Lateral Sclerosis Research Articles

Motor neuron diseases are not exclusively motor; the SSR paradigm.

Motor Neuron Diseases (MNDs), familial and sporadic, are progressive neurodegenerative disorders that, for an extended period in the past, were considered purely motor disorders. During the course of the disease, however, some patients exhibit concomitant non-motor signs; thus, MNDs are currently perceived as multisystem disorders. Assessment of non-motor symptoms is usually performed clinically, although laboratory tests can also be routinely used to objectively evaluate these symptoms. Sympathetic Skin Response (SSR) is an example of a neurophysiological test that has been used in cases of Amyotrophic Lateral Sclerosis, Spinal Muscular Atrophy, and Monomelic Atrophy, mostly to assess Autonomic Nervous System (ANS) disorders. Dysautonomia affects quality of life and life expectancy, as it is involved in cardiovascular events and incidents of sudden death. SSR abnormalities are present even in subclinical involvement of the ANS in MNDs. In this review, we present published research examining SSR findings in various MNDs, and discuss the correlation of SSR findings with clinical symptoms and disease severity, as well as the potential sources of abnormal findings. The aim of this study is to raise clinician awareness of autonomic dysfunction in MNDs and present the benefits of SSR examination in patient care.

Biophysical and spectroscopical insights into structural modulation of species in the aggregation pathway of superoxide dismutase 1

Superoxide dismutase 1 (SOD1) aggregation is implicated in the development of Amyotrophic Lateral Sclerosis (ALS). Despite knowledge of the role of SOD1 aggregation, the mechanistic understanding remains elusive. Our investigation aimed to unravel the complex steps involved in SOD1 aggregation associated with ALS. Therefore, we probed the aggregation using ThT fluorescence, size-exclusion chromatography, and surface-enhanced Raman spectroscopy (SERS). The removal of metal ions and disulfide bonds resulted in the dimers rapidly first converting to an extended monomers then coming together slowly to form non-native dimers. The rapid onset of oligomerization happens above critical non-native dimer concentration. Structural features of oligomer was obtained through SERS. The kinetic data supported a fragmentation-dominant mechanism for the fibril formation. Quercetin acts as inhibitor by delaying the formation of non-native dimer and soluble oligomers by decreasing the elongation rate. Thus, results provide significant insights into the critical steps in oligomer formation and their structure.

Structural insights into the role of reduced cysteine residues in SOD1 amyloid filament formation

The formation of superoxide dismutase 1 (SOD1) filaments has been implicated in amyotrophic lateral sclerosis (ALS). Although the disulfide bond formed between Cys57 and Cys146 in the active state has been well studied, the role of the reduced cysteine residues, Cys6 and Cys111, in SOD1 filament formation remains unclear. In this study, we investigated the role of reduced cysteine residues by determining and comparing cryoelectron microscopy (cryo-EM) structures of wild-type (WT) and C6A/C111A SOD1 filaments under thiol-based reducing and metal-depriving conditions, starting with protein samples possessing enzymatic activity. The C6A/C111A mutant SOD1 formed filaments more rapidly than the WT protein. The mutant structure had a unique paired-protofilament arrangement, with a smaller filament core than that of the single-protofilament structure observed in WT SOD1. Although the single-protofilament form developed more slowly, cross-seeding experiments demonstrated the predominance of single-protofilament morphology over paired protofilaments, regardless of the presence of the Cys6 and Cys111 mutations. These findings highlight the importance of the number of amino acid residues within the filament core in determining the energy requirements for assembly. Our study provides insights into ALS pathogenesis by elucidating the initiation and propagation of filament formation, which potentially leads to deleterious amyloid filaments.

TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm

Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), in which TDP-43, a nuclear RNA-binding protein, forms cytoplasmic inclusions. Here, we have developed a robust and automated method to assess protein self-assembly in the cytoplasm using microtubules as nanoplatforms. Importantly, we have analyzed specifically the self-assembly of full-length TDP-43 and its mRNA binding that are regulated by the phosphorylation of its self-adhesive C-terminus, which is the recipient of many pathological mutations. We show that C-terminus phosphorylation prevents the recruitment of TDP-43 in mRNA-rich stress granules only under acute stress conditions because of a low affinity for mRNA but not under mild stress conditions. In addition, the self-assembly of the C-terminus is negatively regulated by phosphorylation in the cytoplasm which in turn promotes TDP-43 nuclear import. We anticipate that reducing TDP-43 C-terminus self-assembly in the cytoplasm may be an interesting strategy to reverse TDP-43 nuclear depletion in neurodegenerative diseases.

Roles of C/EBPβ/AEP in Neurodegenerative Diseases.

In recent years, an increasing number of studies have shown that increased activation of aspartic endopeptidases (AEPs) is a common symptom in neurodegenerative diseases (NDDs). AEP cleaves amyloid precursor protein (APP), tau (microtubule-associated protein tau), α- synuclein (α-syn), SET (a 39-KDa phosphoprotein widely expressed in various tissues and localizes predominantly in the nucleus), and TAR DNA-binding protein 43 (TDP-43), and promotes their aggregation, contributing to Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) pathogenesis. Abundant evidence supports the notion that CCAAT/enhancer-binding protein β (C/EBPβ)/AEP may play an important role in NDDs. Developing its small molecule inhibitors is a promising treatment of NDDs. However, current research suggests that the pathophysiological mechanism of the C/EBPβ/AEP pathway is very complex in NDDs. This review summarizes the structure of C/EBPβ and AEP, their major physiological functions, potential pathogenesis, their small molecule inhibitors, and how C/EBPβ/AEP offers a novel pathway for the treatment of NDDs.

A role for mitochondria-ER crosstalk in amyotrophic lateral sclerosis 8 pathogenesis.

Protein aggregates in motoneurons, a pathological hallmark of amyotrophic lateral sclerosis, have been suggested to play a key pathogenetic role. ALS8, characterized by ER-associated inclusions, is caused by a heterozygous mutation in VAPB, which acts at multiple membrane contact sites between the ER and almost all other organelles. The link between protein aggregation and cellular dysfunction is unclear. A yeast model, expressing human mutant and WT-VAPB under the control of the orthologous yeast promoter in haploid and diploid cells, was developed to mimic the disease situation. Inclusion formation was found to be a developmentally regulated process linked to mitochondrial damage that could be attenuated by reducing ER-mitochondrial contacts. The co-expression of the WT protein retarded P56S-VAPB inclusion formation. Importantly, we validated these results in mammalian motoneuron cells. Our findings indicate that (age-related) damage to mitochondria influences the propensity of the mutant VAPB to form aggregates via ER-mitochondrial contacts, initiating a series of events leading to disease progression.

Chaperones as Potential Pharmacological Targets for Treating Protein Aggregation Illness.

The three-dimensional structure of proteins, achieved through the folding of the nascent polypeptide chain in vivo, is largely facilitated by molecular chaperones, which are crucial for determining protein functionality. In addition to aiding in the folding process, chaperones target misfolded proteins for degradation, acting as a quality control system within the cell. Defective protein folding has been implicated in a wide range of clinical conditions, including neurodegenerative and metabolic disorders. It is now well understood that the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and Creutzfeldt-Jakob disease shares a common mechanism: the accumulation of misfolded proteins, which aggregate and become toxic to cells. Among the family of molecular chaperones, Heat Shock Proteins (HSPs) are highly expressed in response to cellular stress and play a pivotal role in preventing protein aggregation. Specific chaperones, particularly HSPs, are now recognized as critical in halting the accumulation and aggregation of misfolded proteins in these conditions. Consequently, these chaperones are increasingly considered promising pharmacological targets for the treatment of protein aggregation-related diseases. This review highlights research exploring the potential roles of specific molecular chaperones in disorders characterized by the accumulation of misfolded proteins.

Exploring the role of Tcells in Alzheimer's and other neurodegenerative diseases: Emerging therapeutic insights from the T Cells in the Brain symposium.

This proceedings article summarizes the inaugural "T Cells in the Brain" symposium held at Columbia University. Experts gathered to explore the role of Tcells in neurodegenerative diseases. Key topics included characterization of antigen-specific immune responses, Tcell receptor (TCR) repertoire, microbial etiology in Alzheimer's disease (AD), and microglia-Tcell crosstalk, with a focus on how Tcells affect neuroinflammation and AD biomarkers like amyloid beta and tau. The symposium also examined immunotherapies for AD, including the Valacyclovir Treatment of Alzheimer's Disease (VALAD) trial, and two clinical trials leveraging regulatory Tcell approaches for multiple sclerosis and amyotrophic lateral sclerosis therapy. Additionally, single-cell RNA/TCR sequencing of Tcells and other immune cells provided insights into immune dynamics in neurodegenerative diseases. This article highlights key findings from the symposium and outlines future research directions to further understand the role of Tcells in neurodegeneration, offering innovative therapeutic approaches for AD and other neurodegenerative diseases. HIGHLIGHTS: Researchers gathered to discuss approaches to study Tcells in brain disorders. New technologies allow high-throughput screening of antigen-specific Tcells. Microbial infections can precede several serious and chronic neurological diseases. Central and peripheral Tcell responses shape neurological disease pathology. Immunotherapy can induce regulatory Tcell responses in neuroinflammatory disorders.

Amyotrophic Lateral Sclerosis and Risk of Common Cancer: Mendelian Randomization Interrogation of Causality and Mediation

Amyotrophic Lateral Sclerosis and Risk of Common Cancer: Mendelian Randomization Interrogation of Causality and Mediation

Rapid iPSC-derived neuromuscular junction model uncovers motor neuron dominance in amyotrophic lateral sclerosis cytopathy

The neuromuscular junction (NMJ) is essential for transmitting signals from motor neurons (MNs) to skeletal muscles (SKMs), and its dysfunction can lead to severe motor disorders. However, our understanding of the NMJ is limited by the absence of accurate human models. Although human induced pluripotent stem cell (iPSC)-derived models have advanced NMJ research, their application is constrained by challenges such as limited differentiation efficiency, lengthy generation times, and cryopreservation difficulties. To overcome these limitations, we developed a rapid human NMJ model using cryopreserved MNs and SKMs derived from iPSCs. Within 12 days of coculture, we successfully recreated NMJ-specific connectivity that closely mirrors in vivo synapse formation. Using this model, we investigated amyotrophic lateral sclerosis (ALS) and replicated ALS-specific NMJ cytopathies with SOD1 mutant and corrected isogenic iPSC lines. Quantitative analysis of 3D confocal microscopy images revealed a critical role of MNs in initiating ALS-related NMJ cytopathies, characterized by alterations in the volume, number, intensity, and distribution of acetylcholine receptors, ultimately leading to impaired muscle contractions. Our rapid and precise in vitro NMJ model offers significant potential for advancing research on NMJ physiology and pathology, as well as for developing treatments for NMJ-related diseases.

Factors Reducing Pressure Ulcer Risk and the Importance of Care in ALS Patients: A Comprehensive Review

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by muscle atrophy, weakness, and loss of motor function. ALS patients are often bedridden for extended periods, increasing their risk of pressure ulcers. However, clinical data suggests that the incidence of pressure ulcers in ALS patients is lower compared to other bedridden patients. This review analyzes the factors contributing to reduced pressure ulcer risk in ALS patients, focusing on "pressure redistribution due to muscle atrophy," "stabilized postures caused by joint contractures," and "comprehensive care provided by caregivers." Additionally, this paper discusses a comprehensive approach to pressure ulcer prevention, including nutritional management, skincare, pressure redistribution techniques, and advanced technologies. Challenges in pressure ulcer prevention and the importance of ALS-specific care are also emphasized.

The Role of Amphibian AMPs Against Oxidative Stress and Related Diseases

Amphibians use their skin as an effective defense mechanism against predators and microorganisms. Specialized glands produce antimicrobial peptides (AMPs) that possess antioxidant properties, effectively reducing reactive oxygen species (ROS) levels. These peptides are promising candidates for treating diseases associated with oxidative stress (OS) and redox imbalance, including neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), as well as age-related conditions, like cardiovascular diseases and cancer. This review highlights the multifaceted roles of AMPs and antioxidant peptides (AOPs) in amphibians, emphasizing their protective capabilities against oxidative damage. They scavenge ROS, activate antioxidant enzyme systems, and inhibit cellular damage. AOPs often share structural characteristics with AMPs, suggesting a potential evolutionary connection and similar biosynthetic pathways. Peptides such as brevinin-1FL and Cath-KP demonstrate neuroprotective effects, indicating their therapeutic potential in managing oxidative stress-related diseases. The antioxidant properties of amphibian-derived peptides pave the way for novel therapeutic developments. However, a deeper understanding of the molecular mechanisms underlying these peptides and their interactions with oxidative stress is essential to addressing ROS-related diseases and advancing therapeutic strategies in clinical practice.

The Role of Gut Microbiota-derived Short Chain Fatty Acids in Amyotrophic Lateral Sclerosis

The Role of Gut Microbiota-derived Short Chain Fatty Acids in Amyotrophic Lateral Sclerosis

Deep learning analyses of splicing variants identify the link of PCP4 with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease, with most sporadic cases lacking clear genetic causes. Abnormal pre-mRNA splicing is a fundamental mechanism in neurodegenerative diseases. For example, TAR DNA-binding protein 43 (TDP-43) loss-of-function (LOF) causes widespread RNA mis-splicing events in ALS. Additionally, splicing mutations are major contributors to neurological disorders. However, the role of intronic variants driving RNA mis-splicing in ALS remains poorly understood. To address this, we developed Spliformer to predict RNA splicing. Spliformer is a transformer-based deep learning model trained and tested on splicing events from the GENCODE database, as well as RNA-seq data from blood and central nervous system tissues. We benchmarked Spliformer against SpliceAI and Pangolin using testing datasets and paired whole-genome sequencing (WGS) with RNA-seq data. We further developed the Spliformer-motif model to identify splicing regulatory motifs. We analyzed Clinvar dataset to identify the link of splicing variants with disease pathogenicity. Additionally, we analyzed WGS data of ALS patients and controls to identify common intronic splicing variants linked to ALS risk or disease phenotypes. We also profiled rare intronic splicing variants in ALS patients to identify known or novel ALS-associated genes. Minigene assays were employed to validate candidate splicing variants. Finally, we measured spine density in neurons with a specific gene knockdown or those expressing a TDP-43 disease-causing mutant. Spliformer accurately predicts the possibilities of a nucleotide within a pre-mRNA sequence being a splice donor, acceptor, or neither. Spliformer outperformed SpliceAI and Pangolin in both speed and accuracy in tested splicing events and/or paired WGS/RNA-seq data. Spliformer-motif successfully identified canonical and novel splicing regulatory motifs. In Clinvar dataset, splicing variants are highly related to disease pathogenicity. Genome-wide analyses of common intronic splicing variants nominated one variant linked to ALS progression. Deep learning analyses of WGS data from 1,370 ALS patients revealed rare splicing variants in reported ALS genes (such as PTPRN2 and CFAP410, validated through minigene assays and RNA-seq), and TDP-43 LOF related RNA mis-splicing genes (such as PTPRD). Further genetic analysis and minigene assays nominated PCP4 and TMEM63A as ALS-associated genes. Functional assays demonstrated that PCP4 is critical for maintaining spine density and can rescue spine loss in neurons expressing a disease-causing TDP-43 mutant. In summary, we developed Spliformer and Spliformer-motif that accurately predict and interpret pre-mRNA splicing. Our findings highlight an intronic genetic mechanism driving RNA mis-splicing in ALS and nominate PCP4 as an ALS-associated gene.

Genomic and Transcriptomic Approaches Advance the Diagnosis and Prognosis of Neurodegenerative Diseases

Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), represent a growing societal challenge due to their irreversible progression and significant impact on patients, caregivers, and healthcare systems. Despite advances in clinical and imaging-based diagnostics, these diseases are often detected at advanced stages, limiting the effectiveness of therapeutic interventions. Recent breakthroughs in genomic and transcriptomic technologies, including whole-genome sequencing, single-cell RNA sequencing (scRNA-seq), and CRISPR-based screens, have revolutionized the field, offering new avenues for early diagnosis and personalized prognosis. Genomic approaches have elucidated disease-specific genetic risk factors and molecular pathways, while transcriptomic studies have identified stage-specific biomarkers that correlate with disease progression and severity. Furthermore, genome-wide association studies (GWAS), polygenic risk scores (PRS), and spatial transcriptomics are enabling the stratification of patients based on their risk profiles and prognostic trajectories. Advances in functional genomics have uncovered actionable targets, such as ATXN2 in ALS and TREM2 in AD, paving the way for tailored therapeutic strategies. Despite these achievements, challenges remain in translating genomic discoveries into clinical practice due to disease heterogeneity and the complexity of neurodegenerative pathophysiology. Future integration of genetic technologies holds promise for transforming diagnostic and prognostic paradigms, offering hope for improved patient outcomes and precision medicine approaches.

Validation of the Caregiver Analysis of Reported Experiences with Swallowing Disorders (CARES) Screening Tool for Neurodegenerative Disease.

Swallowing difficulties have a substantial impact on the burden experienced by care partners of individuals with neurodegenerative disease. Given this, there is a clear need to easily identify and quantify the unique aspects of swallowing-related burden. The purpose of this study was to establish the validity and reliability of the Caregiver Analysis of Reported Experiences with Swallowing Disorders (CARES) screening tool in care partners of individuals with neurodegenerative disease. Survey data were collected from an international sample of 212 individuals caring for family members with amyotrophic lateral sclerosis (n = 49), dementia (n = 110), or Parkinson's disease (n = 53). Respondents completed the CARES, Eating Assessment Tool-10, International Dysphagia Diet Standardisation Initiative-Functional Diet Scale, and Zarit Burden Interview. Reliability and validity of the CARES were evaluated via internal consistency alpha coefficients, Spearman's rho correlations, and logistic regression analyses with receiver operating characteristic (ROC) curves. CARES scores demonstrated excellent internal consistency (α = .90-.95) and high test-retest reliability (r = .86-.91). The CARES was found to be valid, as increased swallowing-related burden was associated with increased severity of swallowing difficulties (r = .79 to .84), diet restrictiveness (r = -.50 to -.54), and general caregiver burden (r = .36 to .40). The CARES had excellent discrimination between care partners with and without self-reported swallowing-related burden, with a score of ≥ 4 suggesting a heightened risk of experiencing this burden. Results establish the CARES as a valid and reliable screening tool that can detect burden related to swallowing difficulties among care partners of individuals living with neurodegenerative disease (score ≥ 4). Clinical implementation of the CARES requires the concerted efforts of the larger multidisciplinary team who can collaboratively identify the presence of burden and target the multifaceted sources of burden that a care partner may be experiencing.

'It’s become a theatre’: relational experiences of family carers and persons living with Amyotrophic lateral sclerosis (ALS) after cognitive impairment emerges

Background Amyotrophic lateral sclerosis (ALS) can lead to emotional and psychological distress between persons with ALS and their family carers. Many persons with ALS develop cognitive impairment, which limits their ability to process complex information, interact, and communicate. This cognitive decline adds to caregiver burden. Few studies have explored interpersonal relations between persons with ALS and their family carers. Aim To better understand how ALS-associated cognitive impairment influences close relations. Methods Individual semi-structured in-depth, interviews were conducted once, with four persons with ALS and four family carers. Reflexive thematic analysis was used. Results Increased distance of close relations was identified as the overarching theme. Differences and similarities within the data were identified according to the two main themes. The first main theme, Everyday life together but apart: a demanding role to play, was structured according to three subthemes: Keeping the façade of civility, Demanding daily interaction and communication, and Taken for granted changes in everyday roles. The second main theme, Coping with a lost future, was structured according to the two subthemes, Striving to live in the normal present, and Holding on to self. Conclusions and significance Cognitive impairment following ALS can lead to increased relational distance between persons with ALS and their family carers. To ease their burden, professionals should recognize person with ALS’ and family carers’ relational issues and grief at an early stage. Focusing on their occupational identity and valued occupations that are still-accessible may help persons with ALS and family carers regain meaning in everyday life.

Single-cell RNA sequencing highlights the role of distinct natural killer subsets in sporadic amyotrophic lateral sclerosis

BackgroundNeuroinflammation plays a major role in amyotrophic lateral sclerosis (ALS), and cumulative evidence suggests that systemic inflammation and the infiltration of immune cells into the brain contribute to this process. However, no study has investigated the role of peripheral blood immune cells in ALS pathophysiology using single-cell RNA sequencing (scRNAseq).MethodsWe aimed to characterize immune cells from blood and identify ALS-related immune alterations at single-cell resolution. For this purpose, peripheral blood mononuclear cells (PBMC) were isolated from 14 ALS patients and 14 cognitively unimpaired healthy individuals (HC), matched by age and gender, and cryopreserved until library preparation and scRNAseq. We analyzed differences in the proportions of PBMC, gene expression, and cell-cell communication patterns between ALS patients and HC, as well as their association with plasma neurofilament light (NfL) concentrations, a surrogate biomarker for neurodegeneration. Flow cytometry was used to validate alterations in cell type proportions.ResultsWe identified the expansion of CD56dim natural killer (NK) cells in ALS (fold change = 2; adj. p-value = 0.0051), mainly driven by a specific subpopulation, NK_2 cells (fold change = 3.12; adj. p-value = 0.0001), which represent a mature and cytotoxic CD56dim NK subset. Our results revealed extensive gene expression alterations in NK_2 cells, pointing towards the activation of immune response (adj. p-value = 9.2 × 10− 11) and the regulation of lymphocyte proliferation (adj. p-value = 6.46 × 10− 6). We also identified gene expression changes in other immune cells, such as classical monocytes, and distinct CD8 + effector memory T cells which suggested enhanced antigen presentation via major histocompatibility class-II (adj. p-value = 1.23 × 10− 8) in ALS. The inference of cell-cell communication patterns demonstrated that the interaction between HLA-E and CD94:NKG2C from different lymphocytes to NK_2 cells is unique to ALS blood compared to HC. Finally, regression analysis revealed that the proportion of CD56bright NK cells along with the ALSFRS-r, disease duration, and gender, explained up to 76.4% of the variance in plasma NfL levels.ConclusionOur results reveal a signature of relevant changes occurring in peripheral blood immune cells in ALS and underscore alterations in the proportion, gene expression, and signaling patterns of a cytotoxic and terminally differentiated CD56dim NK subpopulation (NK_2), as well as a possible role of CD56bright NK cells in neurodegeneration.

Thoracic Electric Impedance Tomography Detects Lung Volume Changes in Amyotrophic Lateral Sclerosis.

Spirometry is the conventional means to measure lung function in amyotrophic lateral sclerosis (ALS), but is dependent on patient effort and bulbar strength. We aimed to use electric impedance tomography (EIT), an emerging non-invasive imaging modality, to measure dynamic lung volume changes. Twenty-one patients with ALS underwent sitting and supine spirometry for forced vital capacity (FVC), and sitting and supine EIT. There were 13 patients in the high FVC group (FVC ≥ 80% predicted) and 8 in the low FVC group (FVC < 80% predicted). Additional demographic and clinical data were collected from clinical records. Only the low FVC group had significant loss of lung volumes in the supine position (R2 = 0.89 and p < 0.001). The supine volume loss measurement at 10 min correlated with sitting (r2 = 0.47) and supine FVC (r2 = 0.36), maximum inspiratory (r2 = -0.44) and expiratory pressures (r2 = 0.36) (MIP and MEP), and the ALS Functional Rating Scale-Revised (ALSFRS-R) dyspnea subscore (r2 = 0.36). EIT is an emerging alternative to existing measures of lung function in ALS, but without need for patient effort or bulbar strength. Significant losses in lung volume are seen on supine compared to upright position in patients with respiratory dysfunction. Further study is needed to determine relationships to existing clinical measures.

Patients’ choices regarding ventilatory support affect opioid use in amyotrophic lateral sclerosis

Objective To investigate the impact of different ventilatory support options on opioid use among patients with amyotrophic lateral sclerosis (ALS). Methods We retrospectively reviewed 889 consecutive patients with ALS and enrolled 399 eligible patients. All patients were followed until death or tracheostomy. Clinical characteristics of patients and the timing of initial opioid administration were evaluated. Patients were categorized into four subgroups: (1) 160 patients who never used a ventilator, (2) 120 patients who used only noninvasive ventilation (NIV), (3) 61 patients who transitioned from NIV to tracheostomy and invasive ventilation (TIV), and (4) 58 patients who underwent TIV without prior NIV. We compared the prevalence of opioid use across these groups and assessed its relationship with ventilatory support options using multivariate logistic analysis. Results A total of 130 patients (32.6%) used opioids. The number of patients who used opioids in each group was as follows: 55 (34.4%) in Group 1, 69 (57.5%) in Group 2, 5 (8.2%) in Group 3, and 1 (1.7%) in Group 4 (p < 0.0001). Multivariate logistic analysis revealed that, compared to Group 1, the use of NIV only was positively associated with opioid use (p = 0.002). In contrast, transitioning from NIV to TIV (Group 3) and using TIV only (Group 4) were negatively associated with opioid use (p = 0.0001 and 0.001, respectively). Conclusions The choice of ventilatory support significantly influences opioid use in patients with ALS. Patients who opted against TIV required opioids to relieve distress more commonly than those who chose TIV.