Amyotrophic lateral sclerosis & frontotemporal degeneration最新文献

{"title":"Predictors in late-stage amyotrophic lateral sclerosis.","authors":"Maria Fortuna Baptista, Marta Gromicho, Inês Alves, Miguel Oliveira Santos, Mamede De Carvalho","doi":"10.1080/21678421.2025.2536647","DOIUrl":"https://doi.org/10.1080/21678421.2025.2536647","url":null,"abstract":"<p><p><i>Aim</i>: Prognostic factors in amyotrophic lateral sclerosis (ALS) are defined by clinical features and progression rate at first observation or over follow-up. The prognostic factors associated with late-stage disease are uncertain. We sought to identify factors predicting survival in advanced ALS. <i>Methods</i>: We analyzed data collected from patients followed at our clinic who progressed to late-stage ALS, defined as ALS Functional Rating Scale Revised (ALSFRS-R) ≤ 24 (group A), patients followed for at least 6 months thereafter constituted group B. We studied demographic and clinical variables, including phenotype, sex, age, diagnostic delay (disease duration at diagnosis), noninvasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), early (from diagnosis to ALSFRS-R ≤ 24) and thereafter late functional progression rates (ΔFS), and survival. Multivariable analysis with Cox regression was performed to ascertain predictive factors for survival in late-stage. <i>Results</i>: Group A included 704 patients and group B 260 patients. For group A, predictors associated with shorter survival were bulbar-onset (<i>p</i> = 0.03), and ΔFS at diagnosis and until late stage (<i>p</i> < 0.001). For group B, predictors associated with shorter survival were older age (<i>p</i> = 0.005), bulbar-onset (<i>p</i> = 0.02), shorter diagnostic delay (<i>p</i> < 0.001), ΔFS until late stage (<i>p</i> < 0.02), and late stage ΔFS (<i>p</i> < 0.001), but not ΔFS at diagnosis. <i>Discussion</i>: Similar to the general ALS population, survival in late-stage patients is predicted by age, region of onset, and diagnostic delay. Although ΔFS in later stages is prognostic, the initial ΔFS at diagnosis is not. Therefore, continuous monitoring of functional decline remains crucial for patients already in advanced stages.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":"26 7-8","pages":"659-663"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145310224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALSUntangled #80: ISRIB (Integrated stress response InhiBitor).","authors":"Javier Mascias Cadavid, Anna Mena Bravo, Paul Barkhaus, Benjamin Barnes, Michael Benatar, Sarah Breevoort, Andrew Brown, Gregory T Carter, Jesse Crayle, Juliette Foucher, Terry Heiman-Patterson, Esther Hobson, Carlayne Jackson, Sartaj Jhooty, Elise Mallon, Christopher Mcdermott, Gary Pattee, Kaitlyn Pierce, Erik Pioro, Dylan Ratner, Michael Rivner, Elia Tito, Paul Wicks, Richard Bedlack","doi":"10.1080/21678421.2025.2542919","DOIUrl":"10.1080/21678421.2025.2542919","url":null,"abstract":"<p><p>ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we assess ISRIB, a molecule that attenuates the integrated stress response (ISR). The ISR is an intracellular signaling network through which cells normally respond to stress, but in ALS it appears to be overactive, leading to the formation of \"stress granules\" which some but not all investigators believe can triggerapoptotic cell death. ISRIB can attenuate the formation of these stress granules while still allowing parts of protein synthesis to continue. Pre-clinical data demonstrate that ISRIB is beneficial in cell models of ALS. A small number of patients taking ISRIB in Spain report symptomatic improvements with little or no side effects, though we have not been able to independently verify these benefits. There are no clinical trials evaluating ISRIB in any condition and questions about its solubility and bioavailability have arisen. Currently, we do not have enough evidence to endorse the use of ISRIB for treating ALS. We support further research in disease models and clinical trials to study pharmacokinetics, safety and efficacy.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":" ","pages":"821-824"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"\"The DESCRIBE-ALS-FTD study: a prospective multicenter observational study of the ALS-FTD spectrum\".","authors":"Andreas Hermann, Johannes Prudlo, Elisabeth Kasper, Matthis Synofzik, Oliver Peters, Josef Priller, Elisabeth Dinter, Jens Wiltfang, Inga Zerr, Agnes Flöel, Katharina Bürger, Günter U Höglinger, Johannes Levin, Emrah Düzel, Stefan Teipel, Lukas Beichert, Frederic Brosseron, Michael Wagner, Ingo Frommann, Alfredo Ramirez, Renat Yakupov, Matthias Schmid, Paul Lingor, Christian Haass, Annika Spottke, René Günther, Patrick Weydt, Manuela Neumann, Anja Schneider","doi":"10.1080/21678421.2025.2509617","DOIUrl":"10.1080/21678421.2025.2509617","url":null,"abstract":"<p><p><i>Background:</i> Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) exhibit significant clinical, genetic and neuropathological abnormalities, and are regarded as belonging to a common disease spectrum, referred to as the ALS-FTD spectrum disorders. Our understanding of the underlying mechanisms of these diseases has advanced significantly, including molecular neuropathology, genetics and molecular pathophysiology. The heterogeneity of these diseases poses significant challenges to translational research and drug development, particularly in sporadic cases. Consequently, there is an urgent need to improve patient stratification for the successful execution of future clinical trials. <i>Methods/Results:</i> We here describe the study design of the DESCRIBE-ALS/FTD study which aims to address this research gap by undertaking a systematic sampling of patients from the ALS FTD spectrum, encompassing all possible disease variants. The main objective of the study is to systematically document detailed cross-sectional phenotyping and the temporal progression of motor and neuropsychological abnormalities that occur in both ALS and FTD. Additionally, it seeks to systematically correlate these abnormalities with genetics and potentially predictive biomarkers including longitudinal biomaterial sampling, brain imaging and brain banking. Furthermore, first-degree relatives of patients with disease-causing gene variants undergo the same assessments to also sample presymptomatic risk gene carriers. <i>Conclusion:</i> With this prospective registry study we aim to generate datasets which will help researchers identifying different disease traits in people with sporadic and genetic ALS and FTD and to develop biomarkers to identify preclinical and prodromal disease stages.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":" ","pages":"720-728"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physical activity in amyotrophic lateral sclerosis: a systematic review of the methodologies used to assess a possible association.","authors":"Maham Malik, Taha Bhatti, Emma Hodson-Tole, Gladys Onambele-Pearson, Amina Chaouch","doi":"10.1080/21678421.2025.2488298","DOIUrl":"10.1080/21678421.2025.2488298","url":null,"abstract":"<p><p>Growing evidence suggests that strenuous physical activity (PA) may be associated with an increased risk of developing Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease. However, there are inconsistent findings across studies that may reduce our understanding of any potential associations. We propose that these differences may reflect the tools used to record historical PA. We conducted a systematic review evaluating the risk of developing ALS due to PA. The inclusion criteria were met by 22/113 studies, and an association between increasing PA and ALS was found in 15 studies. Studies that found a positive association were more likely to have longer recall periods and convert data into Metabolic Equivalent of Task values. Studies that did not find an association with increasing PA were more likely to use questionnaires with no validity or reliability data. Questionnaires with validity data all showed at least a moderate correlation of PA compared to objective measures, with reliability ranging from poor to good. Study designs included prospective cohort and case-control, which may also contribute to heterogeneity in findings. This work highlights the need for consensus on the type of questionnaire to use to assess potential associations between PA and ALS.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":" ","pages":"605-622"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Participant, site personnel and sponsor perspectives on decentralized trial features in COURAGE-ALS: a randomized clinical trial.","authors":"Stacy A Rudnicki, Paulos Gebrehiwet, Stuart Kupfer, Fady I Malik, Lisa Meng, Tyrell Simkins, Jenny Wei, Andrew A Wolff, Jeremy M Shefner","doi":"10.1080/21678421.2025.2523941","DOIUrl":"10.1080/21678421.2025.2523941","url":null,"abstract":"<p><strong>Objectives: </strong>To describe participant, site personnel (SP) and sponsor perspectives regarding their experiences with a decentralized clinical trial (DCT).</p><p><strong>Methods: </strong>COURAGE-ALS was a 48-week, double-blind, randomized, phase III, hybrid DCT of reldesemtiv versus placebo for ALS. Fifty participants completed semi-structured interviews at Week ∼22; the majority provided feedback on DCT features. Subsequently, a planned interim analysis led to termination of COURAGE-ALS for futility; 486 participants were randomized and dosed. SP completed an online survey focusing on operational aspects of the hybrid design.</p><p><strong>Results: </strong>RVs influenced the decision to pursue the trial in 13/31 participants. Remotely performing forced vital capacity (FVC) was a concern for 17/43 (40%). Survey response rate for SP was 41% (141/344). The trial was viewed as less time/labour for the site versus a traditional design by 52/136 (38%) of SP. Twenty percent (25/125) agreed their participants liked doing remote FVC assessments; 6% (7/109) of SP reported no challenges in obtaining FVC remotely. Technological problems were commonly reported by SP (71/109, 65%). Biospecimen collection and Revised Amyotrophic Lateral Sclerosis Functional Rating Scale done at in-clinic visits (ICVs) and return visits (RVs) had similar completion rates, FVCs were missed more often at RVs than ICVs (completion rates 82% vs. 96%, <i>p</i> < 0.001).</p><p><strong>Conclusions and relevance: </strong>Participants and SP viewed RVs favorably, despite common technical challenges. RV FVC assessments were more likely to be missed. COURAGE-ALS demonstrated that an interventional hybrid DCT is feasible in ALS but limitations remain that will need to be considered when designing future DCTs.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov (NCT04944784).</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":" ","pages":"812-820"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144509787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the contribution of executive functions to language impairment in ALS.","authors":"Barbara Poletti, Edoardo Nicolò Aiello, Beatrice Curti, Silvia Torre, Giulia De Luca, Claudia D'Ambrosio, Claudia Gendarini, Alessandro Cocuzza, Eleonora Colombo, Alessio Maranzano, Federico Verde, Claudia Morelli, Stefano Messina, Alberto Doretti, Alessia Monti, Vincenzo Silani, Nicola Ticozzi","doi":"10.1080/21678421.2025.2529409","DOIUrl":"10.1080/21678421.2025.2529409","url":null,"abstract":"<p><p><i>Objectives:</i> This study aims to unravel the association between language deficits and executive functions in non-demented amyotrophic lateral sclerosis (ALS) patients by means of 1) assessing the executive determinants of language impairment (LI) and 2) simultaneously testing the effects of both executive and language performances on phonemic verbal fluency (PVF) deficits. <i>Methods: N</i> = 299 non-demented ALS patients underwent the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), being also assessed for behavioral/psychiatric and motor-functional features. Two sets of logistic models were run: the first, regressing an impaired vs. unimpaired performance on each ECAS-Language (ECAS-L) tasks based on each task of the ECAS-Executive Functioning (ECAS-EF); the second, regressing an impaired vs. unimpaired performance on each ECAS-Fluency tasks based on both ECAS-L and ECAS-EF tasks. Within these models, demographic, motor-functional, and psychiatric/behavioral measures were covaried for. <i>Results:</i> Defective <i>Naming</i> and <i>Comprehension</i> performances were predicted by lower scores on the <i>Sentence Completion</i> task (<i>p</i> ≤ 0.002), whilst defective <i>Spelling</i> performances by lower <i>Alternation</i> scores (<i>p</i> < 0.001). Defective performances on <i>Verbal fluency - S</i> and <i>Verbal fluency - C</i> tasks were predicted by lower <i>Backward Digit Span</i> and <i>Sentence Completion</i> scores, respectively (<i>p</i> ≤ 0.008). <i>Discussion:</i> In ALS patients, inhibitory and set-shifting abilities majorly contribute to LI, whilst PVF deficits are mostly linked to dysexecutive features.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":" ","pages":"739-747"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toward therapeutic trials in primary lateral sclerosis.","authors":"Erica Scirocco, Matti D Allen, Elisa Giacomelli, Senda Ajroud-Driss, Jinsy Andrews, Sandra Banack, Peter Bede, Michael Benatar, Ken Cheung, Philippe Corcia, Mamede de Carvalho, Lauren Elman, John K Fink, Angela Genge, Orla Hardiman, Matthew Harms, Daragh Heitzman, Grace Jang, Osamu Kano, Matthew C Kiernan, Ikjae Lee, Albert Ludolph, Paul Mehta, Hande Ozdinler, Kourosh Rezania, Paride Schito, Alexander V Sherman, Vincenzo Silani, Eric Sorenson, Martin R Turner, Leonard Van Den Berg, Hiroshi Mitsumoto, Sabrina Paganoni","doi":"10.1080/21678421.2025.2527123","DOIUrl":"10.1080/21678421.2025.2527123","url":null,"abstract":"<p><p>Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder primarily affecting the upper motor neurons. People living with PLS experience progressive physical and communication disability, which typically evolves slowly over several years. In contrast to amyotrophic lateral sclerosis (ALS), life expectancy is anticipated to be normal. Disease-modifying medications are not available and PLS drug development has been challenging. This review considers recent advances and ongoing initiatives aimed at promoting clinical trial readiness for PLS. Ongoing clinical research efforts include patient registries and biorepositories, natural history studies, outcome measure validation, and biomarker development. These international collaborative efforts are essential for developing the first therapeutic trials for people living with PLS.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":" ","pages":"623-630"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of the \"MND-Prism\" smartphone application as a tool for self-management.","authors":"Sally Neville, Laura Ziser, Anjali Henders, Jane Milne, Shyuan T Ngo, Rebecca Packer, Frederik J Steyn","doi":"10.1080/21678421.2025.2511119","DOIUrl":"10.1080/21678421.2025.2511119","url":null,"abstract":"<p><strong>Background: </strong>Motor Neurone Disease (MND) is a progressive neurodegenerative disease requiring complex, multidisciplinary care. Digital tools, including smartphone applications, offer innovative solutions to streamline self-management and care coordination for patients and caregivers. Here we evaluate the usability and value of the MND-Prism smartphone application as a tool for addressing the self-management and organizational needs of people living with MND (plwMND).</p><p><strong>Methods: </strong>A mixed-methods approach was used to assess MND-Prism within an Australian cohort (<i>n</i> = 31) of plwMND, and their informal and professional carers. Quantitative data included deidentified usage statistics and Mobile Application Rating Scale (uMARS) survey results. Semi-structured interviews (<i>n</i> = 11) provided qualitative insights into user experiences and perspectives.</p><p><strong>Results: </strong>Usage data highlighted varying engagement with MND-Prism functions. uMARS evaluations show above-average satisfaction across engagement, functionality, information, and esthetics, though customization and accessibility scored lower. Five themes were generated from semi-structured interviews with MND-Prism users: Purpose and value, functionality, future needs and monitoring progression, access, and information.</p><p><strong>Conclusion: </strong>MND-Prism shows potential as a self-management tool for MND, addressing critical organizational challenges in care. Participants identified both positive aspects and areas for improvement, particularly in accessibility, customization, and carer integration. These findings provide a foundation for further development and evaluation, ensuring that applications like MND-Prism are responsive to the diverse and evolving needs of the MND community. Future research should validate these findings in larger, more diverse populations and assess the long-term role of digital tools in care coordination and support.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":" ","pages":"673-682"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phase 2, proof-of-concept, placebo-controlled, randomized, multicenter, double-blind study to evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of Usnoflast (ZYIL1) in patients with amyotrophic lateral sclerosis.","authors":"Amit Yeole, Laxmi Khanna, Maulik Doshi, Arvind Sharma, Pratik Uttarwar, Suyog Doshi, Rana Kaushik Kumar, N Venkataramana, Deven Parmar","doi":"10.1080/21678421.2025.2515900","DOIUrl":"10.1080/21678421.2025.2515900","url":null,"abstract":"<p><p><i>Objective</i>: To assess the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of Usnoflast (ZYIL1) in patients with amyotrophic lateral sclerosis (ALS). <i>Methods</i>: Patients with a probable or definite ALS diagnosis were randomized to receive twice daily oral doses (for 12 weeks) of Usnoflast (25 mg, 50 mg, or 75 mg) or placebo. The primary outcome was the change in ALS functional rating scale-revised (ALSFRS-R) total score from baseline to week 12. Secondary outcomes were assessment of PK, change in slow vital capacity (SVC) and serum and cerebrospinal fluid (CSF) levels of neurofilament light (NfL) chain from baseline to week 12, and safety up to 12 weeks. <i>Results</i>: Total 24 patients were enrolled; 71% of those who received Usnoflast had the drug above therapeutic concentration in CSF. In the modified intent-to-treat (mITT) population, least square mean changes (ANCOVA) in ALSFRS-R total score from baseline to week 12 were -1.91 for Usnoflast 25 mg, -3.84 for Usnoflast 50 mg, 0.52 for Usnoflast 75 mg, and -2.26 for placebo arm. Though not significant (<i>p</i> > 0.05), compared with placebo, Usnoflast 75 mg demonstrated a difference of 2.78 (mITT) and 3.28 (per-protocol) in ALSFRS-R total score. Statistical non-significant differences were also observed in changes of SVC% and CSF NfL levels. Usnoflast was well-tolerated at tested doses, and there was no treatment-emergent serious adverse event or death during the study duration. <i>Conclusion</i>: Usnoflast 50 and 75 mg doses were well-tolerated in ALS patients, providing rationale for further studies of Usnoflast in ALS.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":" ","pages":"794-801"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144287396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Type 2 diabetes mellitus, antidiabetics, and the risk of amyotrophic lateral sclerosis.","authors":"Tian-Shin Yeh, Ran S Rotem, Marc G Weisskopf","doi":"10.1080/21678421.2025.2515913","DOIUrl":"10.1080/21678421.2025.2515913","url":null,"abstract":"<p><p><i>Background:</i> Research on the link between Type 2 Diabetes mellitus (T2DM) and amyotrophic lateral sclerosis (ALS) has produced mixed results. The potential role of antidiabetic medications in ALS etiology is also unclear. To contribute to these discussions, we aimed to examine the connections between T2DM, antidiabetic medications, and ALS using data from a large Israeli health fund. <i>Methods:</i> A total of 504 ALS cases diagnosed in 2002-2018 and 42,873 matched controls were considered in this population-based nested case-control study. T2DM was ascertained using diagnosis codes, laboratory test results, and medication use history, employing a 3-year lag from initial ALS diagnosis date to minimize chances for reverse causation. Multivariable-adjusted odds ratios (OR) were estimated for the association between T2DM, antidiabetic medications, and ALS. <i>Results:</i> T2DM overall was not linked with ALS (multivariable-adjusted odds ratio (OR) = 0.94, 95% confidence interval (CI): 0.72-1.23). However, T2DM with a history of insulin use showed a protective association with ALS (OR = 0.29; 95% CI = 0.09-0.92) compared to the non-T2DM group. A similar trend of protective associations with ALS was observed for T2DM with history of use of other antidiabetic medications, but none were statistically significant, and all associations were further attenuated after adjusting for insulin use. <i>Conclusions:</i> We observe a potential protective effect of T2DM-linked insulin use on risk of ALS. Although caution is necessary due to the limited number of ALS cases with insulin exposure, the observed protective association may suggest a biological pathway worth exploring for future therapeutic development.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":" ","pages":"775-783"},"PeriodicalIF":2.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12313232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144555981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}