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Neurological Sciences : Official... Feb 2024This systematic review and meta-analysis aimed to determine the frequency and correlates of fatigue in patients with amyotrophic lateral sclerosis (ALS). (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
This systematic review and meta-analysis aimed to determine the frequency and correlates of fatigue in patients with amyotrophic lateral sclerosis (ALS).
METHODS
Three databases were searched up to 2nd May 2023 to identify studies reporting fatigue frequency in ALS. Studies included had to identify ALS patients through one of ALS diagnostic criteria and measure fatigue by a validated tool with a specific cut-off value. Meta-analysis was conducted using RStudio's "meta" package with a random-effects model. Subgroup analyses and meta-regression explored the relationship between fatigue frequency in ALS and different covariates.
RESULTS
Eleven studies, compromising 1072 patients, met the inclusion criteria and were included in our analysis. The pooled frequency of fatigue across all studies was 48% (95% CI = 40% to 57%). Our subgroup analysis based on the ALSFRS-R revealed a higher frequency of fatigue in studies with lower scores (< 30) compared to those with higher scores (≥ 30), with a pooled frequency of 62% (95% CI = 43% to 79%) and 43% (95% CI = 37% to 49%), respectively. Also, the meta-regression analysis showed a significant negative association between fatigue and ALSFRS-R mean (P = 0.02). The included studies reported an association between fatigue and lower functional status and poorer quality of life in patients with ALS.
CONCLUSION
Our findings suggest that fatigue is prevalent in almost half of ALS patients and is associated with lower functional status and poorer quality of life, highlighting the importance of assessing and managing fatigue in ALS patients.
Topics: Humans; Amyotrophic Lateral Sclerosis; Prevalence; Quality of Life; Fatigue
PubMed: 37837507
DOI: 10.1007/s10072-023-07119-7 -
Sex representation in neurodegenerative and psychiatric disorders' preclinical and clinical studies.Neurobiology of Disease Aug 2023Many studies show the importance of biological sex for the onset, progression, and response to treatment in brain disorders. In line with these reports, health agencies... (Review)
Review
Many studies show the importance of biological sex for the onset, progression, and response to treatment in brain disorders. In line with these reports, health agencies have requested that all trials, both at the clinical and preclinical level, use a similar number of male and female subjects to correctly interpret the results. Despite these guidelines, many studies still tend to be unbalanced in the use of male and female subjects. In this review we consider three neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and three psychiatric disorders: Depression, Attention Deficit Hyperactivity Disorder, and Schizophrenia. These disorders were chosen because of their prevalence and their recognized sex-specific differences in onset, progression, and response to treatment. Alzheimer's disease and Depression demonstrate higher prevalence in females, whereas Parkinson's Disease, Amyotrophic lateral sclerosis, Attention Deficit Hyperactivity Disorder, and schizophrenia show higher prevalence in males. Results from preclinical and clinical studies examining each of these disorders revealed sex-specific differences in risk factors, diagnostic biomarkers, and treatment response and efficacy, suggesting a role for sex-specific therapies in neurodegenerative and neuropsychiatric disorders. However, the qualitative analysis of the percentage of males and females enrolled in clinical trials in the last two decades shows that for most of the disorders, there is still a sex bias in the patients' enrolment.
Topics: Humans; Male; Female; Alzheimer Disease; Parkinson Disease; Amyotrophic Lateral Sclerosis; Attention Deficit Disorder with Hyperactivity
PubMed: 37385457
DOI: 10.1016/j.nbd.2023.106214 -
Cells Jan 2021Since the discovery of the chromosome 9 open reading frame 72 () repeat expansion mutation in 2011 as the most common genetic abnormality in amyotrophic lateral... (Review)
Review
Since the discovery of the chromosome 9 open reading frame 72 () repeat expansion mutation in 2011 as the most common genetic abnormality in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) and frontotemporal dementia (FTD), progress in understanding the signaling pathways related to this mutation can only be described as intriguing. Two major theories have been suggested-(i) loss of function or haploinsufficiency and (ii) toxic gain of function from either repeat RNA or dipeptide repeat proteins (DPRs) generated from repeat-associated non-ATG (RAN) translation. Each theory has provided various signaling pathways that potentially participate in the disease progression. Dysregulation of the immune system, particularly glial cell dysfunction (mainly microglia and astrocytes), is demonstrated to play a pivotal role in both loss and gain of function theories of pathogenesis. In this review, we discuss the pathogenic roles of glial cells in ALS/FTD as evidenced by pre-clinical and clinical studies showing the presence of gliosis in ALS/FTD, pathologic hallmarks in glial cells, including TAR DNA-binding protein 43 (TDP-43) and p62 aggregates, and toxicity of glial cells. A better understanding of these pathways can provide new insights into the development of therapies targeting glial cell abnormalities in ALS/FTD.
Topics: Amyotrophic Lateral Sclerosis; C9orf72 Protein; Frontotemporal Dementia; Humans; Inflammation; Mutation; Neuroglia
PubMed: 33525344
DOI: 10.3390/cells10020249 -
Muscle & Nerve Feb 2022The Midwest has the highest regional prevalence of self-reported amyotrophic lateral sclerosis (ALS) in the United States, but with limited epidemiological studies. We...
INTRODUCTION/AIMS
The Midwest has the highest regional prevalence of self-reported amyotrophic lateral sclerosis (ALS) in the United States, but with limited epidemiological studies. We aimed to explore the characteristics of patients with ALS in the Midwest.
METHODS
This was a retrospective cohort study of participants with ALS deceased between January, 2010, and September, 2020, registered with the ALS Association Mid-America Chapter. Demographics and clinical variables included gender, race/ethnicity, military status, site of onset, interventions (gastrostomy, non-invasive ventilation, tracheostomy), and visits to ALS Association-registered clinics. Disease characteristics were compared to the National ALS Registry, and survival analysis was performed followed by sample augmentation with historical data to estimate survival with hypothetical censoring.
RESULTS
The database included 1447 participants with a mean age at diagnosis of 65.7 ± 11.9 y (>60 y at diagnosis: 72%). The median survival from symptom onset was 28.0 mo (95% confidence limit: 26.3, 29.7); sample augmentation increased this to 41.0 mo (38.5, 43.5). Bulbar onset disease and older age at diagnosis were associated with shorter survival. Participants not followed in ALS-Association registered clinics were more frequently male, had familial onset and tracheostomy. Veterans (N = 298) were older at diagnosis but had similar survival after adjustment for age.
DISCUSSIONS
Our cohort had an older age at onset and more frequent bulbar onset than the National ALS Registry, perhaps reflecting ascertainment biases in each registry. Prospective cohort studies with more clinical and functional data are needed to better characterize ALS in Midwest, veterans, and non-clinic populations, and to optimize care.
Topics: Amyotrophic Lateral Sclerosis; Ethnicity; Humans; Male; Prognosis; Prospective Studies; Retrospective Studies; United States
PubMed: 34708421
DOI: 10.1002/mus.27450 -
Nutrients Jun 2021Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects motor neurons, leading to a relentless paralysis of skeletal... (Review)
Review
Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects motor neurons, leading to a relentless paralysis of skeletal muscles and eventual respiratory failure. Although a small percentage of patients may have a longer survival time (up to 10 years), in most cases, the median survival time is from 20 to 48 months. The pathogenesis and risk factors for ALS are still unclear: among the various aspects taken into consideration, metabolic abnormalities and nutritional factors have been the focus of recent interests. Although there are no consistent findings regarding prior type-2 diabetes, hypercholesterolemia and ALS incidence, abnormalities in lipid and glucose metabolism may be linked to disease progression, leading to a relatively longer survival (probably as a result of counteract malnutrition and cachexia in the advanced stages of the disease). Among potential dietary risk factors, a higher risk of ALS has been associated with an increased intake of glutamate, while the consumption of antioxidant and anti-inflammatory compounds, such as vitamin E, n-3 polyunsaturated fatty acids, and carotenoids, has been related to lower incidence. Poor nutritional status and weight loss in ALS resulting from poor oral intake, progressive muscle atrophy, and the potential hypermetabolic state have been associated with rapid disease progression. It seems important to routinely perform a nutritional assessment of ALS patients at the earliest referral: weight maintenance (if adequate) or gain (if underweight) is suggested from the scientific literature; evidence of improved diet quality (in terms of nutrients and limits for pro-inflammatory dietary factors) and glucose and lipid control is yet to be confirmed, but it is advised. Further research is warranted to better understand the role of nutrition and the underlying metabolic abnormalities in ALS, and their contribution to the pathogenic mechanisms leading to ALS initiation and progression.
Topics: Amyotrophic Lateral Sclerosis; Body Mass Index; Diet; Humans; Malnutrition; Nutritional Status; Risk Factors
PubMed: 34209133
DOI: 10.3390/nu13072273 -
Brain and Behavior Mar 2022Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting cortical and spinal motor neurons. There is a lack of optimal biomarkers to... (Review)
Review
INTRODUCTION
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting cortical and spinal motor neurons. There is a lack of optimal biomarkers to diagnose and prognosticate the ALS patients. C-reactive protein (CRP), an inflammatory marker, has shown promising results in ALS patients.
MATERIALS AND METHODS
PubMed, Embase, and Google Scholar databases were searched from 2000 to June 1, 2021 for suitable studies showing the relationship between CRP and ALS. The concentration of CRP levels was assessed between ALS patients and controls. Further, end outcomes like ALS functional rating scale (ALSFRS-R), survival status, and mortality risks were assessed in relation to CRP levels.
RESULTS
Eleven studies including five case-control, five cohorts, and one randomized control study were assessed. There were 2785 ALS patients and 3446 healthy controls. A significant increment in CRP levels among ALS patients in comparison with healthy controls were seen in most of the studies. ALSFRS-R and disease progression were found to be significantly correlated with CRP levels. Overall accuracy of CRP in CSF was 62% described in a single study.
CONCLUSION
Although CRP has shown promise as a prognostic biomarker, extensive cohort studies are required to assess its prognostic value and accuracy in diagnosing ALS taking into account the confounding factors.
Topics: Amyotrophic Lateral Sclerosis; Biomarkers; C-Reactive Protein; Disease Progression; Humans; Neurodegenerative Diseases
PubMed: 35201675
DOI: 10.1002/brb3.2532 -
Journal of Medical Genetics Feb 2024Amyotrophic lateral sclerosis overlaps aetiologically and genetically with frontotemporal dementia and occurs in both familial and apparently sporadic forms. The most...
BACKGROUND
Amyotrophic lateral sclerosis overlaps aetiologically and genetically with frontotemporal dementia and occurs in both familial and apparently sporadic forms. The most commonly implicated genes are , , and . Penetrance of disease-causing variants in these genes is known to be incomplete, but has not been well studied at population level.
OBJECTIVE
We sought to determine the population-level penetrance of pathogenic and likely pathogenic variants in genes commonly causing amyotrophic lateral sclerosis.
METHODS
Published epidemiological data for amyotrophic lateral sclerosis and frontotemporal dementia were used to calculate expected frequencies of disease-causing variants per gene at population level. Variant data from gnomAD and ClinVar databases were used to ascertain observed numbers of disease-causing variants and to estimate population-level penetrance per gene. Data for were obtained from the published literature.
RESULTS
Maximum population penetrance for either amyotrophic lateral sclerosis or frontotemporal dementia was found to be 33% for (95% CI (20.9 to 53.2)), 54% for (95% CI (32.7 to 88.6)), 38% for (95% CI (21.1 to 69.8)) and 19% for (95% CI (13.0 to 28.4)).
CONCLUSION
Population-level penetrance of amyotrophic lateral sclerosis disease genes is reduced. This finding has implications for the genetic testing and counselling of affected individuals and their unaffected relatives.
Topics: Humans; Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; C9orf72 Protein; Penetrance; Superoxide Dismutase-1
PubMed: 38123999
DOI: 10.1136/jmg-2023-109580 -
Genes Mar 2022Amyotrophic lateral sclerosis (ALS) is the most common type of motor neuron disease whose causes are unclear. The first ALS gene associated with the autosomal dominant...
Amyotrophic lateral sclerosis (ALS) is the most common type of motor neuron disease whose causes are unclear. The first ALS gene associated with the autosomal dominant form of the disease was . This gene has a high rate of rare variants, and an appropriate classification is essential for a correct ALS diagnosis. In this study, we re-evaluated the classification of all previously reported variants ( = 202) from ALSoD, project MinE, and in-house databases by applying the ACMG-AMP criteria to ALS. New bioinformatics analysis, frequency rating, and a thorough search for functional studies were performed. We also proposed adjusting criteria strength describing how to apply them to variants. Most of the previously reported variants have been reclassified as likely pathogenic and pathogenic based on the modified weight of the PS3 criterion, highlighting how in vivo or in vitro functional studies are determining their interpretation and classification. Furthermore, this study reveals the concordance and discordance of annotations between open databases, indicating the need for expert review to adapt the study of variants to a specific disease. Indeed, in complex diseases, such as ALS, the oligogenic inheritance, the presence of genes that act as risk factors and the reduced penetration must be considered. Overall, the diagnosis of ALS remains clinical, and improving variant classification could support genetic data as diagnostic criteria.
Topics: Humans; Amyotrophic Lateral Sclerosis; Computational Biology; Multifactorial Inheritance; Superoxide Dismutase-1
PubMed: 35328090
DOI: 10.3390/genes13030537 -
Zoological Research Mar 2023Amyotrophic lateral sclerosis (ALS) is a devastating motoneuron disease, in which lower motoneurons lose control of skeletal muscles. Degeneration of neuromuscular...
Amyotrophic lateral sclerosis (ALS) is a devastating motoneuron disease, in which lower motoneurons lose control of skeletal muscles. Degeneration of neuromuscular junctions (NMJs) occurs at the initial stage of ALS. Dipeptide repeat proteins (DPRs) from G4C2 repeat-associated non-ATG (RAN) translation are known to cause C9orf72-associated ALS (C9-ALS). However, DPR inclusion burdens are weakly correlated with neurodegenerative areas in C9-ALS patients, indicating that DPRs may exert cell non-autonomous effects, in addition to the known intracellular pathological mechanisms. Here, we report that poly-GA, the most abundant form of DPR in C9-ALS, is released from cells. Local administration of poly-GA proteins in peripheral synaptic regions causes muscle weakness and impaired neuromuscular transmission . The NMJ structure cannot be maintained, as evidenced by the fragmentation of postsynaptic acetylcholine receptor (AChR) clusters and distortion of presynaptic nerve terminals. Mechanistic study demonstrated that extracellular poly-GA sequesters soluble Agrin ligands and inhibits Agrin-MuSK signaling. Our findings provide a novel cell non-autonomous mechanism by which poly-GA impairs NMJs in C9-ALS. Thus, targeting NMJs could be an early therapeutic intervention for C9-ALS.
Topics: Animals; Agrin; Amyotrophic Lateral Sclerosis; C9orf72 Protein; Dipeptides; Disease Models, Animal
PubMed: 36799225
DOI: 10.24272/j.issn.2095-8137.2022.356 -
Neurology India 2022
Topics: Amyotrophic Lateral Sclerosis; Electromyography; Humans; Tongue; Tongue Diseases
PubMed: 35532680
DOI: 10.4103/0028-3886.344609