筋萎縮性側索硬化症

BACKGROUND: Dyspnoea is a prevalent, debilitating symptom in advanced life-limiting illnesses. While opioids and non-pharmacological measures remain foundational, refractory breathlessness presents a major palliative challenge. OBJECTIVES: To critically appraise the evidence regarding patient selection, comparative tolerability, adverse effects and ethical considerations of non-invasive ventilation (NIV) and high-flow nasal therapy (HFNT) in palliative care. METHODS: A comprehensive narrative review of literature from PubMed, Embase and Cochrane Library (from inception to June 2026) and major clinical guidelines was conducted. RESULTS: NIV is best supported in hypercapnic respiratory failure (PaCO >45 mm Hg), showing benefits in chronic obstructive pulmonary disease exacerbations, pulmonary oedema and amyotrophic lateral sclerosis (ALS). In advanced cancer, NIV reduces dyspnoea primarily in hypercapnic patients but mask discomfort and communication barriers limit tolerability. Conversely, HFNT has emerged as a superiorly tolerated option in hypoxemic failure-particularly in end-stage interstitial lung disease (ILD) and advanced cancer-providing significant dyspnoea relief while preserving oral intake and verbal communication until the end of life. Time-limited trials (<1 hour for NIV; 2 hours for HFNT) help identify early responders. Ethical challenges include potential overtreatment and support withdrawal complexities. CONCLUSIONS: Respiratory support selection should be guided by respiratory physiology (hypercapnic vs hypoxemic), explicit goals of care and tolerability. NIV remains optimal for hypercapnic failure, whereas HFNT offers superior comfort and preserves communication in hypoxaemic patients. Robust randomised trials are needed.

Epidemiological studies show an inverse relationship between metabolic disorders and two major neurodegenerative diseases, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Obesity, type 2 diabetes (T2DM), and reduced physical activity increase AD risk, whereas in ALS cardiometabolic factors, particularly T2DM, show inverse, age-dependent associations with disease risk. This review integrates epidemiological, clinical, and experimental evidence to suggest that cell-type-specific energy metabolism underlies these contrasting risk profiles. Neurons and skeletal muscle differ in metabolic organization, substrate use, and redox capacity. Neurons rely mainly on glucose and lactate and have limited fatty acid oxidation, making them vulnerable to lipid overload, insulin resistance, and oxidative stress, hallmarks of AD. In contrast, skeletal muscle is metabolically flexible, efficiently oxidizes fatty acids, and has strong antioxidant defenses, which may protect against ALS. These cell-type-specific metabolic profiles are proposed to causally shape disease susceptibility: neuronal lipid overload and impaired redox homeostasis promote amyloid and tau pathology in AD, whereas preserved muscle fatty acid oxidation and antioxidant capacity support neuromuscular junction stability and delay motor neuron degeneration in ALS. Hypermetabolism, hypothalamic dysfunction, glial-neuronal coupling and lactate shuttling may further shape disease susceptibility. Overall, these patterns likely reflect distinct cellular responses to metabolic stress.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and ultimately fatal neurodegenerative disorder involving multiple systems, with motor neuron degeneration as its primary feature. This disease can be classified into sporadic and familial types. Genes such as SOD1, C9orf72, FUS, and TDP-43 have been identified as the main causative genes for familial ALS. Multiple bioinformatics tools combined with an experimental verification strategy have helped in understanding the association of a selective autophagy pathway called aggrephagy with the disease. RESULTS: The transcriptome data of spinal cord tissue from SOD1-G93A mice was obtained from the Gene Expression Omnibus (GEO) database. Based on the GSE281064 dataset, we investigated aggrephagy-related transcriptional alterations in the SOD1-G93A mouse model of ALS. After comparison with the aggrephagy-related genes (AGGRGs) set included in the GeneCards database, 49 candidate genes closely related to the autophagy process were obtained. Functional enrichment analysis showed these genes participate in extracellular matrix remodeling, hyaluronic acid and glycosaminoglycan metabolism, tumor necrosis factor regulation, and lysosomal function, indicating central roles in inflammation, apoptosis, and metabolic disorders. Based on feature selection algorithms, this study employed machine learning methods such as random forest (RF), extreme gradient boosting (XGBoost), and Boruta to conduct multi-angle screening of candidate genes. The intersection of the results ultimately identified three key genes: Ctsb, Kif11, and S100a6. CONCLUSIONS: In both the training data and external validation data, Ctsb and S100a6 showed significant upregulation and demonstrated excellent discriminatory capabilities. The nomogram constructed based on Ctsb and S100a6 expression showed potential for distinguishing SOD1-G93A model samples from nontransgenic controls. The predicted probability demonstrated the potential of these two as candidate biomarkers. Meanwhile, further validation is needed in larger independent population cohorts in the future. The SOD1-G93A mouse model and SOD1-G93A-expressing NSC34 cell model showed expression patterns of Ctsb and S100a6 consistent with the bioinformatics findings. Through S100a6 overexpression and knockdown experiments in an NSC34 motor neuron-like ALS model, we found that S100a6 impaired autophagy and promoted SOD1 aggregation. These findings further validate its potential as a biomarker and provide new insights into the pathogenesis of ALS.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration and eventual respiratory failure, often first manifesting during sleep. Timely detection of nocturnal respiratory impairment is critical for initiating noninvasive ventilation (NIV), one of the few therapies proven to improve survival. Although polysomnography (PSG) is the reference standard, it is not always readily available in clinical practice. CASE PRESENTATION: We describe a 62-year-old man with spinal-onset ALS who underwent home sleep apnea testing (HSAT) for respiratory assessment. Although standard metrics were within normal limits, careful manual analysis of respiratory signals revealed diaphragmatic dysfunction through position-dependent desaturation and paradoxical breathing. NIV was initiated, resulting in improvements in sleep quality and daytime functioning. CONCLUSIONS: This case illustrates the value of HSAT as a pragmatic and accessible tool for early detection of respiratory involvement in ALS, particularly when combined with detailed waveform inspection in setting where PSG is unavailable. Additionally, it emphasizes the importance of individualized NIV titration and interface optimization to ensure adherence and therapeutic benefit.

Canine degenerative myelopathy (DM) is associated with a missense mutation in the SOD1 gene (c.118G>A), which results in the E40K amino acid substitution and promotes protein aggregation mechanisms similar to those described in human amyotrophic lateral sclerosis. The present study estimated the frequency of the SOD1:c.118G>A mutation in the Cimarrón Uruguayo dog and evaluated its structural and population implications. A total of 82 dogs were genotyped. The mutant allele was detected at a frequency within the range of common variants (q = 0.177), and genotype distribution did not deviate from Hardy-Weinberg equilibrium. Wright-Fisher simulations showed that stochastic processes alone may substantially influence allele-frequency trajectories over time. Additionally, a high-resolution melting (HRM) assay was optimized and enabled clear discrimination of the three genotypes, supporting its use as a rapid genotyping approach. Sanger sequencing of SOD1 exons 2-5 was performed in a subset of individuals to identify additional coding variants. Sequencing revealed no additional non-synonymous variants, except for a synonymous substitution in exon 4. Structural inspection indicated that the E40K substitution does not alter the local hydrogen-bonding pattern but produces a charge inversion that modifies the electrostatic environment surrounding residues 40 and 91. These findings support the hypothesis that electrostatic alterations in this region may contribute to an increased aggregation propensity of mutant SOD1 and provide new insights into the molecular and population context of this mutation in the Cimarrón Uruguayo breed.