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Article: Neurophysiological and clinical biomarkers of secondary progressive multiple sclerosis: A cross-sectional study.

Tartaglia, Matteo / Canevelli, Marco / Malimpensa, Leonardo / Belvisi, Daniele / Baione, Viola / Ferrazzano, Gina / Leodori, Giorgio / Berardelli, Alfredo / Conte, Antonella

Frontiers in neurology

2023 Volume 14, Page(s) 1138600

Abstract: Timely diagnosis of secondary progressive multiple sclerosis (SPMS) represents a clinical challenge. The Frailty Index, a quantitative frailty measure, and the Neurophysiological Index, a combined measure of sensorimotor cortex inhibitory mechanism ... ...

Abstract	Timely diagnosis of secondary progressive multiple sclerosis (SPMS) represents a clinical challenge. The Frailty Index, a quantitative frailty measure, and the Neurophysiological Index, a combined measure of sensorimotor cortex inhibitory mechanism parameters, have recently emerged as promising tools to support SPMS diagnosis. The aim of this study was to explore the possible relationship between these two indices in MS. MS participants underwent a clinical evaluation, Frailty Index administration, and neurophysiological assessment. Frailty and Neurophysiological Index scores were found to be higher in SPMS and correlated with each other, thus suggesting that they may capture similar SPMS-related pathophysiological mechanisms.
Language	English
Publishing date	2023-03-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2023.1138600
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Article: The Impact of Cytomegalovirus Infection on Natural Killer and CD8+ T Cell Phenotype in Multiple Sclerosis.

Perri, Valentina / Zingaropoli, Maria Antonella / Pasculli, Patrizia / Ciccone, Federica / Tartaglia, Matteo / Baione, Viola / Malimpensa, Leonardo / Ferrazzano, Gina / Mastroianni, Claudio Maria / Conte, Antonella / Ciardi, Maria Rosa

Biology

2024 Volume 13, Issue 3

Abstract: Multiple sclerosis (MS) is a debilitating neurological disease that has been classified as an immune-mediated attack on myelin, the protective sheath of nerves. Some aspects of its pathogenesis are still unclear; nevertheless, it is generally established ...

Abstract	Multiple sclerosis (MS) is a debilitating neurological disease that has been classified as an immune-mediated attack on myelin, the protective sheath of nerves. Some aspects of its pathogenesis are still unclear; nevertheless, it is generally established that viral infections influence the course of the disease. Cytomegalovirus (CMV) is a major pathogen involved in alterations of the immune system, including the expansion of highly differentiated cytotoxic CD8+ T cells and the accumulation of adaptive natural killer (NK) cells expressing high levels of the NKG2C receptor. In this study, we evaluated the impact of latent CMV infection on MS patients through the characterization of peripheral NK cells, CD8+ T cells, and NKT-like cells using flow cytometry. We evaluated the associations between immune cell profiles and clinical features such as MS duration and MS progression, evaluated using the Expanded Disability Status Scale (EDSS). We showed that NK cells, CD8+ T cells, and NKT-like cells had an altered phenotype in CMV-infected MS patients and displayed high levels of the NKG2C receptor. Moreover, in MS patients, increased NKG2C expression levels were found to be associated with higher EDSS scores. Overall, these results support the hypothesis that CMV infection imprints the immune system by modifying the phenotype and receptor repertoire of NK and CD8+ T cells, suggesting a detrimental role of CMV on MS progression.
Language	English
Publishing date	2024-02-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology13030154
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Article ; Online: Evaluation of BAFF, APRIL and CD40L in Ocrelizumab-Treated pwMS and Infectious Risk

Zingaropoli, Maria Antonella / Pasculli, Patrizia / Tartaglia, Matteo / Dominelli, Federica / Ciccone, Federica / Taglietti, Ambra / Perri, Valentina / Malimpensa, Leonardo / Ferrazzano, Gina / Iannetta, Marco / Del Borgo, Cosmo / Lichtner, Miriam / Mastroianni, Claudio Maria / Conte, Antonella / Ciardi, Maria Rosa

Biology (Basel). 2023 Apr. 12, v. 12, no. 4

2023

Abstract: Background: The anti-CD20 monoclonal antibody ocrelizumab has been widely employed in the treatment of people with multiple sclerosis (pwMS). However, its B-cell-depleting effect may induce a higher risk of infectious events and alterations in the ... ...

Abstract	Background: The anti-CD20 monoclonal antibody ocrelizumab has been widely employed in the treatment of people with multiple sclerosis (pwMS). However, its B-cell-depleting effect may induce a higher risk of infectious events and alterations in the secretion of B-cell-activating factors, such as BAFF, APRIL and CD40L. Methods: The aim of this study was to investigate plasma BAFF, APRIL and CD40L levels and their relationship with infectious risk in ocrelizumab-treated pwMS at baseline (T0), at 6 months (T6) and at 12 months (T12) after starting the treatment. As a control group, healthy donors (HD) were enrolled too. Results: A total of 38 pwMS and 26 HD were enrolled. At baseline, pwMS showed higher plasma BAFF (p < 0.0001), APRIL (p = 0.0223) and CD40L (p < 0.0001) levels compared to HD. Compared to T0, plasma BAFF levels were significantly increased at both T6 and T12 (p < 0.0001 and p < 0.0001, respectively). Whereas plasma APRIL and CD40L levels were decreased at T12 (p = 0.0003 and p < 0.0001, respectively). When stratifying pwMS according to the development of an infectious event during the 12-month follow-up period in two groups—with (14) and without an infectious event (24)—higher plasma BAFF levels were observed at all time-points; significantly, in the group with an infectious event compared to the group without an infectious event (T0: p < 0.0001, T6: p = 0.0056 and T12: p = 0.0400). Conclusions: BAFF may have a role as a marker of immune dysfunction and of infectious risk.
Keywords	monoclonal antibodies ; risk ; sclerosis ; secretion
Language	English
Dates of publication	2023-0412
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology12040587
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Neural bases of motor fatigue in multiple sclerosis: A multimodal approach using neuromuscular assessment and TMS-EEG.

Leodori, Giorgio / Mancuso, Marco / Maccarrone, Davide / Tartaglia, Matteo / Ianniello, Antonio / Certo, Francesco / Baione, Viola / Ferrazzano, Gina / Malimpensa, Leonardo / Belvisi, Daniele / Pozzilli, Carlo / Berardelli, Alfredo / Conte, Antonella

Neurobiology of disease

2023 Volume 180, Page(s) 106073

Abstract: Motor fatigue is one of the most common symptoms in multiple sclerosis (MS) patients. Previous studies suggested that increased motor fatigue in MS may arise at the central nervous system level. However, the mechanisms underlying central motor fatigue in ...

Abstract	Motor fatigue is one of the most common symptoms in multiple sclerosis (MS) patients. Previous studies suggested that increased motor fatigue in MS may arise at the central nervous system level. However, the mechanisms underlying central motor fatigue in MS are still unclear. This paper investigated whether central motor fatigue in MS reflects impaired corticospinal transmission or suboptimal primary motor cortex (M1) output (supraspinal fatigue). Furthermore, we sought to identify whether central motor fatigue is associated with abnormal M1 excitability and connectivity within the sensorimotor network. Twenty-two patients affected by relapsing-remitting MS and 15 healthy controls (HCs) performed repeated blocks of contraction at different percentages of maximal voluntary contraction with the right first dorsal interosseus muscle until exhaustion. Peripheral, central, and supraspinal components of motor fatigue were quantified by a neuromuscular assessment based on the superimposed twitch evoked by peripheral nerve and transcranial magnetic stimulation (TMS). Corticospinal transmission, excitability and inhibition during the task were tested by measurement of motor evoked potential (MEP) latency, amplitude, and cortical silent period (CSP). M1 excitability and connectivity was measured by TMS-evoked electroencephalography (EEG) potentials (TEPs) elicited by M1 stimulation before and after the task. Patients completed fewer blocks of contraction and showed higher values of central and supraspinal fatigue than HCs. We found no MEP or CSP differences between MS patients and HCs. Patients showed a post-fatigue increase in TEPs propagation from M1 to the rest of the cortex and in source-reconstructed activity within the sensorimotor network, in contrast to the reduction observed in HCs. Post-fatigue increase in source-reconstructed TEPs correlated with supraspinal fatigue values. To conclude, MS-related motor fatigue is caused by central mechanisms related explicitly to suboptimal M1 output rather than impaired corticospinal transmission. Furthermore, by adopting a TMS-EEG approach, we proved that suboptimal M1 output in MS patients is associated with abnormal task-related modulation of M1 connectivity within the sensorimotor network. Our findings shed new light on the central mechanisms of motor fatigue in MS by highlighting a possible role of abnormal sensorimotor network dynamics. These novel results may point to new therapeutical targets for fatigue in MS.
MeSH term(s)	Humans ; Transcranial Magnetic Stimulation/methods ; Multiple Sclerosis/complications ; Electroencephalography ; Evoked Potentials ; Evoked Potentials, Motor
Language	English
Publishing date	2023-03-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2023.106073
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Article: Evaluation of BAFF, APRIL and CD40L in Ocrelizumab-Treated pwMS and Infectious Risk.

Biology

2023 Volume 12, Issue 4

Abstract	Background: The anti-CD20 monoclonal antibody ocrelizumab has been widely employed in the treatment of people with multiple sclerosis (pwMS). However, its B-cell-depleting effect may induce a higher risk of infectious events and alterations in the secretion of B-cell-activating factors, such as BAFF, APRIL and CD40L. Methods: The aim of this study was to investigate plasma BAFF, APRIL and CD40L levels and their relationship with infectious risk in ocrelizumab-treated pwMS at baseline (T0), at 6 months (T6) and at 12 months (T12) after starting the treatment. As a control group, healthy donors (HD) were enrolled too. Results: A total of 38 pwMS and 26 HD were enrolled. At baseline, pwMS showed higher plasma BAFF (
Language	English
Publishing date	2023-04-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology12040587
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Article ; Online: Cladribine and ocrelizumab induce differential miRNA profiles in peripheral blood mononucleated cells from relapsing-remitting multiple sclerosis patients.

Arisi, Ivan / Malimpensa, Leonardo / Manzini, Valeria / Brandi, Rossella / Gosetti di Sturmeck, Tommaso / D'Amelio, Chiara / Crisafulli, Sebastiano / Ferrazzano, Gina / Belvisi, Daniele / Malerba, Francesca / Florio, Rita / Pascale, Esterina / Soreq, Hermona / Salvetti, Marco / Cattaneo, Antonino / D'Onofrio, Mara / Conte, Antonella

Frontiers in immunology

2023 Volume 14, Page(s) 1234869

Abstract: Background and objectives: Multiple sclerosis (MS) is a chronic, progressive neurological disease characterized by early-stage neuroinflammation, neurodegeneration, and demyelination that involves a spectrum of heterogeneous clinical manifestations in ... ...

Abstract	Background and objectives: Multiple sclerosis (MS) is a chronic, progressive neurological disease characterized by early-stage neuroinflammation, neurodegeneration, and demyelination that involves a spectrum of heterogeneous clinical manifestations in terms of disease course and response to therapy. Even though several disease-modifying therapies (DMTs) are available to prevent MS-related brain damage-acting on the peripheral immune system with an indirect effect on MS lesions-individualizing therapy according to disease characteristics and prognostic factors is still an unmet need. Given that deregulated miRNAs have been proposed as diagnostic tools in neurodegenerative/neuroinflammatory diseases such as MS, we aimed to explore miRNA profiles as potential classifiers of the relapsing-remitting MS (RRMS) patients' prospects to gain a more effective DMT choice and achieve a preferential drug response. Methods: A total of 25 adult patients with RRMS were enrolled in a cohort study, according to the latest McDonald criteria before (pre-cladribine, pre-CLA; pre-ocrelizumab, pre-OCRE, time T0) and after high-efficacy DMTs, time T1, 6 months post-CLA ( Results: First, the miRNA profiles of pre-CLA or pre-OCRE RRMS patients compared to healthy controls identified modulated miRNA patterns (40 and seven miRNAs, respectively). A direct comparison of the two pre-treatment groups at T0 and T1 revealed more pro-inflammatory patterns in the pre-CLA miRNA profiles. Moreover, both DMTs emerged as being capable of reverting some dysregulated miRNAs toward a protective phenotype. Both drug-dependent miRNA profiles and specific miRNAs, such as miR-199a-3p, miR-29b-3p, and miR-151a-3p, emerged as potentially involved in these drug-induced mechanisms. This enabled the selection of miRNAs correlated to clinical features and the related miRNA-mRNA network. Discussion: These data support the hypothesis of specific deregulated miRNAs as putative biomarkers in RRMS patients' stratification and DMT drug response.
MeSH term(s)	Adult ; Humans ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics ; Cladribine ; Multiple Sclerosis/drug therapy ; Leukocytes, Mononuclear ; Cohort Studies ; MicroRNAs
Chemical Substances	Cladribine (47M74X9YT5) ; ocrelizumab (A10SJL62JY) ; MicroRNAs
Language	English
Publishing date	2023-12-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1234869
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Article ; Online: Therapeutic choices and disease activity after 2 years of treatment with cladribine: An Italian multicenter study (CladStop).

Schiavetti, Irene / Signori, Alessio / Albanese, Angela / Frau, Jessica / Cocco, Eleonora / Lorefice, Lorena / di Lemme, Sonia / Fantozzi, Roberta / Centonze, Diego / Landi, Doriana / Marfia, Girolama / Signoriello, Elisabetta / Lus, Giacomo / Zecca, Chiara / Gobbi, Claudio / Iodice, Rosa / Malimpensa, Leonardo / Cordioli, Cinzia / Ferraro, Diana /

Ruscica, Francesca / Pasquali, Livia / Repice, Anna / Immovilli, Paolo / Ferrò, Maria Teresa / Bonavita, Simona / Di Filippo, Massimiliano / Abbadessa, Gianmarco / Govone, Flora / Sormani, Maria Pia

European journal of neurology

2024 Volume 31, Issue 6, Page(s) e16250

Abstract: Background and purpose: Cladribine tablets, a purine analogue antimetabolite, offer a unique treatment regimen, involving short courses at the start of the first and second year, with no further treatment needed in years 3 and 4. However, comprehensive ... ...

Abstract	Background and purpose: Cladribine tablets, a purine analogue antimetabolite, offer a unique treatment regimen, involving short courses at the start of the first and second year, with no further treatment needed in years 3 and 4. However, comprehensive evidence regarding patient outcomes beyond the initial 24 months of cladribine treatment is limited. Methods: This retrospective, multicenter study enrolled 204 patients with multiple sclerosis who had completed the 2-year course of cladribine treatment. The primary outcomes were therapeutic choices and clinical disease activity assessed by annualized relapse rate after the 2-year treatment course. Results: A total of 204 patients were enrolled; most patients (75.4%) did not initiate new treatments in the 12 months postcladribine. The study found a significant reduction in annualized relapse rate at the 12-month follow-up after cladribine completion compared to the year prior to starting therapy (0.07 ± 0.25 vs. 0.82 ± 0.80, p < 0.001). Furthermore, patients with relapses during cladribine treatment were more likely to start new therapies, whereas older patients were less likely. The safety profile of cladribine was favorable, with lymphopenia being the primary registered adverse event. Conclusions: This study provides insights into therapeutic choices and disease activity following cladribine treatment. It highlights cladribine's effectiveness in reducing relapse rates and disability progression, reaffirming its favorable safety profile. Real-world data, aligned with previous reports, draw attention to ocrelizumab and natalizumab as common choices after cladribine. However, larger, prospective studies for validation and a more comprehensive understanding of cladribine's long-term impact are necessary.
MeSH term(s)	Humans ; Cladribine/therapeutic use ; Female ; Male ; Adult ; Retrospective Studies ; Middle Aged ; Immunosuppressive Agents/therapeutic use ; Italy ; Multiple Sclerosis, Relapsing-Remitting/drug therapy ; Treatment Outcome ; Multiple Sclerosis/drug therapy
Chemical Substances	Cladribine (47M74X9YT5) ; Immunosuppressive Agents
Language	English
Publishing date	2024-03-28
Publishing country	England
Document type	Journal Article ; Multicenter Study
ZDB-ID	1280785-0
ISSN	1468-1331 ; 1351-5101 ; 1471-0552
ISSN (online)	1468-1331
ISSN	1351-5101 ; 1471-0552
DOI	10.1111/ene.16250
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Article ; Online: Frailty and relapse activity in multiple sclerosis: A longitudinal observation.

Multiple sclerosis and related disorders

2023 Volume 72, Page(s) 104603

Abstract: Recent cross-sectional investigations suggest a relationship between frailty, as measured by Frailty Index (FI), and multiple sclerosis (MS). However, if and how frailty is associated with relapse activity in MS is still unknown. To explore this issue, a ...

Abstract	Recent cross-sectional investigations suggest a relationship between frailty, as measured by Frailty Index (FI), and multiple sclerosis (MS). However, if and how frailty is associated with relapse activity in MS is still unknown. To explore this issue, a one-year follow-up study involving 471 patients was conducted. A univariate regression model showed an inverse association between baseline FI score and the presence of relapse, which was also confirmed in the multivariate model. These results suggest that frailty may reflect pathophysiological mechanisms involved in MS disease activity and that the FI may be used as an enrichment criterion in clinical trials.
MeSH term(s)	Humans ; Aged ; Frailty ; Frail Elderly ; Follow-Up Studies ; Cross-Sectional Studies ; Multiple Sclerosis ; Geriatric Assessment/methods ; Chronic Disease ; Longitudinal Studies
Language	English
Publishing date	2023-03-05
Publishing country	Netherlands
Document type	Letter
ZDB-ID	2645330-7
ISSN	2211-0356 ; 2211-0348
ISSN (online)	2211-0356
ISSN	2211-0348
DOI	10.1016/j.msard.2023.104603
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Article: Neurophysiological and clinical biomarkers of secondary progressive multiple sclerosis: A cross-sectional study.

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Article: The Impact of Cytomegalovirus Infection on Natural Killer and CD8+ T Cell Phenotype in Multiple Sclerosis.

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Article ; Online: Evaluation of BAFF, APRIL and CD40L in Ocrelizumab-Treated pwMS and Infectious Risk

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Article ; Online: Neural bases of motor fatigue in multiple sclerosis: A multimodal approach using neuromuscular assessment and TMS-EEG.

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Article: Evaluation of BAFF, APRIL and CD40L in Ocrelizumab-Treated pwMS and Infectious Risk.

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Article ; Online: Cladribine and ocrelizumab induce differential miRNA profiles in peripheral blood mononucleated cells from relapsing-remitting multiple sclerosis patients.

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Article ; Online: Therapeutic choices and disease activity after 2 years of treatment with cladribine: An Italian multicenter study (CladStop).

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Article ; Online: Frailty and relapse activity in multiple sclerosis: A longitudinal observation.

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