Publications by authors named "Marco Salvetti"

149 Publications

Charting a global research strategy for progressive MS-An international progressive MS Alliance proposal.

Mult Scler 2021 Dec 1:13524585211059766. Epub 2021 Dec 1.

National Multiple Sclerosis Society, New York, NY, USA.

Background: Progressive forms of multiple sclerosis (MS) affect more than 1 million individuals globally. Recent approvals of ocrelizumab for primary progressive MS and siponimod for active secondary progressive MS have opened the therapeutic door, though results from early trials of neuroprotective agents have been mixed. The recent introduction of the term 'active' secondary progressive MS into the therapeutic lexicon has introduced potential confusion to disease description and thereby clinical management.

Objective: This paper reviews recent progress, highlights continued knowledge and proposes, on behalf of the International Progressive MS Alliance, a global research strategy for progressive MS.

Methods: Literature searches of PubMed between 2015 and May, 2021 were conducted using the search terms "progressive multiple sclerosis", "primary progressive multiple sclerosis", "secondary progressive MS". Proposed strategies were developed through a series of in-person and virtual meetings of the International Progressive MS Alliance Scientific Steering Committee.

Results: Sustaining and accelerating progress will require greater understanding of underlying mechanisms, identification of potential therapeutic targets, biomarker discovery and validation, and conduct of clinical trials with improved trial design. Encouraging developments in symptomatic and rehabilitative interventions are starting to address ongoing challenges experienced by people with progressive MS.

Conclusion: We need to manage these challenges and realise the opportunities in the context of a global research strategy, which will improve quality of life for people with progressive MS.
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http://dx.doi.org/10.1177/13524585211059766DOI Listing
December 2021

High-resolution ultrasound of peripheral nerves in late-onset hereditary transthyretin amyloidosis with polyneuropathy: similarities and differences with CIDP.

Neurol Sci 2021 Nov 21. Epub 2021 Nov 21.

Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Sapienza University of Rome, Sant'Andrea Hospital, 1035-39 Grottarossa St., Rome, Italy.

Introduction: Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) remains a diagnostic challenge due to clinical, neurophysiological, and laboratory findings suggestive of other diagnoses, particularly chronic inflammatory demyelinating polyneuropathy (CIDP). In this cross-sectional prospective study, we aimed to investigate the utility of high-resolution ultrasonography of peripheral nerves as a diagnostic tool to differentiate ATTRv-PN from CIDP.

Methods: In 11 treatment-naive patients with genetically confirmed late-onset ATTRv-PN and 25 patients with CIDP, we collected clinical, electrodiagnostic, and high-resolution ultrasonography data of the peripheral nerves. In each patient, we used high-resolution ultrasonography to assess 26 nerve sites.

Results: Of the 11 patients with ATTRv-PN, two had electrodiagnostic study data compatible with a CIDP diagnosis. High-resolution ultrasonography showed that the cross-sectional area of the brachial plexus, median nerve at the axilla, arm, and forearm, ulnar nerve at the forearm, and peroneal nerve at the popliteal fossa were significantly smaller in the 11 ATTRv-PN patients than in CIDP patients. However, in the two patients with electrodiagnostic study data compatible with a CIDP diagnosis, high-resolution nerve ultrasonography data were comparable to those in patients with CIDP.

Conclusion: Although high-resolution ultrasonography of peripheral nerves provides reliable information in patients with ATTRv-PN, its usefulness as a standalone diagnostic tool to differentiate ATTRv-PN from CIDP might be limited.
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http://dx.doi.org/10.1007/s10072-021-05749-3DOI Listing
November 2021

COVID-19 Severity in Multiple Sclerosis: Putting Data Into Context.

Neurol Neuroimmunol Neuroinflamm 2022 01 9;9(1). Epub 2021 Nov 9.

From the Department of Health Sciences (M.P.S., I.S., L.C.), University of Genova; IRCCS Ospedale Policlinico San Martino (M.P.S., M.I.), Genoa; Centro Sclerosi Multipla ASST Spedali Civili di Brescia (C.C., N.D.R.), Montichiari; Neurology Unit (M.F.), Neurorehabilitation Unit (M.F.), and Neurophysiology Unit (M.F.), IRCCS San Raffaele Scientific Institute, Milan; Neuroimaging Research Unit (M.F.), Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan; Vita-Salute San Raffaele University (M.F.), Milan; Department of Neurology and Multiple Sclerosis Center (M.R.), ASST "Papa Giovanni XXIII", Bergamo; Multiple Sclerosis Center (P.I.), Ospedale Guglielmo da Saliceto, Piacenza; Regional Referral Multiple Sclerosis Centre (M.C.), Department of Neurology, University Hospital San Luigi, Orbassano, Torino; AISM Rehabilitation Center (G.B.), Italian MS Society, Genoa; Centro Sclerosi Multipla (E.C.), ATS Sardegna; Dipartimento Scienze Mediche e Sanità Pubblica (E.C.), Università di Cagliari; IRCCS Istituto delle Scienze Neurologiche di Bologna (C.S.), UOSI Riabilitazione Sclerosi Multipla; MS Center (P. Cavalla), Department of Neuroscience, City of Health and Science University Hospital of Turin; Centro SM UOC Neurologia (I. Pesci), Fidenza, AUSL PR; Multiple Sclerosis Research Center (A.Z.), IRCCS Mondino Foundation, Pavia; Multiple Sclerosis Centre (P. Confalonieri), Neuroimmunology Department-"Carlo Besta" Neurological Institute, Milan; Multiple Sclerosis Clinical and Research Unit (G.A.M.), Department of Systems Medicine, Tor Vergata University, Rome; Department of Neurology Multiple Sclerosis Center (P.P.), University of Padua; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI) (M.I.), University of Genoa; Department of Basic Medical Sciences, Neurosciences and Sense Organs (M.T.), University of Bari; Federico II University of Naples (V.B.M.); Department of Advanced Medical and Surgical Sciences (G.T.), University of Campania, Napoli; Università Vita Salute San Raffaele (G.C.), Casa di Cura Privata Del Policlinico, Milan; Research Department (M.A.B.), Italian Multiple Sclerosis Foundation, Genoa; Department of Life Sciences (M.A.B.), University of Siena; Department of Medical and Surgical Sciences and Advanced Technologies (F.P.), GF Ingrassia, University of Catania; Centro Sclerosi Multipla (F.P.), Policlinico Catania, University of Catania; Department of Neuroscience, Mental Health and Sensory Organs (M.S.), Sapienza University of Rome; and Unit of Neurology (M.S.), IRCCS Neuromed, Pozzilli, Isernia, Italy.

Background And Objectives: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population.

Methods: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score > 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ test, and the risk excess was quantified by risk ratios (RRs).

Results: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization ( < 0.001), RR = 2.19 for ICU admission ( < 0.001), and RR = 2.43 for death ( < 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, = 0.04).

Discussion: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon.
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http://dx.doi.org/10.1212/NXI.0000000000001105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579249PMC
January 2022

Muscle MRI in Myotonic Dystrophy type 1 (DM1): refining muscle involvement and implications for clinical trials.

Eur J Neurol 2021 Nov 9. Epub 2021 Nov 9.

Neuromuscular and Rare Disease Centre, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University of Rome, Sant'Andrea Hospital, 00189, Rome, Italy.

Background: Only few studies reported muscle imaging data on small cohorts of patients with Myotonic dystrophy type 1 (DM1). We aimed to investigate the muscle involvement in a large cohort of patients, to refine the pattern of muscle involvement, to better understand the pathophysiological mechanisms of muscle weakness and to identify potential imaging biomarkers for disease activity and severity.

Methods: 134 DM1 patients underwent a cross-sectional muscle MRI study. STIR and T1- sequences in lower and upper body were analysed. Fat replacement, muscle atrophy and STIR positivity were evaluated using three different scales. Correlations between MRI scores, clinical features and genetic background were investigated.

Results: The most frequent pattern of muscle involvement in T1 consisted of fat replacement of the tongue, sternocleidomastoideus, paraspinalis, gluteus minimus, distal quadriceps and gastrocnemius medialis. Degree of fat replacement at MRI correlated with clinical severity and disease duration, but not with CTG expansion. Fat replacement was also detected in milder/asymptomatic patients. More than 80% of patients had STIR positive signal in muscles. Most DM1 patients also showed a variable degree of muscle atrophy regardless MRI signs of fat replacement. A subset of patients (20%) showed a "marbled" muscle appearance.

Conclusions: muscle MRI is a sensitive biomarker of disease severity also for the milder spectrum of disease. STIR hyperintensty seems to precede fat replacement in T1. Beyond fat replacement, STIR positivity, muscle atrophy and "marbled" appearance suggest further mechanisms of muscle wasting and weakness in DM1, representing additional outcome measures and therapeutical targets for forthcoming clinical trials.
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http://dx.doi.org/10.1111/ene.15174DOI Listing
November 2021

The effect of air pollution on COVID-19 severity in a sample of patients with multiple sclerosis.

Eur J Neurol 2021 Nov 4. Epub 2021 Nov 4.

Department of Health Sciences, University of Genova, Genova, Italy.

Background And Purpose: Some studies have shown that air pollution, often assessed by thin particulate matter with diameter below 2.5 µg/m (PM2.5), may contribute to severe COVID-19 courses, as well as play a role in the onset and evolution of multiple sclerosis (MS). However, the impact of air pollution on COVID-19 has never been explored specifically amongst patients with MS (PwMS). This retrospective observational study aims to explore associations between PM2.5 and COVID-19 severity amongst PwMS.

Methods: Data were retrieved from an Italian web-based platform (MuSC-19) which includes PwMS with COVID-19. PM2.5 2016-2018 average concentrations were provided by the Copernicus Atmospheric Monitoring Service. Italian patients inserted in the platform from 15 January 2020 to 9 April 2021 with a COVID-19 positive test were included. Ordered logistic regression models were used to study associations between PM2.5 and COVID-19 severity.

Results: In all, 1087 patients, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died, were included. Based on the multivariate analysis, higher concentrations of PM2.5 increased the risk of worse COVID-19 course (odds ratio 1.90; p = 0.009).

Conclusions: Even if several other factors explain the unfavourable course of COVID-19 in PwMS, the role of air pollutants must be considered and further investigated.
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http://dx.doi.org/10.1111/ene.15167DOI Listing
November 2021

Multiple Sclerosis and SARS-CoV-2: Has the Interplay Started?

Front Immunol 2021 27;12:755333. Epub 2021 Sep 27.

Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy.

Current knowledge on Multiple Sclerosis (MS) etiopathogenesis encompasses complex interactions between the host's genetic background and several environmental factors that result in dysimmunity against the central nervous system. An old-aged association exists between MS and viral infections, capable of triggering and sustaining neuroinflammation through direct and indirect mechanisms. The novel Coronavirus, SARS-CoV-2, has a remarkable, and still not fully understood, impact on the immune system: the occurrence and severity of both acute COVID-19 and post-infectious chronic illness (long COVID-19) largely depends on the host's response to the infection, that echoes several aspects of MS pathobiology. Furthermore, other MS-associated viruses, such as the Epstein-Barr Virus (EBV) and Human Endogenous Retroviruses (HERVs), may enhance a mechanistic interplay with the novel Coronavirus, with the potential to interfere in MS natural history. Studies on COVID-19 in people with MS have helped clinicians in adjusting therapeutic strategies during the pandemic; similar efforts are being made for SARS-CoV-2 vaccination campaigns. In this Review, we look over 18 months of SARS-CoV-2 pandemic from the perspective of MS: we dissect neuroinflammatory and demyelinating mechanisms associated with COVID-19, summarize pathophysiological crossroads between MS and SARS-CoV-2 infection, and discuss present evidence on COVID-19 and its vaccination in people with MS.
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http://dx.doi.org/10.3389/fimmu.2021.755333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503550PMC
October 2021

ADEM after ChAdOx1 nCoV-19 vaccine: A case report.

Mult Scler 2021 Sep 30:13524585211040222. Epub 2021 Sep 30.

Neurology Unit, Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University of Rome, Via di Grottarossa 1035/1039, 00189 Rome, Italy.

Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system (CNS), clinically defined by an acute polyfocal neurological syndrome usually with monophasic course. ADEM often occurs after infections, but 5%-10% of cases are preceded by vaccinations. Several cases of ADEM have been described after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas no case has been reported after adenovirus-vectored or mRNA COVID-19 vaccine administration. Here we describe a case of ADEM presenting 2 weeks after receiving the first dose of ChAdOx1 nCoV-19 vaccine. Patient clinical/magnetic resonance imaging (MRI) status spontaneously improved and rapidly resolved with corticosteroids. A 4-month follow-up showed complete recovery and no relapses.
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http://dx.doi.org/10.1177/13524585211040222DOI Listing
September 2021

Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.

EBioMedicine 2021 Oct 22;72:103581. Epub 2021 Sep 22.

Department of Neurology 2, Careggi University Hospital, Florence, Italy.

Background: In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) affects immune response to antigens. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response.

Methods: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech,Inc or mRNA-1273, Moderna Tx,Inc). A blood collection before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche-Diagnostics). The log-transform of the antibody levels was analyzed by multivariable linear regression.

Findings: 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariable analysis, the antibody levels of patients on ocrelizumab (201-fold decrease (95%CI=128-317), p < 0·001), fingolimod (26-fold decrease (95%CI=16-42), p < 0·001) and rituximab (20-fold decrease (95%CI=10-43), p < 0·001) were significantly reduced as compared to untreated patients. Vaccination with mRNA-1273 resulted in a systematically 3·25-fold higher antibody level (95%CI=2·46-4·27) than with the BNT162b2 vaccine (p < 0·001). The antibody levels on anti-CD20 therapies correlated to the time since last infusion, and rituximab had longer intervals (mean=386 days) than ocrelizumab patients (mean=129 days).

Interpretation: In pwMS, anti-CD20 treatment and fingolimod led to a reduced humoral response to mRNA-based SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·25-higher antibody levels than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 treatment or fingolimod. Combining our data with those on the cellular immune response to vaccines, and including clinical follow-up, will contribute to better define the most appropriate SARS-CoV-2 vaccine strategies in the context of DMTs and MS.

Funding: FISM[2021/Special-Multi/001]; Italian Ministry of Health'Progetto Z844A 5 × 1000'.
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http://dx.doi.org/10.1016/j.ebiom.2021.103581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456129PMC
October 2021

Intestinal Permeability and Circulating CD161+CCR6+CD8+T Cells in Patients With Relapsing-Remitting Multiple Sclerosis Treated With Dimethylfumarate.

Front Neurol 2021 26;12:683398. Epub 2021 Aug 26.

Department of Neuroscience, Mental Health and Sensory Organs, Sapienza University, Rome, Italy.

The changes of the gut-brain axis have been recently recognized as important components in multiple sclerosis (MS) pathogenesis. To evaluate the effects of DMF on intestinal barrier permeability and mucosal immune responses. We investigated intestinal permeability (IP) and circulating CD161+CCR6+CD8+T cells in 25 patients with MS, who met eligibility criteria for dimethyl-fumarate (DMF) treatment. These data, together with clinical/MRI parameters, were studied at three time-points: baseline (before therapy), after one (T1) and 9 months (T2) of treatment. At baseline 16 patients (64%) showed altered IP, while 14 cases (56%) showed active MRI. During DMF therapy we found the expected decrease of disease activity at MRI compared to T0 (6/25 at T1, = 0.035 and 3/25 at T2, < 0.00), and a reduction in the percentage of CD161+CCR6+CD8+ T cells (16/23 at T2; < 0.001). The effects of DMF on gut barrier alterations was variable, without a clear longitudinal pattern, while we found significant relationships between IP changes and drop of MRI activity ( = 0.04) and circulating CD161+CCr6+CD8+ T cells ( = 0.023). The gut barrier is frequently altered in MS, and the CD161+ CCR6+CD8+ T cell-subset shows dynamics which correlate with disease course and therapy.
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http://dx.doi.org/10.3389/fneur.2021.683398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426620PMC
August 2021

MiR-142-3p regulates synaptopathy-driven disease progression in multiple sclerosis.

Neuropathol Appl Neurobiol 2021 Sep 7. Epub 2021 Sep 7.

Unit of Neurology, IRCCS Neuromed, Pozzilli, Italy.

Aim: We recently proposed miR-142-3p as a molecular player in inflammatory synaptopathy, a new pathogenic hallmark of multiple sclerosis (MS) and of its mouse model experimental autoimmune encephalomyelitis (EAE), that leads to neuronal loss independently of demyelination. MiR-142-3p seems to be unique among potential biomarker candidates in MS, since it is an inflammatory miRNA playing a dual role in the immune and central nervous systems. Here, we aimed to verify the impact of miR-142-3p circulating in the cerebrospinal fluid (CSF) of MS patients on clinical parameters, neuronal excitability and its potential interaction with disease modifying therapies (DMTs).

Methods And Results: In a cohort of 151 MS patients, we found positive correlations between CSF miR-142-3p levels and clinical progression, IL-1β signalling as well as synaptic excitability measured by transcranial magnetic stimulation. Furthermore, therapy response of patients with 'low miR-142-3p' to dimethyl fumarate (DMF), an established disease-modifying treatment (DMT), was superior to that of patients with 'high miR-142-3p' levels. Accordingly, the EAE clinical course of heterozygous miR-142 mice was ameliorated by peripheral DMF treatment with a greater impact relative to their wild type littermates. In addition, a central protective effect of this drug was observed following intracerebroventricular and ex vivo acute treatments of EAE wild type mice, showing a rescue of miR-142-3p-dependent glutamatergic alterations. By means of electrophysiology, molecular and biochemical analysis, we suggest miR-142-3p as a molecular target of DMF.

Conclusion: MiR-142-3p is a novel and potential negative prognostic CSF marker of MS and a promising tool for identifying personalised therapies.
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http://dx.doi.org/10.1111/nan.12765DOI Listing
September 2021

Prevalence and predictors of bowel dysfunction in a large multiple sclerosis outpatient population: an Italian multicenter study.

J Neurol 2021 Aug 4. Epub 2021 Aug 4.

MS Center-I Division of Neurology, Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italia, piazza Miraglia, 2, 80138, Naples, Italy.

Introduction: Bowel dysfunction (BD) is reported as a common and disabling symptom in multiple sclerosis (MS) patients. To date, no studies have explored the prevalence of these symptoms in a large multicenter outpatient setting. The aims of the present study are to assess: (i) the prevalence of BD in a large multicenter Italian MS population, and (ii) the correlation between clinico-demographic variables and the severity of BD.

Methods: Each of the nine participating center screened MS patients prospectively: 1100 subjects were enrolled. All patients underwent the Expanded Disability Status Scale (EDSS) and completed the Neurogenic Bowel Dysfunction score (NBDs). Multivariable linear and logistic regression models were used to assess the association between NBDs and several clinico-demographic variables.

Results: Fourteen percent of MS patients showed a moderate/severe BD (NBDs > 10); this percentage increased in patients with high disability, ranging from 26 to 32%. Moderate/severe BD was more frequent in MS patients with: progressive phenotypes, higher disability, older age, and longer disease duration. NBDs severity was predicted by female sex, ambulation impairment and bladder symptoms.

Conclusion: This study confirms the relatively high prevalence of moderate/severe BD in a large, multicenter, unselected, outpatient MS population. BD appears to be mainly associated to female sex and MS-related disability.
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http://dx.doi.org/10.1007/s00415-021-10737-wDOI Listing
August 2021

SARS-CoV-2 serology after COVID-19 in multiple sclerosis: An international cohort study.

Mult Scler 2021 Jul 30:13524585211035318. Epub 2021 Jul 30.

Department of Neuroscience, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy/Unit of Neurology, IRCCS Neuromed, Isernia, Italy.

Background: The MuSC-19 project is an Italian cohort study open to international partners that collects data on multiple sclerosis (MS) patients with COVID-19. During the second wave of the pandemic, serological tests became routinely available.

Objective: To evaluate the seroprevalence of anti-SARS-CoV-2 antibodies according to the use of disease-modifying therapy (DMT) in a subset of patients included in the MuSC-19 data set who had undergone a serological test.

Methods: We evaluated the association between positive serological test results and time elapsed since infection onset, age, sex, Expanded Disability Status Scale score, comorbidities and DMT exposure using a multivariable logistic model.

Results: Data were collected from 423 patients (345 from Italy, 61 from Turkey and 17 from Brazil) with a serological test performed during follow-up. Overall, 325 out of 423 tested patients (76.8%) had a positive serological test. At multivariate analysis, therapy with anti-CD20 was significantly associated with a reduced probability of developing antibodies after COVID-19 (odds ratio (OR) = 0.20,  = 0.002).

Conclusion: Patients with MS maintain the capacity to develop humoral immune response against SARS-COV-2, although to a lesser extent when treated with anti-CD20 drugs. Overall, our results are reassuring with respect to the possibility to achieve sufficient immunization with vaccination.
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http://dx.doi.org/10.1177/13524585211035318DOI Listing
July 2021

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France.

Ann Clin Transl Neurol 2021 08 7;8(8):1738-1744. Epub 2021 Jul 7.

Department of Neurology, CIC INSERM 1434, CHU de Strasbourg, Strasbourg, France.

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39-3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18-0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon.
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http://dx.doi.org/10.1002/acn3.51408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351392PMC
August 2021

Skin biopsy and quantitative sensory assessment in an Italian cohort of ATTRv patients with polyneuropathy and asymptomatic carriers: possible evidence of early non-length dependent denervation.

Neurol Sci 2021 Jun 29. Epub 2021 Jun 29.

Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Sant'Andrea Hospital, Sapienza University of Rome, 1035-39 Grottarossa St., Rome, Italy.

Aim: Study of intraepidermal nerve fiber density (IENFD) by skin biopsy represents a promising tool in the evaluation of patients with ATTRv polyneuropathy (ATTRv-PN). Herein, we retrospectively analyze intraepidermal innervation and quantitative sensory test (QST) data from an Italian cohort of Italian ATTRv-PN patients and asymptomatic carriers aimed to provide insights into early nerve pathological and functional changes in this disease.

Methods: IENFD and QST data of 14 ATTRv-PN patients and 14 asymptomatic carriers were retrospectively analyzed together with clinical and paraclinical data such as disease stage and severity, neuropathic pain scales, and sural SNAP amplitude.

Results: Given an estimated time to the predicted age of onset of symptomatic disease of 20.27 + / - 7.9 years, small nerve fiber loss seems to be unexpectedly early in carriers. Moreover, carriers showed skin denervation at the proximal (thigh) site, suggesting a non-length-dependent neuropathic process. IENFD at ankle correlated with disease severity and other paraclinical variables such as sural nerve potential amplitude and QST parameters. Patients at earlier stages of the disease did not show significant differences in ankle IENFD compared with asymptomatic carriers, but significant differences in terms of QST parameters, small fiber neuropathy symptoms, and neuropathic pain.

Conclusions: Skin biopsy can disclose an early non-length-dependent small fiber loss in ATTRv-PN and, together with QST, could provide a useful insight disease onset and progression.
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http://dx.doi.org/10.1007/s10072-021-05434-5DOI Listing
June 2021

Long-term disability trajectories in relapsing multiple sclerosis patients treated with early intensive or escalation treatment strategies.

Ther Adv Neurol Disord 2021 31;14:17562864211019574. Epub 2021 May 31.

Dipartimento di Neurologia, Neurofisiologia e Neuroriabilitazione, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Background And Aims: No consensus exists on how aggressively to treat relapsing-remitting multiple sclerosis (RRMS) nor on the timing of the treatment. The objective of this study was to evaluate disability trajectories in RRMS patients treated with an early intensive treatment (EIT) or with a moderate-efficacy treatment followed by escalation to higher-efficacy disease modifying therapy (ESC).

Methods: RRMS patients with ⩾5-year follow-up and ⩾3 visits after disease modifying therapy (DMT) start were selected from the Italian MS Registry. EIT group included patients who received as first DMT fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group patients received the high efficacy DMT after ⩾1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score (PS) matched for characteristics at the first DMT. The disability trajectories were evaluated by applying a longitudinal model for repeated measures. The effect of early late start of high-efficacy DMT was assessed by the mean annual Expanded Disability Status Scale (EDSS) changes compared with baseline values (delta-EDSS) in EIT and ESC groups.

Results: The study cohort included 2702 RRMS patients. The PS matching procedure produced 363 pairs, followed for a median (interquartile range) of 8.5 (6.5-11.7) years. Mean annual delta-EDSS values were all significantly ( < 0.02) higher in the ESC group compared with the EIT group. In particular, the mean delta-EDSS differences between the two groups tended to increase from 0.1 (0.01-0.19,  = 0.03) at 1 year to 0.30 (0.07-0.53,  = 0.009) at 5 years and to 0.67 (0.31-1.03,  = 0.0003) at 10 years.

Conclusion: Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression over time.
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http://dx.doi.org/10.1177/17562864211019574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170278PMC
May 2021

MAIT Cells and Microbiota in Multiple Sclerosis and Other Autoimmune Diseases.

Microorganisms 2021 May 24;9(6). Epub 2021 May 24.

Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, 00189 Rome, Italy.

The functions of mucosal-associated invariant T (MAIT) cells in homeostatic conditions include the interaction with the microbiota and its products, the protection of body barriers, and the mounting of a tissue-repair response to injuries or infections. Dysfunction of MAIT cells and dysbiosis occur in common chronic diseases of inflammatory, metabolic, and tumor nature. This review is aimed at analyzing the changes of MAIT cells, as well as of the microbiota, in multiple sclerosis and other autoimmune disorders. Common features of dysbiosis in these conditions are the reduced richness of microbial species and the unbalance between pro-inflammatory and immune regulatory components of the gut microbiota. The literature concerning MAIT cells in these disorders is rather complex, and sometimes not consistent. In multiple sclerosis and other autoimmune conditions, several studies have been done, or are in progress, to find correlations between intestinal permeability, dysbiosis, MAIT cell responses, and clinical biomarkers in treated and treatment-naïve patients. The final aims are to explain what activates MAIT cells in diseases not primarily infective, which interactions with the microbiota are potentially pathogenic, and their dynamics related to disease course and disease-modifying treatments.
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http://dx.doi.org/10.3390/microorganisms9061132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225125PMC
May 2021

Circulating hsa-miR-323b-3p in Huntington's Disease: A Pilot Study.

Front Neurol 2021 5;12:657973. Epub 2021 May 5.

Department of Neurosciences, Centre for Experimental Neurological Therapies (CENTERS), Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy.

The momentum of gene therapy in Huntington's disease (HD) deserves biomarkers from easily accessible fluid. We planned a study to verify whether plasma miRNome may provide useful peripheral "reporter(s)" for the management of HD patients. We performed an exploratory microarray study of whole non-coding RNA profiles in plasma from nine patients with HD and 13 matched controls [eight healthy subjects (HS) and five psychiatric patients (PP) to minimize possible iatrogenic impact on the profile of non-coding RNAs]. We found an HD-specific signature: downregulation of hsa-miR-98 (fold change, -1.5, = 0.0338 HD vs. HS, and fold change, 1.5, = 0.0045 HD vs. PP) and upregulation of hsa-miR-323b-3p (fold change, 1.5, = 0.0007 HD vs. HS, and fold change, 1.5, = 0.0111 HD vs. PP). To validate this result in an independent cohort, we quantify by digital droplet PCR (ddPCR) the presence of the two microRNA in the plasma of 33 HD patients and 49 matched controls (25 HS and 24 PP patients). We were able to confirm that hsa-miR-323b-3p was upregulated in HD and premanifest HD vs. HS and PP: the median values (first-third quartile) were 4.1 (0.9-10.53) and 5.8 (1.9-10.70) vs. 0.69 (0.3-2.75) and 1.4 (0.78-2.70), respectively, < 0.05. No significant difference was found for hsa-miR-98. To evaluate the biological plausibility of the hsa-miR-323b-3p as a component of the disease pathophysiology, we performed a bioinformatic analysis based on its targetome and the huntingtin (HTT) interactome. We found a statistically significant overconnectivity between the targetome of hsa-miR-323b-3p and the HTT interactome ( = 1.48e-08). Furthermore, there was a significant transcription regulation of the HTT interactome by the miR-323b-3p targetome ( = 0.02). The availability of handy, reproducible, and minimally invasive biomarkers coming from peripheral miRNome may be valuable to characterize the illness progression, to indicate new therapeutic targets, and to monitor the effect of disease-modifying treatments. Our data deserve further studies with larger sample size and longitudinal design.
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http://dx.doi.org/10.3389/fneur.2021.657973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131841PMC
May 2021

Signals of pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant in the control of Treg cell proliferative potential.

Immunity 2021 07 17;54(7):1543-1560.e6. Epub 2021 May 17.

Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy; Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Napoli, Italy. Electronic address:

Human CD4CD25FOXP3 regulatory T (Treg) cells are key players in the control of immunological self-tolerance and homeostasis. Here, we report that signals of pseudo-starvation reversed human Treg cell in vitro anergy through an integrated transcriptional response, pertaining to proliferation, metabolism, and transmembrane solute carrier transport. At the molecular level, the Treg cell proliferative response was dependent on the induction of the cystine/glutamate antiporter solute carrier (SLC)7A11, whose expression was controlled by the nuclear factor erythroid 2-related factor 2 (NRF2). SLC7A11 induction in Treg cells was impaired in subjects with relapsing-remitting multiple sclerosis (RRMS), an autoimmune disorder associated with reduced Treg cell proliferative capacity. Treatment of RRMS subjects with dimethyl fumarate (DMF) rescued SLC7A11 induction and fully recovered Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmunity and unveil SLC7A11 as major target for the rescue of Treg cell proliferation.
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http://dx.doi.org/10.1016/j.immuni.2021.04.014DOI Listing
July 2021

A Case of Double Standard: Sex Differences in Multiple Sclerosis Risk Factors.

Int J Mol Sci 2021 Apr 2;22(7). Epub 2021 Apr 2.

Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, 00189 Rome, Italy.

Multiple sclerosis is a complex, multifactorial, dysimmune disease prevalent in women. Its etiopathogenesis is extremely intricate, since each risk factor behaves as a variable that is interconnected with others. In order to understand these interactions, sex must be considered as a determining element, either in a protective or pathological sense, and not as one of many variables. In particular, sex seems to highly influence immune response at chromosomal, epigenetic, and hormonal levels. Environmental and genetic risk factors cannot be considered without sex, since sex-based immunological differences deeply affect disease onset, course, and prognosis. Understanding the mechanisms underlying sex-based differences is necessary in order to develop a more effective and personalized therapeutic approach.
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http://dx.doi.org/10.3390/ijms22073696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037645PMC
April 2021

Different Susceptibility of T and B Cells to Cladribine Depends On Their Levels of Deoxycytidine Kinase Activity Linked to Activation Status.

J Neuroimmune Pharmacol 2021 Apr 14. Epub 2021 Apr 14.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (F.C, A.U.), F.I., N.KdeR., A.U.) and Centre of Excellence for Biomedical Research (F.C., A.U.), University of Genova, Genoa, Italy.

Deoxycytidine kinase (dCK) and 5' deoxynucleotidase (NT5C2) are involved in metabolism of cladribine (2CdA), the immunomodulatory drug for multiple sclerosis; by mediating phosphorylation (activation) or phosphorolysis (deactivation) of 2CdA, respectively, these enzymes promote or prevent its accumulation in the cell, which leads to cell death. In particular, lymphocytes which present with a high intracellular dCK/NT5C2 ratio are more sensitive to 2CdA than other immune cells. We aim at determining if the expression of these enzymes and/or their activity differ in specific progenitor and mature immune cells and are influenced by cellular activation and/or exposure to 2CdA. Flow cytometry analysis showed no difference in dCK/NT5C2 ratio in progenitor and mature immune cells. 2CdA induced apoptosis in stimulated T and B cells and unstimulated B cells. dCK expression was enhanced by 2CdA at mRNA and protein levels in activated T cells and mRNA level in activated B cells. dCK activity, measured through an in-house luminescence release enzyme assay was higher in activated T and B cells, and such an increase was abrogated in activated B cells, but not T cells, upon exposure to 2CdA. These results reveal an important relationship between dCK activity and the effect of 2CdA on B and T cells, according to their activation status. Further study is warranted to evaluate whether dCK activity could, in the future, be a suitable predictive biomarker of lymphocyte response to 2CdA.
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http://dx.doi.org/10.1007/s11481-021-09994-3DOI Listing
April 2021

Drugs used in the treatment of multiple sclerosis during COVID-19 pandemic: a critical viewpoint.

Curr Neuropharmacol 2021 Mar 29. Epub 2021 Mar 29.

Department of Systems Medicine, Tor Vergata University, 00133 Rome. Italy.

Since COVID-19 has emerged as a word public health problem, attention has been focused on how immune suppressive drugs used for the treatment of autoimmune disorders influence the risk for SARS-CoV-2 infection and the development of the acute respiratory distress syndrome (ARDS). Here we discuss the disease-modifying agents approved for the treatment of multiple sclerosis (MS) within this context. Interferon (IFN)-1a and -1b, which display antiviral activity, could be protective in the early stage of COVID-19 infection, although SARS-CoV-2 may have developed resistance to IFNs. However, in the hyper inflammation stage, IFNs may become detrimental by facilitating macrophage invasion in the lung and other organs. Glatiramer acetate and its analogues should not interfere with the development of COVID-19 and may be considered safe. Teriflunomide, a first-line oral drug used in the treatment of relapsing-remitting MS (RRMS) may display antiviral activity by depleting cellular nucleotides necessary for viral replication. The other first-line drug, dimethyl fumarate, may afford protection against SARS-CoV-2 by activating the Nrf-2 pathway and reinforcing the cellular defences against oxidative stress. Concern has been raised on the use of second-line treatments for MS during COVID-19 pandemic. However, this concern is not always justified. For example, fingolimod, might be highly beneficial during the hyperinflammatory stage of COVID-19 for a number of mechanisms including the reinforcement of the endothelial barrier. Caution is suggested for the use of natalizumab, cladribine, alemtuzumab, and ocrelizumab, although MS disease recurrence after discontinuation of these drugs may overcome a potential risk for COVID-19 infection.
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http://dx.doi.org/10.2174/1570159X19666210330094017DOI Listing
March 2021

Changes of clinical, neurophysiological and nerve ultrasound characteristics in CIDP over time: a 3-year follow-up.

J Neurol 2021 Aug 27;268(8):3011-3019. Epub 2021 Feb 27.

Neuromuscular and Rare Disease Center, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, SAPIENZA University of Rome, Sant'Andrea Hospital, Via di Grottarossa 1035-1039, 00189, Rome, Italy.

Objectives: To evaluate, in a prospective study, high-resolution ultrasound (HRUS) changes of nerve segments in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and their relationships with clinical and electrodiagnostic (EDX) characteristics.

Methods: Twenty-three consecutive patients with CIDP were included in a 3-year follow-up (FU) study. Each patient underwent neurologic examination, EDX and HRUS study. HRUS was performed on median, ulnar and peroneal nerves, yielding a total of 319 scanned nerve segments. INCAT and MRC-sum scores, motor nerve conduction velocity (NCV), compound muscle action potential (cMAP) amplitude, and nerve cross-sectional area (NCSA) were collected at baseline and at FU end, and were used for statistical analysis. Twenty-two healthy individuals, matched to patients for age and BMI, served as controls.

Results: NCSA was higher in patients than in controls (p < 0.0001) and showed significant direct correlation with disease severity, and inverse correlation with NCV and cMAP amplitude, both at baseline and at FU end. Disease duration, clinical scores and EDX were predictors of NCSA enlargement at both time points. During FU, NCSA increased in 51% of nerve segments (p = 0.006), in correlation with INCAT increase and with NCV and cMAP reduction. Considering EDX changes in subgroups that reflect the different types of nerve damage, NCSA significantly increased in those nerve segments that from normal EDX switched to prevalent myelinopathic EDX characteristics.

Conclusions: Peripheral nerve size tends to increase over time in patients with CIDP, in correlation with clinical and EDX changes, in particular in those nerve segments that undergo a predominantly demyelinating damage.
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http://dx.doi.org/10.1007/s00415-021-10485-xDOI Listing
August 2021

Operationalization of a frailty index in patients with multiple sclerosis: A cross-sectional investigation.

Mult Scler 2021 10 10;27(12):1939-1947. Epub 2021 Feb 10.

Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy/IRCCS Neuromed, Pozzilli, Italy.

Background: Frailty is an age-related status of increased vulnerability to stressors caused by the accumulation of multiple health deficits. This construct may allow to capture the clinical complexity of patients with multiple sclerosis (MS).

Objective: To investigate the relationship between frailty and the clinical manifestations of MS.

Methods: Patients with MS were consecutively enrolled at five tertiary dedicated services. Disability and fatigue were assessed. The phenotypes of MS were also identified. Frailty was measured using a frailty index (FI), computed by cumulatively considering 42 age-related multidimensional health deficits.

Results: Overall, 745 MS patients (mean age = 48.2 years, standard deviation = 11.7 years; women 68%) were considered. The median FI value was 0.12 (interquartile range = 0.05-0.19) and the 99th percentile was 0.40. FI scores were associated with MS disease duration, disability, fatigue, as well as with the number of previous disease-modifying treatments and current symptomatic therapies. A logistic regression analysis model showed that FI score was independently associated with the secondary progressive phenotype.

Conclusion: Frailty is significantly associated with major characteristics of MS. The findings of the present cross-sectional investigation should be explored in future longitudinal studies.
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http://dx.doi.org/10.1177/1352458520987541DOI Listing
October 2021

Machine Learning Use for Prognostic Purposes in Multiple Sclerosis.

Life (Basel) 2021 Feb 5;11(2). Epub 2021 Feb 5.

Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy.

The course of multiple sclerosis begins with a relapsing-remitting phase, which evolves into a secondarily progressive form over an extremely variable period, depending on many factors, each with a subtle influence. To date, no prognostic factors or risk score have been validated to predict disease course in single individuals. This is increasingly frustrating, since several treatments can prevent relapses and slow progression, even for a long time, although the possible adverse effects are relevant, in particular for the more effective drugs. An early prediction of disease course would allow differentiation of the treatment based on the expected aggressiveness of the disease, reserving high-impact therapies for patients at greater risk. To increase prognostic capacity, approaches based on machine learning (ML) algorithms are being attempted, given the failure of other approaches. Here we review recent studies that have used clinical data, alone or with other types of data, to derive prognostic models. Several algorithms that have been used and compared are described. Although no study has proposed a clinically usable model, knowledge is building up and in the future strong tools are likely to emerge.
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http://dx.doi.org/10.3390/life11020122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914671PMC
February 2021

Predictors of lymphocyte count recovery after dimethyl fumarate-induced lymphopenia in people with multiple sclerosis.

J Neurol 2021 Jun 26;268(6):2238-2245. Epub 2021 Jan 26.

Multiple Sclerosis Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy.

Background: Dimethyl fumarate (DMF) is an oral drug approved for Relapsing Multiple Sclerosis (RMS) patients. Grade III lymphopenia is reported in 5-10% DMF-treated patients. Data on lymphocyte count (ALC) recovery after DMF withdrawal following prolonged lymphopenia are still scarce.

Objectives: To characterize ALC recovery and to identify predictors of slower recovery after DMF interruption.

Methods: Multicenter data from RMS patients who started DMF and developed lymphopenia during treatment were collected. In patients with grade II-III lymphopenia, ALCs were evaluated from DMF withdrawal until reaching lymphocyte counts > 800/mm.

Results: Among 1034 patients who started DMF, we found 198 (19.1%) patients with lymphopenia and 65 patients (6.3%) who discontinued DMF due to persistent grade II-III lymphopenia. Complete data were available for 51 patients. All patients recovered to ALC > 800 cells/mm with a median time of 3.4 months. Lower ALCs at DMF suspension (HR 0.98; p = 0.005), longer disease duration (HR 1.29; p = 0.014) and prior exposure to MS treatments (HR 0.03; p = 0.025) were found predictive of delayed ALC recovery.

Conclusion: ALC recovery after DMF withdrawal is usually rapid, nevertheless it may require longer time in patients with lower ALC count at DMF interruption, longer disease duration and previous exposure to MS treatments, potentially leading to delayed initiation of a new therapy.
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http://dx.doi.org/10.1007/s00415-021-10412-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179888PMC
June 2021

Facing the urgency of therapies for progressive MS - a Progressive MS Alliance proposal.

Nat Rev Neurol 2021 Mar 22;17(3):185-192. Epub 2021 Jan 22.

Department of Neurosciences, Mental Health and Sensory Organs, Centre for Experimental Neurological Therapies (CENTERS), Faculty of Medicine and Psychology, Sapienza University, Rome, Italy.

Therapies for infiltrative inflammation in multiple sclerosis (MS) have advanced greatly, but neurodegeneration and compartmentalized inflammation remain virtually untargeted as in other diseases of the nervous system. Consequently, many therapies are available for the relapsing-remitting form of MS, but the progressive forms remain essentially untreated. The objective of the International Progressive MS Alliance is to expedite the development of effective therapies for progressive MS through new initiatives that foster innovative thinking and concrete advancements. Based on these principles, the Alliance is developing a new funding programme that will focus on experimental medicine trials. Here, we discuss the reasons behind the focus on experimental medicine trials, the strengths and weaknesses of these approaches and of the programme, and why we hope to advance therapies while improving the understanding of progression in MS. We are soliciting public and academic feedback, which will help shape the programme and future strategies of the Alliance.
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http://dx.doi.org/10.1038/s41582-020-00446-9DOI Listing
March 2021

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis.

Ann Neurol 2021 04 9;89(4):780-789. Epub 2021 Feb 9.

Department of Neuroscience, Mental Health, and Sensory Organs, Sapienza University of Rome, Rome, Italy.

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS).

Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results.

Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses.

Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists. ANN NEUROL 2021;89:780-789.
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http://dx.doi.org/10.1002/ana.26028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013440PMC
April 2021

SARS-CoV-2 meta-interactome suggests disease-specific, autoimmune pathophysiologies and therapeutic targets.

F1000Res 2020 17;9:992. Epub 2020 Aug 17.

Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, 00189, Italy.

Severe coronavirus disease 2019 (COVID-19) is associated with multiple comorbidities and is characterized by an auto-aggressive inflammatory state leading to massive collateral damage. To identify preventive and therapeutic strategies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is important to ascertain the molecular interactions between virus and host, and how they translate into disease pathophysiology. We matched virus-human protein interactions of human coronaviruses and other respiratory viruses with lists of genes associated with autoimmune diseases and comorbidities associated to worse COVID-19 course. We then selected the genes included in the statistically significant intersection between SARS-CoV-2 network and disease associated gene sets, identifying a meta-interactome. We analyzed the meta-interactome genes expression in samples derived from lungs of infected humans, and their regulation by IFN-β. Finally, we performed a drug repurposing screening to target the network's most critical nodes. We found a significant enrichment of SARS-CoV-2 interactors in immunological pathways and a strong association with autoimmunity and three prognostically relevant conditions (type 2 diabetes, coronary artery diseases, asthma), that present more independent physiopathological subnetworks. We observed a reduced expression of meta-interactome genes in human lungs after SARS-CoV-2 infection, and a regulatory potential of type I interferons. We also underscored multiple repurposable drugs to tailor the therapeutic strategies. Our data underscored a plausible genetic background that may contribute to the distinct observed pathophysiologies of severe COVID-19. Also, these results may help identify the most promising therapeutic targets and treatments for this condition.
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http://dx.doi.org/10.12688/f1000research.25593.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791351PMC
January 2021

Novel ACTA1 mutation causes late-presenting nemaline myopathy with unusual dark cores.

Neuromuscul Disord 2021 02 30;31(2):139-148. Epub 2020 Nov 30.

Neuromuscular and Rare Disease Centre, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University of Rome, Sant'Andrea Hospital, Rome, Italy.

ACTA1 gene encodes the skeletal muscle alpha-actin, the core of thin filaments of the sarcomere. ACTA1 mutations are responsible of several muscle disorders including nemaline, cores, actin aggregate myopathies and fiber-type disproportion. We report clinical, muscle imaging, histopatological and genetic data of an Italian family carrying a novel ACTA1 mutation. All affected members showed a late-presenting, diffuse muscle weakness with sternocleidomastoideus and temporalis atrophy. Mild dysmorphic features were also detected. The most affected muscles by muscle MRI were rectus abdominis, gluteus minimus, vastus intermedius and both gastrocnemii. Muscle biopsy showed the presence of nemaline bodies with several unusual dark areas at Gomori Trichrome, corresponding to unstructured cores with abundant electrodense material by electron microscopy. The molecular analysis revealed missense variant c.148G>A; p.(Gly50Ser) in the exon 3 of ACTA1, segregating with affected members in the family. We performed a functional essay of fibre contractility showing a higher pCa (a measure of the calcium sensitivity of force) of type 1 fibers compared to control subjects' type 1 muscle fibers. Our findings expand the clinico-pathological spectrum of ACTA1-related congenital myopathies and the genetic spectrum of core-rod myopathies.
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http://dx.doi.org/10.1016/j.nmd.2020.11.012DOI Listing
February 2021

Gender effect on cardiac involvement in myotonic dystrophy type 1.

Eur J Neurol 2021 04 25;28(4):1366-1374. Epub 2020 Dec 25.

Neuromuscular and Rare Disease Center, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Sapienza University, Sant'Andrea Hospital, Rome, Italy.

Background And Purpose: Cardiac involvement is observed in about 80% of subjects with myotonic dystrophy type 1 (DM1) and is mainly characterized by cardiac conduction and/or rhythm abnormalities (CCRAs), possibly leading to sudden cardiac death (SCD). Our objective was to investigate whether the gender difference may influence the cardiac involvement and SCD in DM1.

Methods: We analyzed prevalence and incidence of cardiological abnormalities in males versus females in 151 consecutive DM1 patients over a 35-year follow-up period.

Results: Fifty-five patients, 35 males (62.5%) and 20 females (42.5%), developed some type of CCRA during the follow-up period (mean 7.82 ± 6.21 years). CCRA overall, and specifically cardiac conduction abnormalities (CCAs), were significantly more frequent in males than in females (p = 0.043 and p = 0.031, respectively). CCRAs progressed in 16 males (45.7%) and six females (30%). Twenty-four patients, 14 males (25.0%) and 10 females (21.3%), died during the follow-up. Nine of them, six males (10.7%) and three females (6.4%), had SCD. After correction for Muscular Impairment Rating Scale progression, cytosine thymine-guanine expansion, and follow-up duration, a higher prevalence of CCAs was independently associated with male gender (p = 0.039), but independent association with gender was not detected for CCRAs overall, cardiac rhythm abnormalities, and SCD prevalence, even if prevalence was higher in males than females.

Conclusions: The overall risk of occurrence of CCAs in DM1 is significantly higher in males than females regardless of genetic background and disease severity and progression. Moreover, the data also suggest a similar impact for male gender for CCRAs overall, CCAs, and SCD even if not statistically significant.
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http://dx.doi.org/10.1111/ene.14665DOI Listing
April 2021
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