scholarly journals Monozygotic twin pairs discordant for amyotrophic lateral sclerosis carry both common and unique epigenetic differences relevant to disease

2016 ◽  
Author(s):  
Paul E Young ◽  
Stephen Kum Jew ◽  
Michael E Buckland ◽  
Roger Pamphlett ◽  
Catherine M Suter
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Large Scale ◽  
Cytosine Methylation ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Monozygotic Twin ◽  
Sporadic Als ◽  
High Heritability ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a devastating late-onset neurodegenerative disorder in which only a small proportion of patients carry an identifiable causative genetic lesion. Despite high heritability estimates, a genetic etiology for most sporadic ALS remains elusive. Here we report the epigenetic profiling of five monozygotic twin pairs discordant for ALS in whom previous genome sequencing excluded a genetic basis for their disease discordance. By studying cytosine methylation patterns in peripheral blood DNA we identified thousands of large between-twin differences at individual CpGs. While the specific sites of difference were largely idiosyncratic to a twin pair, a proportion (involving GABA signalling) were common to all affected individuals. In both instances the differences occurred within genes and pathways related to neurobiological function and dysfunction. Our findings reveal widespread changes in epigenetic marks in ALS patients, consistent with an epigenetic contribution to disease. These findings may be exploited to develop blood-based biomarkers of ALS and develop further insight into disease pathogenesis. We expect that our findings will provide a useful point of reference for further large scale studies of sporadic ALS.

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

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).

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.

scholarly journals Cognitive dysfunction in amyotrophic lateral sclerosis: can we predict it?

2021 ◽  
Author(s):  
Fabiola De Marchi ◽  
◽  
Claudia Carrarini ◽  
Antonio De Martino ◽  
Luca Diamanti ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Time Course ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Multisystem Disorder ◽  
Behavioral Impairment ◽  
Behavioral Impairments ◽  
Als Patients ◽  
Disease Stages ◽  
Lateral Sclerosis

Abstract Background and aim Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motoneurons in the brain and spinal cord leading to motor and extra-motor symptoms. Although traditionally considered a pure motor disease, recent evidences suggest that ALS is a multisystem disorder. Neuropsychological alterations, in fact, are observed in more than 50% of patients: while executive dysfunctions have been firstly identified, alterations in verbal fluency, behavior, and pragmatic and social cognition have also been described. Detecting and monitoring ALS cognitive and behavioral impairment even at early disease stages is likely to have staging and prognostic implications, and it may impact the enrollment in future clinical trials. During the last 10 years, humoral, radiological, neurophysiological, and genetic biomarkers have been reported in ALS, and some of them seem to potentially correlate to cognitive and behavioral impairment of patients. In this review, we sought to give an up-to-date state of the art of neuropsychological alterations in ALS: we will describe tests used to detect cognitive and behavioral impairment, and we will focus on promising non-invasive biomarkers to detect pre-clinical cognitive decline. Conclusions To date, the research on humoral, radiological, neurophysiological, and genetic correlates of neuropsychological alterations is at the early stage, and no conclusive longitudinal data have been published. Further and longitudinal studies on easily accessible and quantifiable biomarkers are needed to clarify the time course and the evolution of cognitive and behavioral impairments of ALS patients.

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 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 Orbitofrontal-hypothalamic projections are disrupted in hypermetabolic murine ALS model and human patients

2020 ◽  
Author(s):  
David Bayer ◽  
Stefano Antonucci ◽  
Hans-Peter Müller ◽  
Luc Dupuis ◽  
Tobias Boeckers ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Mouse Model ◽  
Lateral Hypothalamus ◽  
Large Scale ◽  
Energy Homeostasis ◽  
Metabolic Phenotype ◽  
Metabolic Disturbances ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractIncreased catabolism is a new clinical manifestation of Amyotrophic Lateral Sclerosis. A dysfunction of lateral hypothalamus may drive hypermetabolism in ALS; however, Its causes and anatomical substrates are unknown. We hypothesize that disruption cortico-hypothalamic circuits may impair energy homeostasis in ALS. We used rAAV2 for large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik to quantify projections from the forebrain to the latera hypothalamus of the SOD1(G93A) ALS mouse model as well as of the FusΔNLS ALS mouse model. Expanded projections from agranular Insula, ventrolateral orbitofrontal and secondary motor cortex to lateral hypothalamus were found in two independent cohorts of the hypermetabolic SOD1(G93A) ALS model. The non-hypermetabolic FusΔNLS ALS mouse model display a loss of projections from motor cortex but no change in projections from insula and orbitofronal cortex. 3T DTI-MRI data on 83 ALS patients and 65 controls confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. Converging murine and human data demonstrate the selective disruption of hypothalamic inputs in ALS as a factor contributing to the origin of hypermetabolism.Significance statementWe provide a circuit perspective of the recently identified and medically relevant hyper-metabolic phenotype of Amyotrophic Lateral Sclerosis. We demonstrate the selective involvement of orbitofrontal, insular and motor cortex projections to hypothalamus in murine ALS models and in human patients. The enhanced pipeline for large-scale registration, segmentation projections mapping, the identification of new circuits target of neurodegeneration, and the relevance of these circuits in metabolic disturbances make this work relevant not only for the investigation of ALS but also for other neurodegenerative disease as well as for all conditions characterized by systemic energy imbalances.

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 &lt;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 Utility of phrenic nerve ultrasound in amyotrophic lateral sclerosis

2020 ◽  
Author(s):  
Cezar Thomas Suratos ◽  
Naoko Takamatsu ◽  
Hiroki Yamazaki ◽  
Yusuke Osaki ◽  
Tatsuya Fukumoto ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Phrenic Nerve ◽  
Rating Scale ◽  
Neurodegenerative Disorder ◽  
Pulmonary Function Tests ◽  
Cross Sectional ◽  
The Right ◽  
Als Patients ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting the upper and lower motor neurons causing progressive weakness. It eventually involves the diaphragm which leads to respiratory paralysis and subsequently death. Phrenic nerve (PN) conduction studies and diaphragm ultrasound has been studied and correlated with pulmonary function tests in ALS patients. However, PN ultrasonography has not been employed in ALS. This study aims to sonographically evaluate the morphologic appearance of the PN of ALS patients. Thirty-eight ALS patients and 28 normal controls referred to the neurophysiology laboratory of two institutions were retrospectively included in the study. Baseline demographic and clinical variables such as disease duration, ALS Functional Rating Scale-Revised score, and ALS region of onset were collected. Ultrasound was used to evaluate the PN cross-sectional area (CSA) of ALS and control subjects. The mean PN CSA of ALS patients were 1.08 ± 0.39 mm on the right and 1.02 ± 0.34 mm on the left. The PN CSA of ALS patients were significantly decreased compared to controls (p value < 0.00001). The PN CSA of ALS patients was not correlated to any of the demographic and clinical parameters tested. This study demonstrates that ALS patients have a smaller PN size compared to controls using ultrasonography.

Amyotrophic Lateral Sclerosis

2019 ◽  
pp. 664-669
Author(s):  
Jennifer M. Martinez-Thompson ◽  
Nathan P. Staff
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Symptom Onset ◽  
Muscle Wasting ◽  
Neurodegenerative Disorder ◽  
Peak Incidence ◽  
Respiratory Involvement ◽  
Sporadic Als ◽  
Bulbar Dysfunction ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disorder with both upper and lower motor neuron involvement. It presents with weakness, muscle wasting, spasticity involving the limbs, bulbar dysfunction, and, typically later in the disease, respiratory involvement. Up to 20% of patients may also have a frontotemporal-type dementia. Average duration of survival is 2 to 4 years from symptom onset, and the peak incidence is between the ages of 50 and 75 years. Only 10% of patients have familial forms, and the remainder have sporadic ALS.

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