Publications by authors named "Jessica Mandrioli"

116 Publications

Duplication of exons 15 and 16 in Matrin-3: a phenotype bridging amyotrophic lateral sclerosis and immune-mediated disorders.

Neurol Sci 2021 Oct 19. Epub 2021 Oct 19.

Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

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.
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http://dx.doi.org/10.1007/s10072-021-05669-2DOI Listing
October 2021

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.

JAMA Neurol 2021 Oct;78(10):1236-1248

Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

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.
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http://dx.doi.org/10.1001/jamaneurol.2021.2598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406220PMC
October 2021

Coffee and Tea Consumption Impact on Amyotrophic Lateral Sclerosis Progression: A Multicenter Cross-Sectional Study.

Front Neurol 2021 28;12:637939. Epub 2021 Jul 28.

Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

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. 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). 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 ( = 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 ( = 0.028) but not with the number of cup-years. Our study does not support the hypothesis that coffee or tea consumption is associated with the ALS progression rate.
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http://dx.doi.org/10.3389/fneur.2021.637939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356721PMC
July 2021

Evaluation of peripherin in biofluids of patients with motor neuron diseases.

Ann Clin Transl Neurol 2021 08 15;8(8):1750-1754. Epub 2021 Jul 15.

Department of Neurosciences, University of Padova, Padova, Italy.

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.
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http://dx.doi.org/10.1002/acn3.51419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351396PMC
August 2021

The Gut Microbiota-Immunity Axis in ALS: A Role in Deciphering Disease Heterogeneity?

Biomedicines 2021 Jun 29;9(7). Epub 2021 Jun 29.

Department of Clinical and Experimental Medicine, University of Florence, 50134 Florence, Italy.

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.
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http://dx.doi.org/10.3390/biomedicines9070753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301418PMC
June 2021

"Don't call me from the left side…": ischemic stroke in a patient with uncommon vertebral artery dissection.

Neurol Sci 2021 Sep 5;42(9):3909-3910. Epub 2021 Jun 5.

Neurology Clinic, Department of Neuroscience, University Hospital of Modena, via Giardini 1355 Baggiovara, ZIP 41100, Modena, Italy.

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http://dx.doi.org/10.1007/s10072-021-05369-xDOI Listing
September 2021

TeleNeurological evaluation and Support for the Emergency Department (TeleNS-ED): protocol for an open-label clinical trial.

BMJ Open 2021 05 19;11(5):e048293. Epub 2021 May 19.

Neurology Unit, Azienda Ospedaliero-Universitaria di Modena Ospedale Civile di Baggiovara, Modena, Italy

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.
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http://dx.doi.org/10.1136/bmjopen-2020-048293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137206PMC
May 2021

The Impact of Lifetime Alcohol and Cigarette Smoking Loads on Amyotrophic Lateral Sclerosis Progression: A Cross-Sectional Study.

Life (Basel) 2021 Apr 17;11(4). Epub 2021 Apr 17.

Neurology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.

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 ΔFS (derived from the ALS Functional Rating Scale-Revised and disease duration from onset): slow ( = 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 ΔFS 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(ΔFS) was weakly correlated only with the duration of alcohol consumption ( = 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.
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http://dx.doi.org/10.3390/life11040352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072690PMC
April 2021

The unfolded protein response in amyotrophic later sclerosis: results of a phase 2 trial.

Brain 2021 Oct;144(9):2635-2647

3rd Neurology Unit and Motor Neuron Disease Centre, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan 20133, Italy.

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.
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http://dx.doi.org/10.1093/brain/awab167DOI Listing
October 2021

Hsp90-mediated regulation of DYRK3 couples stress granule disassembly and growth via mTORC1 signaling.

EMBO Rep 2021 05 19;22(5):e51740. Epub 2021 Mar 19.

Department of Biomedical, Metabolic and Neural Sciences, Centre for Neuroscience and Nanotechnology, University of Modena and Reggio Emilia, Modena, Italy.

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.
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http://dx.doi.org/10.15252/embr.202051740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097338PMC
May 2021

Risk of Amyotrophic Lateral Sclerosis and Exposure to Particulate Matter from Vehicular Traffic: A Case-Control Study.

Int J Environ Res Public Health 2021 01 22;18(3). Epub 2021 Jan 22.

Department of Biomedical, Metabolic and Neural Sciences, CREAGEN Environmental, Genetic and Nutritional Epidemiology Research Center, University of Modena and Reggio Emilia, 41125 Modena, Italy.

(1) : 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 (PM) as a proxy of vehicular traffic exposure. (2) : 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 PM 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 PM exposure, using an unconditional logistic regression model adjusted for age and sex. (3) : For the 132 study participants (52 cases and 80 controls), the average of annual median and maximum PM concentrations were 5.2 and 38.6 µg/m, respectively. Using fixed cutpoints at 5, 10, and 20 of the annual median PM levels, and compared with exposure <5 µg/m, we found no excess ALS risk at 5-10 µg/m (OR 0.87, 95% CI 0.39-1.96), 10-20 µg/m (0.94, 95% CI 0.24-3.70), and ≥20 µg/m (0.87, 95% CI 0.05-15.01). Based on maximum PM concentrations, we found a statistically unstable excess ALS risk for subjects exposed at 10-20 µg/m (OR 4.27, 95% CI 0.69-26.51) compared with those exposed <10 µg/m. However, risk decreased at 20-50 µg/m (OR 1.49, 95% CI 0.39-5.75) and ≥50 µg/m (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 PM 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) : In this pilot study, we found limited evidence of an increased ALS risk due to long-term exposure at high PM 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.
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http://dx.doi.org/10.3390/ijerph18030973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908475PMC
January 2021

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers.

Mol Neurodegener 2020 10 15;15(1):58. Epub 2020 Oct 15.

Department of Neurosciences, Azienda Ospedaliero Universitaria Modena, Modena, Italy.

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.
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http://dx.doi.org/10.1186/s13024-020-00406-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559190PMC
October 2020

Reply to Comment on "Environmental and Occupational Risk Factors of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study".

Int J Environ Res Public Health 2020 09 7;17(18). Epub 2020 Sep 7.

CREAGEN-Environmental, Genetic and Nutritional Epidemiology Research Center, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

We much appreciate the positive comments and interest concerning our study on the environmental and occupational risk factors of amyotrophic lateral sclerosis (ALS) [...].
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http://dx.doi.org/10.3390/ijerph17186492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559024PMC
September 2020

BAG3 and BAG6 differentially affect the dynamics of stress granules by targeting distinct subsets of defective polypeptides released from ribosomes.

Cell Stress Chaperones 2020 11 21;25(6):1045-1058. Epub 2020 Jul 21.

Centre for Neuroscience and Nanotechnology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

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.
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http://dx.doi.org/10.1007/s12192-020-01141-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591658PMC
November 2020

Tetrodotoxin-Sensitive Neuronal-Type Na Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation.

J Am Heart Assoc 2020 06 29;9(11):e015119. Epub 2020 May 29.

Dorothy M. Davis Heart and Lung Research Institute College of Medicine The Ohio State University Wexner Medical Center Columbus OH.

Background Atrial fibrillation (AF) is a comorbidity associated with heart failure and catecholaminergic polymorphic ventricular tachycardia. Despite the Ca-dependent nature of both of these pathologies, AF often responds to Na channel blockers. We investigated how targeting interdependent Na/Ca dysregulation might prevent focal activity and control AF. Methods and Results We studied AF in 2 models of Ca-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 (nNa) with ryanodine receptors and Na/Ca exchanger. Catecholamine stimulation induced cellular and in vivo atrial arrhythmias in wild-type mice only during pharmacological augmentation of nNa 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 nNa inhibition (tetrodotoxin or riluzole) implicating Na/Ca 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 nNas mediate Na-Ca crosstalk within nanodomains containing Ca release machinery and, thereby, contribute to AF triggers. Disruption of this mechanism by nNa inhibition can effectively prevent AF arising from diverse causes.
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http://dx.doi.org/10.1161/JAHA.119.015119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429002PMC
June 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.

Metallomics 2020 05;12(5):668-681

CREAGEN Research Center of Environmental, Genetic and Nutritional Epidemiology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

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.
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http://dx.doi.org/10.1039/d0mt00051eDOI Listing
May 2020

Living near waterbodies as a proxy of cyanobacteria exposure and risk of amyotrophic lateral sclerosis: a population based case-control study.

Environ Res 2020 07 15;186:109530. Epub 2020 Apr 15.

Department of Medical, Surgical and Advanced Technologies "G.F. Ingrassia", University of Catania, Catania, Italy, Via Santa Sofia, 87, 95123; Environmental and Food Hygiene Laboratory (LIAA). Department "G.F. Ingrassia", University of Catania, Catania, Italy, Via Santa Sofia, 87, 95123.

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.
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http://dx.doi.org/10.1016/j.envres.2020.109530DOI Listing
July 2020

Environmental and Occupational Risk Factors of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study.

Int J Environ Res Public Health 2020 04 22;17(8). Epub 2020 Apr 22.

CREAGEN-Environmental, Genetic and Nutritional Epidemiology Research Center, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

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. 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 ( = 95) and randomly selected population referents ( = 135). We estimated ALS risk by calculating the odds ratio (OR) with its 95% confidence interval (CI) using an unconditional logistic regression model. 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. 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.
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http://dx.doi.org/10.3390/ijerph17082882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216189PMC
April 2020

The NGS technology for the identification of genes associated with the ALS. A systematic review.

Eur J Clin Invest 2020 May 19;50(5):e13228. Epub 2020 May 19.

Laboratory of Toxycology and Advanced Diagnostics, Department of Laboratory Medicine and Pathology, Ospedale Civile S. Agostino Estense, Modena, Italy.

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.
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http://dx.doi.org/10.1111/eci.13228DOI Listing
May 2020

A novel p.N66T mutation in exon 3 of the SOD1 gene: report of two families of ALS patients with early cognitive impairment.

Amyotroph Lateral Scler Frontotemporal Degener 2020 05 6;21(3-4):296-300. Epub 2020 Apr 6.

Department of Neuroscience, Ospedale Civile S. Agostino Estense, Azienda Ospedaliero Universitaria di Modena, Modena, Italy.

: 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.: 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.: 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.
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http://dx.doi.org/10.1080/21678421.2020.1746344DOI Listing
May 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).

BMJ Open 2020 03 24;10(3):e034049. Epub 2020 Mar 24.

'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Torino, Piemonte, Italy.

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.
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http://dx.doi.org/10.1136/bmjopen-2019-034049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202695PMC
March 2020

Clinical and Lifestyle Factors and Risk of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study.

Int J Environ Res Public Health 2020 01 30;17(3). Epub 2020 Jan 30.

CREAGEN-Environmental, Genetic and Nutritional Epidemiology Research Center, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

: 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. : 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. : 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. : 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.
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http://dx.doi.org/10.3390/ijerph17030857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037077PMC
January 2020

Amyotrophic lateral sclerosis incidence following exposure to inorganic selenium in drinking water: A long-term follow-up.

Environ Res 2019 12 14;179(Pt A):108742. Epub 2019 Sep 14.

Department of Epidemiology, Boston University School of Public Health, 715 Albany Street, Boston, MA, United States.

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.
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http://dx.doi.org/10.1016/j.envres.2019.108742DOI Listing
December 2019

FETR-ALS Study Protocol: A Randomized Clinical Trial of Fecal Microbiota Transplantation in Amyotrophic Lateral Sclerosis.

Front Neurol 2019 20;10:1021. Epub 2019 Sep 20.

Instituto di Microbiologia, Università Cattolica del Sacro Cuore, Rome, Italy.

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. 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. 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. This is the first trial with FMT as a potential intervention to modify immunological response to ALS and disease progression at an early stage.
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http://dx.doi.org/10.3389/fneur.2019.01021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763586PMC
September 2019

Influence of selenium on the emergence of neuro tubule defects in a neuron-like cell line and its implications for amyotrophic lateral sclerosis.

Neurotoxicology 2019 12 1;75:209-220. Epub 2019 Oct 1.

Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neuro.2019.09.015DOI Listing
December 2019

Serial ultrasound assessment of diaphragmatic function and clinical outcome in patients with amyotrophic lateral sclerosis.

BMC Pulm Med 2019 Aug 27;19(1):160. Epub 2019 Aug 27.

Respiratory Diseases Unit and Centre for Rare Lung Diseases, Policlinico, University Hospital of Modena, Modena, Italy.

Background: Diaphragmatic assessment by ultrasound (US) is a non-invasive and useful method in the clinical management of patients with Amyotrophic Lateral Sclerosis (ALS). The aim of our observational study was to evaluate the impact of serial assessment of the diaphragmatic function by US on long-term outcomes in a series of patients suffering from ALS and to correlate US indices of diaphragmatic function and respiratory function tests with these outcomes.

Methods: A cohort of 39 consecutive patients has been followed up to 24 months. Both lung volume (forced vital capacity, FVC) and diaphragmatic pressure generating capacity (by sniff inspiratory nasal pressure (SNIP) and by both US thickening fraction, ΔTdi, and the ratio of the thickening fraction between tidal volume and maximal lung capacity, ΔTmax) were recorded at baseline and every 3 months. Parameters were then correlated with outcomes (nocturnal hypoventilation, daily hypercapnia, start of ventilatory support (NIV), and death at 1 year) over time.

Results: The occurrence of ΔTmax > 0.75 increased the risk to start NIV (HR = 5.6, p = 0.001) and to die (HR = 3.7, p = 0.0001) compared with patients maintaining lower values. Moreover, compared with the occurrence of FVC < 50% of predicted, ΔTmax > 0.75 appeared slightly better correlated with NIV commencement within 6 months.

Conclusions: Serial diaphragmatic assessment by ultrasound is a useful and accurate method to predict the initiation of NIV earlier in patients with ALS.
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http://dx.doi.org/10.1186/s12890-019-0924-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712740PMC
August 2019

Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial.

Amyotroph Lateral Scler Frontotemporal Degener 2020 02 7;21(1-2):5-14. Epub 2019 Jul 7.

AB Science, Paris, France.

To assess masitinib in the treatment of ALS. 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 last observation carried forward (LOCF) methodology with sensitivity analyses performed to test robustness. For the primary efficacy population, masitinib ( = 99) showed significant benefit over placebo ( = 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. 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.
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http://dx.doi.org/10.1080/21678421.2019.1632346DOI Listing
February 2020

ALS and FTD: Where RNA metabolism meets protein quality control.

Semin Cell Dev Biol 2020 03 1;99:183-192. Epub 2019 Jul 1.

Centre for Neuroscience and Nanotechnology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.semcdb.2019.06.003DOI Listing
March 2020
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