Prognostic modelling of therapeutic interventions in amyotrophic lateral sclerosis

2002 ◽  
Vol 3 (1) ◽  
pp. 15-21 ◽  
Author(s):  
MR Turner ◽  
M Bakker ◽  
P Sham ◽  
CE Shaw ◽  
PN Leigh ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Therapeutic Interventions ◽  
Prognostic Modelling ◽  
Lateral Sclerosis

scholarly journals BDNF-dependent modulation of axonal transport is selectively impaired in ALS

2021 ◽  
Author(s):  
Andrew P. Tosolini ◽  
James N. Sleigh ◽  
Sunaina Surana ◽  
Elena R. Rhymes ◽  
Stephen D. Cahalan ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Axonal Transport ◽  
Neuronal Development ◽  
Therapeutic Interventions ◽  
Wild Type ◽  
Disease Pathogenesis ◽  
Sciatic Nerves ◽  
Lateral Sclerosis ◽  
Selective Impairment ◽  
Stimulation Of

AbstractAxonal transport ensures long-range delivery of essential cargoes between proximal and distal compartments of neurons, and is needed for neuronal development, function, and survival. Deficits in axonal transport have been detected at pre-symptomatic stages in mouse models of amyotrophic lateral sclerosis (ALS), suggesting that impairments are fundamental for disease pathogenesis. However, the precise mechanisms responsible for the transport deficits and whether they preferentially affect α-motor neuron (MN) subtypes remain unresolved. Here, we report that stimulation of wild-type neurons with brain-derived neurotrophic factor (BDNF) enhances trafficking of signalling endosomes specifically in fast MNs (FMNs). In early symptomatic SOD1G93A mice, FMNs display selective impairment of axonal transport and develop an insensitivity to BDNF stimulation, with pathology upregulating classical non-pro-survival receptors in muscles and sciatic nerves. Altogether, these data indicate that cell- and non-cell autonomous BDNF signalling is impaired in vulnerable SOD1G93A MNs, thus identifying a new key deficit in ALS amenable for future therapeutic interventions.

Dynamic markers of altered gait rhythm in amyotrophic lateral sclerosis

2000 ◽  
Vol 88 (6) ◽  
pp. 2045-2053 ◽  
Author(s):  
Jeffrey M. Hausdorff ◽  
Apinya Lertratanakul ◽  
Merit E. Cudkowicz ◽  
Amie L. Peterson ◽  
David Kaliton ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Control ◽  
Therapeutic Interventions ◽  
Healthy Controls ◽  
Gait Dynamics ◽  
Fluctuation Dynamics ◽  
Distinct Features ◽  
Normal Controls ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a disorder marked by loss of motoneurons. We hypothesized that subjects with ALS would have an altered gait rhythm, with an increase in both the magnitude of the stride-to-stride fluctuations and perturbations in the fluctuation dynamics. To test for this locomotor instability, we quantitatively compared the gait rhythm of subjects with ALS with that of normal controls and with that of subjects with Parkinson's disease (PD) and Huntington's disease (HD), pathologies of the basal ganglia. Subjects walked for 5 min at their usual pace wearing an ankle-worn recorder that enabled determination of the duration of each stride and of stride-to-stride fluctuations. We found that the gait of patients with ALS is less steady and more temporally disorganized compared with that of healthy controls. In addition, advanced ALS, HD, and PD were associated with certain common, as well as apparently distinct, features of altered stride dynamics. Thus stride-to-stride control of gait rhythm is apparently compromised with ALS. Moreover, a matrix of markers based on gait dynamics may be useful in characterizing certain pathologies of motor control and, possibly, in quantitatively monitoring disease progression and evaluating therapeutic interventions.

scholarly journals Antibody-Based Therapeutic Interventions for Amyotrophic Lateral Sclerosis: A Systematic Literature Review

2021 ◽  
Vol 15 ◽  
Author(s):  
Amélie Poulin-Brière ◽  
Edris Rezaei ◽  
Silvia Pozzi
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Passive Immunization ◽  
Therapeutic Interventions ◽  
Original Research ◽  
Motor Impairments ◽  
Research Papers ◽  
Cellular Targets ◽  
Extracellular Molecules ◽  
Present Systematic Review ◽  
Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a mid-life onset neurodegenerative disease that manifests its symptomatology with motor impairments and cognitive deficits overlapping with Frontotemporal Lobar Degeneration (FTLD). The etiology of ALS remains elusive, with various mechanisms and cellular targets implicated, and no treatment can reverse or stop the progression of the pathology. Therapeutic interventions based on passive immunization are gaining attention for neurodegenerative diseases, and FDA recently approved the first antibody-based approach for Alzheimer's disease. The present systematic review of the literature aims to highlight the efforts made over the past years at developing antibody-based strategies to cure ALS. Thirty-one original research papers have been selected where the therapeutic efficacy of antibodies were investigated and described in patients and animal models of ALS. Antibody-based interventions analyzed, target both extracellular molecules implicated in the pathology and intracellular pathogenic proteins known to drive the disease, such as SOD1, TDP-43 or C9ORF72 repeats expansions. The potentials and limitations of these therapeutic interventions have been described and discussed in the present review.

scholarly journals Recent advances in understanding amyotrophic lateral sclerosis and emerging therapies

2020 ◽  
Vol 9 ◽  
Author(s):  
Lauren M Gittings ◽  
Rita Sattler
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Clinical Stage ◽  
Treatment Options ◽  
Therapeutic Interventions ◽  
Current Status ◽  
Stage Of Development ◽  
Recent Advances ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by degeneration of both upper and lower motor neurons and subsequent progressive loss of muscle function. Within the last decade, significant progress has been made in the understanding of the etiology and pathobiology of the disease; however, treatment options remain limited and only two drugs, which exert a modest effect on survival, are approved for ALS treatment in the US. Therefore, the search for effective ALS therapies continues, and over 60 clinical trials are in progress for patients with ALS and other therapeutics are at the pre-clinical stage of development. Recent advances in understanding the genetics, pathology, and molecular mechanisms of ALS have led to the identification of novel targets and strategies that are being used in emerging ALS therapeutic interventions. Here, we review the current status and mechanisms of action of a selection of emerging ALS therapies in pre-clinical or early clinical development, including gene therapy, immunotherapy, and strategies that target neuroinflammation, phase separation, and protein clearance.

scholarly journals Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis

2015 ◽  
Vol 113 (3) ◽  
pp. 614-619 ◽  
Author(s):  
Elizabeth A. Proctor ◽  
Lanette Fee ◽  
Yazhong Tao ◽  
Rachel L. Redler ◽  
James M. Fay ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Therapeutic Strategies ◽  
Therapeutic Interventions ◽  
Neuron Death ◽  
Motor Neuron Death ◽  
Molecular Etiology ◽  
Superoxide Dismutase Gene ◽  
Lateral Sclerosis

Since the linking of mutations in the Cu,Zn superoxide dismutase gene (sod1) to amyotrophic lateral sclerosis (ALS) in 1993, researchers have sought the connection between SOD1 and motor neuron death. Disease-linked mutations tend to destabilize the native dimeric structure of SOD1, and plaques containing misfolded and aggregated SOD1 have been found in the motor neurons of patients with ALS. Despite advances in understanding of ALS disease progression and SOD1 folding and stability, cytotoxic species and mechanisms remain unknown, greatly impeding the search for and design of therapeutic interventions. Here, we definitively link cytotoxicity associated with SOD1 aggregation in ALS to a nonnative trimeric SOD1 species. We develop methodology for the incorporation of low-resolution experimental data into simulations toward the structural modeling of metastable, multidomain aggregation intermediates. We apply this methodology to derive the structure of a SOD1 trimer, which we validate in vitro and in hybridized motor neurons. We show that SOD1 mutants designed to promote trimerization increase cell death. Further, we demonstrate that the cytotoxicity of the designed mutants correlates with trimer stability, providing a direct link between the presence of misfolded oligomers and neuron death. Identification of cytotoxic species is the first and critical step in elucidating the molecular etiology of ALS, and the ability to manipulate formation of these species will provide an avenue for the development of future therapeutic strategies.

scholarly journals Oligodendrocyte Dysfunction in Amyotrophic Lateral Sclerosis: Mechanisms and Therapeutic Perspectives

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 565
Author(s):  
Stefano Raffaele ◽  
Marta Boccazzi ◽  
Marta Fumagalli
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Neurological Diseases ◽  
Therapeutic Interventions ◽  
Oligodendrocyte Precursor Cells ◽  
Oligodendrocyte Precursor ◽  
Spontaneous Regeneration ◽  
The Impact ◽  
Lateral Sclerosis ◽  
Myelin Damage

Myelin is the lipid-rich structure formed by oligodendrocytes (OLs) that wraps the axons in multilayered sheaths, assuring protection, efficient saltatory signal conduction and metabolic support to neurons. In the last few years, the impact of OL dysfunction and myelin damage has progressively received more attention and is now considered to be a major contributing factor to neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). Upon OL injury, oligodendrocyte precursor cells (OPCs) of adult nervous tissue sustain the generation of new OLs for myelin reconstitution, but this spontaneous regeneration process fails to successfully counteract myelin damage. Of note, the functions of OPCs exceed the formation and repair of myelin, and also involve the trophic support to axons and the capability to exert an immunomodulatory role, which are particularly relevant in the context of neurodegeneration. In this review, we deeply analyze the impact of dysfunctional OLs in ALS pathogenesis. The possible mechanisms underlying OL degeneration, defective OPC maturation, and impairment in energy supply to motor neurons (MNs) have also been examined to provide insights on future therapeutic interventions. On this basis, we discuss the potential therapeutic utility in ALS of several molecules, based on their remyelinating potential or capability to enhance energy metabolism.

scholarly journals Updates from the fray: rational off-label and over-the-counter prescribing in amyotrophic lateral sclerosis

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
William Pridmore
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Terminal Condition ◽  
Therapeutic Interventions ◽  
Research Support ◽  
Over The Counter ◽  
Off Label ◽  
Drug Candidates ◽  
Routes Of Administration ◽  
Limited Success ◽  
Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a terminal condition, which is increasing in incidence. Therapeutic interventions have enjoyed limited success. However, research is progressing, with some promising drug candidates emerging. Patients cannot always wait for the results of large trials. The general practitioner has a central role in management of ALS. Objective: To review and summarise available evidence evaluating the disease-modifying and life-extending potential of approved medications available off-label or over the counter. To inform doctors and patients of updates in the field and assist their decision-making. Discussion: Three experimental candidates were deemed to have a reasonable likelihood of efficacy, and doses/routes of administration were clarified. Possibilities for novel therapies were outlined, and the importance of research support was highlighted.

scholarly journals Searching Far and Genome-Wide: The Relevance of Association Studies in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 14 ◽  
Author(s):  
Kelly A. Rich ◽  
Jennifer Roggenbuck ◽  
Stephen J. Kolb
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Complex Disease ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Disease Status ◽  
Therapeutic Interventions ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Disease Associated Genes ◽  
Lateral Sclerosis

Genome-wide association studies (GWAS) and rare variant association studies (RVAS) are applied across many areas of complex disease to analyze variation in whole genomes of thousands of unrelated patients. These approaches are able to identify variants and/or biological pathways which are associated with disease status and, in contrast to traditional linkage studies or candidate gene approaches, do so without requiring multigenerational affected families, prior hypotheses, or known genes of interest. However, the novel associations identified by these methods typically have lower effect sizes than those found in classical family studies. In the motor neuron disease amyotrophic lateral sclerosis (ALS), GWAS, and RVAS have been used to identify multiple disease-associated genes but have not yet resulted in novel therapeutic interventions. There is significant urgency within the ALS community to identify additional genetic markers of disease to uncover novel biological mechanisms, stratify genetic subgroups of disease, and drive drug development. Given the widespread and increasing application of genetic association studies of complex disease, it is important to recognize the strengths and limitations of these approaches. Here, we review ALS gene discovery via GWAS and RVAS.

Aerobic glycolysis in amyotrophic lateral sclerosis and Huntington’s disease

2018 ◽  
Vol 29 (5) ◽  
pp. 547-555 ◽  
Author(s):  
Alexandre Vallée ◽  
Yves Lecarpentier ◽  
Rémy Guillevin ◽  
Jean-Noël Vallée
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Pyruvate Dehydrogenase ◽  
Glucose Transporter ◽  
Aerobic Glycolysis ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Therapeutic Interventions ◽  
Lateral Sclerosis

AbstractNeurodegenerative cells are the sites of numerous metabolic and energetic abnormalities with abnormalities in energy production. Energy is the primary determinant of neuronal viability. In neurodegenerative cells, metabolic enzymes are modified by the dysregulation of the canonical WNT/β-catenin pathway. In amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD), WNT/β-catenin pathway is upregulated. We focused this review on the hypothesis of aerobic glycolysis stimulated by the upregulation of WNT/β-catenin pathway in ALS and HD. Upregulation of WNT/β-catenin pathway induces aerobic glycolysis, named Warburg effect, through activation of glucose transporter (Glut), pyruvate kinase M2 (PKM2), pyruvate dehydrogenase kinase 1 (PDK1), monocarboxylate lactate transporter 1 (MCT-1), lactate dehydrogenase kinase-A (LDH-A), and inactivation of pyruvate dehydrogenase complex (PDH). Aerobic glycolysis consists of a supply of a large part of glucose into lactate regardless of oxygen. Aerobic glycolysis is less efficient in terms of ATP production compared with oxidative phosphorylation because of the shunt of the TCA cycle. Dysregulation of energetic metabolism promotes cell death and disease progression in ALD and HD. Aerobic glycolysis regulation is an attractive mechanism for developing therapeutic interventions.

Automated Acoustic Analysis of Oral Diadochokinesis to Assess Bulbar Motor Involvement in Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 63 (1) ◽  
pp. 59-73 ◽  
Author(s):  
Panying Rong
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Acoustic Analysis ◽  
Speaking Rate ◽  
Disease Stage ◽  
Healthy Controls ◽  
Tongue Movement ◽  
Major Barrier ◽  
Syllable Repetition ◽  
Oral Diadochokinesis ◽  
Lateral Sclerosis

Purpose The purpose of this article was to validate a novel acoustic analysis of oral diadochokinesis (DDK) in assessing bulbar motor involvement in amyotrophic lateral sclerosis (ALS). Method An automated acoustic DDK analysis was developed, which filtered out the voice features and extracted the envelope of the acoustic waveform reflecting the temporal pattern of syllable repetitions during an oral DDK task (i.e., repetitions of /tɑ/ at the maximum rate on 1 breath). Cycle-to-cycle temporal variability (cTV) of envelope fluctuations and syllable repetition rate (sylRate) were derived from the envelope and validated against 2 kinematic measures, which are tongue movement jitter (movJitter) and alternating tongue movement rate (AMR) during the DDK task, in 16 individuals with bulbar ALS and 18 healthy controls. After the validation, cTV, sylRate, movJitter, and AMR, along with an established clinical speech measure, that is, speaking rate (SR), were compared in their ability to (a) differentiate individuals with ALS from healthy controls and (b) detect early-stage bulbar declines in ALS. Results cTV and sylRate were significantly correlated with movJitter and AMR, respectively, across individuals with ALS and healthy controls, confirming the validity of the acoustic DDK analysis in extracting the temporal DDK pattern. Among all the acoustic and kinematic DDK measures, cTV showed the highest diagnostic accuracy (i.e., 0.87) with 80% sensitivity and 94% specificity in differentiating individuals with ALS from healthy controls, which outperformed the SR measure. Moreover, cTV showed a large increase during the early disease stage, which preceded the decline of SR. Conclusions This study provided preliminary validation of a novel automated acoustic DDK analysis in extracting a useful measure, namely, cTV, for early detection of bulbar ALS. This analysis overcame a major barrier in the existing acoustic DDK analysis, which is continuous voicing between syllables that interferes with syllable structures. This approach has potential clinical applications as a novel bulbar assessment.

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