Cuprizone and EAE mouse frontal cortex proteomics revealed proteins altered in multiple sclerosis

AbstractTwo pathophysiological different experimental models for multiple sclerosis were analyzed in parallel using quantitative proteomics in attempts to discover protein alterations applicable as diagnostic-, prognostic-, or treatment targets in human disease. The cuprizone model reflects de- and remyelination in multiple sclerosis, and the experimental autoimmune encephalomyelitis (EAE, MOG1-125) immune-mediated events. The frontal cortex, peripheral to severely inflicted areas in the CNS, was dissected and analyzed. The frontal cortex had previously not been characterized by proteomics at different disease stages, and novel protein alterations involved in protecting healthy tissue and assisting repair of inflicted areas might be discovered. Using TMT-labelling and mass spectrometry, 1871 of the proteins quantified overlapped between the two experimental models, and the fold change compared to controls was verified using label-free proteomics. Few similarities in frontal cortex between the two disease models were observed when regulated proteins and signaling pathways were compared. Legumain and C1Q complement proteins were among the most upregulated proteins in cuprizone and hemopexin in the EAE model. Immunohistochemistry showed that legumain expression in post-mortem multiple sclerosis brain tissue (n = 19) was significantly higher in the center and at the edge of white matter active and chronic active lesions. Legumain was associated with increased lesion activity and might be valuable as a drug target using specific inhibitors as already suggested for Parkinson’s and Alzheimer’s disease. Cerebrospinal fluid levels of legumain, C1q and hemopexin were not significantly different between multiple sclerosis patients, other neurological diseases, or healthy controls.

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Microglial Pruning: Relevance for Synaptic Dysfunction in Multiple Sclerosis and Related Experimental Models

Cells ◽

10.3390/cells10030686 ◽

2021 ◽

Vol 10 (3) ◽

pp. 686

Author(s):

Maria Concetta Geloso ◽

Nadia D’Ambrosi

Keyword(s):

Multiple Sclerosis ◽

Neuronal Death ◽

Environmental Changes ◽

Experimental Models ◽

Synaptic Dysfunction ◽

Synapse Elimination ◽

Neurodegenerative Process ◽

Immune Mediated ◽

Wide Range ◽

Demyelinating Lesions

Microglia, besides being able to react rapidly to a wide range of environmental changes, are also involved in shaping neuronal wiring. Indeed, they actively participate in the modulation of neuronal function by regulating the elimination (or “pruning”) of weaker synapses in both physiologic and pathologic processes. Mounting evidence supports their crucial role in early synaptic loss, which is emerging as a hallmark of several neurodegenerative diseases, including multiple sclerosis (MS) and its preclinical models. MS is an inflammatory, immune-mediated pathology of the white matter in which demyelinating lesions may cause secondary neuronal death. Nevertheless, primitive grey matter (GM) damage is emerging as an important contributor to patients’ long-term disability, since it has been associated with early and progressive cognitive decline (CD), which seriously worsens the quality of life of MS patients. Widespread synapse loss even in the absence of demyelination, axon degeneration and neuronal death has been demonstrated in different GM structures, thus raising the possibility that synaptic dysfunction could be an early and possibly independent event in the neurodegenerative process associated with MS. This review provides an overview of microglial-dependent synapse elimination in the neuroinflammatory process that underlies MS and its experimental models.

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Practice Effects in Mobile Tests of Cognition, Dexterity & Mobility in Multiple Sclerosis Patients: Data Analysis of a Smartphone–Based Observational Study (Preprint)

10.2196/preprints.30394 ◽

2021 ◽

Author(s):

Tim Woelfle ◽

Silvan Pless ◽

Andrea Wiencierz ◽

Ludwig Kappos ◽

Yvonne Naegelin ◽

...

Keyword(s):

Multiple Sclerosis ◽

Neurological Diseases ◽

Clinical Manifestations ◽

Practice Effect ◽

Practice Effects ◽

Linear Phase ◽

Multiple Sclerosis Patients ◽

Personalized Health ◽

Changes Over Time ◽

Minute Walk

BACKGROUND Smartphones and their inbuilt sensors allow for the collection of a wealth of data about their owners. While passively collected data such as step counts can already provide meaningful insights, active tests allow for measuring function in more specific tasks. This could improve disease characterization and monitoring and could potentially support treatment decisions in multiple sclerosis (MS), a multifaceted chronic neurological disease with highly variable clinical manifestations. One challenge that has to be overcome in the assessment of changes over time is the analysis and interpretation of practice effects. OBJECTIVE In this study, we aimed to identify practice effects in active tests for cognition, dexterity, and mobility in user–scheduled, high–frequency, smartphone–based testing. METHODS We analyzed data from 251 self–declared persons with MS with a minimum of 5 weeks of follow–up and at least 5 tests per domain in the Floodlight Open study, a self–enrolment study accessible by smartphone owners from 16 countries. The collected data are openly available for scientists. Using bounded growth mixed models and quantile regression, we characterized practice effects for three different tests: Symbol Digit Modalities Test (SDMT) for cognition, Finger Pinching for dexterity, and Two Minute Walk for mobility. RESULTS Strong practice effects were found for N=4388 SDMT and N=17945 Finger Pinching tests with modelled boundary improvements of 39.6% (38.6%–40.9%) and 85.9% (83.2%–88.9%) over baseline, respectively. Half of the practice effect was reached after 9 repetitions for SDMT and 27 repetitions for Finger Pinching, 90% were reached after 31 and 89 repetitions, respectively. While baseline performance levels were highly variable across participants, no significant differences between the practice effects in low–performers (5th and 25th percentile), median performers and high performers (75th and 95th percentile) were found for SDMT (β = 1.0–1.2 additional correct responses per repetition in the linear phase). Only small differences were observed for Finger Pinching (β = 0.3–0.7 additional successful pinches per repetition in the linear phase). For N=12997 Two Minute Walk tests, no practice effects were observed at all. CONCLUSIONS Smartphone–based tests promise to help monitor disease trajectories of MS and other chronic neurological diseases. Our findings suggest that strong practice effects in cognitive and dexterity functions have to be accounted for in order to identify disease–related changes in these domains, especially in the context of personalized health and in studies with no comparator arm. In contrast, changes in mobility may be more easily interpreted due to the absence of practice effects.

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Rituximab in patients with pediatric multiple sclerosis and other demyelinating disorders of the CNS: Practical considerations

Multiple Sclerosis Journal ◽

10.1177/1352458520932798 ◽

2020 ◽

pp. 135245852093279 ◽

Cited By ~ 1

Author(s):

Angelo Ghezzi ◽

Brenda Banwell ◽

Amit Bar-Or ◽

Tanuja Chitnis ◽

Russell C Dale ◽

...

Keyword(s):

Multiple Sclerosis ◽

Pediatric Patients ◽

Neurological Diseases ◽

Duration Of Treatment ◽

Pediatric Multiple Sclerosis ◽

Immune Mediated ◽

The Central Nervous System ◽

Anti Cd20 ◽

Demyelinating Disorders

Anti-CD20 therapies have established efficacy in the treatment of immune-mediated neurological and non-neurological diseases. Rituximab, one of the first B-cell-directed therapies, is relatively inexpensive compared to newer anti-CD20 molecules, is available in many countries, and has been used off-label in pediatric patients with neuroimmune conditions. The objective of this paper is to describe the experience with rituximab in pediatric multiple sclerosis and other inflammatory immune-mediated disorders of the central nervous system (CNS), and to define a protocol for its use in clinical practice, in particular addressing doses, interval of administration, duration of treatment, and tests to perform at baseline and during follow-up.

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Cell-Based Therapeutic Strategies in Multiple Sclerosis

European Neurological Review ◽

10.17925/enr.2014.09.01.37 ◽

2014 ◽

Vol 9 (1) ◽

pp. 37

Author(s):

Ian Rossman ◽

Jeffrey A Cohen ◽

◽

Keyword(s):

Multiple Sclerosis ◽

Neurological Deficits ◽

Perivascular Spaces ◽

Cns Injury ◽

Surface Receptors ◽

Immune Mediated ◽

Relapsing Remitting ◽

Disease Stages ◽

Ongoing Phase

Multiple sclerosis (MS) is an immune-mediated disease in which acute inflammatory demyelination leads to axonal injury and neurodegeneration, and is manifested clinically by relapsing–remitting neurological deficits superimposed on chronic accumulation of disability. MS treatments are largely immunomodulatory with little, if any, effect on neurodegeneration. Mesenchymal stem cells MSCs) are pluripotent cells derived from adult tissues with intrinsic anti-inflammatory and repair-promoting properties. They cross the blood–brain barrier and target perivascular spaces, which are the sites of inflammatory cell infiltration in MS.In vitro, MSCs can be purified and expanded, labelled for post-transplant tracking and be manipulated to express surface receptors or neurotrophic factors for central nervous system (CNS) targeting or neuroprotection, respectively. Animal models of MS, traumatic CNS injury and neurodegenerative diseases demonstrate clinical and pathological benefits following MSC transplantation. Potentially, MSCs can be used to treat MS patients at various disease stages, which is the current focus of ongoing phase I/II clinical trials at multiple centres.

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Intracellular cytokine profile in T-cell subsets of multiple sclerosis patients: different features in primary progressive disease

Multiple Sclerosis Journal ◽

10.1177/135245850100700302 ◽

2001 ◽

Vol 7 (3) ◽

pp. 145-150 ◽

Cited By ~ 35

Author(s):

J Killestein ◽

B F Den Drijver ◽

W L Van der Graaff ◽

B MJ Uitdehaag ◽

C H Polman ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Peripheral Blood ◽

T Cell Subsets ◽

Primary Progressive ◽

Immunoregulatory Cytokines ◽

Immune Mediated ◽

Distinct Disease ◽

Circulating T Cells ◽

Multiple Sclerosis Patients

Objective: To evaluate the expression of cytokines in both CD4+ and CD8+ T cells derived from peripheral blood of untreated multiple sclerosis (MS) patients with either relapsing-remitting (RR), secondary progressive (SP) or primary progressive (PP) MS and healthy controls (HC). Background: MS is an immune-mediated disease and cytokines have been hypothesized to contribute significantly to disease progression. Compared to the relapse-onset (RR, SP) form of the disease, PPMS patients have different clinical, immunological and pathological features. Surprisingly, the ability of their circulating T cells to produce immunoregulatory cytokines has not been extensively studied so far. Methods: Seventy-two MS patients (24 RR, 26 SP, 22 PP) and 34 HC were studied. Stimulated peripheral blood derived CD4+ and CD8+ T cells were analyzed for IFN-g, IL-2, TNF-a, IL-4, IL-10 and IL-13 production. Results: MS patients express significantly more CD4+ and CD8+ T cells producing IFN-g compared to HC. Compared to the other forms of the disease, PPMS patients display a significant decrease in CD4+ T cells producing IL-2, IL-13 and TNF-a and a significant increase in CD8+ T cells producing IL-4 and IL-10. Conclusions: The data presented here demonstrate that patients with PPMS express less pro- and more anti-inflammatory cytokine producing T cells compared to the relapse-onset form of the disease, confirming the view on PPMS as a distinct disease entity.

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Nitrosative Stress Molecules in Multiple Sclerosis: A Meta-Analysis

Biomedicines ◽

10.3390/biomedicines9121899 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1899

Author(s):

Moritz Förster ◽

Christopher Nelke ◽

Saskia Räuber ◽

Hans Lassmann ◽

Tobias Ruck ◽

...

Keyword(s):

Multiple Sclerosis ◽

Nitrosative Stress ◽

Neurological Diseases ◽

Meta Analysis ◽

Statistical Significance ◽

Unknown Etiology ◽

Immune Mediated ◽

Pubmed Database ◽

The Central Nervous System ◽

Nitrite Nitrate

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system of unknown etiology. As it is still a diagnosis of exclusion, there is an urgent need for biomarkers supporting its diagnosis. Increasing evidence suggests that nitrosative stress may play a pivotal role in the pathogenesis of MS. However, previous reports supporting the role of nitrosative stress molecules as disease biomarkers are inconsistent overall. We therefore systematically analyzed the existing literature to compare the serum and cerebrospinal fluid (CSF) levels of nitrite/nitrate in MS patients with those in patients with noninflammatory other neurological diseases (NIOND) and healthy controls (HC), respectively. We searched the PubMed database and included original articles investigating nitrite/nitrate levels in MS patients and NIOND patients or HC based on predefined selection criteria. Effect sizes were estimated by the standardized mean difference using a random effects model. Our results suggest that MS is associated with higher nitrite/nitrate levels within the CSF compared with patients with NIOND (SMD of 1.51; 95% CI: 0.72, 2.30; p = 0.0008). Likewise, nitrite/nitrate in the CSF of MS patients trends towards increased levels compared with those of HC but does not reach statistical significance (SMD of 3.35; 95% CI: −0.48, 7.19; p = 0.07). Measurement of nitrite/nitrate in the CSF might be a valuable tool facilitating the differentiation of MS and NIOND. Further studies with more homogeneous study criteria are needed to corroborate this hypothesis.

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Silver staining of unconcentrated cerebrospinal fluid in agarose gel (Panagel) electrophoresis.

Clinical Chemistry ◽

10.1093/clinchem/30.5.735 ◽

1984 ◽

Vol 30 (5) ◽

pp. 735-736 ◽

Cited By ~ 9

Author(s):

P D Mehta ◽

S P Mehta ◽

B A Patrick

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Silver Staining ◽

Clinical Laboratory ◽

Neurological Diseases ◽

Agarose Gel ◽

Oligoclonal Igg ◽

Multiple Sclerosis Patients ◽

Coomassie Brilliant ◽

Oligoclonal Igg Bands

Abstract We subjected cerebrospinal fluid (CSF) from 20 patients with multiple sclerosis and 20 patients with other neurological diseases to agarose gel ( Panagel ) electrophoresis followed by staining with silver. Ten microliters of unconcentrated CSF from multiple sclerosis patients containing 0.4 to 0.8 microgram of immunoglobulin G was found to be optimum for detection of oligoclonal IgG bands, so identified by immunofixation. The band patterns for unconcentrated CSF stained with silver were almost identical to those for the same CSF concentrated 40-fold and stained with Coomassie Brilliant Blue. Silver staining thus enables the clinical laboratory to electrophorese unconcentrated CSF on commercially prepared ( Panagel ) plates.

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Physical Activity in Prevention of Risk and Disability in Some Neurological Diseases

Physiotherapy and Health Activity ◽

10.1515/pha-2015-0004 ◽

2014 ◽

Vol 22 (1) ◽

pp. 21-27

Author(s):

Józef Opara

Keyword(s):

Quality Of Life ◽

Physical Activity ◽

Multiple Sclerosis ◽

Physical Disability ◽

Neurological Diseases ◽

Review Of The Literature ◽

Disability Progression ◽

Multiple Sclerosis Patients

Abstract The question of the role of physical activity in preventing disability in neurological diseases is the issue which is not in doubt. There is well known that physical activity in Parkinson`s disease and in Multiple Sclerosis patients is less than is the case in the general population. Numerous scientific studies have confirmed the low physical activity of people with PD and MS. Improving physical activity delays the progress of physical disability and has the effect on increasing the quality of life in those two diseases. In this paper an descriptive review of the literature devoted to the effect of physical activity on risk of PD and its impact on disability progression in PD and MS has been presented. The different recommendations for physical activity and different methods of assessment have been described.

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The Vibration Quantitation Scale (VQS): A Simple, Reproducible Bedside Measure of Sensory Function in Multiple Sclerosis

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100003681 ◽

2004 ◽

Vol 31 (4) ◽

pp. 490-493

Author(s):

J. Carter ◽

T. Wasser ◽

S. Statler ◽

A.D. Rae-Grant

Keyword(s):

Multiple Sclerosis ◽

Tuning Fork ◽

Neurological Diseases ◽

Statistical Significance ◽

Sensory Function ◽

Strongly Correlated ◽

Sensory Abnormalities ◽

Multiple Sclerosis Patients ◽

Disability Severity ◽

Normal Controls

Objectives:To assess the utility of a bedside measure of sensation (the Vibration Quantitation Scale (VQS)) in patients with multiple sclerosis (MS) and in normal controls. To correlate the VQS with the Kurtzke Expanded Disability Severity Score (EDSS) and sensory abnormalities in these patients.Methods:We developed the VQS and tested its performance in patients with MS of various ages, MS types, and EDSS scores. We compared this with controls (normal volunteers or patients with other neurological diseases) who did not have sensory symptoms. In a subgroup, two examiners measured VQS independently at the same patient visit. Astandard C-128 tuning fork was used for the VQS measurement.Results:The VQS had a good inter-observer reproducibility (r=0.920, p<0.001). The VQS fell with increasing age in normals consistent with declining sensory function. The VQS was significantly lower in the multiple sclerosis patients compared with age - matched controls (p<0.001). Abnormalities in VQS were present in patients with brief duration of MS (<5 years) and low EDSS scores, correlating with the presence of sensory abnormalities early in the disease course in some patients. There was a strong correlation between the VQS and EDSS (r=-0.509). The VQS correlated with abnormal sensation in the hands (r=0.310), but did not meet statistical significance for abnormal sensation in the feet or face. Asecond cohort of MS patients was studied using a modified VQS measure (single stimulation, omitting forehead measurement). This reconfirmed the correlation between the modified VQS and EDSS as well as with age. The modified VQS may be useful in clinical practice since it takes little time and is strongly correlated with the EDSS (r=0.578).Conclusion:The VQS provides a continuous sensory scale applicable in most patients with MS, which is measurable with standard bedside equipment, and which may avoid some of the pitfalls of sensory scoring in MS.

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Profile of cytokine gene polymorphisms in Iranian multiple sclerosis patients

Multiple Sclerosis Journal ◽

10.1177/1352458506070237 ◽

2007 ◽

Vol 13 (2) ◽

pp. 253-255 ◽

Cited By ~ 21

Author(s):

A Amirzargar ◽

F Khosravi ◽

S Dianat ◽

F Hushmand ◽

P Maryousef ◽

...

Keyword(s):

Multiple Sclerosis ◽

Gene Polymorphisms ◽

Cytokine Gene ◽

Immune Mediated ◽

Tnf Α ◽

Relapsing Remitting ◽

Cytokine Gene Polymorphisms ◽

Multiple Sclerosis Patients ◽

Relapsing Remitting Multiple Sclerosis

Background Cytokine gene polymorphisms have been extensively studied in association with different diseases. The role of cytokine gene polymorphisms in multiple sclerosis (MS), as a chronic immune-mediated neurodegenerative disease, has been previously reported. Materials and methods DNA samples were collected from 44 patients with relapsing-remitting multiple sclerosis (RRMS) and 140 unrelated healthy subjects. All participants in this study were matched for ethnicity. Cytokine gene SNPs were determined using the PCR-SSP method. Results and discussion We found no significant differences between MS patients and controls in most of the studied cytokine genes. Remarkable results were obtained for IL-2 GG —330 genotype (P = 0.06), IL-6 C —174 allele (P = 0.06), CG and GG genotypes (P < 0.001), and GG (P = 0.02) and CG (P < 0.001) haplotypes, and TNF-α A —238 allele (P < 0.001), GG (P = 0.003) and GA (P < 0.001) haplotypes. These results suggest that polymorphic variations of these pro-inflammatory cytokines play an important role in susceptibility to MS. Multiple Sclerosis 2007; 13: 253–255. http://msj.sagepub.com

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