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Jessica MANDRIOLI
Professore Ordinario
Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze sede ex-Neuroscienze
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Pubblicazioni
2024
- SerpinA1 levels in amyotrophic lateral sclerosis patients: An exploratory study
[Articolo su rivista]
Martinelli, Ilaria; Zucchi, Elisabetta; Simonini, Cecilia; Gianferrari, Giulia; Bedin, Roberta; Biral, Chiara; Ghezzi, Andrea; Fini, Nicola; Carra, Serena; Mandrioli, Jessica
abstract
Background: SerpinA1, a serine protease inhibitor, is involved in the modulation of microglial-mediated inflammation in neurodegenerative diseases. We explored SerpinA1 levels in cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients to understand its potential role in the pathogenesis of the disease. Methods: SerpinA1, neurofilament light (NfL) and heavy (NfH) chain, and chitinase-3-like protein-1 (CHI3L1) were determined in CSF and serum of ALS patients (n = 110) and healthy controls (n = 10) (automated next-generation ELISA), and correlated with clinical parameters, after identifying three classes of progressors (fast, intermediate, slow). Biomarker levels were analyzed for diagnostic power and association with progression and survival. Results: SerpinA1serum was significantly decreased in ALS (median: 1032 μg/mL) compared with controls (1343 μg/mL) (p = 0.02). SerpinA1CSF was elevated only in fast progressors (8.6 μg/mL) compared with slow (4.43 μg/mL, p = 0.01) and intermediate (4.42 μg/mL, p = 0.03) progressors. Moreover, SerpinA1CSF correlated with neurofilament and CHI3L1 levels in CSF. Contrarily to SerpinA1CSF , neurofilament and CHI3L1 concentrations in CSF correlated with measures of disease progression in ALS, while SerpinA1serum mildly related with time to generalization (rho = 0.20, p = 0.04). In multivariate analysis, the ratio between serum and CSF SerpinA1 (SerpinA1 ratio) and NfHCSF were independently associated with survival. Conclusions: Higher SerpinA1CSF levels are found in fast progressors, suggesting SerpinA1 is a component of the neuroinflammatory mechanisms acting upon fast-progressing forms of ALS. Both neurofilaments or CHI3L1CSF levels outperformed SerpinA1 at predicting disease progression rate in our cohort, and so the prognostic value of SerpinA1 alone as a measure remains inconclusive.
2024
- Therapeutic potential of stilbenes in neuropsychiatric and neurological disorders: A comprehensive review of preclinical and clinical evidence
[Articolo su rivista]
Socała, Katarzyna; Żmudzka, Elżbieta; Lustyk, Klaudia; Zagaja, Mirosław; Brighenti, Virginia; Costa, Anna Maria; Andres-Mach, Marta; Pytka, Karolina; Martinelli, Ilaria; Mandrioli, Jessica; Pellati, Federica; Biagini, Giuseppe; Wlaź, Piotr
abstract
: Neuropsychiatric disorders are anticipated to be a leading health concern in the near future, emphasizing an outstanding need for the development of new effective therapeutics to treat them. Stilbenes, with resveratrol attracting the most attention, are an example of multi-target compounds with promising therapeutic potential for a broad array of neuropsychiatric and neurological conditions. This review is a comprehensive summary of the current state of research on stilbenes in several neuropsychiatric and neurological disorders such as depression, anxiety, schizophrenia, autism spectrum disorders, epilepsy, traumatic brain injury, and neurodegenerative disorders. We describe and discuss the results of both in vitro and in vivo studies. The majority of studies concentrate on resveratrol, with limited findings exploring other stilbenes such as pterostilbene, piceatannol, polydatin, tetrahydroxystilbene glucoside, or synthetic resveratrol derivatives. Overall, although extensive preclinical studies show the potential benefits of stilbenes in various central nervous system disorders, clinical evidence on their therapeutic efficacy is largely missing.
2023
- A Variant in TBCD Associated with Motoneuronopathy and Corpus Callosum Hypoplasia: A Case Report
[Articolo su rivista]
Caputo, M.; Martinelli, I.; Fini, N.; Gianferrari, G.; Simonini, C.; Trovato, R.; Santorelli, F. M.; Tessa, A.; Mandrioli, J.; Zucchi, E.
abstract
Mutations in the tubulin-specific chaperon D (TBCD) gene, involved in the assembly and disassembly of the α/β-tubulin heterodimers, have been reported in early-onset progressive neurodevelopment regression, with epilepsy and mental retardation. We describe a rare homozygous variant in TBCD, namely c.881G>A/p.Arg294Gln, in a young woman with a phenotype dominated by distal motorneuronopathy and mild mental retardation, with neuroimaging evidence of corpus callosum hypoplasia. The peculiar phenotype is discussed in light of the molecular interpretation, enriching the literature data on tubulinopathies generated from TBCD mutations.
2023
- Correction to: Italian version of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS): validation and longitudinal performance (Journal of Neurology, (2023), 270, 3, (1452-1456), 10.1007/s00415-022-11483-3)
[Articolo su rivista]
Fortuna, A.; Sabbatini, D.; Frigo, A.; Bello, L.; Calvi, F.; Blasi, L.; Gianferrari, G.; Martinelli, I.; Minicuci, G.; Pegoraro, E.; Mandrioli, J.; Soraru, G.
abstract
The original version of this article unfortunately contained a mistake. The affiliation details for Author ‘’Jessica Mandrioli’’ were incorrectly given as ‘’Neuromuscular Center, S. Bortolo Hospital, Vicenza, Italy’’ but should have been: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy Department of Neuroscience, Neurology Unit, S. Agostino Estense Hospital, Azienda Ospedaliero Universitaria di Modena, Modena, Italy.
2023
- Correction to: Retrospective observational study on the use of acetyl-L-carnitine in ALS
[Articolo su rivista]
Sassi, Serena; Bianchi, Elisa; Diamanti, Luca; Tornabene, Danilo; Sette, Elisabetta; Medici, Doriana; Matà, Sabrina; Leccese, Deborah; Sperti, Martina; Martinelli, Ilaria; Ghezzi, Andrea; Mandrioli, Jessica; Iuzzolino, Valentina Virginia; Dubbioso, Raffaele; Trojsi, Francesca; Passaniti, Carla; D'Alvano, Giulia; Filosto, Massimiliano; Padovani, Alessandro; Mazzini, Letizia; De Marchi, Fabiola; Zinno, Lucia; Nuredini, Andi; Bongioanni, Paolo; Dolciotti, Cristina; Canali, Elena; Toschi, Giulia; Petrucci, Antonio; Perna, Alessia; Riso, Vittorio; Inghilleri, Maurizio; Libonati, Laura; Cambieri, Chiara; Pupillo, Elisabetta
abstract
2023
- Effect of RNS60 in amyotrophic lateral sclerosis: a phase II multicentre, randomized, double-blind, placebo-controlled trial
[Articolo su rivista]
Beghi, Ettore; Pupillo, Elisabetta; Bianchi, Elisa; Bonetto, Valentina; Luotti, Silvia; Pasetto, Laura; Bendotti, Caterina; Tortarolo, Massimo; Sironi, Francesca; Camporeale, Laura; Sherman, Alexander V; Paganoni, Sabrina; Scognamiglio, Ada; De Marchi, Fabiola; Bongioanni, Paolo; Del Carratore, Renata; Caponnetto, Claudia; Diamanti, Luca; Martinelli, Daniele; Calvo, Andrea; Filosto, Massimiliano; Padovani, Alessandro; Piccinelli, Stefano Cotti; Ricci, Claudia; Dalla Giacoma, Stefania; De Angelis, Nicoletta; Inghilleri, Maurizio; Spataro, Rossella; La Bella, Vincenzo; Logroscino, Giancarlo; Lunetta, Christian; Tarlarini, Claudia; Mandrioli, Jessica; Martinelli, Ilaria; Simonini, Cecilia; Zucchi, Elisabetta; Monsurrò, Maria Rosaria; Ricciardi, Dario; Trojsi, Francesca; Riva, Nilo; Filippi, Massimo; Simone, Isabella Laura; Sorarù, Gianni; Spera, Cristina; Florio, Lucia; Messina, Sonia; Russo, Massimo; Siciliano, Gabriele; Conte, Amelia; Saddi, Maria Valeria; Carboni, Nicola; Mazzini, Letizia
abstract
Background and purpose Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. RNS60 is an immunomodulatory and neuroprotective investigational product that has shown efficacy in animal models of ALS and other neurodegenerative diseases. Its administration has been safe and well tolerated in ALS subjects in previous early phase trials. Methods This was a phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial. Participants diagnosed with definite, probable or probable laboratory-supported ALS were assigned to receive RNS60 or placebo administered for 24 weeks intravenously (375 ml) once a week and via nebulization (4 ml/day) on non-infusion days, followed by an additional 24 weeks off-treatment. The primary objective was to measure the effects of RNS60 treatment on selected biomarkers of inflammation and neurodegeneration in peripheral blood. Secondary objectives were to measure the effect of RNS60 on functional impairment (ALS Functional Rating Scale-Revised), a measure of self-sufficiency, respiratory function (forced vital capacity, FVC), quality of life (ALS Assessment Questionnaire-40, ALSAQ-40) and survival. Tolerability and safety were assessed. Results Seventy-four participants were assigned to RNS60 and 73 to placebo. Assessed biomarkers did not differ between arms. The mean rate of decline in FVC and the eating and drinking domain of ALSAQ-40 was slower in the RNS60 arm (FVC, difference 0.41 per week, standard error 0.16, p = 0.0101; ALSAQ-40, difference -0.19 per week, standard error 0.10, p = 0.0319). Adverse events were similar in the two arms. In a post hoc analysis, neurofilament light chain increased over time in bulbar onset placebo participants whilst remaining stable in those treated with RNS60. Conclusions The positive effects of RNS60 on selected measures of respiratory and bulbar function warrant further investigation.
2023
- Effect of tauroursodeoxycholic acid on survival and safety in amyotrophic lateral sclerosis: a retrospective population-based cohort study
[Articolo su rivista]
Zucchi, E.; Musazzi, U. M.; Fedele, G.; Martinelli, I.; Gianferrari, G.; Simonini, C.; Fini, N.; Ghezzi, A.; Caputo, M.; Sette, E.; Vacchiano, V.; Zinno, L.; Anceschi, P.; Canali, E.; Vinceti, M.; Ferro, S.; Mandrioli, J.; Ferri, L.; Gessani, A.; Liguori, R.; Cortelli, P.; Michelucci, R.; Salvi, F.; Bartolomei, I.; Borghi, A. M.; Zini, A.; Rinaldi, R.; Tugnoli, V.; Pugliatti, M.; Codeluppi, L.; Valzania, F.; Stragliati, F.; Nuredini, A.; Romano, S.; D'Orsi, A.; Parrino, L.; Medici, D.; Pilurzi, G.; Terlizzi, E.; Guidetti, D.; De Pasqua, S.; Santangelo, M.; De Massis, P.; Gizzi, M.; Casmiro, M.; Querzani, P.; Morresi, S.; Vitiello, M.; Longoni, M.; Patuelli, A.; Malagu, S.; Bianchi, F.; Dossi, M. C.; Ganino, C.
abstract
Background: Oral tauroursodeoxycholic acid (TUDCA) is a commercial drug currently tested in patients with amyotrophic lateral sclerosis (ALS) both singly and combined with sodium phenylbutyrate. This retrospective study aimed to investigate, in a real-world setting, whether TUDCA had an impact on the overall survival of patients with ALS who were treated with this drug compared to those patients who received standard care only. Methods: This propensity score–matched study was conducted in the Emilia Romagna Region (Italy), which has had an ALS regional registry since 2009. Out of 627 patients with ALS diagnosed from January 1st, 2015 to June 30th, 2021 and recorded in the registry with available information on death/tracheostomy, 86 patients took TUDCA and were matched in a 1:2 ratio with patients who received only usual care according to age at onset, sex, phenotype, diagnostic latency, ALS Functional Rating Scale-Revised (ALSFRS-R) at first visit, disease progression rate at first visit, and BMI at diagnosis. The primary outcome was survival difference (time from onset of symptoms to tracheostomy/death) between TUDCA exposed and unexposed patients. Findings: A total of 86 patients treated with TUDCA were matched to 172 patients who did not receive treatment. TUDCA-exposed patients were stratified based on dosage (less than or equal to 1000 mg/day or greater) and duration (less than or equal to 12 months or longer) of treatment. The median overall survival was 49.6 months (95% CI 41.7–93.5) among those treated with TUDCA and 36.2 months (95% CI 32.7–41.6) in the control group, with a reduced risk of death observed in patients exposed to a higher dosage (defined as ≥ 1000 mg/day) of TUDCA (HR 0.56; 95% CI 0.38–0.83; p = 0.0042) compared to both the control group and those with lower TUDCA dosages (defined as < 1000 mg/day). TUDCA was generally well-tolerated, except for a minority of patients (n = 7, 8.1%) who discontinued treatment due to side effects, primarily gastrointestinal and mild in severity; only 2 adverse events required hospital access but resolved without sequelae. Interpretation: In this population-based exploratory study, patients with ALS who were treated with TUDCA may have prolonged survival compared to patients receiving standard care only. Additional prospective randomized studies are needed to confirm the efficacy and safety of this drug. Funding: Emilia-Romagna Region.
2023
- Factors predicting disease progression in C9ORF72 ALS patients
[Articolo su rivista]
Mandrioli, Jessica; Zucchi, Elisabetta; Martinelli, Ilaria; Van der Most, Laura; Gianferrari, Giulia; Moglia, Cristina; Manera, Umberto; Solero, Luca; Vasta, Rosario; Canosa, Antonio; Grassano, Maurizio; Brunetti, Maura; Mazzini, Letizia; De Marchi, Fabiola; Simonini, Cecilia; Fini, Nicola; Tupler, Rossella; Vinceti, Marco; Chiò, Adriano; Calvo, Andrea
abstract
Objective To unveil clinical features, comorbidities, disease progression and prognostic factors in a population-based cohort of ALS patients carrying C9ORF72 expansion (C9 + ALS). Methods This is a retrospective observational study on ALS patients residing in Emilia Romagna and Piedmont-Valle D'Aosta regions whose data are available through population based registers. We analysed patients who underwent genetic testing, focusing on C9 + ALS subgroup. Results Among 2204 genotyped patients of the two registers, 150 were C9 + ALS. In comparison with patients without mutation, a higher proportion of family history (12.85 vs 68%, p < 0.001) and frontotemporal dementia (3.93% vs 10.67%, p < 0.001) was detected in C9 + ALS. C9 + ALS presented a faster disease progression as measured by monthly decline in ALS Functional Rating Scale-Revised (1.86 +/- 3.30 vs 1.45 +/- 2.35, p < 0.01) and in forced vital capacity (5.90 +/- 5.24 vs 2.97 +/- 3.47, p < 0.01), a shorter diagnostic delay (8.93 +/- 6.74 vs 12.68 +/- 12.86 months, p < 0.01) and earlier onset (58.91 +/- 9.02 vs 65.04 +/- 11.55 years, p < 0.01). Consistently, they reached death or tracheostomy earlier than other patients (31 vs 37 months, HR = 1.52, 95% C.I. 1.27-1.82, p < 0.001). With respect to other genotyped patients, C9 + ALS patients did not present a significantly higher prevalence of concomitant diseases. Independent prognostic factors of survival of C9 + ALS included sex, age, progression rate, presence of frontotemporal dementia and thyroid disorders, with the latter being associated with prolonged ALS survival (43 vs 29 months, HR = 0.42, 95% C.I. 0.24-0.74, p = 0.003). Conclusion Even in the context of a more aggressive disease, C9 + ALS had a longer survival in presence of thyroid disorders. This finding may suggest protective pathogenic pathways in C9 + ALS to be explored, looking for therapeutic strategies to slow disease course.
2023
- Human microglia synthesize neurosteroids to cope with rotenone-induced oxidative stress
[Articolo su rivista]
Lucchi, Chiara; Codeluppi, Alessandro; Filaferro, Monica; Vitale, Giovanni; Rustichelli, Cecilia; Avallone, Rossella; Mandrioli, Jessica; Biagini, Giuseppe
abstract
We obtained evidence that mouse BV2 microglia synthesize neurosteroids dynamically to modify neurosteroid levels in response to oxidative damage caused by rotenone. Here, we evaluated whether neurosteroids could be produced and altered in response to rotenone by the human microglial clone 3 (HMC3) cell line. To this aim, HMC3 cultures were exposed to rotenone (100 nM) and neurosteroids were measured in the culture medium by liquid chromatography with tandem mass spectrometry. Microglia reactivity was evaluated by measuring interleukin 6 (IL-6) levels, whereas cell viability was monitored by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. After 24 hours (h), rotenone increased IL-6 and reactive oxygen species levels by approximately +37% over the baseline, without affecting cell viability; however, microglia viability was significantly reduced at 48 h (p < 0.01). These changes were accompanied by the downregulation of several neurosteroids, including pregnenolone, pregnenolone sulfate, 5α-dihydroprogesterone, and pregnanolone, except for allopregnanolone, which instead was remarkably increased (p < 0.05). Interestingly, treatment with exogenous allopregnanolone (1 nM) efficiently prevented the reduction in HMC3 cell viability. In conclusion, this is the first evidence that human microglia can produce allopregnanolone and that this neurosteroid is increasingly released in response to oxidative stress, to tentatively support the microglia's survival.
2023
- Insight into Elderly ALS Patients in the Emilia Romagna Region: Epidemiological and Clinical Features of Late-Onset ALS in a Prospective, Population-Based Study
[Articolo su rivista]
Gianferrari, Giulia; Martinelli, Ilaria; Simonini, Cecilia; Zucchi, Elisabetta; Fini, Nicola; Caputo, Maria; Ghezzi, Andrea; Gessani, Annalisa; Canali, Elena; Casmiro, Mario; De Massis, Patrizia; Curro' Dossi, Marco; De Pasqua, Silvia; Liguori, Rocco; Longoni, Marco; Medici, Doriana; Morresi, Simonetta; Patuelli, Alberto; Pugliatti, Maura; Santangelo, Mario; Sette, Elisabetta; Stragliati, Filippo; Terlizzi, Emilio; Vacchiano, Veria; Zinno, Lucia; Ferro, Salvatore; Amedei, Amedeo; Filippini, Tommaso; Vinceti, Marco; Errals Group, Null; Mandrioli, Jessica
abstract
: Few studies have focused on elderly (>80 years) amyotrophic lateral sclerosis (ALS) patients, who represent a fragile subgroup generally not included in clinical trials and often neglected because they are more difficult to diagnose and manage. We analyzed the clinical and genetic features of very late-onset ALS patients through a prospective, population-based study in the Emilia Romagna Region of Italy. From 2009 to 2019, 222 (13.76%) out of 1613 patients in incident cases were over 80 years old at diagnosis, with a female predominance (F:M = 1.18). Elderly ALS patients represented 12.02% of patients before 2015 and 15.91% from 2015 onwards (p = 0.024). This group presented with bulbar onset in 38.29% of cases and had worse clinical conditions at diagnosis compared to younger patients, with a lower average BMI (23.12 vs. 24.57 Kg/m2), a higher progression rate (1.43 vs. 0.95 points/month), and a shorter length of survival (a median of 20.77 vs. 36 months). For this subgroup, genetic analyses have seldom been carried out (25% vs. 39.11%) and are generally negative. Finally, elderly patients underwent less frequent nutritional- and respiratory-supporting procedures, and multidisciplinary teams were less involved at follow-up, except for specialist palliative care. The genotypic and phenotypic features of elderly ALS patients could help identify the different environmental and genetic risk factors that determine the age at which disease onset occurs. Since multidisciplinary management can improve a patient's prognosis, it should be more extensively applied to this fragile group of patients.
2023
- Interplay of Metallome and Metabolome in Amyotrophic Lateral Sclerosis: A Study on Cerebrospinal Fluid of Patients Carrying Disease-Related Gene Mutations
[Articolo su rivista]
Solovyev, N.; Lucio, M.; Mandrioli, J.; Forcisi, S.; Kanawati, B.; Uhl, J.; Vinceti, M.; Schmitt-Kopplin, P.; Michalke, B.
abstract
2023
- Italian version of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS): validation and longitudinal performance
[Articolo su rivista]
Fortuna, A.; Sabbatini, D.; Frigo, A.; Bello, L.; Calvi, F.; Blasi, L.; Gianferrari, G.; Martinelli, I.; Minicuci, G.; Pegoraro, E.; Mandrioli, J.; Soraru, G.
abstract
Objective: To validate an Italian version of the Rasch-Built Overall ALS Disability Scale (ROADS) in a broad population of patients and assess its longitudinal performance over time. Methods: 270 ALS patients referring to the Motor Neuron Disease Clinic of the University of Padova and Modena (Italy) accepted to compile the Italian version of the ROADS and results were correlated with the ALSFRSr and ALSAQ-40 scores, FVC values, and creatinine or albumin blood levels. To verify test–retest reliability, patients were asked to fill in a second copy of the scale within 5–7 days. Thirty-nine patients compiled a further copy of questionnaire during the follow up visit (after 133 days on average) which allowed us a longitudinal assessment of the scale. Results: We found a good external construct validity between ROADS and either ALSFRS-R (correlation coefficient = 0.85) or ALSAQ-40 (correlation coefficient = − 0.84). Test–retest reliability was excellent with a concordance-correlation coefficient of 0.93. Yet, we observed a significant correlation between changes over time of the ROADS normalised sum score (− 2.18 point loss per month) and those of both the ALSFRS-R (positive correlation; Rho = 0.64, p ≤ 0.0001) or the ALSAQ-40 (negative correlation; Rho = − 0.60, p = 0.014). Conclusions: The Italian version of ROADS proved to be a reliable marker to monitor overall disability in ALS patients. Further studies are necessary to assess its longitudinal performance.
2023
- Predictors for progression in amyotrophic lateral sclerosis associated to SOD1 mutation: insight from two population-based registries
[Articolo su rivista]
Martinelli, Ilaria; Ghezzi, Andrea; Zucchi, Elisabetta; Gianferrari, Giulia; Ferri, Laura; Moglia, Cristina; Manera, Umberto; Solero, Luca; Vasta, Rosario; Canosa, Antonio; Grassano, Maurizio; Brunetti, Maura; Mazzini, Letizia; De Marchi, Fabiola; Simonini, Cecilia; Fini, Nicola; Vinceti, Marco; Pinti, Marcello; Chiò, Adriano; Calvo, Andrea; Mandrioli, Jessica
abstract
BackgroundUncovering distinct features and trajectories of amyotrophic lateral sclerosis (ALS) associated with SOD1 mutations (SOD1-ALS) can provide valuable insights for patient' counseling and stratification for trials, and interventions timing. Our study aims to pinpoint distinct clinical characteristics of SOD1-ALS by delving into genotype-phenotype correlations and factors that potentially impact disease progression.MethodsThis is a retrospective observational study of a SOD1-ALS cohort from two Italian registers situated in the regions of Emilia-Romagna, Piedmont and Valle d'Aosta.ResultsOut of 2204 genotyped ALS patients, 2.5% carried SOD1 mutations, with a M:F ratio of 0.83. SOD1-ALS patients were younger, and more frequently reported a family history of ALS and/or FTD. SOD1-ALS had a longer survival compared to patients without ALS-associated gene mutations. However, here was considerable variability in survival across distinct SOD1 mutations, with an average survival of less than a year for the L39V, G42S, G73S, D91N mutations. Among SOD1-ALS, multivariate analysis showed that, alongside established clinical prognostic factors such as advanced age at onset and high progression rate at diagnosis, mutations located in exon 2 or within highly conserved gene positions predicted worse survival. Conversely, among comorbidities, cancer history was independently associated with longer survival.InterpretationWithin the context of an overall slower disease, SOD1-ALS exhibits some degree of heterogeneity linked to the considerable genetic diversity arising from the multitude of potential mutations sites and specific clinical prognostic factors, including cancer history. Revealing the factors that modulate the phenotypic heterogeneity of SOD1-ALS could prove advantageous in improving the efficacy of upcoming therapeutic approaches.
2023
- Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis
[Articolo su rivista]
Mandrioli, J.; D'Amico, R.; Zucchi, E.; De Biasi, S.; Banchelli, F.; Martinelli, I.; Simonini, C.; Lo Tartaro, D.; Vicini, R.; Fini, N.; Gianferrari, G.; Pinti, M.; Lunetta, C.; Gerardi, F.; Tarlarini, C.; Mazzini, L.; De Marchi, F.; Scognamiglio, A.; Soraru, G.; Fortuna, A.; Lauria, G.; Bella, E. D.; Caponnetto, C.; Meo, G.; Chio, A.; Calvo, A.; Cossarizza, A.
abstract
In preclinical studies rapamycin was found to target neuroinflammation, by expanding regulatory T cells, and affecting autophagy, two pillars of amyotrophic lateral sclerosis (ALS) pathogenesis. Herein we report a multicenter, randomized, double-blind trial, in 63 ALS patients who were randomly assigned in a 1:1:1 ratio to receive rapamycin 2 mg/m2/day,1 mg/m2/day or placebo (EUDRACT 2016-002399-28; NCT03359538). The primary outcome, the number of patients exhibiting an increase >30% in regulatory T cells from baseline to treatment end, was not attained. Secondary outcomes were changes from baseline of T, B, NK cell subpopulations, inflammasome mRNA expression and activation status, S6-ribosomal protein phosphorylation, neurofilaments; clinical outcome measures of disease progression; survival; safety and quality of life. Of the secondary outcomes, rapamycin decreased mRNA relative expression of the pro-inflammatory cytokine IL-18, reduced plasmatic IL-18 protein, and increased the percentage of classical monocytes and memory switched B cells, although no corrections were applied for multiple tests. In conclusion, we show that rapamycin treatment is well tolerated and provides reassuring safety findings in ALS patients, but further trials are necessary to understand the biological and clinical effects of this drug in ALS.
2023
- Retrospective observational study on the use of acetyl-l-carnitine in ALS
[Articolo su rivista]
Sassi, S.; Bianchi, E.; Diamanti, L.; Tornabene, D.; Sette, E.; Medici, D.; Mata, S.; Leccese, D.; Sperti, M.; Martinelli, I.; Ghezzi, A.; Mandrioli, J.; Iuzzolino, V. V.; Dubbioso, R.; Trojsi, F.; Passaniti, C.; D'Alvano, G.; Filosto, M.; Padovani, A.; Mazzini, L.; De Marchi, F.; Zinno, L.; Nuredini, A.; Bongioanni, P.; Dolciotti, C.; Canali, E.; Toschi, G.; Petrucci, A.; Perna, A.; Riso, V.; Inghilleri, M.; Libonati, L.; Cambieri, C.; Pupillo, E.
abstract
ALCAR (Acetyl-L-carnitine) is a donor of acetyl groups and increases the intracellular levels of carnitine, the primary transporter of fatty acids across the mitochondrial membranes. In vivo studies showed that ALCAR decrease oxidative stress markers and pro-inflammatory cytokines. In a previous double-blind placebo-controlled phase II trial showed positive effects on self-sufficiency (defined as a score of 3+ on the ALSFRS-R items for swallowing, cutting food and handling utensils, and walking) ALSFRS-R total score and FVC. We conducted an observational, retrospective, multicentre, case–control study to provide additional data on the effects of ALCAR in subjects with ALS in Italy. Subjects treated with ALCAR 1.5 g/day or 3 g/day were included and matched with not treated subjects by sex, age at diagnosis, site of onset, and time from diagnosis to baseline, (45 subjects per group). ALCAR 3 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 23 (51.1%) treated subjects (adj. OR 1.18, 95% CI 0.46–3.02). No statistically significant differences were detected in ALSFRS nor FVC nor self-sufficiency. ALCAR 1.5 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 32 (71.1%) treated subjects (adj. OR 0.27, 95% CI 0.10–0.71). For ALSFRS-R, a mean slope of − 1.0 was observed in treated subjects compared to − 1.4 in those not treated (p = 0.0575). No statistically significant difference was detected in the FVC nor self-sufficiency. Additional evidence should be provided to confirm the efficacy of the drug and provide a rationale for the dosage.
2023
- Targeting the NEDP1 enzyme to ameliorate ALS phenotypes through stress granule disassembly
[Articolo su rivista]
Kassouf, Toufic; Shrivastava, Rohit; Meszka, Igor; Bailly, Aymeric; Polanowska, Jolanta; Trauchessec, Helene; Mandrioli, Jessica; Carra, Serena; Xirodimas, Dimitris P
abstract
The elimination of aberrant inclusions is regarded as a therapeutic approach in neurodegeneration. In amyotro-phic lateral sclerosis (ALS), mutations in proteins found within cytoplasmic condensates called stress granules (SGs) are linked to the formation of pathological SGs, aberrant protein inclusions, and neuronal toxicity. We found that inhibition of NEDP1, the enzyme that processes/deconjugates the ubiquitin-like molecule NEDD8, promotes the disassembly of physiological and pathological SGs. Reduction in poly(ADP-ribose) polymerase1 activity through hyper-NEDDylation is a key mechanism for the observed phenotype. These effects are related to improved cell survival in human cells, and in C. elegans, nedp1 deletion ameliorates ALS phenotypes related to animal motility. Our studies reveal NEDP1 as potential therapeutic target for ALS, correlated to the disassembly of pathological SGs.
2023
- The HFE p.H63D (p.His63Asp) Polymorphism Is a Modifier of ALS Outcome in Italian and French Patients with SOD1 Mutations
[Articolo su rivista]
Canosa, A.; Calvo, A.; Mora, G.; Moglia, C.; Brunetti, M.; Barberis, M.; Borghero, G.; Caponnetto, C.; Trojsi, F.; Spataro, R.; Volanti, P.; Simone, I. L.; Salvi, F.; Logullo, F. O.; Riva, N.; Tremolizzo, L.; Giannini, F.; Mandrioli, J.; Tanel, R.; Murru, M. R.; Mandich, P.; Conforti, F. L.; Zollino, M.; Sabatelli, M.; Tarlarini, C.; Lunetta, C.; Mazzini, L.; D’Alfonso, S.; Guy, N.; Meininger, V.; Clavelou, P.; Camu, W.; Chiò, A.
abstract
Background: Data from published studies about the effect of HFE polymorphisms on ALS risk, phenotype, and survival are still inconclusive. We aimed at evaluating whether the p.H63D polymorphism is a modifier of phenotype and survival in SOD1-mutated patients. Methods: We included 183 SOD1-mutated ALS patients. Mutations were classified as severe or mild according to the median survival of the study population. Patients were screened for the HFE p.H63D polymorphism. Survival was calculated using the Kaplan-Meier modeling, and differences were measured by the log-rank test. Multivariable analysis was performed with the Cox proportional hazards model (stepwise backward). Results: SOD1 severe mutation carriers show more frequent familial history for ALS and shorter survival compared to mild mutation carriers. Carriers and non-carriers of the p.H63D polymorphism did not differ in terms of sex ratio, frequency of positive familial history, age at onset, and bulbar/spinal ratio. In univariate and in Cox multivariable analysis using sex, age at onset, site of onset, family history, country of origin, and mutation severity as covariates, p.H63D carriers had a longer survival (p = 0.034 and p = 0.004). Conclusions: We found that SOD1-mutated ALS patients carrying the p.H63D HFE polymorphism have a longer survival compared to non-carriers, independently of sex, age and site of onset, family history, nation of origin, and severity of mutations, suggesting a possible role as disease progression modifier for the p.H63D HFE polymorphism in SOD1-ALS.
2023
- The landscape of cognitive impairment in superoxide dismutase 1-amyotrophic lateral sclerosis
[Articolo su rivista]
Martinelli, I.; Zucchi, E.; Simonini, C.; Gianferrari, G.; Zamboni, G.; Pinti, M.; Mandrioli, J.
abstract
Although mutations in the superoxide dismutase 1 gene account for only a minority of total amyotrophic lateral sclerosis cases, the discovery of this gene has been crucial for amyotrophic lateral sclerosis research. Since the identification of superoxide dismutase 1 in 1993, the field of amyotrophic lateral sclerosis genetics has considerably widened, improving our understanding of the diverse pathogenic basis of amyotrophic lateral sclerosis. In this review, we focus on cognitive impairment in superoxide dismutase 1-amyotrophic lateral sclerosis patients. Literature has mostly reported that cognition remains intact in superoxide dismutase 1-amyotrophic lateral sclerosis patients, but recent reports highlight frontal lobe function frailty in patients carrying different superoxide dismutase 1-amyotrophic lateral sclerosis mutations. We thoroughly reviewed all the various mutations reported in the literature to contribute to a comprehensive database of superoxide dismutase 1-amyotrophic lateral sclerosis genotype-phenotype correlation. Such a resource could ultimately improve our mechanistic understanding of amyotrophic lateral sclerosis, enabling a more robust assessment of how the amyotrophic lateral sclerosis phenotype responds to different variants across genes, which is important for the therapeutic strategy targeting genetic mutations. Cognition in superoxide dismutase 1-amyotrophic lateral sclerosis deserves further longitudinal research since this peculiar frailty in patients with similar mutations can be conditioned by external factors, including environment and other unidentified agents including modifier genes.
2023
- Unique cerebrospinal fluid peptides: potential amyotrophic lateral sclerosis biomarkers and etiological factors
[Articolo su rivista]
Wormser, Uri; Sintov, Amnon; Vinceti, Marco; Mandrioli, Jessica; Brodsky, Berta; Proscura, Elena; Finkelstein, Yoram
abstract
2023
- Withdrawal of mechanical ventilation in amyotrophic lateral sclerosis patients: a multicenter Italian survey
[Articolo su rivista]
Moglia, C.; Palumbo, F.; Veronese, S.; Angelocola, S.; Barone, P.; Bartolomei, I.; Bersano, E.; Bombaci, A.; Borghero, G.; Cabras, S.; Cambieri, C.; Canali, E.; Canosa, A.; Capasso, M.; Caponnetto, C.; Cardinali, P.; Casmiro, M.; Ceccanti, M.; Chio, A.; Consonni, M.; Dalla Bella, E.; De Marchi, F.; De Mattei, F.; D'Errico, E.; Di Pede, F.; Diamanti, L.; Dubbioso, R.; Filippi, M.; Filosto, M.; Fini, N.; Gianferrari, G.; Grassano, M.; Inghilleri, M.; La Bella, V.; Lauria Pinter, G.; Libonati, L.; Logullo, F.; Mandrioli, J.; Manera, U.; Martinelli, I.; Martusciello, G.; Mata, S.; Matteoni, E.; Mazzini, L.; Medici, D.; Miniello, S.; Moret, F.; Nozzoli, C.; Piccirillo, G.; Pilurzi, G.; Riva, N.; Romito, S.; Russo, M.; Salvi, F.; Sette, E.; Silani, V.; Simone, I. L.; Simonini, C.; Spataro, R.; Squintani, G.; Stano, S.; Tanel, R.; Tedeschi, G.; Ticozzi, N.; Toriello, A.; Tremolizzo, L.; Trojsi, F.; Vacchiano, V.; Vasta, R.; Volanti, P.; Zinno, L.; Zucchi, E.; Calvo, A.
abstract
Background: Law 219/2017 was approved in Italy in December 2017, after a years-long debate on the autonomy of healthcare choices. This Law, for the first time in Italian legislation, guarantees the patient’s right to request for withdrawal of life-sustaining treatments, including mechanical ventilation (MV). Objective: To investigate the current status of MV withdrawal in amyotrophic lateral sclerosis (ALS) patients in Italy and to assess the impact of Law 219/2017 on this practice. Methods: We conducted a Web-based survey, addressed to Italian neurologists with expertise in ALS care, and members of the Motor Neuron Disease Study Group of the Italian Society of Neurology. Results: Out of 40 ALS Italian centers, 34 (85.0%) responded to the survey. Law 219/2017 was followed by an increasing trend in MV withdrawals, and a significant increase of neurologists involved in this procedure (p 0.004). However, variations across Italian ALS centers were observed, regarding the inconsistent involvement of community health services and palliative care (PC) services, and the intervention and composition of the multidisciplinary team. Conclusions: Law 219/2017 has had a positive impact on the practice of MV withdrawal in ALS patients in Italy. The recent growing public attention on end-of-life care choices, along with the cultural and social changes in Italy, requires further regulatory frameworks that strengthen tools for self-determination, increased investment of resources in community and PC health services, and practical recommendations and guidelines for health workers involved.
2023
- Young Onset Alzheimer’s Disease Associated with C9ORF72 Hexanucleotide Expansion: Further Evidence for a Still Unsolved Association
[Articolo su rivista]
Vinceti, G.; Gallingani, C.; Zucchi, E.; Martinelli, I.; Gianferrari, G.; Simonini, C.; Bedin, R.; Chiari, A.; Zamboni, G.; Mandrioli, J.
abstract
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are recognized as part of a disease continuum (FTD-ALS spectrum), in which the most common genetic cause is chromosome 9 open reading frame 72 (C9ORF72) gene hexanucleotide repeat expansion. The clinical phenotype of patients carrying this expansion varies widely and includes diseases beyond the FTD-ALS spectrum. Although a few cases of patients with C9ORF72 expansion and a clinical or biomarker-supported diagnosis of Alzheimer’s disease (AD) have been described, they have been considered too sparse to establish a definite association between the C9ORF72 expansion and AD pathology. Here, we describe a C9ORF72 family with pleomorphic phenotypical expressions: a 54-year-old woman showing cognitive impairment and behavioral disturbances with both neuroimaging and cerebrospinal fluid (CSF) biomarkers consistent with AD pathology, her 49-year-old brother with typical FTD-ALS, and their 63-year-old mother with the behavioral variant of FTD and CSF biomarkers suggestive of AD pathology. The young onset of disease in all three family members and their different phenotypes and biomarker profiles make the simple co-occurrence of different diseases an extremely unlikely explanation. Our report adds to previous findings and may contribute to further expanding the spectrum of diseases associated with C9ORF72 expansion.
2022
- Amyotrophic Lateral Sclerosis as an Adverse Drug Reaction: A Disproportionality Analysis of the Food and Drug Administration Adverse Event Reporting System
[Articolo su rivista]
Gaimari, A.; Fusaroli, M.; Raschi, E.; Baldin, E.; Vignatelli, L.; Nonino, F.; De Ponti, F.; Mandrioli, J.; Poluzzi, E.
abstract
Introduction: Amyotrophic lateral sclerosis is a fatal progressive disease with a still unclear multi-factorial etiology. This study focused on the potential relationship between drug exposure and the development of amyotrophic lateral sclerosis by performing a detailed analysis of events reported in the FDA Adverse Event Reporting System database. Methods: The FDA Adverse Event Reporting System quarterly data (January 2004–June 2020) were downloaded and deduplicated. The reporting odds ratios and their 95% confidence intervals were calculated as a disproportionality measure. The robustness of the disproportion was assessed accounting for major confounders (i.e., using a broader query, restricting to suspect drugs, and excluding reports with amyotrophic lateral sclerosis as an indication). Disproportionality signals were prioritized based on their consistency across analyses (reporting odds ratio stability). Results: We retained 1188 amyotrophic lateral sclerosis cases. Sixty-two drugs showed significant disproportionality for amyotrophic lateral sclerosis onset in at least one analysis, and 31 had consistent reporting odds ratio stability, including tumor necrosis factor-alpha inhibitors and statins. Disproportionality signals from ustekinumab, an immunomodulator against interleukins 12–23 used in autoimmune diseases, and the anti-IgE omalizumab were consistent among analyses and unexpected. Conclusions: For each drug emerging as possibly associated with amyotrophic lateral sclerosis onset, biological plausibility, underlying disease, and reverse causality could be argued. Our findings strengthened the plausibility of a precipitating role of drugs primarily through immunomodulation (e.g., tumor necrosis factor-alpha, ustekinumab, and omalizumab), but also by impacting metabolism and the musculoskeletal integrity (e.g., statins and bisphosphonates). Complement and NF-kB dysregulation could represent interesting topics for planning translational mechanistic studies on amyotrophic lateral sclerosis as an adverse drug effect. Graphical abstract: [Figure not available: see fulltext.].
2022
- Case report: p.Glu134del SOD1 mutation in two apparently unrelated ALS patients with mirrored phenotype
[Articolo su rivista]
Gianferrari, Giulia; Martinelli, Ilaria; Simonini, Cecilia; Zucchi, Elisabetta; Fini, Nicola; Carra, Serena; Moglia, Cristina; Mandrioli, Jessica
abstract
: With upcoming personalized approaches based on genetics, it is important to report new mutations in amyotrophic lateral sclerosis (ALS) genes in order to understand their pathogenicity and possible patient responses to specific therapies. SOD1 mutations are the second most frequent genetic cause of ALS in European populations. Here, we describe two seemingly unrelated Italian patients with ALS carrying the same SOD1 heterozygous c.400_402 deletion (p.Glu134del). Both patients had spinal onset in their lower limbs, progressive muscular weakness with respiratory involvement, and sparing bulbar function. In addition to the clinical picture, we discuss the possible pathogenic role of this unfamiliar SOD1 mutation.
2022
- Clinical trials in pediatric ALS: a TRICALS feasibility study.
[Articolo su rivista]
Kliest, T; Van Eijk, Rpa; Al-Chalabi, A; Albanese, A; Andersen, Pm; Amador, Mdm; Bråthen, G; Brunaud-Danel, V; Brylev, L; Camu, W; De Carvalho, M; Cereda, C; Cetin, H; Chaverri, D; Chiò, A; Corcia, P; Couratier, P; De Marchi, F; Desnuelle, C; Van Es, Ma; Esteban, J; Filosto, M; GarcÍa Redondo, A; Grosskreutz, J; Hanemann, Co; Holmøy, T; Høyer, H; Ingre, C; Koritnik, B; Kuzma-Kozakiewicz, M; Lambert, T; Leigh, Pn; Lunetta, C; Mandrioli, J; Mcdermott, Cj; Meyer, T; Mora, Js; Petri, S; Povedano, M; Reviers, E; Riva, N; Roes, Kcb; Rubio, Má; Salachas, F; Sarafov, S; Sorarù, G; Stevic, Z; Svenstrup, K; Møller, At; Turner, Mr; Van Damme, P; Van Leeuwen, Lag; Varona, L; VÁzquez Costa, Jf; Weber, M; Hardiman, O; Van Den Berg, Lh.
abstract
2022
- Duplication of exons 15 and 16 in Matrin-3: a phenotype bridging amyotrophic lateral sclerosis and immune-mediated disorders
[Articolo su rivista]
Caputo, Maria; Zucchi, Elisabetta; Martinelli, Ilaria; Gianferrari, Giulia; Simonini, Cecilia; Amedei, Amedeo; Niccolai, Elena; Gellera, Cinzia; Pensato, Viviana; Mandrioli, Jessica
abstract
: Mutations in Matrin-3 (MATR3) gene have been described in ALS, suggesting a role for this gene in the disease pathogenesis. While most of MATR3 mutations are point mutations, here we report the first case of ALS associated with duplication in exons 15 and 16. The patient presented with limb-onset ALS and a complex past medical history because of Sjögren syndrome, antiphospholipid antibodies positivity, polyallergies, endometriosis, aldosterone-secreting adrenal cortical adenoma, congenital vesicoureteral reflux, and right breast hypoplasia. We discuss MATR3 effect in ALS and the role of this previously undescribed mutation in this peculiar ALS phenotype associated with systemic autoimmunity involvement.
2022
- Epidemiological, Clinical and Genetic Features of ALS in the Last Decade: A Prospective Population-Based Study in the Emilia Romagna Region of Italy
[Articolo su rivista]
Gianferrari, G.; Martinelli, I.; Zucchi, E.; Simonini, C.; Fini, N.; Vinceti, M.; Ferro, S.; Gessani, A.; Canali, E.; Valzania, F.; Sette, E.; Pugliatti, M.; Tugnoli, V.; Zinno, L.; Stano, S.; Santangelo, M.; De Pasqua, S.; Terlizzi, E.; Guidetti, D.; Medici, D.; Salvi, F.; Liguori, R.; Vacchiano, V.; Casmiro, M.; Querzani, P.; Dossi, M. C.; Patuelli, A.; Morresi, S.; Longoni, M.; De Massis, P.; Rinaldi, R.; Borghi, A.; Amedei, A.; Mandrioli, J.
abstract
Increased incidence rates of amyotrophic lateral sclerosis (ALS) have been recently reported across various Western countries, although geographic and temporal variations in terms of incidence, clinical features and genetics are not fully elucidated. This study aimed to describe demographic, clinical feature and genotype–phenotype correlations of ALS cases over the last decade in the Emilia Romagna Region (ERR). From 2009 to 2019, our prospective population-based registry of ALS in the ERR of Northern Italy recorded 1613 patients receiving a diagnosis of ALS. The age-and sex-adjusted incidence rate was 3.13/100,000 population (M/F ratio: 1.21). The mean age at onset was 67.01 years; women, bulbar and respiratory phenotypes were associated with an older age, while C9orf72-mutated patients were generally younger. After peaking at 70–75 years, incidence rates, among women only, showed a bimodal distribution with a second slight increase after reaching 90 years of age. Familial cases comprised 12%, of which one quarter could be attributed to an ALS-related mutation. More than 70% of C9orf72-expanded patients had a family history of ALS/fronto-temporal dementia (FTD); 22.58% of patients with FTD at diagnosis had C9orf72 expansion (OR 6.34, p = 0.004). In addition to a high ALS incidence suggesting exhaustiveness of case ascertainment, this study highlights interesting phenotype–genotype correlations in the ALS population of ERR.
2022
- G507D mutation in FUS gene causes familial amyotrophic lateral sclerosis with a specific genotype-phenotype correlation.
[Articolo su rivista]
Martinelli, Ilaria; Zucchi, Elisabetta; Pensato, Viviana; Gellera, Cinzia; Traynor Bryan, James; Gianferrari, Giulia; Chiò, Adriano; Mandrioli, Jessica
abstract
2022
- Identifying and predicting amyotrophic lateral sclerosis clinical subgroups: a population-based machine-learning study.
[Articolo su rivista]
Faghri, Faraz; Brunn, Fabian; Dadu, Anant; Zucchi, Elisabetta; Martinelli, Ilaria; Mazzini, Letizia; Vasta, Rosario; Canosa, Antonio; Moglia, Cristina; Calvo, Andrea; A Nalls, Michael; H Campbell, Roy; Mandrioli, Jessica; Meletti, Stefano; J Traynor, Bryan; Chiò, Adriano
abstract
2022
- Missense mutation in ATXN2 gene (c.2860C > T) in an amyotrophic lateral sclerosis patient with aggressive disease phenotype
[Articolo su rivista]
Ghezzi, A.; Martinelli, I.; Carra, S.; Mediani, L.; Zucchi, E.; Simonini, C.; Gianferrari, G.; Fini, N.; Cereda, C.; Gellera, C.; Pensato, V.; Mandrioli, J.
abstract
Background: ALS symptoms have been previously described only in the context of ATXN2 CAG expansions, whereas missense mutations of the gene have never been described in ALS patients. Case presentation: We identified a novel missense mutation (c.2860C > T) of ATXN2, for which in silico analysis showed a possible pathogenic effect on protein expression, in a patient presenting an aggressive disease phenotype. Discussion: Our findings raise the possibility for unknown genetic factors interacting with ATXN2 mutations, or for an autonomous pathogenic role for this specific point mutation in ATXN2 gene in driving the clinical phenotype toward ALS. We also found that stress granules in the fibroblasts from the patient entrapped higher amounts of defective ribosomal products compared to fibroblasts from three healthy subjects, suggesting that ATXN2 mutation-related toxicity may have implication in protein quality control.
2022
- Mitochondrial and Endoplasmic Reticulum Alterations in a Case of Amyotrophic Lateral Sclerosis Caused by TDP-43 A382T Mutation
[Articolo su rivista]
Zanini, Giada; Selleri, Valentina; Nasi, Milena; De Gaetano, Anna; Martinelli, Ilaria; Gianferrari, Giulia; Lofaro, Francesco Demetrio; Boraldi, Federica; Mandrioli, Jessica; Pinti, Marcello
abstract
Amyotrophic lateral sclerosis is the most common form of motor neuron disease. Mutations in TARDBP, the gene encoding the RNA-binding protein TDP-43, are responsible for about 5% of familial ALS. Here we report the clinical and biological features of an ALS patients with pA382T mutation in TPD-43 protein. Disease began with right hand muscles weakness, and equally involved upper and lower motor neuron with a classic phenotype, without cognitive impairment. While a family history of neurological diseases was reported, there was no evidence of familial frontotemporal dementia. Cultured fibroblasts from the patient were characterized by profound alterations of cell proteome, which impacts particularly the mitochondrial metabolic pathways and the endoplasmic reticulum. TDP-43 levels were similar to control, healthy fibroblasts, but a higher fraction localized in mitochondria. Mitochondrial network appeared fragmented, and the organelles smaller and more spheric. In agreement with impaired proteome and morphology of mitochondria, basal cell respiration was reduced. Mitochondrial DNA levels appeared normal. However, a higher amount of mitochondrial DNA was present in the cytosol, suggesting a pronounced mitochondrial DNA misplacement which can promote a pro-inflammatory response mediating by cGAS/STING. Thus, this case report further expands the clinical and pathological phenotype of A382T mutation.
2022
- Neutrophils-to-Lymphocyte Ratio Is Associated with Progression and Overall Survival in Amyotrophic Lateral Sclerosis
[Articolo su rivista]
Leone, Maurizio A; Mandrioli, Jessica; Russo, Sergio; Cucovici, Aliona; Gianferrari, Giulia; Lisnic, Vitalie; Muresanu, Dafin Fior; Giuliani, Francesco; Copetti, Massimiliano; The Pooled Resource Open-Access Als Clinical Trials Consortium, Null; Fontana, Andrea
abstract
Background: Amyotrophic lateral sclerosis (ALS) is a devastating and untreatable motor neuron disease, with a 3-5-year survival from diagnosis. Possible prognostic serum biomarkers include albumin, C-reactive protein, ferritin, creatinine, uric acid, hemoglobin, potassium, sodium, calcium, glucose, and the neutrophil-to-lymphocyte ratio (NLR), a marker of subclinical inflammation. Objective: To ascertain the influence of NLR on ALS progression rate and survival. Methods: Cross-sectional multicenter study including 146 consecutive incident and prevalent patients (88 males), aged >18 years, diagnosed according to the El Escorial criteria. The exclusion criteria were: (1) patients with tracheostomy or receiving mechanical ventilation; (2) patients with percutaneous endoscopic gastrostomy; and (3) patients who did not sign the informed consent. The rate of disease progression (ΔFS score) represents the monthly decline of the ALSFRS-R score, and was computed as (48 - total ALSFRS-R at recruitment)/symptom duration in months. Patients were followed up to tracheotomy, death, or the end of the follow-up, whichever occurred first. To validate our findings, we used data retrieved from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database. Results: The median disease duration was 15 (range = 2-30) months. The mean ALSFRS-R score at recruitment was 35.8 ± 8.0 (range: 10-48), and the median ΔFS was 0.66 (range: 0-5.33). Age at onset, at diagnosis, and at recruitment were significantly lower in the lowest NLR tertile. NLR values positively correlated with ΔFS values (r = 0.28): the regression slope of NLR (log-values) was 0.60 (p < 0.001) before and 0.49 (p = 0.006) after adjustment for age at recruitment. The ΔFS score progressively increased from the lowest to the highest NLR tertile: 0.35 (IQR: 0.18-0.93), 0.62 (IQR: 0.25-1.09), and 0.86 (IQR: 0.53-1.92). Patients were followed for a median of 2 years. The mortality rate passed from 15.9 events per 100 person-years in patients belonging to the lowest NLR tertile to 52.8 in those in the highest tertile. The optimal cut-off value which best classified patients with the lowest and the highest mortality rate was set at the NLR value of 2.315. Indeed, the mortality rate of patients with an NLR value above such cut-off was twice the mortality rate of patients with a value below the cut-off (age adjusted hazard ratio (HR): 2.16, 95% confidence interval (CI): 1.32-3.53). In the PRO-ACT validation sample, patients with an NLR value above the cut-off consistently had a higher mortality rate than those with a value below the cut-off (age adjusted HR: 1.17, 95%CI: 1.01-1.35). Conclusions: NLR could be a candidate easy, fast, and low-cost marker of disease progression and survival in ALS. It may be associated with low-grade inflammation either as a direct mirror of the pathological process of disease progression, or as a consequence of neuronal death (reverse causation). However, prospective studies are needed to understand whether NLR changes during the course of the disease, before using it to monitor disease progression in ALS.
2022
- Predicting functional impairment trajectories in amyotrophic lateral sclerosis: a probabilistic, multifactorial model of disease progression
[Articolo su rivista]
Tavazzi, Erica; Daberdaku, Sebastian; Zandonà, Alessandro; Vasta, Rosario; Nefussy, Beatrice; Lunetta, Christian; Mora, Gabriele; Mandrioli, Jessica; Grisan, Enrico; Meletti, Stefano; Tarlarini, Claudia; Calvo, Andrea; Moglia, Cristina; Drory, Vivian; Gotkine, Marc; Chiò, Adriano; Di Camillo, Barbara
abstract
Objective: To employ Artificial Intelligence to model, predict and simulate the amyotrophic lateral sclerosis (ALS) progression over time in terms of variable interactions, functional impairments, and survival. Methods: We employed demographic and clinical variables, including functional scores and the utilisation of support interventions, of 3940 ALS patients from four Italian and two Israeli registers to develop a new approach based on Dynamic Bayesian Networks (DBNs) that models the ALS evolution over time, in two distinct scenarios of variable availability. The method allows to simulate patients' disease trajectories and predict the probability of functional impairment and survival at different time points. Results: DBNs explicitly represent the relationships between the variables and the pathways along which they influence the disease progression. Several notable inter-dependencies were identified and validated by comparison with literature. Moreover, the implemented tool allows the assessment of the effect of different markers on the disease course, reproducing the probabilistically expected clinical progressions. The tool shows high concordance in terms of predicted and real prognosis, assessed as time to functional impairments and survival (integral of the AU-ROC in the first 36 months between 0.80-0.93 and 0.84-0.89 for the two scenarios, respectively). Conclusions: Provided only with measurements commonly collected during the first visit, our models can predict time to the loss of independence in walking, breathing, swallowing, communicating, and survival and it can be used to generate in silico patient cohorts with specific characteristics. Our tool provides a comprehensive framework to support physicians in treatment planning and clinical decision-making.
2022
- Rummeliibacillus suwonensis: First Time Isolation from Human Feces by Culturomics
[Articolo su rivista]
Quaranta, G.; Mandrioli, J.; Bibbo, S.; Guarnaccia, A.; Fancello, G.; Simonini, C.; Amedei, A.; Niccolai, E.; Nannini, G.; Cammarota, G.; Sanguinetti, M.; Masucci, L.
abstract
Gut microbiota is a complex ecosystem composed by trillions of microorganisms that are crucial for human health or disease status. Currently, there are two methodological options to explore its complexity: metagenomics and culturomics. Culturomics is an approach that uses multiple culture conditions (days of incubation, enrichment factors and growth temperature) and MALDI-TOF mass spectrometry for the identification of bacterial species and sequencing when this method fails. In this paper, we describe how Colturomic’s protocol has allowed the first isolation in human sample of Rummeliibacillus suwonensis, a Gram positive, facultative anaerobe bacterium. The bacterium was isolated from feces of a 69 years old male with amyotrophic lateral sclerosis (ALS) recruited for a clinical trial assessing safety and efficacy of fecal microbiota transplantation in ALS. The first isolation of the microorganism dates back to 2013 from the soil of a South Korean mountain area. In this report, morphological description, biochemical characterization and antibiotic susceptibility tests were performed to outline the bacterial properties.
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.
2022
- The Potential Role of Peripheral Oxidative Stress on the Neurovascular Unit in Amyotrophic Lateral Sclerosis Pathogenesis: A Preliminary Report from Human and In Vitro Evaluations
[Articolo su rivista]
Grossini, Elena; Garhwal, Divya; Venkatesan, Sakthipriyan; Ferrante, Daniela; Mele, Angelica; Saraceno, Massimo; Scognamiglio, Ada; Mandrioli, Jessica; Amedei, Amedeo; De Marchi, Fabiola; Mazzini, Letizia
abstract
2022
- Validation of the DYALS (dysphagia in amyotrophic lateral sclerosis) questionnaire for the evaluation of dysphagia in ALS patients
[Articolo su rivista]
Diamanti, Luca; Borrelli, Paola; Dubbioso, Raffaele; Capasso, Margherita; Morelli, Claudia; Lunetta, Christian; Petrucci, Antonio; Mora, Gabriele; Volanti, Paolo; Inghilleri, Maurizio; Tremolizzo, Lucio; Mandrioli, Jessica; Mazzini, Letizia; Vedovello, Marcella; Siciliano, Gabriele; Filosto, Massimiliano; Matà, Sabrina; Montomoli, Cristina
abstract
Background: Dysphagia is a common symptom during the trajectory of ALS, and it can significantly impact on the quality of life and prognosis of patients. Nowadays, no specific tool for the screening of dysphagia in ALS is validated, and the approach is heterogeneous across the Italian centres. Objective: To validate the DYALS (dysphagia in amyotrophic lateral sclerosis) questionnaire, adapting the DYMUS (dysphagia in multiple sclerosis) questionnaire, for the assessment of dysphagia in ALS patients, in order to uniform the evaluations across the Italian ALS network. Methods: We included 197 patients diagnosed with ALS following the El Escorial criteria, in sixteen Italian ALS centres between 1st December 2019 and 1st July 2020. For each patient, we collected clinical and demographic data and obtained ALSFRS-r score, ALSAQ-5 score, DYMUS score, and EAT-10 score. Results: Across the 197 patients, the ratio M/F was 113/84, and the median age was 64 years (IQR 56-72.5). Bulbar patients were 20%, and spinal patients 80%. The median ALSFRSr total score of patients was 35 (IQR 28-39). DYALS score was statistically higher in bulbar ALS than in spinal ALS (median = 6, IQR 4.5-9 vs median = 1, IQR 0-5, z = 6.253, p < 0.0001). DYALS questionnaire showed a high internal consistency (Cronbach's alpha = 0.88). There was a statistically significant correlation between DYALS and EAT-10 (rho = 0.90, p < 0.0001). Conclusions: DYALS scale is reliable, manageable, and easily usable for the screening of dysphagia in ALS. It can be shared with all the Italian ALS centres in order to collect uniform data for therapeutic strategies and clinical trials.
2021
- Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis
[Articolo su rivista]
Johnson, Janel O; Chia, Ruth; Miller, Danny E; Li, Rachel; Kumaran, Ravindran; Abramzon, Yevgeniya; Alahmady, Nada; Renton, Alan E; Topp, Simon D; Gibbs, J Raphael; Cookson, Mark R; Sabir, Marya S; Dalgard, Clifton L; Troakes, Claire; Jones, Ashley R; Shatunov, Aleksey; Iacoangeli, Alfredo; Al Khleifat, Ahmad; Ticozzi, Nicola; Silani, Vincenzo; Gellera, Cinzia; Blair, Ian P; Dobson-Stone, Carol; Kwok, John B; Bonkowski, Emily S; Palvadeau, Robin; Tienari, Pentti J; Morrison, Karen E; Shaw, Pamela J; Al-Chalabi, Ammar; Brown, Robert H; Calvo, Andrea; Mora, Gabriele; Al-Saif, Hind; Gotkine, Marc; Leigh, Fawn; Chang, Irene J; Perlman, Seth J; Glass, Ian; Scott, Anna I; Shaw, Christopher E; Basak, A Nazli; Landers, John E; Chiò, Adriano; Crawford, Thomas O; Smith, Bradley N; Traynor, Bryan J; Smith, Bradley N; Ticozzi, Nicola; Fallini, Claudia; Gkazi, Athina Soragia; Topp, Simon D; Scotter, Emma L; Kenna, Kevin P; Keagle, Pamela; Tiloca, Cinzia; Vance, Caroline; Troakes, Claire; Colombrita, Claudia; King, Andrew; Pensato, Viviana; Castellotti, Barbara; Baas, Frank; Ten Asbroek, Anneloor L M A; McKenna-Yasek, Diane; Mclaughlin, Russell L; Polak, Meraida; Asress, Seneshaw; Esteban-Pérez, Jesús; Stevic, Zorica; D'Alfonso, Sandra; Mazzini, Letizia; Comi, Giacomo P; Del Bo, Roberto; Ceroni, Mauro; Gagliardi, Stella; Querin, Giorgia; Bertolin, Cinzia; van Rheenen, Wouter; Rademakers, Rosa; van Blitterswijk, Marka; Lauria, Giuseppe; Duga, Stefano; Corti, Stefania; Cereda, Cristina; Corrado, Lucia; Sorarù, Gianni; Williams, Kelly L; Nicholson, Garth A; Blair, Ian P; Leblond-Manry, Claire; Rouleau, Guy A; Hardiman, Orla; Morrison, Karen E; Veldink, Jan H; van den Berg, Leonard H; Al-Chalabi, Ammar; Pall, Hardev; Shaw, Pamela J; Turner, Martin R; Talbot, Kevin; Taroni, Franco; García-Redondo, Alberto; Wu, Zheyang; Glass, Jonathan D; Gellera, Cinzia; Ratti, Antonia; Brown, Robert H; Silani, Vincenzo; Shaw, Christopher E; Landers, John E; Dalgard, Clifton L; Adeleye, Adelani; Soltis, Anthony R; Alba, Camille; Viollet, Coralie; Bacikova, Dagmar; Hupalo, Daniel N; Sukumar, Gauthaman; Pollard, Harvey B; Wilkerson, Matthew D; Martinez, Elisa McGrath; Abramzon, Yevgeniya; Ahmed, Sarah; Arepalli, Sampath; Baloh, Robert H; Bowser, Robert; Brady, Christopher B; Brice, Alexis; Broach, James; Campbell, Roy H; Camu, William; Chia, Ruth; Cooper-Knock, John; Ding, Jinhui; Drepper, Carsten; Drory, Vivian E; Dunckley, Travis L; Eicher, John D; England, Bryce K; Faghri, Faraz; Feldman, Eva; Floeter, Mary Kay; Fratta, Pietro; Geiger, Joshua T; Gerhard, Glenn; Gibbs, J Raphael; Gibson, Summer B; Glass, Jonathan D; Hardy, John; Harms, Matthew B; Heiman-Patterson, Terry D; Hernandez, Dena G; Jansson, Lilja; Kirby, Janine; Kowall, Neil W; Laaksovirta, Hannu; Landeck, Natalie; Landi, Francesco; Le Ber, Isabelle; Lumbroso, Serge; Macgowan, Daniel J L; Maragakis, Nicholas J; Mora, Gabriele; Mouzat, Kevin; Murphy, Natalie A; Myllykangas, Liisa; Nalls, Mike A; Orrell, Richard W; Ostrow, Lyle W; Pamphlett, Roger; Pickering-Brown, Stuart; Pioro, Erik P; Pletnikova, Olga; Pliner, Hannah A; Pulst, Stefan M; Ravits, John M; Renton, Alan E; Rivera, Alberto; Robberecht, Wim; Rogaeva, Ekaterina; Rollinson, Sara; Rothstein, Jeffrey D; Scholz, Sonja W; Sendtner, Michael; Shaw, Pamela J; Sidle, Katie C; Simmons, Zachary; Singleton, Andrew B; Smith, Nathan; Stone, David J; Tienari, Pentti J; Troncoso, Juan C; Valori, Miko; Van Damme, Philip; Van Deerlin, Vivianna M; Van Den Bosch, Ludo; Zinman, Lorne; Landers, John E; Chiò, Adriano; Traynor, Bryan J; Angelocola, Stefania M; Ausiello, Francesco P; Barberis, Marco; Bartolomei, Ilaria; Battistini, Stefania; Bersano, Enrica; Bisogni, Giulia; Borghero, Giuseppe; Brunetti, Maura; Cabona, Corrado; Calvo, Andrea; Canale, Fabrizio; Canosa, Antonio; Cantisani, Teresa A; Capasso, Margherita; Caponnetto, Claudia; Cardinali, Patrizio; Carrera, Paola; Casale, Federico; Chiò, Adriano; Colletti,
abstract
Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective: To identify the genetic variants associated with juvenile ALS. Design, setting, and participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main outcomes and measures: De novo variants present only in the index case and not in unaffected family members. Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. Conclusions and relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.
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.
2021
- Coffee and Tea Consumption Impact on Amyotrophic Lateral Sclerosis Progression: A Multicenter Cross-Sectional Study
[Articolo su rivista]
Cucovici, A.; Ivashynka, A.; Fontana, A.; Russo, S.; Mazzini, L.; Mandrioli, J.; Lisnic, V.; Muresanu, D. F.; Leone, M. A.
abstract
Background/objectives: Amyotrophic lateral sclerosis (ALS) is a devastating and still untreatable motor neuron disease. The causes of ALS are unknown, but nutritional factors may impact the rate of disease progression. We aimed to ascertain the influence of coffee and tea consumption on ALS progression rate. Subjects/methods: In this multicenter cross-sectional study, we recruited 241 patients, 96 females, and 145 males; the mean age at onset was 59.9 ± 11.8 years. According to El Escorial criteria, 74 were definite ALS, 77 probable, 55 possible, and 35 suspected; 187 patients had spinal onset and 54 bulbar. Patients were categorized into three groups, according to their ΔFS (derived from ALS Functional Rating Scale-Revised score and disease duration from onset): slow (81), intermediate (80), and fast progressors (80). Results: Current coffee consumers were 179 (74.3%), 34 (14.1%) were non-consumers, and 22 (9.1%) were former consumers, whereas six (2.5%) consumed decaffeinated coffee only. The log-ΔFS was weakly correlated with the duration of coffee consumption (p = 0.034), but not with the number of cup-years, or the intensity of coffee consumption (cups/day). Current tea consumers were 101 (41.9%), 6 (2.5%) were former consumers, and 134 (55.6%) were non-consumers. Among current and former consumers, 27 (25.2%) consumed only green tea, 51 (47.7%) only black tea, and 29 (27.1%) both. The log-ΔFS was weakly correlated only with the consumption duration of black tea (p = 0.028) but not with the number of cup-years. Conclusions: Our study does not support the hypothesis that coffee or tea consumption is associated with the ALS progression rate.
2021
- Evaluation of peripherin in biofluids of patients with motor neuron diseases
[Articolo su rivista]
Sabbatini, D.; Raggi, F.; Ruggero, S.; Seguso, M.; Mandrioli, J.; Cagnin, A.; Briani, C.; Toffanin, E.; Gizzi, M.; Fortuna, A.; Bello, L.; Pegoraro, E.; Musso, G.; Soraru, G.
abstract
Peripherin (PRPH), a type III intermediate filament, assembles with neurofilaments in neurons of the peripheral nervous system, including lower motor neurons (LMN). To evaluate the role of PRPH in LMN degeneration, we assessed PRPH and neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and serum of 91 patients with motor neuron diseases (MND) and 69 controls. Overall, we found PRPH to be more concentrated in serum than in CSF. Serum PRPH resulted significantly increased in MND patients but it was unrelated to CSF-NfL or survival in the amyotrophic lateral sclerosis (ALS) subset. PRPH might represent a marker of LMN involvement.
2021
- Gastrointestinal Status and Microbiota Shaping in Amyotrophic Lateral Sclerosis: A New Frontier for Targeting?
[Capitolo/Saggio]
Mazzini, Letizia; Marchi, Fabiola De; Niccolai, Elena; Mandrioli, Jessica; Amedei, Amedeo
abstract
2021
- Hsp90-mediated regulation of DYRK3 couples stress granule disassembly and growth via mTORC1 signaling
[Articolo su rivista]
Mediani, L.; Antoniani, F.; Galli, V.; Vinet, J.; Carra, A. D.; Bigi, I.; Tripathy, V.; Tiago, T.; Cimino, M.; Leo, G.; Amen, T.; Kaganovich, D.; Cereda, C.; Pansarasa, O.; Mandrioli, J.; Tripathi, P.; Troost, D.; Aronica, E.; Buchner, J.; Goswami, A.; Sterneckert, J.; Alberti, S.; Carra, S.
abstract
Stress granules (SGs) are dynamic condensates associated with protein misfolding diseases. They sequester stalled mRNAs and signaling factors, such as the mTORC1 subunit raptor, suggesting that SGs coordinate cell growth during and after stress. However, the molecular mechanisms linking SG dynamics and signaling remain undefined. We report that the chaperone Hsp90 is required for SG dissolution. Hsp90 binds and stabilizes the dual-specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3) in the cytosol. Upon Hsp90 inhibition, DYRK3 dissociates from Hsp90 and becomes inactive. Inactive DYRK3 is subjected to two different fates: it either partitions into SGs, where it is protected from irreversible aggregation, or it is degraded. In the presence of Hsp90, DYRK3 is active and promotes SG disassembly, restoring mTORC1 signaling and translation. Thus, Hsp90 links stress adaptation and cell growth by regulating the activity of a key kinase involved in condensate disassembly and translation restoration.
2021
- Risk of Amyotrophic Lateral Sclerosis and Exposure to Particulate Matter from Vehicular Traffic: A Case-Control Study
[Articolo su rivista]
Filippini, Tommaso; Mandrioli, Jessica; Malagoli, Carlotta; Costanzini, Sofia; Cherubini, Andrea; Maffeis, Giuseppe; Vinceti, Marco
abstract
(1) Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with still unknown etiology. Some occupational and environmental risk factors have been suggested, including long-term air pollutant exposure. We carried out a pilot case-control study in order to evaluate ALS risk due to particulate matter with a diameter of ≤10 µm (PM10) as a proxy of vehicular traffic exposure. (2) Methods: We recruited ALS patients and controls referred to the Modena Neurology ALS Care Center between 1994 and 2015. Using a geographical information system, we modeled PM10 concentrations due to traffic emissions at the geocoded residence address at the date of case diagnosis. We computed the odds ratio (OR) and 95% confidence interval (CI) of ALS according to increasing PM10 exposure, using an unconditional logistic regression model adjusted for age and sex. (3) Results: For the 132 study participants (52 cases and 80 controls), the average of annual median and maximum PM10 concentrations were 5.2 and 38.6 µg/m3, respectively. Using fixed cutpoints at 5, 10, and 20 of the annual median PM10 levels, and compared with exposure <5 µg/m3, we found no excess ALS risk at 5-10 µg/m3 (OR 0.87, 95% CI 0.39-1.96), 10-20 µg/m3 (0.94, 95% CI 0.24-3.70), and ≥20 µg/m3 (0.87, 95% CI 0.05-15.01). Based on maximum PM10 concentrations, we found a statistically unstable excess ALS risk for subjects exposed at 10-20 µg/m3 (OR 4.27, 95% CI 0.69-26.51) compared with those exposed <10 µg/m3. However, risk decreased at 20-50 µg/m3 (OR 1.49, 95% CI 0.39-5.75) and ≥50 µg/m3 (1.16, 95% CI 0.28-4.82). ALS risk in increasing tertiles of exposure showed a similar null association, while comparison between the highest and the three lowest quartiles lumped together showed little evidence for an excess risk at PM10 concentrations (OR 1.13, 95% CI 0.50-2.55). After restricting the analysis to subjects with stable residence, we found substantially similar results. (4) Conclusions: In this pilot study, we found limited evidence of an increased ALS risk due to long-term exposure at high PM10 concentration, though the high statistical imprecision of the risk estimates, due to the small sample size, particularly in some exposure categories, limited our capacity to detect small increases in risk, and further larger studies are needed to assess this relation.
2021
- Serum neurofilament light as biomarker of seizure-related neuronal injury in status epilepticus
[Articolo su rivista]
Giovannini, G.; Bedin, R.; Ferraro, D.; Vaudano, A. E.; Mandrioli, J.; Meletti, S.
abstract
Biomarkers of neuronal damage in status epilepticus (SE) would be of great relevance for clinical and research purposes. In a retrospective cross-sectional study, serum neurofilament light chain (NfL) levels were measured in patients with SE (30 subjects), patients with drug-resistant epilepsy (30 subjects), and healthy controls (30 subjects). Serum NfL levels were higher in patients with SE (median = 26.15 pg/ml) compared to both epilepsy patients (median = 7.35 pg/ml) and healthy controls (median = 6.81 pg/ml; p <.001). In patients with SE, serum NfL levels showed a high correlation with cerebrospinal fluid (CSF) NfL (τ =.68, p <.001) as well as with CSF total tau (t-tau) levels (τ =.627, p <.001); they were higher in SE lasting >24 h (p =.013), in refractory/superrefractory SE (p =.004), and in patients who died within 30 days or who presented a worsening of clinical conditions (p =.001). Values of >28.8 pg/ml predicted 30-day clinical worsening or death (odds ratio [OR] = 10.83, 95% confidence interval [CI] = 1.96–59.83, p =.006) and SE refractoriness (OR = 9.33, 95% CI = 1.51–57.65, p =.016). In conclusion, serum NfL levels are increased in SE and correlate with SE treatment response, duration, and outcomes, therefore representing a promising biomarker of seizure-related neuronal damage.
2021
- TeleNeurological evaluation and Support for the Emergency Department (TeleNS-ED): protocol for an open-label clinical trial
[Articolo su rivista]
Mandrioli, J.; Santangelo, M.; Luciani, A.; Toscani, S.; Zucchi, E.; Giovannini, G.; Martinelli, I.; Cecoli, S.; Bigliardi, G.; Scanavini, S.; Meletti, S.
abstract
INTRODUCTION: The COVID-19 pandemic compelled health systems to protect patients and medical personnel during transit in hospitals by minimising transfers, prompting the use of telehealth systems. In the field of neurology, telemedicine has been used in emergency settings for acute stroke management between spoke and hub hospital networks, where good outcomes have been achieved. However, data on the use of telemedicine in non-stroke acute neurological conditions accessing the emergency department (ED) are currently missing. METHODS AND ANALYSES: This is an interventional, open-label trial on the use of teleconsultation in the ED for neurological diseases other than stroke. The study aims to develop a remote consultancy system (TeleNeurological Evaluation and Support, TeleNS) for patients with acute neurological symptoms referred to hospital facilities without a 24-hour availability of a neurologist consultant (spoke hospitals). The study population will include 100 ED patients referred to two spoke hospitals in 6 months, who will be asked to perform teleconsultation instead of inperson visits. As a control group, retrospectively available data from patients admitted to the ED of spoke hospitals during the same time period over the last 2 years will be evaluated. The primary objective is to assess whether a TeleNS for the ED guarantees a faster but qualitatively non-inferior diagnostic/therapeutic work-up if compared with inperson examination, assuring the availability of all the necessary examinations and treatments with consistent time-saving. ETHICS AND DISSEMINATION: The trial was designed following the national guidelines on clinical investigation on telemedicine provided by the Italian Ministry of Health and according to the Standard Protocol Items for Randomized Trials statement guidelines. This research protocol was approved by Comitato Etico Area Vasta Emilia Nord in September 2020 (number/identification: 942/2020/DISP/AOUMO SIRER ID 805) and was written without patient involvement. Patients' associations will be involved in the dissemination of study design and results. The results of the study will be presented during scientific symposia or published in scientific journals. TRIAL REGISTRATION NUMBER: NCT04611295.
2021
- The gut microbiota-immunity axis in als: A role in deciphering disease heterogeneity?
[Articolo su rivista]
Niccolai, E.; Di Pilato, V.; Nannini, G.; Baldi, S.; Russo, E.; Zucchi, E.; Martinelli, I.; Menicatti, M.; Bartolucci, G.; Mandrioli, J.; Amedei, A.
abstract
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder with an unknown etiology and no effective treatment, and is characterized by large phenotypic heterogeneity, including variable sites, ages of symptom onset and rates of disease progression. Increasing data support the role of the microbiota-immunity axis in the pathogenesis of neurodegenerative diseases. In the present study, we compared the inflammatory and microbiota profile of ALS patients with different clinical characteristics, with healthy family caregivers. Measuring a panel of 30 inflammatory cytokines in serum and fecal samples, we observed a distinct cytokine profile both at the systemic and intestinal level in patients compared to controls and even in patients with different clinical phenotypes and progression rates. The 16S targeted metagenome analysis revealed slight differences in patients compared to controls as well as in patients with slow progression, marked by the reduction of butyrate-producing bacteria and a decrease of the Firmicutes/Bacteroidetes ratio in ALS. Finally, the short chain fatty acid analysis did not show a different distribution among the groups. If confirmed in a larger number of patients, the inflammatory cytokine profile and the microbial composition could be appropriate biomarker candidates for deciphering ALS heterogeneity.
2021
- The impact of lifetime alcohol and cigarette smoking loads on amyotrophic lateral sclerosis progression: A cross-sectional study
[Articolo su rivista]
Cucovici, A.; Fontana, A.; Ivashynka, A.; Russo, S.; Renna, V.; Mazzini, L.; Gagliardi, I.; Mandrioli, J.; Martinelli, I.; Lisnic, V.; Muresanu, D. F.; Zarrelli, M.; Copetti, M.; Leone, M. A.
abstract
Background—Amyotrophic lateral sclerosis (ALS) is a devastating and untreatable motor neuron disease; smoking and alcohol drinking may impact its progression rate. Objective—To ascertain the influence of smoking and alcohol consumption on ALS progression rates. Methods— Cross-sectional multicenter study, including 241 consecutive patients (145 males); mean age at onset was 59.9 ± 11.8 years. Cigarette smoking and alcohol consumption data were collected at recruitment through a validated questionnaire. Patients were categorized into three groups according to ∆FS (derived from the ALS Functional Rating Scale-Revised and disease duration from onset): slow (n = 81), intermediate (80), and fast progressors (80). Results—Current smokers accounted for 44 (18.3%) of the participants, former smokers accounted for 10 (4.1%), and non-smokers accounted for 187 (77.6%). The age of ALS onset was lower in current smokers than non-smokers, and the ∆FS was slightly, although not significantly, higher for smokers of >14 cigarettes/day. Current alcohol drinkers accounted for 147 (61.0%) of the participants, former drinkers accounted for 5 (2.1%), and non-drinkers accounted for 89 (36.9%). The log(∆FS) was weakly correlated only with the duration of alcohol consumption (p = 0.028), but not with the mean number of drinks/day or the drink-years. Conclusions: This cross-sectional multicenter study suggested a possible minor role for smoking in worsening disease progression. A possible interaction with alcohol drinking was suggested.
2021
- The unfolded protein response in amyotrophic later sclerosis: results of a phase 2 trial
[Articolo su rivista]
Dalla Bella, Eleonora; Bersano, Enrica; Antonini, Giovanni; Borghero, Giuseppe; Capasso, Margherita; Caponnetto, Claudia; Chiò, Adriano; Corbo, Massimo; Filosto, Massimiliano; Giannini, Fabio; Spataro, Rossella; Lunetta, Christian; Mandrioli, Jessica; Messina, Sonia; Monsurrò, Maria Rosaria; Mora, Gabriele; Riva, Nilo; Rizzi, Romana; Siciliano, Gabriele; Silani, Vincenzo; Simone, Isabella; Sorarù, Gianni; Tugnoli, Valeria; Verriello, Lorenzo; Volanti, Paolo; Furlan, Roberto; Nolan, John M; Abgueguen, Emmanuelle; Tramacere, Irene; Lauria, Giuseppe
abstract
: Strong evidence suggests that endoplasmic reticulum stress plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through altered regulation of proteostasis. Robust preclinical findings demonstrated that guanabenz selectively inhibits endoplasmic reticulum stress-induced eIF2α-phosphatase, allowing misfolded protein clearance, reduces neuronal death and prolongs survival in in vitro and in vivo models. However, its safety and efficacy in patients with ALS are unknown. To address these issues, we conducted a multicentre, randomized, double-blind trial with a futility design. Patients with ALS who had displayed an onset of symptoms within the previous 18 months were randomly assigned in a 1:1:1:1 ratio to receive 64 mg, 32 mg or 16 mg of guanabenz or placebo daily for 6 months as an add-on therapy to riluzole. The purpose of the placebo group blinding was to determine safety but not efficacy. The primary outcome was the proportion of patients progressing to higher stages of disease within 6 months as measured using the ALS Milano-Torino staging system, compared with a historical cohort of 200 patients with ALS. The secondary outcomes were the rate of decline in the total revised ALS functional rating scale score, slow vital capacity change, time to death, tracheotomy or permanent ventilation and serum light neurofilament level at 6 months. The primary assessment of efficacy was performed using intention-to-treat analysis. The treatment arms using 64 mg and 32 mg guanabenz, both alone and combined, reached the primary hypothesis of non-futility, with the proportions of patients who progressed to higher stages of disease at 6 months being significantly lower than that expected under the hypothesis of non-futility and a significantly lower difference in the median rate of change in the total revised ALS functional rating scale score. This effect was driven by patients with bulbar onset, none of whom (0/18) progressed to a higher stage of disease at 6 months compared with those on 16 mg guanabenz (4/8; 50%), the historical cohort alone (21/49; 43%; P = 0.001) or plus placebo (25/60; 42%; P = 0.001). The proportion of patients who experienced at least one adverse event was higher in any guanabenz arm than in the placebo arm, with higher dosing arms having a significantly higher proportion of drug-related side effects and the 64 mg arm a significantly higher drop-out rate. The number of serious adverse events did not significantly differ between the guanabenz arms and the placebo. Our findings indicate that a larger trial with a molecule targeting the unfolded protein response pathway without the alpha-2 adrenergic related side-effect profile of guanabenz is warranted.
2021
- “Don’t call me from the left side…”: ischemic stroke in a patient with uncommon vertebral artery dissection
[Articolo su rivista]
Bigliardi, G.; Rosafio, F.; Dell'Acqua, M. L.; Vandelli, L.; Picchetto, L.; Mandrioli, J.; Bertellini, E.; Vallone, S.; Meletti, S.
abstract
2020
- A novel p.N66T mutation in exon 3 of the SOD1 gene: report of two families of ALS patients with early cognitive impairment
[Articolo su rivista]
Martinelli, I.; Zucchi, E.; Gessani, A.; Fini, N.; Chio, A.; Pecoraro, V.; Trenti, T.; Mandrioli, J.
abstract
Introduction: To date more than 180 different mutations in the SOD1 gene have been described in ALS; some of these mutations are associated to peculiar clinical features and have contributed to the understanding of disease heterogeneity. Only 5% of SOD1 mutations involve exon 3. Here we report a novel mutation c.197A > C in the exon 3 of the SOD1 gene in two apparently unrelated ALS families with early respiratory and cognitive impairment. Case report: In the first family two brothers developed ALS in their seventies, with arm weakness followed by bulbar involvement and behavioral breakdown. An unrelated 57-year-old man presented with progressive leg weakness and mild compromised executive functions without known family history for ALS/FTD and underwent invasive ventilation in a few months. A novel missense mutation A to C at codon 197 in exon 3 causing aminoacid substitution of arginine by threonine (N66T) was found for all of them. Harmful consequences of c.197A > C mutation on SOD1 function were suggested by in silico prediction and homology with other known mutations at the same position. Discussion and conclusion: Here, we report two apparently unrelated ALS families carrying a novel SOD1 mutation (N66T), supporting its pathogenic role by primary analysis, and characterized by early bulbar, respiratory, and cognitive involvement. Early cognitive impairment has been rarely described in ALS caused by SOD1 mutations, and mainly in the later phases of the disease. This report provides additional data on the SOD1 mutation spectrum and clinical presentation of ALS, widening phenotypical characterization of SOD1 ALS.
2020
- ALS and FTD: Where RNA metabolism meets protein quality control
[Articolo su rivista]
Mandrioli, J.; Mediani, L.; Alberti, S.; Carra, S.
abstract
Recent genetic and biochemical evidence has improved our understanding of the pathomechanisms that lead to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative diseases with overlapping symptoms and causes. Impaired RNA metabolism, enhanced aggregation of protein-RNA complexes, aberrant formation of ribonucleoprotein (RNP) granules and dysfunctional protein clearance via autophagy are emerging as crucial events in ALS/FTD pathogenesis. Importantly, these processes interact at the molecular level, converging on a common pathogenic cascade. In this review, we summarize key principles underlying ALS and FTD, and we discuss how mutations in genes involved in RNA metabolism, protein quality control and protein degradation meet mechanistically to impair the functionality and dynamics of RNP granules, and how this leads to cellular toxicity and death. Finally, we describe recent advances in understanding signaling pathways that become dysfunctional in ALS/FTD, partly due to altered RNP granule dynamics, but also with stress granule-independent mechanisms and, thus could be promising targets for future therapeutic intervention.
2020
- BAG3 and BAG6 differentially affect the dynamics of stress granules by targeting distinct subsets of defective polypeptides released from ribosomes
[Articolo su rivista]
Mediani, L.; Galli, V.; Carra, A. D.; Bigi, I.; Vinet, J.; Ganassi, M.; Antoniani, F.; Tiago, T.; Cimino, M.; Mateju, D.; Cereda, C.; Pansarasa, O.; Alberti, S.; Mandrioli, J.; Carra, S.
abstract
Stress granules (SGs) are dynamic ribonucleoprotein granules induced by environmental stresses. They play an important role in the stress response by integrating mRNA stability, translation, and signaling pathways. Recent work has connected SG dysfunction to neurodegenerative diseases. In these diseases, SG dynamics are impaired because of mutations in SG proteins or protein quality control factors. Impaired SG dynamics and delayed SG dissolution have also been observed for SGs that accumulate misfolding-prone defective ribosomal products (DRiPs). DRiP accumulation inside SGs is controlled by a surveillance system referred to as granulostasis and encompasses the molecular chaperones VCP and the HSPB8-BAG3-HSP70 complex. BAG3 is a member of the BAG family of proteins, which includes five additional members. One of these proteins, BAG6, is functionally related to BAG3 and able to assist degradation of DRiPs. However, whether BAG6 is involved in granulostasis is unknown. We report that BAG6 is not recruited into SGs induced by different types of stress, nor does it affect SG dynamics. BAG6 also does not replace BAG3’s function in SG granulostasis. We show that BAG3 and BAG6 target different subsets of DRiPs, and BAG3 binding to DRiPs is mediated by HSPB8 and HSP70. Our data support the idea that SGs are sensitive to BAG3-HSP70-bound DRiPs but not to BAG6-bound DRiPs. Additionally, only BAG3 is strongly upregulated in the stress recovery phase, when SGs dissolve. These data exclude a role for BAG6 in granulostasis and point to a more specialized function in the clearance of a specific subset of DRiPs.
2020
- Clinical and Lifestyle Factors and Risk of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study
[Articolo su rivista]
Filippini, Tommaso; Fiore, Maria; Tesauro, Marina; Malagoli, Carlotta; Consonni, Michela; Violi, Federica; Arcolin, Elisa; Iacuzio, Laura; Oliveri Conti, Gea; Cristaldi, Antonio; Zuccarello, Pietro; Zucchi, Elisabetta; Mazzini, Letizia; Pisano, Fabrizio; Gagliardi, Ileana; Patti, Francesco; Mandrioli, Jessica; Ferrante, Margherita; Vinceti, Marco
abstract
Background: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease of the motor neurons. The etiology of ALS remains largely unknown, particularly with reference to the potential environmental determinants. Methods: We performed a population-based case-control study in four provinces from both Northern and Southern Italy in order to assess non-genetic ALS risk factors by collecting through tailored questionnaires information about clinical and lifestyle factors. We estimated ALS risk by calculating odds ratio (OR) with its 95% confidence interval (CI) using unconditional logistic regression models adjusted for sex, age and educational attainment. Results: We recruited 230 participants (95 cases and 135 controls). We found a possible positive association of ALS risk with trauma, particularly head trauma (OR = 2.61, 95% CI 1.19-5.72), electric shock (OR = 2.09, 95% CI 0.62-7.06), and some sports, although at a competitive level only. In addition, our results suggest an increased risk for subjects reporting use of private wells for drinking water (OR = 1.38, 95% CI 0.73-2.27) and for use of herbicides during gardening (OR = 1.95, 95% CI 0.88-2.27). Conversely, there was a suggestion of an inverse association with overall fish consumption (OR = 0.27, 95% CI 0.12-0.60), but with no dose-response relation. Consumption of some dietary supplements, namely those containing amino acids and, in the Southern Italy population, vitamins and minerals such as selenium, seemed associated with a statistically imprecise increased risk. Conclusions: Our results suggest a potential etiologic role a number of clinical and lifestyle factors with ALS risk. However, caution is needed due to some study limitations. These include the small sample size and the low number of exposed subjects, which affect statistical precision of risk estimates, the potential for exposure misclassification, and the uncertainties about mechanisms underpinning the possible association between these factors and disease risk.
2020
- Clinical features and outcomes of the flail arm and flail leg and pure lower motor neuron MND variants: A multicentre Italian study
[Articolo su rivista]
Schito, P.; Ceccardi, G.; Calvo, A.; Falzone, Y. M.; Moglia, C.; Lunetta, C.; Marinou, K.; Ticozzi, N.; Scialo, C.; Soraru, G.; Trojsi, F.; Conte, A.; Tortelli, R.; Russo, M.; Zucchi, E.; Pozzi, L.; Domi, T.; Carrera, P.; Agosta, F.; Quattrini, A.; Fazio, R.; Chio, A.; Sansone, V. A.; Mora, G.; Silani, V.; Volanti, P.; Caponnetto, C.; Querin, G.; Tedeschi, G.; Sabatelli, M.; Logroscino, G.; Messina, S.; Mandrioli, J.; Riva, N.; Filippi, M.
abstract
2020
- Environmental and Occupational Risk Factors of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study
[Articolo su rivista]
Filippini, Tommaso; Tesauro, Marina; Fiore, Maria; Malagoli, Carlotta; Consonni, Michela; Violi, Federica; Iacuzio, Laura; Arcolin, Elisa; Oliveri Conti, Gea; Cristaldi, Antonio; Zuccarello, Pietro; Zucchi, Elisabetta; Mazzini, Letizia; Pisano, Fabrizio; Gagliardi, Ileana; Patti, Francesco; Mandrioli, Jessica; Ferrante, Margherita; Vinceti, Marco
abstract
Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with still unknown etiology. We aimed at investigating the association between environmental and occupational factors with ALS risk. Methods: We performed a population-based case-control study in four Italian provinces (Catania, Modena, Novara, and Reggio Emilia) by administration of tailored questionnaires to ALS cases (n = 95) and randomly selected population referents (n = 135). We estimated ALS risk by calculating the odds ratio (OR) with its 95% confidence interval (CI) using an unconditional logistic regression model. Results: We found a positive association with disease risk for history of occupation in the agricultural sector (OR = 2.09, 95% CI 0.79-7.54), especially for longer than 10 years (OR = 2.72, 95% 1.02-7.20). Overall occupational exposure to solvents also suggested a positive association, especially for thinners (OR = 2.27, 95% CI 1.14-4.54) and paint removers (OR = 2.01, 95% CI 0.90-4.48). Both occupational and environmental exposure to electromagnetic fields show a slightly increased risk with OR = 1.69 (95% CI 0.70-4.09) and 2.41 (95% CI 1.13-5.12), respectively. Occupational but not environmental exposure to pesticides (OR = 1.22, 95% CI 0.63-2.37), particularly fungicides, and exposure to metals (OR = 4.20, 95% CI 1.88-9.38), particularly lead, mercury, and selenium, showed an imprecise but positive association. Finally, there was an indication of increased risk for living in proximity to water bodies. Conclusions: Despite the caution that needs to be used due to some study limitations, such as the low number of exposed subjects and the possibility of recall bias, these results suggest the potential role of some environmental and occupational factors in ALS etiology.
2020
- Exposure to particulate matter and risk of amyotrophic lateral sclerosis: A case-control study in Northern Italy
[Abstract in Rivista]
Filippini, T.; Mandrioli, J.; Malagoli, C.; Cherubini, A.; Maffeis, G.; Vinceti, M.
abstract
Background: Amyotrophic lateral sclerosis (ALS) is progressive neurodegenerative disease with still unknown etiology. Role of occupational and environmental risk factors has been investigated, including outdoor air pollutants, which have been recently associated to an excess disease risk. We carried out a case-control study in order to assess if environmental exposure to particulate matter ≤10 µm (PM10) may increase ALS risk. Methods: We recruited patients referred to the Modena Neurology Unit between 1994-2015 and controls from the Modena province population. Using a validated geographical information system-based dispersion model, we geocoded subjects’ addresses of residence at the time of diagnosis and we estimated outdoor air PM10 concentrations for each subjects. We computed odds ratio (OR) and 95% confidence interval (CI) of ALS according to increasing PM10 exposure, using an unconditional logistic regression model age- and sex-adjusted. Results: For the 132 study participants (52 cases/80 controls), mean of annual average and maximum PM10 concentrations were 5.2 and 38.6µg/m3, respectively. Using fixed cutpoints at 5, 10 and 20 of average annual PM10 concentrations, compared with subjects <5µg/m3, we did not find evidence for an excess ALS risk associated with PM10 exposure, since OR was 0.87 (95% CI 0.39-1.96), 0.94 (0.24-3.70), and 0.87 (0.05-15.01) at 5-10, 10-20 and ≥20µg/m3, respectively. Using maximum annual PM10 concentrations, we found an excess ALS risk for subjects exposed at 10-20µg/m3 (OR=4.27, 0.69-26.51) compared with exposure below 10µg/m3, although the risk tended to decrease at higher PM10 concentrations, with OR of 1.49 (0.39-5.75) at 20-50, and 1.16 (0.98-4.82) at ≥50µg/m3. Conclusions:Our findings do not suggest that PM10exposure is associated with ALS risk. However, some evidence of an increased risk associated with maximum annual exposure concentrations, although statistically imprecise, suggests the need of further investigations, also considering the high concentrations of particulate matter characterizing Northern Italy.
2020
- G-CSF (filgrastim) treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomised, double-blind, placebo-controlled, parallel group, multicentre clinical study (STEMALS-II trial)
[Articolo su rivista]
Salamone, P.; Fuda, G.; Casale, F.; Marrali, G.; Lunetta, C.; Caponnetto, C.; Mazzini, L.; La Bella, V.; Mandrioli, J.; Simone, I. L.; Moglia, C.; Calvo, A.; Tarella, C.; Chio, A.
abstract
Introduction Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurological disorder characterised by a selective degeneration of motor neurons (MNs). Stem cell transplantation is considered as a promising strategy in neurological disorders therapy and the possibility of inducing bone marrow cells (BMCs) to circulate in the peripheral blood is suggested to investigate stem cells migration in degenerated ALS nerve tissues where potentially repair MN damage. Granulocyte-colony stimulating factor (G-CSF) is a growth factor which stimulates haematopoietic progenitor cells, mobilises BMCs into injured brain and it is itself a neurotrophic factor for MN. G-CSF safety in humans has been demonstrated and many observations suggest that it may affect neural cells. Therefore, we decided to use G-CSF to mobilise BMCs into the peripheral circulation in patients with ALS, planning a clinical trial to evaluate the effect of G-CSF administration in ALS patients compared with placebo. Methods and analysis STEMALS-II is a phase II multicentre, randomised double-blind, placebo-controlled, parallel group clinical trial on G-CSF (filgrastim) and mannitol in ALS patients. Specifically, we investigate safety, tolerability and efficacy of four repeated courses of intravenous G-CSF and mannitol administered in 76 ALS patients in comparison with placebo (indistinguishable glucose solution 5%). We determine increase of G-CSF levels in serum and cerebrospinal fluid as CD34 + cells and leucocyte count after treatment; reduction in ALS Functional Rating Scale-Revised Score, forced vital capacity, Scale for Testing Muscle Strength Score and quality of life; the adverse events/reactions during the treatment; changes in neuroinflammation biomarkers before and after treatment. Ethics and dissemination The study protocol was approved by the Ethics Committee of Azienda Ospedaliera Universitaria Città della Salute e della Scienza', Torino, Italy. Results will be presented during scientific symposia or published in scientific journals. Trial registration number Eudract 2014-002228-28.
2020
- Living near waterbodies as a proxy of cyanobacteria exposure and risk of amyotrophic lateral sclerosis: a population based case-control study
[Articolo su rivista]
Fiore, Maria; Parisio, Roberto; Filippini, Tommaso; Mantione, Valerio; Platania, Armando; Odone, Anna; Signorelli, Carlo; Pietrini, Vladimiro; Mandrioli, Jessica; Teggi, Sergio; Costanzini, Sofia; Cristaldi, Antonio; Zuccarello, Pietro; Oliveri Conti, Gea; Nicoletti, Alessandra; Zappia, Mario; Vinceti, Marco; Ferrante, Margherita
abstract
Background: Epidemiological studies highlighted the possibility that exposure to cyanotoxins leads to the development of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Methods: We devised a population-based case-control study in two Italian populations. We used residential proximity of the residence to water bodies as a measure of possible exposure to cyanotoxins. Results: Based on 703 newly-diagnosed ALS cases and 2737 controls, we calculated an ALS odds ratio (OR) of 1.41 (95% CI: 0.72–2.74) for current residence in the vicinity of water bodies, and a slightly lower estimate for historical residence (OR: 1.31; 95% CI: 0.57–2.99). Subjects <65 years and people living in the Northern Italy province of Modena had higher ORs, especially when historical residence was considered. Conclusions: Overall, despite some risk of bias due to exposure misclassification and unmeasured confounding, our results appear to support the hypothesis that cyanotoxin exposure may increase ALS risk.
2020
- Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial
[Articolo su rivista]
Mora, J. S.; Genge, A.; Chio, A.; Estol, C. J.; Chaverri, D.; Hernandez, M.; Marin, S.; Mascias, J.; Rodriguez, G. E.; Povedano, M.; Paipa, A.; Dominguez, R.; Gamez, J.; Salvado, M.; Lunetta, C.; Ballario, C.; Riva, N.; Mandrioli, J.; Moussy, A.; Kinet, J. -P.; Auclair, C.; Dubreuil, P.; Arnold, V.; Mansfield, C. D.; Hermine, O.
abstract
Objective: To assess masitinib in the treatment of ALS. Methods: Double-blind study, randomly assigning 394 patients (1:1:1) to receive riluzole (100 mg/d) plus placebo or masitinib at 4.5 or 3.0 mg/kg/d. Following a blinded transition from phase 2 to phase 2/3, a prospectively defined two-tiered design was implemented based on ALSFRS-R progression rate from disease-onset to baseline (ΔFS). This approach selects a more homogeneous primary efficacy population (“Normal Progressors”, ΔFS < 1.1 points/month) while concurrently permitting secondary assessment of the broader population. Primary endpoint was decline in ALSFRS-R at week-48 (ΔALSFRS-R), with the high-dose “Normal Progressor” cohort being the prospectively declared primary efficacy population. Missing data were imputed via last observation carried forward (LOCF) methodology with sensitivity analyses performed to test robustness. Results: For the primary efficacy population, masitinib (n = 99) showed significant benefit over placebo (n = 102) with a ΔALSFRS-R between-group difference (ΔLSM) of 3.4 (95% CI 0.65–6.13; p = 0.016), corresponding to a 27% slowing in rate of functional decline (LOCF methodology). Sensitivity analyses were all convergent, including the conservative multiple imputation technique of FCS-REGPMM with a ΔLSM of 3.4 (95% CI 0.53–6.33; p = 0.020). Secondary endpoints (ALSAQ-40, FVC, and time-to-event analysis) were also significant. Conversely, no significant treatment-effect according to ΔALSFRS-R was seen for the broader “Normal and Fast Progressor” masitinib 4.5 mg/kg/d cohort, or either of the low-dose (masitinib 3.0 mg/kg/d) cohorts. Rates of treatment-emergent adverse events (AEs) (regardless of causality or post-onset ΔFS) were 88% with masitinib 4.5 mg/kg/d, 85% with 3.0 mg/kg/d, and 79% with placebo. Likewise, rates of serious AE were 31, 23, and 18%, respectively. No distinct event contributed to the higher rate observed for masitinib and no deaths were related to masitinib. Conclusions: Results show that masitinib at 4.5 mg/kg/d can benefit patients with ALS. A confirmatory phase 3 study will be initiated to substantiate these data.
2020
- Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers
[Articolo su rivista]
Zucchi, Elisabetta; Bonetto, Valentina; Sorarù, Gianni; Martinelli, Ilaria; Parchi, Piero; Liguori, Rocco; Mandrioli, Jessica
abstract
Motor neuron diseases (MNDs) are etiologically and biologically heterogeneous diseases. The pathobiology of motor neuron degeneration is still largely unknown, and no effective therapy is available. Heterogeneity and lack of specific disease biomarkers have been appointed as leading reasons for past clinical trial failure, and biomarker discovery is pivotal in today's MND research agenda.In the last decade, neurofilaments (NFs) have emerged as promising biomarkers for the clinical assessment of neurodegeneration. NFs are scaffolding proteins with predominant structural functions contributing to the axonal cytoskeleton of myelinated axons. NFs are released in CSF and peripheral blood as a consequence of axonal degeneration, irrespective of the primary causal event. Due to the current availability of highly-sensitive automated technologies capable of precisely quantify proteins in biofluids in the femtomolar range, it is now possible to reliably measure NFs not only in CSF but also in blood.In this review, we will discuss how NFs are impacting research and clinical management in ALS and other MNDs. Besides contributing to the diagnosis at early stages by differentiating between MNDs with different clinical evolution and severity, NFs may provide a useful tool for the early enrolment of patients in clinical trials. Due to their stability across the disease, NFs convey prognostic information and, on a larger scale, help to stratify patients in homogenous groups. Shortcomings of NFs assessment in biofluids will also be discussed according to the available literature in the attempt to predict the most appropriate use of the biomarker in the MND clinic.
2020
- Reply to comment on “environmental and occupational risk factors of amyotrophic lateral sclerosis: A population-based case-control study”
[Articolo su rivista]
Filippini, T.; Tesauro, M.; Fiore, M.; Malagoli, C.; Consonni, M.; Violi, F.; Iacuzio, L.; Arcolin, E.; Conti, G. O.; Cristaldi, A.; Zuccarello, P.; Zucchi, E.; Mazzini, L.; Pisano, F.; Gagliardi, I.; Patti, F.; Mandrioli, J.; Ferrante, M.; Vinceti, M.
abstract
We much appreciate the positive comments and interest concerning our study on the environmental and occupational risk factors of amyotrophic lateral sclerosis (ALS) [...].
2020
- Tetrodotoxin-Sensitive Neuronal-Type Na+ Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation
[Articolo su rivista]
Munger, M. A.; Olgar, Y.; Koleske, M. L.; Struckman, H. L.; Mandrioli, J.; Lou, Q.; Bonila, I.; Kim, K.; Ramos Mondragon, R.; Priori, S. G.; Volpe, P.; Valdivia, H. H.; Biskupiak, J.; Carnes, C. A.; Veeraraghavan, R.; Gyorke, S.; Radwanski, P. B.
abstract
Background Atrial fibrillation (AF) is a comorbidity associated with heart failure and catecholaminergic polymorphic ventricular tachycardia. Despite the Ca2+-dependent nature of both of these pathologies, AF often responds to Na+ channel blockers. We investigated how targeting interdependent Na+/Ca2+ dysregulation might prevent focal activity and control AF. Methods and Results We studied AF in 2 models of Ca2+-dependent disorders, a murine model of catecholaminergic polymorphic ventricular tachycardia and a canine model of chronic tachypacing-induced heart failure. Imaging studies revealed close association of neuronal-type Na+ channels (nNav) with ryanodine receptors and Na+/Ca2+ exchanger. Catecholamine stimulation induced cellular and in vivo atrial arrhythmias in wild-type mice only during pharmacological augmentation of nNav activity. In contrast, catecholamine stimulation alone was sufficient to elicit atrial arrhythmias in catecholaminergic polymorphic ventricular tachycardia mice and failing canine atria. Importantly, these were abolished by acute nNav inhibition (tetrodotoxin or riluzole) implicating Na+/Ca2+ dysregulation in AF. These findings were then tested in 2 nonrandomized retrospective cohorts: an amyotrophic lateral sclerosis clinic and an academic medical center. Riluzole-treated patients adjusted for baseline characteristics evidenced significantly lower incidence of arrhythmias including new-onset AF, supporting the preclinical results. Conclusions These data suggest that nNaVs mediate Na+-Ca2+ crosstalk within nanodomains containing Ca2+ release machinery and, thereby, contribute to AF triggers. Disruption of this mechanism by nNav inhibition can effectively prevent AF arising from diverse causes.
2020
- The NGS technology for the identification of genes associated with the ALS. A systematic review
[Articolo su rivista]
Pecoraro, V.; Mandrioli, J.; Carone, C.; Chio, A.; Traynor, B. J.; Trenti, T.
abstract
Background: More than 30 causative genes have been identified in familial and sporadic amyotrophic lateral sclerosis (ALS). The next-generation sequencing (NGS) is a powerful and groundbreaking tool to identify disease-associated variants. Despite documented advantages of NGS, its diagnostic reliability needs to be addressed in order to use this technology for specific routine diagnosis. Material and Methods: Literature database was explored to identify studies comparing NGS and Sanger sequencing for the detection of variants causing ALS. We collected data about patients’ characteristics, disease type and duration, NGS and Sanger properties. Results: More than 200 bibliographic references were identified, of which only 14 studies matching our inclusion criteria. Only 2 out of 14 studies compared results of NGS analysis with the Sanger sequencing. Twelve studies screened causative genes associated to ALS using NGS technologies and confirmed the identified variants with Sanger sequencing. Overall, data about more 2,000 patients were analysed. The number of genes that were investigated in each study ranged from 1 to 32, the most frequent being FUS, OPTN, SETX and VCP. NGS identified already known mutations in 21 genes, and new or rare variants in 27 genes. Conclusions: NGS seems to be a promising tool for the diagnosis of ALS in routine clinical practice. Its advantages are represented by an increased speed and a lowest sequencing cost, but patients’ counselling could be problematic due to the discovery of frequent variants of unknown significance.
2020
- The study of levels from redox-active elements in cerebrospinal fluid of amyotrophic lateral sclerosis patients carrying disease-related gene mutations shows potential copper dyshomeostasis
[Articolo su rivista]
Violi, F.; Solovyev, N.; Vinceti, M.; Mandrioli, J.; Lucio, M.; Michalke, B.
abstract
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterized by a loss of function of motor neurons. The etiology of this disorder is still largely unknown. Gene-environment interaction arises as a possible key factor in the development of amyotrophic lateral sclerosis. We assessed the levels of trace metals, copper (Cu), iron (Fe), and manganese (Mn), of 9 amyotrophic lateral sclerosis cases and 40 controls by measuring their content in cerebrospinal fluid. The following trace element species were quantified using ion chromatography-inductively coupled plasma mass spectrometry: univalent copper (Cu-I), divalent Cu (Cu-II), divalent Fe (Fe-II), trivalent Fe (Fe-III), divalent Mn (Mn-II), trivalent Mn (Mn-III), and also unidentified Mn species (Mn-unknown) were present in some samples. When computing the relative risks for amyotrophic lateral sclerosis through an unconditional logistic regression model, we observed a weak and imprecise positive association for iron (Fe III, adjusted odds ratio 1.48, 95% CI 0.46-4.76) and manganese (total-Mn and Mn-II; adjusted odds ratio 1.11, 95% CI 0.74-1.67, and 1.13, 95% CI 0.79-1.61, respectively). Increased risk for copper was found both in the crude analysis (odds ratio 1.14, 95% CI 0.99-1.31) and in multivariable analysis after adjusting for sex, age, and year of storage (1.09, 95% CI 0.90-1.32). Our results suggest a possible positive association between Cu and genetic amyotrophic lateral sclerosis, while they give little indication of involvement of Fe and Mn in disease, though some correlations found also for these elements deserve further investigation.
2019
- Amyotrophic lateral sclerosis incidence following exposure to inorganic selenium in drinking water
[Abstract in Atti di Convegno]
Vinceti, M; Filippini, T; Malagoli, C; Violi, F; Mandrioli, J; Consonni, D; Rothman, Kj; Wise, La
abstract
Background and aim. Some laboratory and epidemiologic studies have documented an association between high intake of the trace element selenium and risk of amyotrophic lateral sclerosis (ALS), a degenerative disease of the motor neurons. There have been few epidemiologic studies of the association.
Methods. From 1986 through 2015, we followed a community cohort in northern Italy that had been inadvertently exposed in the 1974-86 period to drinking water with unusually high levels of selenium, around 8 µg/ml, in its inorganic hexavalent form (selenate). In this cohort, we previously identified a high incidence of ALS during 1986-94. Here we report extended follow-up of this exposed cohort, as well as of an unexposed cohort including over 95,000 municipal residents, for an additional 21 years. We identified incident cases through administrative sources and a specialized registry.
Results. During follow-up, 7 and 112 ALS cases were newly diagnosed in the exposed and unexposed cohorts, respectively, yielding incidence rates of 14 and 5 per 100,000 person-years. A Poisson regression analysis adjusting for age, sex, and calendar year produced an overall rate ratio (RR) for ALS of 2.8 (95% confidence interval (CI) 1.3 - 6) in the entire period of follow-up. The association was stronger earlier than later in follow-up (1986-1994 vs. 1994-2015), and among women than men. All exposed cases were of the sporadic, non-familial form for the disease.
Conclusion. Overall, results from this ‘natural experiment’ indicate a positive association between chronic exposure to inorganic selenium and ALS incidence, with rates in the exposed cohort declining over time after cessation of exposure. Also taking into account the recognized neurotoxicity of selenium, particularly its selective toxicity on motor neurons observed in animal studies, the present study provides additional support for the hypothesis that selenium in its inorganic form increases ALS risk.
2019
- Amyotrophic lateral sclerosis incidence following exposure to inorganic selenium in drinking water: A long-term follow-up
[Articolo su rivista]
Vinceti, M.; Filippini, T.; Malagoli, C.; Violi, F.; Mandrioli, J.; Consonni, D.; Rothman, K. J.; Wise, L. A.
abstract
Some studies have reported an association between overexposure to selenium and risk of amyotrophic lateral sclerosis (ALS), a rare degenerative disease of motor neurons. From 1986 through 2015, we followed a cohort in Northern Italy that had been inadvertently consuming tap water with unusually high concentrations of inorganic hexavalent selenium from 1974 to 1985. We had previously documented an excess incidence of ALS in this cohort during 1986-1994. Here, we report extended follow-up of the cohort for an additional 21 years, encompassing 50,100 person-years of the exposed cohort and 2,233,963 person-years of the unexposed municipal cohort. We identified 7 and 112 incident ALS cases in the exposed and unexposed cohorts, respectively, yielding crude incidence rates of 14 and 5 cases per 100,000 person-years. A Poisson regression analysis, adjusting for age, sex and calendar year, produced an overall incidence rate ratio (IRR) for ALS of 2.8 (95% confidence interval (CI) 1.3, 6), with a substantially stronger IRR in 1986-1994 (8.2, 95% CI 2.7, 24.7) than in 1995-2015 (1.5, 95% CI 0.5, 4.7), and among women (5.1, 95% CI 1.8, 14.3) than men (1.7, 95% CI 0.5, 5.4). Overall, these results indicate an association between high exposure to inorganic selenium, a recognized neurotoxicant, and ALS incidence, with declining rates after cessation of exposure and stronger effects among women.
2019
- Comparative analysis of C9Orf72 and sporadic disease in a large multicenter ALS population: The effect of Male sex on survival of C9Orf72 positive patients
[Articolo su rivista]
Trojsi, F.; Siciliano, M.; Femiano, C.; Santangelo, G.; Lunetta, C.; Calvo, A.; Moglia, C.; Marinou, K.; Ticozzi, N.; Ferro, C.; Scialo, C.; Soraru, G.; Conte, A.; Falzone, Y. M.; Tortelli, R.; Russo, M.; Sansone, V. A.; Chio, A.; Mora, G.; Silani, V.; Volanti, P.; Caponnetto, C.; Querin, G.; Sabatelli, M.; Riva, N.; Logroscino, G.; Messina, S.; Fasano, A.; Monsurro, M. R.; Tedeschi, G.; Mandrioli, J.
abstract
We investigated whether the C9orf72 repeat expansion is associated with specific clinical features, comorbidities, and prognosis in patients with amyotrophic lateral sclerosis (ALS). A cohort of 1417 ALS patients, diagnosed between January 1, 2009 and December 31, 2013 by 13 Italian ALS Referral Centers, was screened for the C9orf72 repeat expansion, and the analyses were performed comparing patients carrying this expansion (ALS-C9Pos) to those negative for this and other explored ALS-related mutations (ALS without genetic mutations, ALSwoGM). Compared to the ALSwoGM group, ALS-C9Pos patients (n = 84) were younger at disease onset, at the first clinical observation and at diagnosis (p < 0.001). After correcting for these differences, we found that ALS-C9Pos patients had higher odds of bulbar onset, diagnosis of frontotemporal dementia (FTD) and family history of ALS, FTD, and Alzheimer's disease and had lower odds of spinal onset, non-invasive ventilation, hypertension and psychiatric diseases than ALSwoGM patients. Among these variables, those related to shorter survival time were: bulbar onset, presence of FTD, hypertension, psychiatric disease, and family history of ALS (p < 0.05). Cox proportional hazards regression multivariate analysis suggested that carrying the C9orf72 repeat expansion was an independent factor negatively impacting on survival time in men (HR 1.58, 95% CI 1.07-2.33, p = 0.021), but not in women (p > 0.05) as well as in the whole sample (p > 0.05). When compared to ALSwoGM, ALS-C9Pos showed an earlier disease onset, no significant diagnostic delay and a higher odds of bulbar onset, FTD and family history of ALS and dementia. Moreover, male sex drove the negative effect of expanded variant on survival, confirming the hypothesis that sex is likely to be a crucial factor in the biology of C9orf72-related disease.
2019
- Exposure to inorganic selenium in drinking water and incidence of amyotrophic lateral sclerosis: a long-term follow-up of a natural experiment
[Poster]
Vinceti, Marco; Filippini, Tommaso; Malagoli, Carlotta; Violi, Federica; Mandrioli, Jessica; Consonni, Dario; Rothman, Kenneth; Wise, LAUREN ANNE
abstract
Background: Some studies have reported an association between overexposure to selenium and risk of amyotrophic lateral sclerosis (ALS), a rare degenerative disease of motor neurons. From 1986 through 2015, we followed a cohort in Northern Italy that had been inadvertently consuming tap water with unusually high concentrations of inorganic hexavalent selenium from 1974 to 1985. Methods: We had previously documented an excess incidence of ALS in this cohort during 1986-1994. Here, we report extended follow-up of the cohort for an additional 21 years, encompassing 50,100 person-years of the exposed cohort and 2,233,963 person-years of the unexposed municipal cohort. We assessed ALS risk using a Poisson regression analysis, adjusting for age, sex and calendar year. Results: We identified 7 and 112 incident ALS cases in the exposed and unexposed cohorts, respectively, yielding crude incidence rates of 14 and 5 cases per 100,000 person-years. The Poisson regression analysis produced an overall incidence rate ratio (IRR) for ALS of 2.8 (95% confidence interval (CI) 1.3, 6), with a substantially stronger IRR in 1986-1994 (8.2, 95% CI 2.7, 24.7) than in 1995-2015 (1.5, 95% CI 0.5, 4.7), and among women (5.1, 95% CI 1.8, 14.3) than men (1.7, 95% CI 0.5, 5.4). Conclusions: Overall, these results indicate an association between high exposure to inorganic selenium, a recognized neurotoxicant, and ALS incidence, with declining rates after cessation of exposure and stronger effects among women.
2019
- FETR-ALS Study Protocol: A Randomized Clinical Trial of Fecal Microbiota Transplantation in Amyotrophic Lateral Sclerosis
[Articolo su rivista]
Mandrioli, J.; Amedei, A.; Cammarota, G.; Niccolai, E.; Zucchi, E.; D'Amico, R.; Ricci, F.; Quaranta, G.; Spanu, T.; Masucci, L.
abstract
Background and Rationale: Among the key players in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), microglia and T regulatory lymphocytes (Treg) are candidate cells for modifying the course of the disease. The gut microbiota (GM) acts by shaping immune tolerance and regulating the Treg number and suppressive function, besides circulating neuropeptides, and other immune cells that play in concert through the gut-brain axis. Previous mouse models have shown an altered enteric flora in early stage ALS, pointing to a possible GM role in ALS pathogenesis. Fecal Microbial Transplantation (FMT) is a well-known therapeutic intervention used to re-establish the proper microenvironment and to modulate enteric and systemic immunity. Methods: We are going to perform a multicenter randomized double-blind clinical trial employing FMT as a therapeutic intervention for ALS patients (NCT0376632). Forty-two ALS patients, at an early stage, will be enrolled with a 2:1 allocation ratio (28 FMT-treated patients vs. 14 controls). Study duration will be 12 months per patient. Three endoscopic procedures for intestinal biopsies in FMT and control groups are predicted at baseline, month 6 and month 12; at baseline and at month 6 fresh feces from healthy donors will be infused at patients in the intervention arm. The primary outcome is a significant change in Treg number between FMT-treated patients and control arm from baseline to month 6. Secondary outcomes include specific biological aims, involving in-depth analysis of immune cells and inflammatory status changes, central and peripheral biomarkers of ALS, besides comprehensive analysis of the gut, saliva and fecal microbiota. Other secondary aims include validated clinical outcomes of ALS (survival, forced vital capacity, and modifications in ALSFRS-R), besides safety and quality of life. Expected Results: We await FMT to increase Treg number and suppressive functionality, switching the immune system surrounding motorneurons to an anti-inflammatory, neuroprotective status. Extensive analysis on immune cell populations, cytokines levels, and microbiota (gut, fecal and saliva) will shed light on early processes possibly leading the degenerative ALS course. Conclusions: This is the first trial with FMT as a potential intervention to modify immunological response to ALS and disease progression at an early stage.
2019
- High‐frequency motor rehabilitation in amyotrophic lateral sclerosis: a randomized clinical trial
[Articolo su rivista]
Zucchi, Elisabetta; Vinceti, Marco; Malagoli, Carlotta; Fini, Nicola; Gessani, Annalisa; Fasano, Antonio; Rizzi, Romana; Sette, Elisabetta; Cavazza, Stefano; Fiocchi, Alena; Buja, Sergio; Faccioli, Tiziana; Storani, Simone; Mandrioli, Jessica
abstract
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2019
- Influence of selenium on the emergence of neuro tubule defects in a neuron-like cell line and its implications for amyotrophic lateral sclerosis
[Articolo su rivista]
Maraldi, T.; Beretti, F.; Anselmi, L.; Franchin, C.; Arrigoni, G.; Braglia, L.; Mandrioli, J.; Vinceti, M.; Marmiroli, S.
abstract
Impairment of the axonal transport system mediated by intracellular microtubules (MTs) is known to be a major drawback in neurodegenerative processes. Due to a growing interest on the neurotoxic effects of selenium in environmental health, our study aimed to assess the relationship between selenium and MTs perturbation, that may favour disease onset over a genetic predisposition to amyotrophic lateral sclerosis. We treated a neuron-like cell line with sodium selenite, sodium selenate and seleno-methionine and observed that the whole cytoskeleton was affected. We then investigated the protein interactome of cells overexpressing αTubulin-4A (TUBA4A) and found that selenium increases the interaction of TUBA4A with DNA- and RNA-binding proteins. TUBA4A ubiquitination and glutathionylation were also observed, possibly due to a selenium-dependent increase of ROS, leading to perturbation and degradation of MTs. Remarkably, the TUBA4A mutants R320C and A383 T, previously described in ALS patients, showed the same post-translational modifications to a similar extent. In conclusion this study gives insights into a specific mechanism characterizing selenium neurotoxicity.
2019
- Pearls & Oy-sters: Paroxysmal dysarthria-ataxia syndrome: Acoustic analysis in a case of antiphospholipid syndrome
[Articolo su rivista]
Gessani, Annalisa; Cavallieri, Francesco; Budriesi, Carla; Zucchi, Elisabetta; Malagoli, Marcella; Contardi, Sara; Mascia, Maria Teresa; Giovannini, Giada; Mandrioli, Jessica
abstract
Pearls:
Paroxysmal dysarthria-ataxia syndrome (PDA), first described by Parker in 1946, is characterized by paroxysmal and stereotyped repeated daily episodes of sudden ataxic symptoms associated with dysarthric speech lasting from few seconds to minutes.1 During the episodes, patients present with slow speech, irregular articulatory breakdown, dysprosodia, hypernasality, variable pitch and loudness, and prolonged intervals, consistent with perceptual characteristics of ataxic dysarthria.2,3
PDA is a rare neurologic manifestation of either genetic or acquired conditions.2 The most frequent genetic diseases occurring with PDA are episodic ataxias, a group of dominantly inherited disorders characterized by transient and recurrent episodes of truncal instability and limbs incoordination triggered by exertion or emotional stress.4 Among acquired conditions, PDA has been reported mainly in multiple sclerosis (MS), in other immunomediated diseases, or in ischemic stroke.5,–,7 The common finding among these diseases is the involvement of cerebellar pathways, specifically the crossed fibers of cerebello-thalamocortical pathway in the lower midbrain. Indeed, most of the reported cases of PDA suggest that the responsible lesion is located in the midbrain, near or in the red nucleus,8 where a lesion frequently reveals with dysarthria.9,10
Oy-sters:
Until now, the pathophysiologic basis of PDA remains unknown, as well as the characterization of dysarthria during PDA.
We present a case of PDA in a patient with antiphospholipid syndrome (APS) evaluated with an acoustic and perceptual analysis of speech to determine the specific pattern of paroxysmal dysarthria.
2019
- Proteostasis and ALS: Protocol for a phase II, randomised, double-blind, placebo-controlled, multicentre clinical trial for colchicine in ALS (Co-ALS)
[Articolo su rivista]
Mandrioli, J.; Crippa, V.; Cereda, C.; Bonetto, V.; Zucchi, E.; Gessani, A.; Ceroni, M.; Chio, A.; D'Amico, R.; Monsurro, M. R.; Riva, Nicoletta; Sabatelli, M.; Silani, V.; Simone, I. L.; Soraru, G.; Provenzani, A.; D'Agostino, V. G.; Carra, S.; Poletti, Arcadio
abstract
Introduction: Disruptions of proteasome and autophagy systems are central events in amyotrophic lateral sclerosis (ALS) and support the urgent need to find therapeutic compounds targeting these processes. The heat shock protein B8 (HSPB8) recognises and promotes the autophagy-mediated removal of misfolded mutant SOD1 and TDP-43 fragments from ALS motor neurons (MNs), as well as aggregating species of dipeptides produced in C9ORF72-related diseases. In ALS-SOD1 mice and in human ALS autopsy specimens, HSPB8 is highly expressed in spinal cord MNs that survive at the end stage of disease. Moreover, the HSPB8-BAG3-HSP70 complex maintains granulostasis, which avoids conversion of dynamic stress granules (SGs) into aggregation-prone assemblies. We will perform a randomised clinical trial (RCT) with colchicine, which enhances the expression of HSPB8 and of several autophagy players, blocking TDP-43 accumulation and exerting crucial activities for MNs function. Methods and analysis: Colchicine in amyotrophic lateral sclerosis (Co-ALS) is a double-blind, placebo-controlled, multicentre, phase II RCT. ALS patients will be enrolled in three groups (placebo, colchicine 0.01 mg/day and colchicine 0.005 mg/day) of 18 subjects treated with riluzole; treatment will last 30 weeks, and follow-up will last 24 weeks. The primary aim is to assess whether colchicine decreases disease progression as measured by ALS Functional Rating Scale - Revised (ALSFRS-R) at baseline and at treatment end. Secondary aims include assessment of (1) safety and tolerability of Colchicine in patiets with ALS; (2) changes in cellular activity (autophagy, protein aggregation, and SG and exosome secretion) and in biomarkers of disease progression (neurofilaments); (3) survival and respiratory function and (4) quality of life. Preclinical studies with a full assessment of autophagy and neuroinflammation biomarkers in fibroblasts, peripheral blood mononuclear cells and lymphoblasts will be conducted in parallel with clinic assessment to optimise time and resources. Ethics and dissemination: The study protocol was approved by the Ethics Committee of Area Vasta Emilia Nord and by Agenzia Italiana del Farmaco (EUDRACT N.2017-004459-21) based on the Declaration of Helsinki. This research protocol was written without patient involvement. Patients' association will be involved in disseminating the study design and results. Results: will be presented during scientific symposia or published in scientific journals.
2019
- Psychiatric Symptoms in Amyotrophic Lateral Sclerosis: Beyond a Motor Neuron Disorder
[Articolo su rivista]
Zucchi, E.; Ticozzi, N.; Mandrioli, J.
abstract
The historical view that Amyotrophic Lateral Sclerosis (ALS) as a pure motor disorder has been increasingly challenged by the discovery of cognitive and behavioral changes in the spectrum of Frontotemporal Dementia (FTD). Less recognized and still significant comorbidities that ALS patients may present are prior or concomitant psychiatric illness, such as psychosis and schizophrenia, or mood disorders. These non-motor symptoms disturbances have a close time relationship with disease onset, may constitute part of a larger framework of network disruption in motor neuron disorders, and may impact ALS patients and families, with regards to ethical choices and end-of-life decisions. This review aims at identifying the most common psychiatric alterations related to ALS and its prognosis, looking at a common genetic background and shared structural brain pathology.
2019
- Serial Ultrasound Assessment of Diaphragmatic Function and Clinical Outcome in Patients with Amyotrophic Lateral Sclerosis.
[Articolo su rivista]
Fantini, Riccardo; Tonelli, Roberto; Castaniere, Ivana; Tabbì, Luca; Pellegrino, Maria Rosaria; Cerri, Stefania; Livrieri, Francesco; Giaroni, Francesco; Monelli, Marco; Ruggieri, Valentina; Fini, Nicola; Mandrioli, Jessica; Clini, Enrico; Marchioni, Alessandro; Stefania, Cerri
abstract
Background: Ultrasound (US) evaluation of the diaphragm may be a non-volitional useful tool in the clinical management of patients with ALS. Aim of the present study was then to evaluate the impact of serial assessment of ΔTmax index on clinical outcomes during the follow-up in these patients and to correlate non-volitional US indices and other volitional measures with these outcomes.
Methods: A cohort of 39 consecutive patients with ALS was followed up to 24 months. At baseline and every 3-month spirometry (forced vital capacity-FVC), sniff inspiratory nasal pressure (SNIP), and US of the diaphragm (ΔTdi and ΔTmax) were recorded. These parameters were correlated with clinical outcomes (hypercapnia, nocturnal hypoventilation, NIV start in the following 6 month, and death within 1 year).
Results: The occurrence of ΔTmax >0.75 during follow-up increased the risk for NIV (HR=5.6, p=0.001) and death (HR=3.7, p=0.0001) compared with patients with stable lower values. The evidence of diaphragmatic dysfunction, i.e. ΔTmax >0.75, occurs 3.2 month earlier than the onset of NIV. Moreover, ΔTmax >0.75 correlated with onset of nocturnal hypoventilation, NIV initiation within 6 months, and death within 12 months, similarly to FVC <50% predicted and better than other functional indices.
Conclusions: Serial monitoring of diaphragmatic ΔTmax by US may be useful to predict initiation of NIV and death in patients with ALS. The occurrence of an abnormal ΔTmax value in the follow-up precedes the decision for starting NIV.
2019
- Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis
[Articolo su rivista]
Bandres-Ciga, S.; Noyce, A. J.; Hemani, G.; Nicolas, A.; Calvo, A.; Mora, G.; Arosio, A.; Barberis, M.; Bartolomei, I.; Battistini, S.; Benigni, M.; Borghero, G.; Brunetti, M.; Cammarosano, S.; Cannas, A.; Canosa, A.; Capasso, M.; Caponnetto, C.; Caredda, C.; Carrera, P.; Casale, F.; Cavallaro, S.; Chio, A.; Colletti, T.; Conforti, F. L.; Conte, A.; Corrado, L.; Costantino, E.; D'Alfonso, S.; Fasano, A.; Femiano, C.; Ferrarese, C.; Fini, N.; Floris, G.; Fuda, G.; Giannini, F.; Grassano, M.; Ilardi, A.; La Bella, V.; Lattante, S.; Logroscino, G.; Logullo, F. O.; Loi, D.; Lunetta, C.; Mancardi, G.; Mandich, P.; Mandrioli, J.; Manera, U.; Marangi, G.; Marinou, K.; Marrali, G.; Marrosu, M. G.; Mazzini, L.; Melis, M.; Messina, S.; Moglia, C.; Monsurro, M. R.; Mosca, L.; Occhineri, P.; Origone, P.; Pani, C.; Penco, S.; Petrucci, A.; Piccirillo, G.; Pirisi, A.; Pisano, F.; Pugliatti, M.; Restagno, G.; Ricci, C.; Rita Murru, M.; Riva, N.; Sabatelli, M.; Salvi, F.; Santarelli, M.; Sideri, R.; Simone, I.; Spataro, R.; Tanel, R.; Tedeschi, G.; Tranquilli, S.; Tremolizzo, L.; Trojsi, F.; Volanti, P.; Zollino, M.; Abramzon, Y.; Arepalli, S.; Baloh, R. H.; Bowser, R.; Brady, C. B.; Brice, A.; Broach, J.; Campbell, R. H.; Camu, W.; Chia, R.; Cooper-Knock, J.; Cusi, D.; Ding, J.; Drepper, C.; Drory, V. E.; Dunckley, T. L.; Eicher, J. D.; Faghri, F.; Feldman, E.; Kay Floeter, M.; Fratta, P.; Geiger, J. T.; Gerhard, G.; Gibbs, J. R.; Gibson, S. B.; Glass, J. D.; Hardy, J.; Harms, M. B.; Heiman-Patterson, T. D.; Hernandez, D. G.; Jansson, L.; Kamel, F.; Kirby, J.; Kowall, N. W.; Laaksovirta, H.; Le Ber, I.; Lumbroso, S.; Macgowan, D. J. L.; Maragakis, N. J.; Mouzat, K.; Murphy, N. A.; Myllykangas, L.; Nalls, M. A.; Orrell, R. W.; Ostrow, L. W.; Pamphlett, R.; Pickering-Brown, S.; Pioro, E.; Pliner, H. A.; Pulst, S. M.; Ravits, J. M.; Renton, A. E.; Rivera, A.; Robbrecht, W.; Rogaeva, E.; Rollinson, S.; Rothstein, J. D.; Salvi, E.; Scholz, S. W.; Sendtner, M.; Shaw, P. J.; Sidle, K. C.; Simmons, Z.; Singleton, A. B.; Stone, D. C.; Sulkava, R.; Tienari, P. J.; Traynor, B. J.; Trojanowski, J. Q.; Troncoso, J. C.; Van Damme, P.; Van Deerlin, V. M.; Van Den Bosch, L.; Zinman, L.; Stone, D. J.
abstract
Objective: To identify shared polygenic risk and causal associations in amyotrophic lateral sclerosis (ALS). Methods: Linkage disequilibrium score regression and Mendelian randomization were applied in a large-scale, data-driven manner to explore genetic correlations and causal relationships between >700 phenotypic traits and ALS. Exposures consisted of publicly available genome-wide association studies (GWASes) summary statistics from MR Base and LD-hub. The outcome data came from the recently published ALS GWAS involving 20,806 cases and 59,804 controls. Multivariate analyses, genetic risk profiling, and Bayesian colocalization analyses were also performed. Results: We have shown, by linkage disequilibrium score regression, that ALS shares polygenic risk genetic factors with a number of traits and conditions, including positive correlations with smoking status and moderate levels of physical activity, and negative correlations with higher cognitive performance, higher educational attainment, and light levels of physical activity. Using Mendelian randomization, we found evidence that hyperlipidemia is a causal risk factor for ALS and localized putative functional signals within loci of interest. Interpretation: Here, we have developed a public resource (https://lng-nia.shinyapps.io/mrshiny) which we hope will become a valuable tool for the ALS community, and that will be expanded and updated as new data become available. Shared polygenic risk exists between ALS and educational attainment, physical activity, smoking, and tenseness/restlessness. We also found evidence that elevated low-desnity lipoprotein cholesterol is a causal risk factor for ALS. Future randomized controlled trials should be considered as a proof of causality. Ann Neurol 2019;85:470–481.
2019
- Spasmodic dysphonia as a presenting symptom of spinocerebellar ataxia type 12
[Articolo su rivista]
Rossi, J.; Cavallieri, F.; Giovannini, G.; Budriesi, C.; Gessani, A.; Carecchio, M.; Di Bella, D.; Sarto, E.; Mandrioli, J.; Contardi, S.; Meletti, S.
abstract
Autosomal dominant spinocerebellar ataxia (SCA) type 12 is a rare SCA characterized by a heterogeneous phenotype. Action tremor of the upper limbs is the most common presenting sign and cerebellar signs can appear subsequently. In many cases, minor signs, like dystonia, can be predominant even at onset. Laryngeal dystonia (spasmodic dysphonia) has been observed only in one case of SCA12 and never reported at disease onset. We present a 61-year-old female who developed spasmodic dysphonia followed by dystonic tremor and subsequent ataxia diagnosed with SCA12. Thus, spasmodic dysphonia can be a presenting symptom of SCA12.
2018
- Cardiovascular diseases may play a negative role in the prognosis of amyotrophic lateral sclerosis
[Articolo su rivista]
Mandrioli, J.; Ferri, L.; Fasano, A.; Zucchi, E.; Fini, N.; Moglia, C.; Lunetta, C.; Marinou, K.; Ticozzi, N.; Drago Ferrante, G.; Scialo, C.; Soraru, G.; Trojsi, F.; Conte, A.; Falzone, Y. M.; Tortelli, R.; Russo, M.; Sansone, V. A.; Mora, G.; Silani, V.; Volanti, P.; Caponnetto, C.; Querin, G.; Monsurro, M. R.; Sabatelli, M.; Chio, A.; Riva, N.; Logroscino, G.; Messina, S.; Calvo, A.
abstract
Background and purpose: Only a few studies have considered the role of comorbidities in the prognosis of amyotrophic lateral sclerosis (ALS) and have provided conflicting results. Methods: Our multicentre, retrospective study included patients diagnosed from 1 January 2009 to 31 December 2013 in 13 referral centres for ALS located in 10 Italian regions. Neurologists at these centres collected a detailed phenotypic profile and follow-up data until death in an electronic database. Comorbidities at diagnosis were recorded by main categories and single medical diagnosis, with the aim of investigating their role in ALS prognosis. Results: A total of 2354 incident cases were collected, with a median survival time from onset to death/tracheostomy of 43 months. According to univariate analysis, together with well-known clinical prognostic factors (age at onset, diagnostic delay, site of onset, phenotype, Revised El Escorial Criteria and body mass index at diagnosis), the presence of dementia, hypertension, heart disease, chronic obstructive pulmonary disease, haematological and psychiatric diseases was associated with worse survival. In multivariate analysis, age at onset, diagnostic delay, phenotypes, body mass index at diagnosis, Revised El Escorial Criteria, dementia, hypertension, heart diseases (atrial fibrillation and heart failure) and haematological diseases (disorders of thrombosis and haemostasis) were independent prognostic factors of survival in ALS. Conclusions: Our large, multicentre study demonstrated that, together with the known clinical factors that are known to be prognostic for ALS survival, hypertension and heart diseases (i.e. atrial fibrillation and heart failure) as well as haematological diseases are independently associated with a shorter survival. Our findings suggest some mechanisms that are possibly involved in disease progression, giving new interesting clues that may be of value for clinical practice and ALS comorbidity management.
2018
- Central pontine myelinolysis and poorly controlled diabetes: MRI’s hints for pathogenesis
[Articolo su rivista]
Fasano, Antonio; Cavallieri, Francesco; Mandrioli, Jessica; Chiari, Annalisa; Nichelli, Paolo
abstract
Dear Sir,
Central pontine myelinolysis (CPM) is usually associated with a rapid correction of hyponatremia [1, 2]. In a patient with chronic hyponatremia, oligodendrocytes in the pons decrease their inner osmolarity to protect them from swelling. Thereafter, any rapid osmotic shift in the opposite direction caused by the hypertonic fluid can induce the swollen cells to shrink, leading to osmotic demyelination [1, 2]. Typical MRI features in CPM are characterized by cytotoxic edema (DWI hyperintensity and ADC hypointensity) consistent with shrinkage of the pontine cells [3]. We describe a case of CPM due to poorly controlled diabetes with brain MRI features compatible with vasogenic edema (DWI and ADC hyperintensity) that may suggest an extracellular space expansion rather than shrinkage of the pontine cells
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
- Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
[Articolo su rivista]
Nicolas, A; Kenna, Kp; Renton, Ae; Ticozzi, N; Faghri, F; Chia, R; Dominov, Ja; Kenna, Bj; Nalls, Ma; Keagle, P; Rivera, Am; van Rheenen, W; Murphy, Na; van Vugt, Jjfa; Geiger, Jt; Van der Spek, Ra; Pliner, Ha; Shankaracharya, ; Smith, Bn; Marangi, G; Topp, Sd; Abramzon, Y; Gkazi, As; Eicher, Jd; Kenna, A; Italsgen, Consortium; Mora, G; Calvo, A; Mazzini, L; Riva, N; Mandrioli, J; Caponnetto, C; Battistini, S; Volanti, P; La Bella, V; Conforti, Fl; Borghero, G; Messina, S; Simone, Il; Trojsi, F; Salvi, F; Logullo, Fo; D'Alfonso, S; Corrado, L; Capasso, M; Ferrucci, L; Genomic Translation for ALS Care (GTAC), Consortium; Moreno, Cam; Kamalakaran, S; Goldstein, Db; ALS Sequencing, Consortium; Gitler, Ad; Harris, T; Myers, Rm; Nygc Als, Consortium; Phatnani, H; Musunuri, Rl; Evani, Us; Abhyankar, A; Zody, Mc; Answer ALS, Foundation; Kaye, J; Finkbeiner, S; Wyman, Sk; LeNail, A; Lima, L; Fraenkel, E; Svendsen, Cn; Thompson, Lm; Van Eyk, Je; Berry, Jd; Miller, Tm; Kolb, Sj; Cudkowicz, M; Baxi, E; Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe), Consortium; Benatar, M; Taylor, Jp; Rampersaud, E; Wu, G; Wuu, J; Slagen, Consortium; Lauria, G; Verde, F; Fogh, I; Tiloca, C; Comi, Gp; Sorarù, G; Cereda, C; French ALS, Consortium; Corcia, P; Laaksovirta, H; Myllykangas, L; Jansson, L; Valori, M; Ealing, J; Hamdalla, H; Rollinson, S; Pickering-Brown, S; Orrell, Rw; Sidle, Kc; Malaspina, A; Hardy, J; Singleton, Ab; Johnson, Jo; Arepalli, S; Sapp, Pc; McKenna-Yasek, D; Polak, M; Asress, S; Al-Sarraj, S; King, A; Troakes, C; Vance, C; de Belleroche, J; Baas, F; Ten Asbroek, Alma; Muñoz-Blanco, Jl; Hernandez, Dg; Ding, J; Gibbs, Jr; Scholz, Sw; Floeter, Mk; Campbell, Rh; Landi, F; Bowser, R; Pulst, Sm; Ravits, Jm; MacGowan, Djl; Kirby, J; Pioro, Ep; Pamphlett, R; Broach, J; Gerhard, G; Dunckley, Tl; Brady, Cb; Kowall, Nw; Troncoso, Jc; Le Ber, I; Mouzat, K; Lumbroso, S; Heiman-Patterson, Td; Kamel, F; Van Den Bosch, L; Baloh, Rh; Strom, Tm; Meitinger, T; Shatunov, A; Van Eijk, Kr; de Carvalho, M; Kooyman, M; Middelkoop, B; Moisse, M; McLaughlin, Rl; Van Es, Ma; Weber, M; Boylan, Kb; Van Blitterswijk, M; Rademakers, R; Morrison, Ke; Basak, An; Mora, Js; Drory, Ve; Shaw, Pj; Turner, Mr; Talbot, K; Hardiman, O; Williams, Kl; Fifita, Ja; Nicholson, Ga; Blair, Ip; Rouleau, Ga; Esteban-Pérez, J; García-Redondo, A; Al-Chalabi, A; Project MinE ALS Sequencing, Consortium; Rogaeva, E; Zinman, L; Ostrow, Lw; Maragakis, Nj; Rothstein, Jd; Simmons, Z; Cooper-Knock, J; Brice, A; Goutman, Sa; Feldman, El; Gibson, Sb; Taroni, F; Ratti, A; Gellera, C; Van Damme, P; Robberecht, W; Fratta, P; Sabatelli, M; Lunetta, C; Ludolph, Ac; Andersen, Pm; Weishaupt, Jh; Camu, W; Trojanowski, Jq; Van Deerlin, Vm; Brown RH, Jr.; van den Berg, Lh; Veldink, Jh; Harms, Mb; Glass, Jd; Stone, Dj; Tienari, P; Silani, V; Chiò, A; Shaw, Ce; Traynor, Bj; Landers, Je
abstract
To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS.
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
- Rapamycin treatment for amyotrophic lateral sclerosis protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial)
[Articolo su rivista]
Mandrioli, J.; D'Amico, R.; Zucchi, E.; Gessani, A.; Fini, N.; Fasano, A.; Caponnetto, C.; Chio, A.; Bella, E. D.; Lunetta, C.; Mazzini, L.; Marinou, K.; Soraru, G.; De Biasi, S.; Lo Tartaro, D.; Pinti, M.; Nichelli, P.; Vicini, R.; Cabona, C.; Calvo, A.; Moglia, C.; Manera, U.; Fuda, G.; Canosa, A.; Ilardi, A.; Lauria, G.; Dalla Bella, E.; Gerardi, F.; Scognamiglio, A.; De Marchi, F.; Mora, G.; Gizzi, M.; Cossarizza, A.
abstract
Introduction: Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions. Rapamycin also expands regulatory T lymphocytes (Treg) and increased Treg levels are associated with slow progression in ALS patients. Therefore, we planned a randomized clinical trial testing Rapamycin treatment in ALS patients. Methods: RAP-ALS is a phase II randomized, double-blind, placebo-controlled, multicenter (8 ALS centers in Italy), clinical trial. The primary aim is to assess whether Rapamycin administration increases Tregs number in treated patients compared with control arm. Secondary aims include the assessment of safety and tolerability of Rapamycin in patients with ALS; the minimum dosage to have Rapamycin in cerebrospinal fluid; changes in immunological (activation and homing of T, B, NK cell subpopulations) and inflammatory markers, and on mTOR downstream pathway (S6RP phosphorylation); clinical activity (ALS Functional Rating Scale-Revised, survival, forced vital capacity); and quality of life (ALSAQ40 scale). Discussion: Rapamycin potentially targets mechanisms at play in ALS (i.e., autophagy and neuroinflammation), with promising preclinical studies. It is an already approved drug, with known pharmacokinetics, already available and therefore with significant possibility of rapid translation to daily clinics. Findings will provide reliable data for further potential trials. Ethics and dissemination: The study protocol was approved by the Ethics Committee of Azienda Ospedaliero Universitaria of Modena and by the Ethics Committees of participating centers (Eudract n. 2016-002399-28) based on the Helsinki declaration.
2018
- Riluzole and other prognostic factors in ALS: a population-based registry study in Italy
[Articolo su rivista]
Mandrioli, Jessica; Malerba, Sara Angela; Beghi, Ettore; Fini, Nicola; Fasano, Antonio; Zucchi, Elisabetta; De Pasqua, Silvia; Guidi, Carlo; Terlizzi, Emilio; Sette, Elisabetta; Ravasio, Alessandro; Casmiro, Mario; Salvi, Fabrizio; Liguori, Rocco; Zinno, Lucia; Handouk, Yasmin; Rizzi, Romana; Borghi, Annamaria; Rinaldi, Rita; Medici, Doriana; Santangelo, Mario; Granieri, Enrico; Mussuto, Vittoria; Aiello, Marina; Ferro, Salvatore; Vinceti, Marco
abstract
In this prospective population-based registry study on ALS survival, we investigated the role of riluzole treatment, together with other clinical factors, on the prognosis in incident ALS cases in Emilia Romagna Region (ERR), Italy.
2018
- Selenium Neurotoxicity and Amyotrophic Lateral Sclerosis: An Epidemiologic Perspective
[Capitolo/Saggio]
Filippini, Tommaso; Michalke, Bernhard; Mandrioli, Jessica; Tsatsakis, Aristidis M.; Weuve, Jennifer; Vinceti, Marco
abstract
.Selenium exposure has been proposed as possible risk factor for amyotrophic lateral sclerosis (ALS), due to the selective toxicity of the trace element, especially in its inorganic forms, toward motor neurons. The epidemiological evidence, in association with laboratory and veterinary findings, linking selenium exposure and ALS risk was originally suggested by the increased ALS mortality in an area characterized by high selenium content in soil, and subsequently confirmed in an Italian community. The latter was unintentionally exposed to high levels of inorganic hexavalent selenium through drinking water, and subsequently showed an increased incidence for neurodegenerative diseases, including ALS and Parkinson’s disease. Review of the epidemiological studies addressing the association between selenium exposure and ALS risk points out important lessons that should be considered in future research, in order to avoid misleading and biased evaluations of selenium’s effects. These include the use of central nervous system indicator of exposure such as cerebrospinal fluid, and the implementation of speciation analysis, due to the different toxic and nutritional properties of the various selenium compounds.
2017
- Acute hemichorea as unusual first multiple sclerosis presentation
[Articolo su rivista]
Giovannini, Giada; Cavallieri, Francesco; Meletti, Stefano; Chiari, Annalisa; Mandrioli, Jessica; Ferraro, Diana; Valzania, Franco
abstract
Patient 1 was a 39-year-old woman with an unremarkable medical history who developed acute involuntary right arm and leg movements. Neurologic examination revealed moderate dysarthria and subcontinuous, choreic movements in her right limbs, prevailing in the arm, which worsened during postural tasks. She occasionally had ballistic movements in her right limbs and abnormal dystonic postures. Continuous peribuccal and tongue involuntary movements were noted. Moreover, bilateral upper limb ataxia, gait and trunk ataxia, and brisk right tendon reflexes were found. There was no strength or sensory loss (video 1 at Neurology.org/cp). Brain MRI revealed a tumefactive, T2/fluid-attenuated inversion recovery (FLAIR) hyperintense, T1 hypointense contrast-enhancing demyelinating lesion in the left cerebral peduncle, extending to the substantia nigra and subthalamic nucleus (STN) (figure, A-C). Multiple hyperintense T2/FLAIR, T1 hypointense, non-contrast-enhancing demyelinating lesions in the hemispheric and periventricular deep white matter, brainstem, and cerebellar hemispheres were also found. All serologic tests were within normal limits. Isoelectric focusing (IEF) revealed 9 CSF oligoclonal bands (OCBs). A diagnosis of multiple sclerosis (MS) was made and the patient was treated with high-dose methylprednisolone with improvement of symptoms.
2017
- Amyotrophic lateral sclerosis and myasthenia gravis: association or chance occurrence?
[Articolo su rivista]
de Pasqua, Silvia; Cavallieri, Francesco; D'Angelo, Roberto; Salvi, Fabrizio; Fini, Nicola; D'Alessandro, Roberto; Rinaldi, Rita; Fasano, Antonio; Mandrioli, Jessica
abstract
Very few cases of patients with myasthenia gravis (MG) who later developed amyotrophic lateral sclerosis (ALS) have been described, although some studies showed that significantly more cases than expected have ALS associated with a prior diagnosis of autoimmune diseases. Our aim was to investigate whether the association of ALS and MG was higher than expected in a population-based study and to describe the clinical features characterizing these patients. In Emilia Romagna Region of Italy, a prospective registry has been collecting all incident ALS cases since 1.1.2009. For each patient, detailed clinical information is collected by caring physicians, including comorbidities. From 1.1.2009 to 31.12.2014, 671 patients were diagnosed with ALS; five patients (0.75%) were also affected by MG. Considering Western Countries incidence rates the occurrence of both the diseases should be a really exceptional event (7.5/10(9)), compared to our findings (1.87/10(7)) (p < 0.01). Patients with ALS and MG had more frequently a bulbar onset and a fast progressive course. These cases of ALS after MG raise the possibility of potential shared immunological dysfunctions, which may be expression of common pathogenic mechanisms, as well as of shared disease-course modulating events.
2017
- C9ORF72 and parkinsonism: Weak link, innocent bystander, or central player in neurodegeneration?
[Articolo su rivista]
Cavallieri, Francesco; Mandrioli, Jessica; Rosafio, Francesca; Contardi, Sara; Fasano, Antonio; Menozzi, Elisa; Caponnetto, Claudia; Chiò, Adriano; Valzania, Franco
abstract
Highlights
•C9ORF72-associated diseases may vary from ALS-FTD complex to movement disorders.
•We describe an atypical DOPA-responsive parkinsonism carrying C9orf72 expansion.
•Penetrance, genotype-phenotype correlations and DOPA-responsiveness are discussed.
2017
- Changes in routine laboratory tests and survival in amyotrophic lateral sclerosis
[Articolo su rivista]
Mandrioli, J; Rosi, E; Fini, N; Fasano, A; Raggi, S; Fantuzzi, Al; Bedogni, G
abstract
The aim of this study is to evaluate the association between changes in routinely prescribed laboratory tests and tracheostomy-free survival in amyotrophic lateral sclerosis (ALS). Two hundred seventy-five ALS patients were retrospectively studied. BMI, forced vital capacity, hemoglobin, hematocrit, lymphocytes, cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, proteins, albumin, creatine-phosphokinase, iron, ferritin, transferrin, glucose, urea, uric acid, and creatinine were measured every 6 months from baseline to 24 months, death or study end, together with the probability of death or tracheostomy. Missing data were handled using multiple imputation chained equations. Hemoglobin (OR = 1.71, 95%CI 1.24–2.36 for IQR increase), hematocrit (OR = 1.87, 95%CI 1.34–2.63 for IQR increase), urea (OR = 1.51, 95%CI 1.21–1.89 for IQR increase), and uric acid (OR = 1.98, 95%CI 1.23–3.20 for IQR increase) were directly associated, while triglycerides (OR = 0.69, 0.51 to 0.93 for IQR increase) were inversely associated with the odds of death or tracheostomy. In our cohort, an increase of hemoglobin, hematocrit, urea, and uric acid was directly associated, and an increase of triglycerides was inversely associated with the odds of death or tracheostomy. Should these findings be replicated in an external cohort, they might help to discriminate ALS progression and patients’ decisions about procedures and end of life.
2017
- Clausola di coscienza e cura nell’assistenza al fine vita
[Articolo su rivista]
De Panfilis, L; Cattaneo, D; Cola, L; Gasparini, M; Porteri, C; Tarquini, D; Tiezzi, A; Veronese, S; Zullo, S; Pucci, E; per il Gruppo di Studio in Bioetica, e Cure Palliative della Società Italiana di Neurologia; Alberti, F; Belardinelli, N; Bologna, F; Borasio, Gd; Caraceni, A; Causarano, Ir; Colombi, L; Congedo, M; Conte, A; Crespi, V; Defanti, Ca; Gasperini, M; Giordano, A; Inghilleri, M; Ingravallo, F; Lugaresi, A; Mandrioli, J; Marogna, M; Maschio, M; Mori, M; Neri, W; Moretto, G; Nichelli, P; Pace, A; Pietrolongo, E; Pistollato, L; Primavera, A; Solari, A; Solaro, C; Tola, Mr
abstract
2017
- Comorbidity of dementia with amyotrophic lateral sclerosis (ALS): insights from a large multicenter Italian cohort
[Articolo su rivista]
Trojsi, F; Siciliano, M; Femiano, C; Santangelo, G; Lunetta, C; Calvo, A; Moglia, C; Marinou, K; Ticozzi, N; Drago Ferrante, G; Scialò, C; Sorarù, G; Conte, A; Falzone, Ym; Tortelli, R; Russo, M; Sansone, Va; Chiò, A; Mora, G; Poletti, B; Volanti, P; Caponnetto, C; Querin, G; Sabatelli, M; Riva, N; Logroscino, G; Messina, S; Fasano, A; Monsurrò, Mr; Tedeschi, G; Mandrioli, J
abstract
2017
- Comparison of questionnaire exposure data to land cover map from geographical information system to assess passive exposure to pesticides: a methodological study
[Abstract in Rivista]
Filippini, T; Malagoli, C; Fiore, M; Violi, F; Costanzini, S; Ledda, C; Mauceri, C; Dimartino, A; Mandrioli, J; Fini, N; Patti, F; Teggi, S; Ferrante, M; Vinceti, M
abstract
Background: Exposure assessment based on questionnaires is frequently implemented in case-control studies, but possible information and recall bias could lead to misclassification of exposure.
Methods: We evaluated passive exposure to pesticides as possible environmental risk factors for amyotrophic lateral scle-rosis (ALS) using a questionnaire mailed to participants in a case-control study in Emilia Romagna and Sicily. Results from questionnaire assessment were com-pared with a remote sensing methodology based on geographical information system, i.e. the land use within a circular 100-meter area around subjects' residence. Since land cover maps were made available only about once every ten years, we used the 2003 and 2009 maps for Emilia-Romagna and Sicily, respectively. Thus, we estimated the percent-age of 'recent' total crop density close to each participant's home, setting positive exposure above 10% of land use. Finally, we calculated the agreement between the two different methodologies using Cohen‟s kappa coefficients for all subjects, cases and controls.
Results and Conclusions: Cohen's kappa was 0.364 (95% CI 0.158-0.569) in total population, 0.378 (0.056-0.700) in cases and 0.354 (0.090-0.618) in controls using the most recent land use map available close to year of case diagnosis. Although a moderate-to-low agreement could be seen between two exposure methods, similar results were found in both cases and controls, suggesting that no recall bias occurred in the most recent period.
In the future, we plan to compare such agreement using historical residence over the 20-30 years prior to diagnosis, in order to validate the long-term exposure to pesticides in subjects.
2017
- Decreased levels of foldase and chaperone proteins are associated with an early-onset amyotrophic lateral sclerosis
[Articolo su rivista]
Filareti, M.; Luotti, S.; Pasetto, L.; Pignataro, M.; Paolella, K.; Messina, P.; Pupillo, E.; Filosto, M.; Lunetta, C.; Mandrioli, J.; Fuda, G.; Calvo, A.; Chio, A.; Corbo, M.; Bendotti, C.; Beghi, E.; Bonetto, V.
abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive upper and lower motor neuron degeneration. One of the peculiar clinical characteristics of ALS is the wide distribution in age of onset, which is probably caused by different combinations of intrinsic and exogenous factors. We investigated whether these modifying factors are converging into common pathogenic pathways leading either to an early or a late disease onset. This would imply the identification of phenotypic biomarkers, that can distinguish the two populations of ALS patients, and of relevant pathways to consider in a therapeutic intervention. Toward this aim a differential proteomic analysis was performed in peripheral blood mononuclear cells (PBMC) from a group of 16 ALS patients with an age of onset ≤55 years and a group of 16 ALS patients with an age of onset ≥75 years, and matched healthy controls. We identified 43 differentially expressed proteins in the two groups of patients. Gene ontology analysis revealed that there was a significant enrichment in annotations associated with protein folding and response to stress. We next validated a selected number of proteins belonging to this functional group in 85 patients and 83 age- and sex-matched healthy controls using immunoassays. The results of the validation study confirmed that there was a decreased level of peptidyl-prolyl cis-trans isomerase A (also known as cyclophilin A), heat shock protein HSP 90-alpha, 78 kDa glucose-regulated protein (also known as BiP) and protein deglycase DJ-1 in PBMC of ALS patients with an early onset. Similar results were obtained in PBMC and spinal cord from two SOD1G93A mouse models with an early and late disease onset. This study suggests that a different ability to upregulate proteins involved in proteostasis, such as foldase and chaperone proteins, may be at the basis of a different susceptibility to ALS, putting forward the development of therapeutic approaches aiming at boosting the protein quality control system.
2017
- Elevated levels of selenium species in cerebrospinal fluid of amyotrophic lateral sclerosis patients with disease-associated gene mutations.
[Articolo su rivista]
Mandrioli, Jessica; Michalke, B; Solovyev, N; Grill, P; Violi, Federica; Lunetta, C; Conte, A; Sansone, Va; Sabatelli, M; Vinceti, Marco
abstract
BACKGROUND:
Although an increasing role of genetic susceptibility has been recognized, the role of environmental risk factors in amyotrophic lateral sclerosis (ALS) etiology is largely uncertain; among neurotoxic chemicals, epidemiological and biological plausibility has been provided for pesticides, the heavy metal lead, the metalloid selenium, and other persistent organic pollutants. Selenium involvement in ALS has been suggested on the basis of epidemiological studies, in vitro investigations, and veterinary studies in which selenium induced a selective toxicity against motor neurons.
OBJECTIVE:
Hypothesizing a multistep pathogenic mechanism (genetic susceptibility and environmental exposure), we aimed to study selenium species in ALS patients carrying disease-associated gene mutations as compared to a series of hospital controls.
METHODS:
Using advanced analytical techniques, we determined selenium species in cerebrospinal fluid sampled at diagnosis in 9 ALS patients carrying different gene mutations (C9ORF72, SOD1, FUS, TARDBP, ATXN2, and TUBA4A) compared to 42 controls.
RESULTS:
In a patient with the tubulin-related TUBA4A mutation, we found highly elevated levels (in μg/L) of glutathione-peroxidase-bound selenium (32.8 vs. 1.0) as well as increased levels of selenoprotein-P-bound selenium (2.4 vs. 0.8), selenite (1.8 vs. 0.1), and selenate (0.9 vs. 0.1). In the remaining ALS patients, we detected elevated selenomethionine-bound selenium levels (0.38 vs. 0.06).
CONCLUSIONS:
Selenium compounds can impair tubulin synthesis and the cytoskeleton structure, as do tubulin-related gene mutations. The elevated selenium species levels in the TUBA4A patient may have a genetic etiology and/or represent a pathogenic pathway through which this mutation favors disease onset, though unmeasured confounding cannot be excluded. The elevated selenomethionine levels in the other patients are also of interest due to the toxicity of this nonphysiological selenium species. Our study is the first to assess selenium exposure in genetic ALS, suggesting an interaction between this environmental factor and genetics in triggering disease onset.
2017
- Environmental and occupational exposure to heavy metals and metalloid and development of amyotrophic lateral sclerosis: a population-based case control study in Emilia-Romagna and Sicily.
[Abstract in Atti di Convegno]
Violi, F; Filippini, T; Malagoli, C; Fiore, M; Ledda, C; Mauceri, C; Dimartino, A; Mandrioli, J; Fini, N; Patti, F; Ferrante, M; Vinceti, M.
abstract
.
2017
- Factors predicting survival in ALS: a multicenter Italian study
[Articolo su rivista]
Calvo, A; Moglia, C; Lunetta, C; Marinou, K; Ticozzi, N; Ferrante, Gd; Scialo, C; Sorarù, G; Trojsi, F; Conte, A; Falzone, Ym; Tortelli, R; Russo, M; Chiò, A; Sansone, Va; Mora, G; Silani, V; Volanti, P; Caponnetto, C; Querin, G; Monsurrò, Mr; Sabatelli, M; Riva, N; Logroscino, G; Messina, S; Fini, N; Mandrioli, J
abstract
The aim of this multicenter, retrospective study is to investigate the role of clinical characteristics and therapeutic intervention on ALS prognosis. The study included patients diagnosed from January 1, 2009 to December 31, 2013 in 13 Italian referral centers for ALS located in 10 Italian regions. Caring neurologists collected a detailed phenotypic profile and follow-up data until death into an electronic database. One center collected also data from a population-based registry for ALS. 2648 incident cases were collected. The median survival time from onset to death/tracheostomy was 44 months (SE 1.18, CI 42-46). According to univariate analysis, factors related to survival from onset to death/tracheostomy were: age at onset, diagnostic delay, site of onset, phenotype, degree of certainty at diagnosis according to revised El Escorial criteria (R-EEC), presence/absence of dementia, BMI at diagnosis, patients' provenance. In the multivariate analysis, age at onset, diagnostic delay, phenotypes but not site of onset, presence/absence of dementia, BMI, riluzole use, R-EEC criteria were independent prognostic factors of survival in ALS. We compared patients from an ALS Registry with patients from tertiary centers; the latter ones were younger, less frequently bulbar, but more frequently familial and definite at diagnosis. Our large, multicenter study demonstrated the role of some clinical and demographic factors on ALS survival, and showed some interesting differences between referral centers' patients and the general ALS population. These results can be helpful for clinical practice, in clinical trial design and to validate new tools to predict disease progression.
2017
- Fattori di rischio ambientali e occupazionali per la sclerosi laterale amiotrofica: uno studio caso-controllo di popolazione in Emilia Romagna e Sicilia
[Abstract in Atti di Convegno]
Violi, F; Filippini, T; Malagoli, C; Fiore, M; Ledda, C; Mauceri, Mc; Dimartino, A; Mandrioli, J; Fini, N; Patti, F; Ferrante, M; Vinceti, M.
abstract
.
2017
- Fattori di rischio ambientali e occupazionali per la sclerosi laterale amiotrofica: uno studio caso-controllo di popolazione in Emilia Romagna e Sicilia.
[Abstract in Atti di Convegno]
Filippini, T; Fiore, M; Violi, F; Malagoli, C; Ledda, C; Mauceri, C; Dimartino, A; Mandrioli, J; Fini, N; Patti, F; Ferrante, M; Vinceti, M.
abstract
Introduzione
La Sclerosi Laterale Amiotrofica (SLA) è una malattia neurodegenerativa che colpisce sia i motoneuroni inferiori del tronco encefalico e del midollo spinale, sia i motoneuroni superiori della corteccia motoria. La perdita di questi neuroni conduce ad atrofia e debolezza muscolare, fascicolazioni e spasticità. Ad eccezione di alcune forme genetiche, l’eziologia rimane tutt’ora ignota.
Obiettivi
Abbiamo realizzato uno studio caso-controllo di popolazione in due province emiliane (Modena, Reggio Emilia) e in una provincia siciliana (Catania), al fine di valutare il ruolo di alcuni fattori ambientali e occupazionali sul rischio di SLA.
Metodi
Al fine di identificare tutti i casi incidenti di SLA diagnosticati nel periodo 2008-2011 nelle tre province in studio sono stati utilizzati i dati provenienti dal Registro SLA della Regione Emilia-Romagna integrato con i flussi informativi degli archivi della banca dati SDO, delle prescrizioni farmacologiche e delle schede di morte. I controlli sono stati estratti con procedura casuale dalla popolazione generale mediante gli archivi degli assistiti AUSL. A ciascun paziente (o alle loro famiglie nel caso di decesso) ed ai relativi controlli è stato inviato per via postale un questionario che prevedeva la raccolta di informazioni personali, cliniche e generali.
Risultati
In totale sono stati raccolti 162 questionari (61 casi e 101 controlli, tasso di risposta medio di 18,5%). I risultati ottenuti dall’analisi dei questionari mostrano un aumentato rischio per aver svolto attività lavorativa in ambito agricolo (odds ratio- OR = 2.44 (intervallo di confidenza – IC 95% 1.02-5.79), per chi avesse svolto attività lavorativa da saldatore OR = 1.25 (IC 95% 0.27-5.80). In riferimento alla storia occupazionale, abbiamo evidenziato un aumentato rischio derivante da esposizione a metalli pesanti, tra cui piombo (OR=3.40, IC 95% 1.40-8.56) e mercurio (OR=6.86, IC 95% 0.75-62.88), e pesticidi, tra cui insetticidi (OR=1.61, IC 95% 0.77-3.34), erbicidi (OR=1.89, IC 95% 0.75-4.77) e fungicidi (OR=1.93, IC 95% 0.70-5.30).
Conclusioni
Sebbene tali risultati debbano essere considerati con cautela per l’eventualità della presenza di bias di selezione e di informazione, tuttavia suggeriscono un potenziale ruolo eziologico nello sviluppo della forma sporadica di SLA di due categorie di sostanze dal potenziale neurotossico come metalli pesanti e pesticidi
2017
- Lead, cadmium and mercury in cerebrospinal fluid and risk of amyotrophic lateral sclerosis: A case-control study
[Articolo su rivista]
Vinceti, Marco; Filippini, Tommaso; Mandrioli, Jessica; Violi, Federica; Bargellini, Annalisa; Weuve, Jennifer; Fini, Nicola; Grill, Peter; Michalke, Bernhard
abstract
Exposure to neurotoxic chemicals such as pesticides, selenium, and heavy metals have been suggested toplay a role in the etiology of amyotrophic lateral sclerosis (ALS). We assessed exposure to lead, cadmium,and mercury in 38 ALS patients (16 men and 22 females) and 38 hospital-admitted controls by using theircerebrospinal fluid (CSF) content as biomarker. We determined CSF heavy metal levels with inductivelycoupled plasma sector field mass spectrometry, according to a methodology specifically developed forthis biological matrix. ALS patients had higher median values for Pb (155 vs. 132 ng/L) but lower levelsfor Cd (36 vs. 72 ng/L) and Hg (196 vs. 217 ng/L). In the highest tertile of exposure, ALS odds ratio was1.39 (95% CI 0.48–4.25) for Pb, 0.29 (0.08–1.04) for Cd and 3.03 (0.52–17.55) for Hg; however, no dose-response relation emerged. Results were substantially confirmed after conducting various sensitivityanalyses, and after stratification for age and sex. Though interpretation of these results is limited by thestatistical imprecision of the estimates, and by the possibility that CSF heavy metal content may notreflect long-term antecedent exposure, they do not lend support to a role of the heavy metals cadmium,lead and mercury in ALS etiology.
2017
- Magnetic fields exposure from high-voltage power lines and risk of amyotrophic lateral sclerosis in two Italian populations
[Articolo su rivista]
Vinceti, Marco; Malagoli, Carlotta; Fabbi, Sara; Kheifets, Leeka; Violi, Federica; Poli, Maurizio; Caldara, Salvatore; Sesti, Daniela; Violanti, Silvia; Zanichelli, Paolo; Notari, Barbara; Fava, Roberto; Arena, Alessia; Calzolari, Roberta; Filippini, Tommaso; Iacuzio, Laura; Arcolin, Elisa; Mandrioli, Jessica; Fini, Nicola; Odone, Anna; Signorelli, Carlo; Patti, Francesco; Zappia, Mario; Pietrini, Vladimiro; Oleari, Paola; Teggi, Sergio; Ghermandi, Grazia; Dimartino, Angela; Ledda, Caterina; Mauceri, Cristina; Sciacca, Salvatore; Fiore, Maria; Ferrante, Margherita
abstract
The aetiology of amyotrophic lateral sclerosis (ALS), a rare and extremely severe neurodegenerative disease, has been
associated with magnetic fields exposure. However, evidence for such a relation in the general population is weak, although
the previous null results might also be due to exposure misclassification, or a relationship might exist only for selected
subgroups. To test such a hypothesis we carried out a population-based case-control study in two Northern and Southern
Italy regions, including 703 ALS cases newly diagnosed from 1998 to 2011 and 2737 controls randomly selected from the
residents in the study provinces. Overall, we found that a residence near high-voltage power lines, within the corridors
yielding a magnetic fields of 0.1 lT, was not associated with an excess disease risk, nor did we identify a dose-response
relationship after splitting the exposed corridor according to the 0.1, 0.2 and 0.4 lT cut-points of exposure. These results
were confirmed taking into account age at onset, period of diagnosis, sex, geographical area, and length of exposure.
Overall, despite the residual possibility of unmeasured confounding or small susceptible subgroups not identified in our
study, these results appear to confirm that the exposure to magnetic fields from power lines occurring in the general
population is not associated with increased ALS risk.
2017
- Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials
[Articolo su rivista]
van Eijk, Rpa; Jones, Ar; Sproviero, W; Shatunov, A; Shaw, Pj; Leigh, Pn; Young, Ca; Shaw, Ce; Mora, G; Mandrioli, J; Borghero, G; Volanti, P; Diekstra, Fp; van Rheenen, W; Verstraete, E; Eijkemans, Mjc; Veldink, Jh; Chio, A; Al-Chalabi, A; van den Berg, Lh; van Es, Ma; For UKMND-LiCALS and LITALS Study, Group
abstract
2017
- Monocytes of patients with amyotrophic lateral sclerosis linked to gene mutations display altered TDP-43 subcellular distribution
[Articolo su rivista]
De Marco, G; Lomartire, A; Calvo, A; Risso, A; De Luca, E; Mostert, M; Mandrioli, J; Caponnetto, C; Borghero, G; Manera, U; Canosa, A; Moglia, C; Restagno, G; Fini, N; Tarella, C; Giordana, Mt; Rinaudo, Mt; Chiò, A
abstract
AIMS:
Cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 (TDP-43) is an early determinant of motor neuron degeneration in most amyotrophic lateral sclerosis (ALS) cases. We previously disclosed this accumulation in circulating lymphomonocytes (CLM) of ALS patients with mutant TARDBP, the TDP-43-coding gene, as well as of a healthy individual carrying the parental TARDBP mutation. Here, we investigate TDP-43 subcellular localization in CLM and in the constituent cells, lymphocytes and monocytes, of patients with various ALS-linked mutant genes.
METHODS:
TDP-43 subcellular localization was analysed with western immunoblotting and immunocytofluorescence in CLM of healthy controls (n = 10), patients with mutant TARDBP (n = 4, 1 homozygous), valosin-containing protein (VCP; n = 2), fused in sarcoma/translocated in liposarcoma (FUS; n = 2), Cu/Zn superoxide dismutase 1 (SOD1; n = 6), chromosome 9 open reading frame 72 (C9ORF72; n = 4), without mutations (n = 5) and neurologically unaffected subjects with mutant TARDBP (n = 2).
RESULTS:
TDP-43 cytoplasmic accumulation was found (P < 0.05 vs. controls) in CLM of patients with mutant TARDBP or VCP, but not FUS, in line with TDP-43 subcellular localization described for motor neurons of corresponding groups. Accumulation also characterized CLM of the healthy individuals with mutant TARDBP and of some patients with mutant SOD1 or C9ORF72. In 5 patients, belonging to categories described to carry TDP-43 mislocalization in motor neurons (3 C9ORF72, 1 TARDBP and 1 without mutations), TDP-43 cytoplasmic accumulation was not detected in CLM or in lymphocytes but was in monocytes.
CONCLUSIONS:
In ALS forms characterized by TDP-43 mislocalization in motor neurons, monocytes display this alteration, even when not manifest in CLM. Monocytes may be used to support diagnosis, as well as to identify subjects at risk, of ALS and to develop/monitor targeted treatments.
2017
- Percutaneous endoscopic gastrostomy, body weight loss and survival in amyotrophic lateral sclerosis: a population-based registry study
[Articolo su rivista]
Fasano, Antonio; Fini, Nicola; Ferraro, Diana; Ferri, Laura; Vinceti, Marco; Errals, ; Mandrioli, Jessica
abstract
Abstract
Objective: To assess the role of percutaneous endoscopic gastrostomy (PEG) insertion, and its timing, on ALS survival, and
to study prognostic factors of survival before and after PEG placement in a population-based setting. Methods: In this
observational population-based, registry study, we enrolled patients with newly- diagnosed ALS, according to the El
Escorial revised criteria, who were resident in the Emilia Romagna Region, and who developed severe dysphagia needing
enteral nutritional support. The primary outcome measure was tracheostomy-free survival after PEG recommendation.
Results: There were 210 patients needing PEG, out of an incident cohort of 545 patients from the Emilia Romagna Registry
for ALS, who were diagnosed between 2009 and 2013. One hundred and ninety-three patients were included in the study,
and 17 were excluded because they were already tracheostomized at the time of PEG placement. Of the 193 patients
included in the study, 152 underwent PEG, whereas 41 did not undergo the procedure. Patients who did not undergo
PEG, among the eligible ones, had the same tracheostomy-free survival from onset as patients who did (25 vs. 32 months,
p¼0.21). Tracheostomy-free survival from PEG recommendation was greater in patients who underwent PEG placement
than in patients who did not (6 vs. 2 months, p¼0.008). Median tracheostomy-free survival from PEG insertion was eight
months (95% CI5–12); 30 days after PEG placement, survival was 89.60%. At Cox multivariable analysis, the hazard of
death or tracheostomy after PEG insertion was significantly influenced by the difference between BMI at the time of the
PEG procedure and BMI at diagnosis (HR 1.05, 95% CI 1.02–1.08; p¼0.002). The hazard of death or tracheostomy was
not affected by the timing of PEG insertion. Conclusions: The present study, although it has some limitations, suggests a
gain of tracheostomy-free survival from the time of PEG recommendation for patients who undergo PEG placement, and,
among patients who undergo PEG, a greater survival if PEG is inserted before a significant weight loss occurs, and if
nutritional support avoids further weight loss. Should this association between prevention of weight loss and better clinical
outcome be confirmed by further studies, it would have important implications for disease management.
2017
- Pesticide exposure assessed through agricultural crop proximity and risk of amyotrophic lateral sclerosis
[Articolo su rivista]
Vinceti, Marco; Filippini, Tommaso; Violi, Federica; Rothman, Kenneth J.; Costanzini, Sofia; Malagoli, Carlotta; Wise, Lauren A.; Odone, Anna; Signorelli, Carlo; Iacuzio, Laura; Arcolin, Elisa; Mandrioli, Jessica; Fini, Nicola; Patti, Francesco; Fermo, Salvatore Lo; Pietrini, Vladimiro; Teggi, Sergio; Ghermandi, Grazia; Scillieri, Renato; Ledda, Caterina; Mauceri, Cristina; Sciacca, Salvatore; Fiore, Maria; Ferrante, Margherita
abstract
Background: Epidemiologic studies have raised the possibility that some pesticide compounds induce the neurodegenerative disease amyotrophic lateral sclerosis (ALS), though the available evidence is not entirely consistent. Methods: We conducted a population-based case-control study in two Italian populations to assess the extent to which residence in the vicinity of agricultural crops associated with the application of neurotoxic pesticides is a risk factor for ALS, using crop acreage in proximity to the residence as an index of exposure. Results: Based on 703 cases and 2737 controls, we computed an ALS odds ratio of 0.92 (95% confidence interval 0.78-1.09) for those in proximity to agricultural land. Results were not substantially different when using alternative exposure categories or when analyzing specific crop types, with the exception of a higher risk related to exposure to citrus orchards and olive groves in Southern Italy, though based on few exposed subjects (N = 89 and 8, respectively). There was little evidence of any dose-response relation between crop proximity and ALS risk, and using long-term residence instead of current residence did not substantially change our estimates. Conclusions: Though our index of exposure is indirect and subject to considerable misclassification, our results offer little support for the hypothesis that neurotoxic pesticide exposure increases ALS risk.
2017
- Pesticides, polychlorinated biphenyls and polycyclic aromatic hydrocarbons in cerebrospinal fluid of amyotrophic lateral sclerosis patients: a case-control study.
[Articolo su rivista]
Vinceti, Marco; Violi, Federica; Tzatzarakis, M; Mandrioli, J; Malagoli, Carlotta; Hatch, Ee; Fini, N; Fasano, Antonio; Rakitskii, Vn; Kalantzi, Oi; Tsatsakis, A.
abstract
Neurotoxic chemicals including several pesticides have been suggested to play a role in the etiology of amyotrophic lateral sclerosis (ALS). We investigated the relation between organochlorine pesticides and their metabolites (OCPs), polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs) in the etiology of sporadic ALS, determining for the first time their levels in cerebrospinal fluid as indicator of antecedent exposure. We recruited 38 ALS patients and 38 controls referred to an Italian clinical center for ALS care, who underwent a lumbar puncture for diagnostic purposes between 1994-2013, and had 1mL of cerebrospinal fluid available for the determination of OCPs, PCBs and PAHs. Many chemicals were undetectable in both case and control CSF samples, and we found little evidence of any increased disease risk according to higher levels of exposure. Among males >60 years, we found a slight but statistically very unstable increased ALS risk with higher levels of the congener PCB 28 and the OCP metabolite p,p'-DDE. Overall, these results do not suggest an involvement of the neurotoxic chemicals investigated in this study in disease etiology, although small numbers limited the precision of our results.
2017
- Protein misfolding, amyotrophic lateral sclerosis and guanabenz: protocol for a phase II RCT with futility design (ProMISe trial)
[Articolo su rivista]
Bella, Ed; Tramacere, I; Antonini, G; Borghero, G; Capasso, M; Caponnetto, C; Chiò, A; Corbo, M; Eleopra, R; Filosto, M; Giannini, F; Granieri, E; Bella, V; Lunetta, C; Mandrioli, J; Mazzini, L; Messina, S; Monsurrò, Mr; Mora, G; Riva, N; Rizzi, R; Siciliano, G; Silani, V; Simone, I; Sorarù, G; Volanti, P; Lauria, G
abstract
Introduction Recent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS. Methods and analyses Protocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial. Ethics and dissemination The study protocol was approved by the Ethics Committee of IRCCS 'Carlo Besta Foundation' of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration.
2017
- Redox speciation of iron, manganese, and copper in cerebrospinal fluid by strong cation exchange chromatography e sector field inductively coupled plasma mass spectrometry.
[Articolo su rivista]
Solovyev, N; Vinceti, Marco; Grill, P; Mandrioli, Jessica; Michalke, B.
abstract
Abstract
A new method of simultaneous redox speciation of iron (II/III), manganese (II/III), and copper (I/II) in cerebrospinal fluid (CSF) has been designed. For the separation of redox species strong cation exchange chromatography (SCX) with isocratic elution was employed. Species were detected using inductively coupled plasma sector field mass spectrometry (ICP-sf-MS), operating at medium resolution. The following parameters were optimized: analytical column, eluent composition and pH, CSF injection volume and dilution factor. Analytical column Dionex IonPac CS5A RFIC 4*250 mm was found to retain and separate species of interest the most effectively under the isocratic elution with a buffer, containing 50 mM ammonium citrate, 7.0 mM pyridine-2,6-dicarboxylic acid at pH = 4.2 and flow rate of 0.8 L min−1. Injection volume of 50 μL with CSF sample dilution of 1/3 (v/v) with the eluent was shown to result in minimal matrix suppression. For species identification, retention time matching with standards was used. The stability of metalloproteins (ferritin, transferrin, and ceruloplasmin) under elution conditions was evaluated. For the quantification of redox species, external calibration was employed. To avoid column contamination, a blank was run after measurement and all quantification values were blank subtracted. For recovery checks, species quantification data was verified against total content of an element, measured by dynamic reaction cell ICP-MS. Recoveries (sum of quantified species vs. total element determinations) were 82.5 ± 22% (Mn), 92 ± 11% (Fe), and 88.7 ± 12% (Cu). The method was tested using 38 real CSF samples. Limits of detection (3σ) for the CSF samples were 0.5 μg L−1, 0.6 μg L−1, and 0.8 μg L−1 for Fe, Mn, and Cu species, respectively. Retention time precision was 1–7.5% (as RSD), whereas peak area RSDs were in the range 5–11%, both depending on the species.
2017
- Trace element speciation in the cerebrospinal fluid samples from the patients with amyotrophic lateral sclerosis?
[Abstract in Atti di Convegno]
Solovyev, N; Mandrioli, J; Vinceti, M; Malagoli, C; Lucio, M; Michalke, B.
abstract
.
2017
- Trace element species and amyotrophic lateral sclerosis with disease associated genetic mutations
[Abstract in Atti di Convegno]
Nikolay, Solovyev; Mandrioli, Jessica; Vinceti, Marco; Malagoli, Carlotta; Marianna, Lucio; Bernhard, Michalke
abstract
Introduction: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with mostly unknown eti-ology. Certain genetic mutations are associated with the disease; however, the role of environmental factors, such as exposure to metals and organic pollutants is also widely discussed in the literature. ALS, as other neurodegenerative disorders, is related to the brain oxidative stress, so the disturbance of redox homeostasis may be anticipated for such elements as selenium (Se), copper (Cu), iron (Fe), and manganese (Mn).
Aim: The aim of the study was to evaluate a possible alteration of trace element (Se, Cu, Mn, and Fe) homeostasis in the ALS patients with disease associated gene mutations.
Methods: We analyzed cerebrospinal fluid (CSF) samples from 9 patients with ALS-associated muta-tions (C9ORF72, SOD1, FUS, TARDBP, ATXN2, and TUBA4A) and 42 age- and gender-matched controls. Advanced speciation techniques were used to quantify redox forms of Cu (I/II), Mn (II/III), and Fe (II/III) and Se species (selenoprotein P, glutathione peroxidase, thioredoxin reductase, selenite, selenate, and human serum bound-Se). For the separation of Se species strong anion exchange chromatography (SAX) was used, whereas Cu, Mn, and Fe redox forms were separated by strong cation exchange (SCX). For the species detection, inductively coupled plasma sector field mass spectrometry (ICP-sf-MS), op-erated at high resolution for Se or medium resolution for Cu, Fe, and Mn was employed. Standard compounds and spikings were used for peak assignment. External calibration vs. matching to the total content of the elements, measured by inductively coupled plasma dynamic reaction cell mass spec-trometry, was used for species quantification.
Results: The analytical schemes of species quantification, using SAX-ICP-sf-MS [1] and SCX-ICP-sf-MS [2], have been optimized. The difference in Cu(II) and some Se species were found to be altered in the CSF of the ALS patients with disease-associated mutations. Also, since multi-element speciation had been performed for the same set of CSF samples, some inter-element correlations were observed (be-tween Fe and Se species, Mn and Fe, Mn and Cu).
Conclusion: Despite the limited sample size, we could presume a distortion in trace element metabo-lism, reflected the altered speciation of Cu and Se in the CSF. However, more insight is required to understand if these findings are an innocent bystander to the pathological changes in the ALS brain or has its own relevant role in the etiopathogenesis of the disease.
2016
- A CASE-CONTROL STUDY OF NEUROTOXIC METALS IN CEREBROSPINAL FLUID AND RISK OF AMYOTROPHIC LATERAL SCLEROSIS
[Abstract in Atti di Convegno]
Vinceti, Marco; Filippini, Tommaso; Mandrioli, Jessica; Fini, Nicola; Salvia, Chiara; Grill, Peter; Michalke, Bernhard
abstract
Many studies have investigated the possible relation between exposure to heavy
metals and risk of amyotrophic lateral sclerosis (ALS). We aimed at assessing
the levels of two neurotoxic metals, cadmium (Cd), lead (Pb) and mercury (Hg)
in cerebrospinal fluid (CSF) of ALS patients and hospital controls. CSF heavy
metal content was determined using inductively coupled plasma sector field mass
spectrometry (ICP-SF-MS) according to methodologies previously established
for biological matrices and specifically for CSF. We obtained CSF samples from
38 ALS cases, including 16 men and 22 women, and from 38 hospital-referred
subjects undergoing lumbar puncture because of suspected but later unconfirmed
neurological disease, with mean age of 55.5 and 52.26 respectively (range 30–
85). Median heavy metal concentrations were higher in ALS cases compared to
controls for Pb (155 vs. 132 ng/l) but lower for Cd (36 vs. 72) and Hg (196 vs.
217). In unconditional multiple logistic regression analysis adjusting for age and
sex, we found a disease odds ratio (OR) for the middle and the upper exposure
tertiles of 0.8 (0.2-2.6) and 1.4 (95% CI 0.5 to 4.2) for Pb, 0.9 (0.3-2.8) and 0.3
(0.1 to 1.0) for Cd, and 12.4 (2.7-57.3) and 3.03 (0.52-17.55) for Hg. We also
conducted sensitivity analyses with log transformed values and with winsorized
values by setting data exceeding the 95th percentile to the 95th percentile, but the
risk estimates did not substantially change. Our results and particularly the lack
of dose-response relations give little support for an involvement of these heavy
metals in ALS etiology, with the possible exception of Hg. However, caution
should be used in the interpretation of these results due to some study limitations,
such as the statistical imprecision of the risk estimates, the hospital-based design
of the study, and the potential for unmeasured confounding.
2016
- A novel neurophysiological finding in essential palatal tremor
[Abstract in Atti di Convegno]
Fasano, A; Cavallieri, F; Menozzi, E; Giovannini, G; Fini, N; Contardi, S; Nichelli, P; Mandrioli, J; Valzania, F
abstract
2016
- ATNX2 is not a regulatory gene in Italian amyotrophic lateral sclerosis patients with C9ORF72 GGGGCC expansion
[Articolo su rivista]
Chiò, A; Mora, G; Sabatelli, M; Caponnetto, C; Lunetta, C; Traynor, Bj; Johnson, Jo; Nalls, Ma; Calvo, A; Moglia, C; Borghero, G; Trojsi, F; La Bella, V; Volanti, P; Simone, I; Salvi, F; Logullo, Fo; Riva, N; Carrera, P; Giannini, F; Mandrioli, J; Tanel, R; Capasso, M; Tremolizzo, L; Battistini, S; Murru, Mr; Origone, P; Zollino, M; Penco, S; Italsgen, Consortium; Sardinials, Consortium; Mazzini, L; D'Alfonso, S; Restagno, G; Brunetti, M; Barberis, M; Conforti, Fl
abstract
There are indications that both familial amyotrophic lateral sclerosis (ALS) and sporadic ALS phenotype and prognosis are partly regulated by genetic and environmental factors, supporting the theory that ALS is a multifactorial disease. The aim of this article was to assess the role of ATXN2 intermediate length repeats in a large series of Italian and Sardinian ALS patients and controls carrying a pathogenetic C9ORF72 GGGGCC hexanucleotide repeat. A total of 1972 ALS cases were identified through the database of the Italian ALS Genetic consortium, a collaborative effort including 18 ALS centers throughout Italy. The study population included: (1) 276 Italian and 57 Sardinian ALS cases who carried the C9ORF72 expansion; (2) 1340 Italian and 299 Sardinian ALS cases not carrying the C9ORF72 expansion. A total of healthy 1043 controls were also assessed. Most Italian and Sardinian cases and controls were homozygous for 22/22 or 23/23 repeats or heterozygous for 22/23 repeats of the ATXN2 gene. ATXN2 intermediate length repeats alleles (≥28) were detected in 3 (0.6%) Italian ALS cases carrying the C9ORF72 expansion, in none of the Sardinian ALS cases carrying the expansion, in 60 (4.3%) Italian cases not carrying the expansion, and in 6 (2.0%) Sardinian ALS cases without C9ORF72 expansion. Intermediate length repeat alleles were found in 12 (1.5%) Italian controls and 1 (0.84%) Sardinian controls. Therefore, ALS patients with C9ORF72 expansion showed a lower frequency of ATXN2 polyQ intermediate length repeats than both controls (Italian cases, p = 0.137; Sardinian cases, p = 0.0001) and ALS patients without C9ORF72 expansion (Italian cases, p = 0.005; Sardinian cases, p = 0.178). In our large study on Italian and Sardinian ALS patients with C9ORF72 GGGGCC hexanucleotide repeat expansion, compared to age-, gender- and ethnic-matched controls, ATXN2 polyQ intermediate length does not represent a modifier of ALS risk, differently from non-C9ORF72 mutated patients
2016
- Acute hemichorea as unusual first multiple sclerosis presentation: two case reports
[Abstract in Atti di Convegno]
Cavallieri, F; Giovannini, G; Menozzi, E; Meletti, S; Chiari, A; Mandrioli, J; Ferraro, D; Contardi, S; Nichelli, P; Valzania, F
abstract
2016
- Amyotrophic lateral sclerosis: a comparison of two staging systems in a population-based study
[Articolo su rivista]
Ferraro, Diana; Consonni, D.; Fini, N.; Fasano, Antonio; DEL GIOVANE, Cinzia; Emilia Romagna Registry for ALS, Group; Mandrioli, Jessica
abstract
Background and purpose: To compare two recently developed staging systems for amyotrophic lateral sclerosis (ALS) [King's College and Milano-Torino staging (MITOS) systems] in an incident, population-based cohort of patients with ALS. Methods: Since 2009, a prospective registry has been recording all incident cases of ALS in the Emilia Romagna region in Italy. For each patient, detailed clinical information, including the ALS functional rating scale score, is collected at each follow-up. Results: Our study on 545 incident cases confirmed that King's College stages occurred at predictable times and were quite evenly spaced out throughout the disease course (occurring at approximately 40%, 60% and 80% of the disease course), whereas MITOS stages were mostly skewed towards later phases of the disease. In the King's College system there was a decrease in survival and an increase in deaths with escalating stages, whereas in the MITOS system survival curves pertaining to intermediate stages overlapped and the number of deaths was fairly homogenous throughout most stages. Conclusions: The King's College staging system had a higher homogeneity (i.e. smaller differences in survival among patients in the same stage) and a higher discriminatory ability (i.e. greater differences in survival among patients in different stages), being more suitable for individualized prognosis and for measuring efficacy of therapeutic interventions.
2016
- Analysis of a peculiar motor speech disorder in a case of probable progressive supranuclear palsy
[Abstract in Atti di Convegno]
Menozzi, E; Cavallieri, F; Gessani, A; Budriesi, C; Molinari, M; Mandrioli, J; Vitetta, F; Nichelli, P; Meletti, S; Chiari, A
abstract
2016
- C9ORF72 hexanucleotide expansion and parkinsonism: weak link, innocent bystander, or central player in neurodegeneration?
[Abstract in Atti di Convegno]
Cavallieri, F; Mandrioli, J; Rosafio, F; Contardi, S; Fasano, A; Menozzi, E; Chiò, A; Valzania, F
abstract
2016
- Clinical implications of double heterozygosity for SPG4 and SPG7 mutations: a case report
[Abstract in Atti di Convegno]
Fasano, A; Falzone, F; Ferri, L; Cavallieri, F; Fini, N; Mandrioli, J
abstract
2016
- DYSARTHRIA IN ALS: AN
OBSERVATIONAL COHORT STUDY
[Abstract in Rivista]
Fasano, A; Budriesi, C; Casalino, S; Fini, N; Falzone, F; Mandrioli, J
abstract
2016
- DYSARTHRIA IN ALS: AN OBSERVATIONAL COHORT STUDY
[Abstract in Atti di Convegno]
Fasano, A; Budriesi, C; Casalino, S; Fini, N; Falzone, F; Mandrioli, J
abstract
2016
- Environmental and occupational risk factors of amyotrophic lateral sclerosis: a population-based case control study
[Abstract in Atti di Convegno]
Violi, Federica; Fiore, Maria; Filippini, Tommaso; Malagoli, Carlotta; Ledda, Caterina; Mauceri, Cristina; Dimartino, Angela; Mandrioli, Jessica; Fini, Nicola; Patti, Francesco; Ferrante, Margherita; Vinceti, Marco
abstract
Background and aims
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor neuron. Its etiology is still largely unknown, except for some rare forms of genetic origin, but environmental factors may have an important role.
Methods
We performed a population case-control study in three Italian provinces (Modena, Reggio Emilia and Catania) in order to assess the possible etiologic role of some environmental factors. We administered 877 questionnaires by mail or by person in a neurological office to collect information about personal, clinical and professional history to ALS cases newly diagnosed in the 2008-2011 period and age- and sex-matched population controls.
Results
Analysis of the returned questionnaires (18,5%, 61 cases and 101 controls) showed an increased risk when examining clinical information for reported trauma (OR 1.20, 95%CI 0.63-2.30), head (OR 3.04, 1.23-7.55) and chest trauma (OR 2.65, 95%CI 0.72-9.78). History of previous fractures has an OR of 1.10 (95%CI 0.58-2.11), but for head fracture OR raised to 5.17 (95%CI 0.53-50.88). With reference to occupational history an excess of risk was found for employment in agriculture (OR 2.44, 95%CI 1.03-5.79) and for welding (OR 1.25, 95%CI 0.27-5.80). Occupational exposure to lead (OR 1.27, 95%CI 0.74-2.17), thinners (OR 1.12, 95%CI 0.66-1.91) and solvents (toluene/xylene) (OR 1.24, 95%CI 0.72-2.13) provide some excess risk. Considering 'extra-working' activities, we found an excess disease risk for hunting (OR 1.69, 95%CI 0.33-8.65), painting (OR 1.46, 95%CI 0.47-4.58), modelling with glue (OR 1.72, 95%CI 0.57-5.17), gardening (OR 1.15, 95%CI 0.64-2.08), football (OR 1.04, 95%CI 0.44-2.47) and pesticides (OR 1.98, 95%CI 0.76-5.12) and herbicides use (OR 2.27, 95%CI 0.72-7.19).
Conclusions
Thoughthese results must be assessed with caution for the risk of selection and information bias, they suggest potential etiologic clues to ALS etiology which are worthy of further study.
2016
- GASTROSTOMY, BODY WEIGHT
LOSS AND SURVIVAL IN AMYOTROPHIC
LATERAL SCLEROSIS: A POPULATIONBASED
STUDY
[Abstract in Rivista]
Fasano, A; Fini, N; Ferraro, D; Ferri, L; Vinceti, M; Mandrioli, J
abstract
2016
- Livelli di piombo, cadmio e mercurio nel liquido cerebrospinale e rischio di sclerosi laterale amiotrofica: uno studio caso-controllo.
[Abstract in Atti di Convegno]
Filippini, Tommaso; Violi, Federica; Mandrioli, Jessica; Bargellini, Annalisa; Weuve, J; Fini, N; Grill, P; Michalke, B; Vinceti, Marco
abstract
.
2016
- Non-neural phenotype of spinal and bulbar muscular atrophy: Results from a large cohort of Italian patients
[Articolo su rivista]
Querin, G.; Bertolin, C.; Da Re, E.; Volpe, M.; Zara, G.; Pegoraro, E.; Caretta, N.; Foresta, C.; Silvano, M.; Corrado, D.; Iafrate, M.; Angelini, L.; Sartori, L.; Pennuto, M.; Gaiani, A.; Bello, L.; Semplicini, C.; Pareyson, D.; Silani, V.; Ermani, M.; Ferlin, A.; Soraru, G.; Mandrioli, J.; Galasso, G.; Mazzini, L.; Romito, S.; Tonin, P.; Scarpelli, M.; Ricci, G.; Siciliano, G.; Petrucci, A.; Massa, R.; Polo, A.; Mariotti, C.; Sagnelli, A.; Palmieri, A.; Briani, C.
abstract
Objective: To carry out a deep characterisation of the main androgen-responsive tissues involved in spinal and bulbar muscular atrophy (SBMA). Methods: 73 consecutive Italian patients underwent a full clinical protocol including biochemical and hormonal analyses, genitourinary examination, bone metabolism and densitometry, cardiological evaluation and muscle pathology. Results: Creatine kinase levels were slightly to markedly elevated in almost all cases (68 of the 73; 94%). 30 (41%) patients had fasting glucose above the reference limit, and many patients had total cholesterol (40; 54.7%), low-density lipoproteins cholesterol (29; 39.7%) and triglyceride (35; 48%) levels above the recommended values. Although testosterone, luteinising hormone and follicle-stimulating hormone values were generally normal, in one-third of cases we calculated an increased Androgen Sensitivity Index reflecting the presence of androgen resistance in these patients. According to the International Prostate Symptom Score (IPSS), 7/70 (10%) patients reported severe lower urinal tract symptoms (IPSS score >19), and 21/73 (30%) patients were moderately symptomatic (IPSS score from 8 to 19). In addition, 3 patients were carriers of an indwelling bladder catheter. Videourodynamic evaluation indicated that 4 of the 7 patients reporting severe urinary symptoms had an overt prostate-unrelated bladder outlet obstruction. Dual-energy X-ray absorptiometry scan data were consistent with low bone mass in 25/61 (41%) patients. Low bone mass was more frequent at the femoral than at the lumbar level. Skeletal muscle biopsy was carried out in 20 patients and myogenic changes in addition to the neurogenic atrophy were mostly observed. Conclusions: Our study provides evidence of a wide non-neural clinical phenotype in SBMA, suggesting the need for comprehensive multidisciplinary protocols for these patients.
2016
- Pesticidi organoclorurati, bifenili policlorurati e idrocarburi aromatici policiclici nel liquido cefalorachidiano di pazienti con sclerosi laterale amiotrofica: uno studio caso-controllo
[Abstract in Atti di Convegno]
Violi, Federica; Tzatzarakis, M; Mandrioli, Jessica; Fini, N; Fasano, Antonio; Malagoli, Carlotta; Tsatsakis, A; Vinceti, Marco
abstract
.
2016
- Radiotherapy treatment of the salivary glands, sialorrhea, and non-invasive mechanical ventilation in amyotrophic lateral sclerosis: what are we doing?
[Articolo su rivista]
Garuti, G; Mandrioli, J; Esquinas, Am.
abstract
2016
- Reduced levels of alpha-1-antitrypsin in cerebrospinal fluid of amyotrophic lateral sclerosis patients: a novel approach for a potential treatment
[Articolo su rivista]
Wormser, Uri; Mandrioli, Jessica; Vinceti, Marco; Fini, Nicola; Sintov, Amnov; Brodsky, Berta; Proskura, Elena; Finkelstein, Yoram
abstract
Abstract
Background: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative motor neuron disease that
involves activation of the immune system and inflammatory response in the nervous system. Reduced level of
the immuno-modulatory and anti-inflammatory protein alpha-1-antitrypsin (AAT) is associated with
inflammation-related pathologies. The objective of the present is to determine AAT levels and IL-23 in the
cerebrospinal fluid (CSF) of ALS patients and control group.
Findings: CSF samples from newly diagnosed ALS patients and age-matched controls were analyzed for AAT and
IL-23 by ELISA and magnetic luminex screening, respectively. A statistically significant reduction of 45 % in mean
AAT levels was observed in the CSF of ALS patients (21.4 μg/ml) as compared to the control group (mean 38.8 μg/ml,
p = 0.013). A statistically significant increase of 30.8 % in CSF mean levels of the pro-inflammatory cytokine IL-23 was
observed in ALS patients (1647 pg/ml) in comparison to the controls (1259 pg/ml, p = 0.012). A negative correlation
coefficient (r = −0.543) was obtained by linear regression analysis of the two measured parameters (p = 0.036).
Conclusions: Reduced AAT and elevated IL-23 CSF levels support the notion of neuroinflammatory process occurring
in ALS patients. Increasing AAT levels in the patients’ nervous system should be further investigated as a new
therapeutic approach and a novel potential tool for ALS treatment.
2016
- THE HFE HIS63ASP POLYMORPHISM
IS A MODIFIER OF ALS OUTCOMES IN
ITALIAN AND FRENCH PATIENTS WITH
SOD1 MUTATIONS
[Abstract in Rivista]
Chio, A; Mora, G; Lunetta, C; Brunetti, M; Barberis, M; Borghero, G; Tarlarini, C; Monsurro`, Mr; Zollino, M; Volanti, P; Italsgen, ; Lattante, S; Meiniger, V; Riva, N; Clavelou, P; Giannini, F; Mandrioli, J; Penco, S; Sabatelli, M; Camu, W
abstract
2016
- The HFE p.HIS63ASP polymorphism modifies ALS outcome in patients with SOD1 mutations
[Abstract in Atti di Convegno]
Chiò, A; Calvo, A; Mora, G; Brunetti, M; Barberis, M; Borghero, G; Caponnetto, C; Monsurrò, Mr; La Bella, V; Volanti, P; Simone, I; Salvi, F; Logullo, F; Nilo, R; Tremolizzo, L; Giannini, F; Mandrioli, J; Tanel, R; Murru, Mr; Mandich, P; Conforti, Fl; Italsgen, Consortium; Sardinials, Consortium; Zollino, M; Lattante, S; Sabatelli, M; Tarlarini, C; Penco, S; Russo, M; Messina, S; Lunetta, C; Meininger, V; Clavelou, P; Camu, W
abstract
2016
- The wide spectrum of cerebrotendinous xanthomatosis: Case report of a rare but treatable disease
[Articolo su rivista]
Rosafio, Francesca; Cavallieri, Francesco; Guaraldi, Pietro; Taroni, Franco; Nichelli, Paolo Frigio; Mandrioli, Jessica
abstract
Cerebrotendinous xanthomatosis (CTX) is an autosomal-recessive disorder of lipid storage caused by mutations in the CYP27A1 gene, coding for a sterol 27-hydroxylase, leading to increased deposition of cholesterol in multiple tissues. CTX is characterized by the association of early non-neurological manifestations and adult-onset neurological dysfunctions (spastic ataxia, dementia, psychiatric disorders, peripheral neuropathy). Early and long-term treatment with chenodeoxycholic acid (CDCA) can slow down neurological symptoms progression, but diagnosis usually has a delay of several years. We report two Italian siblings having quite different phenotypes associated to a G-to-A transition in the c-1263 terminal causing a splicing alteration. This mutation has not been described before in Italy, and has been reported once in Japan. This case widens the clinical and genetic spectrum of Cerebrotendinous Xantomatosis in Italy and would like to suggest the importance of genetic testing in patients with autosomal recessive spastic paraparesis associated with typical non-neurological symptoms.
2016
- Ultrasound assessment of diaphragmatic function in patients with amyotrophic lateral sclerosis.
[Articolo su rivista]
Fantini, R; Mandrioli, J; Zona, S; Antenora, F; Iattoni, A; Monelli, M; Fini, N; Tonelli, Roberto; Clini, Enrico; Marchioni, A.
abstract
Background: Evaluation of diaphragm function in Amyotrophic Lateral Sclerosis (ALS) is critical in determining when to commence non-invasive mechanical ventilation (NIV). Currently, forced vital capacity (FVC) and sniff nasal inspiratory pressure (SNIP) are volitional measures for this evaluation, but require collaboration and are poorly specific. The primary aim of this study was to assess whether diaphragmatic thickness measured by ultrasound (US) correlates with lung function impairment in ALS patients. The secondary aim was then to compare US diaphragm thickness index (Tdi) with a new parameter (Tmax index).
Methods: 41 patients with ALS and 30 healthy subjects were enrolled in the study. All subjects underwent spirometry, SNIP and diaphragm US evaluation, while arterial blood gases were measured in patients only. US assessed diaphragm thickness (Tdi) at tidal volume (Vt) or TLC, and their ratio (Tmax) were recorded. Changes (Δ) in Tdi indices during tidal volume (TdiVt) and maximal inspiration (TdiTLC) were also assessed.
Results: TdiTLC (p <0.001) and Tmax (p= 0.007), but not TdiVt, differed between patients and controls. Significant correlation (p<0.05) was found between TdiTLC, Tmax and FVC. The ROC curve analysis for comparison of individual testing showed better accuracy with Δtmax than with ΔtdiTLC for FVC (AUC 0.76 and 0.27) and SNIP (AUC 0.71 and 0.25).
Conclusions: Diaphragm thickness assessed by ultrasound significantly correlates with global respiratory alterations in patients with ALS. Tmax represents a new US index of early diaphragmatic dysfunction, better related with the routinely performed lung function tests.
2015
- A further Rasch study confirms that ALSFRS-R does not conform to fundamental measurement requirements
[Articolo su rivista]
Franchignoni, F; Mandrioli, J; Giordano, A; Ferro, S; Errals, Group.
abstract
Our objective was to verify and expand previous evidence of psychometric inadequacies in the ALSFRS-R, in a different sample of subjects suffering from ALS. Since 2009, a prospective registry records all incident cases of ALS in Emilia Romagna Region, Italy (4.4 million inhabitants) referred to its 17 neurological departments. For each patient, demographic and clinical information is collected by the physician in charge, including compilation of the ALSFRS-R at each clinical follow-up. Results showed that a confirmatory factor analysis on the three-factor model previously found (bulbar, motor, respiratory function) showed a good fit. Rasch analysis on the whole scale showed the need to collapse some rating categories, confirmed the multidimensionality of the ALSFRS-R, and demonstrated the presence of differential item functioning between patients with spinal versus bulbar onset. Moreover, some items included in the three ALSFRS-R subscales showed a problematic fit to the respective construct they were intended to measure. In conclusion, the interpretation of a total raw score of ALSFRS-R is hampered by ambiguities due to the different metric properties of the three domains the scale aggregates, and their content and structure. This study confirms that a refinement of ALSFRS-R is warranted, pointing to the need to revise its whole structure, and providing detailed guidelines for its revision.
2015
- ATAXIN 2 IS NOT A DISEASE
MODIFIER IN A LARGE SERIES OF ALS PATIENTS CARRYING THE C9ORF72 EXPANSION
[Abstract in Rivista]
Chio, A; Conforti, Fl; Borghero, G; Lunetta, C; Penco, S; Simone, Il; Mazzini, L; Mora, G; Caponnetto, C; Mandrioli, J; Monsurro`, Mr; Battistini, S; Calvo, A; Volanti, P; Brunetti, M; Barberis, M; Mandich, P; D’Alfonso, S; Zollino, M; Sabatelli, M
abstract
2015
- ATXN2 is a modifier of phenotype in ALS patients of Sardinian ancestry
[Articolo su rivista]
Borghero, G.; Pugliatti, M.; Marrosu, F.; Marrosu, M. G.; Murru, M. R.; Floris, G.; Cannas, A.; Parish, L. D.; Cau, T. B.; Loi, D.; Ticca, A.; Traccis, S.; Manera, U.; Canosa, A.; Moglia, C.; Calvo, A.; Barberis, M.; Brunetti, M.; Renton, A. E.; Nalls, M. A.; Traynor, B. J.; Restagno, G.; Chio, A.; Logullo, F. O.; Simone, I.; Logroscino, G.; Salvi, F.; Bartolomei, I.; Capasso, M.; Caponnetto, C.; Mancardi, G.; Mandich, P.; Origone, P.; Conforti, F. L.; Mora, G.; Marinou, K.; Sideri, R.; Lunetta, C.; Penco, S.; Mosca, L.; Nilo, R.; Pinter, G. L.; Corbo, M.; Volanti, P.; Mandrioli, J.; Fini, N.; Georgoulopoulou, E.; Tremolizzo, L.; Maria Rosaria, Monsurro; Tedeschi, G.; Cristillo, V.; la Bella, V.; Spataro, R.; Colletti, T.; Sabatelli, M.; Zollino, M.; Conte, A.; Luigetti, M.; Lattante, S.; Marangi, G.; Santarelli, M.; Petrucci, A.; Giannini, F.; Battistini, S.; Ricci, C.; Casale, F.; Marrali, G.; Fuda, G.; Ossola, I.; Cammarosano, S.; Ilardi, A.; Bertuzzo, D.; Tanel, R.; Pisano, F.; Costantino, E.; Pani, C.; Puddu, R.; Caredda, C.; Piras, V.; Tranquilli, S.; Cuccu, S.; Corongiu, D.; Melis, M.; Milia, A.; Pirisi, A.; Occhineri, P.; Ortu, E.
abstract
Intermediate-length CAG expansions (encoding 27-33 glutamines, polyQ) of the Ataxin2 (ATXN2) gene represent a risk factor for amyotrophic lateral sclerosis (ALS). Recently, it has been proposed that ≥31 CAG expansions may influence ALS phenotype. We assessed whether ATXN2 intermediate-length polyQ expansions influence ALS phenotype in a series of 375 patients of Sardinian ancestry. Controls were 247 neurologically healthy subjects, resident in the study area, age- and gender-matched to cases. The frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (4 patients vs. no control, p = 0.0001). All patients with ≥31 polyQ repeats had a spinal onset versus 73.3% of patients with <31 polyQ repeats. Patients with an increased number of polyQ repeats have a shorter survival than those with <31 repeats (1.2 vs. 4.2 years, p = 0.035). In this large series of ALS patients of Sardinian ancestry, we have found that ≥31 polyQ repeats of the ATXN2 gene influenced patients' phenotype, being associated to a spinal onset and a significantly shorter survival.
2015
- CHCH10 mutations in an Italian cohort of familial and sporadic amyotrophic lateral sclerosis patients
[Articolo su rivista]
Chiò, A; Mora, G; Sabatelli, M; Caponnetto, C; Traynor, Bj; Johnson, Jo; Nalls, Ma; Calvo, A; Moglia, C; Borghero, G; Monsurrò, Mr; La Bella, V; Volanti, P; Simone, I; Salvi, F; Logullo, Fo; Nilo, R; Battistini, S; Mandrioli, J; Tanel, R; Murru, Mr; Mandich, P; Zollino, M; Conforti, Fl; Italsgen, Consortium; Brunetti, M; Barberis, M; Restagno, G; Penco, S; Lunetta, C.
abstract
Mutations in CHCHD10 have recently been described as a cause of frontotemporal dementia (FTD) comorbid with amyotrophic lateral sclerosis (ALS). The aim of this study was to assess the frequency and clinical characteristics of CHCHD10 mutations in Italian patients diagnosed with familial (n = 64) and apparently sporadic ALS (n = 224). Three apparently sporadic patients were found to carry c.100C>T (p.Pro34Ser) heterozygous variant in the exon 2 of CHCHD10. This mutation had been previously described in 2 unrelated French patients with FTD-ALS. However, our patients had a typical ALS, without evidence of FTD, cerebellar or extrapyramidal signs, or sensorineural deficits. We confirm that CHCHD10 mutations account for ∼ 1% of Italian ALS patients and are a cause of disease in subjects without dementia or other atypical clinical signs.
2015
- Cadmium, lead and mercury levels in cerebrospinal fluid and risk of amyotrophic lateral sclerosis – A case-control study.
[Abstract in Atti di Convegno]
Violi, Federica; Filippini, Tommaso; Fini, Nicola; Malagoli, Carlotta; Vinceti, Marco; Bernard, Michalke; Mandrioli, Jessica
abstract
Cadmium, lead and mercury levels in cerebrospinal fluid and risk of amyotrophic lateral sclerosis – A case-control study.
2015
- Erratum: Epidemiology of amyotrophic lateral sclerosis in Emilia Romagna Region (Italy): A population based study (Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration (2014) 15 (262-268))
[Articolo su rivista]
Mandrioli, J.; Biguzzi, S.; Guidi, C.; Venturini, E.; Sette, E.; Terlizzi, E.
abstract
2015
- Erythropoietin in amyotrophic lateral sclerosis: a multicentre, randomised, double blind, placebo controlled, phase III study
[Articolo su rivista]
Lauria, G; Dalla Bella, E; Antonini, G; Borghero, G; Capasso, M; Caponnetto, C; Chiò, A; Corbo, M; Eleopra, R; Fazio, R; Filosto, M; Giannini, F; Granieri, E; La Bella, V; Logroscino, G; Mandrioli, J; Mazzini, L; Monsurrò, Mr; Mora, G; Pietrini, V; Quatrale, R; Rizzi, R; Salvi, F; Siciliano, G; Sorarù, G; Volanti, P; Tramacere, I; Filippini, G; EPOS Trial Study, Group.
abstract
OBJECTIVE:
To assess the efficacy of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS).
METHODS:
Patients with probable laboratory-supported, probable or definite ALS were enrolled by 25 Italian centres and randomly assigned (1:1) to receive intravenous rhEPO 40,000 IU or placebo fortnightly as add-on treatment to riluzole 100 mg daily for 12 months. The primary composite outcome was survival, tracheotomy or >23 h non-invasive ventilation (NIV). Secondary outcomes were ALSFRS-R, slow vital capacity (sVC) and quality of life (ALSAQ-40) decline. Tolerability was evaluated analysing adverse events (AEs) causing withdrawal. The randomisation sequence was computer-generated by blocks, stratified by centre, disease severity (ALSFRS-R cut-off score of 33) and onset (spinal or bulbar). The main outcome analysis was performed in all randomised patients and by intention-to-treat for the entire population and patients stratified by severity and onset. The study is registered, EudraCT 2009-016066-91.
RESULTS:
We randomly assigned 208 patients, of whom 5 (1 rhEPO and 4 placebo) withdrew consent and 3 (placebo) became ineligible (retinal thrombosis, respiratory insufficiency, SOD1 mutation) before receiving treatment; 103 receiving rhEPO and 97 placebo were eligible for analysis. At 12 months, the annualised rate of death (rhEPO 0.11, 95% CI 0.06 to 0.20; placebo: 0.08, CI 0.04 to 0.17), tracheotomy or >23 h NIV (rhEPO 0.16, CI 0.10 to 0.27; placebo 0.18, CI 0.11 to 0.30) did not differ between groups, also after stratification by onset and ALSFRS-R at baseline. Withdrawal due to AE was 16.5% in rhEPO and 8.3% in placebo. No differences were found for secondary outcomes.
CONCLUSIONS:
RhEPO 40,000 IU fortnightly did not change the course of ALS.
2015
- Extrapyramidal and cognitive signs in amyotrophic lateral sclerosis: A population based cross-sectional study
[Articolo su rivista]
Pupillo, E; Bianchi, E; Messina, P; Chiveri, L; Lunetta, C; Corbo, M; Filosto, M; Lorusso, L; Marin, B; Mandrioli, J; Riva, N; Sasanelli, F; Tremolizzo, L; Beghi, E; Eurals, Consortium.
abstract
Our objective was to assess the association between amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia (FTD) and Parkinson's disease (PD). From May 2007 through August 2012 we investigated 146 patients with newly diagnosed ALS and 146 age- and gender-matched controls. Each individual was screened for cardinal extrapyramidal signs (neurological examination) and cognitive dysfunction (Mini Mental State Examination, MMSE and Frontal Assessment Battery, FAB). Results demonstrated that rigidity was present in 8.2% of cases and 2.1% of controls (adjusted odds ratio, adjOR 5.7; 95% CI 1.5-22.0). The corresponding percentages for bradykinesia and postural instability were, respectively, 8.2 vs. 2.7% (adjOR 4.8; 95% CI 1.4-16.5) and 2.7 vs. 9.6% (adjOR 0.3; 95% CI 0.1-0.9). FAB ≤ 13.4 was recorded in 24.8 vs. 9.6%; adjOR 2.9; 95% CI 1.5-5.7). Tremor and abnormal FAB score were predicted by an older age at onset while an abnormal FAB score was associated with cramps and family history of neurodegenerative diseases. In conclusion, our data support the notion that newly diagnosed ALS carries a higher than expected risk of extrapyramidal signs and FTD.
2015
- FATTORI AMBIENTALI DI RISCHIO DELLA SCLEROSI LATERALE AMIOTROFICA: UNO STUDIO CASO-CONTROLLO DI POPOLAZIONE BASATO SU QUESTIONARI ANAMNESTICI
[Abstract in Atti di Convegno]
Violi, F; Fiore, M; Filippini, T; Malagoli, C; Arcolin, E; Iacuzio, L; Ledda, C; Mauceri, C; Dimartino, A; Mandrioli, J; Fini, N; Georgoulopoulou, E; Patti, F; Lo Fermo, S; Sciacca, S; Ferrante, M; Vinceti, M
abstract
Introduzione: La sclerosi laterale amiotrofica (SLA) è una malattia neurodegenerativa progressiva la cui eziologia è ancora sostanzialmente ignota, ad eccezione di alcune rare forme di origine genetica. Numerosi suoi possibili fattori di rischio ambientali sono attualmente oggetto di indagine. Metodi: Abbiamo realizzato uno studio caso-controllo di popolazione nelle province di Modena, Reggio Emilia e Catania, al fine di valutare il ruolo eziologico di alcuni possibili fattori ambientali di rischio. Abbiamo somministrato per via postale un questionario finalizzato alla raccolta di informazioni anamnestiche ai casi di SLA diagnosticati nel periodo 2008-2011 e ad un gruppo di controlli di popolazione appaiati per alcune variabili confondenti. Risultati: Il 35% (n=162, 61 casi e 101 controlli) dei questionari inviati è stato compilato e restituito. In un modello di regressione logistica, i pregressi traumatismi soggetti a valutazione medica sono risultati associati ad un odds ratio (OR) di SLA pari a 1.20 (intervalli di confidenza al 95% (IC 95%) 0.62-2.30), con un valore più elevato (3.04, 1.22-7.55) per traumi alla testa. Gli shock elettrici hanno evidenziato un OR di 2.25 (0.66-7.63). Con riferimento alla storia occupazionale, l’OR associata all’attività lavorativa in ambito agricolo o come saldatore è risultata rispettivamente pari a 2.44 (1.02-5.79) e 1.25 (0.27-5.80). Aver vissuto in zona agricola è stato associato ad un lieve aumento del rischio (OR=1.67, 0.87-3.20), a differenza della pratica sportiva e specificatamente del calcio (OR 0.84 (0.46-1.51) e 1.04 (0.44-2.47). Conclusioni: I risultati ottenuti appaiono di potenziale interesse eziologico e meritevoli di ulteriori approfondimenti, pur tenendo conto del rischio di distorsioni di selezione del campione o di informazione, specie nei pazienti.
2015
- HFE p.H63D polymorphism does not influence ALS phenotype and survival
[Articolo su rivista]
Chiò, A; Mora, G; Sabatelli, M; Caponnetto, C; Lunetta, C; Traynor, Bj; Johnson, Jo; Nalls, Ma; Calvo, A; Moglia, C; Borghero, G; Monsurrò, Mr; La Bella, V; Volanti, P; Simone, I; Salvi, F; Logullo, Fo; Nilo, R; Giannini, F; Mandrioli, J; Tanel, R; Murru, Mr; Mandich, P; Zollino, M; Conforti, Fl; Penco, S; Italsgen, Consortium; Sardinials, Consortium; Brunetti, M; Barberis, M; Restagno, G.
abstract
It has been recently reported that the p.His63Asp polymorphism of the HFE gene accelerates disease progression both in the SOD1 transgenic mouse and in amyotrophic lateral sclerosis (ALS) patients. We have evaluated the effect of HFE p.His63Asp polymorphism on the phenotype in 1351 Italian ALS patients (232 of Sardinian ancestry). Patients were genotyped for the HFE p.His63Asp polymorphism (CC, GC, and GG). All patients were also assessed for C9ORF72, TARDBP, SOD1, and FUS mutations. Of the 1351 ALS patients, 363 (29.2%) were heterozygous (GC) for the p.His63Asp polymorphism and 30 (2.2%) were homozygous for the minor allele (GG). Patients with CC, GC, and GG polymorphisms did not significantly differ by age at onset, site of onset of symptoms, and survival; however, in SOD1 patients with CG or GG polymorphism had a significantly longer survival than those with a CC polymorphism. Differently from what observed in the mouse model of ALS, the HFE p.His63Asp polymorphism has no effect on ALS phenotype in this large series of Italian ALS patients.
2015
- Heterogeneity in ALSFRS-R decline and survival: a population-based study in Italy
[Articolo su rivista]
Mandrioli, J; Biguzzi, S; Guidi, C; Sette, E; Terlizzi, E; Ravasio, A; Casmiro, M; Salvi, F; Liguori, R; Rizzi, R; Pietrini, V; Borghi, A; Rinaldi, R; Fini, N; Chierici, E; Santangelo, M; Granieri, E; Mussuto, V; De Pasqua, S; Georgoulopoulou, E; Fasano, A; Errals, Group; Ferro, S; D'Alessandro, R
abstract
ery few studies examined trend over time of the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and factors influencing it; previous studies, then, included only patients attending tertiary ALS Centres. We studied ALSFRS-R decline, factors influencing this trend and survival in a population-based setting. From 2009 onwards, a prospective registry records all incident ALS cases among residents in Emilia Romagna (population: 4.4 million). For each patient, demographic and clinical details (including ALSFRS-R) are collected by caring physicians at each follow-up. Analysis was performed on 402 incident cases (1279 ALSFRS-R assessments). The average decline of the ALSFRS-R was 0.60 points/month during the first year after diagnosis and 0.34 points/month in the second year. ALSFRS-R decline was heterogeneous among subgroups. Repeated measures mixed model showed that ALSFRS-R score decline was influenced by age at onset (p < 0.01), phenotype (p = 0.01), body mass index (BMI) (p < 0.01), progression rate at diagnosis (ΔFS) (p < 0.01), El Escorial Criteria-Revised (p < 0.01), and FVC% at diagnosis (p < 0.01). Among these factors, at multivariate analysis, only age, site of onset and ΔFS independently influenced survival. In this first population-based study on ALSFRS-R trend, we confirm that ALSFRS-R decline is not homogeneous among ALS patients and during the disease. Factors influencing ALSFRS-R decline may not match with those affecting survival. These disease modifiers should be taken into consideration for trials design and in clinical practice during discussions with patients on prognosis.
2015
- Population density and risk of Amyotrophic Lateral Sclerosis: an Italian population-based study.
[Abstract in Rivista]
Filippini, Tommaso; Malagoli, Carlotta; Violi, Federica; Iacuzio, Laura; Arcolin, Elisa; Nicola, Fini; Georgoulopoulou, Eleni; Mandrioli, Jessica; Vinceti, Marco
abstract
Population density and risk of Amyotrophic Lateral Sclerosis: an Italian population-based study.
2015
- Recurrent cerebrospinal fluid basophilia in neurosarcoidosis
[Articolo su rivista]
Codeluppi, L; Spagnolo, P; Tondelli, M; Malaguti, Mc; Mandrioli, J
abstract
2015
- Risk of ALS and passive long-term residential exposure to pesticides: a population based study.
[Abstract in Rivista]
Violi, Federica; Filippini, Tommaso; Malagoli, Carlotta; Mandrioli, Jessica; Carlo, Signorelli; Aanna, Odone; Margherita, Ferrante; Maria, Fiore; Ledda, C; Cristina, Mauceri; Patti, F; Costanzini, Sofia; Fabbi, Sara; Teggi, Sergio; Vinceti, Marco
abstract
Risk of ALS and passive long-term residential exposure to pesticides: a population based study.
2015
- Risk of ALS and passive residential exposure to pesticides: a population based study.
[Abstract in Atti di Convegno]
Violi, Federica; Filippini, Tommaso; Malagoli, Carlotta; Mandrioli, Jessica; Signorelli, C; Odone, A; Ferrante, M; Fiore, M; Ledda, C; Mauceri, C; Patti, F; Costanzini, Sofia; Fabbi, Sara; Teggi, Sergio; Vinceti, Marco
abstract
. Risk of ALS and passive residential exposure to pesticides: a population based study.
2015
- TUBA4A gene analysis in sporadic amyotrophic lateral sclerosis: identification of novel mutations
[Articolo su rivista]
Pensato, V; Tiloca, C; Corrado, L; Bertolin, C; Sardone, V; Del Bo, R; Calini, D; Mandrioli, J; Lauria, G; Mazzini, L; Querin, G; Ceroni, M; Cantello, R; Corti, S; Castellotti, B; Soldà, G; Duga, S; Comi, Gp; Cereda, C; Sorarù, G; D'Alfonso, S; Taroni, F; Shaw, Ce; Landers, Je; Ticozzi, N; Ratti, A; Gellera, C; Silani, V; Slagen, Consortium
abstract
2015
- VCP AND AUTOPHAGOLYSOSOMAL PATHWAY: GUARDIANS OF PROTEOSTASIS AND STRESS GRANULE DYNAMICS. UNRAVELING THEIR IMPLICATIONS IN ALS
[Poster]
Ganassi, Massimo; Bigi, Ilaria; Seguin, SAMUEL JOSEPH ANDRE'; Morelli, FEDERICA FRANCESCA; Mandrioli, J; Cereda, C; Poletti, A; Carra, Serena
abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease comprising clinically indistinguishable sporadic (s) and familial (f) forms, associated with an aberrant behavior of a number of gene products (SOD1, TDP-43, FUS, UBQLN2, VCP, FIG4, CHMP2B, SQSTM1, C9orf72). Most of these proteins are involved in protein degradation via the ubiquitin proteasome (UPP) or the autophagolysosomal (APLP) pathways, as well as in RNA processing or stress granule (SG) response. In ALS, motoneurons accumulate protein aggregates that contain RNA-binding proteins markers of SGs. Thus, proteostasis (mediated by the protein quality control, PQC) and ribostasis (involving SGs) may be interconnected and their imbalance may participate to ALS. At present, it is largely unknown whether interplay between PQC (chaperones, UPP and APLP) and SG dynamics exists and to what extent deregulated PQC may affect SGs, thereby contributing to ALS. Notably, valosin containing protein (VCP) assists with autophagy SG clearance (1) and we found that inhibition of autophagy, lysosomes and depletion of VCP alter SG size, number and composition, pointing to APLP and chaperone-assisted degradation as interconnected processes. These data imply that imbalances in proteostasis and deregulated APLP, which occur in ALS, will affect SG morphology and composition; thus, defective SG response may also contribute to ALS.
Here, we will: 1) dissect how interplay between PQC, VCP and SGs occurs, identifying new players involved in this process and specific clients whose VCP-assisted/APLP-mediated degradation affects SGs; 2) identify the functional consequences of impaired SG response; 3) test whether boosting chaperone-assisted degradation or client targeting may rescue SG morphology and composition. Using motoneuronal ALS cell models we will characterize the impact of ALS mutants of VCP on SG and proteostasis. In parallel, we will characterize and compare SG morphology and composition in fibroblasts and lymphoblasts derived from ALS patients with mutations in VCP, TDP-43, FUS, SOD1 and C9orf72, as well as in motoneurons derived from ALS-iPSCs. Our approach will provide mechanistic insight on the interplay between VCP, PQC and SGs. It will also demonstrate whether/how SG composition and dynamics are affected in ALS and how this correlates with proteostasis alterations, representing a common pathogenic mechanism; finally, our data will provide the molecular basis for the design of new therapeutic strategy.
2014
- EFFECT OF RILUZOLE TREATMENT IN PATIENTS FROM EMILIA ROMAGNA, ITALY: A POPULATION BASED STUDY
[Abstract in Rivista]
Mandrioli, J; Fini, N; Georgoulopoulou, E; DE PASQUA, S; D’Alessandro, R
abstract
2014
- Epidemiology of amyotrophic lateral sclerosis in Emilia Romagna Region (Italy): A population based study.
[Articolo su rivista]
Mandrioli, Jessica; Biguzzi, S; Guidi, C; Venturini, E; Sette, E; Terlizzi, E; Ravasio, A; Casmiro, M; Salvi, F; Liguori, R; Rizzi, R; Pietrini, V; Chierici, E; Santangelo, M; Granieri, E; Mussuto, V; Borghi, A; Rinaldi, R; Fini, N; Georgoulopoulou, E; De Pasqua, S; Vinceti, Marco; Bonvicini, Federica; Ferro, S; D'Alessandro, R; Errals, Group
abstract
Our objective was to describe incidence and clinical features of ALS from a prospective population-based study in Emilia Romagna Region (ERR). From 2009 onwards, a prospective registry recorded all incident cases of ALS among residents in the ERR (population, 4.4 million inhabitants), involving 17 neurological departments. For each patient, detailed demographic and clinical information was collected by caring physicians. Results showed that from 1 January 2009 to 31 December 2011, 347 patients received a new diagnosis of ALS with a crude incidence rate of 2.63/100,000/year. There was micro-geographic heterogeneity throughout ERR, with higher incidence rates in the low density population (3.27/100,000) (p < 0.01). ALS patients have been more frequently employed in agriculture than the general ERR population (8.64% vs. 4.6%, p < 0.01). Clinical features were similar to those described in previous population based studies. In conclusion, we report incidence rates similar to those reported by European registries, reflecting good accuracy of our prospective study. We confirmed previous studies reporting higher incidence rates in rural areas and among agricultural workers. Although genetics has been gaining increasing importance in ALS aetiology, some epidemiological data are still unexplained. Identifying geographical areas or populations with high incidence rates can be a starting point for identifying environmental risk factors.
2014
- Genetic counselling in ALS: facts, uncertainties and clinical suggestions
[Articolo su rivista]
Chiò, A; Battistini, S; Calvo, A; Caponnetto, C; Conforti, Fl; Corbo, M; Giannini, F; Mandrioli, J; Mora, G; Sabatelli, M; Italsgen, Consortium; Ajmone, C; Mastro, E; Pain, D; Mandich, P; Penco, S; Restagno, G; Zollino, M; Surbone, A.
abstract
The clinical approach to patients with amyotrophic lateral sclerosis (ALS) has been largely modified by the identification of novel genes, the detection of gene mutations in apparently sporadic patients, and the discovery of the strict genetic and clinical relation between ALS and frontotemporal dementia (FTD). As a consequence, clinicians are increasingly facing the dilemma on how to handle genetic counselling and testing both for ALS patients and their relatives. On the basis of existing literature on genetics of ALS and of other late-onset life-threatening disorders, we propose clinical suggestions to enable neurologists to provide optimal clinical and genetic counselling to patients and families. Genetic testing should be offered to ALS patients who have a first-degree or second-degree relative with ALS, FTD or both, and should be discussed with, but not offered to, all other ALS patients, with special emphasis on its major uncertainties. Presently, genetic testing should not be proposed to asymptomatic at-risk subjects, unless they request it or are enrolled in research programmes. Genetic counselling in ALS should take into account the uncertainties about the pathogenicity and penetrance of some genetic mutations; the possible presence of mutations of different genes in the same individual; the poor genotypic/phenotypic correlation in most ALS genes; and the phenotypic pleiotropy of some genes. Though psychological, social and ethical implications of genetic testing are still relatively unexplored in ALS, we recommend multidisciplinary counselling that addresses all relevant issues, including disclosure of tests results to family members and the risk for genetic discrimination.
2014
- I pesticidi quali possibili fattori ambientali di rischio nella sclerosi laterale amiotrofica: uno studio caso-controllo di popolazione in Emilia-Romagna.
[Abstract in Atti di Convegno]
Arcolin, Elisa; Fiore, M; Mandrioli, Jessica; Iacuzio, Laura; Malagoli, Carlotta; Violi, Federica; Filippini, Tommaso; Georgoulopoulou, E; Ledda, C; Mauceri, C; Floridia, A; Di Martino, A; D’Agati, M. G; Fazio, R; Patti, F; Zappia, M; Sciacca, S; Ferrante, M; Vinceti, Marco
abstract
.
2014
- Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis
[Articolo su rivista]
Johnson, J. O.; Pioro, E. P.; Boehringer, A.; Chia, R.; Feit, H.; Renton, A. E.; Pliner, H. A.; Abramzon, Y.; Marangi, G.; Winborn, B. J.; Gibbs, J. R.; Nalls, M. A.; Morgan, S.; Shoai, M.; Hardy, J.; Pittman, A.; Orrell, R. W.; Malaspina, A.; Sidle, K. C.; Fratta, P.; Harms, M. B.; Baloh, R. H.; Pestronk, A.; Weihl, C. C.; Rogaeva, E.; Zinman, L.; Drory, V. E.; Borghero, G.; Mora, G.; Calvo, A.; Rothstein, J. D.; Drepper, C.; Sendtner, M.; Singleton, A. B.; Taylor, J. P.; Cookson, M. R.; Restagno, G.; Sabatelli, M.; Bowser, R.; Chio`, A.; Traynor, B. J.; Moglia, C.; Cammarosano, S.; Canosa, A.; Gallo, S.; Brunetti, M.; Ossola, I.; Marinou, K.; Papetti, L.; Pisano, F.; Pinter, G. L.; Conte, A.; Luigetti, M.; Zollino, M.; Lattante, S.; Marangi, G.; la Bella, V.; Spataro, R.; Colletti, T.; Battistini, S.; Ricci, C.; Caponnetto, C.; Mancardi, G.; Mandich, P.; Salvi, F.; Bartolomei, I.; Mandrioli, J.; Sola, P.; Lunetta, C.; Penco, S.; Monsurro, M. R.; Conforti, F. L.; Tedeschi, G.; Gambardella, A.; Quattrone, A.; Volanti, P.; Floris, G.; Cannas, A.; Piras, V.; Marrosu, F.; Marrosu, M. G.; Murru, M. R.; Pugliatti, M.; Parish, L. D.; Sotgiu, A.; Solinas, G.; Ulgheri, L.; Ticca, A.; Simone, I.; Logroscino, G.; Pirisi, A.
abstract
MATR3 is an RNA- and DNA-binding protein that interacts with TDP-43, a disease protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. Our data provide more evidence supporting the role of aberrant RNA processing in motor neuron degeneration. © 2014 Nature America, Inc. All rights reserved.
2014
- Non-invasive and invasive ventilation and enteral nutrition for ALS in Italy.
[Articolo su rivista]
Fini, N; Georgoulopoulou, E; Vinceti, Marco; Monelli, M; Pinelli, G; Vacondio, P; Giovannini, M; Dallari, R; Marudi, A; Mandrioli, Jessica
abstract
Introduction: We performed a population-based study to assess amyotrophic lateral sclerosis (ALS) survival after noninvasive ventilation (NIV), invasive ventilation (IV), and enteral nutrition (EN). Methods: We included patients diagnosed from 2000 to 2009 in Modena, where a prospective registry and a Motor Neuron Diseases Centre have been active since 2000. Results: Of the 193 incident cases, 47.7% received NIV, 24.3% received tracheostomy, and 49.2% received EN. A total of 10.4% of the patients refused NIV, 31.6% refused IV, and 8.7% refused EN. The median survival times after NIV, IV, and EN were 15, 19, and 9 months, respectively. Of the tracheostomized patients, 79.7% were discharged from the hospital; 73.0% were discharged to home. The median survival times for tracheostomized patients who were cared for at home and in nursing homes were 43 and 2 months, respectively. The multivariate analysis demonstrated that the place of discharge was the only independent prognostic factor after IV (P<0.01). Conclusions: Service organizations may promote adherence to NIV, IV, EN, and influence postprocedure survival. These data may be useful in defining health plans regarding advanced ALS care and in patient counseling.
2014
- PROGNOSTIC FACTORS FOR ALS IN
PATIENTS FROM EMILIA ROMAGNA, ITALY: A POPULATION BASED STUDY
[Abstract in Rivista]
Mandrioli, J; Georgoulopoulou, E; Fini, N; Biguzzi, S; Sette, E; Salvi, F; Pietrini, V; Guidi, C; Terlizzi, E; Rizzi, R; Casmiro, M; Liguori, R; Ravasio, A; D’Alessandro, R
abstract
2014
- Pearls & Oy-sters: rapidly progressive dementia: prions or immunomediated?
[Articolo su rivista]
Cavallieri, Francesco; Mandrioli, Jessica; Tondelli, Manuela; Vitetta, Francesca; Stipa, Carlotta; Vallone, Stefano; Georgoulopoulou, Eleni; Barbi, Filippo; Liguori, Rocco; Parchi, Piero; Nichelli, Paolo Frigio
abstract
The paper presentes a case report of a patient with rapidly progressive dementia. The discussion is focused on the differential diagnosis between Voltage-gated potassium channel antibody–associated encephalitis and sporadic Creutzfeldt-Jakob disease.
2014
- Pesticidi e rischio di sclerosi laterale amiotrofica: il contributo della metodologia gis in uno studio in Emilia-Romagna e in Sicilia.
[Abstract in Atti di Convegno]
Filippini, Tommaso; Fiore, M; Mandrioli, Jessica; Odone, A; Malagoli, Carlotta; Iacuzio, Laura; Arcolin, Elisa; Violi, Federica; Mazzini, F; Rossi, R; Nannini, R; Guermandi, M; Staffilani, F; Marchi, N; Fabbi, Sara; Teggi, Sergio; Costanzini, Sofia; Ghermandi, Grazia; Pietrini, V; Fini, N; Ledda, C; Mauceri, C; Di Martino, A; Patti, F; Sentina, E; Signorelli, C; Ferrante, M; Vinceti, Marco
abstract
.
2014
- Plasma amino acids patterns and age of onset of amyotrophic lateral sclerosis
[Articolo su rivista]
Cecchi, M; Messina, P; Airoldi, L; Pupillo, E; Bandettini di Poggio, M; Calvo, A; Filosto, M; Lunetta, C; Mandrioli, J; Pisa, F; Pastorelli, R; Beghi, E; Eurals, Consortium
abstract
The aim of this study was to verify whether abnormalities in plasma amino acid (AA) levels could be biological correlates of the age of onset in amyotrophic lateral sclerosis (ALS). We undertook plasma AA profiling in a large population comprising 117 newly diagnosed ALS patients and 117 matched controls. ALS patients were stratified in early (58 patients aged < 55 years) versus late onset (59 patients aged > 74 years). We applied a rapid and reproducible method for the analysis of AA using amine reactive isotope coded tags in conjunction with liquid chromatography coupled to Multiple Reaction Monitoring-Mass Spectrometry. Results showed that values of only three AA were significantly different in ALS patients and controls. We found lower levels of leucine and higher levels of glutamate and leucine in early-onset ALS compared to their matched controls. In conclusion, different AA patterns related to the ALS age of onset were found, providing insight into possibly aberrant biochemical pathways that might unlock key pathological pathways.
2014
- Selenium neurotoxicity in humans: Bridging laboratory and epidemiologic studies.
[Articolo su rivista]
Vinceti, Marco; Mandrioli, Jessica; Borella, Paola; Michalke, B; Tsatsakis, A; Finkelstein, Y.
abstract
Selenium is a metalloid of considerable interest in the human from both a toxicological and a nutritional perspective, with a very narrow safe range of intake. Acute selenium intoxication is followed by adverse effects on the nervous system with special clinical relevance, while the neurotoxicity of long-term overexposure is less characterized and recognized. We aimed to address this issue from a public health perspective, focusing on both laboratory studies and the few epidemiologic human studies available, with emphasis on their methodological strengths and limitations. The frequently overlooked differences in toxicity and biological activity of selenium compounds are also outlined. In addition to lethargy, dizziness, motor weakness and paresthesias, an excess risk of amyotrophic lateral sclerosis is the effect on the nervous system which has been more consistently associated with chronic low-level selenium overexposure, particularly to its inorganic compounds. Additional research efforts are needed to better elucidate the neurotoxic effects exerted by selenium overexposure.
2014
- Whole-blood global DNA methylation is increased in amyotrophic lateral sclerosis independently of age of onset
[Articolo su rivista]
Tremolizzo, L; Messina, P; Conti, E; Sala, G; Cecchi, M; Airoldi, L; Pastorelli, R; Pupillo, E; Bandettini Di Poggio, M; Filosto, M; Lunetta, C; Agliardi, C; Guerini, F; Mandrioli, J; Calvo, A; Beghi, E; Ferrarese, C; Eurals, Consortium.
abstract
ALS is a heterogeneous disease that is not well understood. Epigenetic rearrangements are important in complex disorders including motor neuron diseases. The aim of this study was to determine whether whole-blood DNA methylation (DNA MET %) is a potential modifier of age at onset in ALS. DNA MET % was measured as incorporation of [(3)H]dCTP following HpaII cut in 96 ALS patients and 87 controls, comprising: early-onset (< 55 years of age) and late-onset (> 74 years of age). Methionine (Met) and homocysteine (Hcy) plasma levels were assessed by liquid chromatography selected reaction monitoring coupled with isotope-dilution mass spectrometry. Results showed that DNA MET % was increased in ALS patients independently of age of onset. Compared to the other three groups, Hcy plasma levels were reduced in early-onset ALS patients but Met levels were similar. ROC analysis reported Met levels and DNA MET %, respectively, with a slight and moderate discriminative power. In conclusion, increased DNA MET % is a possible marker of epigenetic dysfunction in ALS independently of age of onset. Further studies dissecting biological determinants of phenotypic complexity in ALS may help in developing successful therapeutic strategies.
2013
- ALSFRS-R DECLINE IN PATIENTS FROM
THE EMILIA-ROMAGNA REGISTER FOR ALS
(ERRALS)
[Abstract in Rivista]
Mandrioli, J; Salvi, F; Sette, E; Terlizzi, E; Rizzi, R; Casmiro, M; Liguori, R; Pasquinelli, M; Pietrini, V; Venturini, E; Biguzzi, S; Chierici, E; Guidi, C; Borghi, A; Santangelo, M; Granieri, E; Mussuto, V; Fini, N; DE PASQUA, S; D’Alessandro, R
abstract
2013
- Acyclovir resistance in herpes simplex encephalitis: a case report
[Abstract in Atti di Convegno]
Vandelli, L; Rosafio, F; Rispoli, V; Ariatti, A; Mandrioli, J; Nichelli, P.
abstract
2013
- Cerebrospinal fluid of newly diagnosed amyotrophic lateral sclerosis patients exhibits abnormal levels of selenium species including elevated selenite.
[Articolo su rivista]
Vinceti, Marco; Solovyev, N; Mandrioli, Jessica; Crespi, Cm; Bonvicini, Francesca; Arcolin, Elisa; Georgoulopoulou, Eleni; Michalke, B.
abstract
Exposure to selenium, and particularly to its inorganic forms, has been hypothesized as a risk factor for amyotrophic lateral sclerosis (ALS), a fast progressing motor neuron disease with poorly understood etiology. However, no information is known about levels of inorganic and some organic selenium species in the central nervous system of ALS patients, and recent observations suggest that peripheral biomarkers of exposure are unable to predict these levels for several Se species including the inorganic forms. Using a hospital-referred case-control series and advanced selenium speciation methods, we compared the chemical species of selenium in cerebrospinal fluid from 38 ALS patients to those of 38 reference neurological patients matched on age and gender. We found that higher concentrations of inorganic selenium in the form of selenite and of human serum albumin-bound selenium were associated with increased ALS risk (relative risks 3.9 (95% confidence interval 1.2-11.0) and 1.7 (1.0-2.9) for 0.1μg/L increase). Conversely, lower concentrations of selenoprotein P-bound selenium were associated with increased risk (relative risk 0.2 for 1μg/L increase, 95% confidence interval 0.04-0.8). The associations were stronger among cases age 50 years or older, who are postulated to have lower rates of genetic disease origin. These results suggest that excess selenite and human serum albumin bound-selenium and low levels of selenoprotein P-bound selenium in the central nervous system, which may be related, may play a role in ALS etiology.
2013
- EFFICACY OF ERYTHROPOIETIN IN
AMYOTROPHIC LATERAL SCLEROSIS: A
MULTICENTRE, RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED, PHASE III STUDY
(EPOS TRIAL)
[Abstract in Rivista]
Lauria, G; Borghero, G; Capasso, M; Caponnetto, C; Chiò, A; Corbo, M; Eleopra, R; Fazio, R; Filosto, M; Giannini, F; Granieri, E; LA BELLA, V; Logroscino, G; Mandrioli, J; Mazzini, L; Monsurrò, Mr; Mora, G; Morino, S; Pietrini, V; Quatrale, R; Rizzi, R; Salvi, F; Siciliano, G; Sorar, Ù G; Volanti, P; Filippini, G FOR THE EPOS TRIAL STUDY GROUP
abstract
2013
- Efficacy of erythropoietin in amyotrophic lateral sclerosis: a multicentre, randomised, double blind, placebo controlled, phase III study (IPOS TRIAL)
[Abstract in Atti di Convegno]
Lauria, G; Dalla Bella, E; Borghero, G; Capasso, M; Caponnetto, C; Chiò, A; Corbo, M; Eleopra, R; Fazio, R; Filosto, M; Giannini, F; Granieri, E; La Bella, V; Logroscino, G; Mandrioli, J; Mazzini, L; Monsurrò, Mr; Mora, G; Morino, S; Pietrini, V; Quatrale, R; Rizzi, R; Salvi, F; Siciliano, G; Sorarù, G; Volanti, P; Tramacere, I; Filippini, G.
abstract
2013
- Epidemiologia e fattori ambientali di rischio della sclerosi laterale amiotrofica sporadica: metodologia di uno studio realizzato in ambiente gis.
[Abstract in Atti di Convegno]
Vinceti, Marco; Fiore, M; Odone, A; Signorelli, C; Mandrioli, Jessica; Fini, N; Fabbi, Sara; Teggi, Sergio; Costanzini, Sofia; Ghermandi, Grazia; Iacuzio, Laura; Malagoli, Carlotta; Arcolin, Elisa; Ferrante, M.
abstract
.
2013
- Having brains makes it easier. When neurological involvement enables the diagnosis of a multisystemic disease such as sarcoidosis
[Abstract in Atti di Convegno]
Mirandola, L; Ariatti, A; Fini, N; Vinceti, G; Nichelli, P; Mandrioli, J
abstract
2013
- LHON: Confusing elements and diagnostic challenge
[Abstract in Atti di Convegno]
Rispoli, V; Mandrioli, J; Ariatti, A; Mirandola, L; Vinceti, G; Nichelli, P
abstract
2013
- No evidence of cardiomyopathy in spinal and bulbar muscular atrophy
[Articolo su rivista]
Querin, G; Melacini, P; D'Ascenzo, C; Morandi, L; Mazzini, L; Silani, V; Romito, S; Mandrioli, J; Raimondi, M; Pegoraro, E; Soraru', G.
abstract
OBJECTIVES:
Spinal and bulbar muscular atrophy (SBMA) is a lower motor neuron disease caused by a CAG repeat expansion within the androgen receptor (AR) gene. Toxic nuclear accumulation of mutant AR has been observed in tissues other than nervous system including cardiac muscle. Moreover, CAG polymorphism length within AR has been associated with an increased risk of heart disease.
MATERIALS AND METHODS:
To test the hypothesis of the presence of cardiomyopathy in SBMA, a full cardiac protocol was applied to 25 SBMA patients.
RESULTS:
Patients' age ranged between 32 and 75 years. Cardiologic examination, 12-lead ECG, and echocardiography showed no abnormalities other than those consistent with hypertensive heart disease. One patient showed frequent supraventricular premature beats in absence of other significant arrhythmias at the 24-h ECG Holter.
CONCLUSIONS:
Our findings do not support the hypothesis of a primary cardiomyopathy in SBMA.
2013
- Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels
[Articolo su rivista]
Bartolome, F; Wu, Hc; Burchell, Vs; Preza, E; Wray, S; Mahoney, Cj; Fox, Nc; Calvo, A; Canosa, A; Moglia, C; Mandrioli, J; Chiò, A; Orrell, Rw; Houlden, H; Hardy, J; Abramov, Ay; Plun-Favreau, H.
abstract
Valosin-containing protein (VCP) is a highly expressed member of the type II AAA+ ATPase family. VCP mutations are the cause of inclusion body myopathy, Paget's disease of the bone, and frontotemporal dementia (IBMPFD) and they account for 1%-2% of familial amyotrophic lateral sclerosis (ALS). Using fibroblasts from patients carrying three independent pathogenic mutations in the VCP gene, we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption. This mitochondrial uncoupling results in a significant reduction of cellular ATP production. Decreased ATP levels in VCP-deficient cells lower their energy capacity, making them more vulnerable to high energy-demanding processes such as ischemia. Our findings propose a mechanism by which pathogenic VCP mutations lead to cell death.
Copyright © 2013 Elsevier Inc. All rights reserved.
2013
- Pilot trial of clenbuterol in spinal and bulbar muscular atrophy
[Articolo su rivista]
Querin, G; D'Ascenzo, C; Peterle, E; Ermani, M; Bello, L; Melacini, P; Morandi, L; Mazzini, L; Silani, V; Raimondi, M; Mandrioli, J; Romito, S; Angelini, C; Pegoraro, E; Sorarù, G.
abstract
OBJECTIVE:
To test the efficacy and tolerability of clenbuterol in patients with spinal and bulbar muscular atrophy (SBMA).
METHODS:
Twenty patients with a diagnosis of SBMA were given oral clenbuterol (0.04 mg/d) for 12 months. The primary efficacy end point was the change from baseline of the walking distance covered in 6 minutes at 12 months. Secondary end points included the change over time in muscle strength assessed with the Medical Research Council scale, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and forced vital capacity values. Safety was assessed by a series of laboratory and instrumental tests, as well as reporting of adverse events.
RESULTS:
Sixteen patients completed the study. There was a significant and sustained increase in walking distance covered in 6 minutes and forced vital capacity between the baseline and the 12-month assessments (p < 0.001). No differences were recorded in Medical Research Council or ALSFRS-R scores between baseline and follow-up assessments. Serious side effects, including those on heart function, were absent. A significant increase in serum creatine kinase levels was observed.
CONCLUSIONS:
Our findings suggest a positive effect of clenbuterol on SBMA disease progression.
CLASSIFICATION OF EVIDENCE:
This study provides Class IV evidence that clenbuterol is effective in improving motor function in SBMA.
2013
- TIA: multiple vascular risk factors and vascular anomalies, who is guilty?
[Abstract in Atti di Convegno]
Rispoli, V; Cavallieri, F; Perrone, C; Mandrioli, J; Ariatti, A; Giovannini, G; Monti, G; Nichelli, P
abstract
2013
- TREND OF THE ALSFRS-R IN PATIENTS FROM THE EMILIA-ROMAGNA REGISTER FOR ALS (ERRALS).
[Abstract in Atti di Convegno]
Mandrioli, J; Salvi, F; Sette, E; Terlizzi, E; Rizzi, R; Casmiro, M; Liguori, R; Pasquinelli, M; Pietrini, V; Venturini, E; Biguzzi, S; Chierici, E; Guidi, C; Borghi, A; Santangelo, M; Granieri, E; Mussuto, V; Fini, N; De Pasqua, S; D’Alessandro, R
abstract
2013
- The impact of clinical factors, riluzole and therapeutic interventions on ALS survival: A population based study in Modena, Italy
[Articolo su rivista]
Georgoulopoulou, Eleni; Nicola, Fini; Vinceti, Marco; Marco, Monelli; Paolo, Vacondio; Giorgia, Bianconi; Patrizia, Sola; Nichelli, Paolo Frigio; Mandrioli, Jessica
abstract
The prognostic role of riluzole, enteral nutrition (EN), non-invasive ventilation (NIV) and interdisciplinary care in ALS is still debated. A population based study has been performed focusing on ALS survival, with particular attention to prognostic factors and therapeutic intervention. All patients diagnosed with ALS between 2000 and 2009 and residing in Modena, Italy, have been registered. A centre for motor neuron disease (MND) has been active in our province since 2000, in addition to a prospective registry collecting all incident cases. One hundred and ninety-three incident cases have been collected during the 10 years of the study. Results demonstrated that median survival was 41 months (the overall three-year and five-year survival rates being 54.36% and 28.81%, respectively). Based on univariate analysis, factors related to survival were: age at diagnosis, gender, site of onset, phenotype, riluzole treatment and tracheostomy. In the Cox multivariable model, the factors independently related to a longer survival were age (p < 0.01), site of onset (p = 0.02) and riluzole treatment (p < 0.01), with a median gain in survival of 29 months (patients aged < 55 years compared with patients ≥ 55 years), 20 months (spinal versus bulbar onset), and 12 months (riluzole, yes vs. no), respectively. In conclusion, the study has confirmed the prognostic role of clinical features, but has surprisingly demonstrated that riluzole prolonged life significantly longer than NIV and EN. This observational study described the effects of ALS management in a setting that may approximate routine clinical practice more closely than randomized controlled trial (RCT); effects of uncontrolled potential confounders, however, cannot be excluded.
The prognostic role of riluzole, enteral nutrition (EN), non-invasive ventilation (NIV) and interdisciplinary care in ALS is still debated. A population based study has been performed focusing on ALS survival, with particular attention to prognostic factors and therapeutic intervention. All patients diagnosed with ALS between 2000 and 2009 and residing in Modena, Italy, have been registered. A centre for motor neuron disease (MND) has been active in our province since 2000, in addition to a prospective registry collecting all incident cases. One hundred and ninety-three incident cases have been collected during the 10 years of the study. Results demonstrated that median survival was 41 months (the overall three-year and five-year survival rates being 54.36% and 28.81%, respectively). Based on univariate analysis, factors related to survival were: age at diagnosis, gender, site of onset, phenotype, riluzole treatment and tracheostomy. In the Cox multivariable model, the factors independently related to a longer survival were age (p < 0.01), site of onset (p = 0.02) and riluzole treatment (p < 0.01), with a median gain in survival of 29 months (patients aged < 55 years compared with patients ≥ 55 years), 20 months (spinal versus bulbar onset), and 12 months (riluzole, yes vs. no), respectively. In conclusion, the study has confirmed the prognostic role of clinical features, but has surprisingly demonstrated that riluzole prolonged life significantly longer than NIV and EN. This observational study described the effects of ALS management in a setting that may approximate routine clinical practice more closely than randomized controlled trial (RCT); effects of uncontrolled potential confounders, however, cannot be excluded.
2013
- VOLTAGE-GATED POTASSIUM CHANNEL (VGKC)AUTOANTIBODIES-ASSOCIATED ENCEPHALITIS AND KREUTZFELDT-JAKOB DISEASE: A CASE OF COMPLETE CLINICAL, IMAGING, AND LABORATORY OVERLAP
[Abstract in Atti di Convegno]
Cavallieri, F; Mandrioli, J; Tondelli, M; Vitetta, F; Vallone, S; Georgoulopoulou, E; Barbi, F; Nichelli, P.
abstract
2012
- A pilot trial with clenbuterol in SBMA
[Abstract in Atti di Convegno]
Querin, G; D'Ascenzo, C; Morandi, L; Mazzini, L; Silani, V; Mandrioli, J; Raimondi, M; Romito, S; Marcello, N; Angelini, C; Pegoraro, E; Sorarù, G
abstract
2012
- ALS MANAGEMENT AND SURVIVAL IN MODENA, ITALY: A STUDY ON A TEN-YEARS PROSPECTIVE POPULATION BASED COHORT
[Abstract in Rivista]
Georgoulopoulou, E; Fini, N; Monelli, M; Pinelli, G; Vacondio, P; Sola, P; Nichelli, P; Mandrioli, J
abstract
2012
- ALS management in Modena, Italy: a ten-years prospective study
[Abstract in Atti di Convegno]
Fini, N; Georgoulopoulou, E; Monelli, M; Pinelli, G; Vacondio, P; Sola, P; Nichelli, P; Mandrioli, J
abstract
2012
- ALS survival in Modena Italy: a study on a ten-years prospective population based cohort
[Abstract in Atti di Convegno]
Georgoulopoulou, E; Fini, N; Monelli, M; Pinelli, G; Vacondio, P; Sola, P; Nichelli, P; Mandrioli, J
abstract
2012
- AMYOTROPHIC LATERAL SCLEROSIS IN
EMILIA ROMAGNA, ITALY: A POPULATION
BASED STUDY FROM 2009 TO 2011. THE EMILIAROMAGNA
REGISTER FOR ALS (ERRALS)
[Abstract in Rivista]
Mandrioli, J; Salvi, F; Sette, E; Terlizzi, E; Rizzi, R; Casmiro, M; Liguori, R; Pasquinelli, M; Pietrini, V; Venturini, E; Biguzzi, S; Chierici, E; Guidi, C; Borghi, A; Santangelo, M; Granieri, E; Mussuto, V; Fini, N; DE PASQUA, S; D’Alessandro, R
abstract
2012
- Acute diffusely infiltrating idiopathic inflammatory demyelinating lesion (IIDL)associated with unknown thrombotic thrombocytopenic purpura: a case report
[Abstract in Atti di Convegno]
Barbi, F; Georgoulopoulou, E; Mandrioli, J; Tondelli, M; Fini, N; Nichelli, P; Vitetta, F
abstract
2012
- Acute-onset multifocal motor neuropathy (AMMN) or acute motor conduction block neuropathy (AMCBN): a clinical challenge
[Abstract in Atti di Convegno]
Codeluppi, L; Tondelli, M; Contardi, S; Georgoulopoulou, E; Mandrioli, J; Valzania, F; Galassi, G
abstract
2012
- Amyotrophic Lateral Sclerosis in Emilia Romagna, Italy: a population based study from 2009 to 2011. The Emilia Romagna Register for ALS (ERRALS)
[Abstract in Atti di Convegno]
Mandrioli, J; Salvi, F; Sette, E; Terlizzi, E; Rizzi, R; Casmiro, M; Liguori, R; Pasquinelli, M; Pietrini, V; Venturini, E; Biguzzi, S; Chierici, E; Guidi, C; Borghi, A; Santangelo, M; Granieri, E; Mussuto, V; Fini, N; De Pasqua, S; D'Alessandro, R.
abstract
2012
- Are environmental exposures to selenium, heavy metals, and pesticides risk factors for amyotrophic lateral sclerosis ?
[Articolo su rivista]
Vinceti, Marco; Ilaria, Bottecchi; Anna, Fan; Yoram, Finkelstein; Mandrioli, Jessica
abstract
The etiology of sporadic amyotrophic lateral sclerosis (ALS), the most common form of this degenerative disease of the motor neurons, is still unknown, despite extensive investigation of several genetic and environmental potential risk factors. We have reviewed laboratory and epidemiological studies assessing the role of exposure to neurotoxic chemicals (metalloid selenium; heavy metals mercury, cadmium, and lead; pesticides) in ALS etiology by summarizing the results of these investigations and examining their strengths and limitations. Despite limitations in the exposure assessment methodologies typically used in human studies, we found suggestive epidemiological evidence and biologic plausibility for an association between ALS and antecedent overexposure to environmental selenium and pesticides. The relation with mercury, cadmium, and lead appears weaker.
2012
- C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population
[Articolo su rivista]
Sabatelli, M; Conforti, Fl; Zollino, M; Mora, G; Monsurrò, Mr; Volanti, P; Marinou, K; Salvi, F; Corbo, M; Giannini, F; Battistini, S; Penco, S; Lunetta, C; Quattrone, A; Gambardella, A; Logroscino, G; Simone, I; Bartolomei, I; Pisano, F; Tedeschi, G; Conte, A; Spataro, R; La Bella, V; Caponnetto, C; Mancardi, G; Mandich, P; Sola, P; Mandrioli, J; Renton, Ae; Majounie, E; Abramzon, Y; Marrosu, F; Marrosu, Mg; Murru, Mr; Sotgiu, Ma; Pugliatti, M; Rodolico, C; Italsgen, Consortium; Moglia, C; Calvo, A; Ossola, I; Brunetti, M; Traynor, Bj; Borghero, G; Restagno, G; Chiò, A.
abstract
2012
- C9ORF72 in a Large Series of Italian and Sardinian Familial and Sporadic ALS Patients
[Abstract in Atti di Convegno]
Chio, A; Borghero, G; Sabatelli, M; Corbo, M; Mora, G; Giannini, F; Conforti, F; Penco, S; Calvo, A; Pugliatti, M; Sotgiu, A; Logroscino, G; Traynor, Bj; Renton, A; Majounie, E; Lauria, G; Caponnetto, C; Mandrioli, J; Salvi, F; Volanti, P; La Bella, V; Monsurro, M; Zollino, M; Ossola, I; Brunetti, M; Restagno, G
abstract
2012
- Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72
[Articolo su rivista]
Chiò, A; Borghero, G; Restagno, G; Mora, G; Drepper, C; Traynor, Bj; Sendtner, M; Brunetti, M; Ossola, I; Calvo, A; Pugliatti, M; Sotgiu, Ma; Murru, Mr; Marrosu, Mg; Marrosu, F; Marinou, K; Mandrioli, J; Sola, P; Caponnetto, C; Mancardi, G; Mandich, P; La Bella, V; Spataro, R; Conte, A; Monsurrò, Mr; Tedeschi, G; Pisano, F; Bartolomei, I; Salvi, F; Lauria Pinter, G; Simone, I; Logroscino, G; Gambardella, A; Quattrone, A; Lunetta, C; Volanti, P; Zollino, M; Penco, S; Battistini, S; Italsgen, Consortium; Renton, Ae; Majounie, E; Abramzon, Y; Conforti, Fl; Giannini, F; Corbo, M; Sabatelli, M
abstract
2012
- Environmental risk factors for amyotrophic lateral sclerosis:
methodological issues in epidemiologic studies
[Articolo su rivista]
Vinceti, Marco; M., Fiore; C., Signorelli; A., Odone; M., Tesauro; M., Consonni; Arcolin, Elisa; Malagoli, Carlotta; Mandrioli, Jessica; Marmiroli, Sandra; Sciacca, S. v.; M., Ferrante
abstract
The exact role of environmental risk factors in the etiology of the neurodegenerative disease amyotrophic
lateral sclerosis (ALS) is still unknown. Their hypothetical contribution ranges from a minimal impact to
a major role. Among the environmental factors strictu sensu (i.e., not life-style factors) suspected to play
a role in ALS etiology, we consider pesticides, the metalloid selenium, some heavy metals, magnetic fields
and cyanobacteria. However, the possibility exists that these factors exert their activity only in genetically
susceptible persons and only after long-term exposures, thus further hampering epidemiologic studies. The
recent availability of powerful tools such as population-based ALS registries for case ascertainment and
clustering detection, and of environmental modeling techniques and of geographical information systems,
may yield unique opportunities for offering insight into the etiology of the disease.
2012
- Founder effect hypothesis of D11Y SOD1 mutation in Italian amyotrophic lateral sclerosis patients
[Articolo su rivista]
Lattante, S; Marangi, G; Luigetti, M; Conte, A; Mandrioli, J; Del Grande, A; Zollino, M; Sabatelli, M
abstract
2012
- Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study
[Articolo su rivista]
Majounie, E; Renton, Ae; Mok, K; Dopper, Eg; Waite, A; Rollinson, S; Chiò, A; Restagno, G; Nicolaou, N; Simon-Sanchez, J; van Swieten, Jc; Abramzon, Y; Johnson, Jo; Sendtner, M; Pamphlett, R; Orrell, Rw; Mead, S; Sidle, Kc; Houlden, H; Rohrer, Jd; Morrison, Ke; Pall, H; Talbot, K; Ansorge, O; Adamson, G; Bayer, Aj; Beck, J; Callister, Jb; Blake, Dj; Blumen, Sc; Collinge, J; Dunckley, T; Ealing, J; East, S; Elman, L; Gerhard, A; Guerreiro, Rj; Gwinn, K; Halliwell, N; Hamdalla, Hh; Hewitt, C; Ince, P; Jablonka, S; James, C; Kent, L; Knock, Jc; Lynch, T; Mahoney, C; Mann, D; Neal, J; Norris, D; O'Dowd, S; Richardson, A; Rossor, M; Rothstein, J; Scholz, Sw; Snowden, J; Stephan, Da; Toulson, G; Turner, Mr; Warren, Jd; Young, K; Weng, Yh; Kuo, Hc; Lai, Sc; Huang, Cl; Camuzat, A; Entraingues, L; Guillot-Noël, ; Verpillat, P; Blanc, F; Camu, W; Clerget-Darpoux, F; Corcia, P; Couratier, P; Didic, M; Dubois, B; Duyckaerts, C; Guedj, E; Golfier, V; Habert, Mo; Hannequin, D; Lacomblez, L; Meininger, V; Salachas, F; Levy, R; Michel, Bf; Pasquier, F; Puel, M; Thomas-Anterion, C; Sellal, F; Vercelletto, M; Moglia, C; Cammarosano, S; Canosa, A; Gallo, S; Brunetti, M; Ossola, I; Marinou, K; Papetti, L; Pisano, F; Pinter, Gl; Conte, A; Luigetti, M; Zollino, M; Lattante, S; Marangi, G; la Bella, V; Spataro, R; Colletti, T; Battistini, S; Ricci, C; Caponnetto, C; Mancardi, G; Mandich, P; Salvi, F; Bartolomei, I; Mandrioli, J; Sola, P; Lunetta, C; Penco, S; Monsurrò, Mr; Tedeschi, G; Conforti, Fl; Gambardella, A; Quattrone, A; Volanti, P; Floris, G; Cannas, A; Piras, V; Marrosu, F; Marrosu, Mg; Murru, Mr; Pugliatti, M; Parish, Ld; Sotgiu, A; Solinas, G; Ulgheri, L; Ticca, A; Simone, I; Logroscino, G; Hernandez, Dg; Arepalli, S; Sabatelli, M; Mora, G; Corbo, M; Giannini, F; Calvo, A; Englund, E; Borghero, G; Floris, Gl; Remes, Am; Laaksovirta, H; Mccluskey, L; Trojanowski, Jq; Van Deerlin, Vm; Schellenberg, Gd; Nalls, Ma; Drory, Ve; Lu, Cs; Yeh, Th; Ishiura, H; Takahashi, Y; Tsuji, S; Le Ber, I; Brice, A; Drepper, C; Williams, N; Kirby, J; Shaw, P; Hardy, J; Tienari, Pj; Heutink, P; Morris, Hr; Pickering-Brown, S; Traynor, Bj
abstract
2012
- Internal carotid artery dissection: a rare cause of peripheral facial nerve palsy
[Articolo su rivista]
Fioravanti, Valentina; Vinceti, Giulia; Chiari, Annalisa; Canali, Elena; Nichelli, Paolo Frigio; Mandrioli, Jessica
abstract
NA
2012
- Mutational analysis of the VCP gene in Parkinson's disease
[Articolo su rivista]
Majounie, E; Traynor, Bj; Chiò, A; Restagno, G; Mandrioli, J; Benatar, M; Taylor, Jp; Singleton, Ab
abstract
2012
- Replication of association of CHRNA4 rare variants with sporadic amyotrophic lateral sclerosis: the Italian multicentre study
[Articolo su rivista]
Sabatelli, M; Lattante, S; Conte, A; Marangi, G; Luigetti, M; Del Grande, A; Chiò, A; Corbo, M; Giannini, F; Mandrioli, J; Mora, G; Calvo, A; Restagno, G; Lunetta, C; Penco, S; Battistini, S; Zeppilli, P; Bizzarro, A; Capoluongo, E; Neri, G; Rossini, Pm; Zollino, M
abstract
2012
- Selenium species and heavy metals in cerebrospinal fluid and risk of amyotrophic lateral sclerosis: a hospital-based case-control study
[Abstract in Rivista]
Vinceti, Marco; Mandrioli, Jessica; Bonvicini, Francesca; Arcolin, Elisa; Georgoulopoulou, Eleni; N., Solovjev; B., Michalke
abstract
Background
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease which has been ascribed to overexposure to selenium and some heavy metals, on the basis of epidemiologic evidence and laboratory observations. However, no data are available on the specific involvement of single selenium species, all of which have distinctive biological activities, and limited evidence has also been provided for lead, mercury and cadmium in the human.
Methods
In a hospital-admitted case-control series, we determined the Se compounds and the levels of Cd, Hg and Pb in cerebrospinal fluid samples of thirty-six ALS patients and of thirty-six reference neurological patients. Determinations of Se compounds and of the heavy metals was performed using high pressure liquid chromatography coupled with inductively coupled plasma - dynamic reaction cell - mass spectrometry according to methodologies previously established and described by one of the coauthors (B.M.).
Results
We found an excess concentration of inorganic Se forms, particularly of the hexavalent and tetravalent ones, while organic Se compounds levels were considerably decreased in ALS cases. These differences were more pronounced in older patients and in females. On the converse, no substantial differences in Cd, Hg and Pb concentrations emerged.
Conclusions
These results suggest the occurrence of overexposure to inorganic Se species and decreased levels of Se-containing enzymes in ALS, while they offer little evidence of an involvement of three heavy metals, Cd, Hg and Pb, in the etiopathogenesis of this disease. However, caution must be used when inferring etiological clues from analytical results in patients affected by a severe disease such as ALS, and in hospital-referred controls. Further research on the involvement of Se in ALS etiology is clearly warranted.
2012
- Sensory Loss Mimicking Cauda Equina Syndrome due to Cervical Spinal Lesion in a Patient with Clinically Isolated Syndrome
[Articolo su rivista]
Vinceti, Giulia; Zini, Andrea; Nichelli, Paolo Frigio; Mandrioli, Jessica
abstract
We describe the case of a 39-year-old woman with signs and symptoms suggesting cauda equina syndrome. Lumbosacral magnetic resonance imaging (MRI) demonstrated no lesion at this level, while cervical MRI showed a T2-hyperintense lesion in the middle-right anterolateral region of the cervical spinal cord, which may explain the symptoms by involving the anterior spinothalamic tract. We suggest that in cases with cauda equina syndrome presentation and normal lumbosacral MRI, a cervicodorsal lesion should be considered during diagnostic assessment.
2012
- Subacute combined degenration secondary to pernicious anemia
[Abstract in Atti di Convegno]
Vinceti, G; Codeluppi, L; Galassi, G; Nichelli, P; Mandrioli, J
abstract
2012
- Valosin-containing protein (VCP) mutations in sporadic amyotrophic lateral sclerosis
[Articolo su rivista]
Abramzon, Y; Johnson, Jo; Scholz, Sw; Taylor, Jp; Brunetti, M; Calvo, A; Mandrioli, J; Benatar, M; Mora, G; Restagno, G; Chiò, A; Traynor, Bj
abstract
2011
- A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
[Articolo su rivista]
Renton, Ae; Majounie, E; Waite, A; Simón-Sánchez, J; Rollinson, S; Gibbs, Jr; Schymick, Jc; Laaksovirta, H; van Swieten, Jc; Myllykangas, L; Kalimo, H; Paetau, A; Abramzon, Y; Remes, Am; Kaganovich, A; Scholz, Sw; Duckworth, J; Ding, J; Harmer, Dw; Hernandez, Dg; Johnson, Jo; Mok, K; Ryten, M; Trabzuni, D; Guerreiro, Rj; Orrell, Rw; Neal, J; Murray, A; Pearson, J; Jansen, Ie; Sondervan, D; Seelaar, H; Blake, D; Young, K; Halliwell, N; Callister, Jb; Toulson, G; Richardson, A; Gerhard, A; Snowden, J; Mann, D; Neary, D; Nalls, Ma; Peuralinna, T; Jansson, L; Isoviita, Vm; Kaivorinne, Al; Hölttä-Vuori, M; Ikonen, E; Sulkava, R; Benatar, M; Wuu, J; Chiò, A; Restagno, G; Borghero, G; Sabatelli, M; Calvo, A; Cammarosano, S; Moglia, C; Canosa, A; Gallo, S; Brunetti, M; Ossola, I; Mora, G; Marinou, K; Papetti, L; Conte, A; Luigetti, M; La Bella, V; Spataro, R; Colletti, T; Battistini, S; Giannini, F; Ricci, C; Caponnetto, C; Mancardi, G; Mandich, P; Salvi, F; Bartolomei, I; Mandrioli, J; Sola, P; Corbo, M; Lunetta, C; Penco, S; Monsurrò, Mr; Tedeschi, G; Conforti, Fl; Volanti, P; Floris, G; Cannas, A; Piras, V; Murru, Mr; Marrosu, Mg; Pugliatti, M; Ticca, A; Simone, I; Logroscino, G; Heckerman, D; Rogaeva, E; Zinman, L; Rothstein, Jd; Sendtner, M; Drepper, C; Eichler, Ee; Alkan, C; Abdullaev, Z; Pack, Sd; Dutra, A; Pak, E; Hardy, J; Singleton, A; Williams, Nm; Heutink, P; Pickering-Brown, S; Morris, Hr; Tienari, Pj; Traynor, Bj
abstract
2011
- Amyotrophic lateral sclerosis in Emilia Romagna, Italy: a population based study. The Emilia Romagna Register for ALS (ERRALS)
[Abstract in Atti di Convegno]
Mandrioli, J; Rizzi, R; Sette, E; Terlizzi, E; Salvi, F; Venturini, E; Pietrini, V; Casmiro, M; Chierici, E; Liguori, R; Guidi, C; Granieri, E; Pasquinelli, M; Borghi, A; Santangelo, M; D'Alessandro, R
abstract
2011
- Changing incidence and subtypes of ALS in Modena, Italy: A 10-years prospective study
[Articolo su rivista]
Georgoulopoulou, Eleni; Vinceti, Marco; F., Bonvicini; P., Sola; C. A., Goldoni; G. D., Girolamo; Ferraro, Diana; Nichelli, Paolo Frigio; Mandrioli, Jessica
abstract
We performed a prospective population-based study to describe the temporal pattern of the incidence and prevalence and the clinical features and phenotypes of ALS in Modena, Italy, from 2000 to 2009. From 2000 onwards, a prospective registry has been collecting all cases of incident ALS among residents in the province of Modena. This source was implemented by cases resulting from the provincial hospitals, and by death certificates. Based on 193 newly diagnosed cases, the crude average annual incidence rate of ALS was 2.9 cases per 100,000 person years (py); adjusted incidence rate was 2.8/100,000. The age-standardized incidence rates increased from 2.6 per 100,000 py in 2000-2004 to 2.9 per 100,000 py in 2005-2009, representing an annual increase of approximately 2% throughout the 10-year period. There was a constant increase in prevalence rates throughout the years of the study (from 5.8/100,000 on 31 December 2000 to 11.2/100,000 on 31 December 2009). Median life time was 29 months for patients diagnosed before the year 2000 and 36 months for patients diagnosed from 1 January 2000 (p < 0.01). Thus, we report incidence rates similar to those reported by recent European population based studies, but we observed an increasing trend over the 10 years of the study. The increasing incidence is not explained by aging of the population, and our study raises the question as to whether local environmental or genetic factors are driving this temporal trend. Along with an increasing incidence, we found an important increase in prevalence and survival probably related to access to mutidisciplinary clinics and improvements in symptomatic care of ALS.
2011
- Erratum exome sequencing reveals VCP mutations as a cause of familial ALS
[Articolo su rivista]
Johnson, J. O.; Mandrioli, J.; Benatar, M.; Abramzon, Y.; Van Deerlin, V. M.; Trojanowski, J. Q.; Gibbs, J. R.; Brunetti, M.; Gronka, S.; Wuu, J.; Ding, J.; Mccluskey, L.; Martinez-Lage, M.; Falcone, D.; Hernandez, D. G.; Arepalli, S.; Chong, S.; Schymick, J. C.; Rothstein, J.; Landi, F.; Wang, Y. -D.; Calvo, A.; Mora, G.; Sabatelli, M.; Monsurro, M. R.; Battistini, S.; Salvi, F.; Spataro, R.; Sola, P.; Borghero, G.; Galassi, G.; Scholz, S. W.; Taylor, J. P.; Restagno, G.; Chio, A.; Traynor, B. J.
abstract
2011
- FUS mutations in sporadic amyotrophic lateral sclerosis
[Articolo su rivista]
Lai, Sl; Abramzon, Y; Schymick, Jc; Stephan, Da; Dunckley, T; Dillman, A; Cookson, M; Calvo, A; Battistini, S; Giannini, F; Caponnetto, C; Mancardi, Gl; Spataro, R; Monsurro, Mr; Tedeschi, G; Marinou, K; Sabatelli, M; Conte, A; Mandrioli, J; Sola, P; Salvi, F; Bartolomei, I; Lombardo, F; The Italsgen, Consortium; Mora, G; Restagno, G; Chiò, A; Traynor, Bj
abstract
2011
- Isolated central nervous system sarcoidosis: a difficult diagnosis
[Abstract in Atti di Convegno]
Georgoulopoulou, E; Chiari, A; Malaguti, Mc; Barbi, F; Vandelli, L; Nichelli, P; Mandrioli, J
abstract
2011
- Isolated progressive cognitive impairment and depression in a patient with neuroradiological features suggestive of multiple sclerosis
[Articolo su rivista]
Ferraro, Diana; Simone, ANNA MARIA; Merelli, E.; Mandrioli, J:; Molinari, M. A.; Nichelli, Paolo Frigio; Sola, P.
abstract
We report the case of a woman who started complaining of depression, attention and memory problems at the age of 49. Over the following 6 years, serial neuropsychological assessments showed fluctuating, but overall progressively worsening, performances in tests exploring attention, working memory, language and executivefunctions. Cerebrospinal fluid (CSF) examination showed identical IgG oligoclonal bands in serum and CSF.Neurological examination, to date, only reveals minimal pyramidal and cerebellar signs. Although typical clinical and laboratory evidence indicating a diagnosis of multiple sclerosis (MS) in this patient is lacking, an extensive diagnostic work-up ruled out many other causes of leukoencephalopathy and neuroradiological features strongly suggest this diagnosis. Multiple sclerosis may present with cognitive or neuropsychiatric symptoms; this should be kept in mind, especially in younger patients, even in the absence of ‘‘classical’’ physical symptoms.
2011
- Large proportion of amyotrophic lateral sclerosis cases in Sardinia due to a single founder mutation of the TARDBP gene
[Articolo su rivista]
Chiò, A; Borghero, G; Pugliatti, M; Ticca, A; Calvo, A; Moglia, C; Mutani, R; Brunetti, M; Ossola, I; Marrosu, Mg; Murru, Mr; Floris, G; Cannas, A; Parish, Ld; Cossu, P; Abramzon, Y; Johnson, Jo; Nalls, Ma; Arepalli, S; Chong, S; Hernandez, Dg; Traynor, Bj; Restagno, G; Battistini, S; Giannini, F; Ricci, C; Canosa, A; Gallo, S; Monsurrò, Mr; Tedeschi, G; Mandrioli, J; Sola, P; Salvi, F; Bartolomei, I; Mora, G; Marinou, K; Papetti, L; Conte, A; Sabatelli, M; Luigetti, M; Spataro, R; La Bella, V; Paladino, P; Caponnetto, C; Volanti, P
abstract
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.
2010
- A novel SOD1 mutation in a young amyotrophic lateral sclerosis patient with a very slowly progressive clinical course
[Articolo su rivista]
Georgoulopoulou, E; Gellera, C; Bragato, C; Sola, P; Chiari, A; Bernabei, C; Mandrioli, J
abstract
2010
- Accuracy of death certificates in ALS
[Abstract in Atti di Convegno]
Bernabei, C; Georgoulopoulou, E; Sola, P; Nichelli, P; Mandrioli, J
abstract
2010
- Amyotrophic lateral sclerosis and sarcoidosis: a difficult differential diagnosis.
[Articolo su rivista]
E., Canali; P., Sola; Richeldi, Luca; Spagnolo, Paolo; G., Mora; E., Georgoulopoulou; C., Bernabei; M. C., Malaguti; F., Valzania; Mandrioli, Jessica
abstract
Non disponibile
2010
- Bilateral vocal cord paralysis: a rare onset of amyotrophic lateral sclerosis
[Articolo su rivista]
Bigliardi, G; Malaguti, Mc; Sola, P; Georgoulopoulou, E; Tondelli, M; Barbi, F; Canali, E; Mandrioli, J
abstract
2010
- CHANGES IN THE EPIDEMIOLOGY OF
AMYOTROPHIC LATERAL SCLEROSIS IN MODENA, ITALY, FROM 1990 TO 2009
[Abstract in Rivista]
Georgoulopoulou, E; Sola, P; Bernabei, C; Nichelli, P; Mandrioli, J
abstract
2010
- Cerebrospinal fluid oligoclonal IgM bands and disease outcome in Guillain-Barrè Syndrome
[Abstract in Atti di Convegno]
Ferraro, D; Simone, A; Santangelo, M; Venneri, M; Bedin, R; Galli, V; Mandrioli, J; Galassi, G; Malaguti, Mc; Nichelli, P; Sola, P
abstract
2010
- Cerebrospinal fluid oligoclonal IgM bands in guillain-Barrè syndrome
[Abstract in Atti di Convegno]
Ferraro, D; Simone, A; Venneri, Mg; Mandrioli, J; Bedin, R; Galassi, G; Malaguti, Mc; Nichelli, P; Sola, P
abstract
2010
- Comment on 'Huntington's disease presenting as ALS'
[Articolo su rivista]
Mandrioli, Jessica; Bernabei, Chiara; Georgoulopoulou, Eleni; Nichelli, Paolo Frigio; Cortelli, Pietro; Tupler, Rossella; E., Signaroldi; P., Sola
abstract
This is a case report of patient with concurrent Huntington disease and Amyotrophic Lateral Sclerosis
2010
- Epilepsy in Wilson's Disease: an uncommon association
[Abstract in Atti di Convegno]
Monti, G; Barbi, F; Mandrioli, J; Malaguti, Mc; Ariatti, A; Nichelli, ; P Meletti, S
abstract
2010
- Exome sequencing reveals VCP mutations as a cause of familial ALS
[Articolo su rivista]
Johnson, Jo; Mandrioli, J; Benatar, M; Abramzon, Y; Van Deerlin, Vm; Trojanowski, Jq; Gibbs, Jr; Brunetti, M; Gronka, S; Wuu, J; Ding, J; Mccluskey, L; Martinez-Lage, M; Falcone, D; Hernandez, Dg; Arepalli, S; Chong, S; Schymick, Jc; Rothstein, J; Landi, F; Wang, Yd; Calvo, A; Mora, G; Sabatelli, M; Monsurrò, Mr; Battistini, S; Salvi, F; Spataro, R; Sola, P; Borghero, G; Italsgen, Consortium; Galassi, G; Scholz, Sw; Taylor, Jp; Restagno, G; Chiò, A; Traynor, Bj
abstract
2010
- Exposure to pesticides and risk of amyotrophic lateral sclerosis: a population-based case-control study
[Articolo su rivista]
Bonvicini, Francesca; Marcello, N.; Mandrioli, J.; Pietrini, V.; Vinceti, Marco
abstract
A few epidemiologic studies have suggested an association of agricultural work and pesticidesexposure with a severe degenerative disease of the motor neurons, amyotrophic lateral sclerosis(ALS), though conflicting results have also been provided. We investigated through a populationbasedcase-control study the possible relation between overall occupational exposure to pesticidesand ALS risk in the northern Italy municipality of Reggio Emilia. By administering a questionnaire,we investigated occupational history and leisure-time habits of the 41 ALS patients diagnosed in the1995-2006 period, and of 82 age- and sex-matched randomly sampled population controls. Morecases than controls were found to have been exposed to pesticides for at least six months (31.7% vs13.4%, respectively), in all cases within the occupational environment. In a conditional logistic regressionmodel, we found an excess ALS risk associated with exposure to pesticides, with a relativerisk of 3.6 (95% confidence interval 1.2-10.5). Such association persisted after inclusion in the statisticalanalysis of potential confounders. Despite the limited statistical stability of the risk estimates,these results appear to indicate that occupational exposure to pesticides is a risk factor for ALS,suggesting the need to further investigate this issue.
2010
- FUS mutations in a large series of sporadic and familial ALS
[Abstract in Atti di Convegno]
Moglia, C; Calvo, A; Lai, S; Abramzon, Y; Schymick, Jc; Guerreiro, Rj; Stephan, Da; Dunckley, T; Mutani, R; Mora, G; Gallo, S; Giannini, F; Battistini, S; Salvi, F; Bartolomei, I; Carlesi, C; Siciliano, G; Mandrioli, J; Sola, P; Caponnetto, C; Mancardi, G; Marinou, K; Brunetti, M; Conte, A; Sabatelli, M; Valentino, F; La bella, V; Tedeschi, G; Monsurrò, M; Restagno, G; Traynor, Bj; Chio, A
abstract
2010
- L'approccio multidisciplinare e la continuità di cura nella SLA in provincia di Modena: implicazioni epidemiologiche, cliniche ed assistenziali
[Abstract in Atti di Convegno]
Mandrioli, J; Sola, P; Georgoulopoulou, E; Bernabei, C; Nichelli, P
abstract
2010
- Lithium carbonate in ALS: a treatment failure
[Abstract in Atti di Convegno]
Chio, A; Mora, G; Corbo, M; Caponnetto, C; Mandrioli, J; Salvi, F; Sorarù, G; Mazzini, L; Silani, V; Tola, Mr; Giannini, F; Sabatelli, M; Monsurrò, M; Borghero, G; Simone, I; Perini, M; Patti, F; Marcello, N; Pietrini, V; Pisani, F; Pupillo, E; Calvo, A; Moglia, C; Logroscino, G; Beghi, E
abstract
2010
- Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial
[Articolo su rivista]
Chiò, A; Borghero, G; Calvo, A; Capasso, M; Caponnetto, C; Corbo, M; Giannini, F; Logroscino, G; Mandrioli, J; Marcello, N; Mazzini, L; Moglia, C; Monsurrò, Mr; Mora, G; Patti, F; Perini, M; Pietrini, V; Pisano, F; Pupillo, E; Sabatelli, M; Salvi, F; Silani, V; Simone, Il; Sorarù, G; Tola, Mr; Volanti, P; Beghi, E; LITALS Study, Group
abstract
2010
- Loss of thermal sensation and isolated insular stroke: a case report
[Abstract in Atti di Convegno]
Monti, G; Barbi, F; Chiari, A; Nichelli, P; Mandrioli, J; Malaguti, Mc
abstract
2010
- Mortality data and death certification for amyotrophic lateral sclerosis
[Abstract in Rivista]
Georgoulopoulou, E; Sola, P; Goldoni, Ca; Bernabei, C; Nichelli, P; Mandrioli, J
abstract
2010
- Optic nerve glioma mimicking optic neuritis
[Abstract in Atti di Convegno]
Georgoulopoulou, E; Malaguti, Mc; Mandrioli, J; Pinna, G; Carpeggiani, P; Maiorana, A; Mantovani, A; Monti, G; Barbi, F; Ferraro, D; Nichelli, P; Sola, P.
abstract
2010
- Patologie del sistema nervoso vegetativo
[Capitolo/Saggio]
Mandrioli, J; Cortelli, P
abstract
2010
- Primary progressive multiple sclerosis and generalized myasthenia gravis: an uncommon association
[Articolo su rivista]
Bigliardi, Guido; Mandrioli, Jessica; F., Valzania; Nichelli, Paolo Frigio; N., Casula; Simone, ANNA MARIA; P., Sola
abstract
The co-occurrence of myasthenia gravis (MG) and multiple sclerosis (MS) is rare, and in all the described cases MS had a relapsing-remitting course and the diseases had a benign clinical evolution. We describe herewith a patient with primary progressive MS (PPMS) and generalized MG with severe clinical course. This is the first report on a case of PPMS associated to MG. Studies on the histology and pathogenesis show that neurodegeneration is predominant over inflammation in PPMS, even if cellular and humoral immune-mediated mechanisms are thought to maintain a crucial importance in the development and progression of this form of disease. In the present case, the detection of cerebrospinal fluid IgM oligoclonal bands support the hypothesis of a possible role of antibody-mediated immunity in PPMS and suggest that humoral immunity may take part in the concomitant development of both MS and MG.
2010
- Rapidly progressive amyotrophic lateral sclerosis in a young patient with hereditary neuropathy with liability to pressure palsies
[Articolo su rivista]
Canali, Elena; Chiari, Annalisa; P., Sola; Fioravanti, Valentina; F., Valzania; R., Pentore; Nichelli, Paolo Frigio; Mandrioli, Jessica
abstract
We describe the rare case of a young woman with hereditary neuropathy with liability to compression palsy (HNPP), who developed a rapidly progressive ALS. We suggest that underexpression of PMP22 protein in the nervous system might interfere with motor neuron function by impairing myelin formation and exposure of the axon to injury. Patients with ALS and evidence of demyelination should be screened for HNPP.
2010
- Recurrent encephalopathy of unknown origin in course of complete atrioventriclar block: a case of heart encephalopathy?
[Abstract in Atti di Convegno]
Barbi, F; Malaguti, Mc; Chiari, A; Monti, G; Nichelli, P; Mandrioli, J
abstract
2010
- Syndrome of transient headache and neurological deficit with cerebrospinal fluid lymphocytosis (HANDL): a viral encephalitis mimic
[Abstract in Atti di Convegno]
Barbi, F; Mandrioli, J; Malaguti, Mc; Monti, G; Nichelli, P; Chiari, A
abstract
2010
- Temporal ternds in ALS epidemiology: a study in the province of Modena, Italy, from 1990 to 2009
[Abstract in Atti di Convegno]
Georgoulopoulou, E; Sola, P; Bernabei, C; Nichelli, P; Mandrioli, J
abstract
2009
- A novel SOD1 mutation in a young ALS patient associated with slowly progressive clinical course
[Abstract in Rivista]
Georgoulopoulou, E; Bragato, C; Gellera, C; Sola, P; Bigliardi, G; Bernabei, C; Ferraro, D; Mandrioli, J
abstract
2009
- A possible prognostic role of electromyography in ALS
[Abstract in Rivista]
Bernabei, C; Fioravanti, V; Sola, P; Bigliardi, G; Georgoulopoulou, E; Valzania, F; Malaguti, Mc; Mandrioli, J
abstract
2009
- A study of the CD45 exon 4 C77G polymorphism in a patient affected both by multiple sclerosis and pulmonary Langerhans' cell histiocytosis
[Abstract in Atti di Convegno]
Ferraro, D; Simone, A; Zucchini, P; Bavieri, M; Mandrioli, J; Nichelli, P; Sola, P
abstract
2009
- A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis
[Articolo su rivista]
Chiò, A; Schymick, Jc; Restagno, G; Scholz, Sw; Lombardo, F; Lai, Sl; Mora, G; Fung, Hc; Britton, A; Arepalli, S; Gibbs, Jr; Nalls, M; Berger, S; Kwee, Lc; Oddone, Ez; Ding, J; Crews, C; Rafferty, I; Washecka, N; Hernandez, D; Ferrucci, L; Bandinelli, S; Guralnik, J; Macciardi, F; Torri, F; Lupoli, S; Chanock, Sj; Thomas, G; Hunter, Dj; Gieger, C; Wichmann, He; Calvo, A; Mutani, R; Battistini, S; Giannini, F; Caponnetto, C; Mancardi, Gl; La Bella, V; Valentino, F; Monsurrò, Mr; Tedeschi, G; Marinou, K; Sabatelli, M; Conte, A; Mandrioli, J; Sola, P; Salvi, F; Bartolomei, I; Siciliano, G; Carlesi, C; Orrell, Rw; Talbot, K; Simmons, Z; Connor, J; Pioro, Ep; Dunkley, T; Stephan, Da; Kasperaviciute, D; Fisher, Em; Jabonka, S; Sendtner, M; Beck, M; Bruijn, L; Rothstein, J; Schmidt, S; Singleton, A; Hardy, J; Traynor, Bj
abstract
2009
- Acute motor axonal neuropathy (AMAN) - an atypical presentation
[Abstract in Atti di Convegno]
Barbi, F; Malaguti, Mc; Canali, E; Mandrioli, J; Ariatti, A; Valzania, F; Nichelli, P; Galassi, G
abstract
2009
- Amyotrophic lateral sclerosis and sarcoidosis: ALS mimic or co-occurrence?
[Abstract in Atti di Convegno]
Canali, E; Sola, P; Mora, G; Bernabei, ; C, ; Bigliardi, G; Georgoulopoulou, E; Simone, A; Malaguti, Mc; Mandrioli, J
abstract
2009
- Bilateral vocal cord abductor paralysis: an atypical onset of ALS
[Abstract in Atti di Convegno]
Bigliardi, G; Malaguti, Mc; Sola, P; Tondelli, M; Barbi, F; Canali, E; Nichelli, P; Mandrioli, J
abstract
2009
- CSF basophilia in brainstem encephalopathy: a case report
[Abstract in Atti di Convegno]
Tondelli, M; Malaguti, Mc; Bigliardi, G; Bonacorsi, G; Nichelli, P; Mandrioli, J
abstract
2009
- Cerebrospinal fluid oligoclonal IgM bands in Guillain-Barrè syndrome
[Abstract in Atti di Convegno]
Ferraro, D; Venneri, M; Mandrioli, J; Galassi, G; Bedin, R; Simone, A; Nichelli, P; Sola, P
abstract
2009
- Depression and progressive cognitive impairment as isolated clinical features in a patient with multiple sclerosis
[Abstract in Atti di Convegno]
Ferraro, D; Simone, A; Merelli, E; Mandrioli, J; Molinari, M; Nichelli, P; Sola, P
abstract
2009
- EBV and HHV6 in cerebrospinal fluid and serum of primary progressive multiple sclerosis
[Abstract in Atti di Convegno]
Ferraro, D; Merelli, E; Mandrioli, J; Simone, A; Annecca, R; Meacci, M; Gennari, W; Pecorari, M; Sola, P
abstract
2009
- FUS mutations in a large series of sporadic and familial ALS
[Abstract in Rivista]
Lai, Sl; Abramzony, Yg; Dunckley, T; Stephan, Da; Battistini, S; La Bella, V; Salvi, F; Mandrioli, J; Capponnetto, C; Sicilano, G; Monsurrò, Mr; Mora, G; Sabatelli, M; Brunetti, M; Schymick, Jc; Traynor, Bj; Restagno, G; Chiò, A
abstract
2009
- FUS/TLS mutations in a large series of Italian and American sporadic and familial ALS
[Abstract in Atti di Convegno]
Chio, A; Lai, S; Abramzony, Y; Dunckley, T; Stephan, D; Battistini, S; Giannini, F; La Bella, V; Spataro, S; Salvi, F; Bartolomei, I; Mandrioli, J; Sola, P; Caponnetto, C; Mancardi, G; Siciliano, G; Carlesi, C; Monsurrò, M; Tedeschi, G; Mora, G; Maurinou, K; Sabatelli, M; Conte, A; Brunetti, M; Ossola, I; Calvo, A; Moglia, C; Schymick, J; Traynor, B; Restagno, G
abstract
2009
- Hypokalaemic rhabdomyolisis during prolonged diuretic therapy: the diagnosis may be a challenge
[Abstract in Atti di Convegno]
Bigliardi, G; Malaguti, Mc; Mandrioli, J; Valzania, F; Tondelli, M; Galassi, G
abstract
2009
- Invasive ventilation and causes of death amongst ALS patients in Modena, Italy: a prospective study
[Abstract in Atti di Convegno]
Bigliardi, G; Sola, P; Georgoulopoulou, E; Monelli, M; Verduri, A; Bianconi, G; Vacondio, P; Mandrioli, J
abstract
2009
- Prognosis of ALS: a possible role of electromyography
[Abstract in Atti di Convegno]
Bernabei, C; Fioravanti, V; Sola, P; Bigliardi, G; Georgoulopoulou, E; Valzania, F; Malaguti, Mc; Mandrioli, J
abstract
2009
- Prognosis of primary progressive multiple sclerosis: do cerebrospinal fluid oligoclonal IgM bands play a role?
[Abstract in Atti di Convegno]
Mandrioli, J; Simone, A; Bedin, R; Merelli, E; Ferraro, D; Venneri, Mg; Annecca, R; Nichelli, P; Sola, P
abstract
2009
- Risk stratification of non-traumatic headache in the emergency department
[Articolo su rivista]
D., Grimaldi; F., Nonino; S., Cevoli; A., Vandelli; D'Amico, Roberto; P., Cortelli; Mandrioli, Jessica
abstract
OBJECTIVE: To determine the diagnostic accuracy of an algorithm structured in four clinical scenarios to discriminate benign primary headaches from serious secondary non-traumatic headaches (NTH) in the emergency department (ED). BACKGROUND: NTH is usually a benign symptom but can occasionally result in serious outcome making the disposition of patients with NTH difficult in the ED. DESIGN AND METHODS: Consecutive adults patients referring to 8 EDs of the Emilia-Romagna region in Italy for NTH as the chief complaint were recruited in the study for a 30-day period. ED physicians attributed to each patient one of the four clinical scenarios (1, 2 and 3 identifying serious secondary headaches and scenario 4 identifying benign primary headaches) or an undetermined scenario when none of the four scenarios applied. Reference standards of the study were the head CT scan and a follow-up telephone interview after three months by the ED admission. RESULTS: The test was administered to 256 out of 302 (85%) eligible patients. The analysis (scenario 1,2,3 vs scenario 4) was based on 180 patients who completed the follow-up showing a sensitivity of 100% (95% confidence interval, 81% to 100%) and a specificity of 64% (56% to 71%). The likelihood ratio for a positive test was 2.67 (2.15 to 3.31) and the likelihood ratio for a negative test was 0.04 (0.003 to 0.64). CONCLUSIONS: An algorithm based on four clinical scenarios can be administered to the majority of patients presenting to the ED with the chief complaint of NTH. The algorithm showed a good accuracy in identifying patients with non-life threatening causes of headache and could be used as a risk stratification tool to improve clinical decision- making. Further studies are required to validate this diagnostic algorithm.
2009
- Slowly progressive ALS associated with a novel SOD1 D11Y mutation
[Abstract in Atti di Convegno]
Georgoulopoulou, E; Gellera, C; Bragato, C; Sola, P; Bernabei, C; Ferraro, D; Mandrioli, J
abstract
2009
- Sporadic late onset ataxia: a case of FXTAS and differential diagnosis
[Abstract in Atti di Convegno]
Canali, E; Valzania, F; Nizzoli, S; Mandrioli, J; Malaguti, Mc
abstract
2009
- Two Italian kindreds with familial amyotrophic lateral sclerosis due to FUS mutation
[Articolo su rivista]
Chiò, A; Restagno, G; Brunetti, M; Ossola, I; Calvo, A; Mora, G; Sabatelli, M; Monsurrò, Mr; Battistini, S; Mandrioli, J; Salvi, F; Spataro, R; Schymick, J; Traynor, Bj; LA BELLA, V; Italsgen, Consortium
abstract
2008
- A multifactorial prognostic index in multiple sclerosis. Cerebrospinal fluid IgM oligoclonal bands and clinical features to predict the evolution of the disease
[Articolo su rivista]
Mandrioli, J; Sola, P; Bedin, R; Gambini, M; Merelli, E
abstract
2008
- A possible prognostic role of electromyography in amyotrophic lateral sclerosis
[Abstract in Atti di Convegno]
Fioravanti, V; Sola, P; Bigliardi, G; Georgoulopoulou, E; Valzania, F; Nichelli, P; Mandrioli, J
abstract
2008
- Cerebrospinal fluid oligoclonal IgM pattern in primary progressive multiple sclerosis
[Abstract in Atti di Convegno]
Simone, A; Bedin, R; Mandrioli, J; Merelli, E; Annecca, R; Nichelli, P; Sola, P
abstract
2008
- Differential diagnosis of isolated optic neuritis: a case of neurosyphilis
[Abstract in Atti di Convegno]
Simone, A; Mandrioli, J; Nichelli, P; Sola, P
abstract
2008
- Early noninvasive ventilation does not influence survival in subjects with amyotrophic lateral sclerosis
[Abstract in Atti di Convegno]
Verduri, A; Mandrioli, J; Sola, P; Monelli, M; Guerzoni, P; Fabbri, Lm; Moretti, M
abstract
2008
- Effect of a multidisciplinary amyotrophic lateral sclerosis (ALS) care on ALS survival: an epidemiological study from 1990 to 2007
[Abstract in Atti di Convegno]
Bigliardi, G; Sola, P; Georgoulopoulou, E; Fioravanti, V; Nichelli, P; Mandrioli, J
abstract
2008
- HNPP mutation and motor neuron disease: phenotypic heterogeneity or simply a co-occurrence?
[Abstract in Atti di Convegno]
Canali, E; Chiari, A; Fioravanti, V; Valzania, F; Pentore, R; Nichelli, P; Mandrioli, J
abstract
2008
- Ischemic stroke: a rare onset of churg-strauss syndrome
[Abstract in Atti di Convegno]
Girolami, F; Nizzoli, S; Pentore, R; Sola, P; Nichelli, P; Mandrioli, J
abstract
2008
- Peripheral facial nerve palsy can be rarely caused by internal carotid artery dissection
[Abstract in Atti di Convegno]
Fioravanti, V; Mandrioli, J; Canali, E; Nichelli, P; Chiari, A
abstract
2008
- Serum proteins and lipids status in patients with amyotrophic lateral sclerosis: unclear role on disease progression
[Abstract in Atti di Convegno]
Georgoulopoulou, E; Sola, P; Bigliardi, G; Fioravanti, V; Nichelli, P; Mandrioli, J
abstract
2008
- Teaching NeuroImage: When right atrial myxoma meets patent foramen ovale: a case of paradoxical brain embolism
[Articolo su rivista]
Tondelli, M; Mandrioli, J; Ficarra, G; Pentore, R; Girolami, F; Ghidoni, I; Agnoletto, V
abstract
2007
- Bilateral internal carotid arteries dissection mimicking cluster headache: a case report
[Abstract in Atti di Convegno]
Nizzoli, S; Mandrioli, J; Guaraldi, P; Zini, A; Nichelli, P; Panzetti, P
abstract
2007
- Cauda equina sindrome due to cervical spinal lesions: an atypical onset of multiple sclerosis
[Abstract in Atti di Convegno]
Pugnaghi, M; Zini, A; Nizzoli, S; Girolami, F; Nichelli, P; Mandrioli, J
abstract
2007
- Chorea as the presenting clinical feature of primary antiphospholipid syndrome
[Abstract in Atti di Convegno]
Girolami, F; Zini, A; Nizzoli, S; Pugnaghi, M; Panzetti, P; Mandrioli, J
abstract
2007
- Coexistence of amyotrophic lateral sclerosis and Huntington’s disease
[Abstract in Atti di Convegno]
Mandrioli, J; Nizzoli, S; Panzetti, P; Pentore, R; Cortelli, P; Nichelli, P
abstract
2007
- Esperienza con la trombolisi EV nella Stroke Unit di Modena
[Abstract in Atti di Convegno]
Cavazzuti, M; Casoni, F; Colombo, A; Zini, A; Mandrioli, J; Tondelli, M
abstract
2007
- Focal vertebral artery stenosis mimicking myasthenia: a case report
[Abstract in Atti di Convegno]
Zini, A; Pugnaghi, M; Nizzoli, S; Panzetti, P; Girolami, F; Mandrioli, J
abstract
2007
- Headache and Horner’s syndrome as isolated manifestation of intracranial carotid artery dissection
[Abstract in Atti di Convegno]
Nizzoli, S; Zini, A; Casoni, F; Nichelli, P; Mandrioli, J
abstract
2007
- High concordance between transcranial color coded doppler and transesophageal echocardiography finding in detection and quantification of right-to-left shunts: the importance of a standardized echocardiographic protocol
[Abstract in Atti di Convegno]
Casoni, F; Colombo, A; Zini, A; Sansoni, S; Leonardi, C; Zennaro, Rg; Mandrioli, J; Nichelli, P; Agnoletto, V
abstract
2007
- IL 6, IL10, IL 12, TNF-alfa and IFN-gamma serum levels in secondary progressive multiple sclerosis patients treated with IFN-Beta1B and azathioprine or placebo: a two-years prospective study
[Abstract in Atti di Convegno]
Mandrioli, J; Bedin, R; Manneschi, L; Pesci, I; Montanari, E; Motti, L; Provinciali, L; Scarpini, E; Caputo, D; Tola, Mr; Marrosu, Mg; Ghezzi, A; Cavalla, P; Durelli, L; Merelli, E
abstract
2007
- Intestinal pseudobstruction in Guillain Barrè Syndrome
[Abstract in Atti di Convegno]
Girolami, F; Mandrioli, J; Nizzoli, S; Zini, A; Ariatti, A; Galassi, G
abstract
2007
- L’ictus ischemico in peggioramento (progressing stroke) nella SU di Modena
[Abstract in Atti di Convegno]
Sala, R; Colombo, A; Casoni, F; Mandrioli, J; Zini, A; Cavazzuti, M
abstract
2007
- Mitochondrial complex III deficiency in a case of HCV related noninflammatory myopathy
[Articolo su rivista]
Cortelli, P.; Mandrioli, J.; Zeviani, M.; Lodi, R.; Prata, C.; Pecorari, M.; Orlando, G.; Guaraldi, Giovanni
abstract
not available
2007
- Right atrial myxoma and patent foramen ovale: a rare case of paradoxical brain embolism
[Abstract in Atti di Convegno]
Tondelli, M; Mandrioli, J; Agnoletto, V; Ficarra, G; Pentore, R; Girolami, F; Nichelli, P
abstract
2007
- Spontaneous intracranial hypotension: clinical and neuroimaging features of one year case series
[Abstract in Atti di Convegno]
Mandrioli, J; Zini, A; Nizzoli, S; Panzetti, P; Pentore, R; Sola, P; Nichelli, P
abstract
2007
- Stiff-Person syndrome mimicking motor neuron disease: a case report
[Abstract in Atti di Convegno]
Girolami, F; Zini, A; Meletti, S; Sola, P; Mandrioli, J
abstract
2007
- Wernicke encephalopathy: MR findings at clinical presentation in twenty-six alcoholic and nonalcoholic patients
[Articolo su rivista]
Zuccoli, G; Gallucci, M; Capellades, J; Regnicolo, L; Tumiati, B; Giadás, Tc; Bottari, W; Mandrioli, J; Bertolini, M
abstract
2006
- A prospective epidemiological study on ALS patients in the province of Modena (Italy)
[Abstract in Atti di Convegno]
Mandrioli, J; Moretti, M; Bianconi, G; Nichelli, P; Sola, P
abstract
2006
- Acute stroke care in the Modena Neurology Clinic: epidemiological and clinical features of an electronic database
[Abstract in Atti di Convegno]
Zini, A; Mandrioli, J; Casoni, F; Colombo, A; Nichelli, P; Cavazzuti, M
abstract
2006
- Amyotrophic lateral sclerosis: Prognostic indicators of survival
[Articolo su rivista]
Mandrioli, Jessica; Faglioni, Pietro; Nichelli, Paolo Frigio; P., Sola
abstract
Amyotrophic lateral sclerosis (ALS) has a fatal outcome in about three years, but survival is known to vary considerably, making it difficult to predict disease duration in individual cases. The aim of this study was to investigate possible early prognostic factors of ALS survival. We included 123 probable or definite cases of ALS, with disease onset between 1989 and 1998, and with a follow-up of at least one year. Survival functions were obtained using both the Kaplan-Meier and the actuarial methods. Subgroups, formed on the basis of gender, area of residence, work, and age at and site of onset, were compared using the logrank test and Cox's proportional hazards method (survival functions), and applying the Grizzle, Starmer, Koch (1969), and Koch, Johnson, Tolley (1972) methods (one-year survival probability trends). The survival curves dipped sharply in the first three years, followed by a flattening trend, with 50% of patients dying within 2.5 years, and 89% over seven years. The clinical form with lower limb onset was associated with longer survival than the upper limb onset and bulbar forms (median survival: 39, 27, and 25 months, respectively). Survival was also affected by age at onset (median survival: 34, 27, and 23 months for onset < 60, 60-75, and > 75 years, respectively), area of residence (median survival: 24 months in mountainous areas, 32 elsewhere), and type of work (median survival: 25 months in agricultural workers, 33.5 in others). Gender did not influence survival, whereas percutaneous endoscopic gastrostomy placement and invasive ventilation did. The estimation of individual ALS survival is important to allow the patient to plan for his future and to make optimal use of medical and community resources. Although age at and site of onset, area of residence, and agricultural work were found to influence survival, there remains an unexplained heterogeneous progression of the disease, suggesting the influence of other, as yet unknown, prognostic factors. The identification of a definite set of prognostic factors may allow physicians to make more reliable survival predictions at diagnosis.
2006
- Bilateral internal carotid artery occlusion: clinical features and outcome of a 6-years stroke cohort and literature review
[Abstract in Atti di Convegno]
Nizzoli, S; Mandrioli, J; Zini, A; Casoni, F; Colombo, A; Nichelli, P; Cavazzuti, M
abstract
2006
- Bilateral posterior medullary and cervical stroke: a case report
[Articolo su rivista]
Mandrioli, Jessica; Zini, Andrea; F., Cavalleri; Nichelli, Paolo Frigio; Panzetti, Patrizia
abstract
Spinal strokes are often localised in the anterior spinal artery territory, whereas an involvement of the posterior spinal arteries (PSA) is uncommon, and usually unilateral. Bilateral PSA stroke is exceptional. A 70-year-old woman, after a mild head trauma, presented with cervical pain, left hypoaesthesia and sensitive ataxia, which then extended to the right hemibody, including face. A Doppler ultrasound showed an only systolic flow signal in the left vertebral artery (VA). MR showed a bilateral infarction extending from the posterior medulla oblongata to C4 and a left hypoplasic VA with lack of visualisation of the V3 segment. This case was peculiar, implying a bilateral stroke in the PSA territory, possibly related to a left VA dissection, and in the presence of a dominant PSA, originating from the hypoplasic VA and of hyposupply of posterior radiculomedullary arteries and anastomoses.
2006
- Crescendo TIAs and hemodynamic phenomena: a case report.
[Abstract in Atti di Convegno]
Nizzoli, S; Casoni, F; Colombo, A; Mandrioli, J; Cavazzuti, M; Nichelli, P
abstract
2006
- Do flavan-3-ols from green tea reach the human brain?
[Articolo su rivista]
Zini, Andrea; D., Del Rio; A. J., Stewart; Mandrioli, Jessica; E., Merelli; P., Sola; Nichelli, Paolo Frigio; M., Serafini; F., Brighenti; C. A., Edwards; A., Crozier
abstract
Following acute ingestion of green tea by six human subjects, HPLC-MS 2 analysis revealed that flavan-3-ol methyl, glucuronide and sulfate metabolites appeared in the bloodstream but did not pass through the blood-cerebrospinal fluid barrier. These observations emphasize the discrepancies between in vitro and in vivo evidence on the neuroprotective role of these compounds. If, as has been proposed, green tea exerts neuroprotective effects, this finding indicates that the active components are not flavan-3-ols or their metabolites. Alternatively, a systemic action may be hypothesised whereby dietary flavan-3-ols up-regulate antioxidant defences and/or reduce inflammation, the benefit of which may be effective throughout the body.
2006
- Isolated Hypoglossal nerve palsy due to amyloid cervical arthropathy in long term hemodialysis
[Articolo su rivista]
Mandrioli, J; Zini, A; Cavalleri, F; Vandelli, L; Nichelli, Paolo Frigio; Colombo, A.
abstract
nd
2006
- Primary central nervous system lymphoma: is it histological or molecular diagnosis really necessary?
[Abstract in Atti di Convegno]
Mandrioli, J; Zini, A; Todeschini, A; Nichelli, P; Sola, P
abstract
2006
- Stroke Care nella Clinica Neurologica di Modena: dati epidemiologici e clinici di un registro informatizzato
[Abstract in Atti di Convegno]
Zini, A; Mandrioli, J; Casoni, F; Colombo, A; Nichelli, P; Cavazzuti, M
abstract
2006
- The multifactorial prognostic index: oligoclonal IgM bands and clinical features as predictors of MS evolution
[Abstract in Atti di Convegno]
Sola, P; Mandrioli, J; Bedin, R; Merelli, E
abstract
2006
- Total antioxidant capacity of cerebrospinal fluid is decreased in patients with motor neuron disease
[Articolo su rivista]
Mandrioli, J; Del Rio, D; Zini, A; Nichelli, Paolo Frigio; Merelli, E; Beltrami, D; Cesari, C; Pellegrini, N; Brighenti, F; Sola, P.
abstract
Oxidative stress has been associated with motor neuron disease (MND). The human body has several antioxidant defense systems to repair the damage caused by oxidative stress. The activity of these systems is thought to be reduced in neurodegenerative diseases, which may increase the level of oxidative damage and be a contributing factor to motor neuron death. In the present study, we compared the total antioxidant capacity (TAC) of human serum and cerebrospinal fluid (CSF) of MND patients with that of a control group including patients with migraine, tension headache and psychiatric disorders. Within-subject serum and CSF TAC were strongly correlated (r = 0.639; p = 0.000), and CSF TAC was significantly lower in MND patients as compared to controls after adjustment for known influencing factors (112.7 mu mol Fe/L +/- 11.7 versus 135.2 mu mol Fe/L +/- 19.7; p = 0.012). No differences in serum or CSF TAC were observed among the clinical forms of MND considered in this work. In conclusion, the CSF TAC was strongly correlated with serum TAC, and a decrease in CSF TAC was demonstrated in MND patients compared to controls that was not independent from serum antioxidants, this translating in a systemic (but prevailing in the CNS) oxidative damage in this pathology.
2005
- Cerebrospinal fluid IgM oligoclonal bands as marker for prognosis in multiple sclerosis
[Abstract in Atti di Convegno]
Sola, P; Mandrioli, J; Bedin, R; Merelli, E
abstract
2005
- Endozepines in recurrent stupor
[Articolo su rivista]
Cortelli, P.; Avallone, Rossella; Baraldi, Mario; Zeneroli, Maria Luisa; Mandrioli, J.; Corsi, Lorenzo; Riva, R.; Tuniper, P.; Lugaresi, E.; Baruzzi, A.; Montagna, P.
abstract
Stupor is a condition from which the subject can be aroused only by vigorous stimuli. Most patients with stupor have a diffuse organic cerebral dysfunction. Rarely stupor is recurrent and no specific causes can be found. Patients with idiopathic recurrent stupor were awakened by i.v. administration of an antagonist (flumazenil) of the benzodiazepine recognition site located in the GABA(A) receptor. Since no exogenous benzodiazepines were detected in plasma and cerebrospinal fluid by high performance liquid chromatography, an excess of endogenous benzodiazepine-like compounds (endozepines) was proposed as the cause of stupor. The existence of endozepines, their widespread distribution in the CNS and their involvement in hepatic encephalopathy are established. However, the origin of these compounds, how biosynthesis occurs and the mechanisms and causes through which they alter brain functions are poorly understood. The fact that a number of synthetic benzodiazepines are difficult to detect using conventional techniques and the discovery that some cases of recurrent stupor were caused by fraudulent administration of lorazepam question whether the concept of endozepine recurrent stupor can be sustained. This review summarizes the state of endozepine physiology and pharmacology and the clinical syndromes attributed to their involvement. A diagnostic work-up to define endozepine-induced recurrent stupor is suggested.
2005
- Isolated hypoglossal nerve palsy due to amyloid cervical arthropathy during long term hemodialysis
[Abstract in Atti di Convegno]
Mandrioli, J; Zini, A; Cavalleri, F; Vandelli, L; Nichelli, P; Colombo, A
abstract
2005
- L’impiego della ventilazione meccanica non invasiva (VNI) nel trattamento dell’insufficienza respiratoria acuta (IRA) nei pazienti con sclerosi laterale amiotrofica (SLA)
[Abstract in Atti di Convegno]
Moretti, M; Monelli, M; Sola, P; Mandrioli, J; Serini, R; De Carlo, Mr; Fabbri, Lm
abstract
2005
- Microbiological Patterns in Severe Respiratory Infection of Amyotrophic Lateral Sclerosis (ALS) Requiring Non-Invasive Mechanical Ventilation (NIV)
[Abstract in Atti di Convegno]
De Guglielmo, M; Sola, P; Mandrioli, J; Zanasi, E; Monelli, M; Fabbri, Lm; Moretti, M
abstract
2005
- Prostate cancer: a specific paraneoplastic brainstem syndrome?
[Abstract in Atti di Convegno]
Zini, A; Mandrioli, J; Sola, P; Nichelli, P; Sorgato, P
abstract
2005
- Total antioxidant capacity of cerebrospinal fluid is impaired in patients with motor neuron disease
[Abstract in Atti di Convegno]
Mandrioli, J; Del Rio, D; Zini, A; Merelli, E; Nichelli, P; Beltrami, D; Cesari, C; Pellegrini, N; Brighenti, F; Sola, P
abstract
2004
- Amyotrophic lateral sclerosis in the young: clinical and epidemiological features
[Abstract in Rivista]
Mandrioli, J; Faglioni, P; Sola, P
abstract
2004
- Amyotrophic lateral sclerosis risk factors: a case control study
[Abstract in Atti di Convegno]
Mandrioli, J; Leone, M; Zini, A; Faglioni, P; Sola, P
abstract
2004
- Could mitochondrial haplogroups play a role in sporadic amyotrophic lateral sclerosis?
[Articolo su rivista]
Mancuso, M; Conforti, Fl; Rocchi, A; Tessitore, A; Muglia, M; Tedeschi, G; Panza, D; Monsurrò, M; Sola, P; Mandrioli, J; Choub, A; Delcorona, A; Manca, Ml; Mazzei, R; Sprovieri, T; Filosto, M; Salviati, A; Valentino, P; Bono, F; Caracciolo, M; Simone, Il; La Bella, V; Majorana, G; Siciliano, G; Murri, L; Quattrone, A
abstract
2004
- Decreasing amyotrophic lateral sclerosis mortality: results from 1990 through 2003
[Abstract in Rivista]
Mandrioli, J; Faglioni, P; Sola, P
abstract
2004
- How a vertebral artery dissection may cause a bilateral posterior medullary and cervical stroke: case report
[Abstract in Atti di Convegno]
Mandrioli, J; Zini, A; Colombo, A; Cavalleri, F; Cavazzuti, M; Nichelli, P; Panzetti, P
abstract
2004
- Middle cerebral artery thrombosis in course of parvovirus B19 infection in a young adult: A new risk factor for stroke?
[Articolo su rivista]
Mandrioli, J.; Portolani, M.; Cortelli, P.; Sola, P.
abstract
Previous infection, both of bacterial and viral origin, is reported to represent an independent risk factor for ischemic stroke in children and young adults. The authors describe the case of an immunocompetent young woman who developed a middle cerebral artery thrombosis and stroke in course of a recurrence of human parvovirus B19 (PVB19) infection. A previously healthy 25-year-old woman developed right ataxic hemiparesis, 5 days after the onset of a flulike syndrome. Magnetic resonance imaging of the brain revealed acute multiple left frontal-parietal ischemic lesions. Conventional and magnetic resonance angiograms revealed a stenosis in the left middle cerebral artery. Nested polymerase chain reaction detected PVB19-specific DNA sequences in the cerebrospinal fluid and blood, and serology showed high titers of high avidity immunoglobulin G against PVB19. After 10 days, the patient's recovery was nearly complete. One month later, PVB19 disappeared from the serum, whereas it persisted in the peripheral blood mononuclear cells. This case report suggests that PVB19 infection may play a trigger role in the development of ischemic stroke, and that it should be considered in the screening of infectious risk factors for cerebrovascular diseases in young adults. © 2004 Journal of NeuroVirology.
2004
- Monofocal acute large demyelinating lesion mimicking brain glioma
[Articolo su rivista]
Mandrioli, J; Ficarra, G; Callari, G; Sola, P; Merelli, E
abstract
2004
- Neurogenic T wave inversion in pure left insular stroke associated with hyperhomocysteinaemia
[Articolo su rivista]
Mandrioli, J; Zini, A; Cavazzuti, Milena; Panzetti, Patrizia
abstract
This the case report of a patient who, after a pure insular stroke developed a T wave inversion in absence of evidence of coronary artery disease or cardiac pathology. The case emphasized the functional complexity of the insularcortex, its role in the generation of cardiovascular changes, and the importance of cardiac monitoring in stroke patients
2004
- Oligoclonal IgM in the CSF as putable prognostic marker of severity in multiple sclerosis
[Abstract in Atti di Convegno]
Merelli, E; Mandrioli, J; Bedin, R; Caiazzo, G; Sola, P
abstract
2004
- Putable prognostic biological markers of “benign” multiple sclerosis
[Abstract in Rivista]
Sola, P; Mandrioli, J; Bedin, R; Caiazzo, G; Merelli, E
abstract
2004
- Secondary prevention of stroke and atrial fibrillation: an age dependent decision?
[Abstract in Atti di Convegno]
Zini, A; Mandrioli, J; Colombo, A; Molinari, R; Baraghini, Gf; Nichelli, P; Cavazzuti, M
abstract
2004
- Secondary prevention of stroke and atrial fibrillation: an age-dependent decision?
[Abstract in Atti di Convegno]
Zini, A; Mandrioli, J; Colombo, A; Molinari, R; Baraghini, Gf; Nichelli, P; Cavazzuti, M
abstract
2004
- Stroke unit of Modena: prospective evaluation of a nursing protocol of bedside swallowing screen in acute stroke patients
[Abstract in Atti di Convegno]
Zini, A; Mandrioli, J; Nichelli, P; Pentore, R; Alborini, G; Panzetti, P; Ruggeri, L; Prompicai, F; Cavazzuti, M
abstract
2004
- The Optimal Timing of Non Invasive Ventilation (NIV) in Amyotrophic Lateral Sclerosis (ALS): A Matter of Early Intervention
[Abstract in Rivista]
Moretti, M; De Guglielmo, M; Sola, P; Mandrioli, J; Monelli, M; Fabbri, Lm
abstract
2004
- Tolosa-Hunt syndrome due to actinomycosis of the cavernous sinus: The infections hypothesis revisited
[Articolo su rivista]
Mandrioli, J.; Frank, G.; Sola, P.; Leone, M. E.; Guaraldi, Giovanni; Guaraldi, Pietro; Collina, G.; Roncaroli, F.; Cortelli, P.
abstract
BACKGROUND: The Tolosa-Hunt syndrome is characterized by ophthalmoplegia with unilateral severe retro-orbital pain associated to a granulomatous inflammatory process occupying the cavernous sinus or the superior orbital fissure. The etiology is unknown and diagnosis is based upon a clinical response to steroid treatment and exclusion of neoplasm, trauma, aneurysms, infectious, and inflammatory diseases. CASE DESCRIPTION: A 43-year-old man was admitted because of a 1-week history of acute onset left-sided retro-orbital pain, followed by left sixth cranial nerve palsy. Magnetic resonance imaging was normal and Tolosa-Hunt syndrome was suspected. Steroid treatment controlled pain with recovery of ophthalmoplegia. Four months later, when a good response to treatment was still present, brain magnetic resonance imaging revealed a lesion enlarging the left cavernous sinus, isointense with the gray matter on T1-weighted sequences, hypointense on T2-weighted images, and with homogeneous enhancement after gadolinium injection. Two months later, ocular pain and sixth cranial nerve palsy recurred and new brain magnetic resonance imaging showed an extension of the tissue occupying the left cavernous sinus, over the sella, to the right cavernous sinus, making possible an endoscopic transphenoidal biopsy. RESULTS: Histopathological study revealed a granulomatous aspecific inflammation containing actinomycetes colonies. The patient was treated with intravenous penicillin G followed by amoxicillin per os, with improvement of pain and ophthalmoplegia. A control magnetic resonance imaging 1 month after therapy showed a consistent reduction of the enlarged cavernous sinus, and 3 months later neurological examination and brain magnetic resonance imaging were completely normal. CONCLUSIONS: The present case suggests that the International Classification of Headache Disorders (2nd edition) definition of Tolosa-Hunt syndrome does not reflect the complexity of the syndrome and that some cases of secondary painful ophthalmoplegias can fit the criteria for the primary form. Since the biopsy can only rarely be performed, we agree with other authors that clinical and radiological follow-up should be performed for at least 2 years. Moreover, we propose that in patients with painful ophthalmoplegia having transient response to steroid therapy, a trial with antibiotic therapy should be taken into account.
2003
- ALS epidemiology in Modena, Italy: years 1990-2002
[Abstract in Rivista]
Mandrioli, J; Faglioni, P; Sola, P
abstract
2003
- Autonomic control of the cardiovascular system in ALS.
[Abstract in Atti di Convegno]
Antonelli, F; Mandrioli, J; Sola, P; Cortelli, P
abstract
2003
- Cognitive impairment in patients with motor neuron diseases: a neuropsychological study
[Abstract in Rivista]
Mandrioli, J; Leone, M; Faglioni, P; Sola, P
abstract
2003
- Increasing prevalence and survival in amyotrophic lateral sclerosis in the province of Modena (Italy)
[Abstract in Atti di Convegno]
Mandrioli, J; Faglioni, P; Sola, P
abstract
2003
- Motor neuron diseases and cognitive impairment: a neuropsychological study
[Abstract in Atti di Convegno]
Mandrioli, J; Leone, M; Faglioni, P; Sola, P
abstract
2003
- Painful ophthalmoplegia due to actinomycosis of the cavernous sinus
[Abstract in Rivista]
Mandrioli, J; Sola, P; Leone, M; Collina, G; Frank, G; Cortelli, P
abstract
2003
- Persistent neurogenic T-wave inversion in a recurrent pure left insular stroke due to hyperhomocysteinemia
[Abstract in Atti di Convegno]
Mandrioli, J; Zini, A; Cavazzuti, M; Nichelli, P; Panzetti, P
abstract
2003
- Stroke in young adults in the province of Modena, from 1990-2002: clues to aetiological and epidemiological features
[Abstract in Atti di Convegno]
Zini, A; Mandrioli, J; Nichelli, P; Sola, P; Cavazzuti, M
abstract
2003
- The epidemiology of ALS in Modena, Italy
[Articolo su rivista]
Mandrioli, J; Faglioni, P; Merelli, E; Sola, P
abstract
2003
- Tolosa hunt sindrome due to actinomycosis of the cavernous sinus: a case report and review of literature
[Abstract in Rivista]
Mandrioli, J.; Sola, P.; Leone, M.; Frank, G.; Collina, G.; Guaraldi, Giovanni; Cortelli, P.
abstract
Tolosa hunt sindrome is characterized by ophtalmoplegia with unilateral, severe retro-orbital pain associated to a low grade granulomatous inflammatory process occupying the cavernous sinus or the superior orbital fessure. The etiology in unknown and diagnosis is based upon good clinical response to steroid treatment. Differential diagnosis include neoplasm, trauma, aneurysms, infectious and inflammatory diseases. We report a case of painful ophthalmoplegia caused by actinomycosis of the cavernous sinus.
2003
- Tolosa-Hunt syndrome due to actinomycosis of the cavernous sinus: a case report and review of literature
[Abstract in Atti di Convegno]
Mandrioli, J; Sola, P; Leone, M; Frank, G; Collina, G; Guaraldi, G; Cortelli, P
abstract
2003
- Traumatic intracystic hemorrhage in a case with thalamo-mesencephalic 'expanding lacunae': An uncommon cause of sudden-onset neurological signs
[Articolo su rivista]
Mandrioli, J.; Sola, P.; Lodi, R.; Vallone, S.; Barbiroli, B.; Cortelli, P.
abstract
2003
- Tumor-like multiple sclerosis lesion leading to neurosurgery intervention
[Abstract in Atti di Convegno]
Mandrioli, J; Ficarra, G; Sola, P; Merelli, E
abstract
2002
- Description of a case of meningeal granulomatosis as unique expression of Wegener's disease
[Abstract in Rivista]
Sola, P; Mandrioli, J; Ficarra, G; Mavilla, L; Zanasi, A; Manzini, C; Nichelli, P
abstract
2002
- Juvenile middle cerebral artery thrombosis during of parvovirus B19 infection
[Abstract in Atti di Convegno]
Sola, P; Mandrioli, J; Cortelli, P; Tavani, F; Tamassia, Mg; Portolani, M
abstract
2002
- MV2 (Kuru Plaques) variant of sporadic Creutzfeldt-Jacob disease: peripheral neuropathy is part of the clinical spectrum
[Abstract in Rivista]
Sola, P; Stucchi, C; Capellari, S; Galassi, G; Roncaroli, F; Mandrioli, J; Cortelli, P; Baruzzi, A; Nichelli, P; Parchi, P
abstract
2002
- Meningeal granulomatosis as first presentation of Wegener’s disease
[Abstract in Rivista]
Sola, P; Mandrioli, J; Ficarra, G; Mavilla, L; Merelli, E; Casoni, F; Nichelli, P
abstract
2002
- Meningeal granulomatosis of unknown origin: report of a case
[Abstract in Atti di Convegno]
Mandrioli, J; Cortelli, P; Nichelli, P; Mavilla, L; Ficarra, G; Zanasi, A; Sola, P
abstract
2002
- New insights into the viral theory of amyotrophic lateral sclerosis: study on the possible role of Kaposi's sarcoma-associated virus/human herpesvirus 8
[Articolo su rivista]
Sola, P; Bedin, R; Casoni, F; Barozzi, P; Mandrioli, J; Merelli, E
abstract
2002
- Prognostic factors of survival in amyotrophic lateral sclerosis
[Abstract in Rivista]
Sola, P; Faglioni, P; Merelli, E; Mandrioli, J
abstract
2002
- Progressive sopranuclear palsy: cardiovascular reflexes and heart rate variability
[Abstract in Atti di Convegno]
Pierangeli, G; Magnifico, F; Cevoli, S; Mandrioli, J; Martinelli, P; Montagna, P; Cortelli, P
abstract
2002
- Thalamic peduncular multicystic lesions: a special form of cerebral lacunae. Case report and review of the literature
[Abstract in Atti di Convegno]
Mandrioli, J; Vallone, S; Sola, P; Mavilla, L; Nichelli, P; Cortelli, P
abstract
2001
- Amyotrophic lateral sclerosis in Modena – Italy: an epidemiological survey
[Abstract in Atti di Convegno]
Mandrioli, J; Faglioni, P; Merelli, E; Sola, P
abstract
2001
- Epidemiology of amyotrophic lateral sclerosis in the province of Modena - Italy
[Abstract in Rivista]
Sola, P; Mandrioli, J; Merelli, E; Casoni, F; Faglioni, P
abstract
2001
- Epidemiology of amyotrophic lateral sclerosis in the province of Modena, Italy, years 1990-1999
[Abstract in Atti di Convegno]
Mandrioli, J; Faglioni, P; Sola, P
abstract
2001
- Peripheral neuropathy is part of the clinical spectrum of the MV2 (Kuru-plaques) variant of sporadic Creutzfeldt-Jakob disease
[Abstract in Atti di Convegno]
Stucchi, C; Sola, P; Capellari, S; Galassi, G; Roncaroli, F; Mandrioli, J; Cortelli, P; Baruzzi, A; Nichelli, P; Parchi, P
abstract
2001
- Severe necrotizing skin vasculitis in a MS patient treated with Beta Interferon 1B
[Abstract in Atti di Convegno]
Casoni, F; Bedin, R; Sola, P; Mandrioli, J; Bertolotto, A; Seidenari, S; Merelli, E
abstract