scholarly journals Circulating miR-181a-5p is a prognostic biomarker for amyotrophic lateral sclerosis

2019 ◽  
Author(s):  
Iddo Magen ◽  
Anna Coenen-Stass ◽  
Nancy Yacovzada ◽  
Julian Grosskreutz ◽  
Ching-Hua Lu ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Plasma Levels ◽  
Disease Course ◽  
Fold Reduction ◽  
System Variability ◽  
Als Patients ◽  
Clinical Phenotyping ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a relentless neurodegenerative disease affecting the motor neuron system. Variability in the rate of disease progression has limited the effectiveness of ALS clinical trials. Thus, better outcome measures are desperately needed in order to achieve therapeutic progress. Here, we investigate the potential of plasma cell-free microRNAs as biomarkers to predict ALS progression. We apply an unbiased high-throughput approach to define miRNA levels in a large cohort of ALS patients. Crucially, we conduct our analysis also on longitudinal samples reflecting disease progression, and are able to integrate detailed clinical phenotyping in our analysis. We find miR-181a-5p levels to be stable throughout the disease course and demonstrate that high miR-181a-5p plasma levels predict shortened survival in ALS patients, with a 2.5 fold reduction in median survival for patients with high miR-181a-5p plasma levels. We replicated this finding in an independent validation cohort, where an eight-fold (×8) difference in miR-181a-5p levels between the two prognosis subgroups was robustly measurable by quantitative real time PCR. In conclusion, miR-181a-5p plasma levels can predict disease course in ALS, identifying it as a novel biomarker for patient stratification with the potential to greatly enhance the effectiveness of clinical trials.One Sentence Summaryhigher plasma miR-181a-5p levels increase mortality risk in ALS patients.

scholarly journals Amyotrophic Lateral Sclerosis, a Multisystem Pathology: Insights into the Role of TNFα

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Massimo Tortarolo ◽  
Daniele Lo Coco ◽  
Pietro Veglianese ◽  
Antonio Vallarola ◽  
Maria Teresa Giordana ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Immune System ◽  
Disease Progression ◽  
Protective Role ◽  
Progression Rate ◽  
Neuron Death ◽  
Multisystem Disease ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is considered a multifactorial, multisystem disease in which inflammation and the immune system play important roles in development and progression. The pleiotropic cytokine TNFαis one of the major players governing the inflammation in the central nervous system and peripheral districts such as the neuromuscular and immune system. Changes in TNFαlevels are reported in blood, cerebrospinal fluid, and nerve tissues of ALS patients and animal models. However, whether they play a detrimental or protective role on the disease progression is still not clear. Our group and others have recently reported opposite involvements of TNFR1 and TNFR2 in motor neuron death. TNFR2 mediates TNFαtoxic effects on these neurons presumably through the activation of MAP kinase-related pathways. On the other hand, TNFR2 regulates the function and proliferation of regulatory T cells (Treg) whose expression is inversely correlated with the disease progression rate in ALS patients. In addition, TNFαis considered a procachectic factor with a direct catabolic effect on skeletal muscles, causing wasting. We review and discuss the role of TNFαin ALS in the light of its multisystem nature.

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.

scholarly journals Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Eran Hornstein ◽  
Iddo Magen ◽  
Anna Coenen-Stass ◽  
Nancy Yacovzada ◽  
Julian Grosskreutz ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Neurofilament Light Chain ◽  
Protein Biomarker ◽  
Neurofilament Light ◽  
Risk Of Death ◽  
Novel Mirna ◽  
Independent Replication ◽  
Clinical Phenotyping ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a relentless neurodegenerative syndrome of the human motor neuron system, for which no effective treatment exists. Variability in the rate of disease progression limits the efficacy of ALS clinical trials, suggesting that developing of better biomarkers for prognosis will facilitate therapeutic progress. Here, we applied unbiased next-generation sequencing to investigate the potential of plasma cell-free microRNAs as biomarkers of ALS prognosis, in 252 patients with detailed clinical-phenotyping. First, we identified miRNAs, whose plasma levels remain stable over the course of disease in a longitudinal cohort of 22 patients. Next, we demonstrated that high levels of miR-181, a miRNA enriched in neurons of the brain and spinal cord, predicts a >2 fold risk of death in discovery cohort (126 patients) and an independent replication cohort (additional 122 patients). miR-181 performance is comparable with the established neurofilament light chain (NfL) biomarker and when combined together, miR-181+NfL establish a novel RNA-protein biomarker pair with superior prediction capacity of ALS prognosis. Therefore, plasma miR-181 predicts ALS disease course, and a novel miRNA-protein biomarker approach, based on miR-181+NfL, boosts precision of patient stratification and may greatly enhance the power of clinical trials.

P914: Tracking disease progression in amyotrophic lateral sclerosis (ALS) patients using MUNE and macro-EMG

2014 ◽  
Vol 125 ◽  
pp. S289-S290
Author(s):  
T. Bocci ◽  
E. Giorli ◽  
M. Caleo ◽  
S. Tognazzi ◽  
F. Giannini ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Macro Emg ◽  
Als Patients ◽  
Lateral Sclerosis

scholarly journals Side of Limb-Onset Predicts Laterality of Gray Matter Loss in Amyotrophic Lateral Sclerosis

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Qiuli Zhang ◽  
Cuiping Mao ◽  
Jiaoting Jin ◽  
Chen Niu ◽  
Lijun Bai ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Gray Matter ◽  
Brain Atrophy ◽  
Disease Onset ◽  
Progression Rate ◽  
Imaging Evaluation ◽  
Als Patients ◽  
Lateral Sclerosis ◽  
Limb Onset

Conflicting findings have been reported regarding the lateralized brain abnormality in patients with amyotrophic lateral sclerosis (ALS). In this study, we aimed to investigate the probable lateralization of gray matter (GM) atrophy in ALS patients. We focused on the relationship between the asymmetry in decreased GM volume and the side of disease onset in patients with limb-onset. Structural imaging evaluation of normalized atrophy (SIENAX) and voxel-based morphometry (VBM) were used to assess differences in global and local brain regions in patients with heterogeneous body onset and subgroups with different side of limb-onset. We found global brain atrophy and GM losses in the frontal and parietal areas in each patient group as well as left predominant GM losses in the total cohort. The intriguing findings in subgroup analyses demonstrated that the motor cortex in the contralateral hemisphere of the initially involved limb was most affected. We also found that regional brain atrophy was related to disease progression rate. Our observations suggested that side of limb-onset can predict laterality of GM loss in ALS patients and disease progression correlates with the extent of cortical abnormality.

scholarly journals How COVID-19 pandemic changed our management strategies for amyotrophic lateral sclerosis (ALS) patients: Egyptian study

2021 ◽  
Vol 57 (1) ◽  
Author(s):  
Hebatallah R. Rashed
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
North Africa ◽  
Rating Scale ◽  
Management Strategies ◽  
Office Visits ◽  
Bulbar Onset ◽  
A Prospective Study ◽  
Als Patients ◽  
Lateral Sclerosis

Abstract Background There are several studies that have discussed the efficacy of telemedicine with amyotrophic lateral sclerosis (ALS) patients; however, this approach is still preliminary in Egypt and in North Africa. The objective of the current study is to discuss current experience with telemedicine in monitoring patients in the specialized ALS clinic in Egypt. Efficacy of Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) in monitoring disease progression remotely will be discussed. Results This is a prospective study. Forty-three ALS patients were included in this study in the period between July 1, 2020, and February 6, 2021. Fifty-three telemedicine encounters and 13 post-telemedicine office visits were available. None of the participating patients had COVID-19 infection. Eight patients showed decline in ALSFRS score. ALSFRS-R score reported during telemedicine encounters was confirmed during office visits. Three bulbar onset ALS patients had gastrostomy, and 2 bulbar onset ALS patients had Botox injection for drooling. All eight patients with declining ALSFRS-R were maintained on non-invasive ventilation (NIV) based on their symptoms. Conclusion This is the first study discussing telemedicine in the field of ALS in Egypt and North Africa. ALSFRS-R showed feasibility and reliability in detecting disease progression remotely.

scholarly journals Nine Hole Peg Test and Transcranial Magnetic Stimulation: Useful to Evaluate Dexterity of the Hand and Disease Progression in Amyotrophic Lateral Sclerosis

2019 ◽  
Vol 2019 ◽  
pp. 1-5
Author(s):  
David Czell ◽  
Christoph Neuwirth ◽  
Markus Weber ◽  
Sabine Sartoretti-Schefer ◽  
Andreas Gutzeit ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Motor Neurons ◽  
Fine Motor ◽  
Healthy Controls ◽  
Good Tool ◽  
Resting Motor Threshold ◽  
Als Patients ◽  
Nine Hole Peg Test ◽  
Lateral Sclerosis

Objective. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with involvement of the upper and lower motor neurons. Since the loss of fine motor skills is one of the earliest signs of ALS, the hypothesis was tested if the nine hole PEG test (NHPT) and transcranial magnet stimulation (TMS) with resting-motor threshold (RMT) could be useful in monitoring disease progression. Methods. We examined 28 ALS patients and 27 age-matched healthy controls. ALS patients and healthy controls underwent the nine hole peg test (NHPT) and TMS with RMT. Measurements in patients were repeated after three and six months. Results. At baseline, the median NHPT durations were 1,4-fold longer (p<0.001), and TMS scores showed a significant 0.8-fold smaller score in ALS patients compared with healthy controls (p<0.001). The comparison of three and six months versus baseline revealed significant differences for NHPT durations and ALSFRS-R in patients, whereas TMS scores did not significantly differ in the patients. Conclusion. NHPT seems to be a good tool to evaluate dexterity of the hand and the progression of the disease in ALS patients. TMS RMT to the hand muscles seems to be poorly qualified to evaluate the dexterity of the hand function and the course of the disease.

scholarly journals Monitoring disease progression with plasma creatinine in amyotrophic lateral sclerosis clinical trials

2017 ◽  
Vol 89 (2) ◽  
pp. 156-161 ◽  
Author(s):  
Ruben P A van Eijk ◽  
Marinus J C Eijkemans ◽  
Toby A Ferguson ◽  
Stavros Nikolakopoulos ◽  
Jan H Veldink ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Muscle Strength ◽  
Sample Size ◽  
Disease Progression ◽  
Rating Scale ◽  
Plasma Creatinine ◽  
Rate Of Decline ◽  
Lateral Sclerosis

ObjectivesPlasma creatinine is a predictor of survival in amyotrophic lateral sclerosis (ALS). It remains, however, to be established whether it can monitor disease progression and serve as surrogate endpoint in clinical trials.MethodsWe used clinical trial data from three cohorts of clinical trial participants in the LITRA, EMPOWER and PROACT studies. Longitudinal associations between functional decline, muscle strength and survival with plasma creatinine were assessed. Results were translated to trial design in terms of sample size and power.ResultsA total of 13 564 measurements were obtained for 1241 patients. The variability between patients in rate of decline was lower in plasma creatinine than in ALS functional rating scale–Revised (ALSFRS-R; p<0.001). The average rate of decline was faster in the ALSFRS-R, with less between-patient variability at baseline (p<0.001). Plasma creatinine had strong longitudinal correlations with the ALSFRS-R (0.43 (0.39–0.46), p<0.001), muscle strength (0.55 (0.51–0.58), p<0.001) and overall mortality (HR 0.88 (0.86–0.91, p<0.001)). Using plasma creatinine as outcome could reduce the sample size in trials by 21.5% at 18 months. For trials up to 10 months, the ALSFRS-R required a lower sample size.ConclusionsPlasma creatinine is an inexpensive and easily accessible biomarker that exhibits less variability between patients with ALS over time and is predictive for the patient’s functional status, muscle strength and mortality risk. Plasma creatinine may, therefore, increase the power to detect treatment effects and could be incorporated in future ALS clinical trials as potential surrogate outcome.

scholarly journals Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

2015 ◽  
Vol 112 (26) ◽  
pp. 8100-8105 ◽  
Author(s):  
James C. Dodge ◽  
Christopher M. Treleaven ◽  
Joshua Pacheco ◽  
Samantha Cooper ◽  
Channa Bao ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Drug Targets ◽  
Muscular Atrophy ◽  
Neuromuscular Diseases ◽  
Sensory Neuropathy ◽  
Disease Course ◽  
Hereditary Sensory Neuropathy ◽  
Als Patients ◽  
Lateral Sclerosis

Recent genetic evidence suggests that aberrant glycosphingolipid metabolism plays an important role in several neuromuscular diseases including hereditary spastic paraplegia, hereditary sensory neuropathy type 1, and non-5q spinal muscular atrophy. Here, we investigated whether altered glycosphingolipid metabolism is a modulator of disease course in amyotrophic lateral sclerosis (ALS). Levels of ceramide, glucosylceramide, galactocerebroside, lactosylceramide, globotriaosylceramide, and the gangliosides GM3 and GM1 were significantly elevated in spinal cords of ALS patients. Moreover, enzyme activities (glucocerebrosidase-1, glucocerebrosidase-2, hexosaminidase, galactosylceramidase, α-galactosidase, and β-galactosidase) mediating glycosphingolipid hydrolysis were also elevated up to threefold. Increased ceramide, glucosylceramide, GM3, and hexosaminidase activity were also found in SOD1G93A mice, a familial model of ALS. Inhibition of glucosylceramide synthesis accelerated disease course in SOD1G93A mice, whereas infusion of exogenous GM3 significantly slowed the onset of paralysis and increased survival. Our results suggest that glycosphingolipids are likely important participants in pathogenesis of ALS and merit further analysis as potential drug targets.

scholarly journals A Dynamic Bayesian Network model for simulation of disease progression in Amyotrophic Lateral Sclerosis patients

2017 ◽  
Author(s):  
Alessandro Zandonà ◽  
Matilde Francescon ◽  
Maya Bronfeld ◽  
Andrea Calvo ◽  
Adriano Chiò ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Bayesian Network ◽  
Disease Progression ◽  
Motor Neurons ◽  
Clinical Status ◽  
Dynamic Bayesian Network ◽  
Practice Research ◽  
The Individual ◽  
Lateral Sclerosis

Background. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting upper and lower motor neurons in the brain and spinal cord. The heterogeneity in the course of ALS clinical progression and ultimately survival, coupled with the rarity of this disease, make predicting disease outcome at the level of the individual patient very challenging. Besides, stratification of ALS patients has been known for years as a question of great importance to clinical practice, research and drug development. Methods. In this work, we present a Dynamic Bayesian Network (DBN) model of ALS progression to detect probabilistic relationships among variables included in the Pooled Resource Open-Access ALS Clinical Trials Database (PRO-ACT), which provides records of over 10,700 patients from different clinical trials, and with over 2,869,973 longitudinally collected data measurements. Results. Our model unravels new dependencies among clinical variables in relation to ALS progression, such as the influence of basophil count and creatine kinase on patients’ clinical status and the respiratory functional state, respectively. Furthermore, it provided an indication of ALS temporal evolution, in terms of the most probable disease trajectories across time at the level of both patient population and individual patient. Conclusions. The risk factors identified by out DBN model could allow patients' stratification based on velocity of disease progression and a sensitivity analysis on this latter in response to changes in input variables, i.e. variables measured at diagnosis.

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