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Roberta BEDIN

Personale tecnico amministrativo
Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze sede ex-Neuroscienze

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Pubblicazioni

2023 - Particulate matter exposure from motorized traffic and risk of conversion from mild cognitive impairment to dementia: An Italian prospective cohort study [Articolo su rivista]
Urbano, Teresa; Chiari, Annalisa; Malagoli, Carlotta; Cherubini, Andrea; Bedin, Roberta; Costanzini, Sofia; Teggi, Sergio; Maffeis, Giuseppe; Vinceti, Marco; Filippini, Tommaso
abstract

Background: Based on epidemiologic and laboratory studies, exposure to air pollutants has been linked to many adverse health effects including a higher risk of dementia. In this study, we aimed to evaluate the effect of long-term exposure to outdoor air pollution on risk of conversion to dementia in a cohort of subjects with mild cognitive impairment (MCI). Methods: We recruited 53 Italian subjects newly-diagnosed with MCI. Within a geographical information system, we assessed recent outdoor air pollutant exposure, by modeling air levels of particulate matter with equivalent aerodynamic diameter ≤10 μm (PM10) from motorized traffic at participants' residence. We investigated the relation of PM10 concentrations to subsequent conversion from MCI to any type of dementia. Using a Cox-proportional hazards model combined with a restricted cubic spline model, we computed the hazard ratio (HR) of dementia with its 95% confidence interval (CI) according to increasing PM10 exposure, adjusting for sex, age, and educational attainment. Results: During a median follow up of 47.3 months, 34 participants developed dementia, in 26 cases diagnosed as Alzheimer's dementia. In non-linear restricted spline regression analysis, mean and maximum annual PM10 levels positively correlated with cerebrospinal fluid total and phosphorylated tau proteins concentrations, while they were inversely associated with β-amyloid. Concerning the risk of dementia, we found a positive association starting from above 10 μg/m3 for mean PM10 levels and above 35 μg/m3 for maximum PM10 levels. Specific estimates for Alzheimer's dementia were substantially similar. Adding other potential confounders to the multivariable model or removing early cases of dementia onset during the follow-up had little effect on the estimates. Conclusions: Our findings suggest that exposure to outdoor air pollutants, PM10 in particular, may non-linearly increase conversion from MCI to dementia above a certain ambient air concentration.

2022 - Selenoprotein P Concentrations in the Cerebrospinal Fluid and Serum of Individuals Affected by Amyotrophic Lateral Sclerosis, Mild Cognitive Impairment and Alzheimer’s Dementia [Articolo su rivista]
Urbano, Teresa; Vinceti, Marco; Mandrioli, Jessica; Chiari, Annalisa; Filippini, Tommaso; Bedin, Roberta; Tondelli, Manuela; Simonini, Cecilia; Zamboni, Giovanna; Shimizu, Misaki; Saito, Yoshiro
abstract

Selenoprotein P, a selenium-transporter protein, has been hypothesized to play a role in the etiology of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's dementia (AD). However, data in humans are scarce and largely confined to autoptic samples. In this case-control study, we determined selenoprotein P concentrations in both the cerebrospinal fluid (CSF) and the serum of 50 individuals diagnosed with ALS, 30 with AD, 54 with mild cognitive impairment (MCI) and of 30 controls, using sandwich enzyme-linked immunosorbent assay (ELISA) methods. We found a positive and generally linear association between CSF and serum selenoprotein P concentrations in all groups. CSF selenoprotein P and biomarkers of neurodegeneration were positively associated in AD, while for MCI, we found an inverted-U-shaped relation. CSF selenoprotein P concentrations were higher in AD and MCI than in ALS and controls, while in serum, the highest concentrations were found in MCI and ALS. Logistic and cubic spline regression analyses showed an inverse association between CSF selenoprotein P levels and ALS risk, and a positive association for AD risk, while an inverted-U-shaped relation with MCI risk emerged. Conversely, serum selenoprotein P concentrations were positively associated with risk of all conditions but only in their lower range. Overall, these findings indicate some abnormalities of selenoprotein P concentrations in both the central nervous system and blood associated with ALS and neurocognitive disorders, though in different directions. These alterations may reflect either phenomena of etiologic relevance or disease-induced alterations of nutritional and metabolic status.

2021 - CSF Heavy Neurofilament May Discriminate and Predict Motor Neuron Diseases with Upper Motor Neuron Involvement [Articolo su rivista]
Simonini, Cecilia; Zucchi, Elisabetta; Bedin, Roberta; Martinelli, Ilaria; Gianferrari, Giulia; Fini, Nicola; Sorarù, Gianni; Liguori, Rocco; Vacchiano, Veria; Mandrioli, Jessica
abstract

: Objective: To assess whether phosphorylated neurofilament heavy chain (pNfH) can discriminate different upper motor neuron (UMN) syndromes, namely, ALS, UMN-predominant ALS, primary lateral sclerosis (PLS) and hereditary spastic paraparesis (hSP) and to test the prognostic value of pNfH in UMN diseases. Methods: CSF and serum pNfH were measured in 143 patients presenting with signs of UMN and later diagnosed with classic/bulbar ALS, UMNp-ALS, hSP, and PLS. Between-group comparisons were drawn by ANOVA and receiver operating characteristic (ROC) analysis was performed. The prognostic value of pNfH was tested by the Cox regression model. Results: ALS and UMNp-ALS patients had higher CSF pNfH compared to PLS and hSP (p < 0.001). ROC analysis showed that CSF pNfH could differentiate ALS, UMNp-ALS included, from PLS and hSP (AUC = 0.75 and 0.95, respectively), while serum did not perform as well. In multivariable survival analysis among the totality of UMN patients and classic/bulbar ALS, CSF pNfH independently predicted survival. Among UMNp-ALS patients, only the progression rate (HR4.71, p = 0.01) and presence of multifocal fasciculations (HR 15.69, p = 0.02) were independent prognostic factors. Conclusions: CSF pNfH is significantly higher in classic and UMNp-ALS compared to UMN diseases with a better prognosis such as PLS and hSP. Its prognostic role is confirmed in classic and bulbar ALS, but not among UMNp, where clinical signs remained the only independent prognostic factors.

2020 - Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19 [Articolo su rivista]
Monti, G.; Giovannini, G.; Marudi, A.; Bedin, R.; Melegari, A.; Simone, A. M.; Santangelo, M.; Pignatti, A.; Bertellini, E.; Trenti, T.; Meletti, S.
abstract

2020 - Cerebrospinal fluid kappa and lambda free light chains in oligoclonal band‐negative patients with suspected multiple sclerosis [Articolo su rivista]
Ferraro, Diana; Trovati, Alice; Bedin, Roberta; Natali, Patrizia; Franciotta, Diego; Santangelo, Mario; Camera, Valentina; Vitetta, Francesca; Varani, Manuela; Trenti, Tommaso; Gastaldi, Matteo; De Biasi, Sara; Nasi, Milena; Pinti, Marcello; Meletti, Stefano; Sola, Patrizia
abstract

Cerebrospinal fluid (CSF) free light kappa chains (kappa FLC) may be a more sensitive marker of intrathecal IgG synthesis compared to oligoclonal bands (OCBs). Our aim was to retrospectively determine the additional value of the kappa and lambda index (CSF FLC/serum FLC)/(CSF albumin/serum albumin) in predicting a Multiple Sclerosis (MS) diagnosis in a group of OCB-negative patients with suspected MS.

2020 - Inter-center agreement in the interpretation of oligoclonal bands [Articolo su rivista]
Mariotto, S.; Ferraro, D.; Soldani, F.; Alberti, D.; Bedin, R.; Sola, P.; Gastaldi, M.; Franciotta, D.; Ferrari, S.
abstract

2020 - Kappa Index Versus CSF Oligoclonal Bands in Predicting Multiple Sclerosis and Infectious/Inflammatory CNS Disorders [Articolo su rivista]
Ferraro, Diana; Bedin, Roberta; Natali, Patrizia; Franciotta, Diego; Smolik, Krzysztof; Santangelo, Mario; Immovilli, Paolo; Camera, Valentina; Vitetta, Francesca; Gastaldi, Matteo; Trenti, Tommaso; Meletti, Stefano; Sola, Patrizia
abstract

Cerebrospinal fluid (CSF) kappa free light chains (KFLC) are gaining increasing interest as markers of intrathecal immunoglobulin synthesis. The main aim of this study was to assess the diagnostic accuracy (AUC) of the kappa index (CSF/serum KFLC divided by the CSF/serum albumin ratio) compared to CSF oligoclonal IgG bands (OCB) in predicting Multiple Sclerosis (MS) or a central nervous system infectious/inflammatory disorder (CNSID).

2020 - Plasma neurofilaments correlate with disability in progressive multiple sclerosis patients [Articolo su rivista]
Ferraro, Diana; Guicciardi, Claudio; De Biasi, Sara; Pinti, Marcello; Bedin, Roberta; Camera, Valentina; Vitetta, Francesca; Nasi, Milena; Meletti, Stefano; Sola, Patrizia
abstract

Cerebrospinal fluid (CSF) and blood neurofilaments (NFLs) are markers of axonal damage and are being investigated, mostly in relapsing-remitting (RR) MS, as a marker of disease activity and of response to treatment, while there are less data in progressive MS patients. Primary aim was to measure NFL in plasma samples of untreated patients with primary (PP) and secondary (SP) progressive MS and to correlate them with disability, disease severity, and prior/subsequent disability progression.

2018 - Cerebrospinal Fluid Neurofilaments May Discriminate Upper Motor Neuron Syndromes: A Pilot Study [Articolo su rivista]
Zucchi, Elisabetta; Bedin, Roberta; Fasano, Antonio; Fini, Nicola; Gessani, Annalisa; Vinceti, Marco; Mandrioli, Jessica
abstract

Patients presenting with upper motor neuron (UMN) signs may widely diverge in prognosis, ranging from amyotrophic lateral sclerosis (ALS) to primary lateral sclerosis (PLS) and hereditary spastic paraplegia (hSP). Neurofilaments are emerging as potential diagnostic and prognostic biomarkers for ALS, but the diagnosis of UMN syndromes still relies mostly on clinical long-term observation and on familiarity or genetic confirmation.

2018 - Intrathecal oligoclonal bands synthesis in multiple sclerosis: is it always a prognostic factor? [Articolo su rivista]
Frau, Jessica; Villar, Luisa Maria; Sardu, Claudia; Secci, Maria Antonietta; Schirru, Lucia; Ferraro, Diana; Coghe, Giancarlo; Lorefice, Lorena; Fenu, Giuseppe; Bedin, Roberta; Sola, Patrizia; Marrosu, Maria Giovanna; Cocco, Eleonora
abstract

Oligoclonal IgM (OCMB) and IgG (OCGB) bands were found to be associated with poor multiple sclerosis (MS) prognosis.

2018 - Low levels of progesterone and derivatives in cerebrospinal fluid of patients affected by status epilepticus [Articolo su rivista]
Meletti, Stefano; Lucchi, Chiara; Monti, Giulia; Giovannini, Giada; Bedin, Roberta; Trenti, Tommaso; Rustichelli, Cecilia; Biagini, Giuseppe
abstract

Neurosteroids such as allopregnanolone may play a role in epilepsy as positive modulators of inhibitory currents mediated by γ-aminobutyric acid type A (GABAA ) receptor. Indeed, these molecules have been consistently shown to be anticonvulsants in animal models, but their role is still unclear in patients. For this reason, we investigated neurosteroids in the cerebrospinal fluid (CSF) of patients with status epilepticus (SE) by liquid chromatography tandem-mass spectrometry. Patients were retrospectively identified within subjects who received a lumbar puncture in the 2007-2017 period. Seventy-three patients (median age 65, ranging from 13 to 94 years; 67% women) with SE were evaluated. Controls (n = 52, median age 53, ranging from 16 to 93 years; 65% women) were patients presenting with symptoms for which a lumbar puncture was required by clinical guidelines, and who were negative at the end of the diagnostic work-up. Progesterone was 64% lower in patients with SE (p < 0.001). With respect to progesterone, upstream pregnenolone sulfate and pregnenolone did not change. Instead, downstream 5α-dihydroprogesterone, pregnanolone and allopregnanolone were respectively 49% (p < 0.001), 21% (p < 0.01) and 37% (p < 0.001) lower than in controls. Duration or type of SE, age and sex did not consistently affect CSF neurosteroid levels in the SE cohort. Instead, pregnenolone sulfate (Spearman's ρ = 0.4335, p < 0.01), allopregnanolone (ρ = 0.4121, p < 0.05), and pregnanolone (ρ = 0.592, p < 0.001) levels significantly increased by ageing in controls. We conclude that neurosteroidogenesis is defective in patients with SE. This article is protected by copyright. All rights reserved.

2018 - Post-infectious sensory neuropathy with anti-GT1a and GQ1b antibodies associated with cold urticaria [Articolo su rivista]
Zucchi, Elisabetta; Cavallieri, Francesco; Giovannini, Giada; Antonelli, Francesca; Mascia, Maria Teresa; Bedin, Roberta; Mandrioli, Jessica
abstract

A 64 years-old woman presented subacute onset distal paraesthesia concurrently with cold-induced urticaria, a rare form of physical urticaria. Both the disturbances developed a fortnight after an upper respiratory tract infection. EMG confirmed an exclusively sensory polyneuropathy, with prolongation of distal latencies and reduction of amplitudes. Anti-GQ1b and anti-GT1a antigangliosides antibodies were found in serum. The clinical workout included CSF analysis, cryoglobulin and paraprotein search, neurotropic infective agents, neoplastic markers and extensive autoimmune disease antibodies analysis, all of which resulted negative. Intravenous immunoglobulins were administered, leading to progressive resolution of the sensory disturbance, while a combination of steroid and anti-histaminics treatment was used for the urticaria. The positivity for anti-ganglioside search with an EMG pattern characterized by a mixture of demyelinating and axonal features may suggest a nodo-paranodopathy at early stages. This is the first case of an association between an acute sensory neuropathy and cold urticaria, two immune mediated conditions apparently due to very different hypersensitivity pathways. A proposed mechanism for the co-occurence of these two conditions is presented, whereas this case expands the clinical spectrum of autoimmune diseases associated with anti-GQ1b and anti-GT1a antibodies.

2018 - Ridotta concentrazione del progesterone e di altri neurosteroidi nel liquor di pazienti in stato di male epilettico [Abstract in Atti di Convegno]
Biagini, G.; Lucchi, C.; Monti, G.; Giovannini, G.; Bedin, R.; Rustichelli, C.; Meletti, S.
abstract

Lo stato di male epilettico (SE) costituisce una grave emergenza neurologica. In tale condizione, mediante cromatografia liquida e spettrometria di massa, abbiamo misurato e confrontato i livelli di pregnenolone solfato, pregnenolone, progesterone, 5α-diidroprogesterone, pregnanolone e allopregnanolone nel liquor di pazienti affetti da SE e in una coorte di controllo. Sono stati studiati 73 pazienti ricoverati per SE, con età di 65 anni (intervallo di variazione da 13 a 94 anni), dei quali il 67% donne. I controlli esaminati, pari a 52, avevano età compresa tra 16 e 93 anni (mediana pari a 53), dei quali il 65% donne. I risultati sono stati analizzati con il test di Mann-Whitney. Abbiamo anche correlato le concentrazioni dei neurosteroidi e l’età, il genere, la durata ed il tipo di SE. Il progesterone è risultato essere diminuito del 64% nel liquor dei pazienti con SE (p < 0.001). I neurosteroidi pregnenolone solfato e pregnenolone, precursori del progesterone, sono risultati a livelli analoghi a quelli dei controlli. I derivati del progesterone, al contrario, in particolare il 5α-diidroprogesterone (-49%, p < 0.001), il pregnanolone (-21%, p = 0.005) e l’allopregnanolone (-37%, p < 0.001), sono risultati essere inferiori ai controlli. Le variazioni osservate nei livelli liquorali di neurosteroidi non hanno travato spiegazioni nelle differenze di genere, età o tipo di SE. Inoltre, non sono stati riscontrati effetti dovuti alla durata del SE. In conclusione, questi risultati indicano che vari neurosteroidi anticonvulsivanti sono presenti a ridotte concentrazioni liquorali nei pazienti che presentano un’attività epilettica protratta.

2017 - A multicenter study on the diagnostic significance of a single cerebrospinal fluid IgG band [Articolo su rivista]
Ferraro, Diana; Franciotta, Diego; Bedin, Roberta; Solaro, Claudio; Cocco, Eleonora; Santangelo, Mario; Immovilli, Paolo; Gajofatto, Alberto; Calabrese, Massimiliano; Di Filippo, Massimiliano; Orlandi, Riccardo; Simone, ANNA MARIA; Vitetta, Francesca; Capello, Elisabetta; Giunti, Debora; Murialdo, Alessandra; Frau, Jessica; Mariotto, Sara; Gallina, Antongiulio; Gasperini, Claudio; Sola, Patrizia
abstract

The analysis of paired cerebrospinal fluid (CSF) and serum samples with isolectric focusing (IEF) can yield different patterns which can be of aid in the differential diagnosis of central nervous system (CNS) disorders. Rarely, a single CSF-restricted IgG band, which is not included within these patterns, can be detected in association with inflammatory disorders, multiple sclerosis (MS) above all. However, the diagnostic meaning of this abnormality is still uncertain. The main aim of our multicenter study was to establish the frequency and disease associations of single CSF IgG bands. Differences in the CSF profiles between MS and other diseases, and the follow-up patterns were also evaluated. Medical records of patients who underwent CSF analysis, which included IEF, over a 11.5-year period were retrospectively scrutinized at the participating centers, which used similar IEF techniques. One hundred and fifty-one of 9422 CSF reports (1.6%) showed single CSF-restricted IgG bands. Of the 129 patients with a definite diagnosis, 58.2% had CNS inflammatory-demyelinating diseases (the most frequent being MS: 21.7%), 6.2% tumours, 5.4% inflammatory peripheral nervous system diseases and 30.2% miscellaneous diseases. At follow-up, 3 out of the 10 patients with a repeated CSF analysis had developed an oligoclonal band pattern. Our findings indicate that single CSF IgG bands tend to associate with diseases characterized by the involvement of intrathecal humoral immune responses, and strongly support the notion that this abnormality should be regularly reported, thus alerting clinicians of possible inflammatory disorders of the CNS.

2017 - Cerebrospinal fluid anti-Epstein-Barr virus specific oligoclonal IgM and IgG bands in patients with clinically isolated and Guillain-Barré syndrome [Articolo su rivista]
Ferraro, Diana; Galli, Veronica; Simone, ANNA MARIA; Bedin, Roberta; Vitetta, Francesca; Merelli, Elisa; Nichelli, Paolo Frigio; Sola, Patrizia
abstract

Epstein-Barr virus (EBV) has been implicated in multiple sclerosis (MS) pathogenesis. We aimed to assess the frequency of EBV-specific IgG and IgM oligoclonal bands (OCB) in cerebrospinal fluid (CSF) of 50 patients with clinically isolated syndrome (CIS) and in 27 controls with Guillain-Barré syndrome (GBS). Furthermore, we assessed correlations between the presence of OCB and CIS patients' CSF, MRI, and clinical variables. There was no difference in the proportion of CIS and GB patients with positivity for anti-EBV-specific IgG/IgM OCB. There were no correlations between OCB and analyzed variables, nor were they predictive of a higher disability at 3&nbsp;years.

2017 - Decreased allopregnanolone levels in cerebrospinal fluid obtained during status epilepticus [Articolo su rivista]
Meletti, Stefano; Lucchi, Chiara; Monti, Giulia; Giovannini, Giada; Bedin, Roberta; Trenti, Tommaso; Rustichelli, Cecilia; Biagini, Giuseppe
abstract

Neuroactive steroids are increasingly considered as relevant modulators of neuronal activity. Especially allopregnanolone (AP) and pregnenolone sulfate (PS) have been shown to possess, respectively, anticonvulsant or proconvulsant properties. In view of the potential role of these steroids, we aimed at evaluating AP and PS levels in cerebrospinal fluid (CSF) and blood samples obtained from patients with status epilepticus (SE). To this purpose, we enrolled 41 patients affected by SE and 41 subjects investigated for nonepileptic neurologic disorders. Liquid chromatographic procedures coupled with electrospray tandem mass spectrometry and routine laboratory investigations were performed. Significantly lower AP levels were found in the CSF of patients affected by SE (-30%; p &lt; 0.05, Mann-Whitney test). Notably, AP was not detectable in 28 of 41 patients affected by SE (p &lt; 0.01 vs. controls, Fisher's exact test). In serum, AP levels did not differ in the two considered groups. Conversely, PS was present at similar levels in the investigated groups. Finally, differences in AP levels could not be explained by a variation in CSF albumin content. These findings indicate that AP is defective in the CSF of patients affected by SE. This phenomenon was not dependent on carriers for steroids, such as albumin.

2017 - Diagnostics of anti-MAG antibody polyneuropathy [Articolo su rivista]
Franciotta, Diego; Gastaldi, Matteo; Benedetti, Luana; Garnero, Martina; Biagioli, Tiziana; Brogi, Marco; Costa, Gianna; Fadda, Elisabetta; Andreetta, Francesca; Simoncini, Ornella; Giannotta, Claudia; Bazzigaluppi, Elena; Fazio, Raffaella; Bedin, Roberta; Ferraro, Diana; Mariotto, Sara; Ferrari, Sergio; Galloni, Elisabetta; De Riva, Valentina; Zardini, Elisabetta; Cortese, Andrea; Nobile orazio, Eduardo
abstract

This document presents the guidelines for anti-myelin-associated glycoprotein (MAG) antibody testing that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of sponsoring Italian Association of Neuroimmunology (AINI) congresses. The main clinical information on anti-MAG antibody polyneuropathy, indications and limits of anti-MAG antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.

2017 - Diagnostics of dysimmune peripheral neuropathies [Articolo su rivista]
Franciotta, Diego; Gastaldi, Matteo; Benedetti, Luana; Pesce, Giampaola; Biagioli, Tiziana; Lolli, Francesco; Costa, Gianna; Melis, Cristina; Andreetta, Francesca; Simoncini, Ornella; Giannotta, Claudia; Bazzigaluppi, Elena; Fazio, Raffaella; Bedin, Roberta; Ferraro, Diana; Mariotto, Sara; Ferrari, Sergio; Galloni, Elisabetta; De Riva, Valentina; Zardini, Elisabetta; Cortese, Andrea; Nobile orazio, Eduardo
abstract

This document presents the guidelines for anti-ganglioside antibody testing that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Main clinical information on dysimmune peripheral neuropathies, indications and limits of anti-ganglioside antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.

2016 - Cerebrospinal fluid amounts of HLA-G in dimeric form are strongly associated to patients with MRI inactive multiple sclerosis [Articolo su rivista]
Fainardi, Enrico; Bortolotti, Daria; Bolzani, Silvia; Castellazzi, Massimiliano; Tamborino, Carmine; Roversi, Gloria; Baldi, Eleonora; Caniatti, Maria Luisa; Casetta, Ilaria; Gentili, Valentina; Granieri, Enrico; Rizzo, Roberta; Tola, M. R.; Dallocchio, F.; Bellini, T.; Rotola, A.; Di Luca, D.; Seraceni, S.; Contini, C.; Sabbioni, S.; Negrini, M.; Tognon, M.; Antonelli, T.; Groppo, E.; Gentile, M.; Ceruti, S.; Manfrinato, M. R.; Trentini, A.; Miotto, E.; Ferracin, M.; Mazzoni, E.; Pietrobon, S.; Masini, I.; Rotondo, J. C.; Martini, F.; Baruzzi, A.; Roberto D'Alessandro, R.; Michelucci, R.; Salvi, F.; Stecchi, S.; Scandellari, C.; Terzano, G.; Granella, F.; Nichelli, Paolo Frigio; Sola, P.; Ferraro, Diana; Vitetta, F.; Simone, ANNA MARIA; Bedin, Roberta; Marcello, N.; Motti, L.; Montepietra, S.; Guidetti, D.; Immovilli, P.; Montanari, E.; Pesci, I.; Guareschi, A.; Greco, G.; Santangelo, M.; Mauro, A. M.; Malagù, S.; Rasi, F.; Spadoni, M.; Galeotti, M.; Fiorani, L.; Neri, W.; Ravasio, A.; Pasquinelli, M.; Gutman, S.; Monaldini, C.
abstract

Background: The relevance of human leukocyte antigen (HLA)-G in dimeric form in multiple sclerosis (MS) is still unknown. Objective: To investigate the contribution of cerebrospinal fluid (CSF) HLA-G dimers in MS pathogenesis. Methods: CSF amounts of 78-kDa HLA-G dimers were measured by western blot analysis in 80 MS relapsing-remitting MS (RRMS) patients and in 81 inflammatory and 70 non-inflammatory controls. Results: CSF amounts of 78kDa HLA-G dimers were more frequent in RRMS than in inflammatory (p<0.01) and non-inflammatory controls (p<0.001) and in magnetic resonance imaging (MRI) inactive than in MRI active RRMS (p<0.00001). Conclusion: Our findings suggest that HLA-G dimers may be implicated in termination of inflammatory response occurring in MS.

2016 - Serum IgG against Simian Virus 40 antigens are hampered by high levels of sHLA-G in patients affected by inflammatory neurological diseases, as multiple sclerosis [Articolo su rivista]
Rizzo, Roberta; Pietrobon, Silvia; Mazzoni, Elisa; Bortolotti, D.; Martini, Fernanda; Castellazzi, Massimiliano; Casetta, Ilaria; Fainardi, Enrico; Luca, Dario; Granieri, Enrico; Tognon, Mauro; Granieri, E.; Castellazzi, M.; Casetta, I.; Tola, M. R.; Fainardi, E.; Dallocchio, F.; Bellini, T.; Rizzo, R.; Rotola, A.; Di Luca, D.; Seraceni, S.; Contini, C.; Sabbioni, S.; Negrini, M.; Tognon, M.; Antonelli, T.; Groppo, E.; Gentile, M.; Baldi, E.; Caniatti, M. L.; Ceruti, S.; Manfrinato, M. R.; Trentini, A.; Miotto, E.; Ferracin, M.; Mazzoni, E.; Pietrobon, S.; Masini, I.; Rotondo, J. C.; Martini, F.; Baruzzi, A.; Roberto D'Alessandro, R.; Michelucci, R.; Salvi, F.; Stecchi, S.; Scandellari, C.; Terzano, G.; Granella, F.; Nichelli, Paolo Frigio; Sola, P.; Ferraro, Diana; Vitetta, F.; Simone, ANNA MARIA; Bedin, Roberta; Marcello, N.; Motti, L.; Montepietra, S.; Guidetti, D.; Immovilli, P.; Montanari, E.; Pesci, I.; Guareschi, A.; Greco, G.; Santangelo, M.; Mauro, A. M.; Malagù, S.; Rasi, F.; Spadoni, M.; Galeotti, M.; Fiorani, L.; Neri, W.; Ravasio, A.; Pasquinelli, M.; Gutman, S.; Monaldini, C.
abstract

Background: Many investigators detected the simian polyomavirus SV40 footprints in human brain tumors and neurologic diseases and recently it has been indicated that SV40 seems to be associated with multiple sclerosis (MS) disease. Interestingly, SV40 interacts with human leukocyte antigen (HLA) class I molecules for cell entry. HLA class I antigens, in particular non-classical HLA-G molecules, characterized by an immune-regulatory function, are involved in MS disease, and the levels of these molecules are modified according with the disease status. Objective: We investigated in serum samples, from Italian patients affected by MS, other inflammatory diseases (OIND), non-inflammatory neurological diseases (NIND) and healthy subjects (HS), SV40-antibody and soluble sHLA-G and the association between SV40-prevalence and sHLA-G levels. Methods: ELISA tests were used for SV40-antibodies detection and sHLA-G quantitation in serum samples. Results: The presence of SV40 antibodies was observed in 6 % of patients affected by MS (N = 4/63), 10 % of OIND (N = 8/77) and 15 % of NIND (N = 9/59), which is suggestive of a lower prevalence in respect to HS (22 %, N = 18/83). MS patients are characterized by higher sHLA-G serum levels (13.9 ± 0.9 ng/ml; mean ± St. Error) in comparison with OIND (6.7 ± 0.8 ng/ml), NIND (2.9 ± 0.4 ng/ml) and HS (2.6 ± 0.7 ng/ml) subjects. Interestingly, we observed an inverse correlation between SV40 antibody prevalence and sHLA-G serum levels in MS patients. Conclusion: The data obtained showed a low prevalence of SV40 antibodies in MS patients. These results seems to be due to a generalized status of inability to counteract SV40 infection via antibody production. In particular, we hypothesize that SV40 immune-inhibitory direct effect and the presence of high levels of the immune-inhibitory HLA-G molecules could co-operate in impairing B lymphocyte activation towards SV40 specific peptides.

2015 - Cerebrospinal fluid CXCL13 in clinically isolated syndrome patients: Association with oligoclonal IgM bands and prediction of Multiple Sclerosis diagnosis [Articolo su rivista]
Ferraro, Diana; Galli, Veronica; Vitetta, Francesca; Simone, Anna Maria; Bedin, Roberta; Del Giovane, Cinzia; Morselli, Franca; Filippini, Maria Maddalena; Nichelli, Paolo Frigio; Sola, Patrizia
abstract

Cerebrospinal fluid (CSF) CXCL13 was shown to correlate with markers of intrathecal inflammation and CSF oligoclonal IgM bands (IgMOB) have been associated with a more severe Multiple Sclerosis (MS) course.We correlated CSF CXCL13 levels with clinical, MRI and CSF parameters, including CSF IgMOB, in 110 Clinically Isolated Syndrome (CIS) patients.CSF CXCL13 levels correlated with CSF cell count, total protein, IgG Index and with the presence of CSF IgGOB and IgMOB.CSF CXCL13 levels ≥. 15.4. pg/ml showed a good positive predictive value and specificity for a MS diagnosis and for a clinical relapse within one year from onset.

2015 - Cerebrospinal fluid tau proteins in status epilepticus [Articolo su rivista]
Monti, Giulia; Tondelli, Manuela; Giovannini, Giada; Bedin, Roberta; Nichelli, Paolo Frigio; Trenti, Tommaso; Meletti, Stefano; Chiari, Annalisa
abstract

Tau protein is a phosphorylated microtubule-associated protein, principally localized at neuronal level in the central nervous system (CNS). Tau levels in the cerebrospinal fluid (CSF) are considered to index both axonal and neuronal damage. To date, however, no study has specifically evaluated the CSF levels of tau proteins in patients with status epilepticus (SE). We evaluated these established biomarkers of neuronal damage in patients with SE who received a lumbar puncture during SE between 2007 and 2014. Status epilepticus cases due to acute structural brain damage, including CNS infection, were excluded. Clinical, biological, therapeutic, and follow-up data were collected. Group comparison between patients stratified according to SE response to antiepileptic drugs (AEDs), disability, and epilepsy outcomes were performed. Twenty-eight patients were considered for the analyses (mean age 56years): 14 patients had abnormally high CSF t-tau level, six patients had abnormally high CSF p-tau level, and only three patients had abnormally low Aβ1-42 level. Cerebrospinal fluid t-tau value was higher in patients who developed a refractory SE compared to patients with seizures controlled by AED. Cerebrospinal fluid t-tau values were positively correlated with SE duration and were higher in patients treated with propofol anesthesia compared to patients that had not received this treatment. Patients with higher CSF t-tau had higher risk of developing disability (OR=32.5, p=0.004) and chronic epilepsy (OR=12; p=0.016) in comparison with patients with lower CSF t-tau level. Our results suggest that CSF t-tau level might be proposed as a biomarker of SE severity and prognosis. Prospective studies are needed to evaluate the effects of propofol on tau pathology in this setting. This article is part of a Special Issue entitled "Status Epilepticus".

2015 - Role of cerebrospinal fluid biomarkers to predict conversion to dementia in patients with mild cognitive impairment: a clinical cohort study [Articolo su rivista]
Tondelli, Manuela; Bedin, Roberta; Chiari, Annalisa; Molinari, Maria Angela; Bonifacio, GUENDALINA BEATRICE; Lelli, Nicoletta; Trenti, Tommaso; Nichelli, Paolo Frigio
abstract

Abstract Background: Cerebrospinal fluid (CSF) levels assessment of Aβ1-42 and Tau proteins may be accurate diagnostic biomarkers for the differentiation of preclinical Alzheimer's disease (AD) from age-associated memory impairment, depression and other forms of dementia in patients with mild cognitive impairment (MCI). The aim of our study was to explore the utility of CSF biomarkers in combination with common cognitive markers as predictors for the risk of AD development, and other forms of dementia, and the time to conversion in community patients with MCI. Methods: A group of 71 MCI patients underwent neurological assessment, extended neuropsychological evaluation, routine blood tests, ApoE determination, and lumbar puncture to dose t-tau, p-tau181, Aβ1-42. We investigated baseline CSF and neuropsychological biomarker patterns according to groups stratified with later diagnoses of AD conversion (MCI-AD), other dementia (MCI-NAD) conversion, or clinical stability (sMCI). Results: Baseline Aβ1-42 CSF levels were significantly lower in MCI-AD patients compared to both sMCI and MCI-NAD. Additionally, p-tau181 was higher in the MCI-AD group compared to sMCI. The MCI-AD subgroup analysis confirmed the role of Aβ1-42 in its predictive role of time to conversion: rapid converters had lower Aβ1-42 levels compared to slow converters. Logistic regression and survival analysis further supported the key predictive role of baseline Aβ1-42 for incipient AD and dementia-free survival. Conclusions: Our results confirm the key role of CSF biomarkers in predicting patient conversion from MCI to dementia. The study suggests that CSF biomarkers may also be reliable in a real world clinical setting.

2015 - TIMP-1 resistant matrix metalloproteinase-9 is the predominant serum active isoform associated with MRI activity in patients with multiple sclerosis [Articolo su rivista]
Trentini, Alessandro; Manfrinato, Maria C.; Castellazzi, Massimiliano; Tamborino, Carmine; Roversi, Gloria; Volta, Carlo A.; Baldi, Eleonora; Tola, Maria R.; Granieri, Enrico; Dallocchio, Franco; Bellini, Tiziana; Fainardi, Enrico; Ferraro, Diana; Bedin, Roberta
abstract

Background: The activity of matrix metalloproteinase-9 (MMP-9) depends on two isoforms, an 82 kDa active MMP-9 modulated by its specific tissue inhibitor (TIMP-1), and a 65 kDa TIMP-1 resistant active MMP-9. The relevance of these two enzymatic isoforms in multiple sclerosis (MS) is still unknown. Objective: To investigate the contribution of the TIMP-1 modulated and resistant active MMP-9 iso-forms to MS pathogenesis. Methods: We measured the serum levels of the 82 kDa and TIMP-1 resistant active MMP-9 isoforms by activity assay systems in 86 relapsing-remitting MS (RRMS) patients, categorized according to clinical and magnetic resonance imaging (MRI) evidence of disease activity, and in 70 inflammatory (OIND) and 69 non-inflammatory (NIND) controls. Results: Serum levels of TIMP-1 resistant MMP-9 were more elevated in MS patients than in OIND and NIND (p < 0.05, p < 0.02, respectively). Conversely, 82 kDa active MMP-9 was higher in NIND than in the OIND and MS patients (p < 0.01 and p < 0.00001, respectively). MRI-active patients had higher levels of TIMP-1 resistant MMP-9 and 82 kDa active MMP-9, than did those with MRI inactive MS (p < 0.01 and p < 0.05, respectively). Conclusion: Our findings suggested that the TIMP-1 resistant MMP-9 seem to be the predominantly active isoform contributing to MS disease activity.

2013 - Cerebrospinal fluid oligoclonal IgM bands predict early conversion to clinically definite multiple sclerosis in patients with Clinically Isolated Syndrome. [Articolo su rivista]
Ferraro, Diana; Simone, ANNA MARIA; Bedin, Roberta; Galli, Veronica; Vitetta, F; Federzoni, L; D'Amico, Roberto; Merelli, E; Nichelli, Paolo Frigio; Sola, P.
abstract

We reviewed the records of 391 patients who had presented with a Clinically Isolated Syndrome and selected 205 who had performed a baseline spinal tap and MRI scan. We studied cerebrospinal fluid (CSF) and serum IgM oligoclonal bands (IgMOB) using agarose gel isoelectric focusing and analyzed the impact of baseline clinical, MRI and CSF variables on the risk of conversion to clinically definite multiple sclerosis, i.e. on the risk of a clinical relapse. At survival analysis, a lower age at onset, an onset with optic neuritis and the presence of CSF-restricted IgMOB increased the risk of a relapse. Only the presence of CSF-restricted IgMOB predicted a relapse within one year.

2011 - Primary progressive versus relapsing-onset multiple sclerosis: presence and prognostic value of cerebrospinal fluid oligoclonal IgM [Articolo su rivista]
P., Sola; Mandrioli, Jessica; Simone, ANNA MARIA; Ferraro, Diana; Bedin, Roberta; R., Annecca; Venneri, Maria Grazia; Nichelli, Paolo Frigio; E., Merelli
abstract

Background: There is increasing evidence on cerebrospinal fluid (CSF) oligoclonal IgM (OCIgM) predicting a more aggressive disease course in relapsing-remitting Multiple Sclerosis (MS), while there is a scarcity of data for primary progressive MS (PPMS). Objective: Our aim was to investigate the presence and possible prognostic value of CSF OCIgM in a group of PPMS and in a group of relapsing-onset MS patients. The possible prognostic role of other clinical and biological factors was also evaluated. Methods: We calculated the impact of single clinical and biological factors, including CSF OCIgM at onset, on the probability of reaching an Expanded Disability Status Scale of 3 and 4 in 45 PPMS and 104 relapsing-onset MS patients. Results: CSF OCIgM were found in only 13% of PPMS patients and did not influence the time taken to reach an Expanded Disability Status Scale of 3 and 4. Conversely, they were present in 46% of relapsing-onset MS patients and increased the risk of reaching an Expanded Disability Status Scale of 4. Clinical factors with a negative prognostic value in PPMS were age at onset <30 years and onset with pyramidal symptoms, while onset with sensory symptoms in relapsing-onset MS predicted a more favourable course. Conclusion: This study confirms that, in relapsing-onset MS patients, the presence of CSF OCIgM at onset predicts a worse disease course. In the cohort of PPMS patients, however, CSF OCIgM were rare, suggesting that heterogeneous pathogenetic mechanisms may be involved in the different MS forms.