Voiceprint and machine learning models for early detection of bulbar dysfunction in ALS

Background and Objective: Bulbar dysfunction is a term used in amyotrophic lateral sclerosis (ALS). It refers to motor neuron disability in the corticobulbar area of the brainstem which leads to a dysfunction of speech and swallowing. One of the earliest symptoms of bulbar dysfunction is voice deterioration char-acterized by grossly defective articulation, extremely slow laborious speech, marked hypernasality and severe harshness. Recently, research efforts have focused on voice analysis to capture this dysfunction. The main aim of this paper is to provide a new methodology to diagnose this dysfunction automatically at early stages of the disease, earlier than clinicians can do.Methods: The study focused on the creation of a voiceprint consisting of a pattern generated from the quasi-periodic components of a steady portion of the five Spanish vowels and the computation of the five principal and independent components of this pattern. Then, a set of statistically significant features was obtained using multivariate analysis of variance and the outcomes of the most common supervised classification models were obtained.Results: The best model (random forest) obtained an accuracy, sensitivity and specificity of 88.3%, 85.0% and 95.0% respectively when classifying bulbar vs. control participants but the results worsened when classifying bulbar vs. no-bulbar patients (accuracy, sensitivity and specificity of 78.7%, 80.0% and 77.5% respectively for support vector machines). Due to the great uncertainty found in the annotated corpus of the ALS patients without bulbar involvement, we used a safe semi-supervised support vector machine to relabel the ALS participants diagnosed without bulbar involvement as bulbar and no-bulbar. The perfor-mance of the results obtained increased, especially when classifying bulbar and no-bulbar patients ob-taining an accuracy, sensitivity and specificity of 91.0%, 83.3% and 100.0% respectively for support vector machines. This demonstrates that our model can improve the diagnosis of bulbar dysfunction compared not only with clinicians, but also the methods published to date.Conclusions: The results obtained demonstrate the efficiency and applicability of the methodology pre-sented in this paper. It may lead to the development of a cheap and easy-to-use tool to identify this dysfunction in early stages of the disease and monitor progress

Elevated Cerebrospinal Fluid Proteins and Albumin Determine a Poor Prognosis for Spinal Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease, both in its onset phenotype and in its rate of progression. The aim of this study was to establish whether the dysfunction of the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) measured through cerebrospinal fluid (CSF) proteins and the albumin-quotient (QAlb) are related to the speed of disease progression. An amount of 246 patients diagnosed with ALS were included. CSF and serum samples were determined biochemically for different parameters. Survival analysis based on phenotype shows higher probability of death for bulbar phenotype compared to spinal phenotype (p-value: 0.0006). For the effect of CSF proteins, data shows an increased risk of death for spinal ALS patients as the value of CSF proteins increases. The same model replicated for CSF albumin yielded similar results. Statistical models determined that the lowest cut-off value for CSF proteins able to differentiate patients with a good prognosis and worse prognosis corresponds to CSF proteins >= 0.5 g/L (p-value: 0.0189). For the CSF albumin, the QAlb >= 0.65 is associated with elevated probability of death (p-value: 0.0073). High levels of QAlb are a bad prognostic indicator for the spinal phenotype, in addition to high CSF proteins levels that also act as a marker of poor prognosis

La esclerosis lateral amiotrófica (ELA) desde la Atención Primaria. Epidemiología y características clínico-asistenciales

La ELA es una enfermedad poco frecuente en atención primaria (AP), representa un desafío para el médico de familia especialmente en atención domiciliaria. Objetivo Conocer la incidencia y prevalencia de la ELA en un área de gestión de AP, las características clínicas y la utilización de recursos sanitarios. Diseño Estudio observacional. Emplazamiento Dirección de AP Costa de Ponent, Región Sanitaria Metropolitana Sur, Barcelona, Cataluña, España. Participantes Pacientes con ELA ≥18 años diagnosticados hasta el 01/03/2017. Mediciones principales Edad, sexo, características: forma de inicio (espinal, bulbar, otras), intervalo entre inicio de síntomas y diagnóstico, portadores gastrostomía percutánea, ventilación no invasiva o invasiva. Identificación en AP como paciente crónico complejo o con necesidades paliativas. Inclusión en programas de atención domiciliaria (PAD). Modelo de atención hospitalario. Resultados Ochenta y un pacientes, edad media 65,6 años (±11,7), varones 49,4%. Forma de inicio: espinal 69%, bulbar 21%, otras 4%. Intervalo entre inicio de síntomas y diagnóstico 12 meses. Identificados como paciente crónico complejo o con necesidades paliativas 13,6%, incluidos en PAD 29 pacientes (35,8%). Atendidos en modelo hospitalario integral 79 pacientes (97,5%). Prevalencia 6,1/100.000 habitantes en 2017. Incidencia anual entre 1,2 casos/100.000 habitantes/año en 2012 y 3,5 casos/100.000 habitantes/año en 2016. Conclusiones Utilizar gastrostomía percutánea en la ELA favorece la identificación como paciente crónico complejo o con necesidades paliativas e inclusión en PAD. Utilizar ventilación no invasiva favorece la inclusión en PAD. Los datos de incidencia y prevalencia de ELA son superiores a los descritos previamente en la misma área. Es necesaria la identificación precoz de estos pacientes en los modelos de atención a la cronicidad en equipos de AP

Estudio bibliométrico de la investigación educativa en las universidades de Andalucía en el SSCI (2002-2010)

The ten Andalusian public universities have a total figure of 1312 professors linked to departments related to educational research. According to this, it could be said that there are enough research staff to make educational scientific production visible. Despite the fact that there are previous studies on Spanish educational production, these are not focused in Andalusia as a whole. The goal is to analyse the educational production, indexed in the Social Sciences Citation Index database (SSCI), carried out by researchers affiliated to some of the Andalusian universities. In particular, we analyse co-authorship patterns, diachronic production, language of the publication and the production per university. We utilize usual bibliometrical techniques for collecting and analysing data. We make the search in the SSCI from which we filter the information and download it. We used a local relational database made for this purpose. A standardization process of the author name and institution was made. An exponential rise of the production analysed is observed, partially due to the increment of educational journals that are indexed by the SSCI along the period studied. Spanish journals have the highest production rate. Likewise, a collaboration networks between Andalusian universities and others was revealed. The research articles are the 89.7% of the whole production analysed. The resulting collaboration index is slightly higher than others found in previous studies in the fields of Social Sciences and Education. In addition, it is shown that the collaboration among the Andalusian universities is lowLas diez universidades públicas de Andalucía cuentan con 1312 profesores en departamentos directamente relacionados con la investigación educativa por lo que existe un número de personal docente e investigador (PDI) suficiente para hacer visible la producción científica asociada al sector educativo. Existen estudios sobre la producción educativa española, pero no centrados en la Comunidad Autónoma Andaluza. Por ello consideramos pertinente y de interés abordar un estudio en tal sentido. El objetivo es analizar la producción sobre Educación en el campo de las Ciencias Sociales de los investigadores vinculados a las universidades andaluzas en la base de datos Social Science Citation Index (SSCI). Analizaremos patrones de coautoría, la producción diacrónica, el idioma y la producción por universidades. Se utilizaron técnicas bibliométricas usuales para la toma y análisis de los datos. Se descargó la información utilizando varios filtros y se volcó en una base de datos relacional y ad hoc. Se tomaron los nombres de todo el profesorado universitario andaluz para estandarizar su firma y su institución. Se observó un crecimiento exponencial de la producción generada por el reciente incremento de revistas de Educación en SCCI. El mayor porcentaje de producción está en revistas españolas. Se evidenció la colaboración existente entre universidades de Andalucía y el resto de universidades españolas y norteamericanas. El 89,7% de la producción corresponde a artículos de investigación. La colaboración en estos documentos es ligeramente mayor a otras establecidas en estudios previos sobre Ciencias Sociales o Educación. Asimismo hay la poca colaboración institucional entre las propias universidades andaluzas

Cognitive decline in amyotrophic lateral sclerosis: Neuropathological substrate and genetic determinants

Proteïna TDP-43; Esclerosi lateral amiotròfica; Demència frontotemporalProteína TDP-43; Esclerosis lateral amiotrófica; Demencia frontotemporalTDP-43 protein; Amyotrophic lateral sclerosis; Frontotemporal dementiaCognitive impairment and behavioral changes in amyotrophic lateral sclerosis (ALS) are now recognized as part of the disease. Whether it is solely related to the extent of TDP-43 pathology is currently unclear. We aim to evaluate the influence of age, genetics, neuropathological features, and concomitant pathologies on cognitive impairment in ALS patients. We analyzed a postmortem series of 104 ALS patients and retrospectively reviewed clinical and neuropathological data. We assessed the burden and extent of concomitant pathologies, the role of APOE ε4 and mutations, and correlated these findings with cognitive status. We performed a logistic regression model to identify which pathologies are related to cognitive impairment. Cognitive decline was recorded in 38.5% of the subjects. Neuropathological features of frontotemporal lobar degeneration (FTLD) were found in 32.7%, explaining most, but not all, cases with cognitive impairment. Extent of TDP-43 pathology and the presence of hippocampal sclerosis were associated with cognitive impairment. Mutation carriers presented a higher burden of TDP-43 pathology and FTLD more frequently than sporadic cases. Most cases (89.4%) presented some degree of concomitant pathologies. The presence of concomitant pathologies was associated with older age at death. FTLD, but also Alzheimer’s disease, were the predominant underlying pathologies explaining the cognitive impairment in ALS patients. In sum, FTLD explained the presence of cognitive decline in most but not all ALS cases, while other non-FTLD related findings can influence the cognitive status, particularly in older age groups.SBE is a recipient of the Rio-Hortega post-residency grant from the Instituto de Salud Carlos III, Spain. This study was partially funded by Fundació Marató de TV3 (grant no. 20141610 to EG and no. 20143710 to RRG) and Fondo Europeo de Desarrollo Regional (FEDER) (PI15/01618 to RRG). AA is funded by Departament de Salut de la Generalitat de Catalunya, Pla estratègic de recerca i innovació en salut (PERIS) 2016–2020 (SLT002/16/00329). JG is recipient of the Instituto de Salud Carlos III-FEDER grants (PI16/01673 and PI19/00593

Impact of Early Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis: A multicenter Randomized Controlled Trial

Background and objective: Forced vital capacity (FVC) less than 50% of predicted is one of the main parameters used for Non-Invasive Ventilation (NIV) initiation in Amyotrophic Lateral Sclerosis (ALS). Recent studies suggest that higher values of FVC could be considered as a threshold. The aim of this study is to evaluate whether early use of NIV improves the prognosis of ALS patients compared with standard initiation. Methods: This is a randomized, parallel, multicenter, open-label, controlled clinical trial, with recruitment at the ALS outpatient multidisciplinary units of six Spanish hospitals. Patients were included when their FVC reached the 75% threshold and were randomized by computer, stratifying by center in an allocation ratio of 1:1 to Early NIV (FVC below 75%) or Standard NIV (FVC below 50%) initiation. The primary outcome was time to death or tracheostomy. Trial registration number ClinicalTrials.gov: NCT01641965. Results: Between May 2012 and June 2014, 42 patients were randomized to two groups, 20 to Early NIV and 22 to Standard NIV initiation. We found differences in survival in favor of the intervention group: an incidence of mortality (2.68 [1.87-5.50] vs. 3.33 [1.34-4.80] person-months) and a median survival (25.2 vs. 19.4 months), although without reaching statistical significance (p = 0.267). Conclusions: This trial did not reach the primary endpoint of survival; nevertheless, it is the first Randomized Controlled Trial (RCT) to demonstrate the benefits of early NIV in slowing the decline of respiratory muscle strength and reducing adverse events. Although not all the results reached statistical significance, all the analyzed data favor early NIV. In addition, this study demonstrates good tolerance and compliance with early NIV without quality of sleep impairment. These data reinforce the early respiratory evaluation of ALS patients and NIV initiation with an FVC of around 75%

Comparison of zebrafish and mice knockouts for Megalencephalic Leukoencephalopathy proteins indicates that GlialCAM/MLC1 forms a functional unit

Background: Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) is a rare type of leukodystrophy characterized by astrocyte and myelin vacuolization, epilepsy and early-onset macrocephaly. MLC is caused by mutations in MLC1 or GLIALCAM, coding for two membrane proteins with an unknown function that form a complex specifically expressed in astrocytes at cell-cell junctions. Recent studies in Mlc1-/- or Glialcam-/- mice and mlc1-/- zebrafish have shown that MLC1 regulates glial surface levels of GlialCAM in vivo and that GlialCAM is also required for MLC1 expression and localization at cell-cell junctions. Methods: we have generated and analysed glialcama-/- zebrafish. We also generated zebrafish glialcama-/- mlc1-/- and mice double KO for both genes and performed magnetic resonance imaging, histological studies and biochemical analyses. Results: glialcama-/- shows megalencephaly and increased fluid accumulation. In both zebrafish and mice, this phenotype is not aggravated by additional elimination of mlc1. Unlike mice, mlc1 protein expression and localization are unaltered in glialcama-/- zebrafish, possibly because there is an up-regulation of mlc1 mRNA. In line with these results, MLC1 overexpressed in Glialcam-/- mouse primary astrocytes is located at cell-cell junctions. Conclusions: this work indicates that the two proteins involved in the pathogenesis of MLC, GlialCAM and MLC1, form a functional unit, and thus, that loss-of-function mutations in these genes cause leukodystrophy through a common pathway

Intermediate Repeat Expansion in the ATXN2 Gene as a Risk Factor in the ALS and FTD Spanish Population

Intermediate CAG expansions in the gene ataxin-2 (ATXN2) are a known risk factor for ALS, but little is known about their role in FTD risk. Moreover, their contribution to the risk and phenotype of patients might vary in populations with different genetic backgrounds. The aim of this study was to assess the relationship of intermediate CAG expansions in ATXN2 with the risk and phenotype of ALS and FTD in the Spanish population. Repeat-primed PCR was performed in 620 ALS and 137 FTD patients in three referral centers in Spain to determine the exact number of CAG repeats. In our cohort, >= 27 CAG repeats in ATXN2 were associated with a higher risk of developing ALS (odds ratio [OR] = 2.666 [1.471-4.882]; p = 0.0013) but not FTD (odds ratio [OR] = 1.446 [0.558-3.574]; p = 0.44). Moreover, ALS patients with >= 27 CAG repeats in ATXN2 showed a shorter survival rate compared to those with = 27 repeats in ATXN2 are associated with ALS risk but not with FTD in the Spanish population. ALS patients carrying an intermediate expansion in ATXN2 show more frequent limb onset but a worse prognosis than those without expansions. In patients carrying C9orf72 expansions, the intermediate ATXN2 expansion might increase the penetrance and modify the phenotype

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