scholarly journals Humoral Influence of Repeated Lineage-Negative Stem/Progenitor Cell Administration on Articulatory Functions in ALS Patients

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Anna Sobuś ◽  
Bartłomiej Baumert ◽  
Wioletta Pawlukowska ◽  
Monika Gołąb-Janowska ◽  
Edyta Paczkowska ◽  
...  
Keyword(s):  
Cellular Therapy ◽  
Expression Profiles ◽  
Autologous Bone Marrow ◽  
Trophic Effect ◽  
Cell Therapies ◽  
Sporadic Als ◽  
Mirna Expression Profiles ◽  
Als Patients ◽  
Lateral Sclerosis ◽  
Proinflammatory Factors

Amyotrophic lateral sclerosis (ALS) remains a fatal, neurodegenerative disease frequently leading to dysarthria and impaired swallowing. Better understanding of ALS pathophysiology is prompting the use of humoral cell therapies. Hence, a repeated cellular therapy was applied to ALS patients as an attempt to prevent speech deterioration. Autologous bone marrow-derived lineage-negative (Lin−) cells were intrathecally administered three times at six-week intervals to 42 sporadic ALS patients. Patients were examined for articulatory functions using subjective (VHI) and objective (FDA) scales. Selected trophic, proinflammatory factors and expression profiles of miRNA were measured in cerebrospinal fluid (CSF) and plasma by multiplex Luminex and q-PCR in different timepoints. Of the 42 patients who received the Lin− cells, 6 showed improvement in articulatory functions, 27 remained stable, and 9 deteriorated after 18 weeks of therapy according to FDA scale. Clinical improvement was particularly evident by the 7th day of each cell application and concerned better cough and swallow reflex, soft palate, laryngeal time, pitch, and volume. These results correlated with significant changes in the concentration of various trophic and proinflammatory factors and miRNA expression profiles. A multiple application of Lin− cells proved to be safe and feasible. The repeated procedure can potentate a humoral effect and prevent speech deterioration. A short-lasting trophic effect of each Lin− cells administration was observed on local and systemic level. However, further in-depth studies are necessary to sustain the beneficial effect.

scholarly journals Neuroregenerative Rehabilitation Therapy with long-term Lithium in a Male Amyotrophic Lateral Sclerosis Patient: A Case Report.

2019 ◽  
Vol 6 (2) ◽  
pp. 4337-4344
Author(s):  
Alok Sharma ◽  
Hemangi Sane ◽  
Radhika Pradhan ◽  
Amruta Paranjape ◽  
Nandini Gokulchandran ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mononuclear Cells ◽  
Cellular Therapy ◽  
Amyotrophic Lateral Sclerosis Patient ◽  
Autologous Bone Marrow ◽  
Rehabilitation Therapy ◽  
Novel Approach ◽  
Als Patients ◽  
Lateral Sclerosis

Various cellular therapies are being increasingly investigated for the treatment of Amyotrophic Lateral Sclerosis (ALS), a progressive neurodegenerative disease with selective loss of anterior horn cells. Lithium is known to enhance the potency of transplanted cells, while being well tolerated by ALS patients. Additionally, rehabilitation significantly improves outcomes in various neurodegenerative disorders. We present a 47-year-old male patient suffering from ALS for 2 years, whose treatment involved intrathecal transplantation of autologous Bone Marrow-derived Mononuclear Cells and long-term Lithium, followed by multidisciplinary neurorehabilitation, and standard Riluzole treatment. ALS-FRSr score improved from 39 to 41; FIM remained stable at 101; 6MWT distance improved from 396 m to 480 m and Berg Balance score remained stable at 56 over a span of 18 months. Symptomatic improvements were seen in speech, swallow, stamina, walking and muscle strength; fasciculations and cramps reduced drastically. The highlight of this case is the maintenance of the patient’s condition in view of a degenerative prognosis. Cellular therapy along with long term Lithium and holistic rehabilitation, in addition to standard Riluzole treatment- together termed as Neuroregenerative Rehabilitation Therapy- is a novel approach for halting disease progression and qualitatively improving living conditions for ALS patients and caregivers alike.

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

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.

A-151 Cognitive Impairment in Amyotrophic Lateral Sclerosis

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.

scholarly journals A Study of Gene Expression Changes in Human Spinal and Oculomotor Neurons; Identifying Potential Links to Sporadic ALS

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 448
Author(s):  
Aayan N. Patel ◽  
Dennis Mathew
Keyword(s):  
Gene Expression ◽  
Disease Progression ◽  
Motor Neurons ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Tissue Samples ◽  
Disease Symptoms ◽  
Sporadic Als ◽  
Oculomotor Neurons ◽  
Als Patients

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes compromised function of motor neurons and neuronal death. However, oculomotor neurons are largely spared from disease symptoms. The underlying causes for sporadic ALS as well as for the resistance of oculomotor neurons to disease symptoms remain poorly understood. In this bioinformatic-analysis, we compared the gene expression profiles of spinal and oculomotor tissue samples from control individuals and sporadic ALS patients. We show that the genes GAD2 and GABRE (involved in GABA signaling), and CALB1 (involved in intracellular Ca2+ ion buffering) are downregulated in the spinal tissues of ALS patients, but their endogenous levels are higher in oculomotor tissues relative to the spinal tissues. Our results suggest that the downregulation of these genes and processes in spinal tissues are related to sporadic ALS disease progression and their upregulation in oculomotor neurons confer upon them resistance to ALS symptoms. These results build upon prevailing models of excitotoxicity that are relevant to sporadic ALS disease progression and point out unique opportunities for better understanding the progression of neurodegenerative properties associated with sporadic ALS.

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

2019 ◽  
Vol 20 (10) ◽  
pp. 2550 ◽  
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.

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

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.

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

Neurosurgery ◽  
2005 ◽  
Vol 57 (5) ◽  
pp. 984-989 ◽  
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.

scholarly journals Adjuvant Lineage-Negative Cell Therapy as a Potential Silencer of the Complement-Mediated Immune System in ALS Patients

2021 ◽  
Vol 10 (22) ◽  
pp. 5251
Author(s):  
Anna Sobuś ◽  
Bartłomiej Baumert ◽  
Monika Gołąb-Janowska ◽  
Piotr Kulig ◽  
Edyta Paczkowska ◽  
...  
Keyword(s):  
Immune System ◽  
Cell Therapy ◽  
Complement System ◽  
Autologous Bone Marrow ◽  
Medical Intervention ◽  
Complement Components ◽  
Inflammatory Reactions ◽  
Sporadic Als ◽  
Als Patients ◽  
The Complement System

ALS remains a fatal, neurodegenerative motor neuron disease. Numerous studies seem to confirm that innate immune system is involved in the pathophysiology of ALS. Hence, the assessment of the complement system and attempts to modify its activity remain the target of medical intervention in ALS. In the present study, three intrathecal administrations of autologous bone marrow-derived lineage-negative (Lin–) cells were performed every 6 weeks in 20 sporadic ALS patients. The concentrations of various complement components in the cerebrospinal fluid and plasma at different time points after cell injection were quantified using a Luminex multiplex. The results of the complement system were correlated with the level of leukocytes, neutrophils, lymphocytes, fibrinogen and CRP in the peripheral blood and the functional status of ALS patients using Norris and ALS-FRSr scales. The study showed a statistically significant decrease in plasma C3b concentration in all 7th days after cell application. In parallel, a peak decrease in neutrophil count and CRP level was observed on days 5–7, with a simultaneous maximum clinical improvement on days 7–28 of each Lin– cell administration. Adjuvant Lin– cell therapy appears to have the silencing potential on the complement-mediated immune system and thus suppress pro-inflammatory reactions responsible for neurodegeneration. However, further in-depth studies are necessary to address this issue.

scholarly journals Rare CYLD Variants in Chinese Patients With Amyotrophic Lateral Sclerosis

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.

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

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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