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Lancet (London, England) Oct 2022Amyotrophic lateral sclerosis is a fatal CNS neurodegenerative disease. Despite intensive research, current management of amyotrophic lateral sclerosis remains... (Review)
Review
Amyotrophic lateral sclerosis is a fatal CNS neurodegenerative disease. Despite intensive research, current management of amyotrophic lateral sclerosis remains suboptimal from diagnosis to prognosis. Recognition of the phenotypic heterogeneity of amyotrophic lateral sclerosis, global CNS dysfunction, genetic architecture, and development of novel diagnostic criteria is clarifying the spectrum of clinical presentation and facilitating diagnosis. Insights into the pathophysiology of amyotrophic lateral sclerosis, identification of disease biomarkers and modifiable risks, along with new predictive models, scales, and scoring systems, and a clinical trial pipeline of mechanism-based therapies, are changing the prognostic landscape. Although most recent advances have yet to translate into patient benefit, the idea of amyotrophic lateral sclerosis as a complex syndrome is already having tangible effects in the clinic. This Seminar will outline these insights and discuss the status of the management of amyotrophic lateral sclerosis for the general neurologist, along with future prospects that could improve care and outcomes for patients with amyotrophic lateral sclerosis.
Topics: Amyotrophic Lateral Sclerosis; Biomarkers; Forecasting; Humans; Neurodegenerative Diseases; Prognosis
PubMed: 36116464
DOI: 10.1016/S0140-6736(22)01272-7 -
The Lancet. Neurology May 2022The diagnosis of amyotrophic lateral sclerosis can be challenging due to its heterogeneity in clinical presentation and overlap with other neurological disorders.... (Review)
Review
The diagnosis of amyotrophic lateral sclerosis can be challenging due to its heterogeneity in clinical presentation and overlap with other neurological disorders. Diagnosis early in the disease course can improve outcomes as timely interventions can slow disease progression. An evolving awareness of disease genotypes and phenotypes and new diagnostic criteria, such as the recent Gold Coast criteria, could expedite diagnosis. Improved prognosis, such as that achieved with the survival model from the European Network for the Cure of ALS, could inform the patient and their family about disease course and improve end-of-life planning. Novel staging and scoring systems can help monitor disease progression and might potentially serve as clinical trial outcomes. Lastly, new tools, such as fluid biomarkers, imaging modalities, and neuromuscular electrophysiological measurements, might increase diagnostic and prognostic accuracy.
Topics: Amyotrophic Lateral Sclerosis; Biomarkers; Disease Progression; Electromyography; Humans; Prognosis
PubMed: 35334233
DOI: 10.1016/S1474-4422(21)00465-8 -
Nature Reviews. Disease Primers Oct 2017Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is characterized by the degeneration of both upper and lower motor neurons, which leads to... (Review)
Review
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and eventual paralysis. Until recently, ALS was classified primarily within the neuromuscular domain, although new imaging and neuropathological data have indicated the involvement of the non-motor neuraxis in disease pathology. In most patients, the mechanisms underlying the development of ALS are poorly understood, although a subset of patients have familial disease and harbour mutations in genes that have various roles in neuronal function. Two possible disease-modifying therapies that can slow disease progression are available for ALS, but patient management is largely mediated by symptomatic therapies, such as the use of muscle relaxants for spasticity and speech therapy for dysarthria.
Topics: Amyotrophic Lateral Sclerosis; Humans
PubMed: 28980624
DOI: 10.1038/nrdp.2017.71 -
The New England Journal of Medicine Jul 2017
Review
Topics: Amyotrophic Lateral Sclerosis; Genetic Variation; Humans; Survival Analysis
PubMed: 28700839
DOI: 10.1056/NEJMra1603471 -
Lancet (London, England) Nov 2017Amyotrophic lateral sclerosis is characterised by the progressive loss of motor neurons in the brain and spinal cord. This neurodegenerative syndrome shares... (Review)
Review
Amyotrophic lateral sclerosis is characterised by the progressive loss of motor neurons in the brain and spinal cord. This neurodegenerative syndrome shares pathobiological features with frontotemporal dementia and, indeed, many patients show features of both diseases. Many different genes and pathophysiological processes contribute to the disease, and it will be necessary to understand this heterogeneity to find effective treatments. In this Seminar, we discuss clinical and diagnostic approaches as well as scientific advances in the research fields of genetics, disease modelling, biomarkers, and therapeutic strategies.
Topics: Amyotrophic Lateral Sclerosis; Cause of Death; Chronic Disease; DNA-Binding Proteins; Disease Progression; Female; Genetic Predisposition to Disease; Humans; Male; Survival Rate; TDP-43 Proteinopathies
PubMed: 28552366
DOI: 10.1016/S0140-6736(17)31287-4 -
The American Journal of Managed Care Aug 2018Amyotrophic lateral sclerosis (ALS) is a disease that results in the progressive deterioration and loss of function of the motor neurons in the brain and spinal cord,... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a disease that results in the progressive deterioration and loss of function of the motor neurons in the brain and spinal cord, leading to paralysis. ALS affects approximately 16,000 individuals, with a prognosis for survival of 2 to 5 years. There are 2 types of ALS differentiated by genetics: familial and sporadic (idiopathic). Diagnosis is determined by excluding other conditions and utilizing clinical examinations, laboratory tests, and nerve conduction/electromyography studies. Due to the collection of information from the participation of patients with ALS in registries, biomarkers and genes associated with ALS have been discovered. The best practices for the management of ALS include an interdisciplinary approach aimed at addressing the physical and psychological needs and desires of patients and their families and caregivers.
Topics: Activities of Daily Living; Amyotrophic Lateral Sclerosis; Disease Progression; Early Diagnosis; Genetic Markers; Humans; Quality of Life
PubMed: 30207670
DOI: No ID Found -
Cold Spring Harbor Perspectives in... Aug 2017Amyotrophic lateral sclerosis (ALS) is primarily characterized by progressive loss of motor neurons, although there is marked phenotypic heterogeneity between cases.... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is primarily characterized by progressive loss of motor neurons, although there is marked phenotypic heterogeneity between cases. Typical, or "classical," ALS is associated with simultaneous upper motor neuron (UMN) and lower motor neuron (LMN) involvement at disease onset, whereas atypical forms, such as primary lateral sclerosis and progressive muscular atrophy, have early and predominant involvement in the UMN and LMN, respectively. The varying phenotypes can be so distinctive that they would seem to have differing biology. Because the same phenotypes can have multiple causes, including different gene mutations, there may be multiple molecular mechanisms causing ALS, implying that the disease is a syndrome. Conversely, multiple phenotypes can be caused by a single gene mutation; thus, a single molecular mechanism could be compatible with clinical heterogeneity. The pathogenic mechanism(s) in ALS remain unknown, but active propagation of the pathology neuroanatomically is likely a primary component.
Topics: Amyotrophic Lateral Sclerosis; Disease Progression; Extremities; Frontotemporal Dementia; Humans; Motor Neurons; Mutation; Phenotype
PubMed: 28003278
DOI: 10.1101/cshperspect.a024117 -
The Lancet. Neurology May 2022Amyotrophic lateral sclerosis is a fatal neurodegenerative disease. The discovery of genes associated with amyotrophic lateral sclerosis, commencing with SOD1 in 1993,... (Review)
Review
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease. The discovery of genes associated with amyotrophic lateral sclerosis, commencing with SOD1 in 1993, started fairly gradually. Recent advances in genetic technology have led to the rapid identification of multiple new genes associated with the disease, and to a new understanding of oligogenic and polygenic disease risk. The overlap of genes associated with amyotrophic lateral sclerosis with those of other neurodegenerative diseases is shedding light on the phenotypic spectrum of neurodegeneration, leading to a better understanding of genotype-phenotype correlations. A deepening knowledge of the genetic architecture is allowing the characterisation of the molecular steps caused by various mutations that converge on recurrent dysregulated pathways. Of crucial relevance, mutations associated with amyotrophic lateral sclerosis are amenable to novel gene-based therapeutic options, an approach in use for other neurological illnesses. Lastly, the exposome-the summation of lifetime environmental exposures-has emerged as an influential component for amyotrophic lateral sclerosis through the gene-time-environment hypothesis. Our improved understanding of all these aspects will lead to long-awaited therapies and the identification of modifiable risks factors.
Topics: Amyotrophic Lateral Sclerosis; Genetic Association Studies; Humans; Mutation; Neurodegenerative Diseases
PubMed: 35334234
DOI: 10.1016/S1474-4422(21)00414-2 -
Neurologic Clinics Nov 2015The neuropathologic molecular signature common to almost all sporadic amyotrophic lateral sclerosis (ALS) and most familial ALS is TDP-43 immunoreactive neuronal... (Review)
Review
The neuropathologic molecular signature common to almost all sporadic amyotrophic lateral sclerosis (ALS) and most familial ALS is TDP-43 immunoreactive neuronal cytoplasmic inclusions. The neuropathologic and molecular neuropathologic features of ALS variants, primarily lateral sclerosis and progressive muscular atrophy, are less certain but also seem to share the primary features of ALS. Genetic causes, including mutations in SOD1, TDP-43, FUS, and C9orf72, all have distinctive molecular neuropathologic signatures. Neuropathology will continue to play an increasingly key role in solving the puzzle of ALS pathogenesis.
Topics: Amyotrophic Lateral Sclerosis; C9orf72 Protein; DNA-Binding Proteins; Genetic Variation; Humans; Proteins
PubMed: 26515626
DOI: 10.1016/j.ncl.2015.07.012 -
BMJ (Clinical Research Ed.) Oct 2023Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an... (Review)
Review
Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an effective therapy remains slow. This review summarizes the critical discoveries and outlines the advances in disease characterization, diagnosis, imaging, and biomarkers, along with the current status of approaches to ALS care and treatment. Additional knowledge of the factors driving disease progression and heterogeneity will hopefully soon transform the care for patients with ALS into an individualized, multi-prong approach able to prevent disease progression sufficiently to allow for a dignified life with limited disability.
Topics: Humans; Amyotrophic Lateral Sclerosis; Pathology, Molecular; Disease Progression
PubMed: 37890889
DOI: 10.1136/bmj-2023-075037