Amyotrophic lateral sclerosis specifically onset begins in middle age due to underlying mechanisms.
The sources establish that amyotrophic lateral sclerosis is an adult-onset motor neuron disease, but they do not specifically confirm that onset begins exclusively in middle age due to underlying mechanisms.
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Global variation in prevalence and incidence of amyotrophic lateral sclerosis: a systematic review and meta-analysis.. 2020. https://doi.org/10.1007/s00415-019-09652-y
<h4>Background</h4>Amyotrophic lateral sclerosis (ALS) is a global disease, which adversely affects the life quality of patients and significantly increases the burden of families and society. We aimed to assess the changing incidence, prevalence of ALS around the world.<h4>Methods</h4>We searched Medline, Embase, Web of Science, and Cochrane library to identify articles published until September 9, 2018. Each included study was independently reviewed for methodological quality by two reviewers. We used a random-effects model to summarize individual studies and assessed heterogeneity (I<sup>2</sup>) with the χ<sup>2</sup> test on Cochrane's Q statistic.<h4>Results</h4>We identified 124 studies that were eligible for final inclusion, including 110 studies of incidence and 58 studies of prevalence. The overall crude worldwide ALS prevalence and incidence were 4.42 (95% CI 3.92-4.96) per 1,00,000 population and 1.59 (95% CI 1.39-1.81) per 1,00,000 person-years, respectively. ALS prevalence and incidence increased by age until the age of 70-79. Since 1957, incidence has been significantly rising year by year, and this upward trend was weakened after standardization. The longest survival time were in Asia (ranging from 3.74 years in South Asia to 9.23 years in West Asia).<h4>Conclusions</h4>With the aggravation of population aging and the rapid growth of economy, developing regions following the development pattern of the developed regions may suffer rising ALS prevalence and incidence which may increase their disease burden as well. These data highlight the need for research into underlying mechanism and innovations in health-care systems. 5 Similar content being viewed by others Increasing prevalence 2015–2019 of amyotrophic lateral sclerosis in Sardinia, Italy Article Open access 24 March 2023 Clinical and epidemiological characteristics of amyotrophic lateral sclerosis in an Egyptian cohort Article Open access 30 September 2024 Restless legs syndrome as a comorbidity in amyotrophic lateral sclerosis: a systematic review and meta-analysis Article Open access 04 December 2025 Explore related subjects Discover the latest articles, books and news in related subjects, suggested using machine learning. https://doi.org/10.1136/jnnp-2013-307223 Article PubMed Google Scholar Phukan J, Elamin M, Bede P, Jordan N, Gallagher L, Byrne S, Lynch C, Pender N, Hardiman O (2012) The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry 83:102–108. Int J Epidemiol 46:57–74. https://doi.org/10.1093/ije/dyw061 Article PubMed Google Scholar Chio A, Logroscino G, Traynor BJ, Collins J, Simeone JC, Goldstein LA, White LA (2013) Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology 41:118–130. https://doi.org/10.1159/000351153 Article CAS PubMed PubMed Central Google Scholar D'Ovidio F, d'Errico A, Farina E, Calvo A, Costa G, Chio A (2016) Amyotrophic lateral sclerosis incidence and previous prescriptions of drugs for the nervous system. Neuroepidemiology 47:59–66. https://doi.org/10.1080/21678421.2016.1197942 Article PubMed Google Scholar Tesauro M, Consonni M, Filippini T, Mazzini L, Pisano F, Chio A, Esposito A, Vinceti M (2017) Incidence of amyotrophic lateral sclerosis in the province of Novara, Italy, and possible role of environmental pollution. Amyotroph Lateral Scler Frontotemporal Degener 18:284–290. https://doi.org/10.1080/21678421.2017.1281961 Article CAS PubMed Google Scholar Weil C, Zach N, Rishoni S, Shalev V, Chodick G (2016) Epidemiology of amyotrophic lateral sclerosis: a population-based study in Israel. Neuroepidemiology 47:76–81. https://doi.org/10.1159/000448921 Article PubMed Google Scholar Demetriou CA, Hadjivasiliou PM, Kleopa KA, Christou YP, Leonidou E, Kyriakides T, Zamba-Papanicolaou E (2017) Epidemiology of amyotrophic lateral sclerosis in the Republic of Cyprus: a 25-year retrospective study. Neuroepidemiology 48:79–85. https://doi.org/10.1159/000477126 Article PubMed Google Scholar Kahana E, Alter M, Feldman S (1976) Amyotrophic lateral sclerosis: a population study. J Neurol 212:205–213 Article CAS Google Scholar Okumiya K, Wada T, Fujisawa M, Ishine M, Garcia Del Saz E, Hirata Y, Kuzuhara S, Kokubo Y, Seguchi H, Sakamoto R, Manuaba I, Watofa P, Rantetampang AL, Matsubayashi K (2014) Amyotrophic lateral sclerosis and parkinsonism in Papua, indonesia: 2001–2012 survey results. BMJ open 4:e004353. https://doi.org/10.1136/bmjopen-2013-004353 Article PubMed PubMed Central Google Scholar Boyle MH (1998) Guidelines for evaluating prevalence studies. https://doi.org/10.1371/journal.pone.0035333 Article CAS PubMed PubMed Central Google Scholar Uyan O, Omur O, Agim ZS, Ozoguz A, Li H, Parman Y, Deymeer F, Oflazer P, Koc F, Tan E, Ozcelik H, Basak AN (2013) Genome-wide copy number variation in sporadic amyotrophic lateral sclerosis in the Turkish population: deletion of EPHA3 is a possible protective factor. PLoS ONE 8:e72381. Hum Mol Genet 23:2220–2231. https://doi.org/10.1093/hmg/ddt587 Article CAS PubMed Google Scholar Du Y, Wen Y, Guo X, Hao J, Wang W, He A, Fan Q, Li P, Liu L, Liang X, Zhang F (2018) A Genome-wide expression association analysis identifies genes and pathways associated with amyotrophic lateral sclerosis. Cell Mol Neurobiol 38:635–639. Soc Sci Med 51:887–895 Article Google Scholar A Chio G Mora C Moglia U Manera A Canosa S Cammarosano A Ilardi D Bertuzzo E Bersano P Cugnasco M Grassano F Pisano L Mazzini A Calvo VD Piemonte Register for ALS 2017 Secular trends of amyotrophic lateral sclerosis: the piemonte and valle d'aosta register, JAMA Neurol 74: 1097–1104 10.1001/jamaneurol.2017.1387 Arthur KC, Calvo A, Price TR, Geiger JT, Chio A, Traynor BJ (2016) Projected increase in amyotrophic lateral sclerosis from 2015 to 2040. Nat Commun 7:12408. https://doi.org/10.14336/ad.2018.0327 Article PubMed PubMed Central Google Scholar
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Global variation in prevalence and incidence of amyotrophic lateral sclerosis: a systematic review and meta-analysis.. 2020. https://doi.org/10.1007/s00415-019-09652-y
Amyotrophic lateral sclerosis (ALS) is a global disease, which adversely affects the life quality of patients and significantly increases the burden of families and society. We aimed to assess the changing incidence, prevalence of ALS around the world. We searched Medline, Embase, Web of Science, and Cochrane library to identify articles published until September 9, 2018. Each included study was independently reviewed for methodological quality by two reviewers. We used a random-effects model to summarize individual studies and assessed heterogeneity (I2) with the χ2 test on Cochrane's Q statistic. We identified 124 studies that were eligible for final inclusion, including 110 studies of incidence and 58 studies of prevalence. The overall crude worldwide ALS prevalence and incidence were 4.42 (95% CI 3.92-4.96) per 1,00,000 population and 1.59 (95% CI 1.39-1.81) per 1,00,000 person-years, respectively. ALS prevalence and incidence increased by age until the age of 70-79. Since 1957, incidence has been significantly rising year by year, and this upward trend was weakened after standardization. The longest survival time were in Asia (ranging from 3.74 years in South Asia to 9.23 years in West Asia). With the aggravation of population aging and the rapid growth of economy, developing regions following the development pattern of the developed regions may suffer rising ALS prevalence and incidence which may increase their disease burden as well. These data highlight the need for research into underlying mechanism and innovations in health-care systems. 5 Similar content being viewed by others Increasing prevalence 2015–2019 of amyotrophic lateral sclerosis in Sardinia, Italy Article Open access 24 March 2023 Clinical and epidemiological characteristics of amyotrophic lateral sclerosis in an Egyptian cohort Article Open access 30 September 2024 Restless legs syndrome as a comorbidity in amyotrophic lateral sclerosis: a systematic review and meta-analysis Article Open access 04 December 2025 Explore related subjects Discover the latest articles, books and news in related subjects, suggested using machine learning. https://doi.org/10.1136/jnnp-2013-307223 Article PubMed Google Scholar Phukan J, Elamin M, Bede P, Jordan N, Gallagher L, Byrne S, Lynch C, Pender N, Hardiman O (2012) The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry 83:102–108. Int J Epidemiol 46:57–74. https://doi.org/10.1093/ije/dyw061 Article PubMed Google Scholar Chio A, Logroscino G, Traynor BJ, Collins J, Simeone JC, Goldstein LA, White LA (2013) Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology 41:118–130. https://doi.org/10.1159/000351153 Article CAS PubMed PubMed Central Google Scholar D'Ovidio F, d'Errico A, Farina E, Calvo A, Costa G, Chio A (2016) Amyotrophic lateral sclerosis incidence and previous prescriptions of drugs for the nervous system. Neuroepidemiology 47:59–66. https://doi.org/10.1080/21678421.2016.1197942 Article PubMed Google Scholar Tesauro M, Consonni M, Filippini T, Mazzini L, Pisano F, Chio A, Esposito A, Vinceti M (2017) Incidence of amyotrophic lateral sclerosis in the province of Novara, Italy, and possible role of environmental pollution. Amyotroph Lateral Scler Frontotemporal Degener 18:284–290. https://doi.org/10.1080/21678421.2017.1281961 Article CAS PubMed Google Scholar Weil C, Zach N, Rishoni S, Shalev V, Chodick G (2016) Epidemiology of amyotrophic lateral sclerosis: a population-based study in Israel. Neuroepidemiology 47:76–81. https://doi.org/10.1159/000448921 Article PubMed Google Scholar Demetriou CA, Hadjivasiliou PM, Kleopa KA, Christou YP, Leonidou E, Kyriakides T, Zamba-Papanicolaou E (2017) Epidemiology of amyotrophic lateral sclerosis in the Republic of Cyprus: a 25-year retrospective study. Neuroepidemiology 48:79–85. https://doi.org/10.1159/000477126 Article PubMed Google Scholar Kahana E, Alter M, Feldman S (1976) Amyotrophic lateral sclerosis: a population study. J Neurol 212:205–213 Article CAS Google Scholar Okumiya K, Wada T, Fujisawa M, Ishine M, Garcia Del Saz E, Hirata Y, Kuzuhara S, Kokubo Y, Seguchi H, Sakamoto R, Manuaba I, Watofa P, Rantetampang AL, Matsubayashi K (2014) Amyotrophic lateral sclerosis and parkinsonism in Papua, indonesia: 2001–2012 survey results. BMJ open 4:e004353. https://doi.org/10.1136/bmjopen-2013-004353 Article PubMed PubMed Central Google Scholar Boyle MH (1998) Guidelines for evaluating prevalence studies. https://doi.org/10.1371/journal.pone.0035333 Article CAS PubMed PubMed Central Google Scholar Uyan O, Omur O, Agim ZS, Ozoguz A, Li H, Parman Y, Deymeer F, Oflazer P, Koc F, Tan E, Ozcelik H, Basak AN (2013) Genome-wide copy number variation in sporadic amyotrophic lateral sclerosis in the Turkish population: deletion of EPHA3 is a possible protective factor. PLoS ONE 8:e72381. Hum Mol Genet 23:2220–2231. https://doi.org/10.1093/hmg/ddt587 Article CAS PubMed Google Scholar Du Y, Wen Y, Guo X, Hao J, Wang W, He A, Fan Q, Li P, Liu L, Liang X, Zhang F (2018) A Genome-wide expression association analysis identifies genes and pathways associated with amyotrophic lateral sclerosis. Cell Mol Neurobiol 38:635–639. Soc Sci Med 51:887–895 Article Google Scholar A Chio G Mora C Moglia U Manera A Canosa S Cammarosano A Ilardi D Bertuzzo E Bersano P Cugnasco M Grassano F Pisano L Mazzini A Calvo VD Piemonte Register for ALS 2017 Secular trends of amyotrophic lateral sclerosis: the piemonte and valle d'aosta register, JAMA Neurol 74: 1097–1104 10.1001/jamaneurol.2017.1387 Arthur KC, Calvo A, Price TR, Geiger JT, Chio A, Traynor BJ (2016) Projected increase in amyotrophic lateral sclerosis from 2015 to 2040. Nat Commun 7:12408. https://doi.org/10.14336/ad.2018.0327 Article PubMed PubMed Central Google Scholar Beard JD, Steege AL, Ju J, Lu J, Luckhaupt SE, Schubauer-Berigan MK (2017) Mortality from
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Synchrotron-Based Fourier-Transform Infrared Micro-Spectroscopy of Cerebrospinal Fluid from Amyotrophic Lateral Sclerosis Patients Reveals a Unique Biomolecular Profile. 2023. https://doi.org/10.3390/cells12111451
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, with the most common adult-onset neurodegenerative disorder affecting motoneurons. Although disruptions in macromolecular conformation and homeostasis have been described in association with ALS, the underlying pathological mechanisms are still not completely understood, and unambiguous biomarkers are lacking. Fourier Transform Infrared Spectroscopy (FTIR) of cerebrospinal fluid (CSF) is appealing to extensive interest due to its potential to resolve biomolecular conformation and content, as this approach offers a non-invasive, label-free identification of specific biologically relevant molecules in a few microliters of CSF sample. Here, we analyzed the CSF of 33 ALS patients compared to 32 matched controls using FTIR spectroscopy and multivariate analysis and demonstrated major differences in the molecular contents. A significant change in the conformation and concentration of RNA is demonstrated. Moreover, significantly increased glutamate and carbohydrates are found in ALS. Moreover, key markers of lipid metabolism are strongly altered; specifically, we find a decrease in unsaturated lipids and an increase in peroxidation of lipids in ALS, whereas the total amount of lipids compared to proteins is reduced. Our study demonstrates that FTIR characterization of CSF could represent a powerful tool for ALS diagnosis and reveals central features of ALS pathophysiology.
When does ALS start? ADAR2-GluA2 hypothesis for the etiology of sporadic ALS. 2011. https://doi.org/10.3389/fnmol.2011.00033
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. More than 90% of ALS cases are sporadic, and the majority of sporadic ALS patients do not carry mutations in genes causative of familial ALS; therefore, investigation specifically targeting sporadic ALS is needed to discover the pathogenesis. The motor neurons of sporadic ALS patients express unedited GluA2 mRNA at the Q/R site in a disease-specific and motor neuron-selective manner. GluA2 is a subunit of the AMPA receptor, and it has a regulatory role in the Ca2+-permeability of the AMPA receptor after the genomic Q codon is replaced with the R codon in mRNA by adenosine-inosine conversion, which is mediated by adenosine deaminase acting on RNA 2 (ADAR2). Therefore, ADAR2 activity may not be sufficient to edit all GluA2 mRNA expressed in the motor neurons of ALS patients. To investigate whether deficient ADAR2 activity plays pathogenic roles in sporadic ALS, we generated genetically modified mice (AR2) in which the ADAR2 gene was conditionally knocked out in the motor neurons. AR2 mice showed an ALS-like phenotype with the death of ADAR2-lacking motor neurons. Notably, the motor neurons deficient in ADAR2 survived when they expressed only edited GluA2 in AR2/GluR-BR/R (AR2res) mice, in which the endogenous GluA2 alleles were replaced by the GluR-BR allele that encoded edited GluA2. In heterozygous AR2 mice with only one ADAR2 allele, approximately 20% of the spinal motor neurons expresse
Pathophysiology, Clinical Heterogeneity, and Therapeutic Advances in Amyotrophic Lateral Sclerosis: A Comprehensive Review of Molecular Mechanisms, Diagnostic Challenges, and Multidisciplinary Management Strategies.. 2025. https://doi.org/10.3390/life15040647
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons, leading to muscle atrophy, paralysis, and respiratory failure. This comprehensive review synthesizes the current knowledge on ALS pathophysiology, clinical heterogeneity, diagnostic frameworks, and evolving therapeutic strategies. Mechanistically, ALS arises from complex interactions between genetic mutations (e.g., in <i>C9orf72</i>, <i>SOD1</i>, <i>TARDBP</i> (TDP-43), and <i>FUS</i>) and dysregulated cellular pathways, including impaired RNA metabolism, protein misfolding, nucleocytoplasmic transport defects, and prion-like propagation of toxic aggregates. Phenotypic heterogeneity, manifesting as bulbar-, spinal-, or respiratory-onset variants, complicates its early diagnosis, which thus necessitates the rigorous application of the revised El Escorial criteria and emerging biomarkers such as neurofilament light chain. Clinically, ALS intersects with frontotemporal dementia (FTD) in up to 50% of the cases, driven by shared TDP-43 pathology and <i>C9orf72</i> hexanucleotide expansions. Epidemiological studies have revealed a lifetime risk of 1:350, with male predominance (1.5:1) and peak onset between 50 and 70 years. Disease progression varies widely, with a median survival of 2-4 years post-diagnosis, underscoring the urgency for early intervention. Approved therapies, including riluzole (glutamate modulation), edaravone (antioxidant), and tofersen (antisense oligonucleotide), offer modest survival benefits, while dextromethorphan/quinidine alleviates the pseudobulbar affect. Non-pharmacological treatment advances, such as non-invasive ventilation (NIV), prolong survival by 13 months and improve quality of life, particularly in bulb-involved patients. Multidisciplinary care-integrating physical therapy, respiratory support, nutritional management, and cognitive assessments-is critical to addressing motor and non-motor symptoms (e.g., dysphagia, spasticity, sleep disturbances). Emerging therapies show promise in preclinical models. However, challenges persist in translating genetic insights into universally effective treatments. Ethical considerations, including euthanasia and end-of-life decision-making, further highlight the need for patient-centered communication and palliative strategies.
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