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Frontiers in Immunology 2019Akt is a serine/threonine protein kinase that plays a major role in regulating multiple cellular processes. While the isoforms Akt1 and Akt2 are involved in apoptosis...
Akt is a serine/threonine protein kinase that plays a major role in regulating multiple cellular processes. While the isoforms Akt1 and Akt2 are involved in apoptosis and insulin signaling, respectively, the role for Akt3 remains uncertain. Akt3 is predominantly expressed in the brain, and total deletion of Akt3 in mice results in a reduction in brain size and neurodegeneration following injury. Previously, we found that Akt3 mice have a significantly worse clinical course during myelin-oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), an animal model in which autoreactive immune cells enter the CNS, resulting in inflammation, demyelination, and axonal injury. Spinal cords of Akt3 mice are severely demyelinated and have increased inflammation compared to WT, suggesting a neuroprotective role for Akt3 during EAE. To specifically address the role of Akt3 in neuroinflammation and maintaining neuronal integrity, we used several mouse strains with different manipulations to Akt3. During EAE, Akt3 mice (with enhanced Akt3 kinase activity) had lower clinical scores, a lag in disease onset, a delay in the influx of inflammatory cells into the CNS, and less axonal damage compared to WT mice. A significant increased efficiency of differentiation toward FOXP3 expressing iTregs was also observed in Akt3 mice relative to WT. Mice with a conditional deletion of Akt3 in CD4 T-cells had an earlier onset of EAE symptoms, increased inflammation in the spinal cord and brain, and had fewer FOXP3 cells and mRNA expression. No difference in EAE outcome was observed when Akt3 expression was deleted in neurons (Syn1-CKO). These results indicate that Akt3 signaling in T-cells and not neurons is necessary for maintaining CNS integrity during an inflammatory demyelinating disease.
Topics: Animals; Biomarkers; Demyelinating Diseases; Disease Models, Animal; Disease Susceptibility; Encephalomyelitis, Autoimmune, Experimental; Fluorescent Antibody Technique; Forkhead Transcription Factors; Immunohistochemistry; Immunophenotyping; Mice; Mice, Knockout; Proto-Oncogene Proteins c-akt; RNA, Messenger; Signal Transduction; Spinal Cord; T-Lymphocyte Subsets
PubMed: 31404142
DOI: 10.3389/fimmu.2019.01738 -
Revue Neurologique Jun 2018The diagnosis of multiple sclerosis (MS) and other demyelinating diseases of the central nervous system is challenging, and although the currently available biological... (Review)
Review
The diagnosis of multiple sclerosis (MS) and other demyelinating diseases of the central nervous system is challenging, and although the currently available biological and imaging tools offer considerable support to physicians, these tools often fail to provide a simple and final answer at the time of a first event. Thus, sets of diagnostic criteria have been published and tested on patient cohorts, and are now used in clinical trials and in daily clinical practice. These criteria have evolved over time to take into account physicians' and patients' needs, along with emerging paraclinical tests. The different presentations of MS have given rise to the use of a common classification system to identify patient profiles and adapt care protocols accordingly. This article reviews the various classifications of the forms and diagnostic criteria of MS and related syndromes, including neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSDs), acute disseminated (demyelinating) encephalomyelitis (ADEM) and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Also discussed is their validity in the light of the currently available literature.
Topics: Central Nervous System Diseases; Demyelinating Diseases; Encephalomyelitis, Acute Disseminated; Humans; Inflammation; Multiple Sclerosis; Neuromyelitis Optica; Syndrome
PubMed: 29673575
DOI: 10.1016/j.neurol.2018.01.368 -
Multiple Sclerosis (Houndmills,... Oct 2022Haemorrhagic demyelinating lesions are rare, and little is known about the demyelinating diseases with which they are associated, or how lesional haemorrhage affects...
BACKGROUND
Haemorrhagic demyelinating lesions are rare, and little is known about the demyelinating diseases with which they are associated, or how lesional haemorrhage affects treatment and outcomes.
OBJECTIVE
To examine the clinical characteristics and outcomes of patients with demyelinating lesions and magnetic resonance imaging (MRI) evidence of haemorrhage seen at the Mayo clinic between 1990 and 2018.
METHODS
The Mayo Clinic's medical-record diagnostic-linkage system was used to identify patients with CNS demyelinating disease and parenchymal haemorrhage on brain MRI cross-referenced against a database of patients with pathologically confirmed CNS demyelinating disease. The clinical characteristics, diagnosis, MRI findings, brain histopathology, and outcomes of these patients were reviewed.
RESULTS
Ten patients with haemorrhagic demyelination were identified, including three patients who underwent a brain biopsy. The main findings were that haemorrhagic demyelinating lesions most often occur in atypical forms of demyelination, especially acute haemorrhagic leukoencephalitis (AHL, or Weston-Hurst disease) and tumefactive demyelination, and rarely in multiple sclerosis. A spectrum of outcomes was observed for these patients ranging from complete remission through to high level disability.
CONCLUSION
Lesional haemorrhage is uncommon in demyelinating disease where it is most closely associated with AHL. Bleeding within a demyelinating lesion does not always herald a poor prognosis.
Topics: Brain; Demyelinating Diseases; Hemorrhage; Humans; Magnetic Resonance Imaging; Multiple Sclerosis
PubMed: 35581949
DOI: 10.1177/13524585221094241 -
Internal Medicine Journal May 2018Hypothalamic involvement in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is rare and endocrinopathies involving the hypothalamic-pituitary...
Hypothalamic involvement in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is rare and endocrinopathies involving the hypothalamic-pituitary axis in patients with demyelinating conditions have rarely been reported. We present two cases of MS/NMOSD with associated hypothalamic-pituitary involvement and subsequent hypopituitarism, including the first report of a patient with hypothalamic demyelination causing panhypopituitarism. Differential diagnoses, including alemtuzumab-related and primary pituitary pathology are discussed.
Topics: Aged; Demyelinating Diseases; Female; Humans; Hypopituitarism; Hypothalamus; Middle Aged; Multiple Sclerosis; Neuromyelitis Optica
PubMed: 29722193
DOI: 10.1111/imj.13787 -
Neurological Sciences : Official... Apr 2021Technological advances and greater availability of magnetic resonance imaging have prompted an increment on incidental and unexpected findings within the central nervous... (Review)
Review
BACKGROUND
Technological advances and greater availability of magnetic resonance imaging have prompted an increment on incidental and unexpected findings within the central nervous system. The concept of radiologically isolated syndrome characterizes a group of subjects with images suggestive of demyelinating disease in the absence of a clinical episode compatible with multiple sclerosis. Since the description of this entity, many questions have arisen; some have received responses but others remain unanswered. A panel of experts met with the objective of performing a critical review of the currently available evidence. Definition, prevalence, biological bases, published evidence, and implications on patient management were reviewed. Thirty to 50% of subjects with radiologically isolated syndrome will progress to multiple sclerosis in 5 years. Male sex, age < 37 years old, and spinal lesions increase the risk. These subjects should be evaluated by a multiple sclerosis specialist, carefully excluding alternative diagnosis. An initial evaluation should include a brain and complete spine magnetic resonance, visual evoked potentials, and identification of oligoclonal bands in cerebrospinal fluid. Disease-modifying therapies could be considered when oligoclonal bands or radiological progression is present.
CONCLUSION
At present time, radiologically isolated syndrome cannot be considered a part of the multiple sclerosis spectrum. However, a proportion of patients may evolve to multiple sclerosis, meaning it represents much more than just a radiological finding.
Topics: Adult; Demyelinating Diseases; Evoked Potentials, Visual; Humans; Magnetic Resonance Imaging; Male; Multiple Sclerosis; Oligoclonal Bands
PubMed: 33496891
DOI: 10.1007/s10072-021-05069-6 -
Current Opinion in Pharmacology Oct 2022Amino acids and their derivatives function as building blocks as well as signaling molecules to modulate various cellular processes in living organisms. In mice, amino... (Review)
Review
Amino acids and their derivatives function as building blocks as well as signaling molecules to modulate various cellular processes in living organisms. In mice, amino acids accumulate in demyelinated lesions and return to basal levels during remyelination. Studies have found that amino acids and their metabolites modulate immune activity in the central nervous system (CNS) and influence oligodendrocyte differentiation and remyelination efficiency. In this review, we discuss current studies on amino acid metabolism in the context of CNS remyelination. By understanding the mechanisms of amino acid signaling and metabolism in demyelinated lesions, we may deepen our understanding of compartmentalized CNS inflammation in demyelinating disease like multiple sclerosis (MS) and provide evidence to develop novel pharmacological therapies targeting amino acid metabolism to prevent disease worsening.
Topics: Amino Acids; Animals; Central Nervous System; Demyelinating Diseases; Mice; Microglia; Multiple Sclerosis; Oligodendroglia; Remyelination
PubMed: 36067684
DOI: 10.1016/j.coph.2022.102287 -
Neuroscience Letters Jun 2015Inherited neuropathies known collectively as Charcot-Marie-Tooth disease are one of the most common inherited neurological conditions affecting ∼1 in 2500 people. A... (Review)
Review
Inherited neuropathies known collectively as Charcot-Marie-Tooth disease are one of the most common inherited neurological conditions affecting ∼1 in 2500 people. A heterogenous disorder, CMT is divided into subtypes based on the pattern of inheritance and also by neurophysiological studies. Despite the clinical similarities among patients with demyelinating CMT, it is recognized that this group of disorders is both genetically and phenotypically heterogenous. Understanding the pathogenesis of these disorders requires an intimate knowledge of normal myelin development and homeostasis. Improvements in genetic testing techniques over the last 20 years have contributed majorly to the identification of specific genes, proteins, and molecular pathways that are providing the basis for understanding the disease processes and developing rational approaches to therapy.
Topics: Charcot-Marie-Tooth Disease; Demyelinating Diseases; Humans; Mutation
PubMed: 25625223
DOI: 10.1016/j.neulet.2015.01.059 -
Veterinary Pathology Jan 2018Human idiopathic inflammatory demyelinating diseases (IIDD) are a heterogeneous group of autoimmune inflammatory and demyelinating disorders of the central nervous... (Review)
Review
Human idiopathic inflammatory demyelinating diseases (IIDD) are a heterogeneous group of autoimmune inflammatory and demyelinating disorders of the central nervous system (CNS). These include multiple sclerosis (MS), the most common chronic IIDD, but also rarer disorders such as acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO). Great efforts have been made to understand the pathophysiology of MS, leading to the development of a few effective treatments. Nonetheless, IIDD still require a better understanding of the causes and underlying mechanisms to implement more effective therapies and diagnostic methods. Experimental autoimmune encephalomyelitis (EAE) is a commonly used animal model to study the pathophysiology of IIDD. EAE is principally induced through immunization with myelin antigens combined with immune-activating adjuvants. Nonhuman primates (NHP), the phylogenetically closest relatives of humans, challenged by similar microorganisms as other primates may recapitulate comparable immune responses to that of humans. In this review, the authors describe EAE models in 3 NHP species: rhesus macaques ( Macaca mulatta), cynomolgus macaques ( Macaca fascicularis), and common marmosets ( Callithrix jacchus), evaluating their respective contribution to the understanding of human IIDD. EAE in NHP is a heterogeneous disease, including acute monophasic and chronic polyphasic forms. This diversity makes it a versatile model to use in translational research. This clinical variability also creates an opportunity to explore multiple facets of immune-mediated mechanisms of neuro-inflammation and demyelination as well as intrinsic protective mechanisms. Here, the authors review current insights into the pathogenesis and immunopathological mechanisms implicated in the development of EAE in NHP.
Topics: Animals; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Nervous System Autoimmune Disease, Experimental; Primates
PubMed: 28583039
DOI: 10.1177/0300985817712794 -
Neurology Dec 2018Chronic inflammatory demyelinating polyneuropathy (CIDP) is a form of chronic neuropathy that is presumably caused by heterogeneous immune-mediated processes. Recent... (Review)
Review
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a form of chronic neuropathy that is presumably caused by heterogeneous immune-mediated processes. Recent advances in the search for autoantibodies against components expressed at nodal regions, such as the nodes of Ranvier and paranodes, have substantially contributed to clarifying the pathogenesis of CIDP in a subpopulation of patients. In particular, immunoglobulin G4 (IgG4) antibodies to paranodal junction proteins, including neurofascin-155 and contactin-1, have attracted the attention of researchers. Paranodal dissection resulting from the attachment of IgG4 at paranodal junctions and the absence of macrophage-induced demyelination are characteristic pathologic features in patients who have these antibodies. By contrast, the mechanisms of neuropathy in cases with classical macrophage-induced demyelination remain unclear despite the long-standing recognition of this process in CIDP. In addition to complement-dependent damage provoked by autoantibodies, recent studies have shed light on antibody-dependent phagocytosis by macrophages without participation of complements. However, a direct association between specific autoantibodies and macrophage-induced demyelination has not been reported. Electron microscopic examination of longitudinal sections of sural nerve biopsy specimens suggested that macrophages recognize specific sites of myelinated fibers as the initial target of demyelination. The site that macrophages select to initiate myelin breakdown is located around the nodal regions in some patients and internode in others. Hence, it seems that the components that distinguish between the nodal regions and internode play a pivotal role in the behavior of macrophages that initiate phagocytosis of myelin. Further studies are needed to elucidate the mechanisms underlying macrophage-induced demyelination from this perspective.
Topics: Axons; Demyelinating Diseases; Humans; Macrophages; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating
PubMed: 30429275
DOI: 10.1212/WNL.0000000000006625 -
Acta Neuropathologica Communications Mar 2021Cognitive dysfunction occurs in greater than 50% of individuals with multiple sclerosis (MS). Hippocampal demyelination is a prominent feature of postmortem MS brains...
Cognitive dysfunction occurs in greater than 50% of individuals with multiple sclerosis (MS). Hippocampal demyelination is a prominent feature of postmortem MS brains and hippocampal atrophy correlates with cognitive decline in MS patients. Cellular and molecular mechanisms responsible for neuronal dysfunction in demyelinated hippocampi are not fully understood. Here we investigate a mouse model of hippocampal demyelination where twelve weeks of treatment with the oligodendrocyte toxin, cuprizone, demyelinates over 90% of the hippocampus and causes decreased memory/learning. Long-term potentiation (LTP) of hippocampal CA1 pyramidal neurons is considered to be a major cellular readout of learning and memory in the mammalian brain. In acute slices, we establish that hippocampal demyelination abolishes LTP and excitatory post-synaptic potentials of CA1 neurons, while pre-synaptic function of Schaeffer collateral fibers is preserved. Demyelination also reduced Ca-mediated firing of hippocampal neurons in vivo. Using three-dimensional electron microscopy, we investigated the number, shape (mushroom, stubby, thin), and post-synaptic densities (PSDs) of dendritic spines that facilitate LTP. Hippocampal demyelination did not alter the number of dendritic spines. Surprisingly, dendritic spines appeared to be more mature in demyelinated hippocampi, with a significant increase in mushroom-shaped spines, more perforated PSDs, and more astrocyte participation in the tripartite synapse. RNA sequencing experiments identified 400 altered transcripts in demyelinated hippocampi. Gene transcripts that regulate myelination, synaptic signaling, astrocyte function, and innate immunity were altered in demyelinated hippocampi. Hippocampal remyelination rescued synaptic transmission, LTP, and the majority of gene transcript changes. We establish that CA1 neurons projecting demyelinated axons silence their dendritic spines and hibernate in a state that may protect the demyelinated axon and facilitates functional recovery following remyelination.
Topics: Animals; Astrocytes; Cognitive Dysfunction; Cuprizone; Demyelinating Diseases; Dendritic Spines; Disease Models, Animal; Hippocampus; Long-Term Potentiation; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron; Multiple Sclerosis; Neurons; Post-Synaptic Density; Sequence Analysis, RNA
PubMed: 33648591
DOI: 10.1186/s40478-021-01130-9