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2. Skeletal muscle in amyotrophic lateral sclerosis.

Author

Shefner, Jeremy M, Musaro, Antonio, Ngo, Shyuan T, Lunetta, Christian, Steyn, Frederik J, Robitaille, Richard, Carvalho, Mamede De, Rutkove, Seward, Ludolph, Albert C, and Dupuis, Luc

Subjects
AMYOTROPHIC lateral sclerosis, SKELETAL muscle, MOTOR neuron diseases, MUSCLE weakness, MOTOR neurons, NEMALINE myopathy
Abstract

Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with muscle changes interpreted as a consequence of the progressive loss of motor neurons and neuromuscular junctions. This has led to the prevailing view that the involvement of muscle in ALS is only secondary to motor neuron loss. Skeletal muscle and motor neurons reciprocally influence their respective development and constitute a single functional unit. In ALS, multiple studies indicate that skeletal muscle dysfunction might contribute to progressive muscle weakness, as well as to the final demise of neuromuscular junctions and motor neurons. Furthermore, skeletal muscle has been shown to participate in disease pathogenesis of several monogenic diseases closely related to ALS. Here, we move the narrative towards a better appreciation of muscle as a contributor of disease in ALS. We review the various potential roles of skeletal muscle cells in ALS, from passive bystanders to active players in ALS pathophysiology. We also compare ALS to other motor neuron diseases and draw perspectives for future research and treatment. [ABSTRACT FROM AUTHOR]

Published
2023
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3. Genetic variability in sporadic amyotrophic lateral sclerosis.

Author

Daele, Sien Hilde Van, Moisse, Matthieu, Vugt, Joke J F A van, Zwamborn, Ramona A J, van der Spek, Rick, Rheenen, Wouter van, Eijk, Kristel Van, Kenna, Kevin, Corcia, Philippe, Vourc'h, Patrick, Couratier, Philippe, Hardiman, Orla, McLaughin, Russell, Gotkine, Marc, Drory, Vivian, Ticozzi, Nicola, Silani, Vincenzo, Ratti, Antonia, Carvalho, Mamede de, and Pardina, Jesús S Mora

Subjects
AMYOTROPHIC lateral sclerosis, GENETIC variation, MEDICAL genetics, WHOLE genome sequencing, MEDICAL genomics
Abstract

With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), there is a surge in gene testing for this disease. Although there is ample experience with gene testing for C9orf72 , SOD1 , FUS and TARDBP in familial ALS, large studies exploring genetic variation in all ALS-associated genes in sporadic ALS (sALS) are still scarce. Gene testing in a diagnostic setting is challenging, given the complex genetic architecture of sALS, for which there are genetic variants with large and small effect sizes. Guidelines for the interpretation of genetic variants in gene panels and for counselling of patients are lacking. We aimed to provide a thorough characterization of genetic variability in ALS genes by applying the American College of Medical Genetics and Genomics (ACMG) criteria on whole genome sequencing data from a large cohort of 6013 sporadic ALS patients and 2411 matched controls from Project MinE. We studied genetic variation in 90 ALS-associated genes and applied customized ACMG-criteria to identify pathogenic and likely pathogenic variants. Variants of unknown significance were collected as well. In addition, we determined the length of repeat expansions in C9orf72 , ATXN1 , ATXN2 and NIPA1 using the ExpansionHunter tool. We found C9orf72 repeat expansions in 5.21% of sALS patients. In 50 ALS-associated genes, we did not identify any pathogenic or likely pathogenic variants. In 5.89%, a pathogenic or likely pathogenic variant was found, most commonly in SOD1 , TARDBP , FUS , NEK1 , OPTN or TBK1. Significantly more cases carried at least one pathogenic or likely pathogenic variant compared to controls (odds ratio 1.75; P -value 1.64 × 10−5). Isolated risk factors in ATXN1 , ATXN2 , NIPA1 and/or UNC13A were detected in 17.33% of cases. In 71.83%, we did not find any genetic clues. A combination of variants was found in 2.88%. This study provides an inventory of pathogenic and likely pathogenic genetic variation in a large cohort of sALS patients. Overall, we identified pathogenic and likely pathogenic variants in 11.13% of ALS patients in 38 known ALS genes. In line with the oligogenic hypothesis, we found significantly more combinations of variants in cases compared to controls. Many variants of unknown significance may contribute to ALS risk, but diagnostic algorithms to reliably identify and weigh them are lacking. This work can serve as a resource for counselling and for the assembly of gene panels for ALS. Further characterization of the genetic architecture of sALS is necessary given the growing interest in gene testing in ALS. [ABSTRACT FROM AUTHOR]

Published
2023
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7. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Author

Rheenen, Wouter van, Spek, Rick A. A. van der, Bakker, Mark K., Vugt, Joke J. F. A. van, Hop, Paul J., Zwamborn, Ramona A. J., Klein, Niek de, Westra, Harm Jan, Bakker, Olivier B., Deelen, Patrick, Shireby, Gemma, Needham, Merrilee, Ceroni, Mauro, Simoncini, Costanza, Gagliardi, Stella, Corrado, Lucia, Garton, Fleur C., Mazzini, Letizia, Westeneng, Henk Jan, Ross, Jay P., Valluzzi, Francesco, Aguggia, Marco, Raggi, Flavia, Rini, Augusto, Traynor, Bryan J., Singleton, Andrew B., Ngo, Shyuan T., Corcia, Philippe, Olsen, Catherine M., Hofman, Albert, Van Eijk, Kristel R., Pasterkamp, R. Jeroen, Tittmann, Lukas, Iacoangeli, Alfredo, Mitne Neto, Miguel, Sproviero, Daisy, Cauchi, Ruben J., Ophoff, Roel A., Wiedau Pazos, Martina, Lomen-Hoerth, Catherine, Deerlin, Vivianna M. van, Nicholson, Garth A., Brylev, Lev, Whiteman, David C., Grosskreutz, Julian, Fan, Dongsheng, Couratier, Philippe, Roediger, Annekathrin, Gaur, Nayana, D’alfonso, Sandra, Uitterlinden, André G., Pamphlett, Roger, Fominykh, Vera, Byrne, Ross P., Lieb, Wolfgang, Iazzolino, Barbara, Dekker, Annelot M., Slap Consortium, Demeshonok, Vera, Millecamps, Stéphanie, Ataulina, Anastasia, Rogelj, Boris, Koritnik, Blaž, Zidar, Janez, Ravnik-Glavač, Metka, Franke, Andre, Mcrae, Allan F., Rowe, Dominic B., Peotta, Laura, Cooper-Knock, Johnathan, Glavač, Damjan, Doherty, Mark, Rietschel, Marcella, Stević, Zorica, Drory, Vivian, Meininger, Vincent, Zarrelli, Michele, Povedano, Monica, Gaunt, Tom R., Steyn, Frederik J., Williams, Kelly L., Smith, Bradley N., Cugnasco, Paolo, Papurello, Diego Maria, Nozzoli, Cecilia, Sorarù, Gianni, Mather, Karen A., Ripke, Stephan, Nöthen, Markus M., Sachdev, Perminder S., Henders, Anjali K., Wallace, Leanne, Carvalho, Mamede de, Gromicho, Marta, Pinto, Susana, Marco, Giovanni de, Al Khleifat, Ahmad, Eberle, Michael A., Braun, Alice, Gusmaroli, Graziano, Siciliano, Gabriele, Petri, Susanne, Breen, Gerome, Weber, Markus, Rouleau, Guy A., Rojas García, Ricardo, Silani, Vincenzo, Amouyel, Philippe, Ghiglione, Paolo, Davey Smith, George, Curtis, Charles J., Shatunov, Aleksey, Mill, Jonathan, Mclaughlin, Russell L., Filosto, Massimiliano, Comi, Cristoforo, Gerfo, Annalisa lo, Ferlini, Alessandra, Riva, Nilo, Mora Pardina, Jesus S., Chiveri, Luca, Hardiman, Orla, Torrieri, Maria Claudia, Kenna, Kevin P., Wray, Naomi R., Tsai, Ellen, Runz, Heiko, Franke, Lude, Padovani, Alessandro, Chandran, Siddharthan, Al Chalabi, Ammar, Assialioui, Abdelilah, Labate, Carmelo, Damme, Philip van, Ticozzi, Nicola, Palumbo, Francesca, Inghilleri, Maurizio, Chiò, Adriano, Pal, Suvankar, Lunetta, Christian, Jörk, Alexander, Cichon, Sven, Kraft, Julia, Morrison, Karen E., Ruiz, Luigi, Shaw, Pamela J., Hardy, John, Orrell, Richard W., Sendtner, Michael, Meyer, Thomas, Dion, Patrick A., Calvo, Andrea, Kooyman, Maarten, Başak, Nazli, Gerardi, Francesca, Simone, Isabella L., Kooi, Anneke J. van der, Ratti, Antonia, Ferrandi, Delfina, Fogh, Isabella, Ludolph, Albert C., Moglia, Cristina, Brunetti, Maura, Diamanti, Luca, Barthel, Tabea, Blair, Ian P., Es, Michael A. van, Gallone, Salvatore, Canosa, Antonio, Guerra, Vito, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Ferrarese, Carlo, Nefussy, Beatrice, Theele, Erik, Rinaldi, Fabrizio, Weishaupt, Jochen H., Kiernan, Matthew C., Barberis, Marco, Osmanovic, Alma, Baloh, Robert H., Nordin, Angelica, Lerner, Yossef, Vito, Nicoletta di, Zabari, Michal, Zoccolella, Stefano, Heverin, Mark, Gotkine, Marc, Guaita, Maria Cristina, Brenner, David, Freischmidt, Axel, Sbaiz, Luca, Benyamin, Beben, Glass, Jonathan D., Landers, John E., Tazelaar, Gijs H. P., Rota, Eugenia, Bensimon, Gilbert, Ilse, Benjamin, Brice, Alexis, Durr, Alexandra, Payan, Christine A. M., Saker-Delye, Safa, Wood, Nicholas W., Gentile, Salvatore, Moisse, Matthieu, Topp, Simon, Henderson, Robert D., Rademakers, Rosa, Perrone, Patrizia, Stubendorff, Beatrice, Brown, Robert H., Restuadi, Restuadi, Tremolizzo, Lucio, Mundi, Ciro, Berg, Leonard H. van den, Passarella, Bruno, Delodovici, Maria Luisa, Furlong, Sarah, Bono, Giorgio, Manera, Umberto, Vasta, Rosario, Bombaci, Alessandro, Meineri, Piero, Mauro, Alessandro, Hannon, Eilis, Casale, Federico, Leone, Maurizio, Shaw, Christopher E., Fuda, Giuseppe, Salamone, Paolina, Mathers, Susan, Baird, Denis, Launaro, Nicola, Marchi, Fabiola de, Veldink, Jan H., Gellera, Cinzia, Salachas, François, Witte, Otto W., Andersen, Peter M., Bertolotto, Antonio, Gionco, Maurizio, Leotta, Daniela, Odddenino, Enrico, Slalom Consortium, Tamma, Filippo, Dotta, Michele, Lauria, Giuseppe, Steinbach, Robert, Imperiale, Daniele, Geda, Claudio, Dolzhenko, Egor, Cavallo, Roberto, Pignatta, Pietro, Groen, Ewout J. N., Cotelli, Maria Sofia, Mattei, Marco de, Calabrese, Gianluigi, Sapio, Alessia di, Giardini, Guido, Hübner, Christian A., Corti, Stefania, Bell, Shaughn, Comi, Giancarlo, Mccombe, Pamela A., Tiloca, Cinzia, Parals Consortium, Gawor, Klara, Peverelli, Silvia, Taroni, Franco, Pensato, Viviana, Castellotti, Barbara, Graff, Caroline, Comi, Giacomo P., Cereda, Cristina, Bo, Roberto del, Boero, Giovanni, Slagen Consortium, Vourc’h, Patrick, Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), van Rheenen, Wouter, van der Spek, Rick AA, Bakker, Mark K, van Vugt, Joke JFA, Benyamin, Beben, Veldink, Jan H, SLALOM Consortium, PARALS Consortium, SLAGEN Consortium, SLAP Consortium, van Rheenen, W, van der Spek, R, Bakker, M, van Vugt, J, Hop, P, Zwamborn, R, de Klein, N, Westra, H, Bakker, O, Deelen, P, Shireby, G, Hannon, E, Moisse, M, Baird, D, Restuadi, R, Dolzhenko, E, Dekker, A, Gawor, K, Westeneng, H, Tazelaar, G, van Eijk, K, Kooyman, M, Byrne, R, Doherty, M, Heverin, M, Al Khleifat, A, Iacoangeli, A, Shatunov, A, Ticozzi, N, Cooper-Knock, J, Smith, B, Gromicho, M, Chandran, S, Pal, S, Morrison, K, Shaw, P, Hardy, J, Orrell, R, Sendtner, M, Meyer, T, Basak, N, van der Kooi, A, Ratti, A, Fogh, I, Gellera, C, Lauria, G, Corti, S, Cereda, C, Sproviero, D, D'Alfonso, S, Soraru, G, Siciliano, G, Filosto, M, Padovani, A, Chio, A, Calvo, A, Moglia, C, Brunetti, M, Canosa, A, Grassano, M, Beghi, E, Pupillo, E, Logroscino, G, Nefussy, B, Osmanovic, A, Nordin, A, Lerner, Y, Zabari, M, Gotkine, M, Baloh, R, Bell, S, Vourc'H, P, Corcia, P, Couratier, P, Millecamps, S, Meininger, V, Salachas, F, Mora Pardina, J, Assialioui, A, Rojas-Garcia, R, Dion, P, Ross, J, Ludolph, A, Weishaupt, J, Brenner, D, Freischmidt, A, Bensimon, G, Brice, A, Durr, A, Payan, C, Saker-Delye, S, Wood, N, Topp, S, Rademakers, R, Tittmann, L, Lieb, W, Franke, A, Ripke, S, Braun, A, Kraft, J, Whiteman, D, Olsen, C, Uitterlinden, A, Hofman, A, Rietschel, M, Cichon, S, Nothen, M, Amouyel, P, Traynor, B, Singleton, A, Mitne Neto, M, Cauchi, R, Ophoff, R, Wiedau-Pazos, M, Lomen-Hoerth, C, van Deerlin, V, Grosskreutz, J, Roediger, A, Gaur, N, Jork, A, Barthel, T, Theele, E, Ilse, B, Stubendorff, B, Witte, O, Steinbach, R, Hubner, C, Graff, C, Brylev, L, Fominykh, V, Demeshonok, V, Ataulina, A, Rogelj, B, Koritnik, B, Zidar, J, Ravnik-Glavac, M, Glavac, D, Stevic, Z, Drory, V, Povedano, M, Blair, I, Kiernan, M, Benyamin, B, Henderson, R, Furlong, S, Mathers, S, Mccombe, P, Needham, M, Ngo, S, Nicholson, G, Pamphlett, R, Rowe, D, Steyn, F, Williams, K, Mather, K, Sachdev, P, Henders, A, Wallace, L, de Carvalho, M, Pinto, S, Petri, S, Weber, M, Rouleau, G, Silani, V, Curtis, C, Breen, G, Glass, J, Brown, R, Landers, J, Shaw, C, Andersen, P, Groen, E, van Es, M, Pasterkamp, R, Fan, D, Garton, F, Mcrae, A, Davey Smith, G, Gaunt, T, Eberle, M, Mill, J, Mclaughlin, R, Hardiman, O, Kenna, K, Wray, N, Tsai, E, Runz, H, Franke, L, Al-Chalabi, A, Van Damme, P, van den Berg, L, Veldink, J, Ferrarese, C, Neurology, ANS - Neuroinfection & -inflammation, APH - Methodology, APH - Quality of Care, EURO-NMD, Internal Medicine, Epidemiology, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), van Rheenen, W., Van der Spek, R.A.A., Bakker, M.K., van Vugt, J.J.F.A., Hop, P.J., Zwamborn, R.A.J., de Klein, N., Westra, H.J., Bakker, O.B., Deelen, P., Shireby, G., Hannon, E., Moisse, M., Baird, D., Restuadi, R., Dolzhenko, E., Dekker, A.M., Gawor, K., Westeneng, H.J., Tazelaar, G.H.P., van Eijk, K.R., Kooyman, M., Byrne, R.P., Doherty, M., Heverin, M., Al Khleifat, A., Iacoangeli, A., Shatunov, A., Ticozzi, N., Cooper-Knock, J., Smith, B.N., Gromicho, M., Chandran, S., Pal, S., Morrison, K.E., Shaw, P.J., Hardy, J., Orrell, R.W., Sendtner, M., Meyer, T., van der Kooi, A.J., Ratti, A., Fogh, I., Gellera, C., Lauria, G., Corti, S., Cereda, C., Sproviero, D., D'Alfonso, S., Sorarù, G., Siciliano, G., Filosto, M., Padovani, A., Chiò, A., Calvo, A., Moglia, C., Brunetti, M., Canosa, A., Grassano, M., Beghi, E., Pupillo, E., Logroscino, G., Nefussy, B., Osmanovic, A., Nordin, A., Lerner, Y., Zabari, M., Gotkine, M., Baloh, R.H., Bell, S., Vourc'h, P., Corcia, P., Couratier, P., Millecamps, S., Meininger, V., Salachas, F., Mora Pardina, J.S., Assialioui, A., Rojas-García, R., Dion, P.A., Ross, J.P., Ludolph, A.C., Weishaupt, J.H., Brenner, D., Freischmidt, A., Bensimon, G., Brice, A., Durr, A., Payan, C.A.M., Saker-Delye, S., Wood, N.W., Topp, S., Rademakers, R., Tittmann, L., Lieb, W., Franke, A., Ripke, S., Kraft, J.,Whiteman, David C., Olsen, Catherine M., Uitterlinden, A.G., Hofman, A., Rietschel, M., Cichon, S., Nothen, M.M., Amouyel, P., Comi, G., Riva, N., Lunetta, C., Gerardi, F., Cotelli, M.S., Rinaldi, F., Chiveri, L., Guaita, M.C., Perrone, P., Ceroni, M., Diamanti, L., Ferrarese, C., Tremolizzo, L., Delodovici, M.L., Bono, G., Manera, U., Vasta, R., Bombaci, A., Casale, F., Fuda, G., Salamone, P., Iazzolino, B., Peotta, L., Cugnasco, P., De Marco, G., Torrieri, M.C., Palumbo, F., Gallone, S., Barberis, M., Sbaiz, L., Gentile, S., Mauro, A., Mazzini, L., De Marchi, F., Corrado, L., Bertolotto, A., Gionco, M., Leotta, D., Odddenino, E., Imperiale, D., Cavallo, R., Pignatta, P., De Mattei, M., Geda, C., Papurello, D.M., Gusmaroli, G., Comi, C., Labate, C., Ruiz, L., Ferrandi, D., Rota, E., Aguggia, M., Di Vito, N., Meineri, P., Ghiglione, P., Launaro, N., Dotta, M., Di Sapio, A., Giardini, G., Tiloca, C., Peverelli, S., Taroni, F., Pensato, V., Castellotti, B., Comi, G.P., Del Bo, R., Gagliardi, S., Raggi, F., Simoncini, C., Lo Gerfo, A., Inghilleri, M., Ferlini, A., Simone, I.L., Passarella, B., Guerra, V., Zoccolella, S., Nozzoli, C., Mundi, C., Leone, M., Zarrelli, M., Tamma, F., Valluzzi, F., Calabrese, G., Boero, G., Rini, A., Traynor, B.J., Singleton, A.B., Neto, M.M., Cauchi, R.J., Ophoff, R.A., Wiedau-Pazos, M., Lomen-Hoerth, C., van Deerlin, V.M., Grosskreutz, J., Roediger, A., Gaur, N., Jork, A., Barthel, T., Theele, E., Ilse, B., Stubendorff, B., Witte, O.W., Steinbach, R., Hubner, C.A., Graff, C., Brylev, L., Fominykh, V., Demeshonok, V., Ataulina, A., Rogelj, B., Koritnik, B., Zidar, J., Ravnik-Glavac, M., Glavac, D., Stevic, Z., Drory, V., Povedano, M., Blair, I.P., Kiernan, M.C., Benyamin, B., Henderson, R.D., Furlong, S., Mathers, S., McCombe, P.A, Needham, M., Ngo, S.T., Nicholson, G.A., Pamphlett, R., Rowe, D.B., Steyn, F.J., Williams, K.L., Mather, K.A., Sachdev, P.S., Henders, A.K., Wallace, L., de Carvalho, M., Pinto, S., Petri, S., Weber, M., Rouleau, G.A., Silani, V., Curtis, C.J., Breen, G., Glass, J.D., Brown, R.H., Landers, J.E., Shaw, C.E., Andersen, P.M., Groen, E.J.N, van Es, M.A., Pasterkamp, R.J., Fan, D.S., Garton, F.C., McRae, A.F., Smith, G.D., Gaunt, T.R., Eberle, M.A., Mill, J., McLaughlin, R.L., Hardiman, O., Kenna, K.P., Wray, N.R., Tsai, E.L., Runz, H., Franke, L., Al-Chalabi, A., Van Damme, P., van den Berg, L.H., Veldink, J.H., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine

Subjects
Male, Genetics and heredity, amyotrophic lateral sclerosis, Neurologi, Glutamine, Medizin, Genome-wide association study, Disease, SUSCEPTIBILITY, Genome-wide association studies, DISEASE, Genètica mèdica, 0302 clinical medicine, neurodegenerative disease, genome-wide association study, ALS, gene, autophagy, Risk Factors, amyotrophic lateral sclerosi, RNA-Seq, Amyotrophic lateral sclerosis, disease-modifying therapies, blood [Cholesterol], Genetics, Genetics & Heredity, Neurons, 0303 health sciences, Medical genetics, Neurodegenerative diseases, Genome-wide association, Mendelian randomization, Frontotemporal dementia, Hexanucleotide repeat, Mutant SOD1, Metaanalysis, ALS, Susceptibility, Identification, Brain, Amyotrophic Lateral Sclerosis, Cholesterol, Disease Progression, Female, Humans, Mendelian Randomization Analysis, Microsatellite Repeats, Neurodegenerative Diseases, Quantitative Trait Loci, Genome-Wide Association Study, Mutation, MUTANT SOD1, genetics [Amyotrophic Lateral Sclerosis], medicine.anatomical_structure, Neurology, risk factor, metabolism [Neurons], MENDELIAN RANDOMIZATION, nerve cell, Life Sciences & Biomedicine, quantitative trait locu, Biology, 03 medical and health sciences, Amyotrophic lateral sclerosis -- Diagnosis, blood, ddc:570, medicine, degenerative disease, Motor neuron disease, human, Genomes, GENOME-WIDE ASSOCIATION, gene, Gene, metabolism [Glutamine], METAANALYSIS, 030304 developmental biology, Mendelian randomization analysi, Science & Technology, HEXANUCLEOTIDE REPEAT, meta analysi, IDENTIFICATION, metabolism [Amyotrophic Lateral Sclerosis], FRONTOTEMPORAL DEMENTIA, medicine.disease, metabolism [Brain], genetics [Neurodegenerative Diseases], Expression quantitative trait loci, disease exacerbation, Neuron, gemone, genetic, Vesicle-mediated transport, metabolism, Nervous system -- Degeneration, Esclerosi lateral amiotròfica, 030217 neurology & neurosurgery
Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons., Dutch Research Council (NWO); VENI Scheme Grant; VIDI Grant; Prinses Beatrix Spierfonds; Neuromuscular Fellowship Grant; Medical Research Council (MRC); Clinical Infrastructure Award; Epidemiology Unit; Integrative Epidemiology Unit; Canadian Institutes of Health Research; IWT; National Institute on Aging; National Health and Medical Research Council (NHMRC); Enabling Grant; NHMRC/Australian Research Council Strategic Award; NHMRC; NHMRC Centre of Research Excellence Grant; National Health and Medical Research Council of Australia (NHMRC) Research Fellowship; United Kingdom, Medical Research Council; Economic and Social Research Council; European Union (EU); Horizon 2020; European Community's Health Seventh Framework Programme; EuroMOTOR; European Research Council (ERC); Research and Innovation Programme; EScORIAL; ALS Foundation Netherlands; Alzheimer’s Society PhD Studentship; ARSla Funding; Biogen; University of Bristol; Motor Neurone Disease Association (MNDA); NIHR Maudsley Biomedical Research Centre; Dutch Ministry of Education, Culture, and Science; Netherlands Organization for Scientific Research (NWO; BRAINSCAPES); Gravitation Program; ALS Liga België; National Lottery of Belgium; KU Leuven Opening the Future Fund; KU Leuven Funds, “Een Hart voor ALS”, “Laeversfonds voor ALS Onderzoek” and the “Valéry Perrier Race against ALS Fund”; E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders; ALS Liga België; “Live now” Charity Foundation; Moscow ALS palliative Care Service; Canadian Institutes of Health; Research Australia; Ice Bucket Challenge Grant; NIH Intramural Research Programs; FightMND Mid-Career Fellowship; NIHR Senior Investigator; Sheffield NIHR Biomedical Research Centre; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Biomedical Research Centre; Maudsley NHS Foundation Trust; King’s College London; NIHR Senior Investigator Award; Netherlands Organization for Health Research and Development; Vici Scheme; Netherlands Organization for Health Research and Development STRENGTH Project; PPP Allowance

Published
2021

10. Lumbar trans-spinal direct current stimulation: A modeling-experimental approach to dorsal root ganglia stimulation.

Author

Pereira, Mariana, Fernandes, Sofia Rita, Miranda, Pedro Cavaleiro, and Carvalho, Mamede de

Subjects
DORSAL root ganglia, MOTOR neurons, SPINAL cord, LONG-term synaptic depression, EFFERENT pathways, VERTEBRAE, SPINAL nerve roots
Abstract

Introduction: The excitability of spinal motor neurons (MN) can be altered through subthreshold currents, such as transcutaneous spinal direct-current stimulation (tsDCS). Current evidence shows that tsDCS can interfere with ascending somatosensory pathways and lower motor neurons' (LMN) excitability, which points to its therapeutic potential for repairing altered spinal responses. We aim to define the best tsDCS montage for maximizing the electric field (E-field) in the lumbar spinal cord (L-SC) by computer modeling; and to apply this montage to measure the effect on LMN excitability and somatosensory evoked potentials (SSEP). Methods: A human volume conductor model was obtained from an available database. The E-field distribution was calculated considering three different electrode settings aiming at maximizing the field at L-SC and right dorsal root ganglia (DRG). The best electrode setting was then selected and applied in a blind crossover pseudo-randomized study including 14 subjects. tsDCS was delivered for 15 min (cathodal vs. sham) over L2 vertebra level (4 mA, 144 mC/cm²), and its effect on F-waves, H-reflex (including homosynaptic depression, HD) and SSEPs was investigated in the lower limbs. Results: All simulated montages showed higher current density and E-field magnitudes between the electrodes (>0.15 V/m), with a major longitudinal component and with rostral-caudal direction. The induced E-field involved the sensory ganglia and was maximum in the right T8-left L2 montage, which was the one selected for the experimental protocol. We disclosed a statistically significant increase of the H-reflex amplitude at 0.1 Hz, after cathodal tsDCS (c-tsDCS) on both sides. No other significant change was observed. Discussion: Our results can suggest the c-tsDCS applied to the L-SC and DRG can modulate synaptic efficiency increasing lower motor neurons response to Ia fibers excitation. The possible implications of our findings for treating clinical conditions will be addressed in future studies. [ABSTRACT FROM AUTHOR]

Published
2022
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15. A Malnutrição Associada à Doença e as suas Repercussões em Portugal

Author

Marinho, Anibal, Lopes, Ana, Sousa, Gabriela, Antunes, Henedina, Fonseca, Jorge, Mendes, Lino, Carvalho, Mamede de, Veríssimo, Manuel Teixeira, Carvalho, Nuno, Alves, Paula, and Alves, Paulo

Subjects
2. Zero hunger, Portugal, Malnutrição, Malnutrition, 05 social sciences, Nutritional Status, Avaliação Nutricional, Perturbações da Nutrição, Custos Hospitalares, 010501 environmental sciences, Nutritional assessment, Nutritional disorder, 01 natural sciences, Nutrition Disorders, 3. Good health, Nutrition Assessment, 0502 economics and business, Perturbação alimentar, Hospital Costs, Estado Nutricional, 050203 business & management, 0105 earth and related environmental sciences
Abstract

A malnutrição associada à doença é frequente do ponto de vista clínico, apresentando elevada morbilidade, mortalidade e impacto na qualidade de vida, em especialidades como a medicina interna, a oncologia, a neurologia, a gastroenterologia e a pediatria, entre outras. Estudos realizados em Portugal estimam existirem cerca de 40% de doentes em risco nutricional à data da admissão hospitalar, dependendo do estadio da doença e do grau/severidade. O custo da hospitalização destes doentes, é cerca de 20% superior ao dos doentes com o mesmo grupo de diagnóstico homogéneo, mas sem risco nutricional associado. No nosso país, o acesso dos doentes malnutridos a avaliação, aconselhamento e tratamento nutricional adequados ainda é limitado, mesmo em ambiente hospitalar. Um conhecimento detalhado da malnutrição associada à doença nas referidas especialidades, permitiria uma melhor caracterização da situação em Portugal, e permitiria estabelecer uma estratégia de intervenção clínica e terapêutica, para melhorar este panorama e as suas consequências no nosso país., Medicina Interna, Vol. 26 N.º 1 (2019): Janeiro / Março

Published
2019
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19. Influence of Environment and Lifestyle on Incidence and Progress of Amyotrophic Lateral Sclerosis in A German ALS Population

Author

Korner, Sonja, primary, Kammeyer, Johanna, primary, Zapf, Antonia, primary, Kuzma-Kozakiewicz, Magdalena, primary, Piotrkiewicz, Maria, primary, Kuraszkiewicz, Bożenna, primary, Goszczynska, Hanna, primary, Gromicho, Marta, primary, Grosskreutz, Julian, primary, Andersen, Peter M., primary, Carvalho, Mamede de, primary, and Petri, Susanne, primary

Published
2019
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20. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

Author

McLaughlin, Russell L., Schijven, Dick, Van Rheenen, Wouter, Van Eijk, Kristel R., O'Brien, Margaret, Kahn, René S., Ophoff, Roel A., Goris, An, Bradley, Daniel G., Al-Chalabi, Ammar, Van Den Berg, Leonard H., Luykx, Jurjen J., Hardiman, Orla, Veldink, Jan H., Shatunov, Aleksey, Dekker, Annelot M., Diekstra, Frank P., Pulit, Sara L., Van Der Spek, Rick A.A., Van Doormaal, Perry T.C., Sproviero, William, Jones, Ashley R., Nicholson, Garth A., Rowe, Dominic B., Pamphlett, Roger, Kiernan, Matthew C., Bauer, Denis, Kahlke, Tim, Williams, Kelly, Eftimov, Filip, Fogh, Isabella, Ticozzi, Nicola, Lin, Kuang, Millecamps, Stephanie, Salachas, Francois, Meininger, Vincent, Carvalho, Mamede De, Pinto, Susana, Mora, Jesus S., Rojas-Garcyá, Ricardo, Polak, Meraida, Chandran, Siddharthan, Andersen, Peter M., Pers, Tune H., Hansen, Mark, Hansen, Thomas, Li, Tao, Olsen, Line, Rasmussen, Henrik B., Werge, Thomas, McLaughlin, Russell L., Schijven, Dick, Van Rheenen, Wouter, Van Eijk, Kristel R., O'Brien, Margaret, Kahn, René S., Ophoff, Roel A., Goris, An, Bradley, Daniel G., Al-Chalabi, Ammar, Van Den Berg, Leonard H., Luykx, Jurjen J., Hardiman, Orla, Veldink, Jan H., Shatunov, Aleksey, Dekker, Annelot M., Diekstra, Frank P., Pulit, Sara L., Van Der Spek, Rick A.A., Van Doormaal, Perry T.C., Sproviero, William, Jones, Ashley R., Nicholson, Garth A., Rowe, Dominic B., Pamphlett, Roger, Kiernan, Matthew C., Bauer, Denis, Kahlke, Tim, Williams, Kelly, Eftimov, Filip, Fogh, Isabella, Ticozzi, Nicola, Lin, Kuang, Millecamps, Stephanie, Salachas, Francois, Meininger, Vincent, Carvalho, Mamede De, Pinto, Susana, Mora, Jesus S., Rojas-Garcyá, Ricardo, Polak, Meraida, Chandran, Siddharthan, Andersen, Peter M., Pers, Tune H., Hansen, Mark, Hansen, Thomas, Li, Tao, Olsen, Line, Rasmussen, Henrik B., and Werge, Thomas

Abstract

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10-4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10-7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.

Published
2017

21. O96 Large inter- and intra-rater variation on diagnostic criteria for amyotrophic lateral sclerosis

Author

Johnsen, Birger, primary, Pugdahl, Kirsten, additional, Fuglsang-Frederiksen, Anders, additional, Kollewe, Katja, additional, Paracka, Lejla, additional, Dengler, Reinhard, additional, Camdessanché, Jean-Philippe, additional, Nix, Wilfred, additional, Liguori, Rocco, additional, Schofield, Ian, additional, Maderna, Luca, additional, Czell, David, additional, Neuwirth, Christoph, additional, Weber, Markus, additional, Drory, Vivian, additional, Abraham, Alon, additional, and Carvalho, Mamede De, additional

Published
2017
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24. Characterization of speech from amyotrophic lateral sclerosis by neuromorphic processing

Author

Gómez Vilda, Pedro, Londral, Ana Rita M., Carvalho, Mamede de, Ferrández Vicente, José Manuel, and Rodellar Biarge, M. Victoria

Subjects
Medicina, behavioral disciplines and activities
Abstract

Amyotrophic Lateral Sclerosis is a severe disease, which dramatically reduces the speech communication skills of patients as disease progresses. The present study is devoted to define accurate and objective estimates to characterize the loss of communication skills, to help clinicians and therapists in monitoring disease progression and in deciding on rehabilitation interventions. The methodology proposed is based on the perceptual (neuromorphic)definition of speech dinamics, concentrated in vowel sound in character and duration. We present the results from a longitudinal study carried out in an ALS patient during one year. Discussion addresses future actions.

Published
2013

25. HOME TELEMONITORING OF NON INVASIVE VENTILATION DECREASES HEALTHCARE UTILIZATION IN A PROSPECTIVE CONTROLLED TRIAL OF ALS PATIENTS

Author

Pinto, Anabela Cardoso, Almeida, José Pedro, Pinto, Susana Candeias, Pereira, João, Gouveia, António Oliveira, Carvalho, Mamede De, Department of Physical Medicine and Rehabilitation, University of Lisbon Medical School, Santa Mari, Neuromuscular Unit, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Neuromuscular Unit, Institute of Molecular Medicine, University of Lisbon Medical School, Lisbon, P, Linde Homecare Co, Lisbon, Portugal, Department of Biostatistics, NOVA Medical School - Faculdade de Ciências Médicas (NMS), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), and Neuromuscular Unit, Institute of Molecular Medicine, University of Lisbon Medical School,D Lisbon

Subjects
MOTOR NEURON DISEASE, RESPIRATORY MEDICINE, TELEMETRY
Abstract

International audience; Background. Non-Invasive Ventilation (NIV) is an efficient method for treating respiratory failure in ALS patients. However, it requires a process of adaptation not always achieved because of poor compliance. The role of technology for telemonitoring of NIV compliance is not yet established. Objectives: to compare compliance to NIV and health care utilization of tight follow-up in office visits or with modem communication plus office visits. Design: prospective, single blinded (researchers SP and MC) controlled trial. Population and methods: 40 consecutive, ventilated ALS patients that were by simple random assigned, to a control group (G1, n=20) whose compliance and ventilator parameters settings were assessed during office visits, or to an intervention group (G2, n=20) where patients received a modem device connected to the ventilator (Goodnight®425ST). Results: There were no statistical differences at admission in clinical and demographic characteristics between groups. The amount of intolerant patients was lower in G2 (ns). No differences over time in parameters settings and compliance. The incidence density of changes in parameters settings throughout the survival period with NIV was lower in G2 (p

Published
2010

44. A 3-month-old baby with H1N1 and Guillain-Barré syndrome.

Author

Vasconcelos, Alexandra, Abecasis, Francisco, Monteiro, Rita, Camilo, Cristina, Vieira, Marisa, Carvalho, Mamede de, and Correia, Manuela

Abstract

Majority of children with pandemic influenza A (H1N1)pdm09 experience mild illness with full recovery without treatment. A previously healthy two and a half month-old girl was admitted to our paediatric intensive care unit because of severe respiratory failure with A (H1N1) pdm09 infection. Despite initial clinical improvement all attempts to extubate to non-invasive ventilation were unsuccessful and 2 to 3 weeks after symptom onset she started periods of cardiovascular instability and a progressive neurological deterioration with distal symmetrical progressive motor weakness and areflexia. All investigations were normal except elevated liver enzymes and cerebrospinal fluid examination that revealed elevated protein without pleocytosis. A possible diagnosis of Guillain-Barré syndrome (GBS) was considered and electromyogram was compatible with axonal form of GBS. To our knowledge this is the youngest case of GBS acquired postnatally and the first in children associated with H1N1 virus. [ABSTRACT FROM AUTHOR]

Published
2012
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45. Preface: promoting research in PLS: current knowledge and future challenges.

Author

Mitsumoto, Hiroshi, Turner, Martin R., Ajroud-Driss, Senda, Andres, Patricia, Andrews, Jinsy, Gomez, Estela Area, Atehortua, Juan Marcos Solano, Babu, Suma, Barohn, Richard, Bede, Peter, Benatar, Michael, Chew, Sheena, Conwit, Robin, Corcia, Philippe, Cudkowicz, Merit, Davis, Frank, Carvalho, Mamede de, Drory, Vivian, Elman, Lauren, and Factor-Litvak, Pam

Published
2020
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46. Fibrillation and sharp-waves: Do we need them to diagnose ALS?

Author

Carvalho, Mamede de, Bentes, Carla, Evangelista, Teresinha, and Luis, M L Sales

Subjects
*ELECTROPHYSIOLOGY, *AMYOTROPHIC lateral sclerosis, *MUSCLES, *LIMB regeneration, *VENTRICULAR fibrillation, *ELECTRONICS, *PATIENTS
Abstract

BACKGROUND: Fibrillation/sharp-waves (fibs-sw) are considered an essential neurophysiological marker in Amyotrophic Lateral Sclerosis (ALS). We investigated how frequently an initial electrophysiological (EMG) evaluation, performed in ALS patients, revealed no fibs-sw. METHODS: The initial EMG studies from 68 ALS patients were analysed. The presence of fibs-sw in at least two muscles of each limb and two cranial-innervated muscles was assessed. RESULTS: We observed no fibs-sw in cranial-innervated muscles, and 7/15 bulbar-onset patients had no fibs-sw in limb muscles. Two of 28 upper-limb-onset patients, who had a short history before EMG, showed no fibs-sw. All lower-limb-onset patients had fibs-sw. Generally patients with no fibs-sw had diffuse abundant fasciculations. CONCLUSIONS: The absence of fibs-sw should not necessarily preclude the neurophysiological diagnosis of ALS in bulbar-onset patients. Early affected upper-limb-onset patients might show no fibs-sw, but profuse fasciculations associated with mild to moderate denervation–reinnervation in weak muscles are found. (Amyot Lat Scler 1999: 1:29–32). [ABSTRACT FROM AUTHOR]

Published
1999

47. Nerve conduction studies in amyotrophic lateral sclerosis

Author

Carvalho, Mamede de and Swash, Michael

Abstract

We studied 137 ulnar nerves and abductor digiti minimi (ADM) muscles in 70 patients with amyotrophic lateral sclerosis (ALS), and correlated the results with ADM strength graded on the Medical Research Council (MRC) scale, to address the potential value of a standardized neurophysiological assessment of this nerve–muscle system. The ulnar nerves of 35 normal subjects matched for age, gender, and height served as controls. Reduced compound muscle action potential (CMAP) amplitude and area in the ADM muscle recordings correlated strongly with weakness. Distal motor latency, proximal conduction time, and F-wave frequency were abnormal with minimally detectable weakness. In weaker ADM muscles, conduction velocities and F-wave latencies were also abnormal. Conduction block was never observed and sensory potentials were normal. An “ALS neurophysiological index” was derived from these ulnar nerve studies and consisted of the expression: (CMAP amplitude/DML) × F frequency —, where F frequency was expressed as the number of F responses recorded in 20 trials. This index was strongly correlated with ADM weakness (r = 0.74, P < 0.001). Neurophysiological studies restricted to a single nerve–muscle system, the ulnar nerve/ADM, appear potentially useful in objectively assessing change in ALS. © 2000 John Wiley & Sons, Inc. Muscle Nerve 23: 344–352, 2000

Published
2000
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48. Learning dynamic Bayesian networks from time-dependent and time-independent data: Unraveling disease progression in Amyotrophic Lateral Sclerosis.

Author

Leão, Tiago, Madeira, Sara C., Gromicho, Marta, de Carvalho, Mamede, Carvalho, Alexandra M., and Carvalho, Mamede de

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing patients to quickly lose motor neurons. The disease is characterized by a fast functional impairment and ventilatory decline, leading most patients to die from respiratory failure. To estimate when patients should get ventilatory support, it is helpful to adequately profile the disease progression. For this purpose, we use dynamic Bayesian networks (DBNs), a machine learning model, that graphically represents the conditional dependencies among variables. However, the standard DBN framework only includes dynamic (time-dependent) variables, while most ALS datasets have dynamic and static (time-independent) observations. Therefore, we propose the sdtDBN framework, which learns optimal DBNs with static and dynamic variables. Besides learning DBNs from data, with polynomial-time complexity in the number of variables, the proposed framework enables the user to insert prior knowledge and to make inference in the learned DBNs. We use sdtDBNs to study the progression of 1214 patients from a Portuguese ALS dataset. First, we predict the values of every functional indicator in the patients' consultations, achieving results competitive with state-of-the-art studies. Then, we determine the influence of each variable in patients' decline before and after getting ventilatory support. This insightful information can lead clinicians to pay particular attention to specific variables when evaluating the patients, thus improving prognosis. The case study with ALS shows that sdtDBNs are a promising predictive and descriptive tool, which can also be applied to assess the progression of other diseases, given time-dependent and time-independent clinical observations. [ABSTRACT FROM AUTHOR]

Published
2021
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49. Cortical muscle representation in amyotrophic lateral sclerosis patients: Changes with disease evolution

Author

Carvalho, Mamede de, Miranda, Pedro Cavaleiro, Luís, Maria Lourdes Sales, and Ducla-Soares, Eduardo

Abstract

Transcranial magnetic stimulation (TMS) mapping was performed regularly on 11 patients with amyotrophic lateral sclerosis (ALS). Map area decreased by 25% (P = 0.03) and normalized volume decreased by 47% (P = 0.01) in those patients who were mapped four times over a period of 11.6 months. The center of gravity (CoG) position moved randomly along the interaural line by distances larger than could be explained by experimental error (P = 0.002). Central conduction time, threshold, and motor evoked potential:compound muscle action potential (MEP:CMAP) amplitude ratio did not change significantly with time (P > 0.05). There were significant linear correlations between strength and CMAP amplitude and between map area and volume. No correlation was found between strength or CMAP amplitude and area or volume. The changes in map parameters were attributed primarily to loss of cortical cells. These results indicate that map parameters may be more sensitive to cortical neuronal loss than other TMS parameters. © 1999 John Wiley & Sons, Inc. Muscle Nerve 22: 1684–1692, 1999

Published
1999
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50. Fasciculation potentials: A study of amyotrophic lateral sclerosis and other neurogenic disorders

Author

Carvalho, Mamede de and Swash, Michael

Abstract

We studied fasciculation potentials in amyotrophic lateral sclerosis (ALS), and in other neurogenic disorders, in strength and single-fiber electromyography-matched muscles. Benign fasciculations were studied in 3 normal subjects. Fasciculations were more stable and easier to recruit voluntarily in the early phase of ALS; later, fasciculations were more unstable, more complex, and less likely to be voluntarily recruited. Stable fasciculations, representing part of large, reinnervated motor units, and probably arising from distal axonal sprouts, usually had a higher firing rate than more complex and unstable fasciculations. In weak muscles in ALS, fasciculations were generally more unstable than in other neurogenic disorders. In normal-strength muscles fasciculations are less complex in ALS than in other disorders. Benign fasciculations have a high firing rate and normal morphologic parameters. In ALS fasciculations arise proximally early in the disease and distally in the later stages. Fasciculation may be important in excitotoxic cell death in ALS. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:336–344.

Published
1998
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