Estimation of the prevalence and incidence of motor neuron diseases in two Spanish regions: Catalonia and Valencia

According to the degree of upper and lower motor neuron degeneration, motor neuron diseases (MND) can be categorized into amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) or progressive muscular atrophy (PMA). Although several studies have addressed the prevalence and incidence of ALS, there is a high heterogeneity in their results. Besides this, neither concept has been previously studied in PLS or PMA. Thus, the objective of this study was to estimate the prevalence and incidence of MND, (distinguishing ALS, PLS and PMA), in the Spanish regions of Catalonia and Valencia in the period 2011-2019. Two population-based Spanish cohorts were used, one from Catalonia and the other from Valencia. Given that the samples that comprised both cohorts were not random, i.e., leading to a selection bias, we used a two-part model in which both the individual and contextual observed and unobserved confounding variables are controlled for, along with the spatial and temporal dependence. The prevalence of MND was estimated to be between 3.990 and 6.334 per 100,000 inhabitants (ALS between 3.248 and 5.120; PMA between 0.065 and 0.634; and PLS between 0.046 and 1.896), and the incidence between 1.682 and 2.165 per 100,000 person-years for MND (ALS between 1.351 and 1.754; PMA between 0.225 and 0.628; and PLS between 0.409-0.544). Results were similar in the two regions and did not differ from those previously reported for ALS, suggesting that the proposed method is robust and that neither region presents differential risk or protective factors

Sonoelastography for the Assessment of Muscle Changes in Amyotrophic Lateral Sclerosis: Results of a Pilot Study

©. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the Published Manuscript version of a Published Work that appeared in final form in [Ultrasound in Medicine & Biology]. To access the final edited and published work see [https://doi.org/10.1016/j.ultrasmedbio.2018.08.009]The purpose of this study was to assess the sonoelastographic features of four different muscles in patients with amyotrophic lateral sclerosis compared with healthy controls and to evaluate the relationship of these features to muscle strength and other ultrasonographic variables. Fourteen patients with amyotrophic lateral sclerosis and 20 controls were examined using strain sonoelastography scanning. The RGB channel fraction ratio was analyzed with ImageJ software (Version 1.48). Two main sonoelastographic patterns could be distinguished in the controls: a clear predominance of the blue channel (hard areas) and a more heterogeneous pattern with predominance of the green channel (intermediate stiffness). These patterns were also observed in patients, although a higher green channel score was observed in mildly impaired muscles, whereas a higher blue channel score was observed in the most severely impaired muscle. Sonoelastography may be a good complementary biomarker in the detection and monitoring of muscle changes in amyotrophic lateral sclerosis

Quantitative neuromuscular ultrasound analysis as biomarkers in amyotrophic lateral sclerosis

©2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the Submitted, Accepted, Published, version of a Published Work that appeared in final form in European Radiology . To access the final edited and published work see https://doi.org/10.1007/s00330-018-5943-8Objectives: To assess the differences in morphological and texture parameters of median nerve (MN) and abductor pollicis brevis (APB) between amyotrophic lateral sclerosis (ALS) patients and controls. Methods: The cross-sectional area (CSA) of the MN and the muscle thickness (MTh) of APB were measured bilaterally in 59 recently diagnosed ALS patients and 20 matched healthy controls. Echointensity (EI), echovariation (EV) and grey-level co-occurrence matrix (GLCM) texture features of both structures were also analysed. Correlations between these parameters and clinical variables (muscle strength and disability) were analysed. Results: The CSA of MN was significantly lower in ALS patients (MD = - 1.83 mm2 [95% CI = 2.89; - 0.77 mm2]; p = 0.01). ALS patients showed significantly lower MTh (- 2.23 mm [3.16; - 1.30 mm]; p < 0.001) and EV (- 7.40 [11.5; - 3.33]; p = 0.004) and higher EI (21.2 [11.9; 30.6]; p < 0.001) in the APB muscle. No relevant differences were detected in GLCM features for this muscle. The model including all parameters (CSA for MN and MTh, EI and EV for APB) showed an AUC of 82% (sensitivity 87%; specificity 42%). Muscle strength and disability correlated with APB muscle ultrasound parameters but not with those of the MN. Conclusions: APB muscle ultrasound biomarkers (especially MTh and EI) showed better discrimination capacity and correlation with clinical variables than MN biomarkers. However, the combination of both biomarkers increased their ability to detect LMN impairment, suggesting that both biomarkers could be used in a complementary manner for the diagnosis and progression monitoring in ALS

The mechanistic foundation of Weber’s law

[Abstract] Although Weber's law is the most firmly established regularity in sensation, no principled way has been identified to choose between its many proposed explanations. We investigated Weber's law by training rats to discriminate the relative intensity of sounds at the two ears at various absolute levels. These experiments revealed the existence of a psychophysical regularity, which we term time-intensity equivalence in discrimination (TIED), describing how reaction times change as a function of absolute level. The TIED enables the mathematical specification of the computational basis of Weber's law, placing strict requirements on how stimulus intensity is encoded in the stochastic activity of sensory neurons and revealing that discriminative choices must be based on bounded exact accumulation of evidence. We further demonstrate that this mechanism is not only necessary for the TIED to hold but is also sufficient to provide a virtually complete quantitative description of the behavior of the rats

Facial onset sensory and motor neuronopathy: new cases, cognitive changes and pathophysiology

Purpose of review To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN). Recent findings We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases. Summary FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis–FTD spectrum

Characterizing SOD1 mutations in Spain. The impact of genotype, age, and sex in the natural history of the disease

11 páginas, 3 figuras, 2 tablasIntroduction: The aim of this study is to describe the frequency and distribution of SOD1 mutations in Spain, and to explore those factors contributing to their phenotype and prognosis. Methods: Seventeen centres shared data on amyotrophic lateral sclerosis (ALS) patients carrying pathogenic or likely pathogenic SOD1 variants. Multivariable models were used to explore prognostic modifiers. Results: In 144 patients (from 88 families), 29 mutations (26 missense, 2 deletion/insertion and 1 frameshift) were found in all 5 exons of SOD1, including 7 novel mutations. 2.6% of ALS patients (including 17.7% familial and 1.3% sporadic) were estimated to carry SOD1 mutations. Its frequency varied considerably between regions, due to founder events. The most frequent mutation was p.Gly38Arg (n = 58), followed by p.Glu22Gly (n = 11), p.Asn140His (n = 10), and the novel p.Leu120Val (n = 10). Most mutations were characterized by a protracted course, and some of them by atypical phenotypes. Older age of onset was independently associated with faster disease progression (exp(Estimate) = 1.03 [0.01, 0.05], p = 0.001) and poorer survival (HR = 1.05 [1.01, 1.08], p = 0.007), regardless of the underlying mutation. Female sex was independently associated to faster disease progression (exp(Estimate) = 2.1 [1.23, 3.65], p = 0.012) in patients carrying the p.Gly38Arg mutation, resulting in shorter survival compared with male carriers (236 vs 301 months). Conclusions: These data may help to evaluate the efficacy of SOD1 targeted treatments, and to expand the number of patients that might benefit from these treatments.This study has received funding from: Instituto de Salud Carlos III (21/00737 PI J.F.V.C., 19/01178 PI T.S., PI 19/01543 to R.R.), cofunded by European Regional Development Fund (‘A way to make Europe’); STOPELA (2017/0653); I + D biomedicina 2017 from Comunidad de Madrid ‘ELA-Madrid’ (B2017/BMD-3813 to A.G.-R.); estrategias frente a Enfermedades Neurodegenerativas Ministerio de Sanidad – Comunidad de Madrid B.O.C.M. Num. 142 - Lunes 17 de junio de 2019 - Pág. 10 ‘Estudio genético de la población con ELA de la Comunidad de Madrid’ to A.G.-R. The Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) and the Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) are initiatives from the ISCIII. J.F.V.C., T.S., C.P., M.P., R.R.-G., J.T.S. and R.J.M. are members of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.Peer reviewe

Chemical Analysis of the Brightest Star of the Cetus II Ultrafaint Dwarf Galaxy Candidate

We present a detailed chemical abundance analysis of the brightest star in the ultrafaint dwarf (UFD) galaxy candidate Cetus II from high-resolution Magellan/MIKE spectra. For this star, DES J011740.53-173053, abundances or upper limits of 18 elements from carbon to europium are derived. Its chemical abundances generally follow those of other UFD galaxy stars, with a slight enhancement of the α-elements (Mg, Si, and Ca) and low neutron-capture element (Sr, Ba, and Eu) abundances supporting the classification of Cetus II as a likely UFD. The star exhibits lower Sc, Ti, and V abundances than Milky Way (MW) halo stars with similar metallicity. This signature is consistent with yields from a supernova originating from a star with a mass of ∼11.2 M ⊙. In addition, the star has a potassium abundance of [K/Fe] = 0.81, which is somewhat higher than the K abundances of MW halo stars with similar metallicity, a signature that is also present in a number of UFD galaxies. A comparison including globular clusters and stellar stream stars suggests that high K is a specific characteristic of some UFD galaxy stars and can thus be used to help classify objects as UFD galaxiesFunding for the DES Projects has been provided by the U.S. Department of Energy, the U.S. National Science Foundation, the Ministry of Science and Education of Spain, the Science and Technology Facilities Council of the United Kingdom, the Higher Education Funding Council for England, the National Center for Supercomputing Applications at the University of Illinois at Urbana Champaign, the Kavli Institute of Cosmological Physics at the University of Chicago, the Center for Cosmology and Astro-Particle Physics at the Ohio State University, the Mitchell Institute for Fundamental Physics and Astronomy at Texas A&M University, Financiadora de Estudos e Projetos, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Conselho Nacional de Desenvolvimento Científico e Tecnológico and the Ministério da Ciência, Tecnologia e Inovação, the Deutsche Forschungs-gemeinschaft and the Collaborating Institutions in the Dark Energy Surve

Cumulative Genetic Score and C9orf72 Repeat Status Independently Contribute to Amyotrophic Lateral Sclerosis Risk in 2 Case-Control Studies

[Background and Objectives] Most patients with amyotrophic lateral sclerosis (ALS) lack a monogenic mutation. This study evaluates ALS cumulative genetic risk in an independent Michigan and Spanish replication cohort using polygenic scores.[Methods] Participant samples from University of Michigan were genotyped and assayed for the chromosome 9 open reading frame 72 hexanucleotide expansion. Final cohort size was 219 ALS and 223 healthy controls after genotyping and participant filtering. Polygenic scores excluding the C9 region were generated using an independent ALS genome-wide association study (20,806 cases, 59,804 controls). Adjusted logistic regression and receiver operating characteristic curves evaluated the association and classification between polygenic scores and ALS status, respectively. Population attributable fractions and pathway analyses were conducted. An independent Spanish study sample (548 cases, 2,756 controls) was used for replication.[Results] Polygenic scores constructed from 275 single-nucleotide variation (SNV) had the best model fit in the Michigan cohort. An SD increase in ALS polygenic score associated with 1.28 (95% CI 1.04–1.57) times higher odds of ALS with area under the curve of 0.663 vs a model without the ALS polygenic score (p value = 1 × 10−6). The population attributable fraction of the highest 20th percentile of ALS polygenic scores, relative to the lowest 80th percentile, was 4.1% of ALS cases. Genes annotated to this polygenic score enriched for important ALS pathomechanisms. Meta-analysis with the Spanish study, using a harmonized 132 single nucleotide variation polygenic score, yielded similar logistic regression findings (odds ratio: 1.13, 95% CI 1.04–1.23).[Discussion] ALS polygenic scores can account for cumulative genetic risk in populations and reflect disease-relevant pathways. If further validated, this polygenic score will inform future ALS risk models.National ALS Registry/CDC/ATSDR (1R01TS000289); National ALS Registry/CDC/ATSDR CDCP-DHHS-US (CDC/ATSDR 200-2013-56856); NIEHS K23ES027221; NIEHS R01ES030049; NINDS R01NS127188, ALS Association (20-IIA-532), the Dr. Randall W. Whitcomb Fund for ALS Genetics, the Peter R. Clark Fund for ALS Research, the Scott L. Pranger ALS Clinic Fund, and the NeuroNetwork for Emerging Therapies at the University of Michigan. This work was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (Z01-AG000949-02). Project “ALS Genetic study in Madrid Autonomous Community” funded by “ESTRATEGIAS FRENTE A ENFERMEDADES NEURODEGENERATIVAS” from Spanish Ministry of Health.Peer reviewe

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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