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International Journal of Molecular... Jun 2019Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder of the motor neurons, characterized by focal onset of muscle weakness... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder of the motor neurons, characterized by focal onset of muscle weakness and incessant disease progression. While the presence of concomitant upper and lower motor neuron signs has been recognized as a pathognomonic feature of ALS, the pathogenic importance of upper motor neuron dysfunction has only been recently described. Specifically, transcranial magnetic stimulation (TMS) techniques have established cortical hyperexcitability as an important pathogenic mechanism in ALS, correlating with neurodegeneration and disease spread. Separately, ALS exhibits a heterogeneous clinical phenotype that may lead to misdiagnosis, particularly in the early stages of the disease process. Cortical hyperexcitability was shown to be a robust diagnostic biomarker if ALS, reliably differentiating ALS from neuromuscular mimicking disorders. The present review will provide an overview of key advances in the understanding of ALS pathophysiology and diagnosis, focusing on the importance of cortical hyperexcitability and its relationship to advances in genetic and molecular processes implicated in ALS pathogenesis.
Topics: Amyotrophic Lateral Sclerosis; Cortical Excitability; Electroencephalography; Humans; Transcranial Magnetic Stimulation
PubMed: 31185581
DOI: 10.3390/ijms20112818 -
Neurology Oct 2009To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS). (Review)
Review
Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.
OBJECTIVE
To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS).
METHODS
The authors analyzed studies from 1998 to 2007 to update the 1999 practice parameter. Topics covered in this section include slowing disease progression, nutrition, and respiratory management for patients with ALS.
RESULTS
The authors identified 8 Class I studies, 5 Class II studies, and 43 Class III studies in ALS. Important treatments are available for patients with ALS that are underutilized. Noninvasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), and riluzole are particularly important and have the best evidence. More studies are needed to examine the best tests of respiratory function in ALS, as well as the optimal time for starting PEG, the impact of PEG on quality of life and survival, and the effect of vitamins and supplements on ALS.
RECOMMENDATIONS
Riluzole should be offered to slow disease progression (Level A). PEG should be considered to stabilize weight and to prolong survival in patients with ALS (Level B). NIV should be considered to treat respiratory insufficiency in order to lengthen survival (Level B) and to slow the decline of forced vital capacity (Level B). NIV may be considered to improve quality of life (Level C) [corrected].Early initiation of NIV may increase compliance (Level C), and insufflation/exsufflation may be considered to help clear secretions (Level C).
Topics: Amyotrophic Lateral Sclerosis; Enteral Nutrition; Evidence-Based Medicine; Humans; Lithium Carbonate; Quality of Life; Respiratory Therapy; Riluzole
PubMed: 19822872
DOI: 10.1212/WNL.0b013e3181bc0141 -
Neuroepidemiology 2013Amyotrophic lateral sclerosis (ALS) is relatively rare, yet the economic and social burden is substantial. Having accurate incidence and prevalence estimates would... (Review)
Review
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is relatively rare, yet the economic and social burden is substantial. Having accurate incidence and prevalence estimates would facilitate efficient allocation of healthcare resources.
OBJECTIVE
To provide a comprehensive and critical review of the epidemiological literature on ALS.
METHODS
MEDLINE and EMBASE (1995-2011) databases of population-based studies on ALS incidence and prevalence reporting quantitative data were analyzed. Data extracted included study location and time, design and data sources, case ascertainment methods and incidence and/or prevalence rates. Medians and interquartile ranges (IQRs) were calculated, and ALS case estimates were derived using 2010 population estimates.
RESULTS
In all, 37 articles met the inclusion criteria. In Europe, the median incidence rate (/100,000 population) was 2.08 (IQR 1.47-2.43), corresponding to an estimated 15,355 (10,852-17,938) cases. Median prevalence (/100,000 population) was 5.40 (IQR 4.06-7.89), or 39,863 (29,971-58,244) prevalent cases.
CONCLUSIONS
Disparity in rates among ALS incidence and prevalence studies may be due to differences in study design or true variations in population demographics such as age and geography, including environmental factors and genetic predisposition. Additional large-scale studies that use standardized case ascertainment methods are needed to more accurately assess the true global burden of ALS.
Topics: Amyotrophic Lateral Sclerosis; Global Health; Humans
PubMed: 23860588
DOI: 10.1159/000351153 -
Neuroscience Research Dec 2023Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease, still incurable. The disease is highly heterogenous both genetically and phenotypically.... (Review)
Review
Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease, still incurable. The disease is highly heterogenous both genetically and phenotypically. Therefore, developing efficacious treatments is challenging in many aspects because it is difficult to predict the rate of disease progression and stratify the patients to minimize statistical variability in clinical studies. Moreover, there is a lack of sensitive measures of therapeutic effect to assess whether a pharmacological intervention ameliorates the disease. There is also urgency of markers that reflect a molecular mechanism dysregulated by ALS pathology and can be rescued when a treatment relieves the condition. Here, we summarize and discuss biomarkers tested in multicentered studies and across different laboratories like neurofilaments, the most used marker in ALS clinical studies, neuroinflammatory-related proteins, p75, p-Tau/t-Tau, and UCHL1. We also explore the applicability of muscle proteins and extracellular vesicles as potential biomarkers.
Topics: Humans; Amyotrophic Lateral Sclerosis; Prognosis; Biomarkers; Disease Progression
PubMed: 37689321
DOI: 10.1016/j.neures.2023.09.002 -
Cells Apr 2023Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons for which effective therapies are lacking. One of the... (Review)
Review
Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons for which effective therapies are lacking. One of the most explored areas of research in ALS is the discovery and validation of biomarkers that can be applied to clinical practice and incorporated into the development of innovative therapies. The study of biomarkers requires an adequate theoretical and operational framework, highlighting the "fit-for-purpose" concept and distinguishing different types of biomarkers based on common terminology. In this review, we aim to discuss the current status of fluid-based prognostic and predictive biomarkers in ALS, with particular emphasis on those that are the most promising ones for clinical trial design and routine clinical practice. Neurofilaments in cerebrospinal fluid and blood are the main prognostic and pharmacodynamic biomarkers. Furthermore, several candidates exist covering various pathological aspects of the disease, such as immune, metabolic and muscle damage markers. Urine has been studied less often and should be explored for its possible advantages. New advances in the knowledge of cryptic exons introduce the possibility of discovering new biomarkers. Collaborative efforts, prospective studies and standardized procedures are needed to validate candidate biomarkers. A combined biomarkers panel can provide a more detailed disease status.
Topics: Humans; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Prospective Studies; Biomarkers; Motor Neurons
PubMed: 37190090
DOI: 10.3390/cells12081180 -
Cells Nov 2020Over the past 20 years, there has been a drastically increased understanding of the genetic basis of Amyotrophic Lateral Sclerosis. Despite the identification of more... (Review)
Review
Over the past 20 years, there has been a drastically increased understanding of the genetic basis of Amyotrophic Lateral Sclerosis. Despite the identification of more than 40 different ALS-causing mutations, the accumulation of neurotoxic misfolded proteins, inclusions, and aggregates within motor neurons is the main pathological hallmark in all cases of ALS. These protein aggregates are proposed to disrupt cellular processes and ultimately result in neurodegeneration. One of the main reasons implicated in the accumulation of protein aggregates may be defective autophagy, a highly conserved intracellular "clearance" system delivering misfolded proteins, aggregates, and damaged organelles to lysosomes for degradation. Autophagy is one of the primary stress response mechanisms activated in highly sensitive and specialised neurons following insult to ensure their survival. The upregulation of autophagy through pharmacological autophagy-inducing agents has largely been shown to reduce intracellular protein aggregate levels and disease phenotypes in different in vitro and in vivo models of neurodegenerative diseases. In this review, we explore the intriguing interface between ALS and autophagy, provide a most comprehensive summary of autophagy-targeted drugs that have been examined or are being developed as potential treatments for ALS to date, and discuss potential therapeutic strategies for targeting autophagy in ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; Autophagy; Caloric Restriction; Genetic Predisposition to Disease; Humans; Models, Biological; Molecular Targeted Therapy
PubMed: 33158177
DOI: 10.3390/cells9112413 -
Neurological Sciences : Official... Feb 2021The present review represents an update about the knowledge of the possible role of Cadmium (Cd) in amyotrophic lateral sclerosis (ALS) initiation and its progression.... (Review)
Review
The present review represents an update about the knowledge of the possible role of Cadmium (Cd) in amyotrophic lateral sclerosis (ALS) initiation and its progression. ALS is a neurodegenerative disease that occurs in adulthood; its etiology is unknown and leads to death within a few years from its appearance. Among the various possible causes that can favor the development of the disease, heavy metals cannot be excluded. Cadmium is a heavy metal that does not play a biological role, but its neurotoxicity is well known. Numerous in vitro studies on cell and animal models confirm the toxicity of the metal on the nervous system, but these data are not accompanied by an epidemiological evidence, and, thus, an unclear correlation between Cd and the onset of the disease can be pointed out. On the other hand, a possible multifactorial and synergic mechanism in which Cd may have a role can explain the ALS onset. More efforts in new clinical, biochemical, and epidemiological studies are necessary to better elucidate the involvement of Cd in this lethal disease.
Topics: Amyotrophic Lateral Sclerosis; Animals; Cadmium; Neurodegenerative Diseases
PubMed: 33280067
DOI: 10.1007/s10072-020-04957-7 -
Amyotrophic Lateral Sclerosis :... 2009We have performed a systematic review to summarize current knowledge concerning factors related to survival in ALS and to evaluate the implications of these data for... (Review)
Review
We have performed a systematic review to summarize current knowledge concerning factors related to survival in ALS and to evaluate the implications of these data for clinical trials design. The median survival time from onset to death ranges from 20 to 48 months, but 10-20% of ALS patients have a survival longer than 10 years. Older age and bulbar onset are consistently reported to have a worse outcome. There are conflicting data on gender, diagnostic delay and El Escorial criteria. The rate of symptom progression was revealed to be an independent prognostic factor. Psychosocial factors, FTD, nutritional status, and respiratory function are also related to ALS outcome. The effect of enteral nutrition on survival is still unclear, while NIPPV has been found to improve survival. There are no well established biological markers of progression, although some are likely to emerge in the near future. These findings have relevant implications for the design of future trials. Randomization, besides the type of onset, should take into account age, respiratory status at entry, and a measure of disease progression pre-entry. Alternative trial designs can include the use of natural history controls, the so-called minimization method for treatment allocation, and the futility approach.
Topics: Age of Onset; Amyotrophic Lateral Sclerosis; Biomarkers; Clinical Trials as Topic; Disease Progression; Humans; Nutritional Status; Prognosis; Prospective Studies; Respiration; Retrospective Studies; Severity of Illness Index; Survival Rate
PubMed: 19922118
DOI: 10.3109/17482960802566824 -
Cells Mar 2023Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in the loss of motor function in the central nervous system (CNS) and... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in the loss of motor function in the central nervous system (CNS) and ultimately death. The mechanisms underlying ALS pathogenesis have not yet been fully elucidated, and ALS cannot be treated effectively. Most studies have applied animal or single-gene intervention cell lines as ALS disease models, but they cannot accurately reflect the pathological characteristics of ALS. Induced pluripotent stem cells (iPSCs) can be reprogrammed from somatic cells, possessing the ability to self-renew and differentiate into a variety of cells. iPSCs can be obtained from ALS patients with different genotypes and phenotypes, and the genetic background of the donor cells remains unchanged during reprogramming. iPSCs can differentiate into neurons and glial cells related to ALS. Therefore, iPSCs provide an excellent method to evaluate the impact of diseases on ALS patients. Moreover, patient-derived iPSCs are obtained from their own somatic cells, avoiding ethical concerns and posing only a low risk of immune rejection. The iPSC technology creates new hope for ALS treatment. Here, we review recent studies on iPSCs and their applications in disease modeling, drug screening and cell therapy in ALS, with a particular focus on the potential for ALS treatment.
Topics: Animals; Amyotrophic Lateral Sclerosis; Induced Pluripotent Stem Cells; Neurodegenerative Diseases; Neurons; Cell- and Tissue-Based Therapy
PubMed: 36980310
DOI: 10.3390/cells12060971 -
Current Neurology and Neuroscience... May 2020In amyotrophic lateral sclerosis (ALS), sleep disruption is frequently present and substantially adds to disease burden. This review aims to summarize current knowledge... (Review)
Review
PURPOSE OF REVIEW
In amyotrophic lateral sclerosis (ALS), sleep disruption is frequently present and substantially adds to disease burden. This review aims to summarize current knowledge on causes, pathophysiology, and treatment of sleep disturbances in ALS.
RECENT FINDINGS
Motor neuron degeneration and muscle weakness may lead to muscle cramps, pain, spasticity, immobilization, restless legs, sleep-disordered breathing, and difficulties to clear secretions. Furthermore, existential fears and depression may promote insomnia. Sleep-disordered breathing, and nocturnal hypoventilation in particular, requires ventilatory support which meaningfully prolongs survival and improves health-related quality of life albeit respiratory failure is inevitable. Early indication for non-invasive ventilation can be achieved by inclusion of capnometry in diagnostic sleep studies. Sleep disruption is extremely common in ALS and may arise from different etiologies. The absence of causative therapeutic options for ALS underlines the importance of symptomatic and palliative treatment strategies that acknowledge sleep-related complaints.
Topics: Amyotrophic Lateral Sclerosis; Humans; Polysomnography; Quality of Life; Respiratory Insufficiency; Sleep
PubMed: 32462331
DOI: 10.1007/s11910-020-01047-1