Sensory cortex hyperexcitability predicts short survival in amyotrophic lateral sclerosis

Neurology ◽  
2018 ◽  
Vol 90 (18) ◽  
pp. e1578-e1587 ◽  
Author(s):  
Toshio Shimizu ◽  
Kota Bokuda ◽  
Hideki Kimura ◽  
Tsutomu Kamiyama ◽  
Yuki Nakayama ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Multivariate Analysis ◽  
Action Potential ◽  
Median Nerve ◽  
Rating Scale ◽  
Sensory Cortex ◽  
Peak Amplitude ◽  
Short Survival ◽  
Sporadic Als ◽  
Lateral Sclerosis

ObjectiveTo investigate somatosensory cortex excitability and its relationship to survival prognosis in patients with amyotrophic lateral sclerosis (ALS).MethodsA total of 145 patients with sporadic ALS and 73 healthy control participants were studied. We recorded compound muscle action potential and sensory nerve action potential of the median nerve and the median nerve somatosensory evoked potential (SEP), and we measured parameters, including onset-to-peak amplitude of N13 and N20 and peak-to-peak amplitude between N20 and P25 (N20p-P25p). Clinical prognostic factors, including ALS Functional Rating Scale–Revised, were evaluated. We followed up patients until the endpoints (death or tracheostomy) and analyzed factors associated with survival using multivariate analysis in the Cox proportional hazard model.ResultsCompared to controls, patients with ALS showed a larger amplitude of N20p-P25p in the median nerve SEP. Median survival time after examination was shorter in patients with N20p-P25p ≥8 μV (0.82 years) than in those with N20p-P25p <8 μV (1.68 years, p = 0.0002, log-rank test). Multivariate analysis identified a larger N20p-P25p amplitude as a factor that was independently associated with shorter survival (p = 0.002).ConclusionSensory cortex hyperexcitability predicts short survival in patients with ALS.

scholarly journals MERIDIAN: A phase 2, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of pegcetacoplan in patients with amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Frederico Mennucci de Haidar Jorge ◽  
Angela Genge ◽  
Ammar Al- Chalabi ◽  
Orla Hardiman ◽  
Alice Shen ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Rating Scale ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Open Label ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Sporadic Als ◽  
The Difference ◽  
Lateral Sclerosis

Introduction: Inflammation underlies the pathogenesis of numerous neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In ALS, the complement system has been implicated in the neuropathology of disease and disease progression. Pegcetacoplan, a subcutaneously administered C3 complement inhibitor, is being investigated in hematology, nephrology, and neurology. The current clinical study (NCT04579666) is investigating whether pegcetacoplan can improve survival and function in people diagnosed with apparent sporadic ALS. Objectives and Methodology: Evaluate the efficacy and safety of pegcetacoplan compared to placebo among people diagnosed with ALS in a global, multicenter, randomized, double-blind, placebo-controlled, phase 2 study. Approximately 228 patients diagnosed with apparent sporadic ALS, ≥18 years of age and with an ALS Functional Rating Scale-Revised (ALSFRS-R) score ≥30, slow vital capacity (SVC) ≥60% of the predicted value at screening, and with symptom onset within 72 weeks before screening, are eligible for enrollment. After screening, patients will be randomized 2:1 to treatment groups receiving either subcutaneous pegcetacoplan (1080 mg) or placebo twice weekly for a duration of 52 weeks. The primary efficacy endpoint is the difference in the Combined Assessment of Function and Survival (CAFS) ranked score at 52 weeks after treatment initiation. Additional, secondary functional efficacy (ALSFRS-R, percent SVC, muscle strength, quality of life, and caregiver burden) and safety endpoints will be analyzed at 52 weeks. After the placebo-controlled period, all patients will have the option to receive pegcetacoplan in an open-label period for an additional 52 weeks. Results: This ongoing study is currently enrolling participants. Conclusions: Results of this study will determine the role of complement and C3 inhibition in patients with ALS.

scholarly journals SMN1 copy number as a modifying factor of survival in Serbian patients with sporadic amyotrophic lateral sclerosis

2018 ◽  
Vol 146 (11-12) ◽  
pp. 646-652
Author(s):  
Milos Brkusanin ◽  
Irena Jeftovic-Velkova ◽  
Vladimir Jovanovic ◽  
Stojan Peric ◽  
Jovan Pesovic ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Copy Number ◽  
Rating Scale ◽  
Cox Regression ◽  
Diagnostic Delay ◽  
Susceptibility Genes ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Cox Regression Analysis ◽  
Sporadic Als ◽  
Lateral Sclerosis

Introduction/Objective. Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The majority of cases are apparently sporadic ALS (SALS) with variants in susceptibility genes or sometimes in high-risk ALS genes. Two ALS susceptibility genes are SMN1, whose functional loss causes spinal muscular atrophy (SMA), and a nearly identical SMN2 gene, which modulates SMA severity. In this study we examined the association of copy number variations (CNVs) of SMN1 and SMN2 genes and two additional genes, SERF1 and NAIP, residing in the same genomic region (i.e. 5q13.2 segmental duplication), with SALS in patients from Serbia. Methods. Multiplex ligation-dependent probe amplification was used to determine CNVs of each gene in a clinically well-characterised group of 153 Serbian SALS patients and 153 controls. Results. Individual association between SMN1, SMN2, SERF1 or NAIP CNVs and SALS susceptibility or survival was not found. Survival curves based on the multivariable Cox regression analysis showed that three SMN1 copies, lower ALS Functional Rating Scale Revised (ALSFRS-R) score at the time of diagnosis, faster decline of the ALSFRS-R score over time, and shorter diagnostic delay result in shorter survival of Serbian SALS patients. Conclusion. Clinical variables might be complemented with the SMN1 copy number to improve prediction of survival in Serbian SALS patients.

scholarly journals Prediction of survival in amyotrophic lateral sclerosis: a nationwide, Danish cohort study

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Anne-Lene Kjældgaard ◽  
Katrine Pilely ◽  
Karsten Skovgaard Olsen ◽  
Anders Hedegaard Jessen ◽  
Anne Øberg Lauritsen ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Survival Analysis ◽  
Prognostic Marker ◽  
Palliative Treatment ◽  
Rating Scale ◽  
Prognostic Markers ◽  
Progression Rate ◽  
Duration Of Symptoms ◽  
Sporadic Als ◽  
Lateral Sclerosis

Abstract Introduction Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with great heterogeneity. Biological prognostic markers are needed for the patients to plan future supportive treatment, palliative treatment, and end-of-life decisions. In addition, prognostic markers are greatly needed for the randomization in clinical trials. Objective This study aimed to test the ALS Functional Rating Scale-Revised (ALSFRS-R) progression rate (ΔFS) as a prognostic marker of survival in a Danish ALS cohort. Methods The ALSFRS-R score at test date in association with duration of symptoms, from the onset of symptoms until test date, (defined as ΔFS’) was calculated for 90 Danish patients diagnosed with either probable or definite sporadic ALS. Median survival time was then estimated from the onset of symptoms until primary endpoint (either death or tracheostomy). ΔFS’ was subjected to survival analysis using Cox proportional hazards modelling, log-rank test, and Kaplan-Meier survival analysis. Results and conclusions Both ΔFS’ and age was found to be strong predictors of survival of the Danish ALS cohort. Both variables are easily obtained at the time of diagnosis and could be used by clinicians and ALS patients to plan future supportive and palliative treatment. Furthermore, ΔFS’, is a simple, prognostic marker that predicts survival in the early phase of disease as well as at later stages of the disease.

scholarly journals Serum asymmetric dimethyl arginine level correlates with the progression and prognosis of amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Kensuke Ikenaka ◽  
Yasuhiro Maeda ◽  
Hotta Yuji ◽  
Seiichi Nagano ◽  
Keita Kakuda ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Rating Scale ◽  
Proportional Hazards Model ◽  
Cox Proportional Hazards Model ◽  
No Production ◽  
Adma Level ◽  
Neurofilament Light Chain ◽  
Sporadic Als ◽  
Lateral Sclerosis

Objective: To investigate the association between serum asymmetric dimethylarginine (ADMA) levels and the progression and prognosis of amyotrophic lateral sclerosis (ALS), and to compare cerebrospinal fluid (CSF) and serum ADMA levels with other biomarkers of ALS. Methods: Serum ADMA levels of patients with sporadic ALS (n = 68) and disease control patients (n = 54) were measured using liquid chromatography tandem mass spectrometry. Serum samples were obtained at the time of patient registration for diagnosis. Correlations of ADMA level and other markers (nitric oxide (NO) and neurofilament light chain (NFL) levels) were analyzed. Changes in the ALS Functional Rating Scale Revised (ALSFRSR) score from the onset of disease (ALSFRSR preslope) was used to assess disease progression. Survival was evaluated using the Cox proportional hazards model and Kaplan Meier analysis. Results: The concentration of ADMA in CSF was substantially higher in patients with ALS than in disease controls. Serum ADMA level correlated with CSF ADMA level (r = 0.591, p < 0.0001), and was independently associated with the ALSFRSR preslope (r = 0.505. p < 0.0001). Patients with higher serum ADMA levels had less favorable prognoses. CSF ADMA level significantly correlated with CSF NfL level (r = 0.456, p = 0.0002) but not with NO level (r = 0.194, p = 0.219). Conclusion: ADMA level is an independent biomarker of ALS disease progression and prognosis, and reflects the degree of motor neuron degeneration. The increased ADMA level in ALS patients was not associated with the inhibition of NO production.

scholarly journals Correlations Between Median Nerve Sonography and Conduction Study Results and Functional Scales in Amyotrophic Lateral Sclerosis

2020 ◽  
Author(s):  
Parvaneh Deilami ◽  
Shadi Ghourchian ◽  
Bahram Haghi Ashtiani ◽  
Sara Esmaeili ◽  
Maryam Bahadori ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Median Nerve ◽  
Rating Scale ◽  
Normal Population ◽  
Compound Muscle Action Potential ◽  
Cross Sectional ◽  
Study Results ◽  
Significant Difference ◽  
Als Patients ◽  
Lateral Sclerosis

We aimed to compare the sonographic measurement of median nerve cross-section area (CSA) in patients with Amyotrophic Lateral Sclerosis (ALS) and healthy individuals. The effect of duration of the disease on correlations between paraclinical findings and ALS functional rating scale (ALSFRS) were secondarily aimed to be evaluated. The cross-sectional study was approved by the Ethical Committee of Iran University of Medical Sciences and conducted between January 2017 and December 2018. We evaluated the median nerve surface area by means of sonography in 35 ALS patients and 35 healthy controls. Compound muscle action potential (CMAP) amplitudes during nerve conduction study and ALSFRS were recorded by the same trained specialist. Data were analyzed using SPSS software version 18. We did not find a significant difference between CSA in ALS patients and the normal population (P>0.05). Comparing to normal individuals, the mean CMAP decreased significantly in ALS patients (6.6±3.07 mV versus 10.25±2.2 mV, P<0.001). ALSFRS correlated with both CSA of the median nerve at the wrist (P:<0.001, r:0.78) and the CMAP (P:<0.001, r:0.74) that were confirmed by regression models designed to consider the effect of disease duration on these correlations. CSA was not different between ALS patients and the normal population, but CMAP decreased in ALS patients. ALSFRS correlated with both CSA and CMAP of the median nerve.

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 Clinical Determinants of Disease Progression in Amyotrophic Lateral Sclerosis—A Retrospective Cohort Study

2021 ◽  
Vol 10 (8) ◽  
pp. 1623
Author(s):  
Maria Viktoria Requardt ◽  
Dennis Görlich ◽  
Torsten Grehl ◽  
Matthias Boentert
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Disease Progression ◽  
Rating Scale ◽  
Rapid Decline ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Hazard Ratios ◽  
Sum Score ◽  
Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is ultimately fatal but characterized by substantial phenotypic heterogeneity, which is known to impact long-term course and survival. This study investigated clinical determinants of disease progression and outcome in a large cohort of patients with ALS. Methods: Retrospective analysis included comprehensive data from 625 patients who attended a tertiary ALS centre at least twice. Patients were stratified according to five distinct clinical phenotypes: classical ALS; bulbar ALS; ALS with frontotemporal dementia (ALS-FTD); upper motor neuron predominant (UMNP); and lower motor neuron predominant (LMNP). Results: This study confirmed higher age at symptom onset, shorter latency to diagnosis and more rapid decline in the revised ALS Functional Rating Scale sum score as predictors of poor prognosis. Hazard ratios for shorter survival were higher in patients with ALS-FTD versus classical ALS, and in patients with versus without chronic obstructive pulmonary disease (COPD). Mean survival was longest in the UMNP phenotype group. Conclusions: This study confirmed established predictors of shorter survival in ALS and showed that concomitant COPD in particular relates to poor outcome.

scholarly journals Informal Caregiving in Amyotrophic Lateral Sclerosis (ALS): A High Caregiver Burden and Drastic Consequences on Caregivers’ Lives

2021 ◽  
Vol 11 (6) ◽  
pp. 748
Author(s):  
Pavel Schischlevskij ◽  
Isabell Cordts ◽  
René Günther ◽  
Benjamin Stolte ◽  
Daniel Zeller ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Functional Status ◽  
Disease Severity ◽  
Caregiver Burden ◽  
Rating Scale ◽  
Depression Scale ◽  
Anxiety And Depression ◽  
Daily Routine ◽  
Work Lives ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients’ informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers’ burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients’ CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients’ functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King’s Stages for ALS. The caregivers’ burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers’ burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients’ functional status (rp = −0.555, p < 0.001, n = 242). It was influenced by the CGs’ own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], p < 0.001), patients’ wheelchair dependency (+9.30, 95% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs’ depression (rp = 0.627, p < 0.001, n = 234), anxiety (rp = 0.550, p < 0.001, n = 234), and poorer physical condition (rp = −0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients’ impairment in daily routine (rs = −0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs’ lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs’ work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.

scholarly journals Glutathione S-transferase Omega 2 DD genotype is associated with an increased risk of sporadic amyotrophic lateral sclerosis in Chinese men

2021 ◽  
Vol 49 (7) ◽  
pp. 030006052110332
Author(s):  
Zhiliang Fan ◽  
Hong Jiang ◽  
Xueqin Song ◽  
Yansu Guo ◽  
Xinying Tian
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Healthy Subjects ◽  
Chinese Population ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Glutathione S Transferase ◽  
Genotype Frequencies ◽  
Sporadic Als ◽  
Increased Risk ◽  
Chi Squared ◽  
Lateral Sclerosis

Objective To investigate whether GSTA1, GSTO2, and GSTZ1 are relevant to an increased risk of amyotrophic lateral sclerosis (ALS) in a Chinese population. Methods In this study, 143 sporadic ALS (sALS) patients (83 men, 60 women) and 210 age- and sex-matched healthy subjects were enrolled. Blood samples were collected by venipuncture. Genomic DNA was isolated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) according to the manufacturer’s instructions. The potential associations between ALS and GSTA1, GSTO2, and GSTZ1 polymorphisms were estimated using chi-squared analysis and unconditional logistic regression. Results The D allele and genotype frequencies of GSTO2 were increased in sALS patients compared with healthy subjects, indicating that the GSTO2 DD genotype was associated with an increased risk of sALS (odds ratio [OR] = 3.294, 95% confidence interval [CI] = 1.039–10.448). However, a significant association between the DD genotype and the risk of sALS was evident in men only (OR = 7.167, 95% CI = 1.381–37.202). Conclusion This study revealed that the D allele and genotype frequencies of GSTO2 were increased in sALS patients. The GSTO2 DD genotype was associated with an increased risk of sALS in men in a Chinese population.

scholarly journals Role of Oxidative Stress in the Pathogenesis of Amyotrophic Lateral Sclerosis: Antioxidant Metalloenzymes and Therapeutic Strategies

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 437
Author(s):  
Pavlína Hemerková ◽  
Martin Vališ
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Antioxidant Enzymes ◽  
Oxygen Radicals ◽  
Clinical Symptoms ◽  
Free Oxygen Radicals ◽  
Free Oxygen ◽  
Sporadic Als ◽  
Familial Form ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) affects motor neurons in the cerebral cortex, brainstem and spinal cord and leads to death due to respiratory failure within three to five years. Although the clinical symptoms of this disease were first described in 1869 and it is the most common motor neuron disease and the most common neurodegenerative disease in middle-aged individuals, the exact etiopathogenesis of ALS remains unclear and it remains incurable. However, free oxygen radicals (i.e., molecules containing one or more free electrons) are known to contribute to the pathogenesis of this disease as they very readily bind intracellular structures, leading to functional impairment. Antioxidant enzymes, which are often metalloenzymes, inactivate free oxygen radicals by converting them into a less harmful substance. One of the most important antioxidant enzymes is Cu2+Zn2+ superoxide dismutase (SOD1), which is mutated in 20% of cases of the familial form of ALS (fALS) and up to 7% of sporadic ALS (sALS) cases. In addition, the proper functioning of catalase and glutathione peroxidase (GPx) is essential for antioxidant protection. In this review article, we focus on the mechanisms through which these enzymes are involved in the antioxidant response to oxidative stress and thus the pathogenesis of ALS and their potential as therapeutic targets.

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