Molecular biomarkers associated with respiratory insufficiency in amyotrophic lateral sclerosis

Abstract in proceedings of the Fourth International Congress of CiiEM: Health, Well-Being and Ageing in the 21st Century, held at Egas Moniz’ University Campus in Monte de Caparica, Almada, from 3–5 June 2019.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.info:eu-repo/semantics/publishedVersio

Pathologic expansion in the C9orf72 gene is associated with accelerated decline of respiratory function and decreased survival in amyotrophic lateral sclerosis

Abstract in proceedings of the Fourth International Congress of CiiEM: Health, Well-Being and Ageing in the 21st Century, held at Egas Moniz’ University Campus in Monte de Caparica, Almada, from 3–5 June 2019.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.info:eu-repo/semantics/publishedVersio

Investigating LGALS3BP/90 K glycoprotein in the cerebrospinal fluid of patients with neurological diseases

© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Galectin-3 binding protein (LGALS3BP or 90 K) is a secreted glycoprotein found in human body fluids. Deregulated levels were observed in cancer and infection and its study in neurological diseases is more recent. Here, we have investigated 90 K from human cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS, n = 35) and other neurological diseases (n = 23). CSF was fractionated by ultrafiltration/size-exclusion chromatography (SEC) and eluted fractions were analysed by complementary techniques including immunoblotting, electron microscopy and nano-liquid chromatography-tandem mass spectrometry. A fraction of 90 K appeared as nanoparticles of irregular shape with heterogeneous dimensions of 15-60 nm that co-eluted with extracellular vesicles in SEC. Median levels of 90 K quantified by ELISA were not different between ALS patients (215.8 ng/ml) and controls (213.3 ng/ml) in contrast with the benchmark biomarker for ALS phosphoneurofilament heavy chain (1750 and 345 pg/ml, respectively). A multiregression model supported age is the only independent predictor of 90 K level in both groups (p < 0.05). Significant correlation was found between 90 K levels and age for the ALS group (r = 0.366, p = 0.031) and for all subjects (r = 0.392, p = 0.003). In conclusion, this study unveils the presence of 90 K-containing nanoparticles in human CSF and opens novel perspectives to further investigate 90 K as potential aging marker.This work was supported by Euronanomed 2 ERA-NET project GlioEx (ENMed/0001/2013), Fundação para a Ciência e a Tecnologia (FCT), Portugal; iNOVA4Health Research Unit (LISBOA-01–0145-FEDER-007344), which is cofunded by FCT/Ministério da Ciência e do Ensino Superior, through national funds; and by FEDER under the PT2020 Partnership Agreement.info:eu-repo/semantics/publishedVersio

Cerebrospinal fluid chitinases as biomarkers for Amyotrophic Lateral Sclerosis

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease that affects motor neurons controlling voluntary muscles. Survival is usually 2-5 years after onset, and death occurs due to respiratory failure. The identification of biomarkers would be very useful to help in disease diagnosis and for patient stratification based on, e.g., progression rate, with implications in therapeutic trials. Neurofilaments constitute already-promising markers for ALS and, recently, chitinases have emerged as novel marker targets for the disease. Here, we investigated cerebrospinal fluid (CSF) chitinases as potential markers for ALS. Chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1), chitinase-3-like protein 2 (CHI3L2) and the benchmark marker phosphoneurofilament heavy chain (pNFH) were quantified by an enzyme-linked immunosorbent assay (ELISA) from the CSF of 34 ALS patients and 24 control patients with other neurological diseases. CSF was also analyzed by UHPLC-mass spectrometry. All three chitinases, as well as pNFH, were found to correlate with disease progression rate. Furthermore, CHIT1 was elevated in ALS patients with high diagnostic performance, as was pNFH. On the other hand, CHIT1 correlated with forced vital capacity (FVC). The three chitinases correlated with pNFH, indicating a relation between degeneration and neuroinflammation. In conclusion, our results supported the value of CHIT1 as a diagnostic and progression rate biomarker, and its potential as respiratory function marker. The results opened novel perspectives to explore chitinases as biomarkers and their functional relevance in ALS.We acknowledge iNOVA4Health – UIDB/04462/2020 and UIDP/04462/2020, a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior, through national funds.info:eu-repo/semantics/publishedVersio

Differential Expression of miRNAs in Amyotrophic Lateral Sclerosis Patients

Funding Information: Open access funding provided by FCT|FCCN (b-on). This research was funded by Fundação de Ciência e Tecnologia (FCT), grant numbers PTDC/MEC-NEU/31195/2017, UID/BIM/0009/2020 and UIDP/00009/2020. Publisher Copyright: © 2023, The Author(s).Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control, muscle atrophy and in later stages, death. Diagnosis has an average delay of 1 year after symptoms onset, which impairs early management. The identification of a specific disease biomarker could help decrease the diagnostic delay. MicroRNA (miRNA) expression levels have been proposed as ALS biomarkers, and altered function has been reported in ALS pathogenesis. The aim of this study was to assess the differential expression of plasma miRNAs in ALS patients and two control populations (healthy controls and ALS-mimic disorders). For that, 16 samples from each group were pooled, and then 1008 miRNAs were assessed through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). From these, ten candidate miRNAs were selected and validated in 35 ALS patients, 16 ALS-mimic disorders controls and 15 healthy controls. We also assessed the same miRNAs in two different time points of disease progression. Although we were unable to determine a miRNA signature to use as disease or condition marker, we found that miR-7-2-3p, miR-26a-1-3p, miR-224-5p and miR-206 are good study candidates to understand the pathophysiology of ALS.publishersversionepub_ahead_of_prin

Roles of Vascular Endothelial Growth Factor in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal devastating neurodegenerative disorder, involving progressive degeneration of motor neurons in spinal cord, brainstem, and motor cortex. Riluzole is the only drug approved in ALS but it only confers a modest improvement in survival. In spite of a high number of clinical trials no other drug has proved effectiveness. Recent studies support that vascular endothelial growth factor (VEGF), originally described as a key angiogenic factor, also plays a key role in the nervous system, including neurogenesis, neuronal survival, neuronal migration, and axon guidance. VEGF has been used in exploratory clinical studies with promising results in ALS and other neurological disorders. Although VEGF is a very promising compound, translating the basic science breakthroughs into clinical practice is the major challenge ahead. VEGF-B, presenting a single safety profile, protects motor neurons from degeneration in ALS animal models and, therefore, it will be particularly interesting to test its effects in ALS patients. In the present paper the authors make a brief description of the molecular properties of VEGF and its receptors and review its different features and therapeutic potential in the nervous system/neurodegenerative disease, particularly in ALS

Young-onset rapidly progressive ALS associated with heterozygous FUS mutation

© 2017 World Federation of Neurology on behalf of the Research Group on Motor Neuron DiseasesWe report a 36-years-old Cape Verdean man who presented with respiratory insufficiency due to rapidly progressive sporadic amyotrophic lateral sclerosis (ALS), in whom FUS mutation c.1551C > G (p.Hist517Gln) in heterozygosity was identified, a finding previously described as non-pathogenic. The only previous report on this mutation was in a family from Cape Verde in which four members developed ALS; all were homozygous for the mutation. This case shows that this FUS mutation presents a highly variable penetrance and expressivity.This work was partially supported by OnWebDuals project (JPND-PS/0001/2013) and MG holds a grant from the project. This is an EU Joint Programme - Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisation under the aegis of JPND - www.jpnd.eu: Germany, Bundesministerium für Bildung und Forschung (BMBF); Poland, Narodowe Centrum Badań i Rozwoju (NCBiR); Portugal, Fundação a Ciência e a Tecnologia (FCT); Sweden, Vetenskapsrådet (VR).info:eu-repo/semantics/publishedVersio

Clinical characteristics in amyotrophic lateral sclerosis with Sub-Saharan Africa ancestry: a Portuguese hospital-based cohort study

© 2023 Elsevier B.V. All rights reserved.Amyotrophic lateral sclerosis (ALS) is a rapidly progressive condition characterized by upper and lower motor neuron loss. Over the last decades, epidemiological and clinical data from European, North America and high-incoming Asia-Pacific countries has been extensively collected and analyzed, improving the knowledge regarding ALS. However, ALS had not been reported in Africans until 1955. Even today, data from Africa is scarce. A systematic review on ALS in African patients identified common features when compared with Western ones: a higher male predominance, more frequent younger onset. Other clinical aspects, including cognition, prognosis, genetic, and survival are still a matter of debate. Moreover, there are significant differences between African and Western societies, concerning not only genetic background and environmental factors, but also access to health care system and proper treatments, which particularly may influence survival.Project Brainteaser-Bringing Artificial Intelligence home for a better care of amyotrophic lateral sclerosis and multiple sclerosis funded by the European Union’ Horizon 2020 research and innovation program under Grant Agreement No. GA101017598.info:eu-repo/semantics/publishedVersio

Interleukin-6 and amyotrophic lateral sclerosis

© 2019 Published by Elsevier B.V.Background: IL-6 is an inflammatory cytokine that is a possible factor in progression of the disease. We have investigated venous blood levels of IL-6 in controls and ALS patients in relation to clinical staging and respiratory function. Methods: We studied 82 patients with ALS and 43 age and gender-matched healthy control subjects. Blood was drawn at the same time of day in the mornings to avoid diurnal variation. IL-6 levels were estimated according to a fixed protocol. Clinical measures included ALSFRS-R, vital capacity, and mean bilateral phrenic nerve CMAP amplitude. A multi-regression data analysis was used in addition to conventional statistical methods. Results: IL-6 levels were positively correlated with increasing age in the control group. In ALS patients mean IL-6 levels were raised but the levels were markedly variable from case to case and did not reach significance (p 0.1). In addition to age effects reduction in phrenic nerve CMAP amplitude was correlated with increased IL-6 levels (p 0.026). Conclusions: IL-6 levels were physiologically influenced by aging in controls and by respiratory dysfunction in ALS. There was marked variability in levels from case to case, which might be related to respiratory factors, which cause pulmonary inflammation.This work was partially supported by ONWebDuals (JPND-PS/ 0001/2013), an EU Joint Program - Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND - www.jpnd.eu: Germany, Bundesministerium für Bildung und Forschung (BMBF); Poland, Narodowe Centrum Badań i Rozwoju (NCBiR); Portugal, Fundação a Ciência e a Tecnologia (FCT); Sweden, Vetenskapsrådet (VR).info:eu-repo/semantics/publishedVersio

Novel TBK1 LoF variant in a family with upper motor neuron predominant motor neuron disease

© 2019 Elsevier B.V. All rights reserved.Amyotrophic lateral sclerosis (ALS) is usually sporadic, but 20% of European ancestry cases have a family history of ALS or frontotemporal dementia (FTD). More than 30 genes confer a higher risk for ALS, and C9orf72, TARDBP, SOD1 and FUS account for nearly 70% of all familial (fALS) cases. Tank-binding kinase 1 (TBK1) is an established causal gene associated with 1% of fALS and/or FTD. It codes for a multifunctional kinase involved in multiple cellular processes, such as neuroinflammation and autophagy. Both loss-of-function (LoF) and missense mutations are associated with an increased risk for ALS-FTD spectrum and mutations that cause a 50% reduction of TBK1 protein levels are considered pathogenic.info:eu-repo/semantics/publishedVersio