scholarly journals Mechanisms of Neurodegeneration and Axonal Dysfunction in Progressive Multiple Sclerosis

Biomedicines ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 14 ◽  
Author(s):  
Jorge Correale ◽  
Mariano Marrodan ◽  
María Ysrraelit
Keyword(s):  
Multiple Sclerosis ◽  
Cell Activation ◽  
Neuronal Damage ◽  
Neuronal Loss ◽  
Progressive Multiple Sclerosis ◽  
Demyelinating Lesions ◽  
The Central Nervous System ◽  
Nitrogen Reactive Species ◽  
Gradual Accumulation ◽  
Axonal Dysfunction

Multiple Sclerosis (MS) is a major cause of neurological disability, which increases predominantly during disease progression as a result of cortical and grey matter structures involvement. The gradual accumulation of disability characteristic of the disease seems to also result from a different set of mechanisms, including in particular immune reactions confined to the Central Nervous System such as: (a) B-cell dysregulation, (b) CD8+ T cells causing demyelination or axonal/neuronal damage, and (c) microglial cell activation associated with neuritic transection found in cortical demyelinating lesions. Other potential drivers of neurodegeneration are generation of oxygen and nitrogen reactive species, and mitochondrial damage, inducing impaired energy production, and intra-axonal accumulation of Ca2+, which in turn activates a variety of catabolic enzymes ultimately leading to progressive proteolytic degradation of cytoskeleton proteins. Loss of axon energy provided by oligodendrocytes determines further axonal degeneration and neuronal loss. Clearly, these different mechanisms are not mutually exclusive and could act in combination. Given the multifactorial pathophysiology of progressive MS, many potential therapeutic targets could be investigated in the future. This remains however, an objective that has yet to be undertaken.

827 Central Sleep Apnea in a patient with Multiple Sclerosis

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A322-A323
Author(s):  
Rahul Dasgupta ◽  
Sonja Schütz ◽  
Tiffany Braley
Keyword(s):  
Multiple Sclerosis ◽  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Sleep Disordered Breathing ◽  
Central Sleep Apnea ◽  
Progressive Multiple Sclerosis ◽  
Obstructive Sleep ◽  
Increased Risk ◽  
Demyelinating Lesions ◽  
The Brain

Abstract Introduction Sleep-disordered breathing is common in persons with multiple sclerosis (PwMS), and may contribute to debilitating fatigue and other chronic MS symptoms. The majority of research to date on SDB in MS has focused on the prevalence and consequences of obstructive sleep apnea; however, PwMS may also be at increased risk for central sleep apnea (CSA), and the utility of methods to assess CSA in PwMS warrant further exploration. We present a patient with secondary progressive multiple sclerosis who was found to have severe central sleep apnea on WatchPAT testing. Report of case(s) A 61 year-old female with a past medical history of secondary progressive multiple sclerosis presented with complaints of fragmented sleep. MRI of the brain, cervical spine, and thoracic spine showed numerous demyelinating lesions in the brain, brainstem, cervical, and thoracic spinal cord. Upon presentation, the patient noted snoring, witnessed apneas, and daytime sleepiness. WatchPAT demonstrated severe sleep apnea, with a pAHI of 63.3, and a minimum oxygen saturation of 90%. The majority of the scored events were non-obstructive in nature (73.1% of all scored events), and occurred intermittently in a periodic fashion. Conclusion The differential diagnosis of fatigue in PwMS should include sleep-disordered breathing, including both obstructive and central forms of sleep apnea. Demyelinating lesions in the brainstem (which may contribute to impairment of motor and sensory networks that control airway patency and respiratory drive), and progressive forms of MS, have been linked to both OSA and CSA. The present data illustrate this relationship in a person with progressive MS, and offer support for the WatchPAT as a cost-effective means to evaluate for both OSA and CSA in PwMS, while reducing patient burden. PwMS may be at increased risk for CSA. Careful clinical consideration should be given to ordering appropriate sleep testing to differentiate central from obstructive sleep apnea in PwMS, particularly for patients with demyelinating lesions in the brainstem. Support (if any) 1. Braley TJ, Segal BM, Chervin RD. Obstructive sleep apnea and fatigue in patients with multiple sclerosis. J Clin Sleep Med. 2014 Feb 15;10(2):155–62. doi: 10.5664/jcsm.3442. PMID: 24532998; PMCID: PMC3899317.

Recent advances on immunosuppressive drugs and remyelination enhancers for the treatment of multiple sclerosis

2021 ◽  
Vol 27 ◽  
Author(s):  
Jennifer Cadenas-Fernández ◽  
Pablo Ahumada-Pascual ◽  
Luis Sanz Andreu ◽  
Ana Velasco
Keyword(s):  
Multiple Sclerosis ◽  
Intracellular Signaling ◽  
Demyelinating Disease ◽  
Lipid Synthesis ◽  
Immunosuppressive Drugs ◽  
Nerve Fibers ◽  
Myelin Sheaths ◽  
Demyelinating Lesions ◽  
The Central Nervous System ◽  
Lipid Structures

: Mammalian nervous systems depend crucially on myelin sheaths covering the axons. In the central nervous system, myelin sheaths consist of lipid structures which are generated from the membrane of oligodendrocytes (OL). These sheaths allow fast nerve transmission, protect axons and provide them metabolic support. In response to specific traumas or pathologies, these lipid structures can be destabilized and generate demyelinating lesions. Multiple sclerosis (MS) is an example of a demyelinating disease in which the myelin sheaths surrounding the nerve fibers of the brain and spinal cord are damaged. MS is the leading cause of neurological disability in young adults in many countries, and its incidence has been increasing in recent decades. Related to its etiology, it is known that MS is an autoimmune and inflammatory CNS disease. However, there are no effective treatments for this disease and the immunomodulatory therapies that currently exist have proven limited success since they only delay the progress of the disease. Nowadays, one of the main goals in the MS research is to find treatments which allows the recovery of neurological disabilities due to demyelination. To this end, different approaches, such as modulating intracellular signaling or regulating the lipid metabolism of OLs, are being considered. Here, in addition to immunosuppressive or immunomodulatory drugs that reduce the immune response against myelin sheaths, we review a diverse group of drugs that promotes endogenous remyelination in MS patients and whose use may be interesting as potential therapeutic agents in MS disease. To this end, we compile specific treatments against MS that are currently in the market with remyelination strategies which have entered into human clinical trials for future reparative MS therapies. The method used in this study is a systematic literature review on PubMed, Web of Science and Science Direct databases up to May 31, 2020. To narrow down the search results in databases, more specific keywords, such as, “myelin sheath”, “remyelination”, “demyelination”, “oligodendrocyte” and “lipid synthesis” were used to focus the search. We favoured papers published after January, 2015, but did not exclude earlier seminal papers.

scholarly journals A metabolic perspective on CSF-mediated neurodegeneration in multiple sclerosis

Brain ◽  
2019 ◽  
Vol 142 (9) ◽  
pp. 2756-2774 ◽  
Author(s):  
Maureen Wentling ◽  
Carlos Lopez-Gomez ◽  
Hye-Jin Park ◽  
Mario Amatruda ◽  
Achilles Ntranos ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Neuronal Damage ◽  
Morphological Changes ◽  
Progressive Multiple Sclerosis ◽  
Functional Screening ◽  
Disease Course ◽  
Post Translational Modification ◽  
Neurodegenerative Process ◽  
Relapsing Remitting ◽  
Multiple Sclerosis Patients

Abstract Multiple sclerosis is an autoimmune demyelinating disorder of the CNS, characterized by inflammatory lesions and an underlying neurodegenerative process, which is more prominent in patients with progressive disease course. It has been proposed that mitochondrial dysfunction underlies neuronal damage, the precise mechanism by which this occurs remains uncertain. To investigate potential mechanisms of neurodegeneration, we conducted a functional screening of mitochondria in neurons exposed to the CSF of multiple sclerosis patients with a relapsing remitting (n = 15) or a progressive (secondary, n = 15 or primary, n = 14) disease course. Live-imaging of CSF-treated neurons, using a fluorescent mitochondrial tracer, identified mitochondrial elongation as a unique effect induced by the CSF from progressive patients. These morphological changes were associated with decreased activity of mitochondrial complexes I, III and IV and correlated with axonal damage. The effect of CSF treatment on the morphology of mitochondria was characterized by phosphorylation of serine 637 on the dynamin-related protein DRP1, a post-translational modification responsible for unopposed mitochondrial fusion in response to low glucose conditions. The effect of neuronal treatment with CSF from progressive patients was heat stable, thereby prompting us to conduct an unbiased exploratory lipidomic study that identified specific ceramide species as differentially abundant in the CSF of progressive patients compared to relapsing remitting multiple sclerosis. Treatment of neurons with medium supplemented with ceramides, induced a time-dependent increase of the transcripts levels of specific glucose and lactate transporters, which functionally resulted in progressively increased glucose uptake from the medium. Thus ceramide levels in the CSF of patients with progressive multiple sclerosis not only impaired mitochondrial respiration but also decreased the bioavailability of glucose by increasing its uptake. Importantly the neurotoxic effect of CSF treatment could be rescued by exogenous supplementation with glucose or lactate, presumably to compensate the inefficient fuel utilization. Together these data suggest a condition of ‘virtual hypoglycosis’ induced by the CSF of progressive patients in cultured neurons and suggest a critical temporal window of intervention for the rescue of the metabolic impairment of neuronal bioenergetics underlying neurodegeneration in multiple sclerosis patients.

scholarly journals Perspective of SGLT2 Inhibition in Treatment of Conditions Connected to Neuronal Loss: Focus on Alzheimer’s Disease and Ischemia-Related Brain Injury

2020 ◽  
Vol 13 (11) ◽  
pp. 379
Author(s):  
Michał Wiciński ◽  
Eryk Wódkiewicz ◽  
Karol Górski ◽  
Maciej Walczak ◽  
Bartosz Malinowski
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Damage ◽  
Neurovascular Unit ◽  
Neuronal Loss ◽  
Impact Risk ◽  
Sglt2 Inhibition ◽  
The Central Nervous System ◽  
Cortical Regions ◽  
Endothelial Growth Factor

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are oral anti-hyperglycemic agents approved for the treatment of type 2 diabetes mellitus. Some reports suggest their presence in the central nervous system and possible neuroprotective properties. SGLT2 inhibition by empagliflozin has shown to reduce amyloid burden in cortical regions of APP/PS1xd/db mice. The same effect was noticed regarding tau pathology and brain atrophy volume. Empagliflozin presented beneficial effect on cognitive function, which may be connected to an increase in cerebral brain-derived neurotrophic factor. Canagliflozin and dapagliflozin may possess acetylcholinesterase inhibiting activity, resembling in this matter Alzheimer’s disease-registered therapies. SGLT2 inhibitors may prove to impact risk factors of atherosclerosis and pathways participating both in acute and late stage of stroke. Their mechanism of action can be related to induction in hepatocyte nuclear factor-1α, vascular endothelial growth factor-A, and proinflammatory factors limitation. Empagliflozin may have a positive effect on preservation of neurovascular unit in diabetic mice, preventing its aberrant remodeling. Canagliflozin seems to present some cytostatic properties by limiting both human and mice endothelial cells proliferation. The paper presents potential mechanisms of SGLT-2 inhibitors in conditions connected with neuronal damage, with special emphasis on Alzheimer’s disease and cerebral ischemia.

scholarly journals Impact of Exercise on Immunometabolism in Multiple Sclerosis

2020 ◽  
Vol 9 (9) ◽  
pp. 3038 ◽  
Author(s):  
Remsha Afzal ◽  
Jennifer K Dowling ◽  
Claire E McCoy
Keyword(s):  
Multiple Sclerosis ◽  
Cell Function ◽  
Immune Cell ◽  
Therapeutic Benefits ◽  
Demyelinating Lesions ◽  
Inflammatory State ◽  
Autoimmune Condition ◽  
The Central Nervous System ◽  
Axonal Degradation

Multiple Sclerosis (MS) is a chronic, autoimmune condition characterized by demyelinating lesions and axonal degradation. Even though the cause of MS is heterogeneous, it is known that peripheral immune invasion in the central nervous system (CNS) drives pathology at least in the most common form of MS, relapse-remitting MS (RRMS). The more progressive forms’ mechanisms of action remain more elusive yet an innate immune dysfunction combined with neurodegeneration are likely drivers. Recently, increasing studies have focused on the influence of metabolism in regulating immune cell function. In this regard, exercise has long been known to regulate metabolism, and has emerged as a promising therapy for management of autoimmune disorders. Hence, in this review, we inspect the role of key immunometabolic pathways specifically dysregulated in MS and highlight potential therapeutic benefits of exercise in modulating those pathways to harness an anti-inflammatory state. Finally, we touch upon current challenges and future directions for the field of exercise and immunometabolism in MS.

scholarly journals Hypoperfusion of the Cerebral White Matter in Multiple Sclerosis: Possible Mechanisms and Pathophysiological Significance

2008 ◽  
Vol 28 (10) ◽  
pp. 1645-1651 ◽  
Author(s):  
Jacques De Keyser ◽  
Christel Steen ◽  
Jop P Mostert ◽  
Marcus W Koch
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Adrenergic Receptors ◽  
Perfusion Magnetic Resonance Imaging ◽  
Cerebral White Matter ◽  
Perivascular Spaces ◽  
Axonal Loss ◽  
Normal Appearing White Matter ◽  
Demyelinating Lesions ◽  
The Central Nervous System

Multiple sclerosis (MS) is a disease of the central nervous system characterized by patchy areas of demyelination, inflammation, axonal loss and gliosis, and a diffuse axonal degeneration throughout the so-called normal-appearing white matter (NAWM). A number of recent studies using perfusion magnetic resonance imaging in both relapsing and progressive forms of MS have shown a decreased perfusion of the NAWM, which does not appear to be secondary to axonal loss. The reduced perfusion of the NAWM in MS might be caused by a widespread astrocyte dysfunction, possibly related to a deficiency in astrocytic β2-adrenergic receptors and a reduced formation of cAMP, resulting in a reduced uptake of K+ at the nodes of Ranvier and a reduced release of K+ in the perivascular spaces. Pathologic and imaging studies suggest that ischemic changes might be involved in the development of a subtype of focal demyelinating lesions (type III lesions), and there appears to exist a relationship between decreased white matter perfusion and cognitive dysfunction in patients with MS.

Retinal ganglion cell loss induced by acute optic neuritis in a relapsing model of multiple sclerosis

2006 ◽  
Vol 12 (5) ◽  
pp. 526-532 ◽  
Author(s):  
Kenneth S Shindler ◽  
Yangtai Guan ◽  
Elvira Ventura ◽  
Jean Bennett ◽  
Abdolmohamad Rostami
Keyword(s):  
Multiple Sclerosis ◽  
Optic Neuritis ◽  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Neuronal Loss ◽  
Proteolipid Protein ◽  
Cell Loss ◽  
Retinal Ganglion ◽  
Acute Optic Neuritis ◽  
Demyelinating Lesions

Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are marked by inflammatory demyelinating lesions throughout the central nervous system, including optic nerve. Neuronal loss also occurs in MS and EAE lesions, but it is not known whether neuronal loss occurs secondary to inflammation, or as a primary process. In the current study, the relationship of inflammation to retinal ganglion cell (RGC) loss during acute optic neuritis is examined. RGCs were labelled with Flourogold, and EAE was induced in SJL/J mice by immunization with proteolipid protein peptide 139- 151 (PLP). At various time points, RGCs were counted and optic nerves were examined for inflammatory cell infiltrates. No optic neuritis was detected prior to day 9 following immunization. Incidence of optic neuritis was 30% at day 9 and increased to over 70% by day 11, remaining high through day 18. In contrast, no RGC loss was detected in eyes with optic neuritis until day 14. A 43.1% reduction in RGC numbers at day 14 increased to 50.8% by day 18. No RGC loss occurred in eyes without optic neuritis. The fact that inflammation precedes RGC loss suggests that neuronal loss during optic neuritis occurs secondary to the inflammatory process.

scholarly journals Immunology and Oxidative Stress in Multiple Sclerosis: Clinical and Basic Approach

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Genaro G. Ortiz ◽  
Fermín P. Pacheco-Moisés ◽  
Oscar K. Bitzer-Quintero ◽  
Ana C. Ramírez-Anguiano ◽  
Luis J. Flores-Alvarado ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Tissue Injury ◽  
Autoimmune Disorder ◽  
Demyelinating Lesions ◽  
The Central Nervous System ◽  
The Brain ◽  
And Oxidative Stress

Multiple sclerosis (MS) exhibits many of the hallmarks of an inflammatory autoimmune disorder including breakdown of the blood-brain barrier (BBB), the recruitment of lymphocytes, microglia, and macrophages to lesion sites, the presence of multiple lesions, generally being more pronounced in the brain stem and spinal cord, the predominantly perivascular location of lesions, the temporal maturation of lesions from inflammation through demyelination, to gliosis and partial remyelination, and the presence of immunoglobulin in the central nervous system and cerebrospinal fluid. Lymphocytes activated in the periphery infiltrate the central nervous system to trigger a local immune response that ultimately damages myelin and axons. Pro-inflammatory cytokines amplify the inflammatory cascade by compromising the BBB, recruiting immune cells from the periphery, and activating resident microglia. inflammation-associated oxidative burst in activated microglia and macrophages plays an important role in the demyelination and free radical-mediated tissue injury in the pathogenesis of MS. The inflammatory environment in demyelinating lesions leads to the generation of oxygen- and nitrogen-free radicals as well as proinflammatory cytokines which contribute to the development and progression of the disease. Inflammation can lead to oxidative stress and vice versa. Thus, oxidative stress and inflammation are involved in a self-perpetuating cycle.

Different white matter lesion characteristics correlate with distinct grey matter abnormalities on magnetic resonance imaging in secondary progressive multiple sclerosis

2009 ◽  
Vol 15 (6) ◽  
pp. 687-694 ◽  
Author(s):  
J Furby ◽  
T Hayton ◽  
D Altmann ◽  
R Brenner ◽  
J Chataway ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Grey Matter ◽  
Progressive Multiple Sclerosis ◽  
Secondary Progressive Multiple Sclerosis ◽  
Lesion Volume ◽  
Secondary Degeneration ◽  
Secondary Progressive ◽  
Demyelinating Lesions ◽  
The Relationship

Background Although MRI measures of grey matter abnormality correlate with clinical disability in multiple sclerosis, it is uncertain whether grey matter abnormality measured on MRI is entirely due to a primary grey matter process or whether it is partly related to disease in the white matter. Methods To explore potential mechanisms of grey matter damage we assessed the relationship of white matter T2 lesion volume, T1 lesion volume, and mean lesion magnetisation transfer ratio (MTR), with MRI measures of tissue atrophy and MTR in the grey matter in 117 subjects with secondary progressive multiple sclerosis. Results Grey matter fraction and mean grey matter MTR were strongly associated with lesion volumes and lesion MTR mean ( r = ±0.63–0.72). In contrast, only weak to moderate correlations existed between white matter and lesion measures. In a stepwise regression model, T1 lesion volume was the only independent lesion correlate of grey matter fraction and accounted for 52% of the variance. Lesion MTR mean and T2 lesion volume were independent correlates of mean grey matter MTR, accounting for 57% of the variance. Conclusions Axonal transection within lesions with secondary degeneration into the grey matter may explain the relationship between T1 lesions and grey matter fraction. A parallel accumulation of demyelinating lesions in white and grey matter may contribute to the association of T2 lesion volume and lesion MTR with grey matter MTR.

scholarly journals Alterations in sensorimotor and mesiotemporal cortices and diffuse white matter changes in primary progressive multiple sclerosis detected by adiabatic relaxometry

2020 ◽  
Author(s):  
Pavel Filip ◽  
Michal Dufek ◽  
Silvia Mangia ◽  
Shalom Michaeli ◽  
Martin Bares ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Large Scale ◽  
Diffusion Tensor ◽  
Neuronal Loss ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Primary Progressive ◽  
T1 And T2

Abstract Background: The research of primary progressive multiple sclerosis (PPMS) has not been able to capitalize on recent progresses in advanced MRI protocols searching for disease-specific microstructural changes. Methods: Conventional free precession T1 and T2, and rotating frame adiabatic T1ρ and T2ρ maps in combination with diffusion weighted parameters were acquired in 13 PPMS patients and 13 age and sex-matched controls.Results: T1ρ, a marker of crucial relevance for PPMS due to its sensitivity to neuronal loss, revealed large-scale changes in mesiotemporal structures, sensorimotor cortex and cingulate, in combination with diffuse alterations in the white matter and cerebellum. T2ρ, particularly sensitive to local tissue background gradients and thus indicator of iron accumulation, concurred with similar topography of damage, but of lower extent. Moreover, these adiabatic protocols completely dwarfed the outcomes of both conventional T1 and T2 maps and diffusion tensor/kurtosis approaches –methods previously implicated in the MRI research of PPMS.Conclusion: This study introduces adiabatic T1ρ and T2ρ as elegant markers confirming large-scale cortical grey matter, cerebellar and white matter alterations in PPMS invisible to other in vivo biomarkers.

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