Editorial Board Members’ Collection Series: “Amyotrophic Lateral Sclerosis: The Present and the Future of the Research”

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 10868

Special Issue Editors


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Guest Editor
ALS Center Department of Neurology “Maggiore della Carità” Hospital and University of Piemonte Orientale, 28100 Novara, Italy
Interests: amyotrophic lateral sclerosis; neurodegeneration; genetics; clinical trials; stem cells

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Guest Editor
Department of Health Science, University of Milan, 20122 Milano, Italy
Interests: neurophysiology; electrophysiology; neurodegeneration; neurology; EEG; cognitive neuroscience; neuroscience neuroimaging; physiology; cell biology

Special Issue Information

Dear Colleagues,

This Special Issue gathers a team of experts, both clinicians and basic scientists, to provide a comprehensive update of Amyotrophic Lateral Sclerosis (ALS). ALS is a fatal and uncurable neurodegenerative disease that targets motor neurons, leading to the complete paralysis of all voluntary muscles and death due to respiratory failure within 2-5 years from the onset.

Research in this field has greatly advanced in the last few decades. In this Special Issue, the authors present recent results that offer new insights into various perspectives of the disease from genetic and pathogenetic findings toward diagnosis and prognostic and diagnostic Biomarkers. Moreover, a dedicated session will focus on new insights into the development of advanced therapies for personalized treatments to cure or prevent this devastating disease.

Prof. Dr. Letizia Mazzini
Dr. Tommaso Bocci
Guest Editors

Manuscript Submission Information

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Keywords

  • amyotrophic lateral sclerosis
  • animal models
  • genetics
  • pathogenesis
  • diagnosis
  • clinical trials
  • personalized medicine

Published Papers (5 papers)

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Research

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7 pages, 485 KiB  
Communication
A Clinical Scale for Rating the Severity of Bulbar Lower Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis
by Stefano Zoccolella, Alessia Giugno, Giammarco Milella, Marco Filardi, Alessandro Introna, Angela Fraddosio, Eustachio D’Errico, Valentina Gnoni, Ludovica Tamburrino, Daniele Urso, Francesca Caputo, Salvatore Misceo and Giancarlo Logroscino
Biomedicines 2023, 11(7), 2039; https://doi.org/10.3390/biomedicines11072039 - 20 Jul 2023
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Abstract
Background: Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper (UMN) and lower motor neurons (LMN) in four different body regions (bulbar, cervical, thoracic, and lumbosacral). Over the past decades, several clinical scoring systems have been developed to assess the [...] Read more.
Background: Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper (UMN) and lower motor neurons (LMN) in four different body regions (bulbar, cervical, thoracic, and lumbosacral). Over the past decades, several clinical scoring systems have been developed to assess the UMN and LMN burden in ALS. However, concerning the bulbar LMN burden, the available scoring systems solely assess the presence/absence of bulbar LMN signs without providing a degree of impairment. Therefore, in this study, we proposed a novel scale to stratify subjects with ALS according to the bulbar LMN involvement and assessed its prognostic value. Methods: We developed a four-item scale based on the LMN signs according to the El Escorial criteria. Ten raters, specializing in ALS or neurocognitive disorders, retrospectively applied the scale to the first evaluation of 195 patients with ALS. Cohen’s kappa (Cohen’s k) and an intra-class correlation coefficient (ICC) were used to assess the inter-rater reliability. The Kaplan–Mayer estimator was used to estimate survival distribution according to the bulbar scale scores. Results: The raters showed a substantial to excellent agreement with Cohen’s k, ranging from 0.834 to 0.975, with an overall ICC of 0.922 (95% CI = 0.906–0.936). The survival distribution was statistically different across the three bulbar scale scores (χ2(2) = 9.50, p < 0.01). Conclusions: Our bulbar LMN scale represents a reliable measure of the bulbar LMN signs in ALS. This easy-to-administer clinical scale could provide unique information in phenotyping and predicting survival in ALS. Full article
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11 pages, 2647 KiB  
Article
Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects
by Wenjing Wang, Linjing Zhang, Kailin Xia, Tao Huang and Dongsheng Fan
Biomedicines 2023, 11(5), 1359; https://doi.org/10.3390/biomedicines11051359 - 04 May 2023
Cited by 2 | Viewed by 2423
Abstract
Background: Observational studies suggest that statins may affect amyotrophic lateral sclerosis (ALS). However, they are limited by confounding and reverse causality biases. Therefore, we aimed to investigate the potential causal associations between statins and ALS using a mendelian randomization (MR) approach. Methods: Two-sample [...] Read more.
Background: Observational studies suggest that statins may affect amyotrophic lateral sclerosis (ALS). However, they are limited by confounding and reverse causality biases. Therefore, we aimed to investigate the potential causal associations between statins and ALS using a mendelian randomization (MR) approach. Methods: Two-sample MR and drug-target MR were performed. Exposure sources included GWAS summary statistics of statin use, low-density-lipoprotein cholesterol (LDL-C), HMGCR-mediated LDL-C and LDL-C response to statins. Results: Genetic predisposition to statin medication was associated with increased ALS risk (OR = 1.085, 95% CI = 1.025–1.148, p = 0.005). After removing SNPs significantly associated with statin use from the instrumental variables (IVs), LDL-C-related higher ALS risk was absent (before removing: OR = 1.075, 95% CI = 1.013–1.141, p = 0.017; after removing: OR = 1.036, 95% CI = 0.949–1.131, p = 0.432). HMGCR-mediated LDL-C (OR = 1.033, 95% CI = 0.823–1.296, p = 0.779) and blood LDL-C response to statins (OR = 0.998, 95% CI = 0.991–1.005, p = 0.538) had no association with ALS. Conclusions: Here, we show that statins may be a risky exposure that increases ALS risk independent of the lowering effect of LDL-C in peripheral circulation. This provides insights into ALS development and prevention. Full article
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22 pages, 4417 KiB  
Article
Discovery of Biomarkers for Amyotrophic Lateral Sclerosis from Human Cerebrospinal Fluid Using Mass-Spectrometry-Based Proteomics
by Sungtaek Oh, Yura Jang and Chan Hyun Na
Biomedicines 2023, 11(5), 1250; https://doi.org/10.3390/biomedicines11051250 - 23 Apr 2023
Cited by 3 | Viewed by 2560
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons, which eventually may lead to death. Critical to the mission of developing effective therapies for ALS is the discovery of biomarkers that can illuminate [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons, which eventually may lead to death. Critical to the mission of developing effective therapies for ALS is the discovery of biomarkers that can illuminate mechanisms of neurodegeneration and have diagnostic, prognostic, or pharmacodynamic value. Here, we merged unbiased discovery-based approaches and targeted quantitative comparative analyses to identify proteins that are altered in cerebrospinal fluid (CSF) from patients with ALS. Mass spectrometry (MS)-based proteomic approaches employing tandem mass tag (TMT) quantification methods from 40 CSF samples comprising 20 patients with ALS and 20 healthy control (HC) individuals identified 53 proteins that are differential between the two groups after CSF fractionation. Notably, these proteins included both previously identified ones, validating our approach, and novel ones that have the potential for expanding biomarker repertoire. The identified proteins were subsequently examined using parallel reaction monitoring (PRM) MS methods on 61 unfractionated CSF samples comprising 30 patients with ALS and 31 HC individuals. Fifteen proteins (APOB, APP, CAMK2A, CHI3L1, CHIT1, CLSTN3, ERAP2, FSTL4, GPNMB, JCHAIN, L1CAM, NPTX2, SERPINA1, SERPINA3, and UCHL1) showed significant differences between ALS and the control. Taken together, this study identified multiple novel proteins that are altered in ALS, providing the foundation for developing new biomarkers for ALS. Full article
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Review

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27 pages, 2062 KiB  
Review
Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders
by Fabiola De Marchi, Ivana Munitic, Lea Vidatic, Eliša Papić, Valentino Rački, Jerneja Nimac, Igor Jurak, Gabriela Novotni, Boris Rogelj, Vladimira Vuletic, Rajka M. Liscic, Jason R. Cannon, Emanuele Buratti, Letizia Mazzini and Silva Hecimovic
Biomedicines 2023, 11(10), 2793; https://doi.org/10.3390/biomedicines11102793 - 14 Oct 2023
Cited by 4 | Viewed by 2005
Abstract
Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer’s (AD) disease, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann–Pick type C disease with primarily juvenile onset. [...] Read more.
Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer’s (AD) disease, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann–Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation. Full article
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31 pages, 2218 KiB  
Review
Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder
by Fabiola De Marchi, Toni Franjkic, Paride Schito, Tommaso Russo, Jerneja Nimac, Anna A. Chami, Angelica Mele, Lea Vidatic, Jasna Kriz, Jean-Pierre Julien, Gordana Apic, Robert B. Russell, Boris Rogelj, Jason R. Cannon, Marco Baralle, Federica Agosta, Silva Hecimovic, Letizia Mazzini, Emanuele Buratti and Ivana Munitic
Biomedicines 2023, 11(6), 1599; https://doi.org/10.3390/biomedicines11061599 - 31 May 2023
Cited by 7 | Viewed by 2421
Abstract
Proteinopathy and neuroinflammation are two main hallmarks of neurodegenerative diseases. They also represent rare common events in an exceptionally broad landscape of genetic, environmental, neuropathologic, and clinical heterogeneity present in patients. Here, we aim to recount the emerging trends in amyotrophic lateral sclerosis [...] Read more.
Proteinopathy and neuroinflammation are two main hallmarks of neurodegenerative diseases. They also represent rare common events in an exceptionally broad landscape of genetic, environmental, neuropathologic, and clinical heterogeneity present in patients. Here, we aim to recount the emerging trends in amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorder. Our review will predominantly focus on neuroinflammation and systemic immune imbalance in ALS and FTD, which have recently been highlighted as novel therapeutic targets. A common mechanism of most ALS and ~50% of FTD patients is dysregulation of TAR DNA-binding protein 43 (TDP-43), an RNA/DNA-binding protein, which becomes depleted from the nucleus and forms cytoplasmic aggregates in neurons and glia. This, in turn, via both gain and loss of function events, alters a variety of TDP-43-mediated cellular events. Experimental attempts to target TDP-43 aggregates or manipulate crosstalk in the context of inflammation will be discussed. Targeting inflammation, and the immune system in general, is of particular interest because of the high plasticity of immune cells compared to neurons. Full article
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