International Journal of Molecular Sciences

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Open AccessEditorial

Amyotrophic Lateral Sclerosis as a Systemic Disease

by Viviana Moresi

Int. J. Mol. Sci. 2023, 24(8), 7083; https://doi.org/10.3390/ijms24087083 - 11 Apr 2023

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Abstract

The goal of this Special Issue is to report new research progress and reviews concerning amyotrophic lateral sclerosis (ALS) [...] Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis as a Systemic Disease)

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Open AccessArticle

Distinct Plasma Immune Profile in ALS Implicates sTNFR-II in pAMPK/Leptin Homeostasis

by Vincent Picher-Martel, Hejer Boutej, Alexandre Vézina, Pierre Cordeau, Hannah Kaneb, Jean-Pierre Julien, Angela Genge, Nicolas Dupré and Jasna Kriz

Int. J. Mol. Sci. 2023, 24(6), 5065; https://doi.org/10.3390/ijms24065065 - 7 Mar 2023

Cited by 6 | Viewed by 2134

Abstract

Amyotrophic lateral sclerosis (ALS) is a clinically highly heterogeneous disease with a survival rate ranging from months to decades. Evidence suggests that a systemic deregulation of immune response may play a role and affect disease progression. Here, we measured 62 different immune/metabolic mediators [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a clinically highly heterogeneous disease with a survival rate ranging from months to decades. Evidence suggests that a systemic deregulation of immune response may play a role and affect disease progression. Here, we measured 62 different immune/metabolic mediators in plasma of sporadic ALS (sALS) patients. We show that, at the protein level, the majority of immune mediators including a metabolic sensor, leptin, were significantly decreased in the plasma of sALS patients and in two animal models of the disease. Next, we found that a subset of patients with rapidly progressing ALS develop a distinct plasma assess immune–metabolic molecular signature characterized by a differential increase in soluble tumor necrosis factor receptor II (sTNF-RII) and chemokine (C-C motif) ligand 16 (CCL16) and further decrease in the levels of leptin, mostly dysregulated in male patients. Consistent with in vivo findings, exposure of human adipocytes to sALS plasma and/or sTNF-RII alone, induced a significant deregulation in leptin production/homeostasis and was associated with a robust increase in AMP-activated protein kinase (AMPK) phosphorylation. Conversely, treatment with an AMPK inhibitor restored leptin production in human adipocytes. Together, this study provides evidence of a distinct plasma immune profile in sALS which affects adipocyte function and leptin signaling. Furthermore, our results suggest that targeting the sTNF-RII/AMPK/leptin pathway in adipocytes may help restore assess immune–metabolic homeostasis in ALS. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis as a Systemic Disease)

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15 pages, 1611 KiB

Open AccessArticle

Functional Characterization of a Familial ALS-Associated Missense TBK1 (p-Arg573Gly) Mutation in Patient-Derived Lymphoblasts

by Gracia Porras, Silvana Ruiz, Inés Maestro, Daniel Borrego-Hernández, Alberto G. Redondo, Ana Martínez and Ángeles Martín-Requero

Int. J. Mol. Sci. 2023, 24(3), 2847; https://doi.org/10.3390/ijms24032847 - 2 Feb 2023

Cited by 4 | Viewed by 2497

Abstract

The goal of this work was to elucidate the pathogenic mechanism of an ALS-associated missense mutation, p.Arg573Gly (R573G), in the TBK1 gene. In particular, we seek to analyze the influence of this variant on the cellular levels and the function of TBK1 in [...] Read more.

The goal of this work was to elucidate the pathogenic mechanism of an ALS-associated missense mutation, p.Arg573Gly (R573G), in the TBK1 gene. In particular, we seek to analyze the influence of this variant on the cellular levels and the function of TBK1 in immortalized cells from an ALS patient. The patient (Code# E7) belonged to a Spanish family with autosomal dominant disease manifesting in the sixth decade as either dementia or ALS. Four control individuals without signs of neurological disease were also included in this study. Our results indicate that the R375G TBK1 mutation did not affect the levels of mRNA nor the total TBK1 content; however, we observed a significant decrease in the levels of TBK1 phosphorylation, which is essential for TBK1 activity, as well as a significant reduction in the phosphorylation of p62 and RIPK1, known substrates for TBK1. Lymphoblasts from the R573G TBK1 mutation carrier patient display pathological TDP-43 homeostasis, showing elevated levels of phosphorylated TDP-43 and accumulation of the protein in the cytosolic compartment. In addition, the functional decrease in TBK1 activity observed in the E7 patient did not alter the autophagy flux, but it seems to be enough to increase ROS levels as well as the expression of pro-inflammatory cytokine IL-6. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis as a Systemic Disease)

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24 pages, 2808 KiB

Open AccessArticle

SOMAscan Proteomics Identifies Novel Plasma Proteins in Amyotrophic Lateral Sclerosis Patients

by Elena Berrone, Giovanna Chiorino, Francesca Guana, Valerio Benedetti, Claudia Palmitessa, Marina Gallo, Andrea Calvo, Federico Casale, Umberto Manera, Alessandra Favole, Paola Crociara, Camilla Testori, Valerio Carta, Carlotta Tessarolo, Antonio D’Angelo, Giovanni De Marco, Maria Caramelli, Adriano Chiò, Cristina Casalone and Cristiano Corona

Int. J. Mol. Sci. 2023, 24(3), 1899; https://doi.org/10.3390/ijms24031899 - 18 Jan 2023

Cited by 6 | Viewed by 3966

Abstract

Amyotrophic lateral sclerosis (ALS) is a complex disease characterized by the interplay of genetic and environmental factors for which, despite decades of intense research, diagnosis remains rather delayed, and most therapeutic options fail. Therefore, unravelling other potential pathogenetic mechanisms and searching for reliable [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a complex disease characterized by the interplay of genetic and environmental factors for which, despite decades of intense research, diagnosis remains rather delayed, and most therapeutic options fail. Therefore, unravelling other potential pathogenetic mechanisms and searching for reliable markers are high priorities. In the present study, we employ the SOMAscan assay, an aptamer-based proteomic technology, to determine the circulating proteomic profile of ALS patients. The expression levels of ~1300 proteins were assessed in plasma, and 42 proteins with statistically significant differential expression between ALS patients and healthy controls were identified. Among these, four were upregulated proteins, Thymus- and activation-regulated chemokine, metalloproteinase inhibitor 3 and nidogen 1 and 2 were selected and validated by enzyme-linked immunosorbent assays in an overlapping cohort of patients. Following statistical analyses, different expression patterns of these proteins were observed in the familial and sporadic ALS patients. The proteins identified in this study might provide insight into ALS pathogenesis and represent potential candidates to develop novel targeted therapies. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis as a Systemic Disease)

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11 pages, 1952 KiB

Open AccessCommunication

Sex and HDAC4 Differently Affect the Pathophysiology of Amyotrophic Lateral Sclerosis in SOD1-G93A Mice

by Alessandra Renzini, Eva Pigna, Marco Rocchi, Alessia Cedola, Giuseppe Gigli, Viviana Moresi and Dario Coletti

Int. J. Mol. Sci. 2023, 24(1), 98; https://doi.org/10.3390/ijms24010098 - 21 Dec 2022

Cited by 4 | Viewed by 2328

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a devastating adult-onset neurodegenerative disease, with ineffective therapeutic options. ALS incidence and prevalence depend on the sex of the patient. Histone deacetylase 4 (HDAC4) expression in skeletal muscle directly correlates with the progression of ALS, pointing to the [...] Read more.

Amyotrophic Lateral Sclerosis (ALS) is a devastating adult-onset neurodegenerative disease, with ineffective therapeutic options. ALS incidence and prevalence depend on the sex of the patient. Histone deacetylase 4 (HDAC4) expression in skeletal muscle directly correlates with the progression of ALS, pointing to the use of HDAC4 inhibitors for its treatment. Contrarily, we have found that deletion of HDAC4 in skeletal muscle worsened the pathological features of ALS, accelerating and exacerbating skeletal muscle loss and negatively affecting muscle innervations in male SOD1-G93A (SOD1) mice. In the present work, we compared SOD1 mice of both sexes with the aim to characterize ALS onset and progression as a function of sex differences. We found a global sex-dependent effects on disease onset and mouse lifespan. We further investigated the role of HDAC4 in SOD1 females with a genetic approach, and discovered morpho-functional effects on skeletal muscle, even in the early phase of the diseases. The deletion of HDAC4 decreased muscle function and exacerbated muscle atrophy in SOD1 females, and had an even more dramatic effect in males. Therefore, the two sexes must be considered separately when studying ALS. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis as a Systemic Disease)

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20 pages, 3860 KiB

Open AccessArticle

Connexin 30 Deficiency Ameliorates Disease Progression at the Early Phase in a Mouse Model of Amyotrophic Lateral Sclerosis by Suppressing Glial Inflammation

by Yu Hashimoto, Ryo Yamasaki, Senri Ko, Eriko Matsuo, Yuko Kobayakawa, Katsuhisa Masaki, Dai Matsuse and Noriko Isobe

Int. J. Mol. Sci. 2022, 23(24), 16046; https://doi.org/10.3390/ijms232416046 - 16 Dec 2022

Cited by 4 | Viewed by 2367

Abstract

Connexin 30 (Cx30), which forms gap junctions between astrocytes, regulates cell adhesion and migration, and modulates glutamate transport. Cx30 is upregulated on activated astroglia in central nervous system inflammatory lesions, including spinal cord lesions in mutant superoxide dismutase 1 (mSOD1) transgenic amyotrophic lateral [...] Read more.

Connexin 30 (Cx30), which forms gap junctions between astrocytes, regulates cell adhesion and migration, and modulates glutamate transport. Cx30 is upregulated on activated astroglia in central nervous system inflammatory lesions, including spinal cord lesions in mutant superoxide dismutase 1 (mSOD1) transgenic amyotrophic lateral sclerosis (ALS) model mice. Here, we investigated the role of Cx30 in mSOD1 mice. Cx30 was highly expressed in the pre-onset stage in mSOD1 mice. mSOD1 mice with knockout (KO) of the Cx30 gene (Cx30KO-mSOD1 mice) showed delayed disease onset and tended to have an extended survival period (log-rank, p = 0.09). At the progressive and end stages of the disease, anterior horn cells were significantly preserved in Cx30KO-mSOD1 mice. In lesions of these mice, glial fibrillary acidic protein/C3-positive inflammatory astroglia were decreased. Additionally, the activation of astrocytes in Cx30KO-mSOD1 mice was reduced compared with mSOD1 mice by gene expression microarray. Furthermore, expression of connexin 43 at the pre-onset stage was downregulated in Cx30KO-mSOD1 mice. These findings suggest that reduced expression of astroglial Cx30 at the early disease stage in ALS model mice protects neurons by attenuating astroglial inflammation. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis as a Systemic Disease)

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20 pages, 5034 KiB

Open AccessArticle

Different Intermolecular Interactions Drive Nonpathogenic Liquid–Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43

by Yu-Teng Zeng, Lu-Lu Bi, Xiao-Feng Zhuo, Ling-Yun Yang, Bo Sun and Jun-Xia Lu

Int. J. Mol. Sci. 2022, 23(23), 15227; https://doi.org/10.3390/ijms232315227 - 3 Dec 2022

Cited by 4 | Viewed by 2582

Abstract

The liquid–liquid phase separation (LLPS) of proteins has been found ubiquitously in eukaryotic cells, and is critical in the control of many biological processes by forming a temporary condensed phase with different bimolecular components. TDP-43 is recruited to stress granules in cells and [...] Read more.

The liquid–liquid phase separation (LLPS) of proteins has been found ubiquitously in eukaryotic cells, and is critical in the control of many biological processes by forming a temporary condensed phase with different bimolecular components. TDP-43 is recruited to stress granules in cells and is the main component of TDP-43 granules and proteinaceous amyloid inclusions in patients with amyotrophic lateral sclerosis (ALS). TDP-43 low complexity domain (LCD) is able to de-mix in solution, forming the protein condensed droplets, and amyloid aggregates would form from the droplets after incubation. The molecular interactions regulating TDP-43 LCD LLPS were investigated at the protein fusion equilibrium stage, when the droplets stopped growing after incubation. We found the molecules in the droplet were still liquid-like, but with enhanced intermolecular helix–helix interactions. The protein would only start to aggregate after a lag time and aggregate slower than at the condition when the protein does not phase separately into the droplets, or the molecules have a reduced intermolecular helix–helix interaction. In the protein condensed droplets, a structural transition intermediate toward protein aggregation was discovered involving a decrease in the intermolecular helix–helix interaction and a reduction in the helicity. Our results therefore indicate that different intermolecular interactions drive LLPS and fibril formation. The discovery that TDP-43 LCD aggregation was faster through the pathway without the first protein phase separation supports that LLPS and the intermolecular helical interaction could help maintain the stability of TDP-43 LCD. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis as a Systemic Disease)

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12 pages, 958 KiB

Open AccessArticle

Circular RNA Expression and Interaction Patterns Are Perturbed in Amyotrophic Lateral Sclerosis

by Chiara Aquilina-Reid, Samuel Brennan, Ashton Curry-Hyde, Guus M. Teunisse, The NYGC ALS Consortium and Michael Janitz

Int. J. Mol. Sci. 2022, 23(23), 14665; https://doi.org/10.3390/ijms232314665 - 24 Nov 2022

Cited by 10 | Viewed by 2228

Abstract

Circular RNAs (circRNAs) are a type of long noncoding RNA that are highly abundant and highly conserved throughout evolution and exhibit differential expression patterns in various tissue types in multiple diseases, including amyotrophic lateral sclerosis (ALS). The most well-known function of circRNAs is [...] Read more.

Circular RNAs (circRNAs) are a type of long noncoding RNA that are highly abundant and highly conserved throughout evolution and exhibit differential expression patterns in various tissue types in multiple diseases, including amyotrophic lateral sclerosis (ALS). The most well-known function of circRNAs is their ability to act as microRNA (miRNA) sponges. This entails circRNA binding to miRNA, which would otherwise target and degrade messenger RNA, thus affecting gene expression. This study analyzed ALS patient samples from three spinal cord regions to investigate circular transcriptome perturbation and circular RNA–microRNA–mRNA interactions. Using stringent statistical parameters, we identified 92 differentially expressed circRNAs across the spinal cord tissues with the aim of identifying specific circRNAs with biomarker potential. We also found evidence for differential expression of 37 linear RNAs possibly due to miRNA sequestration by circRNAs, thus revealing their potential as novel biomarkers and therapeutic candidates for ALS. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis as a Systemic Disease)

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15 pages, 3035 KiB

Open AccessArticle

Hemizygous Granzyme A Mice Expressing the hSOD1G93A Transgene Show Slightly Extended Lifespan

by Laura Moreno-Martinez, Llipsy Santiago, Miriam de la Torre, Ana Cristina Calvo, Julián Pardo and Rosario Osta

Int. J. Mol. Sci. 2022, 23(21), 13554; https://doi.org/10.3390/ijms232113554 - 4 Nov 2022

Cited by 1 | Viewed by 2176

Abstract

Granzyme A (gzmA), a serine protease involved in the modulation of the inflammatory immune response, is found at an elevated level in the serum from ALS patients. However, the influence of gzmA on the progression of ALS remains unclear. The aim of our [...] Read more.

Granzyme A (gzmA), a serine protease involved in the modulation of the inflammatory immune response, is found at an elevated level in the serum from ALS patients. However, the influence of gzmA on the progression of ALS remains unclear. The aim of our work was to assess whether the absence of gzmA in an ALS murine model could help slow down the progression of the disease. Homozygous and hemizygous gzmA-deficient mice expressing the hSOD1G93A transgene were generated, and survival of these mice was monitored. Subsequently, gene and protein expression of inflammatory and oxidative stress markers was measured in the spinal cord and quadriceps of these mice. We observed the longest lifespan in gzmA+/− mice. GzmA gene and protein expression was downregulated in the spinal cord and serum from gmzA+/− mice, confirming that the increased survival of hemizygous mice is correlated with lower levels of gzmA. In addition, mRNA and protein levels of glutathione reductase (GSR), involved in oxidative stress, were found downregulated in the spinal cord and quadriceps of gmzA+/− mice, together with lower IL-1β and IL-6 mRNA levels in hemyzigous mice. In summary, our findings indicate for the first time that reduced levels, but not the absence, of gzmA could slightly ameliorate the disease progression in this animal model. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis as a Systemic Disease)

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17 pages, 1981 KiB

Open AccessArticle

Swim Training Affects on Muscle Lactate Metabolism, Nicotinamide Adenine Dinucleotides Concentration, and the Activity of NADH Shuttle Enzymes in a Mouse Model of Amyotrophic Lateral Sclerosis

by Karol Cieminski, Damian Jozef Flis, Katarzyna Patrycja Dzik, Jan Jacek Kaczor, Mariusz Roman Wieckowski, Jedrzej Antosiewicz and Wieslaw Ziolkowski

Int. J. Mol. Sci. 2022, 23(19), 11504; https://doi.org/10.3390/ijms231911504 - 29 Sep 2022

Cited by 5 | Viewed by 2372

Abstract

In this study, we aim to verify whether swim training can improve lactate metabolism, NAD⁺ and NADH levels, as well as modify the activity of glycolytic and NADH shuttle enzymes and monocarboxylate transporters (MCTs) in skeletal muscle of amyotrophic lateral sclerosis (ALS) [...] Read more.

In this study, we aim to verify whether swim training can improve lactate metabolism, NAD⁺ and NADH levels, as well as modify the activity of glycolytic and NADH shuttle enzymes and monocarboxylate transporters (MCTs) in skeletal muscle of amyotrophic lateral sclerosis (ALS) mice. ALS mice (SOD1G93A) (n = 7 per group) were analyzed before the onset of ALS, at first disease symptoms (trained and untrained), and the last stage of disease (trained and untrained), and then compared with a wild-type (WT) group of mice. The blood lactate and the skeletal muscle concentration of lactate, NAD⁺ and NADH, MCT1 and MCT4 protein levels, as well as lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) activities in skeletal muscle were determined by fluorometric, Western blotting, liquid chromatography-MS3 spectrometry, and spectrometric methods. In the untrained terminal ALS group, there were decreased blood lactate levels (p < 0.001) and increased skeletal muscle lactate levels (p < 0.05) as compared with a WT group of mice. The amount of nicotinamide adenine dinucleotides in the ALS groups were also significantly reduced as well as LDH activity and the level of MCT1. Swim training increased lactate levels in the blood (p < 0.05 vs. ALS TERMINAL untrained). In addition, cytosolic MDH activity and the cMDH/LDH 2.1 ratio were significantly higher in trained vs. untrained mice (p < 0.05). The data indicate significant dysfunction of lactate metabolism in ALS mice, associated with a reduction in muscle anaerobic metabolism and NADH transporting enzymes, as well as swim-induced compensation of energy demands in the ALS mice. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis as a Systemic Disease)

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14 pages, 772 KiB

Open AccessArticle

TMEM106B Acts as a Modifier of Cognitive and Motor Functions in Amyotrophic Lateral Sclerosis

by Arianna Manini, Antonia Ratti, Alberto Brusati, Alessio Maranzano, Isabella Fogh, Silvia Peverelli, Stefano Messina, Davide Gentilini, Federico Verde, Barbara Poletti, Claudia Morelli, Vincenzo Silani and Nicola Ticozzi

Int. J. Mol. Sci. 2022, 23(16), 9276; https://doi.org/10.3390/ijms23169276 - 17 Aug 2022

Cited by 9 | Viewed by 2080

Abstract

The transmembrane protein 106B (TMEM106B) gene is a susceptibility factor and disease modifier of frontotemporal dementia, but few studies have investigated its role in amyotrophic lateral sclerosis. The aim of this work was to assess the impact of the TMEM106B rs1990622 [...] Read more.

The transmembrane protein 106B (TMEM106B) gene is a susceptibility factor and disease modifier of frontotemporal dementia, but few studies have investigated its role in amyotrophic lateral sclerosis. The aim of this work was to assess the impact of the TMEM106B rs1990622 (A–major risk allele; G–minor allele) on phenotypic variability of 865 patients with amyotrophic lateral sclerosis. Demographic and clinical features were compared according to genotypes by additive, dominant, and recessive genetic models. Bulbar onset was overrepresented among carriers of the AA risk genotype, together with enhanced upper motor neuron involvement and poorer functional status in patients harboring at least one major risk allele (A). In a subset of 195 patients, we found that the homozygotes for the minor allele (GG) showed lower scores at the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen, indicating a more severe cognitive impairment, mainly involving the amyotrophic lateral sclerosis-specific cognitive functions and memory. Moreover, lower motor neuron burden predominated among patients with at least one minor allele (G). Overall, we found that TMEM106B is a disease modifier of amyotrophic lateral sclerosis, whose phenotypic effects encompass both sites of onset and functional status (major risk allele), motor functions (both major risk and minor alleles), and cognition (minor allele). Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis as a Systemic Disease)

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Review

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16 pages, 1419 KiB

Open AccessReview

Diffusion Tensor Imaging in Amyotrophic Lateral Sclerosis: Machine Learning for Biomarker Development

by Anna Behler, Hans-Peter Müller, Albert C. Ludolph and Jan Kassubek

Int. J. Mol. Sci. 2023, 24(3), 1911; https://doi.org/10.3390/ijms24031911 - 18 Jan 2023

Cited by 14 | Viewed by 3872

Abstract

Diffusion tensor imaging (DTI) allows the in vivo imaging of pathological white matter alterations, either with unbiased voxel-wise or hypothesis-guided tract-based analysis. Alterations of diffusion metrics are indicative of the cerebral status of patients with amyotrophic lateral sclerosis (ALS) at the individual level. [...] Read more.

Diffusion tensor imaging (DTI) allows the in vivo imaging of pathological white matter alterations, either with unbiased voxel-wise or hypothesis-guided tract-based analysis. Alterations of diffusion metrics are indicative of the cerebral status of patients with amyotrophic lateral sclerosis (ALS) at the individual level. Using machine learning (ML) models to analyze complex and high-dimensional neuroimaging data sets, new opportunities for DTI-based biomarkers in ALS arise. This review aims to summarize how different ML models based on DTI parameters can be used for supervised diagnostic classifications and to provide individualized patient stratification with unsupervised approaches in ALS. To capture the whole spectrum of neuropathological signatures, DTI might be combined with additional modalities, such as structural T1w 3-D MRI in ML models. To further improve the power of ML in ALS and enable the application of deep learning models, standardized DTI protocols and multi-center collaborations are needed to validate multimodal DTI biomarkers. The application of ML models to multiparametric MRI/multimodal DTI-based data sets will enable a detailed assessment of neuropathological signatures in patients with ALS and the development of novel neuroimaging biomarkers that could be used in the clinical workup. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis as a Systemic Disease)

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32 pages, 2245 KiB

Open AccessReview

Sensory Involvement in Amyotrophic Lateral Sclerosis

by Miguel A. Rubio, Mireia Herrando-Grabulosa and Xavier Navarro

Int. J. Mol. Sci. 2022, 23(24), 15521; https://doi.org/10.3390/ijms232415521 - 8 Dec 2022

Cited by 16 | Viewed by 10672

Abstract

Although amyotrophic lateral sclerosis (ALS) is pre-eminently a motor disease, the existence of non-motor manifestations, including sensory involvement, has been described in the last few years. Although from a clinical perspective, sensory symptoms are overshadowed by their motor manifestations, this does not mean [...] Read more.

Although amyotrophic lateral sclerosis (ALS) is pre-eminently a motor disease, the existence of non-motor manifestations, including sensory involvement, has been described in the last few years. Although from a clinical perspective, sensory symptoms are overshadowed by their motor manifestations, this does not mean that their pathological significance is not relevant. In this review, we have made an extensive description of the involvement of sensory and autonomic systems described to date in ALS, from clinical, neurophysiological, neuroimaging, neuropathological, functional, and molecular perspectives. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis as a Systemic Disease)

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