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AJNR. American Journal of Neuroradiology Sep 2020Radiologically isolated syndrome refers to an entity in which white matter lesions fulfilling the criteria for multiple sclerosis occur in individuals without a history... (Review)
Review
Radiologically isolated syndrome refers to an entity in which white matter lesions fulfilling the criteria for multiple sclerosis occur in individuals without a history of a clinical demyelinating attack or alternative etiology. Since its introduction in 2009, the diagnostic criteria of radiologically isolated syndrome and its clinical relevance have been widely debated by neurologists and radiologists. The aim of the present study was to review the following: 1) historical evolution of radiologically isolated syndrome criteria, 2) clinical and imaging findings in adults and children with radiologically isolated syndrome, 3) imaging features of patients with radiologically isolated syndrome at high risk for conversion to MS, and 4) challenges and controversies for work-up, management, and therapeutic interventions of patients with radiologically isolated syndrome.
Topics: Adult; Child; Demyelinating Diseases; Female; Humans; Magnetic Resonance Imaging; Male; Multiple Sclerosis; Radiologists
PubMed: 32763896
DOI: 10.3174/ajnr.A6649 -
International Journal of Molecular... Jul 2022The etiology of multiple sclerosis (MS), a demyelinating disease affecting the central nervous system (CNS), remains obscure. Although apoptosis of oligodendrocytes and... (Review)
Review
The etiology of multiple sclerosis (MS), a demyelinating disease affecting the central nervous system (CNS), remains obscure. Although apoptosis of oligodendrocytes and neurons has been observed in MS lesions, the contribution of this cell death process to disease pathogenesis remains controversial. It is usually considered that MS-associated demyelination and axonal degeneration result from neuroinflammation and an autoimmune process targeting myelin proteins. However, experimental data indicate that oligodendrocyte and/or neuronal cell death may indeed precede the development of inflammation and autoimmunity. These findings raise the question as to whether neural cell apoptosis is the key event initiating and/or driving the pathological cascade, leading to clinical functional deficits in MS. Similarly, regarding axonal damage, a key pathological feature of MS lesions, the roles of inflammation-independent and cell autonomous neuronal processes need to be further explored. While oligodendrocyte and neuronal loss in MS may not necessarily be mutually exclusive, particular attention should be given to the role of neuronal apoptosis in the development of axonal loss. If proven, MS could be viewed primarily as a neurodegenerative disease accompanied by a secondary neuroinflammatory and autoimmune process.
Topics: Apoptosis; Demyelinating Diseases; Humans; Inflammation; Multiple Sclerosis; Neurodegenerative Diseases
PubMed: 35886931
DOI: 10.3390/ijms23147584 -
Journal of Neurodevelopmental Disorders Dec 2019The mitochondrial aminoacyl-tRNA synthetase proteins (mt-aaRSs) are a group of nuclear-encoded enzymes that facilitate conjugation of each of the 20 amino acids to its... (Review)
Review
BACKGROUND
The mitochondrial aminoacyl-tRNA synthetase proteins (mt-aaRSs) are a group of nuclear-encoded enzymes that facilitate conjugation of each of the 20 amino acids to its cognate tRNA molecule. Mitochondrial diseases are a large, clinically heterogeneous group of disorders with diverse etiologies, ages of onset, and involved organ systems. Diseases related to mt-aaRS mutations are associated with specific syndromes that affect the central nervous system and produce highly characteristic MRI patterns, prototypically the DARS2, EARS, and AARS2 leukodystrophies, which are caused by mutations in mitochondrial aspartyl-tRNA synthetase, mitochondria glutamate tRNA synthetase, and mitochondrial alanyl-tRNA synthetase, respectively. BODY: The disease patterns emerging for these leukodystrophies are distinct in terms of the age of onset, nature of disease progression, and predominance of involved white matter tracts. In DARS2 and EARS2 disorders, earlier disease onset is typically correlated with more significant brain abnormalities, rapid neurological decline, and greater disability. In AARS2 leukodystrophy cases reported thus far, there is nearly invariable progression to severe disability and atrophy of involved brain regions, often within a decade. Although most mutations are compound heterozygous inherited in an autosomal recessive fashion, homozygous variants are found in each disorder and demonstrate high phenotypic variability. Affected siblings manifest disease on a wide spectrum.
CONCLUSION
The syndromic nature and selective vulnerability of white matter tracts in these disorders suggests there may be a shared mechanism of mitochondrial dysfunction to target for study. There is evidence that the clinical variability and white matter tract specificity of each mt-aaRS leukodystrophy depend on both canonical and non-canonical effects of the mutations on the process of mitochondrial translation. Furthermore, different sensitivities to the mt-aaRS mutations have been observed based on cell type. Most mutations result in at least partial retention of mt-aaRS enzyme function with varied effects on the mitochondrial respiratory chain complexes. In EARS2 and AARS2 cells, this appears to result in cumulative impairment of respiration. Mt-aaRS mutations may also affect alternative biochemical pathways such as the integrated stress response, a homeostatic program in eukaryotic cells that typically confers cytoprotection, but can lead to cell death when abnormally activated in response to pathologic states. Systematic review of this group of disorders and further exploration of disease mechanisms in disease models and neural cells are warranted.
Topics: Amino Acyl-tRNA Synthetases; Animals; Brain; Demyelinating Diseases; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Neurodevelopmental Disorders
PubMed: 31839000
DOI: 10.1186/s11689-019-9292-y -
Multiple Sclerosis and Related Disorders Nov 2022Clinical onset of multiple sclerosis (MS) and myelin-oligodendrocyte-glycoprotein-antibody-associated disease (MOGAD) has been reported in association with...
BACKGROUND
Clinical onset of multiple sclerosis (MS) and myelin-oligodendrocyte-glycoprotein-antibody-associated disease (MOGAD) has been reported in association with SARS-CoV-2-vaccination. There is uncertainty as to whether this is causality (denovo disease) or temporal coincidence (manifestation of a preexisting, subclinical neuroinflammation).
OBJECTIVES
Comparing the clinical characteristics of MS-patients versus patients with MS (PwMS) whose clinical onset occurred independently of vaccination (MS).
METHODS
Consecutive patients with clinical onset ≤30 days after SARS-CoV-2-vaccination were included. Clinical data, cerebrospinal fluid (CSF) parameters and magnetic resonance imaging (MRI) as well as optical coherence tomography (OCT) data were compared to an age- and sex-matched MS-cohort.
RESULTS
We identified 5 MS and 1 MOGAD patients who developed their clinical onset ≤ 30 days after SARS-CoV-2-vaccination. Clinical characteristics, CSF, MRI and OCT parameters from MS patients were comparable to the MS cohort and showed evidence of preexisting subclinical CNS disease. The single case with MOGAD clearly differed from PwMS in higher CSF cell counts, remission of MRI lesions during follow-up, and absence of oligoclonal bands.
CONCLUSIONS
Our case series indicates that MS patients showed a rather typical initial manifestation in temporal association with SARS-CoV-2-vaccination and harbored preexisting subclinical neuroinflammation. This argues against the denovo development of MS in this cohort.
Topics: Humans; Autoantibodies; COVID-19; COVID-19 Vaccines; Demyelinating Diseases; Multiple Sclerosis; SARS-CoV-2; Vaccination
PubMed: 36126540
DOI: 10.1016/j.msard.2022.104175 -
International Journal of Molecular... May 2021Herpes simplex virus type 1 (HSV-1) is a neurotropic alphaherpesvirus that can infect the peripheral and central nervous systems, and it has been implicated in... (Review)
Review
Herpes simplex virus type 1 (HSV-1) is a neurotropic alphaherpesvirus that can infect the peripheral and central nervous systems, and it has been implicated in demyelinating and neurodegenerative processes. Transposable elements (TEs) are DNA sequences that can move from one genomic location to another. TEs have been linked to several diseases affecting the central nervous system (CNS), including multiple sclerosis (MS), a demyelinating disease of unknown etiology influenced by genetic and environmental factors. Exogenous viral transactivators may activate certain retrotransposons or class I TEs. In this context, several herpesviruses have been linked to MS, and one of them, HSV-1, might act as a risk factor by mediating processes such as molecular mimicry, remyelination, and activity of endogenous retroviruses (ERVs). Several herpesviruses have been involved in the regulation of human ERVs (HERVs), and HSV-1 in particular can modulate HERVs in cells involved in MS pathogenesis. This review exposes current knowledge about the relationship between HSV-1 and human ERVs, focusing on their contribution as a risk factor for MS.
Topics: Animals; Biological Evolution; DNA Transposable Elements; Demyelinating Diseases; Disease Susceptibility; Endogenous Retroviruses; Herpes Simplex; Herpesvirus 1, Human; Humans; Multiple Sclerosis; Retroelements
PubMed: 34072259
DOI: 10.3390/ijms22115738 -
Psychiatrike = Psychiatriki 2019Numerous lines of evidence implicate myelin and oligodendrocyte function as critical processes affecting neuronal connectivity, which is a central abnormality in... (Review)
Review
Numerous lines of evidence implicate myelin and oligodendrocyte function as critical processes affecting neuronal connectivity, which is a central abnormality in schizophrenia. Neurodevelopmental models related to dysmyelination have suggested its relation with different schizophrenia-like symptoms. Post-mortem studies in patients with schizophrenia have reported 14-22% reduction in the density and the quantity of oligodendrocytes. Several myelin-related candidate genes have been linked oligodendrocyte and myelin dysfunction with neurocircuitry abnormalities in schizophrenia. A number of myelin gene knockout mice models exhibit schizophrenia-like behaviours, and genomic, especially GWAS, studies identified new schizophrenia loci related to oligodendrocyte genetic polymorphisms. It is known that myelin acts as electrical insulation for the ensheathed axon, which helps to preserve the amplitude and to increase the conduction velocity of the propagating axon potential. A growing body of evidence points towards the involvement of dysmyelination of the prefrontal cortex in the development of the cognitive symptoms of psychosis. Neuroimaging investigations have linked processing speed to brain anatomical connectivity, and have pointed the role of processing speed among the predictors of clinical changes in schizophrenia. The dysmyelination-induced delays in patients with psychosis may cause a discrepancy in sensory feedback mechanisms, which results in prediction error. The myelin abnormalities and the resulting conduction delays vary during the course of the multiple sclerosis and this type of cycles are possibly associated with fluctuations in conduction velocity in psychosis. It is worthy of note that the major histocompatibility complex (MHC) is responsible for the genetic overlap in both multiple sclerosis and schizophrenia. Multiple sclerosis manifests sensory and motor symptoms, and schizophrenia disordered cognition and emotion. Having in mind the interdependent relationship of oligodendrocytes and the axons they myelinate, we could suggest that both multiple sclerosis and schizophrenia may use in central nervous system a common pathway of disordered information-processing. Recent research suggests that adaptive myelination could normalize neuronal electrical excitability, which in turn can modify myelin plasticity, resulting to neural activity and behavior modulation. We may suggest that interventions that preserve white matter integrity or ameliorate white matter disruption may enhance information-processing and functional outcome in psychosis.
Topics: Animals; Demyelinating Diseases; Humans; Mental Processes; Mice; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology
PubMed: 31685456
DOI: 10.22365/jpsych.2019.303.245 -
Science Advances Mar 2023Autoimmune central nervous system (CNS) demyelinating diseases are a major public health burden and poorly controlled by current immunosuppressants. More precise...
Autoimmune central nervous system (CNS) demyelinating diseases are a major public health burden and poorly controlled by current immunosuppressants. More precise immunotherapies with higher efficacy and fewer side effects are sought. We investigated the effectiveness and mechanism of an injectable myelin-based antigenic polyprotein MMPt (myelin oligodendrocyte glycoprotein, myelin basic protein and proteolipid protein, truncated). We find that it suppresses mouse experimental autoimmune encephalomyelitis without major side effects. MMPt induces rapid apoptosis of the encephalitogenic T cells and suppresses inflammation in the affected CNS. Intravital microscopy shows that MMPt is taken up by perivascular F4/80 cells but not conventional antigen-presenting dendritic cells, B cells, or microglia. MMPt-stimulated F4/80 cells induce reactive T cell immobilization and apoptosis in situ, resulting in reduced infiltration of inflammatory cells and chemokine production. Our study reveals alternative mechanisms that explain how cognate antigen suppresses CNS inflammation and may be applicable for effectively and safely treating demyelinating diseases.
Topics: Animals; Mice; Inflammation; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Apoptosis; B-Lymphocytes; Drug-Related Side Effects and Adverse Reactions
PubMed: 36857453
DOI: 10.1126/sciadv.abo2810 -
Acta Neurologica Belgica Aug 2021The coronavirus disease of 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), that already appeared as a global pandemic.... (Review)
Review
The coronavirus disease of 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), that already appeared as a global pandemic. Presentation of the disease often includes upper respiratory symptoms like dry cough, dyspnea, chest pain, and rhinorrhea that can develop to respiratory failure, needing intubation. Furthermore, the occurrence of acute and subacute neurological manifestations such as stroke, encephalitis, headache, and seizures are frequently stated in patients with COVID-19. One of the reported neurological complications of severe COVID-19 is the demolition of the myelin sheath. Indeed, the complex immunological dysfunction provides a substrate for the development of demyelination. Nevertheless, few published reports in the literature describe demyelination in subjects with COVID-19. In this short narrative review, we discuss probable pathological mechanisms that may trigger demyelination in patients with SARS-CoV-2 infection and summarize the clinical evidence, confirming SARS-CoV-2 condition as a risk factor for the destruction of myelin.
Topics: COVID-19; Demyelinating Diseases; Humans; SARS-CoV-2
PubMed: 33934300
DOI: 10.1007/s13760-021-01691-5 -
Neuroscience Letters Jan 2021Development of peripheral nervous system (PNS) myelin involves a coordinated series of events between growing axons and the Schwann cell (SC) progenitors that will... (Review)
Review
Development of peripheral nervous system (PNS) myelin involves a coordinated series of events between growing axons and the Schwann cell (SC) progenitors that will eventually ensheath them. Myelin sheaths have evolved out of necessity to maintain rapid impulse propagation while accounting for body space constraints. However, myelinating SCs perform additional critical functions that are required to preserve axonal integrity including mitigating energy consumption by establishing the nodal architecture, regulating axon caliber by organizing axonal cytoskeleton networks, providing trophic and potentially metabolic support, possibly supplying genetic translation materials and protecting axons from toxic insults. The intermediate steps between the loss of these functions and the initiation of axon degeneration are unknown but the importance of these processes provides insightful clues. Prevalent demyelinating diseases of the PNS include the inherited neuropathies Charcot-Marie-Tooth Disease, Type 1 (CMT1) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and the inflammatory diseases Acute Inflammatory Demyelinating Polyneuropathy (AIDP) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). Secondary axon degeneration is a common feature of demyelinating neuropathies and this process is often correlated with clinical deficits and long-lasting disability in patients. There is abundant electrophysiological and histological evidence for secondary axon degeneration in patients and rodent models of PNS demyelinating diseases. Fully understanding the involvement of secondary axon degeneration in these diseases is essential for expanding our knowledge of disease pathogenesis and prognosis, which will be essential for developing novel therapeutic strategies.
Topics: Animals; Arthrogryposis; Axons; Charcot-Marie-Tooth Disease; Demyelinating Diseases; Hereditary Sensory and Motor Neuropathy; Humans; Nerve Degeneration; Polyneuropathies; Schwann Cells
PubMed: 33359733
DOI: 10.1016/j.neulet.2020.135595 -
Frontiers in Immunology 2020Multiple Sclerosis (MS) is traditionally considered an autoimmune-mediated demyelinating disease, the pathoetiology of which is unknown. However, the key question... (Review)
Review
Multiple Sclerosis (MS) is traditionally considered an autoimmune-mediated demyelinating disease, the pathoetiology of which is unknown. However, the key question remains whether autoimmunity is the initiator of the disease (outside-in) or the consequence of a slow and as yet uncharacterized cytodegeneration (oligodendrocytosis), which leads to a subsequent immune response (inside-out). Experimental autoimmune encephalomyelitis has been used to model the later stages of MS during which the autoimmune involvement predominates. In contrast, the cuprizone (CPZ) model is used to model early stages of the disease during which oligodendrocytosis and demyelination predominate and are hypothesized to precede subsequent immune involvement in MS. Recent studies combining a boost, or protection, to the immune system with disruption of the blood brain barrier have shown CPZ-induced oligodendrocytosis with a subsequent immune response. In this Perspective, we review these recent advances and discuss the likelihood of an inside-out vs. an outside-in pathoetiology of MS.
Topics: Animals; Autoimmunity; Central Nervous System; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Disease Progression; Encephalomyelitis, Autoimmune, Experimental; Humans; Mice; Multiple Sclerosis; Oligodendroglia
PubMed: 33117365
DOI: 10.3389/fimmu.2020.572186