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1. The role of peripheral immunity in ALS: a population‐based study

Author

Maurizio Grassano, Umberto Manera, Fabiola De Marchi, Paolo Cugnasco, Enrico Matteoni, Margherita Daviddi, Luca Solero, Alessandro Bombaci, Francesca Palumbo, Rosario Vasta, Antonio Canosa, Paolina Salamone, Giuseppe Fuda, Federico Casale, Letizia Mazzini, Andrea Calvo, Cristina Moglia, and Adriano Chiò

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Systemic inflammation has been proposed as a relevant mechanism in amyotrophic lateral sclerosis (ALS). Still, comprehensive data on ALS patients' innate and adaptive immune responses and their effect on the clinical phenotype are lacking. Here, we investigate systemic immunity in a population‐based ALS cohort using readily available hematological indexes. Methods We collected clinical data and the complete blood count (CBC) at diagnosis in ALS patients from the Piemonte and Valle d'Aosta Register for ALS (PARALS) from 2007 to 2019. Leukocytes populations, neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), systemic‐immune‐inflammation index (SII), and lymphocyte‐to‐monocyte ratio (LMR) were derived from CBC. All variables were analyzed for association with clinical features in the entire cohort and then in sex‐ and age‐based subgroups. Results Neutrophils (P = 0.001) and markers of increased innate immunity (NLR, P = 0.008 and SII, P = 0.006) were associated with a faster disease progression. Similarly, elevated innate immunity correlated with worse pulmonary function and shorter survival. The prognosis in women also correlated with low lymphocytes (P = 0.045) and a decreased LMR (P = 0.013). ALS patients with cognitive impairment exhibited lower monocytes (P = 0.0415). Conclusions and Relevance The dysregulation of the systemic immune system plays a multifaceted role in ALS. More specifically, an elevated innate immune response is associated with faster progression and reduced survival. Conversely, ALS patients with cognitive impairment showed a reduction in monocyte count. Additionally, immune response varied according to sex and age, thus suggesting that involved immune pathways are patient specific. Further studies will help translate those findings into clinical practice or targeted treatments.

Published
2023
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2. Effects of intracellular calcium accumulation on proteins encoded by the major genes underlying amyotrophic lateral sclerosis

Author

Giovanni De Marco, Annarosa Lomartire, Umberto Manera, Antonio Canosa, Maurizio Grassano, Federico Casale, Giuseppe Fuda, Paolina Salamone, Maria Teresa Rinaudo, Sebastiano Colombatto, Cristina Moglia, Adriano Chiò, and Andrea Calvo

Subjects
Medicine, Science
Abstract

Abstract The aetiology of Amyotrophic Lateral Sclerosis (ALS) is still poorly understood. The discovery of genetic forms of ALS pointed out the mechanisms underlying this pathology, but also showed how complex these mechanisms are. Excitotoxicity is strongly suspected to play a role in ALS pathogenesis. Excitotoxicity is defined as neuron damage due to excessive intake of calcium ions (Ca2+) by the cell. This study aims to find a relationship between the proteins coded by the most relevant genes associated with ALS and intracellular Ca2+ accumulation. In detail, the profile of eight proteins (TDP-43, C9orf72, p62/sequestosome-1, matrin-3, VCP, FUS, SOD1 and profilin-1), was analysed in three different cell types induced to raise their cytoplasmic amount of Ca2+. Intracellular Ca2+ accumulation causes a decrease in the levels of TDP-43, C9orf72, matrin3, VCP, FUS, SOD1 and profilin-1 and an increase in those of p62/sequestosome-1. These events are associated with the proteolytic action of two proteases, calpains and caspases, as well as with the activation of autophagy. Interestingly, Ca2+ appears to both favour and hinder autophagy. Understanding how and why calpain-mediated proteolysis and autophagy, which are physiological processes, become pathological may elucidate the mechanisms responsible for ALS and help discover new therapeutic targets.

Published
2022
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3. Markers of blood-brain barrier disruption increase early and persistently in COVID-19 patients with neurological manifestations

Author

Valentina Bonetto, Laura Pasetto, Ilaria Lisi, Marco Carbonara, Rosalia Zangari, Erica Ferrari, Veronica Punzi, Silvia Luotti, Nicola Bottino, Bruno Biagianti, Cristina Moglia, Giuseppe Fuda, Roberta Gualtierotti, Francesco Blasi, Ciro Canetta, Nicola Montano, Mauro Tettamanti, Giorgia Camera, Maria Grimoldi, Giulia Negro, Nicola Rifino, Andrea Calvo, Paolo Brambilla, Francesco Biroli, Alessandra Bandera, Alessandro Nobili, Nino Stocchetti, Maria Sessa, and Elisa R. Zanier

Subjects
COVID-19, neurological damages, blood-brain barrier, inflammation, blood biomarkers, critical care, Immunologic diseases. Allergy, RC581-607
Abstract

BackgroundCoronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with disorders affecting the peripheral and the central nervous system. A high number of patients develop post-COVID-19 syndrome with the persistence of a large spectrum of symptoms, including neurological, beyond 4 weeks after infection. Several potential mechanisms in the acute phase have been hypothesized, including damage of the blood-brain-barrier (BBB). We tested weather markers of BBB damage in association with markers of brain injury and systemic inflammation may help in identifying a blood signature for disease severity and neurological complications.MethodsBlood biomarkers of BBB disruption (MMP-9, GFAP), neuronal damage (NFL) and systemic inflammation (PPIA, IL-10, TNFα) were measured in two COVID-19 patient cohorts with high disease severity (ICUCovid; n=79) and with neurological complications (NeuroCovid; n=78), and in two control groups free from COVID-19 history, healthy subjects (n=20) and patients with amyotrophic lateral sclerosis (ALS; n=51). Samples from COVID-19 patients were collected during the first and the second wave of COVID-19 pandemic in Lombardy, Italy. Evaluations were done at acute and chronic phases of the COVID-19 infection.ResultsBlood biomarkers of BBB disruption and neuronal damage are high in COVID-19 patients with levels similar to or higher than ALS. NeuroCovid patients display lower levels of the cytokine storm inducer PPIA but higher levels of MMP-9 than ICUCovid patients. There was evidence of different temporal dynamics in ICUCovid compared to NeuroCovid patients with PPIA and IL-10 showing the highest levels in ICUCovid patients at acute phase. On the contrary, MMP-9 was higher at acute phase in NeuroCovid patients, with a severity dependency in the long-term. We also found a clear severity dependency of NFL and GFAP levels, with deceased patients showing the highest levels.DiscussionThe overall picture points to an increased risk for neurological complications in association with high levels of biomarkers of BBB disruption. Our observations may provide hints for therapeutic approaches mitigating BBB disruption to reduce the neurological damage in the acute phase and potential dysfunction in the long-term.

Published
2022
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4. Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis: The TUDCA-ALS trial protocol

Author

Alberto Albanese, Albert Christian Ludolph, Christopher J. McDermott, Philippe Corcia, Philip Van Damme, Leonard H. Van den Berg, Orla Hardiman, Gilberto Rinaldi, Nicola Vanacore, Brian Dickie, TUDCA-ALS Study Group, Paolo Tornese, Antoniangela Cocco, Maria Lo Giudice, Michela Matteoli, Eliana Lauranzano, Maria Luisa Malosio, Chiara Adriana Elia, Flavia Lombardo, Flavia Mayer, Maria Puopolo, Stefania Spila Alegiani, Adriano Chiò, Umberto Manera, Cristina Moglia, Andrea Calvo, Paolina Salamone, Giuseppe Fuda, Carlo Colosimo, Cristina Spera, Prabha Cristina Ranchicchio, Giuseppe Stipa, Domenico Frondizi, Christian Lunetta, Valeria Sansone, Claudia Tarlarini, Francesca Gerardi, Vincenzo Silani, Alberto Doretti, Eleonora Colombo, Gianluca Demirtzidis, Gioacchino Tedeschi, Francesca Trojsi, Carla Passaniti, Stefania Ballestrero, Johannes Dorst, Ulrike Weiland, Andrea Fromm, Maximilian Wiesenfarth, Katharina Kandler, Simon Witzel, Markus Otto, Joachim Schuster, Thomas Meyer, André Maier, Dagmar Kettemann, Susanne Petri, Lars Müschen, Camilla Wohnrade, Anastasia Sarikidi, Alma Osmanovic, Julian Grosskreutz, Annekathrin Rödiger, Robert Steinbach, Benjamin Ilse, Uta Smesny, Robert Untucht, René Günther, Maximilian Vidovic, Pamela Shaw, Alexis Collins, Helen Wollff, Theresa Walsh, Lee Tuddenham, Mbombe Kazoka, David White, Stacy Young, Benjamin Thompson, Daniel Madarshahian, Suresh K. Chhetri, Amina Chaouch, Carolyn A. Young, Heike Arndt, Oliver C Hanemann, Thomas Lambert, Stephane Beltran, Philippe Couratier, Florence Esselin, William Camu, Elisa De, La Cruz, Gwendal Lemasson, Pegah Masrori, Sinead Maguire, Liz Fogarty, Toyosi Atoyebi, and Niamh Ní Obáin

Subjects
amyotrophic lateral sclerosis, therapy, clinical trial, phase III, bile acids, Neurology. Diseases of the nervous system, RC346-429
Abstract

BackgroundAmyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative rare disease that affects motor neurons in the brain, brainstem, and spinal cord, resulting in progressive weakness and atrophy of voluntary skeletal muscles. Although much has been achieved in understanding the disease pathogenesis, treatment options are limited, and in Europe, riluzole is the only approved drug. Recently, some other drugs showed minor effects.MethodsThe TUDCA-ALS trial is a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The study aims to enroll 320 patients in 25 centers across seven countries in Europe. Enrolled patients are randomized to one of two treatment arms: TUDCA or identical placebo by oral route. The study measures disease progression during the treatment period and compares it to natural progression during a no-treatment run-in phase. Clinical data and specific biomarkers are measured during the trial. The study is coordinated by a consortium composed of leading European ALS centers.ConclusionThis trial is aimed to determine whether TUDCA has a disease-modifying activity in ALS. Demonstration of TUDCA efficacy, combined with the validation of new biomarkers, could advance ALS patient care.Clinical trial registrationClinicalTrials.gov, identifier: NCT03800524.

Published
2022
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5. Guidelines to the Practice of Anesthesia: Revised Edition 2023

Author

Gregory Dobson, Anthony Chau, Justine Denomme, Giuseppe Fuda, Conor McDonnell, Ian McIntyre, Andrew D. Milne, Robert Milkovich, Kathryn Sparrow, Yongjun Wang, and Christopher Young

Subjects
Anesthesiology and Pain Medicine, General Medicine
Published
2023

6. The transcription factor Nurr1 is upregulated in amyotrophic lateral sclerosis patients and SOD1-G93A mice

Author

Valeria Valsecchi, Marina Boido, Francesca Montarolo, Michela Guglielmotto, Simona Perga, Serena Martire, Santina Cutrupi, Andrea Iannello, Nadia Gionchiglia, Elena Signorino, Andrea Calvo, Giuseppe Fuda, Adriano Chiò, Antonio Bertolotto, and Alessandro Vercelli

Subjects
als, sod1-g93a mice, motor neuron disease, neuroinflammation, nurr1, Medicine, Pathology, RB1-214
Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both lower and upper motor neurons (MNs) in the central nervous system. ALS etiology is highly multifactorial and multifarious, and an effective treatment is still lacking. Neuroinflammation is a hallmark of ALS and could be targeted to develop new therapeutic approaches. Interestingly, the transcription factor Nurr1 has been demonstrated to have an important role in the inflammatory process in several neurological disorders, such as Parkinson's disease and multiple sclerosis. In the present paper, we demonstrate for the first time that Nurr1 expression levels are upregulated in the peripheral blood of ALS patients. Moreover, we investigated Nurr1 function in the SOD1-G93A mouse model of ALS. Nurr1 was strongly upregulated in the spinal cord during the asymptomatic and early symptomatic phases of the disease, where it promoted the expression of brain-derived neurotrophic factor mRNA and the repression of NFκB pro-inflammatory targets, such as inducible nitric oxide synthase. Therefore, we hypothesize that Nurr1 is activated in an early phase of the disease as a protective endogenous anti-inflammatory mechanism, although not sufficient to reverse disease progression. On the basis of these observations, Nurr1 could represent a potential biomarker for ALS and a promising target for future therapies.

Published
2020
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7. 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)

Author

Adriano Chiò, Christian Lunetta, Federico Casale, Letizia Mazzini, Andrea Calvo, Cristina Moglia, Jessica Mandrioli, Isabella Laura Simone, Giuseppe Fuda, Paolina Salamone, Giuseppe Marrali, Claudia Caponnetto, Vincenzo La Bella, Corrado Tarella, A Bombaci, M Brunetti, S Cammarosano, A Canosa, C Calvo, M Daviddi, G De Marco, P Cugnasco, M Grassano, B Iazzolino, A Ilardi, C Lauritano, A Lomartire, U Manera, L Solero, MC Torrieri; R Vasta, M Gilestro, VE Muccio; P Omedé, F Gerardi, C Cabona, G Novi, E Bersano, F De Marchi, R Spataro, R. Scimè, A Fasano, N Fini, A Gessani, E D’Errico, and A Scarafino

Subjects
Medicine
Abstract

IntroductionAmyotrophic 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 analysisSTEMALS-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 disseminationThe 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 numberEudract 2014-002228-28.

Published
2020
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10. The Role of CHI3L1 Plasmatic Levels in Amyotrophic Lateral Sclerosis

Author

Alessandro Bombaci, Umberto Manera, Giovanni De Marco, Federico Casale, Paolina Salamone, Giuseppe Fuda, Giulia Marchese, Barbara Iazzolino, Laura Peotta, Cristina Moglia, Andrea Calvo, and Adriano Chiò

Subjects
clinical_neurology
Abstract

(1) Background: Motor neuron diseases (MNDs) are fatal neurodegenerative diseases. Biomarkers could help in defining patients’ prognosis and stratification. Beyond neurofilaments, chitinases are a promising family of possible biomarker, which correlate with neuroinflammatory status. We evaluated plasmatic levels of CHI3L1 in MNDs, MND mimics and healthy controls (HCs); (2) Methods: We used Sandwich ELISA to quantify CHI3L1 in plasma samples from 44 MNDs, 7 HSP, 9 MND mimics and 19 HCs. We collect also ALSFRSr scale, MRC scale, spirometry, mutational status, progression rate (PR), blood sampling, neuropsychological evaluation; (3) Results: Plasma levels of CHI3L1 resulted to be different among groups (p= 0.005). Particularly, MND mimics showed higher CHI3L1 levels compared to MNDs and HCs. CHI3LI levels did not differ among PMA, PLS and ALS and we do not find correlation among CHI3L1 levels and clinical scores, spirometry parameters, PR, and neuropsychological features. Of note, red blood cells count and haemoglobin correlated with CHI3L1 levels (respectively, p

Published
2023

12. Guidelines to the Practice of Anesthesia – Revised Edition 2022

Author

Gregory Dobson, Lucie Filteau, Giuseppe Fuda, Ian McIntyre, Andrew D. Milne, Robert Milkovich, Kathryn Sparrow, Yongjun Wang, and Christopher Young

Subjects
Canada, Anesthesiology and Pain Medicine, Anesthesiology, Humans, Anesthesia, Patient Care, General Medicine, Anesthesiologists
Abstract

The Guidelines to the Practice of Anesthesia Revised Edition 2022 (the Guidelines) were prepared by the Canadian Anesthesiologists' Society (CAS), which reserves the right to determine their publication and distribution. The Guidelines are subject to revision and updated versions are published annually. The Guidelines to the Practice of Anesthesia Revised Edition 2022 supersedes all previously published versions of this document. Although the CAS encourages Canadian anesthesiologists to adhere to its practice guidelines to ensure high-quality patient care, the CAS cannot guarantee any specific patient outcome. Anesthesiologists should exercise their own professional judgement in determining the proper course of action for any patient's circumstances. The CAS assumes no responsibility or liability for any error or omission arising from the use of any information contained in its Guidelines to the Practice of Anesthesia.RéSUMé: Le Guide d’exercice de l’anesthésie, version révisée 2022 (le Guide), a été préparé par la Société canadienne des anesthésiologistes (SCA), qui se réserve le droit de décider des termes de sa publication et de sa diffusion. Le Guide est soumis à révision et des versions mises à jour sont publiées chaque année. Le Guide d’exercice de l’anesthésie, version révisée 2022, remplace toutes les versions précédemment publiées de ce document. Bien que la SCA incite les anesthésiologistes du Canada à se conformer à son guide d’exercice pour assurer une grande qualité des soins dispensés aux patients, elle ne peut garantir les résultats d’une intervention spécifique. Les anesthésiologistes doivent exercer leur jugement professionnel pour déterminer la méthode d’intervention la mieux adaptée à l’état de leur patient. La SCA n’accepte aucune responsabilité ou imputabilité de quelque nature que ce soit découlant d’erreurs ou d’omissions ou de l’utilisation des renseignements contenus dans son Guide d’exercice de l’anesthésie.

Published
2021

13. Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis: The TUDCA-ALS trial protocol

Author

Albanese Alberto, Ludolph, Albert Christian, McDermott, Christopher J, Corcia, Philippe, Van Damme, Philip, Van den Berg, Leonard H, Hardiman, Orla, Rinaldi, Gilberto, Vanacore, Nicola, Dickie, Brian, TUDCA-ALS Study Group, Paolo Tornese, Antoniangela Cocco, Maria Lo Giudice, Michela Matteoli, Eliana Lauranzano, Maria Luisa Malosio, Chiara Adriana Elia, Flavia Lombardo, Flavia Mayer, Maria Puopolo, Stefania Spila Alegiani, Adriano Chiò, Umberto Manera, Cristina Moglia, Andrea Calvo, Paolina Salamone, Giuseppe Fuda, Carlo Colosimo, Cristina Spera, Prabha Cristina Ranchicchio, Giuseppe Stipa, Domenico Frondizi, Christian Lunetta, Valeria Sansone, Claudia Tarlarini, Francesca Gerardi, Vincenzo Silani, Alberto Doretti, Eleonora Colombo, Gianluca Demirtzidis, Gioacchino Tedeschi, Francesca Trojsi, Carla Passaniti, Stefania Ballestrero, Johannes Dorst, Ulrike Weiland, Andrea Fromm, Maximilian Wiesenfarth, Katharina Kandler, Simon Witzel, Markus Otto, Joachim Schuster, Thomas Meyer, André Maier, Dagmar Kettemann, Susanne Petri, Lars Müschen, Camilla Wohnrade, Anastasia Sarikidi, Alma Osmanovic, Julian Grosskreutz, Annekathrin Rödiger, Robert Steinbach, Benjamin Ilse, Uta Smesny, Robert Untucht, René Günther, Maximilian Vidovic, Pamela Shaw, Alexis Collins, Helen Wollff, Theresa Walsh, Lee Tuddenham, Mbombe Kazoka, David White, Stacy Young, Benjamin Thompson, Daniel Madarshahian, Suresh K Chhetri, Amina Chaouch, Carolyn A Young, Heike Arndt, Oliver C Hanemann, Thomas Lambert, Stephane Beltran, Philippe Couratier, Florence Esselin, William Camu, Elisa De, La Cruz, Gwendal Lemasson, Pegah Masrori, Sinead Maguire, Liz Fogarty, Toyosi Atoyebi, Niamh Ní Obáin, Tornese, Paolo, Cocco, Antoniangela, Giudice, Maria Lo, Matteoli, Michela, Lauranzano, Eliana, Malosio, Maria Luisa, Adriana Elia, Chiara, Lombardo, Flavia, Mayer, Flavia, Puopolo, Maria, Alegiani, Stefania Spila, Chiò, Adriano, Manera, Umberto, Moglia, Cristina, Calvo, Andrea, Salamone, Paolina, Fuda, Giuseppe, Colosimo, Carlo, Spera, Cristina, Ranchicchio, Prabha Cristina, Stipa, Giuseppe, Frondizi, Domenico, Lunetta, Christian, Sansone, Valeria, Tarlarini, Claudia, Gerardi, Francesca, Silani, Vincenzo, Doretti, Alberto, Colombo, Eleonora, Demirtzidis, Gianluca, Tedeschi, Gioacchino, Trojsi, Francesca, Passaniti, Carla, Ballestrero, Stefania, Dorst, Johannes, Weiland, Ulrike, Fromm, Andrea, Wiesenfarth, Maximilian, Kandler, Katharina, Witzel, Simon, Otto, Markus, Schuster, Joachim, Meyer, Thomas, Maier, André, Kettemann, Dagmar, Petri, Susanne, Müschen, Lars, Wohnrade, Camilla, Sarikidi, Anastasia, Osmanovic, Alma, Grosskreutz, Julian, Rödiger, Annekathrin, Steinbach, Robert, Ilse, Benjamin, Smesny, Uta, Untucht, Robert, Günther, René, Vidovic, Maximilian, Shaw, Pamela, Collins, Alexis, Wollff, Helen, Walsh, Theresa, Tuddenham, Lee, Kazoka, Mbombe, White, David, Young, Stacy, Thompson, Benjamin, Madarshahian, Daniel, Chhetri, Suresh K, Chaouch, Amina, Young, Carolyn A, Arndt, Heike, Hanemann, Oliver C, Lambert, Thomas, Beltran, Stephane, Couratier, Philippe, Esselin, Florence, Camu, William, De, Elisa, Cruz, La, Lemasson, Gwendal, Masrori, Pegah, Maguire, Sinead, Fogarty, Liz, Atoyebi, Toyosi, Obáin, Niamh Ní, Alberto, Albanese, Albert Christian, Ludolph, Christopher J, Mcdermott, Philippe, Corcia, Philip, Van Damme, Leonard H, Van den Berg, Orla, Hardiman, Gilberto, Rinaldi, Nicola, Vanacore, Brian, Dickie, Study Group, TUDCA-ALS, Lo Giudice, Maria, Luisa Malosio, Maria, Spila Alegiani, Stefania, Cristina Ranchicchio, Prabha, Dorst, Johanne, Otto, Marku, Meyer, Thoma, Müschen, Lar, Collins, Alexi, K Chhetri, Suresh, A Young, Carolyn, C Hanemann, Oliver, Lambert, Thoma, and Ní Obáin, Niamh

Subjects
bile acids, amyotrophic lateral sclerosis, therapy, Neurology, bile acid, clinical trial, phase III, amyotrophic lateral sclerosi, Neurology (clinical), ddc:610
Abstract

BackgroundAmyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative rare disease that affects motor neurons in the brain, brainstem, and spinal cord, resulting in progressive weakness and atrophy of voluntary skeletal muscles. Although much has been achieved in understanding the disease pathogenesis, treatment options are limited, and in Europe, riluzole is the only approved drug. Recently, some other drugs showed minor effects.MethodsThe TUDCA-ALS trial is a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The study aims to enroll 320 patients in 25 centers across seven countries in Europe. Enrolled patients are randomized to one of two treatment arms: TUDCA or identical placebo by oral route. The study measures disease progression during the treatment period and compares it to natural progression during a no-treatment run-in phase. Clinical data and specific biomarkers are measured during the trial. The study is coordinated by a consortium composed of leading European ALS centers.ConclusionThis trial is aimed to determine whether TUDCA has a disease-modifying activity in ALS. Demonstration of TUDCA efficacy, combined with the validation of new biomarkers, could advance ALS patient care.Clinical trial registrationClinicalTrials.gov, identifier: NCT03800524.

Published
2022

14. The role of peripheral immunity in ALS: a population-based study

Author

Maurizio Grassano, Umberto Manera, Fabiola De Marchi, Paolo Cugnasco, Enrico Matteoni, Margherita Daviddi, Luca Solero, Alessandro Bombaci, Francesca Palumbo, Rosario Vasta, Antonio Canosa, Paolina Salamone, Giuseppe Fuda, Federico Casale, Letizia Mazzini, Andrea Calvo, Cristina Moglia, and Adriano Chiò

Abstract

BackgroundSystemic inflammation has been proposed as a relevant mechanism in Amyotrophic Lateral Sclerosis (ALS). Recent evidence shows that an increased inflammatory status correlates with survival in ALS. Still, comprehensive data on ALS patients’ innate and adaptive immune responses and their effect on the clinical phenotype are lacking. Here, we investigate the role and characteristics of systemic immunity in a population-based ALS cohort using readily available hematological indexes that reflect changes in innate and adaptive immunity.MethodsWe collected the complete blood count (CBC) at diagnosis in ALS patients from the Piemonte and Valle d’Aosta Register for ALS (PARALS) from 2007 to 2019. Demographic and clinical data were collected using registry data. Leukocytes populations, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII) and lymphocyte-to-monocyte ratio (LMR) were derived from CBC. All variables were analyzed for association with clinical features in the entire cohort and then in sex- and age-based subgroups. Logistic, linear and Cox regression models were used as appropriate.ResultsAfter adjustment for relevant covariates, neutrophils (p=0.001) and markers of increased innate immunity (NLR, p=0.008 and SII, p=0.006) were associated with a faster disease progression. Similarly, elevated innate immunity markers correlated with worse pulmonary function and shorter survival. Sex-based differences emerged, as the prognosis in women also correlated with a low lymphocyte (p=0.045) and a decreased LMR (p=0.013). ALS patients with cognitive impairment exhibited lower levels of monocytes (p=0.0415) and, although only in later-onset ALS (age at onset > 70 years), lower lymphocytes (p=0.006) and increased NLR (p=0.021) and SII (p=0.030).Conclusions and RelevanceOur results confirm that a dysregulated systemic immune system participates in ALS progression. More specifically, an elevated innate immune response is associated with faster progression and reduced survival. The immune response varied according to sex and age, thus prompting the speculation that involved immune pathways are patient-specific. Finally, we observed that ALS patients with greater cognitive impairment showed a reduction in monocytes count. Those data revealed that systemic inflammation plays a multifaceted role in ALS: further studies will help translate those findings into clinical practice or targeted treatments.

Published
2022

15. Plasma CHI3L1 in Amyotrophic Lateral Sclerosis: A Potential Differential Diagnostic Biomarker

Author

Alessandro Bombaci, Umberto Manera, Giovanni De Marco, Federico Casale, Paolina Salamone, Giuseppe Fuda, Giulia Marchese, Barbara Iazzolino, Laura Peotta, Cristina Moglia, Andrea Calvo, and Adriano Chiò

Subjects
General Medicine
Abstract

(1) Background: Motor neuron diseases (MNDs) are fatal neurodegenerative diseases. Biomarkers could help with defining patients’ prognoses and stratifications. Besides neurofilaments, chitinases are a promising family of possible biomarkers which correlate with neuroinflammatory status. We evaluated the plasmatic levels of CHI3L1 in MNDs, MND mimics, and healthy controls (HCs). (2) Methods: We used a sandwich ELISA to quantify the CHI3L1 in plasma samples from 44 MND patients, 7 hereditary spastic paraplegia (HSP) patients, 9 MND mimics, and 19 HCs. We also collected a ALSFRSr scale, MRC scale, spirometry, mutational status, progression rate (PR), blood sampling, and neuropsychological evaluation. (3) Results: The plasma levels of the CHI3L1 were different among groups (p = 0.005). Particularly, the MND mimics showed higher CHI3L1 levels compared with the MND patients and HCs. The CHI3L1 levels did not differ among PMA, PLS, and ALS, and we did not find a correlation among the CHI3L1 levels and clinical scores, spirometry parameters, PR, and neuropsychological features. Of note, the red blood cell count and haemoglobin was correlated with the CHI3L1 levels (respectively, p < 0.001, r = 0.63; p = 0.022, and r = 0.52). (4) Conclusions: The CHI3L1 plasma levels were increased in the MND mimics cohort compared with MNDs group. The increase of CHI3L1 in neuroinflammatory processes could explain our findings. We confirmed that the CHI3L1 plasma levels did not allow for differentiation between ALS and HCs, nor were they correlated with neuropsychological impairment.

Published
2023

16. Telemedicine for patients with amyotrophic lateral sclerosis during COVID-19 pandemic: an Italian ALS referral center experience

Author

Adriano Chiò, Martina Arcari, Maria Claudia Torrieri, Rosario Vasta, Laura Peotta, Umberto Manera, Paolina Salamone, Margherita Daviddi, Francesca Palumbo, Fabrizio D'Ovidio, Antonio Canosa, Sara Cabras, Alessandro Bombaci, Giuseppe Fuda, Luca Solero, Barbara Iazzolino, Francesca Di Pede, Enza Mastro, Filippo De Mattei, Enrico Matteoni, Antonio Ilardi, Andrea Calvo, Silvia Giusiano, Maurizio Grassano, and Cristina Moglia

Subjects
Male, Telemedicine, motor neuron diseases, Coronavirus disease 2019 (COVID-19), Clinical Neurology, Speech Therapy, Tertiary Care Centers, 03 medical and health sciences, 0302 clinical medicine, Ambulatory care, Pandemic, medicine, Humans, Psychology, remote consultation, Amyotrophic lateral sclerosis, COVID-19, telemedicine, Aged, Patient Care Team, Remote Consultation, SARS-CoV-2, business.industry, Amyotrophic Lateral Sclerosis, Disease Management, Patient Preference, Middle Aged, medicine.disease, Phone call, Italy, Neurology, Patient Satisfaction, Referral center, Female, Neurology (clinical), Medical emergency, business, 030217 neurology & neurosurgery
Abstract

We describe the telemedicine experience of an Italian ALS tertiary Center during COVID-19 pandemic. A total of 144 visits were scheduled between 6th March and 6th April 2020. These mostly consisted of neurological or psychological visits (139, 96.5%). One hundred thirty-nine (96.5%) visits were performed as telemedicine and mostly via phone call (112, 80.6%). Three (2.1%) visits were considered as urgent and maintained as outpatient care. Additionally, patients were still able to telephone, being put through directly to their neurologists. Many requests of contact were addressed at getting information about the scheduled visits or examinations (45, 43.3%). Globally, patients and caregivers were satisfied with the telemedicine service. However, the majority (85, 65.9%) would prefer a face-to-face visit. In conclusion, telemedicine could be considered a good complement to face-to-face care, even after social restrictions have been eased.

Published
2020

17. Brain 18fluorodeoxyglucose-positron emission tomography changes in amyotrophic lateral sclerosis with TARDBP mutations

Author

Antonio Canosa, Andrea Calvo, Cristina Moglia, Rosario Vasta, Francesca Palumbo, Giuseppe Fuda, Francesca Di Pede, Sara Cabras, Vincenzo Arena, Andrea Novara, Paolina Salamone, Enrico Matteoni, Luca Sbaiz, Salvatore Gallone, Maurizio Grassano, Umberto Manera, Adriano Chiò, and Marco Pagani

Subjects
FUNCTIONAL IMAGING, CEREBRAL METABOLISM, Amyotrophic Lateral Sclerosis, Brain, NUCLEAR MEDICINE, ALS, PET, Humans, Mutation, Positron-Emission Tomography, Psychiatry and Mental health, Surgery, Neurology (clinical)
Published
2022

18. Identifying and predicting amyotrophic lateral sclerosis clinical subgroups: a population-based machine-learning study

Author

Faraz Faghri, Fabian Brunn, Anant Dadu, Elisabetta Zucchi, Ilaria Martinelli, Letizia Mazzini, Rosario Vasta, Antonio Canosa, Cristina Moglia, Andrea Calvo, Michael A Nalls, Roy H Campbell, Jessica Mandrioli, Bryan J Traynor, Adriano Chiò, Umberto Manera, Francesca Palumbo, Alessandro Bombaci, Maurizio Grassano, Maura Brunetti, Federico Casale, Giuseppe Fuda, Paolina Salamone, Barbara Iazzolino, Laura Peotta, Paolo Cugnasco, Giovanni De Marco, Maria Claudia Torrieri, Salvatore Gallone, Marco Barberis, Luca Sbaiz, Salvatore Gentile, Alessandro Mauro, Fabiola De Marchi, Lucia Corrado, Sandra D'Alfonso, Antonio Bertolotto, Daniele Imperiale, Marco De Mattei, Salvatore Amarù, Cristoforo Comi, Carmelo Labate, Fabio Poglio, Luigi Ruiz, Lucia Testa, Eugenia Rota, Paolo Ghiglione, Nicola Launaro, Alessia Di Sapio, Nicola Fini, Giulia Gianferrari, Cecilia Simonini, Stefano Meletti, Rocco Liguori, Veria Vacchiano, Fabrizio Salvi, Ilaria Bartolomei, Roberto Michelucci, Pietro Cortelli, Rita Rinaldi, Anna Maria Borghi, Andrea Zini, Elisabetta Sette, Valeria Tugnoli, Maura Pugliatti, Elena Canali, Luca Codeluppi, Franco Valzania, Lucia Zinno, Giovanni Pavesi, Doriana Medici, Giovanna Pilurzi, Emilio Terlizzi, Donata Guidetti, Silvia De Pasqua, Mario Santangelo, Patrizia De Massis, Martina Bracaglia, Mario Casmiro, Pietro Querzani, Simonetta Morresi, Marco Longoni, Alberto Patuelli, Susanna Malagù, Marco Currò Dossi, Simone Vidale, Salvatore Ferro, Faghri F., Brunn F., Dadu A., Chio A., Calvo A., Moglia C., Canosa A., Manera U., Vasta R., Palumbo F., Bombaci A., Grassano M., Brunetti M., Casale F., Fuda G., Salamone P., Iazzolino B., Peotta L., Cugnasco P., De Marco G., Torrieri M.C., Gallone S., Barberis M., Sbaiz L., Gentile S., Mauro A., Mazzini L., De Marchi F., Corrado L., D'Alfonso S., Bertolotto A., Imperiale D., De Mattei M., Amaru S., Comi C., Labate C., Poglio F., Ruiz L., Testa L., Rota E., Ghiglione P., Launaro N., Di Sapio A., Mandrioli J., Fini N., Martinelli I., Zucchi E., Gianferrari G., Simonini C., Meletti S., Liguori R., Vacchiano V., Salvi F., Bartolomei I., Michelucci R., Cortelli P., Rinaldi R., Borghi A.M., Zini A., Sette E., Tugnoli V., Pugliatti M., Canali E., Codeluppi L., Valzania F., Zinno L., Pavesi G., Medici D., Pilurzi G., Terlizzi E., Guidetti D., De Pasqua S., Santangelo M., De Massis P., Bracaglia M., Casmiro M., Querzani P., Morresi S., Longoni M., Patuelli A., Malagu S., Curro Dossi M., Vidale S., Ferro S., Nalls M.A., Campbell R.H., and Traynor B.J.

Subjects
Cohort Studies, Machine Learning, Health Information Management, Amyotrophic Lateral Sclerosis, Medicine (miscellaneous), Cluster Analysis, Humans, Decision Sciences (miscellaneous), Health Informatics, ALS, population based study, Article, United States, Retrospective Studies
Abstract

Amyotrophic lateral sclerosis (ALS) is known to represent a collection of overlapping syndromes. Various classification systems based on empirical observations have been proposed, but it is unclear to what extent they reflect ALS population substructures. We aimed to use machine-learning techniques to identify the number and nature of ALS subtypes to obtain a better understanding of this heterogeneity, enhance our understanding of the disease, and improve clinical care.In this retrospective study, we applied unsupervised Uniform Manifold Approximation and Projection [UMAP]) modelling, semi-supervised (neural network UMAP) modelling, and supervised (ensemble learning based on LightGBM) modelling to a population-based discovery cohort of patients who were diagnosed with ALS while living in the Piedmont and Valle d'Aosta regions of Italy, for whom detailed clinical data, such as age at symptom onset, were available. We excluded patients with missing Revised ALS Functional Rating Scale (ALSFRS-R) feature values from the unsupervised and semi-supervised steps. We replicated our findings in an independent population-based cohort of patients who were diagnosed with ALS while living in the Emilia Romagna region of Italy.Between Jan 1, 1995, and Dec 31, 2015, 2858 patients were entered in the discovery cohort. After excluding 497 (17%) patients with missing ALSFRS-R feature values, data for 42 clinical features across 2361 (83%) patients were available for the unsupervised and semi-supervised analysis. We found that semi-supervised machine learning produced the optimum clustering of the patients with ALS. These clusters roughly corresponded to the six clinical subtypes defined by the Chiò classification system (ie, bulbar, respiratory, flail arm, classical, pyramidal, and flail leg ALS). Between Jan 1, 2009, and March 1, 2018, 1097 patients were entered in the replication cohort. After excluding 108 (10%) patients with missing ALSFRS-R feature values, data for 42 clinical features across 989 patients were available for the unsupervised and semi-supervised analysis. All 1097 patients were included in the supervised analysis. The same clusters were identified in the replication cohort. By contrast, other ALS classification schemes, such as the El Escorial categories, Milano-Torino clinical staging, and King's clinical stages, did not adequately label the clusters. Supervised learning identified 11 clinical parameters that predicted ALS clinical subtypes with high accuracy (area under the curve 0·982 [95% CI 0·980-0·983]).Our data-driven study provides insight into the ALS population substructure and confirms that the Chiò classification system successfully identifies ALS subtypes. Additional validation is required to determine the accuracy and clinical use of these algorithms in assigning clinical subtypes. Nevertheless, our algorithms offer a broad insight into the clinical heterogeneity of ALS and help to determine the actual subtypes of disease that exist within this fatal neurodegenerative syndrome. The systematic identification of ALS subtypes will improve clinical care and clinical trial design.US National Institute on Aging, US National Institutes of Health, Italian Ministry of Health, European Commission, University of Torino Rita Levi Montalcini Department of Neurosciences, Emilia Romagna Regional Health Authority, and Italian Ministry of Education, University, and Research.For the Italian and German translations of the abstract see Supplementary Materials section.

Published
2022

19. Validation of the Italian version of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) administered to patients and their caregivers

Author

Umberto Manera, Luca Solero, Christina Nicole Fournier, Antonio Canosa, Rosario Vasta, Alessandro Bombaci, Maurizio Grassano, Francesca Palumbo, Maria Claudia Torrieri, Paolina Salamone, Federico Casale, Giuseppe Fuda, Cristina Moglia, Andrea Calvo, and Adriano Chiò

Subjects
rasch analysis, Neurology, Caregivers, Amyotrophic lateral sclerosis, functional rating scale, Activities of Daily Living, Amyotrophic Lateral Sclerosis, Disease Progression, Humans, Reproducibility of Results, Disabled Persons, Neurology (clinical)
Published
2021

20. Brain

Author

Antonio, Canosa, Andrea, Calvo, Cristina, Moglia, Rosario, Vasta, Francesca, Palumbo, Giuseppe, Fuda, Francesca, Di Pede, Sara, Cabras, Vincenzo, Arena, Andrea, Novara, Paolina, Salamone, Enrico, Matteoni, Luca, Sbaiz, Salvatore, Gallone, Maurizio, Grassano, Umberto, Manera, Adriano, Chiò, and Marco, Pagani

Subjects
Positron-Emission Tomography, Amyotrophic Lateral Sclerosis, Mutation, Brain, Humans
Published
2021

21. A novel splice site

Author

Antonio, Canosa, Annarosa, Lomartire, Giovanni, De Marco, Maurizio, Grassano, Maura, Brunetti, Umberto, Manera, Rosario, Vasta, Paolina, Salamone, Giuseppe, Fuda, Luca, Sbaiz, Salvatore, Gallone, Cristina, Moglia, Andrea, Calvo, and Adriano, Chiò

Subjects
Adult, Male, Amyotrophic Lateral Sclerosis, Mutation, Leukocytes, Mononuclear, Humans, RNA-Binding Protein FUS, Exons, Middle Aged
Published
2021

22. Excitotoxicity and genetics of amyotrophic lateral sclerosis: effects of intracellular calcium accumulation on proteins encoded by the major genes underlying the disease

Author

Giovanni DE MARCO, Annarosa Lomartire, Umberto Manera, Antonio Canosa, Maurizio Grassano, Federico Casale, Giuseppe Fuda, Paolina Salamone, Maria Teresa Rinaudo, Sebastiano Colombatto, Cristina Moglia, Adriano Chiò, and Andrea Calvo

Abstract

The aetiology of Amyotrophic Lateral Sclerosis (ALS), a fatal and incurable disease caused by motor neuron degeneration, is still poorly understood. The discovery of genetic forms of ALS helped to shed light on the mechanisms underlying this pathology, but also showed how complex these mechanisms are. Excitotoxicity is one of the processes strongly suspected to play a role in motor neuron degeneration in ALS. This process consists in neuron damage due to excessive intake of calcium ions (Ca2+) by the cell. This study aims to find a relationship between the proteins coded by the most relevant genes associated with ALS and excitotoxicity. In detail, the profile of eight proteins (TDP-43, C9ORF72, p62/SQSTM1, matrin3, VCP, FUS, SOD1 and profilin-1), was analysed in three different cell types induced to raise their cytoplasmic amount of Ca2+. Intracellular Ca2+ accumulation causes a significant decrease in the levels of TDP-43, C9ORF72, matrin3, VCP, FUS, SOD1 and profilin-1 and an increase in p62/SQSTM1. These events are associated to the proteolytic action of two proteases, calpains and caspases, as well as to the activation of autophagy, a process responsible for the degradation and recycling of cytoplasmic components. Interestingly, Ca2+ appears to both favour and hinder autophagy. The discovery of when Ca2+ levels become toxic for the cell, as well as understanding why the physiological processes of calpain proteolysis and autophagy become pathological, may elucidate the mechanisms responsible for ALS and help discover new therapeutic targets.

Published
2021

23. Amyotrophic lateral sclerosis caregiver burden and patients��� quality of life during COVID-19 pandemic

Author

Paolina Salamone, Alessandro Bombaci, Cristina Moglia, Laura Peotta, Barbara Iazzolino, Giuseppe Fuda, Andrea Calvo, Silvia Giusiano, Francesca Palumbo, Adriano Chiò, Maria Claudia Torrieri, Martina Arcari, Rosario Vasta, Umberto Manera, Enrico Matteoni, Sara Cabras, Filippo DeMattei, Luca Solero, Francesca Di Pede, Enza Mastro, Maurizio Grassano, Antonio Canosa, and Margherita Daviddi

Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), COVID-19 pandemic, Caregiver Burden, 03 medical and health sciences, Social support, 0302 clinical medicine, Cost of Illness, Quality of life, Surveys and Questionnaires, Pandemic, Humans, Medicine, Amyotrophic lateral sclerosis, Pandemics, ALS, caregiver burden, QOL, SARS-CoV-2, business.industry, Amyotrophic Lateral Sclerosis, COVID-19, Caregiver burden, medicine.disease, humanities, Caregivers, Neurology, Communicable Disease Control, Cohort, Quality of Life, Physical therapy, Neurology (clinical), General health, business, 030217 neurology & neurosurgery
Abstract

Objective: To assess patients Quality of life (QoL) and the burden of their caregivers during Covid-19 pandemic and specifically the impact of two-month lockdown period. Methods: In April 2020, a total of 60 patients and 59 caregivers were administered by phone scales assessing patients��� QoL (McGill QoL Questionnaire), general health status (EQ-5D-5L), and caregiver burden (Zarit Burden Interview). The administration was repeated one month after the end of lockdown measures, with the addition of a qualitative questionnaire (COVID-QoL Questionnaire) exploring family reorganization and personal perception of lock down. Results: QoL and perceived health status did not worsen during lockdown, while caregiver burden increased (p = 0.01). Patient���s QoL and caregiver burden were inversely correlated at T1 (ZBI total score mildly correlated with Mc Gill existential subscore, p = 0.02, rho = 0.30 and with Mc Gill total score, p = 0.05, rho = 0.265). No significant correlations were found at T2. According to the COVID-QoL questionnaire, caregivers perceived lower family help compared to patients (p Conclusions: Restricted measures of lockdown period during COVID-19 pandemic did not result in a significant reduction of QoL in our cohort of ALS patients, while caregiver burden significantly increased. ALS motor impairment may have played a role in the unchanged life conditions of patients. Instead, the restriction of family help for primary caregivers could be responsible of their increased burden, reflecting the importance of a wide social support in the management of this clinical condition.

Published
2021
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24. Tailoring patients��� enrollment in ALS clinical trials: the effect of disease duration and vital capacity cutoffs

Author

Gabriele Mora, Cristina Moglia, Giuseppe Fuda, Maria Claudia Torrieri, Nicola Launaro, Antonio Canosa, Letizia Mazzini, Andrea Calvo, Paolina Salamone, Alessio Mattei, Umberto Manera, Maurizio Grassano, Fabiola De Marchi, Rosario Vasta, Adriano Chiò, and Paolo Cugnasco

Subjects
medicine.medical_specialty, Vital capacity, randomized clinical trials, Time Factors, Disease duration, Vital Capacity, law.invention, FEV1/FVC ratio, Randomized controlled trial, Amyotrophic lateral sclerosis, eligibility criteria, forced vital capacity, law, Internal medicine, medicine, Humans, business.industry, Mortality rate, Amyotrophic Lateral Sclerosis, medicine.disease, Clinical trial, Neurology, Spirometry, Disease Progression, sense organs, Neurology (clinical), business
Abstract

Objective: To evaluate how Amyotrophic Lateral Sclerosis (ALS) patients��� mortality rates change, based on different levels of forced vital capacity (FVC) and disease duration, providing a scheme of mortality rates of a real population of ALS patients to improve the design of future RCTs. Methods: One random spirometry for each ALS patient was selected during four time intervals from disease onset: (1) ���12 months; (2) ���18 months; (3) ���24 months; (4) ���36 months. Date of spirometry corresponded to date of trial entry, while time interval onset-spirometry to disease duration at enrollment. Mortality rates from inclusion were computed at different time intervals. Based on progression rates, patients were stratified in slow, intermediate and fast progressors. Survival from recruitment was calculated depending on FVC, disease duration and progression rate. Results: We included 659 patients in group 1, 888 in group 2, 1019 in group 3 and 1102 in group 4. Mortality rates were higher in each group at reducing the FVC cutoff used for recruitment (p p Conclusions: This is a simple model for setting eligibility criteria, based on mortality rates of patients depending on FVC and disease duration, to select the best population for RCTs, tailored to trials��� primary endpoints and duration.

Published
2021
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25. A novel splice site FUS mutation in a familial ALS case: effects on protein expression

Author

Andrea Calvo, Paolina Salamone, Adriano Chiò, Giuseppe Fuda, Luca Sbaiz, Salvatore Gallone, Maura Brunetti, Giovanni de Marco, Rosario Vasta, Antonio Canosa, Umberto Manera, Cristina Moglia, Maurizio Grassano, and Annarosa Lomartire

Subjects
Amyotrophic lateral sclerosis, FUS, loss of function, splice site mutation, Splice site mutation, Intron, Biology, medicine.disease, Peripheral blood mononuclear cell, Molecular biology, Protein expression, Neurology, RNA splicing, Mutation (genetic algorithm), medicine, Neurology (clinical), Loss function
Abstract

Objective: To investigate the impact of a novel heterozygous FUS mutation in the acceptor splice site of intron 14 (c.1542 ��� 1 g > t) on protein expression in Peripheral Blood Mononuclear Cells (PBMC) from a familial ALS patient. Methods: PBMC were isolated for mRNA analysis (cDNA synthesis, sequencing and one-step RT-PCR), Western Immunoblot (WI), and Immunofluorescence (IF). Results: cDNA analysis revealed the skipping of exon 15 and a premature stop codon at c.228. RT-PCR showed reduced FUS mRNA by more than half compared to a healthy control (HC) and an ALS patient without genetic mutations (wtALS). In WI FUS band intensity in the proband was 30���50% compared to HC and wtALS. An antibody expected to detect only the wild-type protein did not reveal any reduction of FUS band intensity compared to the other antibodies. IF showed no difference among HC, wtALS, and the proband. Discussion: The reduction of FUS mRNA and protein in PBMC suggests the absence of the truncated protein, probably due to nonsense-mediated decay, leading to loss of function.

Published
2021
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26. The transcription factor Nurr1 is up-regulated in amyotrophic lateral sclerosis patients and SOD1-G93A mice

Author

Francesca Montarolo, Antonio Bertolotto, Elena Signorino, Giuseppe Fuda, Alessandro Vercelli, Andrea Calvo, Simona Perga, Marina Boido, Michela Guglielmotto, Andrea Iannello, Adriano Chiò, Serena Martire, Valeria Valsecchi, Santina Cutrupi, Nadia Gionchiglia, Valsecchi, Valeria, Boido, Marina, Montarolo, Francesca, Guglielmotto, Michela, Perga, Simona, Martire, Serena, Cutrupi, Santina, Iannello, Andrea, Gionchiglia, Nadia, Signorino, Elena, Calvo, Andrea, Fuda, Giuseppe, Chiò, Adriano, Bertolotto, Antonio, and Vercelli, Alessandro

Subjects
Male, SOD1-G93A mice, Nitric Oxide Synthase Type II, lcsh:Medicine, Medicine (miscellaneous), Disease, Mice, Superoxide Dismutase-1, Immunology and Microbiology (miscellaneous), Neuroinflammation, Neurotrophic factors, Nuclear Receptor Subfamily 4, Group A, Member 2, Medicine, Amyotrophic lateral sclerosis, Promoter Regions, Genetic, Motor Neurons, biology, NF-kappa B, Middle Aged, Up-Regulation, Nitric oxide synthase, Nurr1, medicine.anatomical_structure, Spinal Cord, Female, Research Article, lcsh:RB1-214, Transcriptional Activation, Central nervous system, Neuroscience (miscellaneous), Mice, Transgenic, General Biochemistry, Genetics and Molecular Biology, lcsh:Pathology, Animals, Humans, RNA, Messenger, Motor neuron disease, Transcription factor, business.industry, Brain-Derived Neurotrophic Factor, Multiple sclerosis, Amyotrophic Lateral Sclerosis, lcsh:R, medicine.disease, Gene Expression Regulation, Astrocytes, Cancer research, biology.protein, ALS, SOD1-G93A mice, motor neuron disease, neuroinflammation, Nurr1, ALS, business, Transcription Factors
Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both lower and upper motor neurons (MNs) in the central nervous system. ALS etiology is highly multifactorial and multifarious, and an effective treatment is still lacking. Neuroinflammation is a hallmark of ALS and could be targeted to develop new therapeutic approaches. Interestingly, the transcription factor Nurr1 has been demonstrated to have an important role in the inflammatory process in several neurological disorders, such as Parkinson's disease and multiple sclerosis. In the present paper, we demonstrate for the first time that Nurr1 expression levels are upregulated in the peripheral blood of ALS patients. Moreover, we investigated Nurr1 function in the SOD1-G93A mouse model of ALS. Nurr1 was strongly upregulated in the spinal cord during the asymptomatic and early symptomatic phases of the disease, where it promoted the expression of brain-derived neurotrophic factor mRNA and the repression of NFκB pro-inflammatory targets, such as inducible nitric oxide synthase. Therefore, we hypothesize that Nurr1 is activated in an early phase of the disease as a protective endogenous anti-inflammatory mechanism, although not sufficient to reverse disease progression. On the basis of these observations, Nurr1 could represent a potential biomarker for ALS and a promising target for future therapies., Summary: We hypothesize that the transcription factor Nurr1 is activated in the early phase of the neurodegenerative disease amylotrophic lateral sclerosis (ALS), probably as a neuroprotective endogenous mechanism. Nurr1 might represent a promising target for ALS therapy.

Published
2020

27. A20 in Multiple Sclerosis and Parkinson’s Disease: Clue to a Common Dysregulation of Anti-Inflammatory Pathways?

Author

Adriano Chiò, Serena Martire, Antonio Bertolotto, Alberto Marchet, Simona Perga, Andrea Calvo, Francesca Montarolo, Daniela Leotta, Giuseppe Fuda, and Nicole Desiree Navone

Subjects
Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Neurology, Parkinson's disease, medicine.drug_class, Gene Expression, Inflammation, Disease, Toxicology, Anti-inflammatory, Multiple sclerosis, Pathogenesis, 03 medical and health sciences, Alzheimer’s diseases, 0302 clinical medicine, Alzheimer Disease, medicine, Humans, RNA, Messenger, NF-kB, Amyotrophic lateral sclerosis, Tumor Necrosis Factor alpha-Induced Protein 3, Aged, Aged, 80 and over, Neuroscience (all), business.industry, General Neuroscience, Age Factors, Parkinson Disease, Middle Aged, medicine.disease, A20/TNFAIP3, Parkinson diseases, Systemic chronic inflammation, 030104 developmental biology, Italy, Immunology, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Chronic inflammation significantly contributes to the pathogenesis of several neurodegenerative disorders. In physiological conditions, a chronic inflammatory state is prevented through the termination of the acute inflammatory response once the triggering insult is eliminated. Several mechanisms regulate the resolution of inflammation. Among these, a potent inhibitor of the pro-inflammatory NF-kB signaling known as A20 has emerged as a key player. Recent studies have shown reduced blood levels of A20 in the patients of diverse chronic inflammatory diseases. Similar results have also been demonstrated in patients of multiple sclerosis (MS), a neurodegenerative disease characterized by persisting inflammation. In the present study, we investigate whether other similar neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) also demonstrate deregulated levels of A20 expression as compared to healthy controls (HC) and treatment-naive MS patients. Our results confirm previous data that the A20 expression is reduced in whole blood of MS patients as compared to HC. Additionally, we demonstrate that significantly diminished A20 expression is also evident in PD patients. The dysregulation of the A20 pathway could then contribute to the persistence of inflammation in these disorders. It would thus be interesting to investigate further whether such commonly deregulated pathways between different inflammatory diseases could represent novel targets for therapy.

Published
2017

28. Risk Factors Involved in Central-to-Radial Arterial Pressure Gradient During Cardiac Surgery

Author

Pierre Couture, Annik Fortier, André Y. Denault, Denis Bouchard, Alain Deschamps, Giuseppe Fuda, and Jean Lambert

Subjects
Male, medicine.medical_specialty, Vasopressins, Comorbidity, 030204 cardiovascular system & hematology, law.invention, Constriction, Electrocardiography, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Risk Factors, 030202 anesthesiology, law, Internal medicine, medicine.artery, Cardiopulmonary bypass, Humans, Vasoconstrictor Agents, Medicine, Arterial Pressure, Drug Interactions, Prospective Studies, Cardiac Surgical Procedures, Radial artery, Intraoperative Complications, Pressure gradient, Aged, Cardiopulmonary Bypass, medicine.diagnostic_test, business.industry, Middle Aged, Cardiac surgery, surgical procedures, operative, Anesthesiology and Pain Medicine, Blood pressure, Radial Artery, Cardiology, Female, business, circulatory and respiratory physiology
Abstract

A central-to-radial arterial pressure gradient may occur after cardiopulmonary bypass (CPB), which, in some patients, may last for a prolonged time after CPB. Whenever there is a pressure gradient, the radial artery pressure measure may underestimate a more centrally measured systemic pressure, which may result in a misguided therapeutic strategy. It is clinically important to identify the risk factors that may predict the appearance of a central-to-radial pressure gradient, because more central sites of measurements might then be considered to monitor systemic arterial pressure in high-risk patients. The objective of this study was to assess preoperative and intraoperative risk factors for central-to-radial pressure gradient.Seventy-three patients undergoing cardiac surgery using CPB were included in this prospective observational study. A significant central-to-radial arterial pressure gradient was defined as a difference of 25 mm Hg in systolic pressure or 10 mm Hg in mean arterial pressure for a minimum of 5 minutes. Preoperative data included demographics, presence of comorbidities, and medications. Intraoperative data included type of surgery, CPB and aortic clamping time, use of inotropic drugs, and vasodilators or vasopressors agents. The diameter of the radial and femoral artery was measured before the induction of anesthesia using B-mode ultrasonography.Thirty-three patients developed a central-to-radial arterial pressure gradient (45%). Patients with a significant pressure gradient had a smaller weight (71.0 ± 16.9 vs 79.3 ± 17.3 kg, P = 0.041), a smaller height (162.0 ± 9.6 vs 166.3 ± 8.6 cm, P = 0.047), a smaller radial artery diameter (0.24 ± 0.03 vs 0.29 ± 0.05 cm, P0.001), and were at a higher risk as determined by the Parsonnet score (30.3 ± 24.9 vs 17.0 ± 10.9, P = 0.007). In addition, a longer aortic clamping time (85.8 ± 51.0 vs 64.2 ± 29.3 minutes, P = 0.036), mitral and complex surgery (P = 0.007 and P = 0.017, respectively), and administration of vasopressin (P = 0.039) were identified as potential independent predictors of a central-to-radial pressure gradient. By using multivariate logistic regression analysis, the following independent risk factors were identified: Parsonnet score (odds ratio [OR], 1.076; 95% confidence interval [CI], 1.027-1.127, P = 0.002), aortic clamping time90 minutes (OR, 8.521; 95% CI, 1.917-37.870, P = 0.005), and patient height (OR, 0.933, 95% CI, 0.876-0.993, P = 0.029). The relative risk (RR) estimates remained statistically significant for the Parsonnet score and the aortic clamping time ≥90 minutes (RR, 1.010; 95% CI, 1.003-1.018, P = 0.009 and RR, 2.253; 95% CI, 1.475-3.443, P0.001 respectively) while showing a trend for patient height (RR, 0.974; 95% CI, 0.948-1.001, P = 0.058).Central-to-radial gradients are common in cardiac surgery. The threshold for using a central site for blood pressure monitoring should be low in small, high-risk patients undergoing longer surgical interventions to avoid inappropriate administration of vasopressors and/or inotropic agents.

Published
2016

29. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Aude Nicolas, Kevin P. Kenna, Alan E. Renton, Nicola Ticozzi, Faraz Faghri, Ruth Chia, Janice A. Dominov, Brendan J. Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick A. Van der Spek, Hannah A. Pliner, null Shankaracharya, Bradley N. Smith, Giuseppe Marangi, Simon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, Gabriele Mora, Andrea Calvo, Letizia Mazzini, Nilo Riva, Jessica Mandrioli, Claudia Caponnetto, Stefania Battistini, Paolo Volanti, Vincenzo La Bella, Francesca L. Conforti, Giuseppe Borghero, Sonia Messina, Isabella L. Simone, Francesca Trojsi, Fabrizio Salvi, Francesco O. Logullo, Sandra D’Alfonso, Lucia Corrado, Margherita Capasso, Luigi Ferrucci, Cristiane de Araujo Martins Moreno, Sitharthan Kamalakaran, David B. Goldstein, Aaron D. Gitler, Tim Harris, Richard M. Myers, Hemali Phatnani, Rajeeva Lochan Musunuri, Uday Shankar Evani, Avinash Abhyankar, Michael C. Zody, Julia Kaye, Steven Finkbeiner, Stacia K. Wyman, Alex LeNail, Leandro Lima, Ernest Fraenkel, Clive N. Svendsen, Leslie M. Thompson, Jennifer E. Van Eyk, James D. Berry, Timothy M. Miller, Stephen J. Kolb, Merit Cudkowicz, Emily Baxi, Michael Benatar, J. Paul Taylor, Evadnie Rampersaud, Gang Wu, Joanne Wuu, Giuseppe Lauria, Federico Verde, Isabella Fogh, Cinzia Tiloca, Giacomo P. Comi, Gianni Sorarù, Cristina Cereda, Philippe Corcia, Hannu Laaksovirta, Liisa Myllykangas, Lilja Jansson, Miko Valori, John Ealing, Hisham Hamdalla, Sara Rollinson, Stuart Pickering-Brown, Richard W. Orrell, Katie C. Sidle, Andrea Malaspina, John Hardy, Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Peter C. Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, José Luis Muñoz-Blanco, Dena G. Hernandez, Jinhui Ding, J. Raphael Gibbs, Sonja W. Scholz, Mary Kay Floeter, Roy H. Campbell, Francesco Landi, Robert Bowser, Stefan M. Pulst, John M. Ravits, Daniel J.L. MacGowan, Janine Kirby, Erik P. Pioro, Roger Pamphlett, James Broach, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle Le Ber, Kevin Mouzat, Serge Lumbroso, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, Robert H. Baloh, Tim M. Strom, Thomas Meitinger, Aleksey Shatunov, Kristel R. Van Eijk, Mamede de Carvalho, Maarten Kooyman, Bas Middelkoop, Matthieu Moisse, Russell L. McLaughlin, Michael A. Van Es, Markus Weber, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Karen E. Morrison, A. Nazli Basak, Jesús S. Mora, Vivian E. Drory, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Orla Hardiman, Kelly L. Williams, Jennifer A. Fifita, Garth A. Nicholson, Ian P. Blair, Guy A. Rouleau, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Ekaterina Rogaeva, Lorne Zinman, Lyle W. Ostrow, Nicholas J. Maragakis, Jeffrey D. Rothstein, Zachary Simmons, Johnathan Cooper-Knock, Alexis Brice, Stephen A. Goutman, Eva L. Feldman, Summer B. Gibson, Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip Van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, William Camu, John Q. Trojanowski, Vivianna M. Van Deerlin, Robert H. Brown, Leonard H. van den Berg, Jan H. Veldink, Matthew B. Harms, Jonathan D. Glass, David J. Stone, Pentti Tienari, Vincenzo Silani, Adriano Chiò, Christopher E. Shaw, Bryan J. Traynor, John E. Landers, Isabella Simone, Giancarlo Logroscino, Ilaria Bartolomei, Maria Rita Murru, Emanuela Costantino, Carla Pani, Roberta Puddu, Carla Caredda, Valeria Piras, Stefania Tranquilli, Stefania Cuccu, Daniela Corongiu, Maurizio Melis, Antonio Milia, Francesco Marrosu, Maria Giovanna Marrosu, Gianluca Floris, Antonino Cannas, Gianluigi Mancardi, Paola Origone, Paola Mandich, Sebastiano Cavallaro, Kalliopi Marinou, Riccardo Sideri, Silvana Penco, Lorena Mosca, Giuseppe Lauria Pinter, Massimo Corbo, Paola Carrera, Nicola Fini, Antonio Fasano, Lucio Tremolizzo, Alessandro Arosio, Carlo Ferrarese, Gioacchino Tedeschi, Maria Rosaria Monsurrò, Giovanni Piccirillo, Cinzia Femiano, Anna Ticca, Enzo Ortu, Rossella Spataro, Tiziana Colletti, Marcella Zollino, Amelia Conte, Marco Luigetti, Serena Lattante, Marialuisa Santarelli, Antonio Petrucci, Maura Pugliatti, Angelo Pirisi, Leslie D. Parish, Patrizia Occhineri, Fabio Giannini, Claudia Ricci, Michele Benigni, Tea B. Cau, Daniela Loi, Cristina Moglia, Maura Brunetti, Marco Barberis, Gabriella Restagno, Federico Casale, Giuseppe Marrali, Giuseppe Fuda, Irene Ossola, Stefania Cammarosano, Antonio Canosa, Antonio Ilardi, Umberto Manera, Maurizio Grassano, Raffaella Tanel, Fabrizio Pisano, Neil A. Shneider, Stephen Goutman, Siddharthan Chandran, Suvankar Pal, George Manousakis, Stanley H. Appel, Ericka Simpson, Leo Wang, Summer Gibson, Richard Bedlack, David Lacomis, Dhruv Sareen, Alexander Sherman, Lucie Bruijn, Michelle Penny, Andrew S. Allen, Stanley Appel, Richard S. Bedlack, Braden E. Boone, Robert Brown, John P. Carulli, Alessandra Chesi, Wendy K. Chung, Elizabeth T. Cirulli, Gregory M. Cooper, Julien Couthouis, Aaron G. Day-Williams, Patrick A. Dion, Yujun Han, Sebastian D. Hayes, Angela L. Jones, Jonathan Keebler, Brian J. Krueger, Brittany N. Lasseigne, Shawn E. Levy, Yi-Fan Lu, Tom Maniatis, Slavé Petrovski, Alya R. Raphael, Zhong Ren, Katherine B. Sims, John F. Staropoli, Lindsay L. Waite, Quanli Wang, Jack R. Wimbish, Winnie W. Xin, Justin Kwan, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Noah Zaitlen, Gregory A. Cox, Steve Finkbeiner, Efthimios Dardiotis, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos A. Patsopoulos, Joshua Dubnau, Avindra Nath, Stacia Wyman, Alexander LeNail, Jenny Van Eyk, Stephan Züchner, Rebecca Schule, Jacob McCauley, Sumaira Hussain, Anne Cooley, Marielle Wallace, Christine Clayman, Richard Barohn, Jeffrey Statland, John Ravits, Andrea Swenson, Carlayne Jackson, Jaya Trivedi, Shaida Khan, Jonathan Katz, Liberty Jenkins, Ted Burns, Kelly Gwathmey, James Caress, Corey McMillan, Lauren Elman, Erik Pioro, Jeannine Heckmann, Yuen So, David Walk, Samuel Maiser, Jinghui Zhang, Fabiola De Marchi, Stefania Corti, Mauro Ceroni, Gabriele Siciliano, Massimiliano Filosto, Maurizio Inghilleri, Silvia Peverelli, Claudia Colombrita, Barbara Poletti, Luca Maderna, Roberto Del Bo, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Viviana Pensato, Barbara Castellotti, Vincent Meininger, Gérard Besson, Emmeline Lagrange, Pierre Clavelou, Nathalie Guy, Philippe Couratier, Patrick Vourch, Véronique Danel, Emilien Bernard, Gwendal Lemasson, Ahmad Al Kheifat, Peter Andersen, Adriano Chio, Jonathan Cooper-Knock, Annelot Dekker, Vivian Drory, Alberto Garcia Redondo, Marc Gotkine, Winston Hide, Alfredo Iacoangeli, Jonathan Glass, Kevin Kenna, Matthew Kiernan, John Landers, Russell McLaughlin, Jonathan Mill, Miguel Mitne Neto, Mattieu Moisse, Jesus Mora Pardina, Karen Morrison, Stephen Newhouse, Susana Pinto, Sara Pulit, Pamela Shaw, Chris Shaw, William Sproviero, Gijs Tazelaar, Philip van Damme, Leonard van den Berg, Rick van der Spek, Kristel van Eijk, Michael van Es, Joke van Vugt, Jan Veldink, Mayana Zatz, Denis C. Bauer, Natalie A. Twine, Department of Neurosciences, Pentti Tienari / Principal Investigator, Neurologian yksikkö, Research Programs Unit, Clinicum, Research Programme for Molecular Neurology, University of Helsinki, Medicum, Department of Pathology, HUS Neurocenter, Nicolas A., Kenna K.P., Renton A.E., Ticozzi N., Faghri F., Chia R., Dominov J.A., Kenna B.J., Nalls M.A., Keagle P., Rivera A.M., van Rheenen W., Murphy N.A., van Vugt J.J.F.A., Geiger J.T., Van der Spek R.A., Pliner H.A., Shankaracharya, Smith B.N., Marangi G., Topp S.D., Abramzon Y., Gkazi A.S., Eicher J.D., Kenna A., Logullo F.O., Simone I.L., Logroscino G., Salvi F., Bartolomei I., Borghero G., Murru M.R., Costantino E., Pani C., Puddu R., Caredda C., Piras V., Tranquilli S., Cuccu S., Corongiu D., Melis M., Milia A., Marrosu F., Marrosu M.G., Floris G., Cannas A., Capasso M., Caponnetto C., Mancardi G., Origone P., Mandich P., Conforti F.L., Cavallaro S., Mora G., Marinou K., Sideri R., Penco S., Mosca L., Lunetta C., Pinter G.L., Corbo M., Riva N., Carrera P., Volanti P., Mandrioli J., Fini N., Fasano A., Tremolizzo L., Arosio A., Ferrarese C., Trojsi F., Tedeschi G., Monsurro M.R., Piccirillo G., Femiano C., Ticca A., Ortu E., La Bella V., Spataro R., Colletti T., Sabatelli M., Zollino M., Conte A., Luigetti M., Lattante S., Santarelli M., Petrucci A., Pugliatti M., Pirisi A., Parish L.D., Occhineri P., Giannini F., Battistini S., Ricci C., Benigni M., Cau T.B., Loi D., Calvo A., Moglia C., Brunetti M., Barberis M., Restagno G., Casale F., Marrali G., Fuda G., Ossola I., Cammarosano S., Canosa A., Ilardi A., Manera U., Grassano M., Tanel R., Pisano F., Mazzini L., Messina S., D'Alfonso S., Corrado L., Ferrucci L., Harms M.B., Goldstein D.B., Shneider N.A., Goutman S.A., Simmons Z., Miller T.M., Chandran S., Pal S., Manousakis G., Appel S.H., Simpson E., Wang L., Baloh R.H., Gibson S.B., Bedlack R., Lacomis D., Sareen D., Sherman A., Bruijn L., Penny M., Moreno C.D.A.M., Kamalakaran S., Allen A.S., Boone B.E., Brown R.H., Carulli J.P., Chesi A., Chung W.K., Cirulli E.T., Cooper G.M., Couthouis J., Day-Williams A.G., Dion P.A., Gitler A.D., Glass J.D., Han Y., Harris T., Hayes S.D., Jones A.L., Keebler J., Krueger B.J., Lasseigne B.N., Levy S.E., Lu Y.-F., Maniatis T., McKenna-Yasek D., Myers R.M., Petrovski S., Pulst S.M., Raphael A.R., Ravits J.M., Ren Z., Rouleau G.A., Sapp P.C., Sims K.B., Staropoli J.F., Waite L.L., Wang Q., Wimbish J.R., Xin W.W., Phatnani H., Kwan J., Broach J., Arcila-Londono X., Lee E.B., Van Deerlin V.M., Fraenkel E., Ostrow L.W., Baas F., Zaitlen N., Berry J.D., Malaspina A., Fratta P., Cox G.A., Thompson L.M., Finkbeiner S., Dardiotis E., Hornstein E., MacGowan D.J.L., Heiman-Patterson T., Hammell M.G., Patsopoulos N.A., Dubnau J., Nath A., Musunuri R.L., Evani U.S., Abhyankar A., Zody M.C., Kaye J., Wyman S.K., LeNail A., Lima L., Rothstein J.D., Svendsen C.N., Van Eyk J.E., Maragakis N.J., Kolb S.J., Cudkowicz M., Baxi E., Benatar M., Taylor J.P., Wu G., Rampersaud E., Wuu J., Rademakers R., Zuchner S., Schule R., McCauley J., Hussain S., Cooley A., Wallace M., Clayman C., Barohn R., Statland J., Swenson A., Jackson C., Trivedi J., Khan S., Katz J., Jenkins L., Burns T., Gwathmey K., Caress J., McMillan C., Elman L., Pioro E.P., Heckmann J., So Y., Walk D., Maiser S., Zhang J., Silani V., Gellera C., Ratti A., Taroni F., Lauria G., Verde F., Fogh I., Tiloca C., Comi G.P., Soraru G., Cereda C., De Marchi F., Corti S., Ceroni M., Siciliano G., Filosto M., Inghilleri M., Peverelli S., Colombrita C., Poletti B., Maderna L., Del Bo R., Gagliardi S., Querin G., Bertolin C., Pensato V., Castellotti B., Camu W., Mouzat K., Lumbroso S., Corcia P., Meininger V., Besson G., Lagrange E., Clavelou P., Guy N., Couratier P., Vourch P., Danel V., Bernard E., Lemasson G., Laaksovirta H., Myllykangas L., Jansson L., Valori M., Ealing J., Hamdalla H., Rollinson S., Pickering-Brown S., Orrell R.W., Sidle K.C., Hardy J., Singleton A.B., Johnson J.O., Arepalli S., Polak M., Asress S., Al-Sarraj S., King A., Troakes C., Vance C., de Belleroche J., ten Asbroek A.L.M.A., Munoz-Blanco J.L., Hernandez D.G., Ding J., Gibbs J.R., Scholz S.W., Floeter M.K., Campbell R.H., Landi F., Bowser R., Kirby J., Pamphlett R., Gerhard G., Dunckley T.L., Brady C.B., Kowall N.W., Troncoso J.C., Le Ber I., Heiman-Patterson T.D., Kamel F., Van Den Bosch L., Strom T.M., Meitinger T., Shatunov A., Van Eijk K.R., de Carvalho M., Kooyman M., Middelkoop B., Moisse M., McLaughlin R.L., Van Es M.A., Weber M., Boylan K.B., Van Blitterswijk M., Morrison K.E., Basak A.N., Mora J.S., Drory V.E., Shaw P.J., Turner M.R., Talbot K., Hardiman O., Williams K.L., Fifita J.A., Nicholson G.A., Blair I.P., Esteban-Perez J., Garcia-Redondo A., Al-Chalabi A., Al Kheifat A., Andersen P.M., Chio A., Cooper-Knock J., Dekker A., Redondo A.G., Gotkine M., Hide W., Iacoangeli A., Kiernan M., Landers J.E., Mill J., Neto M.M., Pardina J.M., Newhouse S., Pinto S., Pulit S., Robberecht W., Shaw C., Sproviero W., Tazelaar G., Van Damme P., van den Berg L.H., van Vugt J., Veldink J.H., Zatz M., Bauer D.C., Twine N.A., Rogaeva E., Zinman L., Brice A., Feldman E.L., Ludolph A.C., Weishaupt J.H., Trojanowski J.Q., Stone D.J., Tienari P., Shaw C.E., Traynor B.J., ITALSGEN Consortium, Genomic Translation ALS Care GTAC, ALS Sequencing Consortium, NYGC ALS Consortium, Answer ALS Fdn, Clinical Res ALS Related Disorders, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consor, Medical Research Council (MRC), ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Università cattolica del Sacro Cuore [Roma] (Unicatt), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Lunar and Planetary Laboratory [Tucson] (LPL), University of Arizona, Università degli studi di Torino (UNITO), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), New York Genome Center [New York], New York Genome Center, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), St Jude Children's Research Hospital, Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University College of London [London] (UCL), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), King‘s College London, University of New Haven [Connecticut], Princeton University, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), University Medical Center [Utrecht], Deutsches Forschungszentrum für Künstliche Intelligenz GmbH = German Research Center for Artificial Intelligence (DFKI), Mayo Clinic [Jacksonville], Trinity College Dublin, Maurice Wohl Clinical Neuroscience Institut, Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Repositório da Universidade de Lisboa, Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke J F A, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Null, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Logullo, Fo, Murru, Mr, Marrosu, Mg, Conforti, Fl, Pinter, Gl, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Parish, Ld, Cau, Tb, Moreno, Cristiane de Araujo Martin, Kamalakaran, Sitharthan, Goldstein, David B, Gitler, Aaron D, Harris, Tim, Myers, Richard M, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, Lenail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W, Sidle, Katie C, Malaspina, Andrea, Hardy, John, Singleton, Andrew B, Johnson, Janel O, Arepalli, Sampath, Sapp, Peter C, McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, Ten Asbroek, Anneloor L M A, Muñoz-Blanco, José Lui, Hernandez, Dena G, Ding, Jinhui, Gibbs, J Raphael, Scholz, Sonja W, Floeter, Mary Kay, Campbell, Roy H, Landi, Francesco, Bowser, Robert, Pulst, Stefan M, Ravits, John M, Macgowan, Daniel J L, Kirby, Janine, Pioro, Erik P, Pamphlett, Roger, Broach, Jame, Gerhard, Glenn, Dunckley, Travis L, Brady, Christopher B, Kowall, Neil W, Troncoso, Juan C, Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D, Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H, Strom, Tim M, Meitinger, Thoma, Shatunov, Aleksey, Van Eijk, Kristel R, de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Ba, Moisse, Matthieu, Mclaughlin, Russell L, Van Es, Michael A, Weber, Marku, Boylan, Kevin B, Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E, Basak, A Nazli, Mora, Jesús S, Drory, Vivian E, Shaw, Pamela J, Turner, Martin R, Talbot, Kevin, Hardiman, Orla, Williams, Kelly L, Fifita, Jennifer A, Nicholson, Garth A, Blair, Ian P, Rouleau, Guy A, Esteban-Pérez, Jesú, García-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W, Maragakis, Nicholas J, Rothstein, Jeffrey D, Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexi, Goutman, Stephen A, Feldman, Eva L, Gibson, Summer B, Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C, Andersen, Peter M, Weishaupt, Jochen H, Camu, William, Trojanowski, John Q, Van Deerlin, Vivianna M, Brown, Robert H, van den Berg, Leonard H, Veldink, Jan H, Harms, Matthew B, Glass, Jonathan D, Stone, David J, Tienari, Pentti, Silani, Vincenzo, Chiò, Adriano, Shaw, Christopher E, Traynor, Bryan J, Landers, John E, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Male, Als gene, Genome-wide association study, FAMILIAL ALS, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, 0302 clinical medicine, 80 and over, Psychology, Aetiology, Aged, 80 and over, 0303 health sciences, French ALS Consortium, Kinesin, KINESIN HEAVY-CHAIN, Cognitive Sciences, Human, Hereditary spastic paraplegia, Neuroscience(all), Single-nucleotide polymorphism, TARGETED DISRUPTION, Article, 03 medical and health sciences, Genetics, Humans, Amino Acid Sequence, Loss function, Aged, HEXANUCLEOTIDE REPEAT, Neuroscience (all), MUTATIONS, Amyotrophic Lateral Sclerosis, 3112 Neurosciences, 1702 Cognitive Science, medicine.disease, ITALSGEN Consortium, Answer ALS Foundation, 030104 developmental biology, ALS Sequencing Consortium, Human medicine, 1109 Neurosciences, 030217 neurology & neurosurgery, 0301 basic medicine, [SDV]Life Sciences [q-bio], Kinesins, Neurodegenerative, Genetic analysis, Genome, AMYOTROPHIC-LATERAL-SCLEROSIS, 3124 Neurology and psychiatry, Cohort Studies, Pathogenesis, Loss of Function Mutation, Missense mutation, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, NYGC ALS Consortium, General Neuroscience, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, Middle Aged, Phenotype, Settore MED/26 - NEUROLOGIA, Neurological, Project MinE ALS Sequencing Consortium, Female, Adult, Biology, GENOTYPE IMPUTATION, Genome-Wide Association Study, Young Adult, NO, Rare Diseases, medicine, SLAGEN Consortium, Gene, 030304 developmental biology, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Neurology & Neurosurgery, Human Genome, Neurosciences, AXONAL-TRANSPORT, Brain Disorders, Family member, DNA-DAMAGE, MOTOR-NEURONS, 3111 Biomedicine, Cohort Studie, Genomic Translation for ALS Care (GTAC) Consortium, Amyotrophic Lateral Sclerosi
Abstract

© 2018 Elsevier Inc., 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.

Published
2018

30. NADPH oxidases 2 activation in patients with Parkinson's disease

Author

Umberto Manera, Antonio Ilardi, Leonardo Lopiano, Paolina Salamone, Maurizio Zibetti, Giuseppe Fuda, Andrea Calvo, Giuseppe Marrali, Adriano Chiò, and Federico Casale

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Parkinson's disease, Neurology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, NOX2, Neuroinflammation, medicine, Humans, In patient, Aged, business.industry, Parkinson Disease, Middle Aged, medicine.disease, 030104 developmental biology, Oxidative stress, Immunology, NADPH Oxidase 2, Geriatrics and Gerontology, Neurology (clinical), Female, business, 030217 neurology & neurosurgery
Published
2018

31. Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis

Author

Giuseppe Fuda, Paolo Messina, Ettore Beghi, Massimiliano Filosto, Massimo Corbo, Mauro Pignataro, Valentina Bonetto, Caterina Bendotti, Laura Pasetto, Silvia Luotti, Adriano Chiò, Jessica Mandrioli, Melania Filareti, Christian Lunetta, Elisabetta Pupillo, Katia Paolella, and Andrea Calvo

Subjects
0301 basic medicine, Chaperone, Disease, Peripheral blood mononuclear cell, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Biomarkers, Foldase, Protein folding, Response to stress, Heat shock protein, medicine, Amyotrophic lateral sclerosis, Molecular Biology, Original Research, biology, medicine.disease, Phenotype, 030104 developmental biology, Proteostasis, Chaperone (protein), Immunology, biology.protein, Age of onset, 030217 neurology & neurosurgery, Neuroscience
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.

Published
2017
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32. Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis : a randomised, double-blind, placebo-controlled, phase 2 trial

Author

Stephen DeWall, Karen E. Morrison, Alain Destée, Andrea Calvo, Annelot M. Dekker, Francesca Barbieri, Philip Van Damme, James D. Berry, Robert D. Henderson, Claude Desnuelle, Johannes Dorst, Linda O. Nichols, Jerzy Daniluk, Sonja Koerner, Adriano Chiò, Kristiana Salmon, Pierre-François Pradat, Albert C. Ludolph, Genevieve Matte, Harutoshi Fujimura, Gaëlle Bruneteau, Stewart Bates, Giuseppe Fuda, Torsten Grehl, Usha Gungabissoon, Andrea Sylvia Winkler, Byung Jo Kim, Eleanor Ramsey, Christen Shoesmith, Peggy Ho, Matthew C. Kiernan, Rodrigo Refoios Camejo, Saiju Jacob, Rob Stubbs, Thomas M. Ringer, Jonathan Bullman, Stephan A Botez, Michael A. van Es, Xenia Kobeleva, Stefano Milleri, Wim Robberecht, William Huynh, Mary Lou Watson, Mieko Ogino, Seung Hyun Kim, Chris Parkinson, Diane Boswell, Stephen J. Kolb, Jeremy M. Shefner, Katja Kollewe, Jane R. Temple, Paul Rees, Julian Grosskreutz, Deven Chauhan, K. Nishiyama, Leonard H. van den Berg, Marloes Stam, Susanne Petri, Rami Massie, Darryl Menezes, Tino Prell, Anthony Lynch, Raul Juntas-Morales, Andreas Funke, P. Nigel Leigh, Lawrence Korngut, Angela Genge, Cathy Alsop, Margie C. Zoing, Arseniy Lavrov, Rajat Mohindra, Anne E. Visser, Susanne Abdulla, Veronique Danel-Brunaud, William Camu, Matt Davies, Amy Lee, Erik Steinberg, Lorne Zinman, Jeffrey Price, Marie Helene Soriani, Matthew S Devine, Vincent Meininger, Géraldine Lautrette, Herman Sullivan, Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], University Medical Center [Utrecht], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Universität Ulm - Ulm University [Ulm, Allemagne], Università degli studi di Torino (UNITO), Brighton and Sussex Medical School (BSMS), The University of Sydney, Barrow Neurological Institute, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), University of Birmingham [Birmingham], University of Southampton, Hannover Medical School [Hannover] (MHH), GlaxoSmithKline, Glaxo Smith Kline, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de Neurologie [CHU Limoges], CHU Limoges, McGill University, and Université Côte d'Azur (UCA)

Subjects
0301 basic medicine, Male, International Cooperation, law.invention, Clinical Trial, Phase II, Electrocardiography, 0302 clinical medicine, Randomized controlled trial, law, Medicine, Depression (differential diagnoses), Aged, 80 and over, Age Factors, Middle Aged, Clinical Trial, Phase II, 3. Good health, Multicenter Study, Treatment Outcome, RC0346, Randomized Controlled Trial, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, psychological phenomena and processes, Adult, medicine.medical_specialty, Adolescent, Nogo Proteins, Placebo, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Young Adult, Double-Blind Method, Internal medicine, mental disorders, Journal Article, Humans, Immunologic Factors, Adverse effect, Aged, business.industry, Ozanezumab, Amyotrophic Lateral Sclerosis, Survival Analysis, Surgery, Discontinuation, Clinical trial, 030104 developmental biology, Respiratory failure, Neurology (clinical), business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Summary Background Neurite outgrowth inhibitor A (Nogo-A) is thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). A monoclonal antibody against Nogo-A showed a positive effect in the SOD1 G93A mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. Therefore, we aimed to assess the safety and efficacy of ozanezumab in patients with ALS. Methods This randomised, double-blind, placebo-controlled, phase 2 trial was done in 34 centres in 11 countries. Patients aged 18–80 years with a diagnosis of familial or sporadic ALS were randomly assigned (1:1), centrally according to a computer-generated allocation schedule, to receive ozanezumab (15 mg/kg) or placebo as intravenous infusions over 1 h every 2 weeks for 46 weeks, followed by assessments at week 48 and week 60. Patients and study personnel were masked to treatment assignment. The primary outcome was a joint-rank analysis of function (ALS Functional Rating Scale-Revised) and overall survival, analysed at 48 weeks in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01753076, and with GSK-ClinicalStudyRegister.com, NOG112264, and is completed. Findings Between Dec 20, 2012, and Nov 1, 2013, we recruited 307 patients, of whom 303 were randomly assigned to receive placebo (n=151) or ozanezumab (n=152). The adjusted mean of the joint-rank score was −14·9 (SE 13·5) for the ozanezumab group and 15·0 (13·6) for the placebo group, with a least squares mean difference of −30·0 (95% CI −67·9 to 7·9; p=0·12). Overall, reported adverse events, serious adverse events, and adverse events leading to permanent discontinuation of study drug or withdrawal from study were similar between the treatment groups, except for dyspepsia (ten [7%] in the ozanezumab group vs four [3%] in the placebo group), depression (11 [7%] vs five [3%]), and diarrhoea (25 [16%] vs 12 [8%]). Respiratory failure was the most common serious adverse event (12 [8%] vs seven [5%]). At week 60, the number of deaths was higher in the ozanezumab group (20 [13%]) than in the placebo group (16 [11%]), mainly as a result of respiratory failure (ten [7%] vs five [3%]). Two deaths were considered related to the study drug (bladder transitional cell carcinoma in the ozanezumab group and cerebrovascular accident in the placebo group). Interpretation Ozanezumab did not show efficacy compared with placebo in patients with ALS. Therefore, Nogo-A does not seem to be an effective therapeutic target in ALS. Funding GlaxoSmithKline.

Published
2017

33. NADPH oxidase 2 (NOX2) enzyme activation in patients with chronic inflammatory demyelinating polyneuropathy

Author

Dario Cocito, Cristiana Caorsi, Paolina Salamone, Federico Casale, Leonardo Lopiano, Antonio Amoroso, Adriano Chiò, Giuseppe Fuda, Giuseppe Marrali, Paolo Cugnasco, and Andrea Calvo

Subjects
0301 basic medicine, Adult, Male, Chronic inflammatory demyelinating polyneuropathy, CIDP, Granulocyte, Pharmacology, medicine.disease_cause, Monocytes, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Neuroinflammation, Medicine, Humans, Whole blood, Aged, NADPH oxidase, biology, business.industry, Monocyte, Immunoglobulins, Intravenous, ROS, Middle Aged, medicine.disease, 3. Good health, Respiratory burst, Enzyme Activation, Inflammatory disease, 030104 developmental biology, medicine.anatomical_structure, chemistry, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating, Neurology, NADPH oxidases, Oxidative stress, Neurology (clinical), Immunology, biology.protein, Female, business, Reactive Oxygen Species, 030217 neurology & neurosurgery, Nicotinamide adenine dinucleotide phosphate
Abstract

Background and purpose Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immunomediated condition affecting the peripheral nervous system where probably macrophages are the primary effector cells for demyelination. Reactive oxygen species (ROS), catalyzed by the NOX family of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzymes, can induce peroxidation and are potentially injurious to myelin. Our aim was to assess the activity of NOX2, an isoform of NOX, in a series of CIDP patients and to analyze the effect of intravenous immunoglobulin (IVIg) on NOX2. Methods Thirty CIDP patients treated with IVIg and 30 control subjects were enrolled. To evaluate NOX2 activity, neutrophil and monocyte oxidative burst was measured directly in fresh whole blood using the Phagoburst™ assay, a fluorescence-activated cell sorting method. The mean fluorescence intensity, emitted in response to different stimuli, leads to the production of ROS and corresponds to the percentage of oxidizing cells and their enzymatic activity. Results Mean fluorescence intensity values for granulocyte and monocyte burst in patients (mean 633.3, SD 191; mean 111.8, SD 28.5) were different from those measured in healthy controls (granulocytes, mean 436.6, SD 137.0, P = 0.0003; monocytes, mean 78.2, SD 17.3, P = 0.000001). Moreover, IVIg administration increased both granulocyte (P = 0.005) and monocyte (P = 0.0009) burst. Conclusion Our findings demonstrate that oxidative burst is significantly increased in CIDP patients and that treatment with IVIg enhances oxidative values, thus representing a possible IVIg therapeutic effect linked to a regulatory effect of ROS. Based on this, the development of treatments targeting the specific activation of NOX may be beneficial in autoimmune disorders.

Published
2016

34. Persistent idiopathic hypoglossal nerve palsy: A motor neuron disease-mimic syndrome?

Author

Adriano Chiò, Umberto Manera, Antonio Canosa, Cristina Moglia, Stefania Cammarosano, Giuseppe Fuda, Davide Bertuzzo, Andrea Calvo, Antonio Ilardi, Ilardi, A, Moglia, C, Cammarosano, S, Canosa, A, Bertuzzo, D, Manera, U, Fuda, G, Chiò, A, and Calvo, A.

Subjects
Male, Hypoglossal Nerve Palsy, Adolescent, Unknown aetiology, business.industry, ALS mimic syndrome, Disease, Anatomy, Hypoglossal Nerve Diseases, Motor neuron, medicine.disease, Skull, medicine.anatomical_structure, Neurology, medicine, Humans, Settore MED/26 - Neurologia, Neurology (clinical), Motor Neuron Disease, Amyotrophic lateral sclerosis, business
Abstract

Unilateral isolated hypoglossal nerve palsy (IHNP) is a condition (1–7) usually symptomatic of a pathology of the skull base (6,8). In rare cases, IHNP remains of unknown aetiology and is classifie...

Published
2015

35. NADPH oxidase (NOX2) activity is a modifier of survival in ALS

Author

Marco Barberis, Federico Casale, Cristiana Caorsi, Gabriella Restagno, Davide Bertuzzo, Maura Brunetti, Antonio Amoroso, Adriano Chiò, Cristina Moglia, Giuseppe Marrali, Andrea Calvo, Paolina Salamone, Antonio Canosa, and Giuseppe Fuda

Subjects
Genetically modified mouse, Male, medicine.medical_specialty, Pathology, SOD1, Flow cytometry, Internal medicine, medicine, Humans, Amyotrophic lateral sclerosis, Aged, chemistry.chemical_classification, Reactive oxygen species, NADPH oxidase, Membrane Glycoproteins, biology, medicine.diagnostic_test, Chemistry, Amyotrophic Lateral Sclerosis, NADPH Oxidases, Middle Aged, medicine.disease, Respiratory burst, Enzyme Activation, Survival Rate, Endocrinology, Enzyme, Neurology, NADPH Oxidase 2, cardiovascular system, biology.protein, Female, Neurology (clinical), circulatory and respiratory physiology
Abstract

NADPH-oxidases (NOX) catalyze the formation of reactive oxygen species (ROS), which play a role in the development of neurological diseases, particularly those generated by the phagocytic isoform NOX2. Increased ROS has been observed in the amyotrophic lateral sclerosis (ALS) SOD1 transgenic mouse, and in this preclinical model the inactivation of NOX2 decreases ROS production and extends survival. Our aim was to evaluate NOX2 activity measuring neutrophil oxidative burst in a cohort of 83 ALS patients, and age- and gender-matched healthy controls. Oxidative burst was measured directly in fresh blood using Phagoburst™ assay by flow cytometry. Mean fluorescence intensity (MFI), emitted in response to different stimuli, leads to produce ROS and corresponds to the percentage of oxidizing cells and their enzymatic activity (GeoMean). No difference was found between the MFI values in cases and controls. NOX2 activity was independent from gender and age, and in patients was not related to disease duration, site of onset (bulbar vs. spinal), or ALSFRS-R score. However, patients with a NOX2 activity lower than the median value showed a 1-year increase of survival from onset (p = 0.011). The effect of NOX2 was independent from other known prognostic factors. These findings are in keeping with the observations in the mouse model of ALS, and demonstrate the strong role of NOX2 in modifying progression in ALS patients. A proper modulation of NOX2 activity might hold therapeutic potential for ALS.

Published
2014

36. UNC13A influences survival in Italian amyotrophic lateral sclerosis patients: a population-based study

Author

Antonio Canosa, Irene Ossola, Gabriele Mora, Maura Brunetti, Bryan J. Traynor, Gabriella Restagno, Marco Barberis, Umberto Manera, Cristina Moglia, Giuseppe Fuda, Luigi Ferrucci, Adriano Chiò, and Andrea Calvo

Subjects
Oncology, Aging, medicine.medical_specialty, Pathology, Population, 03 medical and health sciences, 0302 clinical medicine, UNC13A, prognositc factor, Interquartile range, Internal medicine, Genotype, medicine, Amyotrophic lateral sclerosis, Risk factor, education, 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, General Neuroscience, medicine.disease, Minor allele frequency, Cohort, Neurology (clinical), Geriatrics and Gerontology, Age of onset, business, 030217 neurology & neurosurgery, Developmental Biology
Abstract

The common variant rs12608932, located within an intron of UNC13A gene on chromosome 19p13.3, has been suggested to influence susceptibility to amyotrophic lateral sclerosis (ALS), as well as survival, in patients of north European descent. To examine this possibility further, we evaluated the association of rs12608932 with susceptibility and survival in a population-based cohort of 500 Italian ALS patients and 1457 Italian control samples. Although rs12608932 was not associated with ALS susceptibility in our series (p = 0.124), it was significantly associated with survival under the recessive model (median survival for AA/AC genotypes = 3.5 years [interquartile range, 2.2-6.4]; CC = 2.5 years [interquartile range, 1.6-4.2]; p = 0.017). Furthermore, rs12608932 genotype remained an independent prognostic factor in Cox multivariable analysis adjusting for other factors known to influence survival (p = 0.023). Overall, minor allele carrier status of rs12608932 was strongly associated with an approximate 1-year reduction of survival in ALS patients, making it a significant determinant of phenotype variation. The identification of UNC13A as a modifier of prognosis among sporadic ALS patients potentially provides a new therapeutic target aimed at slowing disease progression.

Published
2012

37. Risk factor for central to radial pressure gradient in cardiac surgery

Author

Jean Lambert, Alain Deschamps, Giuseppe Fuda, Antonio Su, André Y. Denault, and Denis Bouchard

Subjects
Radial pressure, medicine.medical_specialty, Anesthesiology and Pain Medicine, business.industry, Pain medicine, Anesthesia, Anesthesiology, Medicine, General Medicine, Risk factor, business, Cardiac surgery
Published
2008

38. C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population

Author

Mario, Sabatellia, Francesca Luisa Conforti, Marcella, Zollinoc, Gabriele, Morad, Maria Rosaria Monsurrò, Paolo, Volanti, Kalliopi, Marinoud, Fabrizio, Salvig, Massimo, Corbo, Fabio, Giannini, Stefania, Battistini, Silvana, Penco, Christian, Lunetta, Aldo, Quattrone, Antonio, Gambardella, Giancarlo, Logroscino, Isabella, Simone, Ilaria, Bartolomei, Fabrizio, Pisano, Gioacchino, Tedeschi, Amelia, Conte, Rossella, Spataro, Vincenzo La Bella, Claudia, Caponnetto, Gianluigi, Mancardi, Paola, Mandich, Patrizia, Sola, Jessica, Mandrioli, Renton, Alan E., Elisa, Majounie, Yevgeniya, Abramzon, Francesco, Marrosu, Maria Giovanna Marrosu, Maria Rita Murru, Maria Alessandra Sotgiu, Maura, Pugliatti, Rodolico, Carmelo, the ITALSGEN Consortium: Stefania Cammarosano, Giuseppe, Fuda, Antonio, Canosa, Sara, Gallo, Laura, Papetti, Giuseppe Lauria Pinter, Marco, Luigetti, Serena, Lattante, Giuseppe, Marangi, Tiziana, Colletti, Claudia, Ricci, Paola, Origone, Gianluca, Floris, Antonino, Cannas, Valeria, Piras, Emanuela, Costantino, Carla, Pani, Parish, Leslie D., Paola, Cossu, Giuliana, Solinas, Lucia, Ulgheri, Anna, Ticca, Francesco, Izzo, Anna, Laiola, Francesca, Trojsi, Portaro, Simona, William, Sproviero, Cristina, Moglia, Andrea, Calvo, Irene, Ossola, Maura, Brunetti, Traynor, Bryan J., Giuseppe, Borghero, Gabriella, Restagno, Adriano, Chiò, Sabatelli, M, Conforti, Fl, Zollino, M, Mora, G, Monsurro', Maria Rosaria, 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, Gioacchino, 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: Cammarosano, Stefania, Fuda, Giuseppe, Canosa, Antonio, Gallo, Sara, Papetti, Laura, Lauria Pinter, Giuseppe, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Colletti, Tiziana, Ricci, Claudia, Origone, Paola, Floris, Gianluca, Cannas, Antonino, Piras, Valeria, Costantino, Emanuela, Pani, Carla, Parish, Leslie D, Cossu, Paola, Solinas, Giuliana, Lucia, U. l. g. h. e. r. i., Ticca, Anna, Izzo, Francesco, Laiola, Anna, Trojsi, Francesca, Portaro, Simona, Sproviero, William, Moglia, C, Calvo, A, Ossola, I, Brunetti, M, Traynor, Bj, Borghero, G, Restagno, G, Chiò, A., Sabatelli, M., Conforti, F., Zollino, M., Mora, G., Monsurrò, M., 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, A., Majounie, E., Abramzon, Y., Marrosu, F., Marrosu, M., Murru, M., Sotgiu, M., Pugliatti, M., Rodolico, C., Italsgen, C., Moglia, C., Calvo, A., Ossola, I., Brunetti, M., Traynor, B., Borghero, G., and Restagno, G.

Subjects
Male, Aging, Survival, Pedigree chart, Settore MED/03 - GENETICA MEDICA, Repetitive Sequences, 0302 clinical medicine, C9orf72, Polymorphism (computer science), Risk Factors, Prevalence, Amyotrophic lateral sclerosis, Genetics, 0303 health sciences, education.field_of_study, General Neuroscience, Single Nucleotide, Middle Aged, 3. Good health, Settore MED/26 - NEUROLOGIA, Italy, Female, Settore MED/26 - Neurologia, Frontotemporal dementia, Genetic Markers, Population, C9ORF72, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Polymorphism, education, amyotrophic lateral sclerosis, C9orf672, frontotemporal dementia, survival, Amyotrophic lateral sclerosi, 030304 developmental biology, Repetitive Sequences, Nucleic Acid, sporadic, C9orf72 Protein, Nucleic Acid, Amyotrophic lateral sclerosis, C9ORF72, Frontotemporal dementia, Survival, Genetic Variation, Proteins, medicine.disease, Settore BIO/18 - Genetica, Neurology (clinical), Geriatrics and Gerontology, ALS, Trinucleotide repeat expansion, 030217 neurology & neurosurgery, Developmental Biology
Abstract

It has been recently reported that a large proportion of patients with familial amyotrophic lateral sclerosis (familial ALS) and frontotemporal dementia (FTD) are associated with a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We have assessed 1,757 Italian sporadic ALS cases, 133 from Sardinia, 101 from Sicily, and 1,523 from mainland Italy. Sixty (3.7%) of 1,624 mainland Italians and Sicilians and 9 (6.8%) of the 133 Sardinian sporadic ALS cases carried the pathogenic repeat expansion. None of the 619 regionally-matched control samples (1,238 chromosomes) carried the expansion. Twenty-five cases (36.2%) had behavioral FTD in addition to ALS. FTD or unspecified dementia was also detected in 19 pedigrees (27.5%) in first-degree relatives of ALS patients. Cases carrying the C9ORF72 hexanucleotide expansion survived one year less than cases who did not carry this mutation. In conclusion, we found that C9ORF72 hexanucloetide repeat expansions represents a sizeable proportion of apparent sporadic ALS in the Italian and Sardinian population, representing by far the commonest mutation in Italy and the second more common in Sardinia.

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