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The time course of amyotrophic lateral sclerosis (ALS). Time is represented along the x-axis; physical health and molecular damage are represented along the y-axis. With time, molecular damage increases in a step-wise way until it reaches a threshold, at which point physical health declines, representing disease onset. People with a family history of ALS may have a large genetic predisposition to ALS and so need fewer steps to reach the level of molecular damage that causes disease, corresponding to a younger age of onset. Lack of exposure to sufficient risk factors means that the disease does not manifest, even if a genetic cause is present, explaining reduced penetrance. There is not a 1:1 mapping of risk factors and steps, as the steps represent molecular hits that lead to cellular damage rather than actual exposures. Once physical symptoms have started, progression shows a log-linear decline until the onset of respiratory symptoms, where decline is exponential. Clinical and functional involvement can be measured by the King's clinical staging and Milano-Torino staging (MiToS) systems. A dotted line represents the hypothetical trajectory in an unaffected individual. Black arrows represent genetic and environmental risk factors. Numbers indicate remaining molecular hits until disease onset.
Source publication
Amyotrophic lateral sclerosis is a neurodegenerative disease predominantly affecting upper and lower motor neurons, resulting in progressive paralysis and death from respiratory failure within 2 to 3 years. The peak age of onset is 55 to 70 years, with a male predominance. The causes of amyotrophic lateral sclerosis are only partly known, but they...
Citations
... The peak age of onset for ALS is between 55 and 70 years, with a male predominance. 94 The study highlighted the potential influence of age at symptom onset 46 and genetic factors on hippocampal atrophy in ALS patients. 30 40,41,43,44,52,54,63,64,67,69,[73][74][75]78,[81][82][83][84] The hippocampus is essential in episodic memory, learning, and recall. ...
Background and Objective
Amyotrophic lateral sclerosis (ALS) is a progressive motor and extra‐motor neurodegenerative disease. This systematic review aimed to examine MRI biomarkers and neuropsychological assessments of the hippocampal and parahippocampal regions in patients with ALS.
Methods
A systematic review was conducted in the Scopus and PubMed databases for studies published between January 2000 and July 2023. The inclusion criteria were (1) MRI studies to assess hippocampal and parahippocampal regions in ALS patients, and (2) studies reporting neuropsychological data in patients with ALS.
Results
A total of 46 studies were included. Structural MRI revealed hippocampal atrophy, especially in ALS‐FTD, involving specific subregions (CA1, dentate gyrus). Disease progression and genetic factors impacted atrophy patterns. Diffusion tensor imaging (DTI) showed increased mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and decreased fractional anisotropy (FA) in the hippocampal tracts and adjacent regions, indicating loss of neuronal and white matter integrity. Functional MRI (fMRI) revealed reduced functional connectivity (FC) between the hippocampus, parahippocampus, and other regions, suggesting disrupted networks. Perfusion MRI showed hypoperfusion in parahippocampal gyri. Magnetic resonance spectroscopy (MRS) found changes in the hippocampus, indicating neuronal loss. Neuropsychological tests showed associations between poorer memory and hippocampal atrophy or connectivity changes. CA1‐2, dentate gyrus, and fimbria atrophy were correlated with worse memory.
Conclusions
The hippocampus and the connected regions are involved in ALS. Hippocampal atrophy disrupted connectivity and metabolite changes correlate with cognitive and functional decline. Specific subregions can be particularly affected. The hippocampus is a potential biomarker for disease monitoring and prognosis.
... Over the past year, significant research helps to identifying number of genes related to fALS and sALS [4]. Approximately 70% of fALS cases are caused by the most commonly altered genes; superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9ORF72), TAR DNA-binding protein 43 (TARDBP), and fused in sarcoma (FUS) [5][6][7][8]. Despite this, fALS accounts for about 10% of reported cases, whereas the genetic basis of sALS is largely unclear [4], nevertheless C9ORF72 is well-known, it only contributes around 5% of sALS cases [9]. ...
... According to the literature, up to 85% of cases are sporadic (sALS) [23], and of this group, 50% demonstrate behavioral, cognitive, and dementia-like impairments [24], and up to 15% of ALS patients are also diagnosed with frontotemporal dementia (FTD) [25][26][27]. The age of onset of the disease in this spectrum varies, and according to the literature, cases under the age of 40 are rare, and for sporadic forms of the disease, the average age is considered to be between 55 and 70 years [28]. Cognitive impairment has been found in up to 70% of patients, with later onset over 65 years resulting in a higher cognitive impairment [29]. ...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by wide clinical and biological heterogeneity, with a large proportion of ALS patients also exhibiting frontotemporal dementia (FTD) spectrum symptoms. This project aimed to characterize risk subtypes of the H1 haplotype within the MAPT (microtubule-associated protein tau) gene, according to their possible effect as a risk factor and as a modifying factor in relation to the age of disease onset. One hundred patients from Bulgaria with sporadic ALS were genotyped for the variants rs1467967, rs242557, rs1800547, rs3785883, rs2471738, and rs7521. Haploview 4.2 and SHEsisPlus were used to reconstruct haplotype frequencies using genotyping data from the 1000 Genomes project as controls. Genotype–phenotype correlation was investigated in the context of age of disease onset and risk of disease development. While the individual variants of the subtypes do not influence the age of onset of the disease, a correlation was found between the specific haplotype GGAGCA (H1b) and the risk of developing sALS, with results showing that individuals harboring this haplotype have a nearly two-fold increased risk of developing sALS compared to other H1 subtypes. The results from this study suggest that fine transcriptional regulation at the MAPT locus can influence the risk of ALS.
... Neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, impose a substantial burden on patients, caregivers, and healthcare systems worldwide (GBD, 2019Dementia Forecasting Collaborators, 2022Feigin et al., 2020). Despite decades of research, the underlying mechanisms driving disease progression and variability in patient survival remain incompletely understood (Martin et al., 2017;Robinson et al., 2023). Genetic factors have been increasingly recognized as crucial contributors to the pathogenesis and progression of neurodegeneration. ...
Motivation: For a number of neurological diseases, such as Alzheimer’s disease,
amyotrophic lateral sclerosis, and many others, certain genes are known to be
involved in the disease mechanism. A common question is whether a structural
variant in any such gene may be related to drug response in clinical trials and how
this relationship can contribute to the lifecycle of drug development.
Results: To this end, we introduce VariantSurvival, a tool that identifies changes in
survival relative to structural variants within target genes. VariantSurvival matches
annotated structural variants with genes that are clinically relevant to neurological
diseases. A Cox regression model determines the change in survival between the
placebo and clinical trial groups with respect to the number of structural variants in
the drug target genes. We demonstrate the functionality of our approach with the
exemplary case of the SETX gene. VariantSurvival has a user-friendly and
lightweight graphical user interface built on the shiny web application package
... ALS, a rapidly progressing neurodegenerative disease affecting the motor neurons in the spinal cord and brain stem, is characterized by muscle weakness that starts in one region of the body and gradually disseminates to other parts. While the exact causative factors remain unknown, pathologic events such as oxidative stress, interference with axonal transport by neurofilaments, glutamate-induced excitotoxicity and intracellular aggregate-mediated cytotoxicity have been proposed to drive disease progression [44]. However, there is strong evidence that inflammation plays a significant role in the progression of ALS. ...
Historically, cannabis has been valued for its pain-relieving, anti-inflammatory, and calming properties. Ancient civilizations like the Egyptians, Greeks, and Chinese medicines recognized their therapeutic potential. The discovery of the endocannabinoid system, which interacts with cannabis phytoconstituents, has scientifically explained how cannabis affects the human immune system, including the central nervous system (CNS). This review explores the evolving world of cannabis-based treatments, spotlighting its diverse applications. By researching current research and clinical studies, we probe into how cannabinoids like Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) help to manage conditions ranging from chronic pain, persistent inflammation, cancer, inflammatory bowel disease, and neurological disorders to even viral diseases such as Human Immunodeficiency virus (HIV), SARS-CoV-2. and the emerging monkeypox. The long-term recreational use of cannabis can develop into cannabis use disorder (CUD), and therefore, understanding the factors contributing to the development and maintenance of cannabis addiction, including genetic predisposition, neurobiological mechanisms, and environmental influences, will be timely. Shedding light on the adverse impacts of CUD underscores the importance of early intervention, effective treatment approaches, and public health initiatives to address this complex issue in an evolving landscape of cannabis policies and perceptions.
... Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a neurodegenerative disorder that causes progressive weakness in the muscles that control movement and breathing (1,2). The incidence of ALS is approximately 1-2.6 cases per 100,000 person-years and a prevalence of about 6 cases per 100,000 persons (3). ...
... However, the lifetime risk of developing ALS is about 1 in 300 by the age of 80, which is similar to the risk of multiple sclerosis in the UK and Ireland (4,5). There is a significant diagnostic delay in ALS, typically about a year, which seems to be independent of the healthcare system and is probably related to low recognition by primary care physicians (1,6). As a result, those attending specialist centers tend to be those with a better prognosis, who are younger, and who are more motivated (7). ...
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in progressive weakness of skeletal muscles including respiratory muscles. Epidemiological and clinical aspects of ALS are derived from a few world regions with very little representation of low- and middle-income countries. We therefore set out to determine the epidemiological and clinical phenotype of individuals with ALS in Ethiopia. Methods: Multicenter retrospective analysis was conducted using clinical records from ALS patients seen in Ethiopia at Tikur Anbessa Specialized Hospital and Yehuleshet specialty clinic between January 2016 and August 2021. The data collected included clinical characteristics, disease-related symptoms, a revised ALS functional rating scale, and medications. Results: Patients in Ethiopia had a younger age of onset with a mean age of disease onset of 51.9 years. 2.9% of patients had juvenile ALS, and the male-to-female ratio was almost 2:1. 4.9% had a positive family history of the disease. 68% of patients had spinal region involvement at onset, while 32% had bulbar region involvement at onset. Riluzole was used by 31% of ALS patients. 20.6% of patients had some respiratory symptoms, but none received a standard respiratory function assessment. 33.3% of patients were wheelchair-bound. Conclusion: In this retrospective study spanning 5 years, we examined the clinical phenotype of ALS in Ethiopian patients. Our findings suggest that most patients had clinically definite ALS with spinal region involvement. Further research, including genetic and epigenetic information, is necessary to understand the early onset of the disease in Ethiopia.
... The most common mutations in familial ALS are in the SOD1 and C9orf72 genes, together explaining roughly 50% of all familial cases (10). C9orf72 is the most common genetic cause of ALS and can be found in 30% of familial cases and up to 10% of the sporadic forms (11). Another important player is the TARDBP gene, encoding TDP-43 protein, which regulates RNA-expression in cells and is found in the vast majority of cellular inclusions in ALS patients (11). ...
... C9orf72 is the most common genetic cause of ALS and can be found in 30% of familial cases and up to 10% of the sporadic forms (11). Another important player is the TARDBP gene, encoding TDP-43 protein, which regulates RNA-expression in cells and is found in the vast majority of cellular inclusions in ALS patients (11). Although it is evident that they play an important role in the development of ALS, environmental factors are hard to identify, and it has been difficult to make definitive statements about the causal relationship to the disease (10,11). ...
... Another important player is the TARDBP gene, encoding TDP-43 protein, which regulates RNA-expression in cells and is found in the vast majority of cellular inclusions in ALS patients (11). Although it is evident that they play an important role in the development of ALS, environmental factors are hard to identify, and it has been difficult to make definitive statements about the causal relationship to the disease (10,11). ...
Amyotrophic lateral sclerosis (ALS) represents a progressive neurodegenerative disease that affects motor neurons in the brain and spinal cord leading to the impairment of volun-tary muscle control and eventually death. It accounts for about 80%-90% of all motor neu-ron diseases, and is characterized by a marked variability in terms of clinical forms, gene-tics, survival rate and diagnostic particularities. A diagnosis of ALS or one of the variants comes with a great burden for the patient and patient’s family because of the high morbidi-ty and mortality rate of this disorder. As a consequence, it is mandatory to optimize the ac-curacy of the diagnostic process of ALS spectrum for providing the best clinical manage-ment and quality of life for patients and avoiding diagnostic mistakes. Our review focuses on the general and particular aspects of ALS and its variants in an effort to improve the process of diagnosis, therapy and exclusion of mimics of this group of diseases and to pro-vide the latest findings in this field. Keywords: amyotrophic lateral sclerosis, rehabilitation in ALS, flail leg, flail arm, progres-sive muscular atrophy.
... The most common mutations in familial ALS are in the SOD1 and C9orf72 genes, together explaining roughly 50% of all familial cases (10). C9orf72 is the most common genetic cause of ALS and can be found in 30% of familial cases and up to 10% of the sporadic forms (11). Another important player is the TARDBP gene, encoding TDP-43 protein, which regulates RNA-expression in cells and is found in the vast majority of cellular inclusions in ALS patients (11). ...
... C9orf72 is the most common genetic cause of ALS and can be found in 30% of familial cases and up to 10% of the sporadic forms (11). Another important player is the TARDBP gene, encoding TDP-43 protein, which regulates RNA-expression in cells and is found in the vast majority of cellular inclusions in ALS patients (11). Although it is evident that they play an important role in the development of ALS, environmental factors are hard to identify, and it has been difficult to make definitive statements about the causal relationship to the disease (10,11). ...
... Another important player is the TARDBP gene, encoding TDP-43 protein, which regulates RNA-expression in cells and is found in the vast majority of cellular inclusions in ALS patients (11). Although it is evident that they play an important role in the development of ALS, environmental factors are hard to identify, and it has been difficult to make definitive statements about the causal relationship to the disease (10,11). ...
Amyotrophic lateral sclerosis (ALS) represents a progressive neurodegenerative disease that affects motor neurons in the brain and spinal cord leading to the impairment of volun-tary muscle control and eventually death. It accounts for about 80%-90% of all motor neu-ron diseases, and is characterized by a marked variability in terms of clinical forms, gene-tics, survival rate and diagnostic particularities. A diagnosis of ALS or one of the variants comes with a great burden for the patient and patient’s family because of the high morbidi-ty and mortality rate of this disorder. As a consequence, it is mandatory to optimize the ac-curacy of the diagnostic process of ALS spectrum for providing the best clinical manage-ment and quality of life for patients and avoiding diagnostic mistakes. Our review focuses on the general and particular aspects of ALS and its variants in an effort to improve the process of diagnosis, therapy and exclusion of mimics of this group of diseases and to pro-vide the latest findings in this field.
... Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons in the brain and spinal cord, leading to death in 3 to 5 years (1). Genetic and environmental factors contribute to pathogenesis (2), with a heritability of up to 60% (3). There is considerable variation in motor symptoms, which may include limb weakness, slurred speech, swallowing difficulties, and muscle twitching (4). ...
Amyotrophic lateral sclerosis and Parkinson's disease are neurodegenerative diseases of the motor system which are now recognized also to affect non-motor pathways. Non-motor symptoms have been acknowledged as important determinants of quality of life in Parkinson's disease, and there is increasing interest in understanding the extent and role of non-motor symptoms in amyotrophic lateral sclerosis. We therefore reviewed what is known about non-motor symptoms in amyotrophic lateral sclerosis, using lessons from Parkinson's disease.
... And in this also comprise metals, radiation field, physical exertion, contagions, chemicals, fungi, bacteria, prions, cell organ connected ecology, acetylcholine neuron inflammation, protein related abnormalities, advanced power spending otherwise input and continuing disability of microtubules, sugar biotransformation, intermediate poverties in neuronal transfer, autoimmunity, reaction of physical composition inside the astroglia, microglia & low to high disturbing mind wound. [3][4][5] In western populations, the incidence of motor neuron disease including Australia is about 2-3/100000 and with a national prevalence of about 8/100000. 6 Currently, approximately 1500 Australian patients which suffer from the motor neuron disease. ...
Motor neuron disorder is a neurodegenerative disorder that causes weakness, respiratory muscle and also
bulbar and respiratory failure cause death. Generally motor neuron disorder is sporadic but in some cases
roughly 10 is got inherited. According to current studies the new motor neuron disorder genes are found.
Pathologically motor neuron disorder & clinically miscellaneous, neuroprotective and remedial targets have
been delicate to identified. According to these studies, in motor neuron disorder the evolution growth
are similar as bettered understanding of the colorful clinical phenotypes, the boundlessness together
the frntotemporal madness, part of genetics, development of standard of care and the global clinical
trialspipelines. The vestige of riluzole medicine only disorder modification drug which utilized for the
disorder treatment. These drugs have power to improve the cycle of living. In the operation of motor neuron
disorder the intensive treatment are important which can be multifunctional. And noninvasive respiratory
therapy that involves the delivery of air or a mixture of oxygen combined with other gases by positive
pressure into the lungs which can improves the chances of living in MND cases in case of disturbance of
exhalation and inhalation. Motor neuron disorder is found further generally in males than females. Motor
neuron disease is shown the dropping of neuron in the kidney, spinal cord and mind which show by both
up and down motor neuron symptoms & signs they affect arms, bulbar & respiration.
