vomiting, joint pain, abdominal pain, fever and weight loss was found to have gait ataxia and positive titres. He deteriorated despite appropriate antibiotics and developed confusion and disorientation. Lumbar puncture revealed lymphocytosis with high protein and low glucose. MRI showed diffuse demyelination. Pulse steroids resulted in rapid clinical, biochemical and radiological recovery.
Topics: Adult; Anti-Bacterial Agents; Brain Diseases; Brucellosis; Demyelinating Diseases; Diagnosis, Differential; Drug Therapy, Combination; Glucocorticoids; Humans; Male; Methylprednisolone; Prednisolone
PubMed: 32152068
DOI: 10.1136/bcr-2019-233798