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In amyotrophic lateral sclerosis (ALS) lower plasma creatinine level has been associated with shorter survival and faster functional decline. It has not been clear if creatinine is associated with respiratory outcome. We analyzed retrospectively a population of unselected ALS patients. Multiple-regression and Cox-regression analyses were performed. We included 233 patients, mean age 62.8, mean disease duration of 18.6 months. At baseline, creatinine was significantly associated with ALSFRS-R, but not with its decline rate. No predictive value was disclosed for FVC, its decline rate, or with survival. We did not confirm that creatinine is a marker of respiratory outcome.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with clinical and etiological heterogeneity and a complex genetic contribution. Clinical, neuropathological, and genetic evidence revealed that ALS and frontotemporal dementia (FTD) are in part of a single disease continuum. Genetic causes have been identified in sporadic (SALS) and familial patients (FALS) and the recurrent genetic factor underlying ALS and FTD is the C9orf72 hexanucleotide repeat expansion (HRE). However, in our population, the concomitance of ALS and FTD cannot be explained by C9orf72 HRE in many FALS and SALS cases. Our aim is to further understand the genetic basis of ALS in Portuguese patients. 34 patients with FALS or SALS-FTD, negative for C9orf72 HRE, were screened for rare variants in a panel of 29 relevant genes by next-generation sequencing. We detected 15 variants in 11 genes, one classified as pathogenic in TARDBP, two as likely pathogenic in TARDBP and PRPH, and the others as variants of unknown significance (VUS). Gene variants, including VUS, were found in 41.2% FALS patients and 40% SALS-FTD. In most patients, no potential pathogenic variants were found. Our results emphasize the need to enhance the efforts to unravel the genetic architecture of ALS-FTD. info:eu-repo/semantics/publishedVersion

© 2021 Elsevier B.V. All rights reserved., Background: The role of cardiovascular risk factors in amyotrophic lateral sclerosis (ALS) is controversial. A favourable profile has been found in ALS patients, but previous studies have not specifically considered the profile in different disease phenotypes. Methods: Demographic data, smoking habits, lifetime exercise, and medical history including diabetes mellitus, arterial hypertension, hypercholesterolemia, hypertriglyceridemia, stroke, and cardiac events, were analysed in ALS patients and in controls with other neurological disorders, utilising a standardized questionnaire applied by the same neurologist. In ALS patients the results were analysed according to their different phenotypes. Univariate analyses and multinomial logistic models were applied to estimate the odds ratios (ORs) and confidence intervals (CIs) for covariates, to test potential modifiers and their effects. Results: 500 consecutively assessed adult ALS patients (mean age 65.6, 47% women, and 136 bulbar-onset) and 327 age and gender-matched controls were studied. Patients with spinal-onset ALS took more exercise (p = 0.012), reported less hypertension (p = 0.002) and had fewer cardiac events (p = 0.012). Multinomial regression analysis showed that men without hypertension have a higher risk of having spinal-onset ALS (p < 0.001) while female with hypertension have a higher risk of having bulbar-onset ALS (p = 0.033). Conclusions: Risk-factors in ALS can be influenced by gender and phenotype. This study suggests that men with spinal ALS are healthier, exercise more and have lower rate of hypertension, but females with bulbar-onset ALS are more prone to hypertension. The complex interplay between exercise, diet and comorbidities with ALS phenotype requires further investigation., This study is included in the ONWebDUALS project (JPND-PS/0001/2013) initiative. This is an EU Joint Program – Neurodegenerative Disease Research (JPND) project – Fundação para a Ciência e a Tecnologia (JPND-PS/0001/2013).

© 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.

Previous genetic studies have identified local population structure within the Netherlands; however their resolution is limited by use of unlinked markers and absence of external reference data. Here we apply advanced haplotype sharing methods (ChromoPainter/fineSTRUCTURE) to study fine-grained population genetic structure and demographic change across the Netherlands using genome-wide single nucleotide polymorphism data (1,626 individuals) with associated geography (1,422 individuals). We identify 40 haplotypic clusters exhibiting strong north/south variation and fine-scale differentiation within provinces. Clustering is tied to country-wide ancestry gradients from neighbouring lands and to locally restricted gene flow across major Dutch rivers. North-south structure is temporally stable, with west-east differentiation more transient, potentially influenced by migrations during the middle ages. Despite superexponential population growth, regional demographic estimates reveal population crashes contemporaneous with the Black Death. Within Dutch and international data, GWAS incorporating fine-grained haplotypic covariates are less confounded than standard methods., Genetic variation in modern humans can reveal information about a population’s history and migration patterns. Here, the authors describe the ancestry and geospatial genetic structure of the Netherlands, and demonstrate the utility of haplotype-based covariates in genome-wide association studies.

A hexanucleotide repeat expansion in the C9orf72 gene is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. It has been described before four patients with multiple sclerosis (MS) and C9orf72-ALS. However, C9orf72 positivity is not associated with increased risk of MS. Inflammatory pathways related to NF-κB have been linked to ALS and MS, and appear to be important in C9orf72-ALS patients. A 42-year-old woman presented with progressive bulbar symptoms for 9 months. Neurological examination disclosed spastic dysarthria, atrophic tongue with fasciculations, brisk jaw and limb tendon reflexes, and bilateral Hoffman sign. Electrophysiological assessment confirmed ALS. Brain MRI revealed multiple and bilateral juxtacortical and periventricular inflammatory changes, some with gadolinium-enhancement, configuring a probable MS-like pattern. CSF evaluation was unremarkable, with no oligoclonal bands. Visual and somatosensory evoked potentials were normal. Follow-up brain MRI 6 months later showed two new lesions in two relatively characteristic locations of MS, with no gadolinium-enhancement. Genetic screening revealed a C9orf72 expansion. As patient had no clinical manifestation of MS, a diagnosis of radiologically isolated syndrome was considered. We speculate that these demyelinating lesions might facilitate expressivity of C9orf72 expansion, through NF-κB activation. This plausible association may lead to the identification of a therapeutic target in this subgroup of C9orf72-ALS patients.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle paralysis. Respiratory complications are the main cause of death in ALS. For this reason, initial respiratory status and its decline over disease progression are strong independent predictors of survival. Riluzole, a glutamatergic neurotransmission inhibitor, is the only drug that has shown to extend survival. Therefore, both novel molecular biomarkers and treatment strategies are needed. Transforming growth factor-β (TGF-β) family cytokines are important regulators of cell fate affecting both neurogenesis and neurodegeneration. Several studies demonstrate that TGF-β signalling protects neurons from glutamate-mediated excitotoxicity, a recognized mechanism underlying the pathogenesis of various neurodegenerative disorders such as ALS. Recent studies report dysregulations of the TGF-β system as a common feature of neurodegenerative disorders. The upregulation of this system has been linked with ALS progression. We have quantified TGF-β1, TGF-β2 and TGF-β3 serum levels in 23 ALS patients and 12 healthy controls, our preliminary results support the hypothesis that TGF-β3 levels can be a marker disease severity ALS. Further results are necessary to confirm this hypothesis.

© 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.

© 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).

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease for which the existing candidate biomarkers (neurofilaments) have low specificity. Changes in blood IgG N-glycosylation have been observed in several diseases, including ALS, whereas cerebrospinal fluid (CSF) IgG has been less studied. Here, we characterized N-glycans of CSF IgG from ALS patients in comparison with a control group of other neurological diseases. Cerebrospinal fluid was collected from patients with ALS (n = 26) and other neurological diseases (n = 10). N-Glycans were released from CSF purified IgG with peptide N-glycosidase F, labeled with 2-aminobenzamide and analyzed by NP-HPLC chromatography in combination with exoglycosidase digestion and MALDI-TOF mass spectrometry. The N-glycosylation profile of ALS CSF IgG consisted of diantennary N-glycans predominantly with proximal fucose and some bisecting GlcNAc; agalacto-, mono-, and digalactosylated as well as α2,6-sialylated structures were detected. Differences between ALS and control patients were observed; most relevant was the increase in ALS CSF IgG of the level of galactosylated structures defined here as Gal-index (median 46.87 and 40.50% for ALS and controls, respectively; p = 0.006). The predictive value of the Gal-index (AUC = 0.792, p = 0.007) considering ROC analysis had potential utility as a diagnostic test for ALS and was comparable to that of phosphoneurofilament heavy chain (AUC = 0.777, p = 0.011), which was used as benchmark marker for our group of patients. The results provide the basis to further explore the potential of IgG N-glycan galactosylation as biomarker for ALS by using larger cohorts of patients and controls.

© 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.

Objectives The club cell protein (CC-16) is a biomarker associated with respiratory distress and pulmonary inflammation. We evaluated CC-16 as a candidate biomarker for respiratory failure in amyotrophic lateral sclerosis (ALS). Materials and methods We studied 81 ALS patients and 30 matched controls. We used an ALS-related measure of functional capacity, and tested forced vital capacity (FVC) and the amplitude of the diaphragmatic response by phrenic nerve stimulation (PhrenAmpl). Plasma CC-16 levels were measured in venous blood. Kaplan-Meier survival curves were plotted to evaluate risk to non-invasive ventilation and death in patients with abnormal CC-16 levels. Results CC-16 levels were significantly raised in ALS patients (10.56 ng/mL ± 6.84 vs 8.34 ng/mL ± 3.10, P = .02), and in 17% of them, CC-16 level was above the upper cutoff value (mean + 2.5SD). CC-16 levels did not correlate with age, onset region, disease duration, functional status, FVC, and PhrenAmpl. In patients with increased CC-16 level, the risk of non-invasive was greater in the following 6 months (P = .01) and tended to have higher mortality in the following 30 months (P = .07). Conclusions We propose that increased CC-16 levels is a marker of lung inflammatory response that associated with ventilatory insufficiency are related to impending respiratory failure, not fully predicted by conventional respiratory tests. The latter are limited by the moment of testing.

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.

Mutation frequency of the 2 main amyotrophic lateral sclerosis (ALS)-related genes, C9orf72 and SOD1, varies considerably across the world. We analyzed those genes in a large population of Portuguese ALS patients (n = 371) and recorded demographic and clinical features. Familial ALS (FALS) was disclosed in 11.6% of patients. Mutations in either SOD1 or C9orf72 were found in 9.2% of patients and accounted for 40% of FALS and 5.2% of sporadic ALS. SOD1 mutations were rare (0.83%), but a novel and probably disease-causing mutation was identified: p.Ala152Pro (c.457GC). The C9orf72 hexanucleotide repeat expansion was the commonest abnormality, accounting for 4.6% of sporadic ALS and 37.5% of FALS; in these patients, Frontotemporal Dementia was prevalent. This first report on the frequency of C9orf72 hexanucleotide repeat expansion and SOD1 mutations in Portuguese ALS patients reiterate that the genetic architecture of ALS varies among different geographic regions. The mutations incidence in ALS patients (∼10%) and associated phenotypes suggest that genetic tests should be offered to more patients, and other genes should be investigated in our population.

© IOS Press and the authors. All rights reserved, INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease of the motor system. It has been hypothesised that red blood cells (RBCs) may be involved in the disease process by the release of damaging molecules. OBJECTIVE: The aim of this ex vivo study is to compare RBCs biochemical and hemorheological parameters between ALS patients and healthy donors to identify novel biomarkers of the ALS disease. METHODS: We included 82 ALS patients and 40 gender age-matched healthy donors. We performed quantification of erythrocyte aggregation and deformability, nitric oxide (NO) efflux from RBCs, acetylcholinesterase (AChE) enzyme activity and intraerythrocytic concentration of nitrite, nitrate and S-nitrosogluthatione (GSNO). RESULTS: Erythrocyte deformability and AChE activity were increased in patients with ALS in comparison to healthy donors. NO efflux from RBCs and concentration of intraerythrocytic nitrite were lower in ALS patients. In patients, we found that for higher NO range of values the respiratory function is worse and that for higher AChE range of values the RBCs nitrite content increase. CONCLUSION: The results of the present study indicate that NO efflux from RBCs and RBCs AChE should be further explored as potential biomarkers for ALS.