Journal articles: 'Amyotrophic lateral sclerosis – Pathophysiology'

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Voitenkov, Vladislav B., and E. V. Ekusheva. "Pain in amyotrophic lateral sclerosis." Journal of Clinical Practice 10, no. 2 (August 17, 2019): 66–73. http://dx.doi.org/10.17816/clinpract10266-73.

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In this review, we discuss different aspects of pain syndrome in patients with amyotrophic lateral sclerosis: etiology, incidence, pathophysiology and main clinical features. Also we review the modern approaches to the treatment of pain in amyotrophic lateral sclerosis. Pain is actually not rare in this condition: it appears in 80% of patients, affecting their quality of life and functional activity, leading to the development of depressive and anxiety disorders. Pain in amyotrophic lateral sclerosis is often overlooked by clinicians, since their attention may focus on the motor symptoms of the disease. Thus, a more careful approach is needed to diagnose and treat pain in amyotrophic lateral sclerosis.

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Fawad, Laiba, and Mehrab Tahir. "Emerging Therapies in Amyotrophic Lateral Sclerosis." Molecular Medicine Communications 2, no. 01 (June 30, 2022): 31–42. http://dx.doi.org/10.55627/mmc.002.001.0041.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of cortical and spinal motor neurons, leading to weakness, muscle atrophy, and, in a substantial number of patients, cognitive impairment. Most patients die within 2 to 5 years of diagnosis. The disease initiates from the death of upper and lower motor neurons leading to a degeneration of motor pathways and the paralytic effects of the disease. The disease has huge economic costs as well. FDA has approved two drugs, riluzole, and edaravone for the treatment of ALS. However, these drugs provide modest benefits in mortality and/or function. Recent developments in the understanding of the underlying pathophysiologic processes that contribute to ALS have led to the development of numerous investigational therapies, with several now in phase 3 trials. This article highlights the epidemiology, pathophysiology, and several current and emerging treatment options for ALS including stem cell therapy.

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Vucic, Steve, and Matthew Kiernan. "Pathophysiology of Neurodegeneration in Familial Amyotrophic Lateral Sclerosis." Current Molecular Medicine 9, no. 3 (April 1, 2009): 255–72. http://dx.doi.org/10.2174/156652409787847173.

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Coupé, Christophe, and Paul H. Gordon. "Amyotrophic Lateral Sclerosis – Clinical Features, Pathophysiology and Management." European Neurological Review 8, no. 1 (2012): 38. http://dx.doi.org/10.17925/enr.2013.08.01.38.

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Amyotrophic lateral sclerosis (ALS), first described by Jean-Martin Charcot 145 years ago, is an age-related neurodegenerative disorder that leads to destruction of motor neurons. The disease begins focally in the central nervous system then spreads inexorably. The clinical diagnosis, defined by progressive upper and lower motor neuron findings, is confirmed by electromyogram. Additional testing excludes other conditions. The disease is heterogeneous, but most patients die of progressive weakness and respiratory failure less than 3 years from symptom onset. Like other neurodegenerative diseases, ALS is thought to have genetic and environmental causes. Five to 10 % of cases are inherited. Genetic factors, age, tobacco use and athleticism may contribute to sporadic ALS, but major causes are unidentified for most patients. Complex pathophysiological processes, including mitochondrial dysfunction, aggregation of misfolded protein, oxidative stress, excitotoxicity, inflammation and apoptosis, involve both motor neurons and surrounding glial cells. There is clinical and pathological overlap with other neurodegenerative diseases, particularly frontotemporal dementia. One medication, riluzole, which was approved in 1996, prolongs survival by several months. Numerous ensuing clinical trials have been negative. Researchers currently aim to slow disease progression by targeting known pathophysiological pathways. Approaches under examination are directed at muscle protein, energetic balance, cell replacement and protein aggregation. Until the causes and more robust neuroprotective agents are identified, symptomatic therapies can help improve expectancy and quality of life. Palliative care ensures dignity in advanced stages.

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Dilliott, Allison A., Catherine M. Andary, Meaghan Stoltz, Andrey A. Petropavlovskiy, Sali M. K. Farhan, and Martin L. Duennwald. "DnaJC7 in Amyotrophic Lateral Sclerosis." International Journal of Molecular Sciences 23, no. 8 (April 7, 2022): 4076. http://dx.doi.org/10.3390/ijms23084076.

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Protein misfolding is a common basis of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Misfolded proteins, such as TDP-43, FUS, Matrin3, and SOD1, mislocalize and form the hallmark cytoplasmic and nuclear inclusions in neurons of ALS patients. Cellular protein quality control prevents protein misfolding under normal conditions and, particularly, when cells experience protein folding stress due to the fact of increased levels of reactive oxygen species, genetic mutations, or aging. Molecular chaperones can prevent protein misfolding, refold misfolded proteins, or triage misfolded proteins for degradation by the ubiquitin–proteasome system or autophagy. DnaJC7 is an evolutionarily conserved molecular chaperone that contains both a J-domain for the interaction with Hsp70s and tetratricopeptide domains for interaction with Hsp90, thus joining these two major chaperones’ machines. Genetic analyses reveal that pathogenic variants in the gene encoding DnaJC7 cause familial and sporadic ALS. Yet, the underlying ALS-associated molecular pathophysiology and many basic features of DnaJC7 function remain largely unexplored. Here, we review aspects of DnaJC7 expression, interaction, and function to propose a loss-of-function mechanism by which pathogenic variants in DNAJC7 contribute to defects in DnaJC7-mediated chaperoning that might ultimately contribute to neurodegeneration in ALS.

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Parakh, Sonam, Damian M. Spencer, Mark A. Halloran, Kai Y. Soo, and Julie D. Atkin. "Redox Regulation in Amyotrophic Lateral Sclerosis." Oxidative Medicine and Cellular Longevity 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/408681.

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results from the death of upper and lower motor neurons. Due to a lack of effective treatment, it is imperative to understand the underlying mechanisms and processes involved in disease progression. Regulations in cellular reduction/oxidation (redox) processes are being increasingly implicated in disease. Here we discuss the possible involvement of redox dysregulation in the pathophysiology of ALS, either as a cause of cellular abnormalities or a consequence. We focus on its possible role in oxidative stress, protein misfolding, glutamate excitotoxicity, lipid peroxidation and cholesterol esterification, mitochondrial dysfunction, impaired axonal transport and neurofilament aggregation, autophagic stress, and endoplasmic reticulum (ER) stress. We also speculate that an ER chaperone protein disulphide isomerase (PDI) could play a key role in this dysregulation. PDI is essential for normal protein folding by oxidation and reduction of disulphide bonds, and hence any disruption to this process may have consequences for motor neurons. Addressing the mechanism underlying redox regulation and dysregulation may therefore help to unravel the molecular mechanism involved in ALS.

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Sanghai, Nitesh, and Geoffrey K. Tranmer. "Hydrogen Peroxide and Amyotrophic Lateral Sclerosis: From Biochemistry to Pathophysiology." Antioxidants 11, no. 1 (December 27, 2021): 52. http://dx.doi.org/10.3390/antiox11010052.

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Free radicals are unstable chemical reactive species produced during Redox dyshomeostasis (RDH) inside living cells and are implicated in the pathogenesis of various neurodegenerative diseases. One of the most complicated and life-threatening motor neurodegenerative diseases (MND) is amyotrophic lateral sclerosis (ALS) because of the poor understanding of its pathophysiology and absence of an effective treatment for its cure. During the last 25 years, researchers around the globe have focused their interest on copper/zinc superoxide dismutase (Cu/Zn SOD, SOD1) protein after the landmark discovery of mutant SOD1 (mSOD1) gene as a risk factor for ALS. Substantial evidence suggests that toxic gain of function due to redox disturbance caused by reactive oxygen species (ROS) changes the biophysical properties of native SOD1 protein thus, instigating its fibrillization and misfolding. These abnormal misfolding aggregates or inclusions of SOD1 play a role in the pathogenesis of both forms of ALS, i.e., Sporadic ALS (sALS) and familial ALS (fALS). However, what leads to a decrease in the stability and misfolding of SOD1 is still in question and our scientific knowledge is scarce. A large number of studies have been conducted in this area to explore the biochemical mechanistic pathway of SOD1 aggregation. Several studies, over the past two decades, have shown that the SOD1-catalyzed biochemical reaction product hydrogen peroxide (H2O2) at a pathological concentration act as a substrate to trigger the misfolding trajectories and toxicity of SOD1 in the pathogenesis of ALS. These toxic aggregates of SOD1 also cause aberrant localization of TAR-DNA binding protein 43 (TDP-43), which is characteristic of neuronal cytoplasmic inclusions (NCI) found in ALS. Here in this review, we present the evidence implicating the pivotal role of H2O2 in modulating the toxicity of SOD1 in the pathophysiology of the incurable and highly complex disease ALS. Also, highlighting the role of H2O2 in ALS, we believe will encourage scientists to target pathological concentrations of H2O2 thereby halting the misfolding of SOD1.

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Rothstein, Jeffrey D. "TDP-43 in amyotrophic lateral sclerosis: Pathophysiology or patho-babel?" Annals of Neurology 61, no. 5 (2007): 382–84. http://dx.doi.org/10.1002/ana.21155.

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Souza, Paulo Victor Sgobbi de, Wladimir Bocca Vieira de Rezende Pinto, Marco Antônio Troccoli Chieia, and Acary Souza Bulle Oliveira. "Clinical and genetic basis of familial amyotrophic lateral sclerosis." Arquivos de Neuro-Psiquiatria 73, no. 12 (October 13, 2015): 1026–37. http://dx.doi.org/10.1590/0004-282x20150161.

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Amyotrophic lateral sclerosis represents the most common neurodegenerative disease leading to upper and lower motor neuron compromise. Although the vast majority of cases are sporadic, substantial gain has been observed in the knowledge of the genetic forms of the disease, especially of familial forms. There is a direct correlation between the profile of the mutated genes in sporadic and familial forms, highlighting the main role ofC9orf72 gene in the clinical forms associated with frontotemporal dementia spectrum. The different genes related to familial and sporadic forms represent an important advance on the pathophysiology of the disease and genetic therapeutic perspectives, such as antisense therapy. The objective of this review is to signal and summarize clinical and genetic data related to familial forms of amyotrophic lateral sclerosis.

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Renga, Vijay. "Brain Connectivity and Network Analysis in Amyotrophic Lateral Sclerosis." Neurology Research International 2022 (February 7, 2022): 1–20. http://dx.doi.org/10.1155/2022/1838682.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no effective treatment or cure. ALS is characterized by the death of lower motor neurons (LMNs) in the spinal cord and upper motor neurons (UMNs) in the brain and their networks. Since the lower motor neurons are under the control of UMN and the networks, cortical degeneration may play a vital role in the pathophysiology of ALS. These changes that are not apparent on routine imaging with CT scans or MRI brain can be identified using modalities such as diffusion tensor imaging, functional MRI, arterial spin labelling (ASL), electroencephalogram (EEG), magnetoencephalogram (MEG), functional near-infrared spectroscopy (fNIRS), and positron emission tomography (PET) scan. They can help us generate a representation of brain networks and connectivity that can be visualized and parsed out to characterize and quantify the underlying pathophysiology in ALS. In addition, network analysis using graph measures provides a novel way of understanding the complex network changes occurring in the brain. These have the potential to become biomarker for the diagnosis and treatment of ALS. This article is a systematic review and overview of the various connectivity and network-based studies in ALS.

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van Eijk, Ruben P. A., Stavros Nikolakopoulos, Kit C. B. Roes, Lindsay Kendall, Steve S. Han, Arseniy Lavrov, Noam Epstein, et al. "Innovating Clinical Trials for Amyotrophic Lateral Sclerosis." Neurology 97, no. 11 (July 27, 2021): 528–36. http://dx.doi.org/10.1212/wnl.0000000000012545.

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Development of effective treatments for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology, and methodologic design challenges. We have evaluated 2 major themes in the design of pivotal, phase 3 clinical trials for ALS—(1) patient selection and (2) analytical strategy—and discussed potential solutions with the European Medicines Agency. Several design considerations were assessed using data from 5 placebo-controlled clinical trials (n = 988), 4 population-based cohorts (n = 5,100), and 2,436 placebo-allocated patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework that naturally adapts the trial duration when inaccurate assumptions are made at the design stage, such as enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria, and minimizing exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve as a blueprint for future clinical trials in this population.

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Mahoney, Colin J., Rebekah M. Ahmed, William Huynh, Sicong Tu, Jonathan D. Rohrer, Richard S. Bedlack, Orla Hardiman, and Matthew C. Kiernan. "Pathophysiology and Treatment of Non-motor Dysfunction in Amyotrophic Lateral Sclerosis." CNS Drugs 35, no. 5 (May 2021): 483–505. http://dx.doi.org/10.1007/s40263-021-00820-1.

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Morgan, Stephen, Stephanie Duguez, and William Duddy. "Personalized Medicine and Molecular Interaction Networks in Amyotrophic Lateral Sclerosis (ALS): Current Knowledge." Journal of Personalized Medicine 8, no. 4 (December 13, 2018): 44. http://dx.doi.org/10.3390/jpm8040044.

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Multiple genes and mechanisms of pathophysiology have been implicated in amyotrophic lateral sclerosis (ALS), suggesting it is a complex systemic disease. With this in mind, applying personalized medicine (PM) approaches to tailor treatment pipelines for ALS patients may be necessary. The modelling and analysis of molecular interaction networks could represent valuable resources in defining ALS-associated pathways and discovering novel therapeutic targets. Here we review existing omics datasets and analytical approaches, in order to consider how molecular interaction networks could improve our understanding of the molecular pathophysiology of this fatal neuromuscular disorder.

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Liu, Guan-Ting, Chi-Shin Hwang, Chia-Hung Hsieh, Chih-Hao Lu, Sunny Li-Yun Chang, Jin-Ching Lee, Chien-Fu Huang, and Hao-Teng Chang. "Eosinophil-Derived Neurotoxin Is Elevated in Patients with Amyotrophic Lateral Sclerosis." Mediators of Inflammation 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/421389.

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Background and Objectives. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons in the brainstem, motor cortex, and spinal cord. Oxidative stress and neuroinflammation have been implicated in the pathophysiology of ALS. Members of the family of damage-associated molecular patterns, including reactive oxygen species, high-mobility group box 1, and eosinophil-derived neurotoxin (EDN), may participate in pathological conditions. In this study, we aim to discover new biomarker for detecting ALS.Materials and Methods. We examined 44 patients with ALS, 41 patients with Alzheimer’s disease, 41 patients with Parkinson’s disease, and 44 healthy controls. The concentration of serum EDN was measured using an enzyme-linked immunosorbent assay.Results. EDN levels were significantly increased 2.17-fold in the serum of patients with ALS as compared with healthy controls (P<0.05). No correlation between the levels of serum EDN and various clinical parameters of ALS was found. Moreover, the levels of serum EDN in patients with Parkinson’s disease and Alzheimer’s disease and healthy controls were similar.Conclusion. A higher level of serum EDN was found specifically in patients with ALS, indicating that EDN may participate in the pathophysiology of ALS.

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Sun, Yu, Annabel J. Curle, Arshad M. Haider, and Gabriel Balmus. "The role of DNA damage response in amyotrophic lateral sclerosis." Essays in Biochemistry 64, no. 5 (October 2020): 847–61. http://dx.doi.org/10.1042/ebc20200002.

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Abstract Amyotrophic lateral sclerosis (ALS) is a rapidly disabling and fatal neurodegenerative disease. Due to insufficient disease-modifying treatments, there is an unmet and urgent need for elucidating disease mechanisms that occur early and represent common triggers in both familial and sporadic ALS. Emerging evidence suggests that impaired DNA damage response contributes to age-related somatic accumulation of genomic instability and can trigger or accelerate ALS pathological manifestations. In this review, we summarize and discuss recent studies indicating a direct link between DNA damage response and ALS. Further mechanistic understanding of the role genomic instability is playing in ALS disease pathophysiology will be critical for discovering new therapeutic avenues.

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Goutman, Stephen A., Orla Hardiman, Ammar Al-Chalabi, Adriano Chió, Masha G. Savelieff, Matthew C. Kiernan, and Eva L. Feldman. "Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis." Lancet Neurology 21, no. 5 (May 2022): 465–79. http://dx.doi.org/10.1016/s1474-4422(21)00414-2.

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Obrador, Elena, Rosario Salvador, Rafael López-Blanch, Ali Jihad-Jebbar, Soraya L. Vallés, and José M. Estrela. "Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis." Antioxidants 9, no. 9 (September 22, 2020): 901. http://dx.doi.org/10.3390/antiox9090901.

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Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron (MN) disease. Its primary cause remains elusive, although a combination of different causal factors cannot be ruled out. There is no cure, and prognosis is poor. Most patients with ALS die due to disease-related complications, such as respiratory failure, within three years of diagnosis. While the underlying mechanisms are unclear, different cell types (microglia, astrocytes, macrophages and T cell subsets) appear to play key roles in the pathophysiology of the disease. Neuroinflammation and oxidative stress pave the way leading to neurodegeneration and MN death. ALS-associated mitochondrial dysfunction occurs at different levels, and these organelles are involved in the mechanism of MN death. Molecular and cellular interactions are presented here as a sequential cascade of events. Based on our present knowledge, the discussion leads to the idea that feasible therapeutic strategies should focus in interfering with the pathophysiology of the disease at different steps.

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Reis, Carlos Henrique Melo, Marco Orsini, Marco Antônio Araujo Leite, Marcos RG de Freitas, Jano Alves de Souza, Victor Hugo Bastos, Carlos Bruno, Mariane Doelinger Barbosam, Celmir Vilaça, and Acary Bulle Oliveira. "AMYOTROPHIC LATERAL SCLEROSIS: HOW TO UNDERSTAND SUCH A DIVERSE AND ENTANGLED PATHOPHYSIOLOGY?" American Journal of Microbiology 5, no. 1 (January 1, 2014): 1–2. http://dx.doi.org/10.3844/ajmsp.2014.1.2.

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Cunha-Oliveira, Teresa, Liliana Montezinho, Catarina Mendes, Omidreza Firuzi, Luciano Saso, Paulo J. Oliveira, and Filomena S. G. Silva. "Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention." Oxidative Medicine and Cellular Longevity 2020 (November 15, 2020): 1–29. http://dx.doi.org/10.1155/2020/5021694.

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Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease or Charcot disease, is a fatal neurodegenerative disease that affects motor neurons (MNs) and leads to death within 2–5 years of diagnosis, without any effective therapy available. Although the pathological mechanisms leading to ALS are still unknown, a wealth of evidence indicates that an excessive reactive oxygen species (ROS) production associated with an inefficient antioxidant defense represents an important pathological feature in ALS. Substantial evidence indicates that oxidative stress (OS) is implicated in the loss of MNs and in mitochondrial dysfunction, contributing decisively to neurodegeneration in ALS. Although the modulation of OS represents a promising approach to protect MNs from degeneration, the fact that several antioxidants with beneficial effects in animal models failed to show any therapeutic benefit in patients raises several questions that should be analyzed. Using specific queries for literature search on PubMed, we review here the role of OS-related mechanisms in ALS, including the involvement of altered mitochondrial function with repercussions in neurodegeneration. We also describe antioxidant compounds that have been mostly tested in preclinical and clinical trials of ALS, also describing their respective mechanisms of action. While the description of OS mechanism in the different mutations identified in ALS has as principal objective to clarify the contribution of OS in ALS, the description of positive and negative outcomes for each antioxidant is aimed at paving the way for novel opportunities for intervention. In conclusion, although antioxidant strategies represent a very promising approach to slow the progression of the disease, it is of utmost need to invest on the characterization of OS profiles representative of each subtype of patient, in order to develop personalized therapies, allowing to understand the characteristics of antioxidants that have beneficial effects on different subtypes of patients.

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Trias, Emiliano, Sofia Ibarburu, Romina Barreto-Núñez, and Luis Barbeito. "Significance of aberrant glial cell phenotypes in pathophysiology of amyotrophic lateral sclerosis." Neuroscience Letters 636 (January 2017): 27–31. http://dx.doi.org/10.1016/j.neulet.2016.07.052.

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Veyrat-Durebex, C., P. Corcia, A. Dangoumau, F. Laumonnier, E. Piver, P. H. Gordon, C. R. Andres, P. Vourc’h, and H. Blasco. "Advances in Cellular Models to Explore the Pathophysiology of Amyotrophic Lateral Sclerosis." Molecular Neurobiology 49, no. 2 (November 7, 2013): 966–83. http://dx.doi.org/10.1007/s12035-013-8573-9.

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Ferri, Laura, Paola Ajdinaj, Marianna Gabriella Rispoli, Claudia Carrarini, Filomena Barbone, Damiano D’Ardes, Margherita Capasso, et al. "Diabetes Mellitus and Amyotrophic Lateral Sclerosis: A Systematic Review." Biomolecules 11, no. 6 (June 10, 2021): 867. http://dx.doi.org/10.3390/biom11060867.

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Background: Amyotrophic Lateral Sclerosis (ALS) is a degenerative disorder which affects the motor neurons. Growing evidence suggests that ALS may impact the metabolic system, including the glucose metabolism. Several studies investigated the role of Diabetes Mellitus (DM) as risk and/or prognostic factor. However, a clear correlation between DM and ALS has not been defined. In this review, we focus on the role of DM in ALS, examining the different hypotheses on how perturbations of glucose metabolism may interact with the pathophysiology and the course of ALS. Methods: We undertook an independent PubMed literature search, using the following search terms: ((ALS) OR (Amyotrophic Lateral Sclerosis) OR (Motor Neuron Disease)) AND ((Diabetes) OR (Glucose Intolerance) OR (Hyperglycemia)). Review and original articles were considered. Results: DM appears not to affect ALS severity, progression, and survival. Contrasting data suggested a protective role of DM on the occurrence of ALS in elderly and an opposite effect in younger subjects. Conclusions: The actual clinical and pathophysiological correlation between DM and ALS is unclear. Large longitudinal prospective studies are needed. Achieving large sample sizes comparable to those of common complex diseases like DM is a challenge for a rare disease like ALS. Collaborative efforts could overcome this specific issue.

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Cutler, Alicia A., Theodore Eugene Ewachiw, Giulia A. Corbet, Roy Parker, and Brad B. Olwin. "Myo-granules Connect Physiology and Pathophysiology." Journal of Experimental Neuroscience 13 (January 2019): 117906951984215. http://dx.doi.org/10.1177/1179069519842157.

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A hallmark of many neuromuscular diseases including Alzheimer disease, inclusion body myositis, amyotrophic lateral sclerosis, frontotemporal lobar dementia, and ocular pharyngeal muscular dystrophy is large cytoplasmic aggregates containing the RNA-binding protein, TDP-43. Despite acceptance that cytoplasmic TDP-43 aggregation is pathological, cytoplasmic TDP-43 assemblies form in healthy regenerating muscle. These recently discovered ribonucleoprotein assemblies, termed myo-granules, form in healthy muscle following injury and are readily cleared as the myofibers mature. The formation and dissolution of myo-granules during normal muscle regeneration suggests that these amyloid-like oligomers may be functional and that perturbations in myo-granule kinetics or composition may promote pathological aggregation.

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Teive, Hélio A. G., Renato P. Munhoz, Carlos Henrique F. Camargo, and Olivier Walusinski. "Yawning in neurology: a review." Arquivos de Neuro-Psiquiatria 76, no. 7 (July 2018): 473–80. http://dx.doi.org/10.1590/0004-282x20180057.

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ABSTRACT Yawning is a stereotyped physiological behavior that can represent a sign or symptom of several conditions, such as stroke, parakinesia brachialis oscitans, parkinsonism, Parkinson’s disease and epilepsy. More rarely, it can occur in patients with intracranial hypertension, brain tumor, multiple sclerosis, migraine, Chiari malformation type I, and amyotrophic lateral sclerosis. Drug-induced yawning is an uncommon clinical condition and yawning in patients with autism or schizophrenia is very rare. The aim of this review is to describe in detail the occurrence of the phenomenon in such conditions, and its’ phenomenology and pathophysiology.

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Menon, Parvathi, and Steve Vucic. "The Upper Motor Neuron—Improved Knowledge from ALS and Related Clinical Disorders." Brain Sciences 11, no. 8 (July 21, 2021): 958. http://dx.doi.org/10.3390/brainsci11080958.

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Upper motor neuron (UMN) is a term traditionally used for the corticospinal or pyramidal tract neuron synapsing with the lower motor neuron (LMN) in the anterior horns of the spinal cord. The upper motor neuron controls resting muscle tone and helps initiate voluntary movement of the musculoskeletal system by pathways which are not completely understood. Dysfunction of the upper motor neuron causes the classical clinical signs of spasticity, weakness, brisk tendon reflexes and extensor plantar response, which are associated with clinically well-recognised, inherited and acquired disorders of the nervous system. Understanding the pathophysiology of motor system dysfunction in neurological disease has helped promote a greater understanding of the motor system and its complex cortical connections. This review will focus on the pathophysiology underlying progressive dysfunction of the UMN in amyotrophic lateral sclerosis and three other related adult-onset, progressive neurological disorders with prominent UMN signs, namely, primary lateral sclerosis, hereditary spastic paraplegia and primary progressive multiple sclerosis, to help promote better understanding of the human motor system and, by extension, related cortical systems.

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Yu, Haelim, Seung Hyun Kim, Min-Young Noh, Sanggon Lee, and Yongsoon Park. "Effect of Dietary Fiber Intake on the Prognosis of Amyotrophic Lateral Sclerosis." Current Developments in Nutrition 5, Supplement_2 (June 2021): 1107. http://dx.doi.org/10.1093/cdn/nzab053_100.

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Abstract Objectives The gut microbiota has been suggested to associate with the pathophysiology of amyotrophic lateral sclerosis (ALS), and thus prebiotic effect of fiber could play an important role on pathophysiology of ALS. The present study aimed to investigate the effect of dietary fiber intake on the disease progression rate (∆FS) and survival time among Korean ALS patients. Methods A total of 272 Korean sporadic ALS patients diagnosed according to the revised EI Escorial criteria were recruited during 2011–2019, and were followed until the occurrence of events or the end of September 2020. The events were defined as percutaneous endoscopic gastrostomy, tracheostomy, or death. Intake of dietary fibers was calculated based on 24-hour dietary recall, and divided into five major fiber-rich foods: vegetables, fruits, grains, legumes, and nuts/seeds. Results There were higher proportion of participants with lower than the mean value of ∆FS (0.75) in the highest tertile of total fiber and vegetable fiber intake than those in the lowest tertile. Kaplan–Meier analysis showed that participants in the highest tertile for vegetable fiber intake had longer survival. Cox regression analysis showed that intake of vegetable fiber was negatively associated with risk for events after adjustment. Notably, vegetable fiber intake was negatively correlated with pro-inflammatory cytokine such as interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein-1 in the cerebrospinal fluid. Conclusions In conclusion, this study showed that vegetable fiber intake was negatively associated to the ∆FS and shorter survival time, suggesting that vegetable fiber intake could influence the prognosis of ALS. Further clinical trials are needed to confirm whether supplementation of dietary fiber improves the prognosis in ALS. Funding Sources This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT).

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Duranti, Elisa, and Chiara Villa. "Molecular Investigations of Protein Aggregation in the Pathogenesis of Amyotrophic Lateral Sclerosis." International Journal of Molecular Sciences 24, no. 1 (December 31, 2022): 704. http://dx.doi.org/10.3390/ijms24010704.

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Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder characterized by selective loss of lower and upper motor neurons (MNs) in the brain and spinal cord, resulting in paralysis and eventually death due to respiratory insufficiency. Although the fundamental physiological mechanisms underlying ALS are not completely understood, the key neuropathological hallmarks of ALS pathology are the aggregation and accumulation of ubiquitinated protein inclusions within the cytoplasm of degenerating MNs. Herein, we discuss recent insights into the molecular mechanisms that lead to the accumulation of protein aggregates in ALS. This will contribute to a better understanding of the pathophysiology of the disease and may open novel avenues for the development of therapeutic strategies.

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Obrador, Elena, Rosario Salvador-Palmer, Rafael López-Blanch, Ryan W. Dellinger, and José M. Estrela. "NAD+ Precursors and Antioxidants for the Treatment of Amyotrophic Lateral Sclerosis." Biomedicines 9, no. 8 (August 12, 2021): 1000. http://dx.doi.org/10.3390/biomedicines9081000.

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Charcot first described amyotrophic lateral sclerosis (ALS) between 1865 and 1874 as a sporadic adult disease resulting from the idiopathic progressive degeneration of the motor neuronal system, resulting in rapid, progressive, and generalized muscle weakness and atrophy. There is no cure for ALS and no proven therapy to prevent it or reverse its course. There are two drugs specifically approved for the treatment of ALS, riluzol and edaravone, and many others have already been tested or are following clinical trials. However, at the present moment, we still cannot glimpse a true breakthrough in the treatment of this devastating disease. Nevertheless, our understanding of the pathophysiology of ALS is constantly growing. Based on this background, we know that oxidative stress, alterations in the NAD+-dependent metabolism and redox status, and abnormal mitochondrial dynamics and function in the motor neurons are at the core of the problem. Thus, different antioxidant molecules or NAD+ generators have been proposed for the therapy of ALS. This review analyzes these options not only in light of their use as individual molecules, but with special emphasis on their potential association, and even as part of broader combined multi-therapies.

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Granatiero, Veronica, Csaba Konrad, Kirsten Bredvik, Giovanni Manfredi, and Hibiki Kawamata. "Nrf2 signaling links ER oxidative protein folding and calcium homeostasis in health and disease." Life Science Alliance 2, no. 5 (October 2019): e201900563. http://dx.doi.org/10.26508/lsa.201900563.

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We report a signaling pathway linking two fundamental functions of the ER, oxidative protein folding, and intracellular calcium regulation. Cells sense ER oxidative protein folding through H2O2, which induces Nrf2 nuclear translocation. Nrf2 regulates the expression of GPx8, an ER glutathione peroxidase that modulates ER calcium levels. Because ER protein folding is dependent on calcium, this pathway functions as rheostat of ER calcium levels. Protein misfolding and calcium dysregulation contribute to the pathophysiology of many diseases, including amyotrophic lateral sclerosis, in which astrocytic calcium dysregulation participates in causing motor neuron death. In human-derived astrocytes harboring mutant SOD1 causative of familial amyotrophic lateral sclerosis, we show that impaired ER redox signaling decreases Nrf2 nuclear translocation, resulting in ER calcium overload and increased calcium-dependent cell secretion, leading to motor neuron death. Nrf2 activation in SOD1 mutant astrocytes with dimethyl fumarate restores calcium homeostasis and ameliorates motor neuron death. These results highlight a regulatory mechanism of intracellular calcium homeostasis by ER redox signaling and suggest that this mechanism could be a therapeutic target in SOD1 mutant astrocytes.

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Vázquez-Costa, J. F., M. Campins-Romeu, J. J. Martínez-Payá, J. I. Tembl, M. E. del Baño-Aledo, J. Ríos-Díaz, V. Fornés-Ferrer, M. J. Chumillas, and T. Sevilla. "New insights into the pathophysiology of fasciculations in amyotrophic lateral sclerosis: An ultrasound study." Clinical Neurophysiology 129, no. 12 (December 2018): 2650–57. http://dx.doi.org/10.1016/j.clinph.2018.09.014.

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Gordon, Paul. "Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials." Aging and Disease 04, no. 05 (2013): 295–310. http://dx.doi.org/10.14336/ad.2013.0400295.

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Gulla, Surendra, Dakshayani Lomada, Anusha Lade, Reddanna Pallu, and Madhava C. Reddy. "Role of Prostaglandins in Multiple Sclerosis." Current Pharmaceutical Design 26, no. 7 (March 25, 2020): 730–42. http://dx.doi.org/10.2174/1381612826666200107141328.

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: Multiple sclerosis (MS) is an autoimmune demyelinating disorder with chronic inflammation in the central nervous system, manifested by both physical and cognitive disability. Neuroinflammation and neurodegeneration are the phenomena that appear in the central nervous system associated with various neurodegenerative disorders, including MS, Alzheimer’s diseases, amyotrophic lateral sclerosis and Parkinson’s disease. Prostaglandins are one of the major mediators of inflammation that exhibit an important function in enhancing neuroinflammatory and neurodegenerative processes. These mediators would help understand the pathophysiology of MS as the combination of antagonists or agonists of prostaglandins receptors could be beneficial during the treatment of MS. The present review focuses on the role played by different prostaglandins and the enzymes which produced them in the etiopathogenesis of MS.

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Mori, Akihisa, Brittany Cross, Shinichi Uchida, Jill Kerrick Walker, and Robert Ristuccia. "How Are Adenosine and Adenosine A2A Receptors Involved in the Pathophysiology of Amyotrophic Lateral Sclerosis?" Biomedicines 9, no. 8 (August 17, 2021): 1027. http://dx.doi.org/10.3390/biomedicines9081027.

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Adenosine is extensively distributed in the central and peripheral nervous systems, where it plays a key role as a neuromodulator. It has long been implicated in the pathogenesis of progressive neurogenerative disorders such as Parkinson’s disease, and there is now growing interest in its role in amyotrophic lateral sclerosis (ALS). The motor neurons affected in ALS are responsive to adenosine receptor function, and there is accumulating evidence for beneficial effects of adenosine A2A receptor antagonism. In this article, we focus on recent evidence from ALS clinical pathology and animal models that support dynamism of the adenosinergic system (including changes in adenosine levels and receptor changes) in ALS. We review the possible mechanisms of chronic neurodegeneration via the adenosinergic system, potential biomarkers and the acute symptomatic pharmacology, including respiratory motor neuron control, of A2A receptor antagonism to explore the potential of the A2A receptor as target for ALS therapy.

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de Luna, Noemí, Álvaro Carbayo, Oriol Dols-Icardo, Janina Turon-Sans, David Reyes-Leiva, Ignacio Illan-Gala, Ivonne Jericó, et al. "Neuroinflammation-Related Proteins NOD2 and Spp1 Are Abnormally Upregulated in Amyotrophic Lateral Sclerosis." Neurology - Neuroimmunology Neuroinflammation 10, no. 2 (December 2, 2022): e200072. http://dx.doi.org/10.1212/nxi.0000000000200072.

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Background and ObjectivesAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknown etiology and poorly understood pathophysiology. There is no specific biomarker either for diagnosis or prognosis. The aim of our study was to investigate differentially expressed proteins in the CSF and serum from patients with ALS to determine their role in the disease process and evaluate their utility as diagnostic or prognostic biomarkers.MethodsWe performed mass spectrometry in the CSF from 3 patients with ALS and 3 healthy controls (HCs). The results were compared with motor cortex dysregulated transcripts obtained from 11patients with sporadic ALS and 8 HCs. Candidate proteins were tested using ELISA in the serum of 123 patients with ALS, 30 patients with Alzheimer disease (AD), 28 patients with frontotemporal dementia (FTD), and 102 HCs. Patients with ALS, AD, and FTD were prospectively recruited from January 2003 to December 2020. A group of age-matched HCs was randomly selected from the Sant Pau Initiative on Neurodegeneration cohort of the Sant Pau Memory Unit.ResultsNucleotide-binding oligomerization domain–containing protein 2 (NOD2) and osteopontin (Spp1) were differentially expressed in the CSF and the motor cortex transcriptome of patients with ALS compared with that in HCs (p< 0.05). NOD2 and Spp1 levels were significantly higher in sera from patients with ALS than in HCs (p< 0.001). Receiver operating characteristic analysis showed an area under the curve of 0.63 for NOD2 and 0.81 for Spp1. NOD2 levels were significantly lower in patients with AD and FTD than in patients with ALS (p< 0.0001), but we found no significant differences in Spp1 levels between patients with ALS, AD (p= 0.51), and FTD (p= 0.42). We found a negative correlation between Spp1 levels and ALS functional rating scale (r= −0.24,p= 0.009).DiscussionOur discovery-based approach identified NOD2 as a novel biomarker in ALS and adds evidence to the contribution of Spp1 in the disease process. Both proteins are involved in innate immunity and autophagy and are increased in the serum from patients with ALS. Our data support a relevant role of neuroinflammation in the pathophysiology of the disease and may identify targets for disease-modifying treatments in ALS. Further longitudinal studies should investigate the diagnostic and prognostic value of NOD2 and Spp1 in clinical practice.

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Corcia, Philippe, Peter Bede, Pierre-François Pradat, Philippe Couratier, Steve Vucic, and Mamede de Carvalho. "Split-hand and split-limb phenomena in amyotrophic lateral sclerosis: pathophysiology, electrophysiology and clinical manifestations." Journal of Neurology, Neurosurgery & Psychiatry 92, no. 10 (July 20, 2021): 1126–30. http://dx.doi.org/10.1136/jnnp-2021-326266.

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting the upper and lower motor neurons. A key clinical feature of ALS is the absence of accurate, early-stage diagnostic indicators. ‘Split-hand syndrome’ was first described in ALS at the end of the last century and a considerable body of literature suggests that the split-hand phenomenon may be an important clinical feature of ALS. Considering the published investigations, it is conceivable that the ‘split-hand syndrome’ results from the associated upper and lower motor neuron degeneration, whose interaction remains to be fully clarified. Additionally, other split syndromes have been described in ALS involving upper or lower limbs, with a nuanced description of clinical and neurophysiological manifestations that may further aid ALS diagnosis. In this review, we endeavour to systematically present the spectrum of the ‘split syndromes’ in ALS from a clinical and neurophysiology perspective and discuss their diagnostic and pathogenic utility.

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Reichenstein, Irit, Chen Eitan, Sandra Diaz-Garcia, Guy Haim, Iddo Magen, Aviad Siany, Mariah L. Hoye, et al. "Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology." Science Translational Medicine 11, no. 523 (December 18, 2019): eaav5264. http://dx.doi.org/10.1126/scitranslmed.aav5264.

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Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease.

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Shibuya, K., K. Kanai, S. Misawa, S. Isose, Y. Noto, Y. Fujimaki, S. Nasu, Y. Sekiguchi, and S. Kuwabara. "P7-11 Axonal excitability properties in patient with amyotrophic lateral sclerosis: Pathophysiology in “split hand”." Clinical Neurophysiology 121 (October 2010): S143. http://dx.doi.org/10.1016/s1388-2457(10)60587-1.

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Renzini, Alessandra, Eva Pigna, Marco Rocchi, Alessia Cedola, Giuseppe Gigli, Viviana Moresi, and Dario Coletti. "Sex and HDAC4 Differently Affect the Pathophysiology of Amyotrophic Lateral Sclerosis in SOD1-G93A Mice." International Journal of Molecular Sciences 24, no. 1 (December 21, 2022): 98. http://dx.doi.org/10.3390/ijms24010098.

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Amyotrophic Lateral Sclerosis (ALS) is a devastating adult-onset neurodegenerative disease, with ineffective therapeutic options. ALS incidence and prevalence depend on the sex of the patient. Histone deacetylase 4 (HDAC4) expression in skeletal muscle directly correlates with the progression of ALS, pointing to the use of HDAC4 inhibitors for its treatment. Contrarily, we have found that deletion of HDAC4 in skeletal muscle worsened the pathological features of ALS, accelerating and exacerbating skeletal muscle loss and negatively affecting muscle innervations in male SOD1-G93A (SOD1) mice. In the present work, we compared SOD1 mice of both sexes with the aim to characterize ALS onset and progression as a function of sex differences. We found a global sex-dependent effects on disease onset and mouse lifespan. We further investigated the role of HDAC4 in SOD1 females with a genetic approach, and discovered morpho-functional effects on skeletal muscle, even in the early phase of the diseases. The deletion of HDAC4 decreased muscle function and exacerbated muscle atrophy in SOD1 females, and had an even more dramatic effect in males. Therefore, the two sexes must be considered separately when studying ALS.

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Kanekura, Kohsuke, Yoshiaki Yamanaka, Tamami Miyagi, and Masahiko Kuroda. "Chemically oligomerizable TDP-43: a novel chemogenetic tool for studying the pathophysiology of amyotrophic lateral sclerosis." Neural Regeneration Research 17, no. 11 (2022): 2434. http://dx.doi.org/10.4103/1673-5374.335803.

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Gold, Bruce G. "The pathophysiology of proximal neurofilamentous giant axonal swellings: Implications for the pathogenesis of amyotrophic lateral sclerosis." Toxicology 46, no. 2 (October 1987): 125–39. http://dx.doi.org/10.1016/0300-483x(87)90123-5.

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Geevasinga, Nimeshan, and Steve Vucic. "Role Of spinal mechanisms in the pathophysiology of the split hand sign in amyotrophic lateral sclerosis." Muscle & Nerve 58, no. 4 (May 17, 2018): 470–71. http://dx.doi.org/10.1002/mus.26139.

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Imai, Yuzuru, Hongrui Meng, Kahori Shiba-Fukushima, and Nobutaka Hattori. "Twin CHCH Proteins, CHCHD2, and CHCHD10: Key Molecules of Parkinson’s Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia." International Journal of Molecular Sciences 20, no. 4 (February 20, 2019): 908. http://dx.doi.org/10.3390/ijms20040908.

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Mutations of coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and 10 (CHCHD10) have been found to be linked to Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and/or frontotemporal lobe dementia (FTD). CHCHD2 and CHCHD10 proteins, which are homologous proteins with 54% identity in amino acid sequence, belong to the mitochondrial coiled-coil-helix-coiled-coil-helix (CHCH) domain protein family. A series of studies reveals that these twin proteins form a multimodal complex, producing a variety of pathophysiology by the disease-causing variants of these proteins. In this review, we summarize the present knowledge about the physiological and pathological roles of twin proteins, CHCHD2 and CHCHD10, in neurodegenerative diseases.

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Carillo Jr, Romeu, Maria Filomena Xavier Mendes, Maria Solange Gosik, Domingos José Vaz Do Cabo, Raquel Bruno Kalile, and Renata Garcia Lino. "From Hahnemann to the Physiology of the Complex Systems in Practice." International Journal of High Dilution Research - ISSN 1982-6206 17, no. 2 (July 16, 2021): 04. http://dx.doi.org/10.51910/ijhdr.v17i2.919.

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Background: Amyotrophic Lateral Sclerosis is a progressive and fatal neurodegenerative disease that affects motor neurons and has two forms, one familial and the other sporadic. Wilson´s disease is a genetic disorder, autosomal recessive, which causes changes in copper metabolism. Methodology: In this paper, the author presents two clinical cases of patients with amyotrophic lateral sclerosis (ALS) and Wilson's disease (WD), showing the evolution of each one from the beginning of the homeopathic treatment, whose prescription was based on the theory of Complex Systems of Carillo. Results and Discussion: Understanding the pathophysiology of each chronic disease, and recognizing the syndromic nature of the absolute majority of natural chronic diseases, allows us to use the most indicated drugs for every case and shows the best way to prescribe these medications. Treating chronic diseases based on clear and well-defined principles. Based in this principle, the concepts of Prioritization of Systems, related organic injury,emunctorial block and equalization are applied in both clinical cases.The identification of the latter avoids homeopathic aggravations, essential for patients in severe states. Conclusion: The theoretical bases for the understanding of clinical cases, in the Complex Systems Model of Carillo, with its 8 elements, namely: Structure (material body); Self-regulation (immaterial); Organization Pattern; Dissipation; Autopoiesis; Adaptation; Cognition and Consciousness, allow an expanded understanding of the health disease process.

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Van den Bos, Mehdi A. J., Mana Higashihara, Nimeshan Geevasinga, Parvathi Menon, Matthew C. Kiernan, and Steve Vucic. "Imbalance of cortical facilitatory and inhibitory circuits underlies hyperexcitability in ALS." Neurology 91, no. 18 (October 3, 2018): e1669-e1676. http://dx.doi.org/10.1212/wnl.0000000000006438.

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ObjectiveTo determine the relative contribution of inhibitory and facilitatory circuits in the development of cortical hyperexcitability in amyotrophic lateral sclerosis (ALS).MethodsIn this cross-sectional study, cortical excitability was assessed in 27 patients with ALS, and results compared to 25 healthy controls. In addition, a novel neurophysiologic measure of cortical function, short-interval intracortical facilitation (SICF), was assessed reflecting activity of the facilitatory circuits.ResultsThere was a significant increase in SICF (ALS −18.51 ± 1.56%, controls −8.52 ± 1.21%, p < 0.001) in patients with ALS that was accompanied by a reduction of short-interval intracortical inhibition (ALS 3.94 ± 1.29%, controls 14.23 ± 1.18%, p < 0.001) and cortical silent period duration (p = 0.034). The index of excitation, a biomarker reflecting the contribution of inhibitory and facilitatory circuit activity, was significantly increased in patients with ALS (82.79 ± 6.01%) compared to controls (36.15 ± 3.44, p < 0.001), suggesting a shift toward cortical excitation. Increased excitation correlated with upper motor neuron signs (R2 = 0.235, p = 0.016) and greater functional disability as reflected by a correlation with the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised score (R2 = 0.335, p = 0.002).ConclusionsThe present study established that cortical hyperexcitability is a key contributor to ALS pathophysiology, mediated through dysfunction of inhibitory and facilitatory intracortical circuits. Therapies aimed at restoring the cortical inhibitory imbalance provide novel avenues for future therapeutic targets.

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Chen, Jian-Hua, Nao-Xin Huang, Tian-Xiu Zou, and Hua-Jun Chen. "Brain Cortical Complexity Alteration in Amyotrophic Lateral Sclerosis: A Preliminary Fractal Dimensionality Study." BioMed Research International 2020 (March 21, 2020): 1–6. http://dx.doi.org/10.1155/2020/1521679.

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Objective. Fractal dimensionality (FD) analysis provides a quantitative description of brain structural complexity. The application of FD analysis has provided evidence of amyotrophic lateral sclerosis- (ALS-) related white matter degeneration. This study is aimed at evaluating, for the first time, FD alterations in a gray matter in ALS and determining its association with clinical parameters. Materials and Methods. This study included 22 patients diagnosed with ALS and 20 healthy subjects who underwent high-resolution T1-weighted imaging scanning. Disease severity was assessed using the revised ALS Functional Rating Scale (ALSFRS-R). The duration of symptoms and rate of disease progression were also assessed. The regional FD value was calculated by a computational anatomy toolbox and compared among groups. The relationship between cortical FD values and clinical parameters was evaluated by Spearman correlation analysis. Results. ALS patients showed decreased FD values in the left precentral gyrus and central sulcus, left circular sulcus of insula (superior segment), left cingulate gyrus and sulcus (middle-posterior part), right precentral gyrus, and right postcentral gyrus. The FD values in the right precentral gyrus were positively correlated to ALSFRS-R scores (r=0.44 and P=0.023), whereas negatively correlated to the rate of disease progression (r=−0.41 and P=0.039). Meanwhile, the FD value in the left circular sulcus of the insula (superior segment) was negatively correlated to disease duration (r=−0.51 and P=0.010). Conclusions. Our results suggest an ALS-related reduction in structural complexity involving the gray matter. FD analysis may shed more light on the pathophysiology of ALS.

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Kim, Wanil, Do-Yeon Kim, and Kyung-Ha Lee. "RNA-Binding Proteins and the Complex Pathophysiology of ALS." International Journal of Molecular Sciences 22, no. 5 (March 5, 2021): 2598. http://dx.doi.org/10.3390/ijms22052598.

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Genetic analyses of patients with amyotrophic lateral sclerosis (ALS) have identified disease-causing mutations and accelerated the unveiling of complex molecular pathogenic mechanisms, which may be important for understanding the disease and developing therapeutic strategies. Many disease-related genes encode RNA-binding proteins, and most of the disease-causing RNA or proteins encoded by these genes form aggregates and disrupt cellular function related to RNA metabolism. Disease-related RNA or proteins interact or sequester other RNA-binding proteins. Eventually, many disease-causing mutations lead to the dysregulation of nucleocytoplasmic shuttling, the dysfunction of stress granules, and the altered dynamic function of the nucleolus as well as other membrane-less organelles. As RNA-binding proteins are usually components of several RNA-binding protein complexes that have other roles, the dysregulation of RNA-binding proteins tends to cause diverse forms of cellular dysfunction. Therefore, understanding the role of RNA-binding proteins will help elucidate the complex pathophysiology of ALS. Here, we summarize the current knowledge regarding the function of disease-associated RNA-binding proteins and their role in the dysfunction of membrane-less organelles.

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van den Bos, Mehdi A. J., Nimeshan Geevasinga, Mana Higashihara, Parvathi Menon, and Steve Vucic. "Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques." International Journal of Molecular Sciences 20, no. 11 (June 10, 2019): 2818. http://dx.doi.org/10.3390/ijms20112818.

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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.

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Gavriilaki, Maria, Vasilios K. Kimiskidis, and Eleni Gavriilaki. "Precision Medicine in Neurology: The Inspirational Paradigm of Complement Therapeutics." Pharmaceuticals 13, no. 11 (October 26, 2020): 341. http://dx.doi.org/10.3390/ph13110341.

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Precision medicine has emerged as a central element of healthcare science. Complement, a component of innate immunity known for centuries, has been implicated in the pathophysiology of numerous incurable neurological diseases, emerging as a potential therapeutic target and predictive biomarker. In parallel, the innovative application of the first complement inhibitor in clinical practice as an approved treatment of myasthenia gravis (MG) and neuromyelitis optica spectrum disorders (NMOSD) related with specific antibodies raised hope for the implementation of personalized therapies in detrimental neurological diseases. A thorough literature search was conducted through May 2020 at MEDLINE, EMBASE, Cochrane Library and ClinicalTrials.gov databases based on medical terms (MeSH)” complement system proteins” and “neurologic disease”. Complement’s role in pathophysiology, monitoring of disease activity and therapy has been investigated in MG, multiple sclerosis, NMOSD, spinal muscular atrophy, amyotrophic lateral sclerosis, Parkinson, Alzheimer, Huntington disease, Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy, stroke, and epilepsy. Given the complexity of complement diagnostics and therapeutics, this state-of-the-art review aims to provide a brief description of the complement system for the neurologist, an overview of novel complement inhibitors and updates of complement studies in a wide range of neurological disorders.

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Trojsi, Francesca, Giulia D’Alvano, Simona Bonavita, and Gioacchino Tedeschi. "Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?" International Journal of Molecular Sciences 21, no. 10 (May 21, 2020): 3647. http://dx.doi.org/10.3390/ijms21103647.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, although multiple genetic risk factors have been recently revealed also in sporadic ALS (SALS). The pathological expansion of a hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic mutation identified in familial ALS, detected also in 5–10% of SALS patients. C9orf72-related ALS phenotype appears to be dependent on several modifiers, including demographic factors. Sex has been reported as an independent factor influencing ALS development, with men found to be more susceptible than women. Exposure to both female and male sex hormones have been shown to influence disease risk or progression. Moreover, interplay between genetics and sex has been widely investigated in ALS preclinical models and in large populations of ALS patients carrying C9orf72 repeat expansion. In light of the current need for reclassifying ALS patients into pathologically homogenous subgroups potentially responsive to targeted personalized therapies, we aimed to review the recent literature on the role of genetics and sex as both independent and synergic factors, in the pathophysiology, clinical presentation, and prognosis of ALS. Sex-dependent outcomes may lead to optimizing clinical trials for developing patient-specific therapies for ALS.

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Haouari, Shanez, Christian Robert Andres, Debora Lanznaster, Sylviane Marouillat, Céline Brulard, Audrey Dangoumau, Devina Ung, et al. "Study of Ubiquitin Pathway Genes in a French Population with Amyotrophic Lateral Sclerosis: Focus on HECW1 Encoding the E3 Ligase NEDL1." International Journal of Molecular Sciences 24, no. 2 (January 9, 2023): 1268. http://dx.doi.org/10.3390/ijms24021268.

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The ubiquitin pathway, one of the main actors regulating cell signaling processes and cellular protein homeostasis, is directly involved in the pathophysiology of amyotrophic lateral sclerosis (ALS). We first analyzed, by a next-generation sequencing (NGS) strategy, a series of genes of the ubiquitin pathway in two cohorts of familial and sporadic ALS patients comprising 176 ALS patients. We identified several pathogenic variants in different genes of this ubiquitin pathway already described in ALS, such as FUS, CCNF and UBQLN2. Other variants of interest were discovered in new genes studied in this disease, in particular in the HECW1 gene. We have shown that the HECT E3 ligase called NEDL1, encoded by the HECW1 gene, is expressed in neurons, mainly in their somas. Its overexpression is associated with increased cell death in vitro and, very interestingly, with the cytoplasmic mislocalization of TDP-43, a major protein involved in ALS. These results give new support for the role of the ubiquitin pathway in ALS, and suggest further studies of the HECW1 gene and its protein NEDL1 in the pathophysiology of ALS.

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Journal articles on the topic 'Amyotrophic lateral sclerosis – Pathophysiology'

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