Treatment with non-specific HDAC inhibitors administered after disease onset does not delay evolution in a mouse model of progressive multiple sclerosis

Objectives: We aimed at designing a nomogram, a prediction tool, to predict the individual’s risk of conversion to secondary progressive multiple sclerosis (SPMS) at the time of multiple sclerosis (MS) onset. Methods: One derivation and three validation cohorts were established. The derivation cohort included 8825 relapsing-onset MS patients in Sweden. A nomogram was built based on a survival model with the best statistical fit and prediction accuracy. The nomogram was validated using data from 3967 patients in the British Columbia cohort, 176 patients in the ACROSS and 2355 patients in FREEDOMS/FREEDOMS II extension studies. Results: Sex, calendar year of birth, first-recorded Expanded Disability Status Scale (EDSS) score, age at the first EDSS and age at disease onset showed significant predictive ability to estimate the risk of SPMS conversion at 10, 15 and 20 years. The nomogram reached 84% (95% confidence intervals (CIs): 83–85) internal and 77% (95% CI: 76–78), 77% (95% CI: 70–85) and 87% (95% CI: 84–89) external accuracy. Conclusions: The SPMS nomogram represents a much-needed complementary tool designed to assist in decision-making and patient counselling in the early phase of MS. The SPMS nomogram may improve outcomes by prompting timely and more efficacious treatment for those with a worse prognosis.

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Inflammatory Demyelinating Central Nervous System Diseases in Childhood: Clinical and Paraclinical Profiles in 133 Patients

Autoimmune Diseases ◽

10.1155/2012/957802 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6

Author(s):

Derya Kaya ◽

Egemen İdiman ◽

Serkan Özakbaş

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Nervous System ◽

Disease Onset ◽

Progressive Multiple Sclerosis ◽

Western Turkey ◽

Mri Features ◽

Cranial Mri ◽

Multiple Sclerosis Patients ◽

Demyelinating Disorders

In a retrospective review of patients with acquired demyelinating disorders of the central nervous system, 133 patients (5.6%) whose diseases started in childhood, were selected from 2369 patients, who had medical records in the Neurology Department of Dokuz Eylul University. Out of 133, 98 had relapsing remitting multiple sclerosis, 21 had secondary progressive multiple sclerosis, 8 had clinically isolated syndrome, 3 had neuromyelitis optica, 2 had Marburg disease, and 1 had radiologically isolated syndrome. In 55 patients (41.3%), disease onset was before age 16. Polysymptomatic presentation (22.6%) was the most common initial feature. The EDSS scores ranged from 0 to 9 with a median of 2.0 () for 126 patients. MRI records of 111 patients were obtained. 97 patients had clinically definite multiple sclerosis. 11 MS patients (11.3%) did not initially present the diagnostic MRI features. All of the remaining multiple sclerosis patients fulfilled Barkhof-Tintore criteria (100%) and 88.7% fulfilled KIDMUS criteria. Cranial MRI of NMO patients was normal. Our findings demonstrate some important clinical and paraclinical features that can help the literature on acquired demyelinating disorders of childhood by utilizing data from Western Turkey.

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Periorbital nociception in a progressive multiple sclerosis mouse model is dependent on TRPA1 channel activation

10.5327/1516-3180.610 ◽

2021 ◽

Author(s):

Diéssica Padilha Dalenogare ◽

Diulle Spat Peres ◽

Maria Fernanda Pessano Fialho ◽

Gabriela Trevisan dos Santos

Keyword(s):

Multiple Sclerosis ◽

Mouse Model ◽

Mechanical Allodynia ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Progressive Multiple Sclerosis ◽

Autoimmune Encephalomyelitis ◽

Transient Receptor ◽

Multiple Sclerosis Patients ◽

Santa Maria

Background: Headache is one of the main painful symptoms described by multiple sclerosis patients. Previously, it was described that neuropathic pain-like behaviors were dependent on transient receptor potential ankyrin 1 (TRPA1) activation in a progressive multiple sclerosis model induced by experimental autoimmune encephalomyelitis (PMS- EAE) in mice. Objective: Here, we aimed to investigate if periorbital mechanical allodynia induced by PMS-EAE was also related to TRPA1 activation. Design and setting: Federal University of Santa Maria, Santa Maria, RS, Brazil. Methods: To induce a PMS-EAE we used female C57BL/6 wild-type and TRPA1- deficient (Trpa1-/-) mice. By the von Frey test, periorbital mechanical allodynia development was observed, and the nociception peak occurred 14 days after induction. At nociception peak day, the mice were treated with sumatriptan, TRPA1 antagonists (HC-030031, A-967079, metamizole, and propyphenazone. Results: The development of mechanical allodynia was showed as well as the antinociceptive effects for all treatments in induced mice. A significant reduction of TRPA1 expression was detected. Conclusion: Thus, these results suggest that headache-like symptoms induced by the PMS-EAE mouse model might occurring by TRPA1 activation.

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Loss of Neurologic Reserve in Progressive Multiple Sclerosis

Neurology Clinical Practice ◽

10.1212/cpj.0000000000001106 ◽

2021 ◽

pp. 10.1212/CPJ.0000000000001106

Author(s):

Joep Killestein ◽

Maria Liguori

Keyword(s):

Multiple Sclerosis ◽

Phenotypic Variability ◽

Disease Onset ◽

Progressive Multiple Sclerosis ◽

Clinical Progression ◽

Primary Progressive ◽

Inflammatory Phase ◽

Relapsing Remitting ◽

Neurologic Disability ◽

Inflammatory Component

Phenotypic variability in multiple sclerosis (MS) remains poorly understood. At disease onset, the majority of MS patients exhibit a relapsing–remitting MS (RRMS) disease course, and in spite of the availability of effective anti-inflammatory disease-modifying therapies (DMTs), a substantial proportion of patients will eventually evolve into a secondary progressive MS (SPMS) phase.1 Apart from SPMS, about 15% of MS patients show clinical progression from onset without clear remissions, i.e., primary progressive MS (PPMS). The Lublin panel revising the definitions of the clinical course of MS in 2013 acknowledged that some evidence supports PPMS representing a distinct, noninflammatory or at least less inflammatory form of MS.2 The panel emphasized that a spectrum of progressive MS phenotypes exists and that any differences between a secondary and primary progressive course are relative rather than absolute.2 There are data to suggest that in MS the acute inflammatory phase is followed by a chronic state that may include a “smoldering” condition in which inflammation as well as myelin and axonal degeneration may coexist.1 The transition of RRMS into SPMS is characterized by gradual worsening of neurologic disability independently of the occurrence of superimposed relapses.1,2 Currently available therapeutic options in both SP and PPMS are only modestly effective and the approved DMT mainly target the inflammatory component of the disease.1

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An MRI study of Chlamydia pneumoniae infection in Italian multiple sclerosis patients

Multiple Sclerosis Journal ◽

10.1191/1352458503ms944oa ◽

2003 ◽

Vol 9 (5) ◽

pp. 467-471 ◽

Cited By ~ 16

Author(s):

L ME Grimaldi ◽

A Pincherle ◽

F Martinelli-Boneschi ◽

M Filippi ◽

F Patti ◽

...

Keyword(s):

Multiple Sclerosis ◽

Chlamydia Pneumoniae ◽

Neurological Diseases ◽

Disease Onset ◽

Progressive Multiple Sclerosis ◽

Relapsing Remitting ◽

The Central Nervous System ◽

Magnetic Resonance Imaging Mri ◽

Multiple Sclerosis Patients ◽

Mri Study

We amplified sequences of the Chlamydia pneumoniae (C P) major-outer membrane protein in the cerebrospinal fluid (CSF) from 23 of 107 (21.5%) relapsing-remitting or secondary progressive multiple sclerosis (MS) patients and two of 77 (2.6%) patients with other neurological diseases (OND) (P =0.00022). C P+ patients showed magnetic resonance imaging (MRI) evidence of more active disease (P =0.02) compared to CP-MS patients and tended to have an anticipation of age at disease onset (32.39-12 versus 28.59-10 years; P =ns) causing a longer disease duration (7.59-5 versus 4.49-4 years; P =0.016) at the time of clinical evaluation. These findings, although indirectly, suggest that C P infection of the central nervous system (C NS) might affect disease course in a subgroup of MS patients.

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Characterization of brain lesions in a mouse model of progressive multiple sclerosis

Experimental Neurology ◽

10.1016/j.expneurol.2010.08.017 ◽

2010 ◽

Vol 226 (1) ◽

pp. 148-158 ◽

Cited By ~ 32

Author(s):

H. Levy ◽

Y. Assaf ◽

D. Frenkel

Keyword(s):

Multiple Sclerosis ◽

Mouse Model ◽

Progressive Multiple Sclerosis ◽

Brain Lesions

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Elevated sCD40L in Secondary Progressive Multiple Sclerosis in Comparison to Non-progressive Benign and Relapsing Remitting Multiple Sclerosis

Journal of Central Nervous System Disease ◽

10.1177/11795735211050712 ◽

2021 ◽

Vol 13 ◽

pp. 117957352110507

Author(s):

Qi Wu ◽

Qin Wang ◽

Jennifer Yang ◽

Jacob WS Martens ◽

Elizabeth A Mills ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Plasma Levels ◽

Disease Onset ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Secondary Progressive ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

Background: The long-term prognosis of relapsing-remitting multiple sclerosis (RRMS) is usually unfavorable as most patients transition to secondary progressive multiple sclerosis (SPMS) with accumulative disability. A rare form of non-progressive multiple sclerosis (MS) also exists, known as benign MS (BMS or NPMS), which lacks disease progression defined as Expanded Disability Status Scale (EDSS) ≤3 after 15 years of disease onset without treatment. Purpose: Our study aims to identify soluble plasma factors predicting disease progression in multiple sclerosis (MS). Research Design and Study Sample: We utilized Luminex multiplex to analyze plasma levels of 33 soluble factors, comparing 32 SPMS patients to age-, sex-, and disease duration-matched non-progressive BMS patients, as well as to RRMS patients and healthy controls. Results: Plasma levels of EGF, sCD40L, MCP1/CCL2, fractalkine/CX3CL1, IL-13, Eotaxin, TNFβ/LTα, and IL-12p40 were significantly different between the various types of MS. Plasma sCD40L was significantly elevated in SPMS compared to BMS and RRMS. The combination of MCP1/CCL2 and sCD40L discriminated between RRMS and SPMS. MCP1/CCL2 was found to be the most effective classifier between BMS and RRMS, while BMS was most effectively distinguished from SPMS by the combination of sCD40L and IFNγ levels. Conclusions: These differences may facilitate personalized precision medicine and aid in the discovery of new therapeutic targets for disease progression through the improvement of patient stratification.

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S100B Protein as a Therapeutic Target in Multiple Sclerosis: The S100B Inhibitor Arundic Acid Protects from Chronic Experimental Autoimmune Encephalomyelitis

International Journal of Molecular Sciences ◽

10.3390/ijms222413558 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13558

Author(s):

Chiara Camponeschi ◽

Maria De Carluccio ◽

Susanna Amadio ◽

Maria Elisabetta Clementi ◽

Beatrice Sampaolese ◽

...

Keyword(s):

Multiple Sclerosis ◽

Mouse Model ◽

Experimental Autoimmune Encephalomyelitis ◽

Disease Onset ◽

Treated Group ◽

S100b Protein ◽

Autoimmune Encephalomyelitis ◽

Experimental Autoimmune Encephalomyelitis Mouse ◽

Clinical Scores ◽

Experimental Autoimmune

S100B is an astrocytic protein behaving at high concentration as a damage-associated molecular pattern molecule. A direct correlation between the increased amount of S100B and inflammatory processes has been demonstrated, and in particular, the inhibitor of S100B activity pentamidine has been shown to ameliorate clinical scores and neuropathologic-biomolecular parameters in the relapsing-remitting experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. This study investigates the effect of arundic acid (AA), a known inhibitor of astrocytic S100B synthesis, in the chronic experimental autoimmune encephalomyelitis, which is another mouse model of multiple sclerosis usually studied. By the daily evaluation of clinical scores and neuropathologic-molecular analysis performed in the spinal cord, we observed that the AA-treated group showed lower severity compared to the vehicle-treated mice, particularly in the early phase of disease onset. We also observed a significant reduction of astrocytosis, demyelination, immune infiltrates, proinflammatory cytokines expression and enzymatic oxidative reactivity in the AA-treated group. Overall, our results reinforce the involvement of S100B in the development of animal models of multiple sclerosis and propose AA targeting the S100B protein as a focused potential drug to be considered for multiple sclerosis treatment.

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Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis

Journal of Clinical Investigation ◽

10.1172/jci33464 ◽

2008 ◽

Vol 118 (4) ◽

pp. 1532-1543 ◽

Cited By ~ 144

Author(s):

Alexandre S. Basso ◽

Dan Frenkel ◽

Francisco J. Quintana ◽

Frederico A. Costa-Pinto ◽

Sanja Petrovic-Stojkovic ◽

...

Keyword(s):

Multiple Sclerosis ◽

Mouse Model ◽

Progressive Multiple Sclerosis ◽

Axonal Loss

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Diagnostic uncertainty during the transition to secondary progressive multiple sclerosis: Multicenter study in Argentina

Multiple Sclerosis Journal ◽

10.1177/1352458520924586 ◽

2020 ◽

pp. 135245852092458 ◽

Cited By ~ 1

Author(s):

Juan Ignacio Rojas ◽

Liliana Patrucco ◽

Ricardo Alonso ◽

Orlando Garcea ◽

Norma Deri ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Onset ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Multicenter Cohort Study ◽

Diagnostic Uncertainty ◽

Secondary Progressive ◽

Kaplan Meier ◽

Relapsing Remitting ◽

Time Required

Background: A period of diagnostic uncertainty often characterizes the clinical transition from relapsing to secondary progressive multiple sclerosis (SPMS). Objective: The aim of this study was to describe the length of time required to reclassify relapsing-remitting MS (RRMS) patients who have clinically transitioned to SPMS (diagnosis uncertainty). Methods: This is a retrospective multicenter cohort study conducted in Argentina, identifying in every center all patients with diagnosis of MS who transitioned from RRMS to SPMS during the follow-up. We identified the dates of the last definitive RRMS and first definitive SPMS diagnoses for diagnostic uncertainty. The time required to reclassify RRMS who transitioned to SPMS and the time from disease onset to reclassify SPMS were calculated using the Kaplan–Meier method. Results: A total of 170 patients were included, where the mean age at disease onset (first symptom) was 36 ± 6 years; the length of time required to reclassify RRMS patients who transitioned to SPMS was 3.3 ± 1.1 years (range = 1–7 years); and the time from disease onset to classify SPMS was 19.4 ± 8.5 years (range = 16–35 years). Conclusion: A period of diagnostic uncertainty regarding the transition from RRMS to SPMS was present in many of our patients, with a mean time of 3.3 years.

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