GP.2 Changes in Leptin, CCL16 and sTNF-RII as a distinctive plasma immune
                        profile in patients with fast progressing ALS

Background: Amyotrophic lateral sclerosis (ALS) is highly heterogeneous with survival rate ranging from months to decades. Approximately 10-20% of patients develop a rapidly progressive disease and may die within the first year. Therefore, there is an increasing need for an early detection of unique molecular signatures associated with more aggressive forms of disease as it may help identify therapeutic targets. Methods: To identify a unique molecular signature in fast progressing patients, we recruited 45 sporadic ALS (sALS) patients and 35 age-matched healthy controls and measured 62 immune markers in plasma using cytokines array. Results: We found that leptin was significantly downregulated in plasma of sALS patients and more importantly in fast progressing disease. Immune markers CCL16 and sTNF-RII were significantly increased in rapidly progressing disease. We also found that leptin was significantly downregulated in plasma of SOD1G93A mice across disease stage. This was caused by an increased in levels of phospho-AMPK in mice adipocytes and in adipocytes exposed to fast sALS patients’ plasma. Conclusions: We propose that the combination of decreased plasma leptin levels and up-regulation in CCL16/sTNF-RII may be used as a prognostic biomarker to identify fast progressing ALS patients. This unique immune/metabolic profile may cause dysfunction in metabolic homeostasis.

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Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis

Scientific Reports ◽

10.1038/s41598-020-80378-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

James C. Dodge ◽

Jinlong Yu ◽

S. Pablo Sardi ◽

Lamya S. Shihabuddin

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Cholesterol Homeostasis ◽

Cholesterol Oxidation ◽

Therapeutic Approaches ◽

Cellular Survival ◽

Sporadic Als ◽

Human Motor ◽

Als Patients ◽

Lateral Sclerosis

AbstractAberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that is due to motor neuron (MN) death. Cellular toxicity from excess cholesterol is averted when it is enzymatically oxidized to oxysterols and bile acids (BAs) to promote its removal. In contrast, the auto oxidation of excess cholesterol is often detrimental to cellular survival. Although oxidized metabolites of cholesterol are altered in the blood and CSF of ALS patients, it is unknown if increased cholesterol oxidation occurs in the SC during ALS, and if exposure to oxidized cholesterol metabolites affects human MN viability. Here, we show that in the SOD1G93A mouse model of ALS that several oxysterols, BAs and auto oxidized sterols are increased in the lumbar SC, plasma, and feces during disease. Similar changes in cholesterol oxidation were found in the cervical SC of sporadic ALS patients. Notably, auto-oxidized sterols, but not oxysterols and BAs, were toxic to iPSC derived human MNs. Thus, increased cholesterol oxidation is a manifestation of ALS and non-regulated sterol oxidation likely contributes to MN death. Developing therapeutic approaches to restore cholesterol homeostasis in the SC may lead to a treatment for ALS.

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A-151 Cognitive Impairment in Amyotrophic Lateral Sclerosis

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acab062.169 ◽

2021 ◽

Vol 36 (6) ◽

pp. 1205-1205

Author(s):

Etiane Navarro ◽

Charles J Golden

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Cognitive Impairment ◽

Literature Review ◽

Cognitive Impairments ◽

Empirical Literature ◽

Sporadic Als ◽

Neuropsychological Assessments ◽

Familial Als ◽

Als Patients ◽

Lateral Sclerosis

Abstract Objective Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease caused by degeneration of the upper and lower motor neurons. This literature review examines the recurring etiology of cognitive impairments in ALS through empirical literature. The current study explores ALS across different subtypes and potential cognitive impairments. Two classifications are primarily examined ALS, and ALS with frontotemporal dementia (ALS-FTD). Involving three categories: familial inheritance pattern, genetic mutation, or sporadic. Neuropsychological studies affirm cognitive impairments in individuals diagnosed with ALS and ALS-FTD. Data Selection Data was culled from the American Psychological Association (PsycInfo), PubMed, Google Scholar. Terms used in this literature review include cognitive impairment in ALS and ALS-FTD, executive function deficiencies in ALS, neuropsychology in ALS, neuropsychological deficits in ALS, neuropsychological assessments for ALS, cognitive impairments in familial ALS, genetic ALS, and sporadic ALS, familial ALS, sporadic ALS, genetic mutations involved in ALS. Search dates December 20–23 of 2020 and March 3–4 of 2021. A total of 40 studies were examined. Data Synthesis ALS-patients demonstrate a significant cognitive impairment. However, influencing comorbidities accompanying the disease may be contributing to these impairments. Researchers employed neuroimaging and neuropsychological batteries to further understand influencing factors involved in ALS and cognition. Conclusions Researchers now understand ALS as a multi-symptomatic disorder and acknowledge the presence of cognitive impairments at various encased levels. There are limitations in neuropsychological batteries that accommodate for executive dysfunctions observed in ALS patients. Future studies should explore neuropsychological assessments that accommodate for motor deficits and dysarthria when assessing cognitive impairment in ALS patients.

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Impact of Pharmacological Inhibition of Hydrogen Sulphide Production in the SOD1G93A-ALS Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms20102550 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2550 ◽

Cited By ~ 3

Author(s):

Alida Spalloni ◽

Viviana Greco ◽

Giulia Ciriminna ◽

Victor Corasolla Carregari ◽

Federica Marini ◽

...

Keyword(s):

Hydrogen Sulphide ◽

Histological Evaluation ◽

Dual Inhibitor ◽

Number Of Factors ◽

Sporadic Als ◽

Sulphide Production ◽

High Concentrations ◽

Als Patients ◽

H2s Production ◽

Lateral Sclerosis

A number of factors can trigger amyotrophic lateral sclerosis (ALS), although its precise pathogenesis is still uncertain. In a previous study done by us, poisonous liquoral levels of hydrogen sulphide (H2S) in sporadic ALS patients were reported. In the same study very high concentrations of H2S in the cerebral tissues of the familial ALS (fALS) model of the SOD1G93A mouse, were measured. The objective of this study was to test whether decreasing the levels of H2S in the fALS mouse could be beneficial. Amino-oxyacetic acid (AOA)—a systemic dual inhibitor of cystathionine-β-synthase and cystathionine-γ lyase (two key enzymes in the production of H2S)—was administered to fALS mice. AOA treatment decreased the content of H2S in the cerebral tissues, and the lifespan of female mice increased by approximately ten days, while disease progression in male mice was not affected. The histological evaluation of the spinal cord of the females revealed a significant increase in GFAP positivity and a significant decrease in IBA1 positivity. In conclusion, the results of the study indicate that, in the animal model, the inhibition of H2S production is more effective in females. The findings reinforce the need to adequately consider sex as a relevant factor in ALS.

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Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy

Journal of Neuromuscular Diseases ◽

10.3233/jnd-200531 ◽

2021 ◽

Vol 8 (1) ◽

pp. 25-38

Author(s):

Marisa Cappella ◽

Pierre-François Pradat ◽

Giorgia Querin ◽

Maria Grazia Biferi

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Amyotrophic Lateral Sclerosis ◽

Muscular Atrophy ◽

Monogenic Disease ◽

Sporadic Als ◽

Pathological Mechanism ◽

Huge Impact ◽

Als Patients ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating and incurable motor neuron (MN) disorder affecting both upper and lower MNs. Despite impressive advances in the understanding of the disease’s pathological mechanism, classical pharmacological clinical trials failed to provide an efficient cure for ALS over the past twenty years. Two different gene therapy approaches were recently approved for the monogenic disease Spinal muscular atrophy, characterized by degeneration of lower MNs. This milestone suggests that gene therapy-based therapeutic solutions could be effective for the treatment of ALS. This review summarizes the possible reasons for the failure of traditional clinical trials for ALS. It provides then a focus on the advent of gene therapy approaches for hereditary forms of ALS. Specifically, it describes clinical use of antisense oligonucleotides in three familial forms of ALS, caused by mutations in SOD1, C9orf72 and FUS genes, respectively.. Clinical and pre-clinical studies based on AAV-mediated gene therapy approaches for both familial and sporadic ALS cases are presented as well. Overall, this overview highlights the potential of gene therapy as a transforming technology that will have a huge impact on treatment perspective for ALS patients and on the design of future clinical trials.

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Incidence and Characteristics of Spinal Decompression Surgery after the Onset of Symptoms of Amyotrophic Lateral Sclerosis

Neurosurgery ◽

10.1227/01.neu.0000180028.64385.d3 ◽

2005 ◽

Vol 57 (5) ◽

pp. 984-989 ◽

Cited By ~ 18

Author(s):

Daniel Yoshor ◽

Arnett Klugh ◽

Stanley H. Appel ◽

Lanny J. Haverkamp

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Symptom Onset ◽

Spinal Surgery ◽

Foot Drop ◽

Spinal Decompression ◽

Sporadic Als ◽

Number Of Patients ◽

Als Patients ◽

The Impact ◽

Lateral Sclerosis

Abstract OBJECTIVE: The high incidence of spondylosis in patients at the mean age of onset (55.7 yr) of amyotrophic lateral sclerosis (ALS) can make recognition of ALS as a cause of weakness difficult. METHODS: To assess the impact of this diagnostic dilemma on neurosurgical practice, we performed a retrospective analysis of a database of more than 1500 patients with motor neuron disease. RESULTS: Of 1131 patients with typical, sporadic ALS, 47 (4.2%) underwent decompressive spinal surgery after the onset of retrospectively recognized symptoms of ALS. Among 55 operations in 47 ALS patients, 86% yielded no improvement, 9% produced minor improvement, and only 5% provided significant benefit. Cervical decompression was performed in 56%, lumbar in 42%, and thoracic in 2%. Foot drop was a symptom prompting surgery in 11 patients, and in 10, this finding was subsequently attributed solely to ALS. No differences between ALS patients who underwent spinal decompression and other ALS patients were noted regarding age at symptom onset, severity of impairment at time of diagnosis, or rate of disease progression. Not surprisingly, patients who had spinal surgery tended to have a longer interval between retrospectively recognized symptom onset and diagnosis of ALS. CONCLUSION: A small but significant number of patients with unrecognized ALS undergo spinal surgery that in retrospect may be inappropriate. The possibility of ALS must be considered in the evaluation of patients with weakness even in the presence of radiographic evidence of spondylosis and nerve root or spinal cord impingement.

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Rare CYLD Variants in Chinese Patients With Amyotrophic Lateral Sclerosis

Frontiers in Genetics ◽

10.3389/fgene.2021.740052 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaojing Gu ◽

Yongping Chen ◽

Qianqian Wei ◽

Yanbing Hou ◽

Bei Cao ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Rare Variants ◽

Chinese Patients ◽

Causative Gene ◽

Missense Variants ◽

Whole Exome ◽

Sporadic Als ◽

Als Patients ◽

Lateral Sclerosis

Background: CYLD Lysine 63 Deubiquitinase gene (CYLD) was recently identified to be a novel causative gene for frontal temporal dementia (FTD)-amyotrophic lateral sclerosis (ALS). In the current study, we aimed to (1) systematically screen the mutations of CYLD in a large cohort of Chinese ALS patients, (2) study the genotype–phenotype correlation, and (3) explore the role of CYLD in ALS via rare variants burden analysis.Methods: A total of 978 Chinese sporadic ALS (sALS) patients and 46 familial ALS (fALS) patients were sequenced with whole-exome sequencing and analyzed rare variants in CYLD with minor allele frequency <0.1%.Results: In total, seven rare missense variants in CYLD have been identified in 7 (0.72%) patients among 978 sALS patients. Two (4.3%) rare missense variants were identified among the 46 fALS cases, in which one patient was diagnosed as having comorbidity of ALS and progressive supranuclear palsy (PSP). Moreover, the burden analysis indicated no enrichment of rare variants in CYLD among patients with ALS.Conclusion: In conclusion, our study extended the genotype and phenotype of CYLD in ALS, but the pathogenicity of these variants needs to be further verified. Moreover, burden analysis argued against the role of CYLD in the pathogenesis of ALS. More studies from different ethnicities would be needed.

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Clinical and Molecular Landscape of ALS Patients with SOD1 Mutations: Novel Pathogenic Variants and Novel Phenotypes. A Single ALS Center Study

International Journal of Molecular Sciences ◽

10.3390/ijms21186807 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6807

Author(s):

Emilien Bernard ◽

Antoine Pegat ◽

Juliette Svahn ◽

Françoise Bouhour ◽

Pascal Leblanc ◽

...

Keyword(s):

Superoxide Dismutase 1 ◽

Sod1 Gene ◽

Copper Zinc Superoxide Dismutase ◽

Pathogenic Variants ◽

Zinc Superoxide Dismutase ◽

Sporadic Als ◽

Copper Zinc ◽

Molecular Landscape ◽

Als Patients ◽

Lateral Sclerosis

Mutations in the copper zinc superoxide dismutase 1 (SOD1) gene are the second most frequent cause of familial amyotrophic lateral sclerosis (ALS). Nearly 200 mutations of this gene have been described so far. We report all SOD1 pathogenic variants identified in patients followed in the single ALS center of Lyon, France, between 2010 and 2020. Twelve patients from 11 unrelated families are described, including two families with the not yet described H81Y and D126N mutations. Splice site mutations were detected in two families. We discuss implications concerning genetic screening of SOD1 gene in familial and sporadic ALS.

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Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?

International Journal of Molecular Sciences ◽

10.3390/ijms21103647 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3647 ◽

Cited By ~ 1

Author(s):

Francesca Trojsi ◽

Giulia D’Alvano ◽

Simona Bonavita ◽

Gioacchino Tedeschi

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Disease Risk ◽

Genetic Mutation ◽

Chromosome 9 ◽

Patient Specific ◽

Reading Frame ◽

Hexanucleotide Repeat ◽

Sporadic Als ◽

Als Patients ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, although multiple genetic risk factors have been recently revealed also in sporadic ALS (SALS). The pathological expansion of a hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic mutation identified in familial ALS, detected also in 5–10% of SALS patients. C9orf72-related ALS phenotype appears to be dependent on several modifiers, including demographic factors. Sex has been reported as an independent factor influencing ALS development, with men found to be more susceptible than women. Exposure to both female and male sex hormones have been shown to influence disease risk or progression. Moreover, interplay between genetics and sex has been widely investigated in ALS preclinical models and in large populations of ALS patients carrying C9orf72 repeat expansion. In light of the current need for reclassifying ALS patients into pathologically homogenous subgroups potentially responsive to targeted personalized therapies, we aimed to review the recent literature on the role of genetics and sex as both independent and synergic factors, in the pathophysiology, clinical presentation, and prognosis of ALS. Sex-dependent outcomes may lead to optimizing clinical trials for developing patient-specific therapies for ALS.

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Glial Cells in Amyotrophic Lateral Sclerosis

Neurology Research International ◽

10.1155/2011/718987 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 62

Author(s):

Jurate Lasiene ◽

Koji Yamanaka

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Glial Cells ◽

Motor Neurons ◽

Premature Death ◽

Active Role ◽

Sporadic Als ◽

Neuron Damage ◽

Als Patients ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an adult motor neuron disease characterized by premature death of upper and lower motor neurons. Two percent of ALS cases are caused by the dominant mutations in the gene for superoxide dismutase 1 (SOD1) through a gain of toxic property of mutant protein. Genetic and chimeric mice studies using SOD1 models indicate that non-neuronal cells play important roles in neurodegeneration through non-cell autonomous mechanism. We review the contribution of each glial cell type in ALS pathology from studies of the rodent models and ALS patients. Astrogliosis and microgliosis are not only considerable hallmarks of the disease, but the intensity of microglial activation is correlated with severity of motor neuron damage in human ALS. The impaired astrocytic functions such as clearance of extracellular glutamate and release of neurotrophic factors are implicated in disease. Further, the damage within astrocytes and microglia is involved in accelerated disease progression. Finally, other glial cells such as NG2 cells, oligodendrocytes and Schwann cells are under the investigation to determine their contribution in ALS. Accumulating knowledge of active role of glial cells in the disease should be carefully applied to understanding of the sporadic ALS and development of therapy targeted for glial cells.

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Progesterone and cortisol levels in sporadic amyotrophic lateral sclerosis (sALS): correlation with prognostic factors

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci.2011.006 ◽

2011 ◽

Vol 6 (1) ◽

Author(s):

Gisella Gargiulo Monachelli ◽

Maria Meyer ◽

Gabriel Rodríguez ◽

Laura Garay ◽

Roberto E. Sica ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Prognostic Factors ◽

Neurodegenerative Disorder ◽

Neuronal Damage ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Sporadic Als ◽

Bulbar Onset ◽

Als Patients ◽

Short Time ◽

Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder. Worse prognostic factors in ALS are: (a) advanced age, (b) bulbar onset, and (c) short time between onset and diagnosis. Progesterone (PROG) has been associated with neuroprotective and promyelinating activities in injury, ischemia and degeneration of the central and peripheral nervous system. Cortisol is connected to the response to stress situations and could contribute to neuronal damage. The goals of this study were: (i) to investigate whether PROG levels are modified by ALS prognostic factors and (ii) to determine whether cortisol follows the same pattern. We determined serum steroid levels in 27 patients with sporadic ALS (sALS) and 21 controls. Both steroid hormones showed significantly increased levels in ALS patients versus controls (mean±SEM: PROG ALS vs. control: 0.54±0.05 vs. 0.39±0.04 ng/mL, p<0.05; cortisol ALS vs. control: 17.02±1.60 vs. 11.83±1.38 μg/dL, p<0.05).

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