@article {pmid42020662,
year = {2026},
author = {Abati, E and Saccomanno, D and Alberti, C and Anastasia, A and Gagliardi, D and Ferri, E and Arosio, B and D Angelo, G and Cima, R and Bassi, MT and Oldoni, S and Comi, GP and Rizzo, F and Corti, SP},
title = {Investigating the role of serum NfL, FGF21, NCAM1 and GDF15 as disease biomarkers for Charcot-Marie-Tooth type 2A.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42020662},
issn = {2045-2322},
support = {GMR23T2153//Fondazione Telethon/ ; Ricerca Corrente 2024 MoH//Ministero della Salute/ ; GR-2018-12365358//Ministero della Salute/ ; },
mesh = {*Charcot-Marie-Tooth Disease/blood/diagnosis/genetics ; Humans ; Biomarkers/blood ; *Growth Differentiation Factor 15/blood ; Female ; *Fibroblast Growth Factors/blood ; Male ; Animals ; Middle Aged ; Adult ; *Neurofilament Proteins/blood ; Mice ; Mice, Transgenic ; Aged ; Case-Control Studies ; Neural Cell Adhesion Molecules/blood ; },
abstract = {Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common axonal form of inherited peripheral neuropathy, caused by mutations in the mitofusin 2 (MFN2) gene that impair mitochondrial fusion and axonal transport, ultimately leading to progressive neurodegeneration. The identification of accessible molecular biomarkers may improve diagnostic accuracy, enable patient stratification, and support the development and monitoring of emerging therapies. We investigated serum levels of neurofilament light chain (NfL), neural cell adhesion molecule 1 (NCAM1), growth differentiation factor 15 (GDF15), and fibroblast growth factor 21 (FGF21) in CMT2A patients (n = 15), healthy controls (n = 10), and neurological disease controls (n = 16; amyotrophic lateral sclerosis [ALS], n = 10, spinal muscular atrophy type 3 [SMA3], n = 6), evaluating their utility as diagnostic and monitoring biomarkers. In parallel, serum NfL levels were assessed in transgenic Thy1-MFN2*R94Q mice, a validated preclinical model of CMT2A. Serum NfL levels were significantly elevated in CMT2A patients compared to healthy controls, a finding corroborated in transgenic mice. Notably, NfL levels in CMT2A patients were higher than in SMA3 but lower than in ALS patients, supporting the ability of this biomarker to discriminate between clinically overlapping neuromuscular conditions. Higher NfL levels were associated with younger age, earlier disease onset, and shorter disease duration, suggesting a role as a marker of early disease burden. However, no significant correlation was observed with clinical severity scores or electrophysiological measures. Serum FGF21 levels were also significantly elevated in CMT2A patients compared to controls, whereas NCAM1 and GDF15 levels did not differ significantly between groups. These findings support the role of serum NfL as a translational biomarker of axonal damage in CMT2A, capable of distinguishing affected individuals from both healthy and neurological disease controls. The concomitant elevation of FGF21 further underscores the contribution of mitochondrial dysfunction to CMT2A pathophysiology. Together, these results highlight the potential of serum biomarkers to refine diagnostic workflows and facilitate therapeutic development and future clinical trials for CMT2A.},
}

*Charcot-Marie-Tooth Disease/blood/diagnosis/genetics
Humans
Biomarkers/blood
*Growth Differentiation Factor 15/blood
Female
*Fibroblast Growth Factors/blood
Male
Animals
Middle Aged
Adult
*Neurofilament Proteins/blood
Mice
Mice, Transgenic
Aged
Case-Control Studies
Neural Cell Adhesion Molecules/blood

@article {pmid42183628,
year = {2026},
author = {Wei, Z and Zhang, M and Tang, W and Singh, BK and Zhiwei, Z and Lei, Z and Goh Kim Wee, J and Tan Rui En, F and Jingxiu, H and Qiaoyang, S and Bin, X and Priyanka, G and Xuyang, AS and Li, Z and Han-Ming, S and King, TE},
title = {CHCHD2 and CHCHD10 promoted autophagic clearance of protein aggregates via GABARAPs.},
journal = {Autophagy},
volume = {},
number = {},
pages = {},
doi = {10.1080/15548627.2026.2678427},
pmid = {42183628},
issn = {1554-8635},
abstract = {Mutations in mitochondrial protein CHCHD2 and its paralog CHCHD10 were identified in patients with Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) or Alzheimer disease (AD). CHCHD2 and CHCHD10 mutations caused neurodegeneration in model animals as seen in patients, but their pathophysiological roles remain elusive. Here we reported a direct role of CHCHD2 and CHCHD10 in autophagy. We identified a protein complex composing of CHCHD2-CHCHD10-C1QBP/p32-Atg8-family proteins (ATG8s), in which each molecule interacted with another. CHCHD2, CHCHD10 and C1QBP/p32 associated with ATG8s, preferentially, GABARAPs. Disease-associated CHCHD2 and CHCHD10 mutations exhibited varied interaction with ATG8s. By binding to GABARAPs, CHCHD2 and CHCHD10 underwent autophagic degradation, and recruited the ULK1 complex. Autophagy initiation defects occurred upon transient knockdown of CHCHD2, and also in human iPSC-derived CHCHD2[-/-] or CHCHD2[T61I] dopaminergic neurons. Importantly, CHCHD2 and CHCHD10 promoted autophagy. CHCHD2 reduced protein aggregates in cells and toxic SNCA/α-synuclein species in mouse striatum. Our study thus revealed mitochondrial proteins CHCHD2 and CHCHD10 as both autophagy substrates and autophagy activators and laid groundwork for therapy targeting patients with neurodegeneration.},
}

@article {pmid42183665,
year = {2026},
author = {Tavaglione, L and Madonia, N and Corrado, L and Comi, C and D'Alfonso, S and Mazzini, L and De Marchi, F},
title = {Expanding the phenotypic spectrum of SOD1‑related ALS: upper motor neuron predominance in a p.D91A case.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/17582024.2026.2676822},
pmid = {42183665},
issn = {1758-2032},
abstract = {Mutations in superoxide dismutase 1 SOD1 are the second most common genetic cause of ALS, usually associated with prevalent lower motor neuron phenotypes. We describe a 66-year-old woman with slowly progressive spastic paraparesis, initially diagnosed as primary lateral sclerosis, who carried a heterozygous p.D91A mutation. Clinical and neurophysiological findings indicated predominant upper motor neuron involvement, an unusual presentation for this mutation. This case broadens the SOD1 phenotypic spectrum and highlights the importance of early genetic testing in atypical motor syndromes, given the availability of targeted therapies where diagnostic delay may limit benefit.},
}

@article {pmid42183747,
year = {2026},
author = {Ma, G and Shi, Y and Qiu, J and Ren, C and Shao, K and Shu, X},
title = {Cumulative Environmental Burden and Neurodegenerative Disease Mortality: A National Ecological Study in the United States.},
journal = {American journal of epidemiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/aje/kwag114},
pmid = {42183747},
issn = {1476-6256},
abstract = {Neurodegenerative diseases (NDDs) represent a growing cause of mortality and disability among aging populations worldwide. However, the relationship between cumulative, multi-domain environmental exposures and NDD mortality remains poorly characterized. This study aimed to examine the association between comprehensive environmental quality and NDD mortality in the United States. We used the Environmental Quality Index (EQI) from 2000 to 2005 to characterize cumulative environmental exposure. Associations between EQI quintiles and NDD mortality, including dementia, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, were examined using Bayesian interval-censored mixed-effects models. During 2006-2020, among 3.66 million NDD deaths, poorer environmental quality (Q5 vs. Q1) was associated with mortality rate differences of 24.72 (95% CrI: 22.43, 27.06) per 100,000 at 5-year lag, 26.74 (95% CrI: 24.34, 29.21) at 10-year lag, and 22.74 (95% CrI: 20.49, 25.13) at 15-year lag. Within each lag period, a clear dose-response pattern was consistently observed across EQI quintiles. Furthermore, associations were most pronounced for the air quality, followed by sociodemographic disadvantage. In addition, demographic and geographic heterogeneity was observed across sex, race, census regions, urbanicity, climate zone and county economic type. These findings underscore the need for integrated, place-based environmental health policies targeting neurodegeneration prevention.},
}

@article {pmid42183749,
year = {2026},
author = {Trad, G and Lenglet, T and Querin, G and Blancho, S and Marchand-Pauvert, V and Hogrel, JY and Pradat, PF},
title = {Beyond outcomes: patients' lived experience of exoskeleton-assisted gait training in amyotrophic lateral sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2026.2674021},
pmid = {42183749},
issn = {2167-9223},
abstract = {OBJECTIVES: To explore patients' expectations and lived experience of Atalante exoskeleton-assisted gait training in amyotrophic lateral sclerosis (ALS).

METHODS: In the EXALS study (NCT06199284), 10 ambulatory ALS participants completed 18 sessions of Atalante exoskeleton-assisted gait training. After completion of the intervention phase, post-training semi-structured interviews were audio-recorded, transcribed verbatim, and analyzed using inductive qualitative content analysis approach. Structured interview items were summarized descriptively.

RESULTS: Ten participants reported positive expectations and experiences. Initial expectations most often included contributing to research (5/10), maintaining walking ability (4/10), and improving gait quality/balance (3/10). Expectation fulfillment was high (very satisfied: 7/10). The rehabilitative aspect was most frequently ranked as most reflective of the experience (rank 1: 4/10), followed by motivational/recreational (rank 2: 4/10), psychological/emotional was most often ranked last (rank 5: 5/10). Participants described perceived benefits including improved upright posture, stability, reduced stiffness, smoother gait, and reduced fear of falling, though some effects were described as short-lived. Three-word summaries were predominantly positive (8/10), commonly "interesting" and "motivating," with occasional negatives (tiring/heavy/repetitive/disappointing; 2/10). Compared with conventional physiotherapy, sessions were perceived as more dynamic and walking-focused, with a structured, innovative, closely supervised set-up. Suggested improvements centered on increasing access/dose, expanding walking space and training content, and enhancing safety/user control. Most participants would continue training if available (8/10), most commonly preferring two sessions per week (4/8).

CONCLUSIONS: Exoskeleton-assisted gait training was experienced as acceptable and meaningful. Translating this into practice will require aligning future protocols with patient priorities, autonomy/safety, access and delivery logistics, and broader functional content alongside quantitative evaluation.},
}

@article {pmid42185781,
year = {2026},
author = {Fujiwara, Y and Hashiguchi, A and Yamashiro, S and Seno, H and Ohya, Y and Yasutomi, D and Fujisaki, N and Kido, M and Suwazono, S and Tokashiki, T},
title = {Association between creatinine-to-cystatin C ratio and ALSFRS-R across clinical phenotypes.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-04983-6},
pmid = {42185781},
issn = {1471-2377},
abstract = {BACKGROUND: Reliable and accessible biomarkers for amyotrophic lateral sclerosis (ALS) are scarce. Creatinine (Cre) reflects muscle mass, whereas cystatin C (CysC) may reflect neurodegeneration without being directly influenced by muscle mass; however, both have limitations. We aimed to investigate whether the creatinine-to-cystatin C ratio (Cre/CysC) was cross-sectionally associated with functional status in patients with ALS.

METHODS: We retrospectively analyzed 30 patients diagnosed with ALS at the National Organization Hospital Okinawa Hospital between 2021 and 2024. Baseline ALS Functional Rating Scale-Revised (ALSFRS-R) scores and serum Cre and CysC levels were recorded. Associations with the ALSFRS-R were assessed using Spearman's correlation, with subgroup analyses by sex, site of onset, age at diagnosis, body mass index (BMI), and diagnostic delay. Multivariable analyses were performed to examine the independent association between Cre/CysC and ALSFRS-R while accounting for relevant clinical covariates.

RESULTS: Cre/CysC showed a stronger cross-sectional correlation with ALSFRS-R (rs=0.648, p = 0.0001) than Cre alone (rs =0.427) or CysC (rs =-0.119). Exploratory subgroup analyses showed generally positive associations in several subgroups, although no statistically significant association was observed in the small bulbar-onset subgroup. In multivariable analysis adjusted for age at onset and diagnostic delay, Cre/CysC remained independently associated with ALSFRS-R (β = 20.1, 95% CI 6.41-33.9, p = 0.006). Given the small sample size and cross-sectional design, these findings should be interpreted as exploratory.

CONCLUSIONS: Cre/CysC showed a stronger cross-sectional association with functional status than either marker alone. Because it is derived from routine laboratory tests, Cre/CysC may represent a simple exploratory measure associated with functional status in ALS. However, the present findings do not establish prognostic utility or fully account for disease stage and biological heterogeneity. Prospective longitudinal studies incorporating disease progression measures and broader clinical and genetic characterization are warranted.},
}

@article {pmid42186042,
year = {2026},
author = {Salgueiro, AM and Ferreira-Marques, M and Ribeiro, RFN and Lopes, SM and Pereira, D and Costa, DG and Santana, MM and de Almeida, LP and Cavadas, C},
title = {Ketogenic diet as a therapeutic strategy for neurodegenerative diseases: from mechanisms to translational challenges.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42186042},
issn = {2047-9158},
support = {UIDB/04539/2020//Fundação para a Ciência e a Tecnologia/ ; UIDP/04539/2020//Fundação para a Ciência e a Tecnologia/ ; LA/P/0058/2020(JPND/ 0001/2022//Fundação para a Ciência e a Tecnologia/ ; DOI: 10.54499/JPND/0001/2022; JPND/0002/2022//Fundação para a Ciência e a Tecnologia/ ; DOI: 10.54499/JPND/0002/2022//Fundação para a Ciência e a Tecnologia/ ; SFRH/BD/120023/2016; 2020.04850.BD//Fundação para a Ciência e a Tecnologia/ ; 2022.11293.BD//Fundação para a Ciência e a Tecnologia/ ; GeneT project-The Gene Therapy CoE at the Center of Portugal (Project ID: 101059981//HORIZON EUROPE Widening participation and spreading excellence/ ; DOI: 10.3030/101059981); GCure - From Gene to Cure//HORIZON EUROPE Widening participation and spreading excellence/ ; ID: 101186929//HORIZON EUROPE Widening participation and spreading excellence/ ; DOI:10.3030/101186929; GeneH - Excellence Hub for Advancing Innovation in Gene Therapy//HORIZON EUROPE Widening participation and spreading excellence/ ; ID: 101186939//HORIZON EUROPE Widening participation and spreading excellence/ ; DOI: 10.3030/101186939//HORIZON EUROPE Widening participation and spreading excellence/ ; },
mesh = {Humans ; *Diet, Ketogenic/methods ; *Neurodegenerative Diseases/diet therapy/metabolism ; Animals ; *Translational Research, Biomedical/methods ; Gastrointestinal Microbiome/physiology ; Oxidative Stress/physiology ; },
abstract = {The ketogenic diet (KD) is increasingly recognized as a promising therapeutic strategy for neurodegenerative disorders because of its multifaceted impacts on key pathophysiological mechanisms. This review explores the molecular pathways through which KD may protect against neurodegeneration, including the use of ketone bodies as alternative energy substrates, reduction of oxidative stress and inflammation, modulation of autophagy and protein aggregation, and impact on the gut microbiome. The potential benefits of KD are explored across neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, based on both preclinical and clinical evidence that supports its feasibility. However, challenges in long-term safety, patient adherence, and clinical practicality limit its widespread adoption. This review underscores the potential of KD for treating neurodegeneration on the basis of current scientific evidence while highlighting the need for further research to optimize its application and address existing gaps.},
}

Humans
*Diet, Ketogenic/methods
*Neurodegenerative Diseases/diet therapy/metabolism
Animals
*Translational Research, Biomedical/methods
Gastrointestinal Microbiome/physiology
Oxidative Stress/physiology

@article {pmid42186501,
year = {2026},
author = {AlSabah, AA and Reda, H},
title = {SOD1 amyotrophic lateral sclerosis associated with Neurosarcoidosis: a case report and review of the literature.},
journal = {Oxford medical case reports},
volume = {2026},
number = {5},
pages = {omag078},
pmid = {42186501},
issn = {2053-8855},
abstract = {We describe a 37-year-old man with coexisting amyotrophic lateral sclerosis (ALS) caused by a mutation in superoxide dismutase 1 (SOD1) and probable neurosarcoid myeloradiculitis. The concurrence of the two rare conditions posed significant diagnostic and therapeutic challenges. We discuss the diagnostic timeline, therapeutic interventions, outcomes over half a decade of care, and a review of relevant literature.},
}

@article {pmid42186604,
year = {2026},
author = {Albadri, Z and Häbel, H and Thorslund, K and Grönhagen, C and Seifert, O},
title = {Associations between bullous pemphigoid and comorbidities: A Swedish nationwide cohort study of 5,738 patients.},
journal = {Journal of multimorbidity and comorbidity},
volume = {16},
number = {},
pages = {26335565261455676},
pmid = {42186604},
issn = {2633-5565},
abstract = {BACKGROUND: Bullous pemphigoid (BP) has been linked to neurological and psychiatric disorders, but no nationwide population-based study has comprehensively examined the association of various comorbidities in BP patients in Sweden.

OBJECTIVES: To investigate the associations between BP and various comorbidities, comparing these conditions before and after BP diagnosis with a matched control group.

METHODS: A nationwide cohort study was conducted in Sweden from 2005 to 2016, including 5,738 BP cases and 17,167 age, sex and county of residence matched controls. Multivariable Cox proportional hazard regression models were used to calculate hazard ratios (HR). Univariable logistic regression assessed pre-diagnosis comorbidities, generating prevalence odds ratios (POR) with 95% confidence intervals (CI).

RESULTS: BP was associated with a significantly higher overall HR for comorbidity (HR: 2.20, 95% CI: 2.08-2.33). Before BP diagnosis, the overall comorbidity was significantly increased POR 2.72 (95% CI: 2.56-2.90). Pre-diagnosis association included dementia, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia, unipolar/bipolar disorders, suicide, diabetes, stroke, systemic lupus erythematosus, systemic sclerosis, psoriasis, lichen planus, alopecia areata, and vitiligo. After diagnosis, the overall hazard ratio (HR) for comorbidities was highest within the first year (HR 2.88, 95% CI: 2.68-3.10) and remained elevated beyond one year (HR 1.57, 95% CI: 1.44-1.71). Post-diagnosis associations remained elevated for dementia, Parkinson's disease, epilepsy, schizophrenia, unipolar/bipolar, diabetes, psoriasis, lichen planus and autoimmune diseases such as systemic sclerosis and Sjögren's syndrome.

CONCLUSION: BP is strongly associated with neurodegenerative, psychiatric, autoimmune, and metabolic comorbidities before and after diagnosis, highlighting their clinical significance as predisposing and prognostic factors in BP patients.},
}

@article {pmid42186910,
year = {2026},
author = {Tong, VS and Pontell, ME},
title = {Invited Commentary on: Islam et al.'s "Evaluating Appropriateness of Interfacility Transfers for Patients with Facial Trauma Including Acute Orbital Floor Fractures".},
journal = {Facial plastic surgery & aesthetic medicine},
volume = {},
number = {},
pages = {26893614261452862},
doi = {10.1177/26893614261452862},
pmid = {42186910},
issn = {2689-3622},
}

@article {pmid42187212,
year = {2026},
author = {Kibreab, F and Haraburda, A and Albaba, YAA and Yong, AC and Shah, K and Buthelezi, S and Chan, VF},
title = {A scoping review of theoretical and measurement approaches to women's empowerment in low-and middle-income countries' capacity-building interventions.},
journal = {Global health action},
volume = {19},
number = {1},
pages = {2676412},
doi = {10.1080/16549716.2026.2676412},
pmid = {42187212},
issn = {1654-9880},
mesh = {*Developing Countries ; *Empowerment ; Humans ; Female ; *Capacity Building/organization & administration ; *Women's Rights ; Entrepreneurship ; Gender Equity ; *Power, Psychological ; },
abstract = {Women's empowerment is critical for achieving gender equality and sustainable development in low-and-middle-income countries (LMICs). Capacity-building interventions, such as vocational training, microfinance, and digital literacy programmes, are frequently employed to foster empowerment. However, wide variation exists in how empowerment is defined, theorised, and measured, limiting comparability across studies. This scoping review mapped the conceptual foundations, theoretical frameworks, and measurement approaches used in capacity-building interventions for women entrepreneurs in LMICs. The review followed Arksey and O'Malley's framework and was reported in line with PRISMA-ScR guidelines. Searches were conducted in PubMed, Scopus, Web of Science, and JSTOR, complemented by grey literature from major development agencies (2010-2024). Eligible studies focused on capacity-building interventions targeting women entrepreneurs in LMICs. Two reviewers independently screened and extracted data, which were synthesised thematically. Of 11,109 records identified, 25 met inclusion criteria. Most studies were cross-sectional, conducted in sub-Saharan Africa (48%) and South Asia (32%). While 76% defined empowerment, 60% did not employ any explicit theoretical or conceptual framework. Among those that did, frameworks, such as Kabeer's, Longwe's, and Malhotra et al.'s were used inconsistently. Economic empowerment was the most frequently assessed domain, often measured through income or business performance, while social, political, and psychological dimensions were seldom examined. Indicators were heterogeneous and largely self-reported. Conceptual ambiguity and inconsistent measurement hinder progress in women's empowerment research in LMICs. Future studies should adopt theoretically grounded, multidimensional, and context-sensitive frameworks to capture empowerment as a dynamic process beyond economic gains.},
}

*Developing Countries
*Empowerment
Humans
Female
*Capacity Building/organization & administration
*Women's Rights
Entrepreneurship
Gender Equity
*Power, Psychological

@article {pmid42187452,
year = {2026},
author = {Kolukisa Birgec, B and Toprak, B and Mullen, AB},
title = {Assessment of Respiratory Rate and Simulated Apnea Utilizing the PneumoWave Biosensor: In Vitro and In Vivo Validation.},
journal = {Biosensors},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/bios16050256},
pmid = {42187452},
issn = {2079-6374},
support = {YLSY2018/YLSY2020//Mi̇lli̇ Eği̇ti̇m Bakanliği/ ; },
mesh = {Humans ; *Biosensing Techniques ; *Respiratory Rate/physiology ; *Apnea/diagnosis/physiopathology ; Monitoring, Physiologic ; Male ; Adult ; Female ; Manikins ; },
abstract = {Accurate monitoring of respiratory rates is critical for early detection of a range of clinical conditions. However, standard manual counting or inadequate clinical monitoring often fails to provide reliable measurements. This study evaluated and validated the PneumoWave biosensor for respiratory rate measurement across a broad physiological range and different body postures (45°, 90°, and 180°) in both in vitro and in vivo settings. In vitro validation was performed using a SimMan ALS manikin operated at respiratory settings of 6-30 breaths per minute, with 10 s periods of simulated apnea. In vivo validation involved 20 healthy volunteers performing metronome-guided breathing while wearing bilateral PneumoWave biosensors. In vitro results demonstrated an excellent correlation between biosensors and manikin respiratory settings and captured all apnea events (r = 0.99, ICC = 0.99). In vivo findings showed good agreement with direct observational count (r = 0.99, R[2] = 0.99, ICC = 0.99), with 97% of apnea events captured by both devices in all positions. Body postures had no significant impact on biosensor accuracy. These findings demonstrate that the PneumoWave biosensor provides accurate and reliable respiratory monitoring and supports its potential as a robust, non-invasive tool for continuous clinical and remote patient monitoring.},
}

Humans
*Biosensing Techniques
*Respiratory Rate/physiology
*Apnea/diagnosis/physiopathology
Monitoring, Physiologic
Male
Adult
Female
Manikins

@article {pmid42187823,
year = {2026},
author = {Hayden, E and Kebe, A and Chen, S and Chumley, A and Xia, C and El-Zein, W and Zhong, Q and Ju, S},
title = {RNA-Binding Protein TAF15 Suppresses Toxicity in a Yeast Model of FUS Proteinopathy.},
journal = {Journal of fungi (Basel, Switzerland)},
volume = {12},
number = {5},
pages = {},
doi = {10.3390/jof12050341},
pmid = {42187823},
issn = {2309-608X},
support = {1R15NS109804-01A1/NS/NINDS NIH HHS/United States ; },
abstract = {Mutations in an RNA-binding protein FUS are known to cause familial amyotrophic lateral sclerosis (ALS). Since this discovery, mutations in several other RNA-binding proteins (RBPs) have also been linked to ALS. Some of these ALS-associated RBPs have been shown to colocalize with ribonucleoprotein (RNP) granules such as stress granules and processing bodies (p-bodies). Increasing evidence has emerged supporting a hypothesis that the impaired clearance, inappropriate assembly, and dysregulation of RNP granules play a role in ALS. Through the genome-scale overexpression screening of a yeast model of FUS toxicity, we found that TAF15, a human RBP with a similar protein domain structure and belonging to the same FET protein family as FUS, suppresses FUS toxicity in yeast. The suppression by TAF15 is specific to FUS and not found in other yeast models of neurodegenerative disease-associated proteins. We showed that the RNA recognition motif (RRM) of TAF15 is required for its suppression of FUS toxicity. Furthermore, FUS and TAF15 physically interact, and the C-terminus of TAF15 is required for both the physical protein-protein interaction and its protection against FUS toxicity. Finally, while FUS induces and colocalizes with both stress granules and p-bodies, TAF15 only induces and colocalizes with p-bodies. Importantly, the co-expression of FUS and TAF15 induces more p-bodies than individually expressing each gene alone, and FUS toxicity is exacerbated in yeast that is deficient in p-body formation. Overall, our findings suggest a role of increased p-body formation in the suppression of FUS toxicity by TAF15.},
}

@article {pmid42188341,
year = {2026},
author = {Buccarello, L and Montagna, C and Di Matteo, S and Mangione, R and Carota, G and Sibbitts, J and Jarosova, R and Lunte, SM and Lazzarino, G and Caruso, G},
title = {The Bright and Dark Sides of Nitric Oxide in Neurodegenerative Diseases.},
journal = {Journal of personalized medicine},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/jpm16050246},
pmid = {42188341},
issn = {2075-4426},
abstract = {Nitric oxide (NO) plays an important role in neuronal communication, synaptic plasticity and vascular regulation. Due to its important function in neuronal homeostasis, NO imbalance is associated with neurodegeneration. Specifically, in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and frontotemporal lobar degeneration (FTLD), an excessive amount of NO, mostly produced by inducible NO synthase (iNOS), reacts with superoxide to form peroxynitrite, driving oxidative/nitrosative stress, mitochondrial dysfunction, and aberrant protein modifications. In AD, NO dysregulation promotes amyloid-β (Aβ) accumulation, tau hyperphosphorylation and synaptic loss, creating a self-perpetuating cycle of neuronal damage. NO's dual role, protective at physiological levels but harmful if overproduced, underscores the therapeutic potential of antioxidant compounds that restore the balance of NO/NOS (especially iNOS) while preserving physiological functions. However, despite the emerging role of antioxidant-based therapeutic approaches, clinical translation is limited by the complexity of NO signaling and the absence of safe, specific NOS inhibitors. By targeting the molecular switch from protective to toxic, NO activity may offer new personalized treatment avenues for neurodegenerative diseases.},
}

@article {pmid42188687,
year = {2026},
author = {Fajkić, A and Belančić, A and Pilipović, K and Rački, V and Mežnarić, S and Janković, T and Gkrinia, EMM and Vitezić, D and Mršić-Pelčić, J},
title = {Nanotube-Assisted Motor Neuron and Neuromuscular Junction Stabilization in Spinal Muscular Atrophy: A Hypothesis for Adjunctive Therapy.},
journal = {Neurology international},
volume = {18},
number = {5},
pages = {},
doi = {10.3390/neurolint18050087},
pmid = {42188687},
issn = {2035-8385},
abstract = {Spinal muscular atrophy (SMA) therapies that restore SMN expression improve survival and motor function but often fail to fully stabilize distal motor units or sustain endurance. We propose a hypothesis-driven adjunctive approach, intended to complement SMN-restoring therapies, in which localized nanotube-enabled interfaces acting at or near the distal motor unit and neuromuscular junction enhance neuromuscular transmission reliability in surviving, remodeled motor units. The model predicts a temporal cascade: improved junctional reliability and reduced activity-dependent failure, followed by consistent motor unit output across repeated activation, and ultimately, enhanced endurance and functional reserve. Phenotype-specific responsiveness identifies patients most likely to benefit, specifically those with preserved-but-limited residual motor unit substrate accompanied by measurable neuromuscular junction instability. Drawing on shared mechanisms from ALS, spinal cord injury, and other neuromuscular disorders, we discuss mechanistic, translational, safety, regulatory, and ethical considerations. This framework links objective physiological constructs to functional outcomes, offering a mechanistically grounded path for adjunctive therapy development in SMA and related conditions.},
}

@article {pmid42189100,
year = {2026},
author = {Lockhart, ENS},
title = {Cybernetic Feedback: an Apt Realignment of Batterham et al.'s Three-Body Problem of Suicide (2025).},
journal = {Journal of evaluation in clinical practice},
volume = {32},
number = {4},
pages = {e70487},
doi = {10.1111/jep.70487},
pmid = {42189100},
issn = {1365-2753},
}

@article {pmid42190746,
year = {2026},
author = {Zheng, P and Chen, L},
title = {Comments on Wu et al's "The efficacy and adverse reactions of 755 nm picosecond alexandrite laser on the treatment of nevus of Ota at different endpoints".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2026.03.126},
pmid = {42190746},
issn = {1097-6787},
}

@article {pmid42174979,
year = {2026},
author = {Faujour, C and Bouee, S and Emery, C and Jannot, AS},
title = {Evaluating the Role of Order and Time Information for Classifying Sequences of Healthcare Events Derived from Claims Data.},
journal = {Studies in health technology and informatics},
volume = {336},
number = {},
pages = {879-883},
doi = {10.3233/SHTI260305},
pmid = {42174979},
issn = {1879-8365},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; *Insurance Claim Review/statistics & numerical data ; },
abstract = {Sequences of healthcare events from claims data are increasingly used for predictive modeling. Despite the rise in popularity of neural networks, the benefit of modeling event order and timing remains underexplored. We simulated patient trajectories using parameters estimated from claims data including 22,000 amyotrophic lateral sclerosis (ALS) cases and 22,000 age and gender-matched controls. The simulation reproduced irregular event timing and condition-related activity that increased near an incident diagnosis. We compared three model families for population classification: frequency-based models, sequential models (long short-term memory and Transformer architectures) capturing event order, and sequential models incorporating temporal information. Performance was evaluated using the area under the ROC curve (AUC) at multiple time points before diagnosis. Sequential models outperformed frequency-based baselines by about +0.06 AUC on average, confirming the benefit of modeling event order. Adding time information provided no noticeable improvement, and results were stable across different time encoding and scaling methods. These findings suggest that, in claims-based classification tasks, event order captures most of the useful temporal signal, while explicit time encoding offers limited additional benefit under similar conditions.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/epidemiology
*Insurance Claim Review/statistics & numerical data

@article {pmid42175187,
year = {2026},
author = {Yadav, R and Pragya, P and Agastinose Ronickom, JF},
title = {Identification of Reliable Biomarkers for ALS Through Machine Learning Approach.},
journal = {Studies in health technology and informatics},
volume = {336},
number = {},
pages = {1705-1709},
doi = {10.3233/SHTI260516},
pmid = {42175187},
issn = {1879-8365},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Humans ; *Machine Learning ; Biomarkers/analysis ; Gene Expression Profiling/methods ; Transcriptome ; Algorithms ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and limited diagnostic biomarkers. Identifying robust molecular biomarkers for ALS remains a major challenge due to disease heterogeneity and high-dimensional gene expression data. In this study, we developed a machine learning (ML) based pipeline integrating transcriptome data and feature selection to identify potential ALS biomarkers. RNA-Seq data of motor neuron disease patients and healthy controls were obtained from publicly available GEO datasets, followed by preprocessing was performed. We implemented two ensembled ML models such as eXtreme gradient boosting (XGBoost) and random forest (RF) algorithms under a five-fold stratified cross-validation framework to identify the differentially expressed genes. These models were evaluated using the performance metrics. We identified top 10 genes ranked by feature importance from the XGBoost and RF models. Notably, the DCN (Decorin) gene appears consistently in the top 10 features of both models, underscoring its stability and biological relevance. Both ML models exhibited excellent classification performance, with RF achieving 98.8% accuracy and XGBoost achieving 97.6% accuracy, alongside consistently high sensitivity, specificity, precision, and F1-score values. This work highlights the utility of transcriptomic data and ML in identifying key genes as biomarkers for diagnostic and therapeutic potential in ALS.},
}

*Amyotrophic Lateral Sclerosis/genetics/diagnosis
Humans
*Machine Learning
Biomarkers/analysis
Gene Expression Profiling/methods
Transcriptome
Algorithms

@article {pmid42177450,
year = {2026},
author = {Ghasemi, F and Khoshnam Rad, N and Rashidinejad, B and Nasrollahzadeh, M},
title = {Pulmonary toxocariasis presenting as migratory pulmonary infiltrates and mediastinal lymphadenopathy: a case report and literature review.},
journal = {BMC pulmonary medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12890-026-04362-4},
pmid = {42177450},
issn = {1471-2466},
abstract = {BACKGROUND: Pulmonary toxocariasis, caused by the nematode Toxocara canis or T. cati, is an underdiagnosed cause of eosinophilic lung disease with highly variable radiological presentation that often mimics malignancy or other eosinophilic conditions.

CASE PRESENTATION: A 53-year-old female smoker presented with progressive dyspnea and cough. Initial chest CT revealed right lower lobe consolidation with mediastinal lymphadenopathy (station 4R with short-axis diameters 12 mm), raising concern for lung cancer. Bronchoscopy with EBUS-TBNA was non-diagnostic. The patient was empirically started on dexamethasone (8 mg daily, tapered over 3 months) for suspected organizing pneumonia. During steroid taper, her symptoms recurred with delayed emergence of peripheral eosinophilia (670/µL; initial absolute eosinophil count on presentation was 90/µL), elevated IgE (456 IU/mL), and serial CT scans demonstrating migratory pulmonary infiltrates involving the right lower, right middle, and left lower lobes. A history of raw beef liver consumption prompted serological testing, which confirmed Toxocara canis infection. Treatment with albendazole alone (400 mg twice daily for 14 days, without corticosteroids) resulted in complete clinical and radiological resolution.

LITERATURE REVIEW: We searched PubMed and Scopus (January 2014 - February 2026) for English- and French-language case reports of pulmonary toxocariasis. Fourteen new cases were identified and analyzed alongside the 12 cases from Ranasuriya et al.'s [1] review. These 26 cases demonstrate marked radiologic heterogeneity: multiple bilateral nodules (50%), consolidations (23%), pleural effusion (27%), and migratory infiltrates (8%). Pleural effusion has emerged as a distinct manifestation in seven recent cases. Delayed eosinophilia occurred in 12% of cases. Immunocompromised states (including primary ciliary dyskinesia, hematologic malignancies, and immunosuppressive therapy) were present in 23% of cases and may predispose to atypical presentations.

CONCLUSION: Pulmonary toxocariasis should be considered in patients with migratory infiltrates, unexplained eosinophilic pleural effusion, or lung nodules with eosinophilia. A meticulous dietary and exposure history is essential. Diagnosis is confirmed by serology, and patients respond well to albendazole therapy.},
}

@article {pmid42177561,
year = {2026},
author = {Sharma, S and Cortés-Pérez, C and Bird, S and Di Curzio, D and Vandenakker, A and Schellenberg, K and Douville, RN},
title = {ERVK activity in CD8[+] T cell immune cell compartment in patients with ALS.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03871-7},
pmid = {42177561},
issn = {1742-2094},
support = {19-IIA-489//ALS Association/ ; 19-IIA-489//ALS Association/ ; },
abstract = {Endogenous retrovirus-K (ERVK) expression has been associated with Amyotrophic Lateral Sclerosis (ALS), and its viral proteins can be detected in affected brain and spinal cord tissues. Despite confirmation of ERVK load in the blood of patients with ALS, few studies have examined ERVK protein expression in immune cells. ERVK produces an enzyme called integrase (IN), which can cause DNA damage during the integration of viral DNA into the host genome. Given that genomic instability is a hallmark of ALS, we hypothesized that the ERVK IN enzyme may also be expressed in lymphoid and myeloid-derived immune cells of patients. Peripheral blood mononuclear cells (PBMC) were isolated from blood specimens using Ficoll isolation, and either flash-frozen for western blot analyses or affixed onto slides using the cytospin technique for subsequent confocal microscopy analysis. Image analysis of confocal micrographs revealed that ERVK IN expression was significantly elevated in CD3[+]CD8[+] T cells from a subset of patients with ALS as compared to controls. CD3[+]CD8[+] T cells in ALS exhibit enhanced number and size of ERVK IN puncta within the nucleus and at the plasma membrane. The DNA damage load, as measured by marker γH2AX, was strongly associated with ERVK IN levels in both controls and patients with ALS. Stratification of molecular data based on clinical parameters showed an association of elevated ERVK IN load in CD8[+] T cells from patients with ALS with lower ALSFRS-R and higher King's scores, as well as a significant decline in lung function metrics. In bulk PBMC from patients with ALS, ERVK IN was associated with expression of immune checkpoint marker PD-1, but not T cell exhaustion marker TOX. ERVK IN in CD14[+]CD11b[+] myeloid cells was also elevated, with ERVK[+] cells exhibiting notable membrane ruffling typical of immune cell activation and increased expression of HLA-DR. However, ERVK IN expression in monocytes was not correlated with clinical metrics in patients with ALS. This work points to the use of ERVK IN in CD8[+] cytotoxic T cells as a blood biomarker for ALS clinical trials, especially those focused on testing the efficacy of antivirals as a therapeutic strategy for ALS.},
}

@article {pmid42177632,
year = {2026},
author = {Schimmack, U and Soto, MD},
title = {A response to Pek et al.'s commentary on Z-curve: clarifying the assumptions of selection models.},
journal = {Cognition & emotion},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/02699931.2026.2678998},
pmid = {42177632},
issn = {1464-0600},
abstract = {Pek et al. (2026. What does a Z-curve analysis tell us? Cognition & Emotion, 1-16) comment on Soto and Schimmack (2025. Credibility of results in emotion science: A z-curve analysis of results in the journals Cognition & Emotion and Emotion. Cognition & Emotion) and raise concerns about the use of z-curve to evaluate the credibility of emotion research. Their central criticism is based on simulations showing that z-curve can overestimate the expected discovery rate when selection operates not only at the level of statistical significance but also within the set of significant results as a function of effect size. This point is correct: if researchers selectively publish larger significant effects while suppressing smaller significant ones, selection models that assume threshold-based filtering can be biased. However, this limitation is not unique to z-curve and applies equally to other selection models used in meta-analysis. More importantly, there is currently little empirical evidence for effect-size bias, while there is ample evidence of selection based on significance. Under these more realistic conditions, z-curve provides informative estimates of (a) selection bias, (b) the expected replication rate, and (c) the false positive risk. Our results also demonstrate substantial inflation of effect size estimates in traditional meta-analyses that ignore selection processes. For these reasons, we reject the recommendation to rely solely on standard meta-analytic approaches and advocate for the use of selection models to obtain more realistic estimates.},
}

@article {pmid42178739,
year = {2026},
author = {Paquet, A and Touzel-Deschênes, L and Roy, V and Saikali, S and Dupré, N and Gros-Louis, F},
title = {Proteomic Analysis of Corpora Amylacea Extracted From Post-mortem Brain of MAiD-end-of-life Sporadic ALS Patients.},
journal = {Brain and behavior},
volume = {16},
number = {5},
pages = {e71486},
doi = {10.1002/brb3.71486},
pmid = {42178739},
issn = {2162-3279},
support = {//tier-1 Canada Research Chair/ ; //CHU de Québec Foundation-Desjardins/ ; /CAPMC/CIHR/Canada ; //Canada Foundation for Innovation/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Proteomics/methods ; Male ; Female ; Aged ; Middle Aged ; *Brain/metabolism/pathology ; *Inclusion Bodies/metabolism/pathology ; Biomarkers/metabolism ; Aged, 80 and over ; Autopsy ; Proteome ; },
abstract = {PURPOSE: Corpora amylacea (CA) are starch-like inclusions that accumulate in the central nervous system (CNS) with aging and are enriched in neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS). Although often regarded as waste reservoirs, their cellular origins, molecular composition, and pathological significance remain poorly understood.

METHODS: Here, we performed an unbiased proteomic analysis of purified CAs isolated from post-mortem brains of sporadic ALS patients and controls.

FINDINGS: In-depth mass spectrometry identified 4,470 proteins, of which 658 were quantified, revealing distinct ALS-specific proteomic signatures. Enriched proteins included markers of cytoskeletal remodeling, mitochondrial dysfunction, and proteostasis disruption, as well as known ALS-associated proteins such as TDP-43 and neurofilament proteins. These findings demonstrate that CAs serve as reservoirs of dysfunctional, disease-relevant proteins and capture key pathological processes in ALS.

CONCLUSION: By applying an unbiased proteomic approach to purified CAs, this study provides the first comprehensive map of their protein content in ALS, supporting their potential as biomarker sources and as a source of mechanistic insights into neurodegeneration.

SIGNIFICANCE: Unbiased analyses of CAs in the context of ALS have yet to be undertaken. This study provides the first proteomic profiling of purified CAs, isolated from ALS patient brains using biochemical methods, revealing that CAs harbor disease-relevant proteins implicated in sporadic ALS. By demonstrating that CAs act as reservoirs of dysfunctional proteins related to metabolism, cytoskeletal organization, and proteostasis, our findings highlight their potential as a novel source of ALS-specific mechanistic insight into disease pathology.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/pathology
Proteomics/methods
Male
Female
Aged
Middle Aged
*Brain/metabolism/pathology
*Inclusion Bodies/metabolism/pathology
Biomarkers/metabolism
Aged, 80 and over
Autopsy
Proteome

@article {pmid42178909,
year = {2026},
author = {Debnath, J and Leidal, AM},
title = {Membrane ATG8ylation in secretory autophagy.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/15548627.2026.2676796},
pmid = {42178909},
issn = {1554-8635},
abstract = {Mammalian Atg8-family (ATG8) proteins are crucial for macroautophagic/autophagic degradation in the lysosome and facilitate non-degradative processes including multiple distinct forms of unconventional protein secretion. These secretion pathways, collectively termed secretory autophagy, depend upon ATG8 conjugated to membranes to both specify and traffic molecules for extracellular release. Here, we review the current understanding of how membrane ATG8ylation supports secretory autophagy, and propose a cell biological framework for classifying the growing repertoire of secretory autophagy pathways based on membrane ATG8ylation at discrete intracellular vesicular intermediates. Finally, we detail the emerging roles of these pathways in physiology and disease.Abbreviations: Aβ, amyloid-β; Acb1, acyl-coA-binding 1; ALS, amyotrophic lateral sclerosis; APP, amyloid beta precursor protein; APEX2, ascorbate peroxidase; ATG, autophagy related; AWOL, autophagosome-mediated exit without lysis; BafA1, bafilomycin A1; BirA*, mutant BirA biotin ligase; BMI, body-mass index; CASM, ATG8 conjugation at single membranes; DAMPs, danger/damage-associated molecular patterns; DBI, diazepam binding inhibitor, acyl-CoA binding protein; DSS, dextran sodium sulfate; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum intermediate compartment; ESCRT, endosomal complexes required for transport; EVs, extracellular vesicles; EVPs, extracellular vesicles and particles; HMGB1, high mobility group box 1; IDE, insulin degrading enzyme; IFNB, interferon beta; ILV, intralumenal vesicles; LANDO, LC3-associated endocytosis; LAP, LC3-associated phagocytosis; LIR, LC3 interacting region; LDELS, LC3-dependent EV loading and secretion; LLOMe, L-leucyl-L-leucine methyl ester hydrobromide; M2, influenza A virus matrix 2, MAD, migratory autolysosome disposal; miRNAs, microRNAs; M-MDSC, monocytic myeloid derived suppressor cells; MVEs, multivesicular endosomes; PAMPs, pathogen-associated molecular patterns; P-bodies, processing bodies; PE, phosphatidylethanolamine; PD, Parkinson disease; PS, phosphatidylserine; RBPs, RNA binding proteins; R-EV, RAB22A-induced extracellular vesicle; SLC2A1, solute carrier family 2 member 1; TFRC, transferrin receptor; TGN, trans-Golgi network; TMED10, transmembrane p24 trafficking protein 10; THU, TMED10-channeled unconventional secretion; SALI, secretory autophagy during lysosome inhibition; SCF, SKP1-CUL1-F-box; SNAREs, soluble NSF attachment protein receptors.},
}

@article {pmid42178983,
year = {2026},
author = {Liu, JQ and Liu, H and Sun, YX and Li, Y and Liu, X and Wang, LQ and Yang, Z and Fu, Q and Xu, X and Chen, J and Zhang, Y and Zhou, J and Le, W and Cui, M and Liang, Y},
title = {Protein Disulfide Isomerase Disassembles TDP-43/G3BP1 Condensates and Antagonizes TDP-43 Pathological Aggregates.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e16846},
doi = {10.1002/advs.202516846},
pmid = {42178983},
issn = {2198-3844},
support = {U1967221//National Natural Science Foundation of China/ ; 32071212//National Natural Science Foundation of China/ ; U1967221//National Natural Science Foundation of China/ ; 22022601//National Natural Science Foundation of China/ ; 2024YFA1307300//National Key Research and Development Program of China/ ; 2023ZD0507202//National Major Science and Technology Projects of China/ ; },
abstract = {Cytoplasmic mislocalization and aggregation of transactive response DNA-binding protein-43 (TDP-43) is a common pathological feature of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease with TDP-43 pathology (AD-TDP); the exact role of protein disulfide isomerase (PDI), an enzyme with chaperone activity, in modulating the pathological behavior of TDP-43 is unknown. In this study, we report that wild-type PDI, through its specific interaction with TDP-43, markedly attenuates phase separation of TDP-43, competitively displaces G3BP1 to disassemble TDP-43/G3BP1 condensates, and further counteracts the pathological mislocalization, abnormal phosphorylation, and pathological aggregation of TDP-43 through the b' domain of the enzyme. Ultimately, this alleviates mitochondrial damage and neuronal toxicity caused by TDP-43 aggregation and suppresses UNC13A cryptic splicing in stressed cells. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP-43 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS and AD-TDP patients. These findings not only provide new insights into the pathogenic mechanisms of TDP-43 in neurodegenerative diseases such as ALS and AD-TDP, but also propose PDI as a potential therapeutic target.},
}

@article {pmid42180530,
year = {2026},
author = {Zhao, W and Lai, Y and Li, Z and Yuan, Z and Wen, Z and Zhang, L},
title = {Targeting non-apoptotic regulated cell death (RCD) to treat neurodegenerative diseases.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {5},
pages = {2601-2644},
pmid = {42180530},
issn = {2211-3835},
abstract = {Regulated cell death (RCD) is well-known as a controlled form of cell death regulated by one or more cascading signaling pathways. Over the past few decades, increasing evidence has implicated various non-apoptotic forms of RCD in neurons-including ferroptosis, parthanatos, necroptosis, pyroptosis, autophagic cell death, paraptosis, and cuproptosis-in the pathogenesis of neurodegenerative diseases (NDs) and their associated clinical manifestations. We provide an in-depth analysis of the associations between these RCDs and NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), and highlight the potential of modulating non-apoptotic RCD subtypes as neuroprotective targets. Besides, we highlight the crosstalk mechanisms among different non-apoptotic RCDs in NDs and the key targets regulating the crosstalk, which hold significant promise for developing dual-functional inhibitors that precisely modulate the pathological microenvironment and overcome drug resistance. As our understanding of death signaling networks deepens, such strategies may lead to breakthrough therapies for multiple NDs. Moreover, we further discuss the emerging small molecule compounds targeting non-apoptotic RCDs and their current research progress in clinical trials for the treatment of NDs, which may provide novel directions for related drugs. This comprehensive analysis paves the way for future research and therapeutic strategies aimed at harnessing non-apoptotic RCD pathways to mitigate neurodegeneration and improve patient outcomes.},
}

@article {pmid42181829,
year = {2026},
author = {Kuru Çolak, T and Akçay, B and Weiss, HR and Nan, X and Elliott, L and Akkoyunlu, SZ and Borysov, M},
title = {Treatment outcomes across curve patterns and severities in adolescent idiopathic scoliosis treated with a pattern-specific CAD-CAM brace.},
journal = {Frontiers in rehabilitation sciences},
volume = {7},
number = {},
pages = {1826976},
pmid = {42181829},
issn = {2673-6861},
abstract = {BACKGROUND: Whether treatment outcomes differ according to curve pattern or baseline severity in adolescents with idiopathic scoliosis (AIS) remains a subject of debate. In particular, it is unclear whether pattern-specific, CAD-CAM-designed brace systems provide comparable effectiveness across different curvature types. This study aimed to evaluate the influence of curve pattern and initial curve magnitude on treatment outcomes in AIS patients treated with a pattern-specific CAD-CAM-designed brace.

METHODS: A retrospective analysis was conducted on female AIS patients aged 10-14 years (Risser 0-2) treated between 2015 and 2024. Cobb angle and angle of trunk rotation (ATR) were used as primary outcome measures. Data from four international clinics were analyzed for changes in spinal curvature and curve pattern.

RESULTS: A total of 145 patients were included (mean age 12.2 years; mean Cobb angle 38.4° ± 11.4°). Post-treatment, mean Cobb angle and ATR values decreased significantly (p < 0.001). The overall treatment success rate was 91%, with no significant differences based on apex vertebra location (p = 0.459), ALS patterns (p = 0.705), or baseline curve severity (p = 0.274).

CONCLUSION: In this multicenter cohort of skeletally immature adolescents with idiopathic scoliosis, pattern-specific brace treatment was associated with significant reductions in both radiographic curvature and trunk rotation. Improvements were observed across different curve patterns and baseline severities. However, given the retrospective design and absence of a comparison group, these findings should be interpreted with caution. Prospective controlled studies are warranted to further validate these observations.},
}

@article {pmid42182254,
year = {2026},
author = {Fonda, BD and Murray, DT},
title = {Phosphorylation Mimicking Mutations Cause TDP-43 to Adopt Different Fibril Conformations.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.14.725298},
pmid = {42182254},
issn = {2692-8205},
abstract = {UNLABELLED: The Tar-DNA Binding Protein-43 C-terminal region, TDP43LC, has been previously shown to form amyloid-like fibrils with distinct folds in ALS and FTD. In both diseases, proteinaceous inclusions contain TDP43 C-terminal protein fragments as well as phosphorylated TDP43. Here, we use solution NMR to show that soluble phosphomimetic TDP43LC, P-TDP43LC, is structurally similar to wild-type TDP43LC. Disperse P-TDP43LC, like wild-type protein, contains a central helical region flanked by long disordered regions. Despite this similarity, our turbidity measurements, imaging, and kinetic assays show that P-TDP43LC has different aggregation behavior than wild-type protein. Using solid state NMR measurements we find that that phosphomimetic mutations alter the wild-type fibril conformation. Electrostatic repulsion from negatively charged sidechains, despite having little effect on the soluble protein's structure, perturbs amyloid-like fibril formation and selects for a different conformation in vitro. These results shed light on the structural role of TDP43LC phosphorylation in fibril formation in disease.

SYNOPSIS: Phosphomimetic mutations at ALS and FTD neurodegeneration-associated sites in an amyloid forming protein perturbs the aggregated structure compared to wild-type protein.},
}

@article {pmid42182325,
year = {2026},
author = {Chauhan, BS and Brennan, MA and Forstmeier, PC and Yifu, H and Godfrey, RK and Van Keuren-Jensen, K and Sattler, R and Ichida, J and Zarnescu, DC},
title = {C9orf72 -associated G4C2 hexanucleotide repeat expression in Drosophila mushroom bodies causes age dependent TDP-43 pathology and dementia relevant phenotypes mediated in part by the glypican Dlp/GPC6.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.08.723849},
pmid = {42182325},
issn = {2692-8205},
abstract = {Hexanucleotide repeat expansions (HREs) in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet the age-, sex-, repeat-length-, and circuit-specific influence on the pathology of neurons remains incompletely understood. Here, we established a Drosophila model of C9orf72 -associated dementia by expressing G4C2 repeats in mushroom body neurons (MBNs), a brain region critical for memory, locomotion, and sleep. Expression of 44X G4C2 repeats ((G4C2) 44X) led to progressive axonal thinning, age-dependent accumulation of Repeat Associated Non-AUG (RAN) translated GR-GFP dipeptide repeat (DPR) puncta, premature nuclear-to-cytoplasmic mislocalization of endogenous TDP-43, increased caspase, reduced lifespan and a loss of presynaptic active zones. Behaviorally, (G4C2) 44X expression caused locomotor hyperactivity, altered spatial working memory, and fragmentation of sleep architecture in an age- and sex-dependent manner, recapitulating core features of FTD. Surprisingly, the shorter (G4C2) 12X repeat, traditionally considered a control, also produced detectable RAN translation and intermediate phenotypes in aging MBNs, suggesting that length- and tissue-associated factors modulate repeat toxicity. We further identified a repeat-length- and age-dependent reduction of the glypican Dally-like protein (Dlp) in (G4C2) 44X consistent with disrupted Wnt-related signaling linked to TDP-43 proteinopathies. Restoring Dlp expression in MBNs mitigated locomotor and working-memory alterations, and loss of presynaptic active zones. In contrast, axonal degeneration, TDP-43 mislocalization, and lifespan were not significantly improved by restoring Dlp, suggesting that multiple mechanisms contribute to G4C2-induced toxicity. Supporting our findings in Drosophila MBNs, a CRISPRi screen in TDP-43 knock-down iNeurons identified GPC6, a human ortholog of Dlp, as a significant contributor to TDP-43 dependent synaptic loss. Together, our findings reveal an aging-sensitive, circuit-specific model of C9orf72 -associated neurodegeneration and highlight roles for DPR accumulation and Dlp/GPC6 dependent synaptic loss in FTD pathomechanisms.},
}

@article {pmid42183197,
year = {2026},
author = {Dashti, M and AlAbdulghafour, F and AlMutairi, O and Mohammad, A and Malik, MZ and AlRefaie, K and Nizam, R and Jacob, S and Chalabi, A and Al Khleifat, A and Al-Mulla, F},
title = {Classical HLA class II associations with ALS in Kuwait reveal a DR7-DQ2.2 risk haplotype.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1820694},
pmid = {42183197},
issn = {1664-3224},
mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics/immunology ; Kuwait ; Middle Aged ; Female ; *Haplotypes ; *Genetic Predisposition to Disease ; Aged ; Alleles ; Adult ; Genome-Wide Association Study ; *Histocompatibility Antigens Class II/genetics ; *HLA-DQ Antigens/genetics ; },
abstract = {BACKGROUND: Genome-wide association studies have implicated the human leukocyte antigen/major histocompatibility complex (HLA/MHC) region in amyotrophic lateral sclerosis (ALS) susceptibility, and immune dysregulation is increasingly recognised as a modifier of disease course. High-resolution HLA data for ALS remain confined to European and East Asian ancestries. We tested whether classical HLA class I and class II variation contributes to ALS susceptibility in a Kuwaiti cohort.

METHODS: We analysed 38 unrelated ALS cases (mean age, 57.4 years; 63.2% male) and 150 population-matched controls (mean age, 57.0 years) from Kuwait. HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 alleles were typed at two-field resolution using HLA-HD from next-generation sequencing (NGS) data. Allele, haplotype, and amino-acid residue associations were tested in BIGDAWG with locus-specific Bonferroni correction, with additional across-locus sensitivity analysis. Significant class II residues were mapped onto AlphaFold 3 structural models and interpreted alongside published class II crystal structures.

RESULTS: No class I allele, haplotype, or residue remained significant after correction. In class II, DQA1*02:01 [odds ratio (OR) = 3.18, 95% confidence interval (CI) 1.67 to 5.95, p c = 0.0007], DRB1*07:01 (OR = 3.00, 95% CI: 1.58-5.59, p c = 0.001), and DQB1*02:02 (OR = 2.48, 95% CI: 1.28-4.69, p c = 0.03) were enriched in cases. The extended haplotype DQA1*02:01~DQB1*02:02~DRB1*07:01 (DR7-DQ2.2) conferred increased odds of ALS (OR = 3.11, 95% CI: 1.53-6.19, p c = 0.002). Amino-acid residue analysis identified convergent risk positions in DQα1 (positions 47, 52, and 54; OR = 3.18, p c = 0.006) and DRβ1 (positions 11, 13, 14, 25, and 30; OR = 2.84, p c = 0.03) that map to the peptide-binding groove and correspond to the defining motifs of DQA1*02:01 and DRB1*07:01.

CONCLUSION: Using high-resolution NGS-based HLA typing in a Kuwaiti cohort, we identified a class II risk signal for ALS centred on the DR7-DQ2.2 haplotype with convergent residue-level support in the peptide-binding domains. These findings support a contribution of class II-restricted antigen presentation to ALS susceptibility and warrant functional validation and replication in larger, independent Middle Eastern cohorts.},
}

Humans
Male
*Amyotrophic Lateral Sclerosis/genetics/immunology
Kuwait
Middle Aged
Female
*Haplotypes
*Genetic Predisposition to Disease
Aged
Alleles
Adult
Genome-Wide Association Study
*Histocompatibility Antigens Class II/genetics
*HLA-DQ Antigens/genetics

@article {pmid42174808,
year = {2026},
author = {Bosoni, P and Vazifehdan, M and Aidos, H and Alves, I and Birolo, G and Faggioli, G and González-Martínez, S and Gromicho, M and Jovanović, A and Kostić, B and Longato, E and Manera, U and Tavazzi, E and Tavazzi, E and Bellazzi, R and Bergamaschi, R and Fernanda Cabrera, M and Chiò, A and de Carvalho, M and di Camillo, B and Fariselli, P and Ferro, N and Madeira, SC and Dagliati, A},
title = {Environmental Personal Exposure Clusters to Investigate Multiple Sclerosis and Amyotrophic Lateral Sclerosis Progression.},
journal = {Studies in health technology and informatics},
volume = {336},
number = {},
pages = {173-177},
doi = {10.3233/SHTI260131},
pmid = {42174808},
issn = {1879-8365},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/physiopathology ; *Multiple Sclerosis/diagnosis/epidemiology ; *Environmental Exposure/analysis ; Disease Progression ; Male ; Female ; Middle Aged ; *Volatile Organic Compounds/analysis ; Prognosis ; Cluster Analysis ; Adult ; *Environmental Monitoring/methods ; },
abstract = {Reliable prognosis in Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS) is hampered by data scarcity and variability. Beyond clinical variables, evidence suggests that environmental data can help capture disease trajectories. We investigated whether personal environmental measures can be organized into stable patterns that inform prognosis. In a multicenter cohort, 293 patients with MS or ALS were equipped with Atmotube air-quality sensors. We normalized volatile organic compound (VOC) time series and computed Dynamic Time Warping distances to capture temporal similarity. Hierarchical clustering yielded five daily exposure clusters, which were profiled using Atmotube variables (season, day type, humidity, temperature) and patient self-reports (work status, time outdoors), and evaluated by day-level differences between personal and fixed-station variables. These clusters can support interpolation of missing wearable intervals and generation of context-aware exposure estimates, thereby strengthening environmental inputs for prognostic modeling in MS and ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/physiopathology
*Multiple Sclerosis/diagnosis/epidemiology
*Environmental Exposure/analysis
Disease Progression
Male
Female
Middle Aged
*Volatile Organic Compounds/analysis
Prognosis
Cluster Analysis
Adult
*Environmental Monitoring/methods

@article {pmid42174849,
year = {2026},
author = {Ferraro, PM and Narteni, S and Lenatti, M and Oliveri, F and Gemelli, C and Cabona, C and Uccelli, A and Paglialonga, A and Mongelli, M and Schenone, A},
title = {A Consensus Clustering Approach to Amyotrophic Lateral Sclerosis Phenotyping.},
journal = {Studies in health technology and informatics},
volume = {336},
number = {},
pages = {338-342},
doi = {10.3233/SHTI260173},
pmid = {42174849},
issn = {1879-8365},
mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/classification ; Humans ; Phenotype ; Cluster Analysis ; Consensus ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS) phenotyping is a challenging task due to its heterogeneous nature and low prevalence. In this paper, we introduce a data-driven approach to support the characterization of ALS phenotypes based on clinical data from a battery of examinations. A consensus clustering method is proposed to identify stable clusters across multiple random data sub-samples, with the objective of discovering whether the retrieved patients' groups and related features align with clinical phenotypes and medical knowledge. Results suggest consistent profiles for bulbar onset ALS patients, driven by onset characteristics, whereas spinal onset ALS patients exhibit greater within-phenotype heterogeneity.},
}

*Amyotrophic Lateral Sclerosis/diagnosis/classification
Humans
Phenotype
Cluster Analysis
Consensus

@article {pmid42174910,
year = {2026},
author = {Strube, T and Weltermann, L and Weber, J and Defosse, J},
title = {Guideline-Aligned Machine Learning for Predicting Ondansetron Administration at the End of Anaesthesia: Explainable Decision Support for PONV Prophylaxis.},
journal = {Studies in health technology and informatics},
volume = {336},
number = {},
pages = {570-574},
doi = {10.3233/SHTI260235},
pmid = {42174910},
issn = {1879-8365},
mesh = {*Ondansetron/administration & dosage ; *Machine Learning ; Humans ; *Postoperative Nausea and Vomiting/prevention & control ; *Decision Support Systems, Clinical/standards ; *Practice Guidelines as Topic ; *Antiemetics/administration & dosage ; },
abstract = {Artificial Intelligence (AI) and Clinical Practice Guidelines (CPGs) both aim to support clinical decision-making but may provide conflicting suggestions. This manuscript presents a Guideline-Aligned Machine Learning (GAML) model to predict ondansetron administration at the end of anaesthesia, based on Gan et al.'s Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting (PONV). n= 16,240 anaesthesia protocols were analysed for risk factors and administered PONV prophylaxes. Logistic regression, multinomial naïve Bayes, and CatBoost classifiers were trained on 80% of protocols with 12-fold cross-validation; optimal thresholds were set by the mean F1-maximising cut-off across folds. Models were evaluated on the remaining 20%, achieving high accuracy (90 ± 1%) and moderate precision and recall (60 ± 5%, 75 ± 4%) across all models. A SHAP decision plot was further computed on the test set to visualise predictor contributions and illustrate a potential interactive preoperative planning interface. Overall, GAML is a promising basis for explainable decision support in clinical care.},
}

*Ondansetron/administration & dosage
*Machine Learning
Humans
*Postoperative Nausea and Vomiting/prevention & control
*Decision Support Systems, Clinical/standards
*Practice Guidelines as Topic
*Antiemetics/administration & dosage

@article {pmid41963935,
year = {2026},
author = {Zhang, B and Shang, D},
title = {Commentary on "Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells".},
journal = {Molecular cancer},
volume = {25},
number = {1},
pages = {},
pmid = {41963935},
issn = {1476-4598},
support = {2025AHGXZK40703//Anhui Provincial Department of Education Natural Science Research Youth Project/ ; 2025byjbgs064//Bengbu Medical University "Jie Bang Gua Shuai" Research Project/ ; 82374248//National Natural Science Foundation of China/ ; },
abstract = {We recently carefully read the article titled “Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells” published by Chu-An Wang et al. in Molecular Cancer. While this study provides valuable insights into tumor-immune crosstalk, we raise two points for clarification to enhance its precision. First, the manuscript classifies T2N0M0 samples as stage II pancreatic ductal adenocarcinoma (PDAC), which conflicts with the eighth edition of the AJCC Cancer Staging Manual that designates T2N0M0 as stage IB. Second, the authors used pancreatic stellate cells (PSCs) as a surrogate for fibroblasts to model stromal effects, but accumulating evidence indicates that PSCs and fibroblasts are not equivalent. To address this, we integrated single-cell, spatial, and bulk transcriptomic data from multiple cohorts. Our analyses revealed substantial differences between fibroblasts and stellate cells in abundance (fibroblasts enriched in primary pancreatic cancer tumor tissues), prognostic relevance (high fibroblasts associated with poorer survival, high stellate cells with better prognosis), spatial distribution (fibroblasts localized around malignant tumor cells), and intercellular communication (fibroblasts as stronger signal senders to malignant tumor cells). These findings confirm that PSCs cannot accurately represent fibroblasts in PDAC. We emphasize that clarifying these points will not undermine the study’s significance but will strengthen its rigor and comparability. Wang et al.’s work remains a valuable contribution to understanding PDAC progression, and we anticipate these clarifications will further advance stromal-immune crosstalk research in PDAC.},
}

@article {pmid42170793,
year = {2026},
author = {Michelon, H and Lefèvre-Dognin, C and Paquereau, J and Guidoni, R and Boudy, V and Ruiz, F and Vallet, T},
title = {Acceptability of Atropine Eyedrops Administered Sublingually for Sialorrhea Treatment Related to Neurological Conditions.},
journal = {Pharmacology research & perspectives},
volume = {14},
number = {3},
pages = {e70250},
doi = {10.1002/prp2.70250},
pmid = {42170793},
issn = {2052-1707},
mesh = {Humans ; *Sialorrhea/drug therapy/etiology ; *Atropine/administration & dosage ; Male ; Middle Aged ; Cross-Sectional Studies ; Female ; Adult ; Ophthalmic Solutions/administration & dosage ; Aged ; Administration, Sublingual ; *Nervous System Diseases/complications ; France ; *Patient Acceptance of Health Care ; *Cholinergic Antagonists/administration & dosage ; },
abstract = {Off-label use of anticholinergic agents (atropine eye drops) administered sublingually are a first-line treatment in standard clinical practice in France to treat sialorrhea in patients with neurological conditions. The ability and willingness to using and administering such medication have become key factors to ensure safe and effective therapy. Given that the critical aspects for ophthalmic product development differ from those for oral medicine, the objectives of this study were to investigate patient acceptability of atropine eye drops for treating sialorrhea. A multi-centric, cross-sectional study using the CAST-ClinSearch Acceptability Score Test methodology was conducted in France between February 2021 and April 2023. In total, 31 evaluations were collected. Most patients were males (74.2%) and the mean age was 51.6 ± 20 years. Poor acceptability was reported in real-life settings. A lack of a suitable administration device combined with excessive saliva flow and patient disabilities made it difficult to ensure the required dose intake. Due to the bitter taste of the drug, poor palatability of the product appeared to be a key concern for oral administration. Designing a suitable form of atropine in accordance with the specificities of patients with neurological disabilities is needed to ensure the effective treatment of sialorrhea.},
}

Humans
*Sialorrhea/drug therapy/etiology
*Atropine/administration & dosage
Male
Middle Aged
Cross-Sectional Studies
Female
Adult
Ophthalmic Solutions/administration & dosage
Aged
Administration, Sublingual
*Nervous System Diseases/complications
France
*Patient Acceptance of Health Care
*Cholinergic Antagonists/administration & dosage

@article {pmid42170807,
year = {2026},
author = {Renou, Q and Néant, N and Destere, A and Lagoutte-Renosi, J and Grégoire, M and Parant, F and Lalanne, S and Lemaitre, F and Gandia, P and Venisse, N and Bouchet, S and Lê, MP and Muret, P and Peytavin, G and Solas, C and Benaboud, S and , },
title = {External Evaluation of Population Pharmacokinetic Models of Cabotegravir, During Its Oral and Intramuscular Administration in HIV-Infected Patients.},
journal = {CPT: pharmacometrics & systems pharmacology},
volume = {15},
number = {6},
pages = {e70180},
doi = {10.1002/psp4.70180},
pmid = {42170807},
issn = {2163-8306},
support = {ANRS 0255//Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS)/Maladies Infectieuses Emergentes/ ; ANRS 0691b//Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS)/Maladies Infectieuses Emergentes/ ; },
mesh = {Humans ; *HIV Infections/drug therapy ; Injections, Intramuscular ; *Models, Biological ; Female ; Male ; *Anti-HIV Agents/pharmacokinetics/administration & dosage ; Administration, Oral ; Middle Aged ; Adult ; *Pyridones/pharmacokinetics/administration & dosage ; Prospective Studies ; Diketopiperazines ; },
abstract = {Cabotegravir (CAB), combined with rilpivirine, is the first long-acting injectable therapy approved for HIV-1 maintenance treatment. While adherence and patient satisfaction have been improved, pharmacokinetic (PK) variability remains a concern. Two population PK models have been developed: one based on data from phase I-III trials and the other on routine clinical data. However, neither model has undergone thorough external evaluation. The aim of this study was to evaluate the predictive performance of these models using an independent prospective dataset to evaluate their suitability to support model-informed precision dosing (MIPD). External validation was performed using data from the French observational and multicenter (n = 14) ANRS0255 CARLAPOP study (736 HIV-infected patients, representing 2192 concentrations). Models were implemented using MONOLIX software and evaluated using goodness-of-fit, prediction-based, and simulation-based diagnostics. For Han's model, regarding plasma concentrations following intramuscular administration, Median Prediction Error (MDPE) was -1.2% (PRED) and -4.4% (IPRED); Median Absolute Prediction Error (MDAPE) was 36.6% (PRED) and 17.9% (IPRED). For Thoueille's model, MDPE was -24.2% (PRED) and -9.2% (IPRED); MDAPE was 39.0% (PRED) and 15.3% (IPRED). However, < 70% of predictions were within a 20% error margin with both models. Graphical analyses of Thoueille's model showed systemic bias, particularly in women, nonsmokers, and patients with higher body mass index. Therefore, neither model was considered reliable enough for MIPD application in our population. Although Han et al.'s model demonstrated higher predictive performances, further improvements are required before it can be reliably applied for MIPD in daily routine.},
}

Humans
*HIV Infections/drug therapy
Injections, Intramuscular
*Models, Biological
Female
Male
*Anti-HIV Agents/pharmacokinetics/administration & dosage
Administration, Oral
Middle Aged
Adult
*Pyridones/pharmacokinetics/administration & dosage
Prospective Studies
Diketopiperazines

@article {pmid42171198,
year = {2026},
author = {Tian, J and Jin, Z and Chi, Y and Wang, P and Sun, H},
title = {Targeting lipid nanoparticle mediated co-delivery of edaravone and kaempferol for amyotrophic lateral sclerosis therapy.},
journal = {Nanoscale},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6nr00300a},
pmid = {42171198},
issn = {2040-3372},
abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by a progressive and selective loss of motor neurons in the central nervous system, particularly in the brain and spinal cord. However, the main cellular mechanisms and cell death pathways leading to motor neuron degeneration have not yet been clarified. Research indicates evidence of ferroptosis in ALS, and the natural compound kaempferol has been demonstrated to inhibit neuronal ferroptosis. However, damage to the blood-brain barrier (BBB) prevents the drug from penetrating the central nervous system, which significantly reduces its therapeutic efficacy. Here, we developed a targeted delivery system named Eda/Kae@Lip-RGD (EKLR), which consisted of liposome-grafted RGD peptides for the co-delivery of the drugs kaempferol and edaravone, capable of crossing the BBB to provide co-delivery of kaempferol and edaravone for combined treatment of ALS. As expected, treatment with EKLR for one month significantly slowed down weight loss and improved athletic performance in SOD1[G93A] transgenic mice. Mechanistically, this nanomedicine suppressed ferroptosis by upregulating the antioxidant proteins GPX4 and SLC7A11, alongside the downregulation of Nrf2 and ACSL4 levels, thus collectively preserving neuronal integrity. Meanwhile, EKLR restored the normal morphology and the survival rate of neurons and maintained the mitochondrial structure and morphological integrity. Accordingly, this nanoplatform may represent a distinctive and potentially effective strategy for achieving neuroprotection in ALS as well as in other disorders of the central nervous system.},
}

@article {pmid42171508,
year = {2026},
author = {Ramos, S and Watson, MD and Lee, JC},
title = {Kinetics and Spatial Distribution of β-Sheet Development in TDP-43CTD Condensate Maturation.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00226},
pmid = {42171508},
issn = {1948-7193},
abstract = {Cytosolic inclusions of aggregated TAR DNA-binding protein 43 (TDP-43) are hallmarks of neurodegenerative disorders such as amyotrophic lateral sclerosis and frontotemporal lobar dementia. A prevailing hypothesis suggests that TDP-43 condensates undergo a liquid-to-solid transition during maturation, involving the formation of β-sheet-rich, amyloid-like aggregates. To test this hypothesis, we sought to study the temporal and spatial evolution of protein secondary structure within individual condensates by Raman spectroscopy. We measured in vitro β-sheet development of the C-terminal domain of TDP-43 (TDP-43CTD) at the single-condensate level under physiological solution conditions. All condensates showed apparent single-exponential kinetics (k = 1.6 × 10[-5] s[-1]) for the disordered-to-β-sheet transformation, as indicated by increased amide-I intensity and a shift of the amide-III band to lower energy. Interestingly, the water bend-libration band exhibited a slower rate (k = 4.0 × 10[-6] s[-1]), suggesting that changes in the water environment lag behind protein conformational rearrangement. Further, Raman maps revealed that protein density is highest near the condensate center, whereas β-sheet content is mostly uniform in the interior of the condensate. The unexpected difference between the spatial distributions of β-sheet content and protein density challenges the typical concentration-dependent model of protein aggregation. Importantly, rare events were captured where condensates exhibited spatially asymmetric β-sheet development, revealing localized structural heterogeneity not detectable by ensemble measurements. Collectively, these results provide insight into the temporal and spatial dynamics of protein structure within TDP-43CTD condensates and demonstrate the utility of Raman spectral imaging for tracking condensate maturation.},
}

@article {pmid42171861,
year = {2026},
author = {Condorelli, GA and Iozzia, A and Bonifacio, D and Pelin, A},
title = {TDP-43 Acetylation at the Neuroimmune Interface: A Hypothesis-Driven Framework for Peripheral Inflammatory Stratotypes in ALS.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42171861},
issn = {1573-6903},
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/immunology ; Humans ; Acetylation ; *DNA-Binding Proteins/metabolism ; Animals ; *Inflammation/metabolism/immunology ; Blood-Brain Barrier/metabolism ; *Neuroimmunomodulation/physiology ; },
abstract = {Transactive Response Deoxyribonucleic Acid-Binding Protein-43 (TDP-43) acetylation may couple motor-neuron degeneration to systemic immune orchestration in Amyotrophic Lateral Sclerosis (ALS). Upon nuclear clearance and mislocalisation, TDP-43 enters the periphery; acetylation shapes its conformation, trafficking and immunogenicity. This narrative review synthesises single-cell transcriptomics, proteomic immunoprofiling and clinical inflammatory phenotyping to examine whether site-specific acetylated TDP-43 species may be associated with peripheral inflammatory signatures relevant to ALS immunopathology. By integrating separate datasets on acetylated TDP-43, monocyte phenotypes and cytokine modules, we propose two provisional endotypes characterised by monocyte reprogramming, cytokine modules and Blood-Brain Barrier (BBB) dysfunction-each representing clinically actionable pathways. Framed as a provisional neuroimmune interface, the acetylation state is considered here as a plausible molecular correlate and potential therapeutic entry point: a measurable clue to inform pharmacological targeting and, potentially, a modifiable target via p300CREB-Binding Protein (CBP)-Histone Deacetylase (HDAC) axes or sirtuin activity. Recasting TDP-43 from neuropathological hallmark to immunoactive sentinel supports a shift from descriptive nosology to stratified immunotherapy, in which treatment allocation is informed by acetylation-defined peripheral signatures.},
}

*Amyotrophic Lateral Sclerosis/metabolism/immunology
Humans
Acetylation
*DNA-Binding Proteins/metabolism
Animals
*Inflammation/metabolism/immunology
Blood-Brain Barrier/metabolism
*Neuroimmunomodulation/physiology

@article {pmid42172922,
year = {2026},
author = {Myers, S and Kraus, E and Davis, ES and Murillo, A and Ng, SC and Sachs, T and Davids, JS and Kenzik, KM},
title = {Ostomy and Anastomotic Leak Differences Among Rural and Urban Surgical Colon Cancer Patients.},
journal = {The Journal of surgical research},
volume = {324},
number = {},
pages = {59-66},
doi = {10.1016/j.jss.2026.04.017},
pmid = {42172922},
issn = {1095-8673},
abstract = {INTRODUCTION: Rural populations experience higher morbidity and mortality after resection of colon cancer (CC) than urban populations. Ostomy creation may obviate or reduce the severity of anastomotic leaks (ALs); however, this practice is surgeon-dependent. Differences in rural-urban ostomy practices and AL following CC resection are unknown.

METHODS: We identified patients who underwent CC resection between 2014 and 2019 from the Surveillance, Epidemiology, and End Results-Medicare database and characterized ostomy practices. We used multivariable logistic regression to evaluate rural-urban differences in AL and readmissions, with and without ostomies. Oaxaca-Blinder nonlinear effect decomposition was used to analyze the proportion of rural-urban difference in AL explained by age, sex, race, Charlson Comorbidity Index, stage of cancer, surgical approach, surgeon specialty, and ostomy creation.

RESULTS: Among 28,031 individuals (17.9% rural), rural patients underwent ostomy surgery less often than urban (47.6% versus 52.4%, P< 0.0001). The rate of AL was higher among rural patients with ostomies (8.6% versus 7.0%, P= 0.0069), and rural ostomy patients were discharged with postacute care services less often (43.8% versus 47.3%, P= 0.0034). Resection by a general surgeon was associated with higher odds of AL only among urban patients (versus colorectal, OR = 1.27; 95% CI = 1.13-1.42). Surgical approach explained 37.5% of the rural-urban AL disparity, surgeon specialty explained 21.5%, and ostomy surgery only explained 2.6% of the difference.

CONCLUSIONS: Ostomy surgery explained a small proportion of the rural-urban AL disparity, while surgical approach explained over a third of the higher AL risk among rural populations. Surgical approach should be prioritized in interventions to improve CC surgical outcomes among rural populations.},
}

@article {pmid42173382,
year = {2026},
author = {Braza, AJ and Viñas-Bastart, M and Sureda-Rosich, M and García-Parra, B and Guiu-Segura, JM and Modamio, P},
title = {Tofersen in SOD1-associated amyotrophic lateral sclerosis: From molecular mechanisms to regulatory milestones.},
journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences},
volume = {223},
number = {},
pages = {107563},
doi = {10.1016/j.ejps.2026.107563},
pmid = {42173382},
issn = {1879-0720},
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive and ultimately fatal neurodegenerative disorder characterized by degeneration of upper and lower motor neurons. Mutations in the superoxide dismutase 1 (SOD1) gene account for approximately 2% of ALS cases and are associated with toxic protein misfolding and aggregation. Tofersen is an antisense oligonucleotide therapy designed to reduce the synthesis of mutant SOD1 protein through targeted mRNA degradation. While this strategy represents a gene-specific therapeutic approach for a subset of ALS patients, evidence regarding its efficacy, effectiveness and long-term outcomes continues to be evaluated in clinical trials and post-marketing studies.

OBJECTIVE: First, to describe the molecular mechanisms underlying SOD1-associated ALS and second, to analyze the therapeutic development, clinical outcomes, and regulatory evolution of tofersen.

METHODS: A narrative review was conducted in PubMed on preclinical and clinical studies published from 2016 through late 2025, complemented by an analysis of public registries and regulatory documentation. Clinical trials were identified through ClinicalTrials.gov and the Clinical Trials Information System (CTIS), and official reports from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were reviewed to contextualize their development and regulatory evaluation.

RESULTS: Fifty-three publications were identified, of which 20 met predefined inclusion criteria after screening and full-text review. Preclinical studies showed reduced mutant SOD1 expression and prolonged survival in transgenic models. Phase I-II trials demonstrated safety, favorable pharmacokinetics, and dose-dependent reductions in SOD1 in the cerebrospinal fluid and plasma neurofilament light chain (NfL) levels. Although the phase III VALOR trial did not meet the primary ALSFRS-R endpoint (a validated questionnaire-based functional rating scale-revised for determining ALS disease progression) at 28 weeks, significant reductions in the surrogate biomarker NfL indicated target engagement and supported accelerated regulatory approval. Extension data suggested potential clinical benefit with early treatment. Ongoing studies, including ATLAS in presymptomatic carriers, and real-world European data support continued evaluation, alongside accelerated regulatory approvals by FDA and EMA.

CONCLUSION: Tofersen marks a paradigm shift in ALS management, establishing the foundation for precision medicine in neurodegenerative diseases. Its ongoing evaluation in the ATLAS trial will determine whether early intervention can prevent or delay disease onset in presymptomatic SOD1 mutation carriers.},
}

@article {pmid42174751,
year = {2026},
author = {Grouls, A and Leavell, YL and Mehta, AK and Kojimoto, G and O'Riordan, DL and Maiser, S and Kluger, BM and Pantilat, SZ and Bischoff, KE},
title = {Embedding Palliative Care Clinicians in ALS Teams Improves ALS Clinicians' Confidence in Their Patient Management and Satisfaction With Palliative Care.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70291},
pmid = {42174751},
issn = {1097-4598},
support = {A142921//ALS Association/ ; },
abstract = {INTRODUCTION/AIMS: Specialty palliative care (SPC) can improve symptoms and well-being for people living with ALS. Few studies capture how ALS clinicians utilize or are impacted by SPC. We sought to understand how the presence of SPC clinicians on ALS teams impacts ALS clinicians' referrals to and satisfaction with SPC.

METHODS: We conducted a survey of interdisciplinary ALS clinicians to understand their confidence in their team's care, SPC referral patterns, and satisfaction with SPC. We compared responses from ALS clinicians with and without SPC in their team.

RESULTS: 141 ALS clinicians completed the survey, having primarily neurology, nursing, and therapy backgrounds. ALS clinicians who had SPC embedded in their team reported more confidence in their team's ability to address pain (63.3% v 37.4%, p < 0.001), dyspnea (88.8% v 70.8%, p = 0.05), and end-of-life needs (71.4% v 52.1%, p = 0.005). They reported fewer SPC referral barriers and referred to SPC for different reasons. ALS clinicians with SPC on their team were more satisfied with SPC's ability to help with motor symptoms (92.7% v 71.4%, p = 0.02), dyspnea (98.3% v 86.7%, p = 0.04), and care coordination (90.0% v 73.5%, p = 0.04).

DISCUSSION: The presence of SPC embedded within multidisciplinary ALS teams is associated with ALS clinicians feeling more confident in their team's ability to address certain care needs, more satisfied with the care provided by SPC, and experiencing fewer barriers to involving SPC. Additional research should explore how embedding SPC on ALS teams impacts patient outcomes.},
}

@article {pmid42166281,
year = {2026},
author = {Harden, KP},
title = {In praise of scientific open relationships: Commentary on Caspi et al. (2026).},
journal = {Journal of psychopathology and clinical science},
volume = {135},
number = {4},
pages = {505-506},
pmid = {42166281},
issn = {2769-755X},
support = {//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; /DA/NIDA NIH HHS/United States ; },
mesh = {Humans ; *Mental Disorders ; *Biomedical Research ; },
abstract = {This commentary responds to arguments presented in Caspi et al.'s (see record 2026-80066-001) viewpoint article. I endorse the authors' overall argument but note that exactly how many mental disorders one needs to study at a time will likely depend on the specific research question. I also describe how transdiagnostic research requires strong norms of data and credit sharing. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

Humans
*Mental Disorders
*Biomedical Research

@article {pmid42166316,
year = {2026},
author = {Meca, A and Cruz, B and Cruz, I and Hinojosa, Z and Nguyễn, M and Gonzales-Backen, M},
title = {Revisiting the two-factor model of ethnic-racial and U.S. identity exploration among Hispanic college students.},
journal = {Cultural diversity & ethnic minority psychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/cdp0000810},
pmid = {42166316},
issn = {1099-9809},
abstract = {OBJECTIVE: Establishing a positive ethnic-racial identity (ERI) and U.S. identity (USI) is an important cultural asset capable of promoting positive adjustment. Although exploration has been identified as the fundamental process underlying ERI and USI development, existing research has largely utilized a unidimensional conceptualization. The present study sought to replicate Syed et al.'s (2013) findings, which differentiated between two forms of ERI exploration, search (i.e., reflection/talking to others) and participation (i.e., involvement in events/experiences), and extend to USI. Moreover, we sought to examine the unique associations between ERI and USI exploration with resolution and negative affect.

METHOD: The sample included 416 Hispanic/Latine college students (83.7% female; Mage = 20.57 years) recruited from a psychology department participant pool at a public Hispanic-serving institution in South Florida in 2017. Participants completed the online survey at their convenience in exchange for course credit.

RESULTS: Findings provided support for the differentiation between ERI and USI search and participation, which were uniquely and differentially associated with resolution and negative affect.

CONCLUSION: Our study highlights the need to move beyond unidimensional conceptualizations of exploration. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid42166520,
year = {2026},
author = {Marques Couto, C and De Melo Queiroz, E and Souza Lima, W and Camilla De Lima Santos, S and José Moreira Nascimento, O},
title = {Clinical characterization and natural history of ALS8/VAPB p.Pro56Ser: upper motor neurone signs, survival, and functional milestones in 78 patients.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2026.2674020},
pmid = {42166520},
issn = {2167-9223},
abstract = {OBJECTIVE: Amyotrophic lateral sclerosis type 8 (ALS8), caused by the VAPB p.Pro56Ser mutation, is a rare familial motor neurone disease with an incompletely characterized profile. We aimed to characterize the clinical phenotype, upper motor neurone (UMN) sign prevalence, survival, and functional milestones.

METHODS: We retrospectively analyzed 78 patients with ALS8 confirmed via molecular testing or familial linkage analysis from 57 apparently unrelated families. UMN signs were assessed using a five-item composite of pyramidal signs. Survival and milestones were estimated using Kaplan-Meier analysis.

RESULTS: Median age at onset was 44.9 years; 51% were men. Onset was lumbar in 94%, proximally predominant. UMN signs were present in 53 patients; none exhibited clonus. At admission, 51% had spinal-onset ALS, 42% progressive muscular atrophy (PMA) and 6% flail leg; 30% of patients with PMA subsequently developed UMN signs. Survival was 21.9 years; times to wheelchair dependence and noninvasive ventilation were 7.0 and 10.0 years, respectively. Bulbar involvement occurred in 17 (21.8%) patients, predominantly as dysphonia. UMN status did not affect survival (p = 0.312). The standardized mortality ratio was 4.54 (95% CI 2.77-7.01), supporting disease-related excess mortality.

CONCLUSIONS: ALS8 is a slowly progressive motor neurone disease with lumbar onset, ascending progression, and frequent but subtle UMN signs. Survival was markedly prolonged but functional decline followed a predictable sequence. These findings expand the phenotypic characterization of ALS8 and support genetic counseling and anticipatory management.},
}

@article {pmid42167402,
year = {2026},
author = {Ballesteros, AL and Rodriguez-Cañamero, S and Martín-Conty, JL and Polonio-López, B and Pozo-Vegas, CD and López-Izquierdo, R and Martín-Rodríguez, F and Sanz-García, A},
title = {Effect of Glycemia and Diabetes on Early Warning Scores Performance in Prehospital Patients With Acute Illness: Multicenter, Prospective, Cohort Study.},
journal = {Mayo Clinic proceedings},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.mayocp.2026.05.008},
pmid = {42167402},
issn = {1942-5546},
abstract = {OBJECTIVE: To determine how glycemia and diabetes affect the performance of the NEWS and mSOFA scores to predict 30-day mortality in patients with acute illnesses requiring EMS assistance.

PARTICIPANTS AND METHODS: This prospective, multicenter cohort study evaluated 14,726 adults with acute illness attended by advanced life support (ALS) units and helicopter emergency medical services (HEMS) between January 1, 2019, and December 1, 2025. Associations between glucose levels (hypoglycemia, normoglycemia, hyperglycemia), diabetic status, and 30-day mortality were analyzed. Predictive capacity (area under the receiver operating characteristic curve, AUC-ROC) of NEWS and mSOFA stratified by metabolic groups was assessed and compared.

RESULTS: A nonlinear U-shaped relationship was observed between glycemia and mortality. mSOFA outperformed NEWS (AUC-ROC 0.877 vs 0.822). Under hyperglycemia, NEWS performance decreased (AUC-ROC 0.764), while mSOFA remained more stable (AUC-ROC 0.815). Both scores performed better in nondiabetic patients (AUC-ROC >0.82) than in diabetics with complications, suggesting stress hyperglycemia in nondiabetics reflects greater acute severity.

CONCLUSIONS: mSOFA showed greater robustness and more stable predictive performance than NEWS with glycemic variability, particularly in nondiabetic patients with stress hyperglycemia, suggesting glucose serves as a universal biomarker of acute severity across prehospital acute illness. These findings support potential value of prehospital POCT to improve critical patient identification and risk stratification where resources and infrastructure allow.},
}

@article {pmid42168009,
year = {2026},
author = {Corcia, P and Bernard, E and de la Cruz, E and Danel, V and Soriani, MH and Guy, N and Esselin, F and Bruneteau, G and Pradat, PF and Goutines, V and Catherine, J and Eyraud, N and Cheve, P and Fernandez, A and Erazo, D and Couratier, P},
title = {Primary Lateral Sclerosis French National Diagnostic and Care Protocol.},
journal = {Revue neurologique},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurol.2026.04.006},
pmid = {42168009},
issn = {0035-3787},
abstract = {Primary lateral sclerosis (PLS) is a rare neurodegenerative motor neuron disease characterized by progressive and selective involvement of the central motor neuron within the bulbar and spinal regions. It is estimated to account for 1-5% of motor neuron diseases and typically presents in the fifth or sixth decade of life, with a slight male predominance. According to current consensus criteria, the diagnosis relies on the demonstration of progressive upper motor neuron dysfunction in the absence of lower motor neuron involvement, with persistence of isolated upper motor neuron signs for at least four years in order to exclude a slowly progressive upper motor neuron-predominant form of amyotrophic lateral sclerosis (ALS). The French Motor Neuron Disease Network (FILSLAN) developed a National Diagnostic and Care Protocol (PNDS) with the aim of standardizing diagnostic criteria, optimizing differential diagnosis, and providing evidence-based recommendations for therapeutic management and follow-up across the national territory. These recommendations were elaborated in accordance with the methodological framework of the French National Authority for Health for rare diseases. The protocol provides practical guidance for establishing PLS as a diagnosis of exclusion, distinguishing it from ALS and hereditary spastic paraplegias, and organizing appropriate clinical and paraclinical investigations. It also outlines indications for genetic testing in selected cases and defines a multidisciplinary management strategy centered on symptomatic treatment, early rehabilitation, respiratory and nutritional surveillance, and psychosocial support. Given the slower progression of PLS compared with ALS, biannual multidisciplinary follow-up is generally appropriate. This protocol aims to harmonize clinical practice and improve patient care while acknowledging the current absence of disease-modifying therapies.},
}

@article {pmid42168859,
year = {2026},
author = {Levin, AB and Joshi, Y and Vaidhya, N and Kantianis, J and Macdonald, PS},
title = {Anaesthetics considerations for organ retrieval in the voluntary assisted dying patient - case report.},
journal = {BMC anesthesiology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12871-026-03921-w},
pmid = {42168859},
issn = {1471-2253},
abstract = {BACKGROUND: Voluntary assisted dying (VAD) is now legalised in several countries. Organ donation after VAD provides unique moral and logistical challenges. This report highlights the role of the anaesthetist in such cases.

CASE PRESENTATION: A 50-year-old man with end-stage amyotrophic lateral sclerosis underwent VAD and became an organ donor. Anaesthetic and logistical considerations during procurement are described. Advances in organ retrieval after VAD and psychosocial implications are briefly outlined.

CONCLUSIONS: Organ donation after VAD presents unique opportunities and challenges. The anaesthetist plays a key role in ensuring both dignity for the patient and optimal conditions for organ retrieval.},
}

@article {pmid42169130,
year = {2026},
author = {Sarti, A and Mandrioli, J and Costanzini, S and Balbo, GX and Malagoli, C and Martini, N and Despini, F and Violi, F and Malavolti, M and Martinelli, I and Giacchino, M and Donelli, G and Canali, E and Zinno, L and Teggi, S and Vinceti, M and Filippini, T},
title = {Green space exposure and risk of amyotrophic lateral sclerosis: a population-based case-control study in Northern Italy.},
journal = {Environmental health : a global access science source},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12940-026-01311-w},
pmid = {42169130},
issn = {1476-069X},
support = {"PRIN 2022" (No. 2022MHMRPR)//Ministero dell'Università e della Ricerca/ ; "UNIMORE FAR 2023"//Università Degli Studi di Modena e Reggio Emilia/ ; },
abstract = {BACKGROUND: The contribution of environmental determinants in the etiology of amyotrophic lateral sclerosis (ALS) is still unclear. Among the various environmental factors, exposure to green spaces, also known as greenness, is attracting considerable interest as many studies have reported its beneficial associations to health outcomes, particularly to neurodegenerative diseases.

METHODS: To investigate the relation between greenness and ALS risk, we conducted a population-based case-control study in a Northern Italy population (from Modena, Reggio Emilia and Parma provinces), including 499 cases of ALS newly-diagnosed from 1998 to 2011 and 1,935 sex-, age-, and province-matched controls randomly selected from study provinces residents. We evaluated the association between greenness in the proximity of residence and ALS risk, assessing exposure through multiple satellite-based and land-use derived indices, both conventional and novel devised, for a total of six indices, each providing specific information, including annual and seasonal Normalized Difference Vegetation Index (NDVI), NDVI-weighted to green areas, green cover ratio, accessibility index, and their combined Green Exposure Index (GEI). We used conditional logistic regression models to evaluate disease risk for increasing exposure through both fixed-categories and non-linear restricted cubic splines.

RESULTS: We observed a non-linear U-shaped association between greenness and ALS risk with increased odds ratios at both low and high levels. Results were more defined when using NDVI-based indices, while the associations were smoother when considering GEI. The higher risk at low levels may be related to lower accessibility to green spaces with lower physical activity and higher exposure to outdoor air pollutants, whilst elevated greenness may reflect higher exposure to neurotoxic pesticides. These results were confirmed also after adjustment for potential confounders, namely magnetic fields and light at night. Sex stratified analysis yielded similar results, except for more distinct associations in females for GEI.

CONCLUSIONS: Despite the limitations due to possible unmeasured confounding and exposure misclassification related to the use of residential data, our results provide evidence of an inverse association between intermediate residential greenness and ALS risk, and may have public health implications including disease prevention and urban planning.},
}

@article {pmid42170697,
year = {2026},
author = {Prasun, P and Rasberry, M},
title = {Expanding Spectrum of FIG4-Related Neurological Disorders of Lysosomal Homeostasis: Case Report and Overview of the Potential Genotype-Phenotype Correlations.},
journal = {Clinical genetics},
volume = {},
number = {},
pages = {},
doi = {10.1111/cge.70185},
pmid = {42170697},
issn = {1399-0004},
abstract = {Biallelic loss-of-function variants in FIG4 are associated with Charcot-Marie-Tooth disease type 4J, a progressive peripheral sensorimotor demyelinating polyneuropathy. Biallelic null FIG4 variants cause Yunis-Varon syndrome, a severe neurological disorder characterized by global developmental delay, hypotonia, brain malformations, skeletal defects, dysmorphic facial features, and juvenile lethality. In the past few years, many individuals with combined central and peripheral nervous system disease associated with biallelic FIG4 variants have been described. In addition, certain heterozygous FIG4 variants are associated with amyotrophic lateral sclerosis. We describe an individual with global developmental delay, hypotonia, cerebral hypomyelination, peripheral hypomyelinating polyneuropathy, frequent fractures, and juvenile ossifying fibroma. The spectrum of clinical presentation of FIG4-related disorders is increasingly being recognized. Our observations expand the phenotypic spectrum of FIG4-related neurological disorders. In addition, we provide an overview of the potential genotype-phenotype correlations of this expanding group of disorders of lysosomal homeostasis.},
}

@article {pmid42160473,
year = {2026},
author = {Kim, S and Curtis, SE and Iacono, D and Mehdiyoun, NF and Mitchell, L and Genge, A and Brandt, AU and , and Mancini, M},
title = {Types and frequencies of adverse events across clinical trials for patients with amyotrophic lateral sclerosis: an analysis of the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/21678421.2026.2667290},
pmid = {42160473},
issn = {2167-9223},
abstract = {OBJECTIVE: Symptoms of amyotrophic lateral sclerosis (ALS) may present as adverse events (AEs) in ALS clinical trials. Identifying anticipated AEs independent of investigational drug is crucial for trial design and required by the FDA for safety reporting and assessment in drug development. This study describes anticipated AEs and their predicted incidence in ALS trials, leveraging data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.

METHODS: Placebo-treated people living with ALS (age ≥18 years, disease duration ≤36 months, ≥50% of predicted vital capacity at screening) were included. A confirmed diagnosis per the El Escorial criteria was required for a sensitivity analysis. Reported AEs were grouped based on pathophysiology and implications in clinical management and safety monitoring. AEs were further consolidated, with seven anticipated groups pre-specified for analysis. AE incidence proportions (IPs) and rates in person-years were estimated.

RESULTS: The analysis included 1,388 participants (mean [SD] age: 56.8 [11.3] years; mean [SD] disease duration: 1.4 [0.6] years). IP was ≥5% for 24 AE groups, highest for falls and injuries (18.8%), headaches (13.5%), muscle weakness (13.1%), and gastrointestinal signs and symptoms (13.1%). Of seven pre-specified AE groups, falls, injuries, and fractures were the most frequent (23.0%), followed by severe respiratory failure and disorders including dyspnea (19.1%) and dysphagia (10.5%). Sensitivity analysis results were comparable (n = 931), although IPs were generally lower.

CONCLUSIONS: These new findings will facilitate a systematic approach for safety monitoring and reporting in ALS trials, enable detection of true safety signals that may be obscured by these events, and support clinical development.},
}

@article {pmid42160478,
year = {2026},
author = {Cosijn, FS and van Unnik, JWJ and Exalto, LG and de Groot, LN and Weemering, DN and van Rijssen, RC and Vink, RG and van den Berg, LH and van Eijk, RPA},
title = {Clinical drug development in amyotrophic lateral sclerosis: industry-reported challenges and opportunities.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2026.2671167},
pmid = {42160478},
issn = {2167-9223},
abstract = {OBJECTIVE: The pharmaceutical industry plays a pivotal role in amyotrophic lateral sclerosis (ALS) drug development, yet the challenges and priorities remain largely unexplored. This study aims to identify industry-perceived opportunities for ALS and examine industry perspectives on trial design.

METHODS: A survey study was conducted among pharmaceutical companies involved in ALS drug development. The survey was based on literature review and interviews with industry experts. Final survey topics included scientific and operational challenges as well as preferred design settings for phase 2 and 3 clinical trials. Respondents were asked to rank trial-related topics using Likert scales.

RESULTS: In total, 53 industry professionals responded, representing 42 international companies. Respondents identified three major scientific challenges: heterogeneity in disease progression, lack of reliable biomarkers, and insensitive efficacy measures. Insufficient funding, high dropout rates, and staffing shortages emerged as main operational barriers. For phase 2 trials, neurofilament light chain was most often prioritized as primary outcome, whereas the ALS Functional Rating Scale-Revised was prioritized for phase 3, although priority rankings varied considerably among respondents. Expected median sample sizes were 100 patients (range 20-300) for phase 2 and 300 patients (range 60-800) for phase 3. Overall, 58% of the respondents indicated that standardizing aspects of trial design could enhance trial quality and success rates.

CONCLUSIONS: This study provides an overview of the industry-perceived challenges, exposing strategic knowledge gaps related to disease and clinical heterogeneity. Standardization of key trial design elements may help mitigate these challenges and better align ALS drug development efforts.},
}

@article {pmid42160479,
year = {2026},
author = {Catley, CS and Hoedt, EC and Pockney, P and Keely, S and Hedley, KE},
title = {Unravelling Anastomotic Leak: Biological Mechanisms Underlying Intestinal Healing After Resection.},
journal = {American journal of physiology. Gastrointestinal and liver physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpgi.00071.2026},
pmid = {42160479},
issn = {1522-1547},
support = {//University of Newcastle Australia (UON)/ ; //Australian Government (Federal Government)/ ; G2300020//nswgov | NSW Health (The NSW Health)/ ; },
abstract = {Understanding intestinal healing following resection and anastomosis is a challenging topic due to the complexity of underlying mechanisms. Anastomotic healing follows the fundamental phases of normal wound repair; however, the intestinal anastomosis represents a unique biological environment in which factors such as the structure of the intestines as well as the microbiome, may modify the healing process. Disruptions in any of the healing phases such as the inflammatory, proliferative and remodelling phase may result in severe complications, characterised by the intraluminal contents leaking out into the extraluminal space, termed an anastomotic leak (AL). Despite decades of surgical advancements, we are still no closer in understanding the underlying AL aetiology. It is clear that ALs are multifactorial in nature and contributed to by patient, technical and biological-related factors, however, emerging evidence suggests that biological mechanisms may play a more significant role in AL pathology than originally believed. Evidence points to an interplay between epithelial healing, tissue oxygenation and the resident microbiome in influencing mucosal healing at the anastomotic site. However, the precise contribution of these factors in failed anastomotic healing and AL aetiology remains unclear. In this review, we examine the phases of healing, discuss the existing literature on biological factors affecting anastomotic healing and the advancements made to improve AL rates by targeting the healing response.},
}

@article {pmid42160515,
year = {2026},
author = {Zhang, M and Yang, W and Wang, J and Zou, B and Zheng, JC and Wu, Q and Gao, G},
title = {Immunotherapeutic landscape of amyotrophic lateral sclerosis: A bibliometric analysis of research trends, translational priorities, and collaboration networks (2006-2025).},
journal = {Human vaccines & immunotherapeutics},
volume = {22},
number = {1},
pages = {2664985},
doi = {10.1080/21645515.2026.2664985},
pmid = {42160515},
issn = {2164-554X},
mesh = {*Amyotrophic Lateral Sclerosis/therapy/immunology ; Humans ; *Bibliometrics ; *Immunotherapy/methods/trends ; *Translational Research, Biomedical/trends ; Animals ; },
abstract = {Amyotrophic lateral sclerosis (ALS) remains a major therapeutic challenge, with immune dysregulation increasingly recognized as a critical driver of disease progression. Despite extensive mechanistic research, no immunotherapeutic approach has achieved consistent disease-modifying effects, raising questions about whether this translational gap reflects biological complexity or structural misalignment within the research ecosystem. To characterize the intellectual evolution of ALS immunotherapeutics research, identify immune targets with translational potential, and evaluate collaboration patterns that may influence translational efficiency, we performed a bibliometric analysis of 2,256 publications indexed in Web of Science and Scopus using network-based approaches including co-citation clustering, keyword co-occurrence, and citation burst detection implemented in CiteSpace, VOSviewer, and R-Bibliometrix. Publication output increased 8.4-fold over the study period, delineating three developmental phases. Thematic analyses revealed a shift from early emphasis on microglial biology and SOD1-based models toward recent focus areas including the gut-brain axis, C9orf72-associated immune dysregulation, and advanced immunomodulatory strategies. Collaboration networks remain predominantly regional despite strong contributions from the United States, Europe, and Asia, with limited integration between mechanistic research groups and clinical trial consortia. Among immune-directed therapeutic strategies, regulatory T cell modulation and microglial-targeted approaches exhibit the highest translational readiness. These findings suggest that the lack of effective ALS immunotherapeutics reflects not only biological complexity but also structural and strategic misalignment within the research ecosystem. This bibliometric analysis provides a systems-level framework to guide more integrated translational strategies in ALS immunotherapeutics development.},
}

*Amyotrophic Lateral Sclerosis/therapy/immunology
Humans
*Bibliometrics
*Immunotherapy/methods/trends
*Translational Research, Biomedical/trends
Animals

@article {pmid42161327,
year = {2026},
author = {Vallikivi, JK and Kooyman, M and , and Kirby, J and Nigel Leigh, P and Iacoangeli, A and Al-Chalabi, A and Al Khleifat, A},
title = {CYP2D6 variants in amyotrophic lateral sclerosis: an association study of risk and survival.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag178},
pmid = {42161327},
issn = {1460-2156},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapeutic options. Riluzole remains the only widely available disease-modifying treatment for ALS, yet its survival benefit is modest and likely to vary substantially between patients. Cytochrome P450 2D6 (CYP2D6), is a highly polymorphic enzyme that contributes to interindividual variability in the metabolism of many drugs. CYP2D6 is also expressed in the brain, and experimental and translational studies indicate that brain CYP2D activity can influence local metabolism of neuroactive compounds. Accordingly, CYP2D6 poor function variants have been examined as susceptibility modifiers in the development of other neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease, with heterogenous evidence; however, the role of CYP2D6 in ALS has not been established.},
}

@article {pmid42161687,
year = {2026},
author = {Carter, TE and Gunarathna, I},
title = {Reassessing malaria-transmitting mosquito evolution with a neotropical lens.},
journal = {Trends in parasitology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.pt.2026.05.006},
pmid = {42161687},
issn = {1471-5007},
abstract = {Tennessen et al.'s study addresses longstanding knowledge gaps regarding the evolutionary drivers of a major Neotropical malaria vector, Anopheles darlingi. Through extensive whole-genome analysis, they revealed geographically structured An. darlingi populations with no evidence of sympatric species and strong signals of widespread insecticide resistance through convergent evolution.},
}

@article {pmid42161891,
year = {2026},
author = {Liu, Y and Shi, K and Zhang, M and Wei, J and Feng, M and Dayan, FE and Tao, X and Feng, Z},
title = {Establishment of a versatile virus-based system for elucidating herbicide resistance in Galium aparine.},
journal = {Plant physiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/plphys/kiag285},
pmid = {42161891},
issn = {1532-2548},
abstract = {Herbicide resistance challenges sustainable weed management in crop fields. However, the lack of gene manipulation tools for weeds hinders studies of herbicide resistance evolution and regulation. Here, we identified that tobacco mosaic virus (TMV) can systemically infect Galium aparine, a noxious broadleaf weed common in wheat and rapeseed fields, among thirteen broadleaf weeds. The TMV-based expression system can be used to elucidate herbicide resistance in G. aparine. We demonstrated that virus-based expression of BAR, ALS and its site-directed mutagenized form in G. aparine plants can impart herbicide resistance. To expand the application of this system in metabolic resistance studies, ten upregulated P450 genes in the tribenuron-methyl-resistant G. aparine population plants were identified. Expression of these P450 genes in G. aparine via this system enhanced tribenuron-methyl resistance in G. aparine plants. Additionally, we confirmed Eleusine indica CYP81A104 functions in herbicide resistance through heterologous expression in G. aparine plants, suggesting that this system can be used to investigate the roles of genes from other weed species. The TMV vector-based assay system enabled the functional validation of weed genes within two months, which is shorter than the time required in other heterologous expression systems (i.e., stable expression of weed genes in rice or Arabidopsis). Thus, this virus-based system provides insights into target-site and/or metabolic-based resistance mechanisms to herbicides in G. aparine and possibly in other weed species.},
}

@article {pmid42162572,
year = {2026},
author = {Mehta, AK and Steele, SU and Shah, I and Wang, K and Booth, A and Swain, C and Desai, A and Popli, KA and Maragakis, NJ and Wright, R},
title = {Improving ALS Clinic Care Through Experience-Based Co-Design: A Participatory Action Research Study.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70279},
pmid = {42162572},
issn = {1097-4598},
support = {//Harold Young Scholarship/ ; },
abstract = {INTRODUCTION/AIMS: Multidisciplinary clinics (MDCs) are the standard of care for amyotrophic lateral sclerosis (ALS), yet little is known about how well they meet patient and care partner needs, or how stakeholder engagement can be used to strengthen these services. The aim of this study was to explore the experiences of people living with ALS (pALS), care partners (cALS), and staff in an ALS MDC to identify care gaps and collaboratively develop improvement strategies.

METHODS: We conducted a six-stage experience-based co-design (EBCD) study comprising narrative interviews with pALS, cALS, and ALS clinic staff, followed by validation events and co-design workshops. Data were analyzed using reflexive thematic analysis. Priority areas for improvement were identified through collaborative ranking and translated into actionable interventions through iterative working groups.

RESULTS: A total of 11 pALS, eight cALS, and 10 clinic staff participated. Two shared priority domains were identified: (1) communication and relationships across the care continuum, and (2) navigational and supportive resources. Stakeholders unanimously identified communication and relationships between cALS and staff as the highest priority for improving MDC care delivery. Key strategies included pre-visit orientation materials, pacing information delivery aligned with patient readiness, and incorporating digital tools to enhance flexible access to resources.

DISCUSSION: Curated, iterative education is essential for pALS and cALS across the disease trajectory. Improvement strategies developed through equitable stakeholder partnership may yield different, and potentially more patient-centered priorities for ALS MDC care delivery than strategies developed by any single stakeholder group alone.},
}

@article {pmid42162905,
year = {2026},
author = {Alamri, MA and Afzal, M and Pandey, SN and Afzal, O and Akela, MA and Rekha, A},
title = {Exosomal miRNA in cerebrospinal fluid as biomarkers for neurodegenerative disease.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {121094},
doi = {10.1016/j.cca.2026.121094},
pmid = {42162905},
issn = {1873-3492},
abstract = {Cerebrospinal fluid protein biomarkers, such as the Aβ42/Aβ40 ratio, phosphorylated tau, and neurofilament light chain, have significantly advanced the diagnostic process for Alzheimer's disease. Nonetheless, these biomarkers face challenges in effectively distinguishing Alzheimer's disease from frontotemporal dementia or Parkinson's disease from dementia with Lewy bodies. This limitation arises from overlapping protein profiles and the variability inherent in immunoassay techniques. A complementary class of analytes is exosomal microRNAs in cerebrospinal fluid, where these non-coding RNAs are secreted by neurons, astrocytes, and microglia, are resistant to RNase degradation, and have a disease-specific expression pattern. This review critically evaluates the existing evidence of cerebrospinal fluid exosomal miRNAs as diagnostic biomarkers in Alzheimer's disease, frontotemporal dementia, Parkinson's disease, dementia with Lewy bodies, and amyotrophic lateral sclerosis. Exosome isolation techniques and detection platform characteristics were compared using RT-qPCR, droplet digital PCR, and small RNA sequencing. Pre-analytical factors, such as collection protocols, hemolysis contamination, freeze-thaw cycling, and circadian sampling variation, were assessed. miRNA profiling data based on disease stratification, receiver operating characteristic performance of the combinatorial panel, and strategies combining exosomal miRNAs with core cerebrospinal fluid proteins were synthesized. This article brings together disease-specific miRNA signatures, pre-analytical standardization needs, and diagnostic accuracy analyses in a translational model to fill the literature gap and form the basis for developing exosomal miRNA panels for rigorously validated clinical laboratory practice.},
}

@article {pmid42163674,
year = {2026},
author = {Qi, M and Fei, L and Cui, W and Ho, PW and Lee, SM and Li, J and Zhang, Z},
title = {Unraveling the Pathological Mechanisms and Biomarkers of Amyotrophic Lateral Sclerosis: A Comprehensive Review.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X431460260227095109},
pmid = {42163674},
issn = {1875-6190},
abstract = {Amyotrophic lateral sclerosis (ALS) is an devastating neurodegenerative disorder with a very fast course and a very high fatality rate. The review discusses the intricate pathophysiology of ALS, such as the alterations caused by the genetic mutations of the C9orf72 and SOD1 genes, the misfolding and aggregation of proteins, oxidative stress, the excitotoxicity of glutamate, neuroinflammation, malfunctions in mitochondria, and axonal transport. Heterogeneity of the disease makes the development of biomarkers in ALS challenging; however, some promising candidates have been identified. Protein aggregation markers, including TDP-43 and SOD1, oxidative stress markers, such as 8-oxodG, neuroinflammatory markers, such as CRP and MCP-1, and neurological injury markers, such as NfL and pNfH, have potential in diagnosis, monitoring, and prediction. The miRNAs and particular metabolites can also provide clues to the molecular basis of ALS. The creation of biomarkers is challenged by the presence of a significant amount of disease heterogeneity and the lack of animal model reliability. The review highlights the importance of further research on biomarkers aimed at improving the diagnosis, treatment, and development of drugs for ALS. It supports the concept of a systematic biomarker development process, including genetic testing and molecular subgroup analysis, to enhance diagnostic accuracy and prognostic prediction capabilities. Exploring the interrelationship between the pathological process of ALS and the treatment based on multi-biomarker strategies is crucial for achieving effective management of this disease. As our understanding of ALS deepens, we expect to discover more new biomarkers in the future. This will significantly improve the diagnosis, treatment, and overall management of this devastating diseas.},
}

@article {pmid42163677,
year = {2026},
author = {Tiwari, D and Mukherjee, A and Singh, S},
title = {Interplay of NMDAR and AMPAR in the Pathophysiology of Alzheimer's, Parkinson, ALS, Huntington's, and Epilepsy: An Update in Therapeutic Perspective.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X466249260418090832},
pmid = {42163677},
issn = {1875-6190},
abstract = {Glutamate-mediated excitotoxicity is a central driver of neurodegeneration and represents a shared pathogenic mechanism across neurodegenerative diseases and epilepsy, with N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid recep-tors (AMPARs) occupying central roles in synaptic plasticity, Ca[2+] signalling, and neuronal survival. Dysregulation of these receptors disrupts the balance between pro-survival and pro-death pathways, accelerating neuronal loss in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lat-eral sclerosis (ALS), Huntington's disease (HD), and epilepsy. Disease-specific triggers converge on common patterns of receptor dysregulation, including a shift toward extrasynaptic NMDAR signal-ling and the pathological emergence of Ca[2+]-permeable AMPARs (CP-AMPAR), ultimately driving synaptic failure and neuronal loss. Although numerous NMDAR and AMPAR-directed modulators have demonstrated neuroprotective efficacy in preclinical models, clinical translation has been lim-ited by inadequate spatial, kinetic, and subunit selectivity, as well as adverse effects arising from the disruption of physiological glutamatergic transmission. In this review, we synthesize the literature published between June 1990 and March 2025 to develop an integrative framework that links recep-tor localization, downstream Ca[2+]-dependent signalling, astrocytic regulation, mitochondrial dys-function, and disease progression across these disorders. By critically evaluating both successful and failed therapeutic strategies, we provide insight into evident research gaps in the field and the neces-sity of addressing them to develop precise multi-target approaches at both the genetic and cellular levels as next-generation therapeutics. Such an approach would be essential to move beyond indis-criminate receptor blockade strategies, which have repeatedly proven ineffective over the decades, and towards a future of durable neuroprotection.},
}

@article {pmid42164014,
year = {2026},
author = {Cheung, N},
title = {Symptom-Level Precision Neurology in Amyotrophic Lateral Sclerosis (ALS): Linking Microglial Pruning, Mitochondrial Nicotinamide Adenine Dinucleotide (NAD+) Compensation, and Autophagy Failure Across the Aging Spectrum.},
journal = {Cureus},
volume = {18},
number = {5},
pages = {e109147},
pmid = {42164014},
issn = {2168-8184},
abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurological disease with limited disease-modifying treatment options and, for many patients, a short survival window. The clinical course varies widely. Limb weakness, bulbar impairment, respiratory decline, fine-motor dysfunction, cognitive change, mood symptoms, and fatigue may each appear at different times and progress at different rates. This variability suggests that motor neuron loss alone may not fully explain the patient-level pattern of symptoms. This article is a narrative hypothesis framework, not a clinical guideline or a validated stratification tool. Established ALS biology, associative genomic findings, preclinical observations, computational predictions, and author-derived hypotheses are therefore separated throughout the article. This review brings together four interlinked studies by the current author as a primary hypothesis-generating corpus, which proposes that synaptic plasticity fragility may initiate a microglial pruning continuum shared by major depressive disorder and ALS, while ALS-specific progression may depend on mitochondrial stress, oxidized nicotinamide adenine dinucleotide (NAD+) compensation failure, and collapse of autophagy under aging-related limits. The model presented here maps symptom domains to vulnerable circuit compartments and separates three broad biological states: compensated plasticity, fragile plasticity, and network collapse. A compact mechanistic formulation is used to describe the balance between pruning pressure, glutamatergic burden, and aging stress on one side, and oxidative phosphorylation capacity, NAD+ reserve, and autophagic clearance on the other. The framework also incorporates opposing phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) pathway patterns that may distinguish ALS from frontotemporal dementia (FTD) within an aging context. The result is a falsifiable, biomarker-oriented hypothesis model for future studies, not an evidence-based diagnostic or therapeutic algorithm.},
}

@article {pmid42164185,
year = {2026},
author = {Albesher, AA and Muflehi, NA and Hakami, YA and Barnawi, JA and Softah, RE and Al Ghalib, LH and Bukhari, MA and Almotiri, RA and Algethami, MS and Mahboob, SW and Hakami, RK and Alsaad, A},
title = {Top 50 Cited Articles on the Treatment of Major Depressive Disorder.},
journal = {Cureus},
volume = {18},
number = {4},
pages = {e107337},
pmid = {42164185},
issn = {2168-8184},
abstract = {Major depressive disorder (MDD) is a common mental health disorder and is one of the leading causes of disability. Numerous treatment modalities have been studied for MDD, from interventions to psychotherapies. However, no exhaustive investigation has yet provided an overview of influential research on MDD treatments. Studies do not cover influential efforts occurring in the form of a comprehensive bibliometric review. This bibliometric study aims to fill this gap by thoroughly examining the characteristics of the 50 most cited articles on MDD treatment and providing an essential understanding of the intellectual structure and historical development over time. To guarantee a comprehensive research collection of trends in the treatment of MDD, we reviewed 50 pertinent papers without limiting the search by publication year, and the data collection was performed in a neutral manner. The search focuses on extensive citations from other publications and categorizes them according to their frequencies. Between 1989 and 2018, the top 50 MDD treatment publications received 96-1,837 citations (median 210, IQR 121-299). The 2000s and 2010s had a high level of publication activity (21 articles each, 42% per decade). Geographically, the United States (24, 48%), Canada (12, 24%), and the United Kingdom (5, 10%) dominated the journals. The majority of study types were randomized controlled trials (RCTs) (32, 64%), followed by systematic reviews/meta-analyses (16, 32%) and prospective cohorts (2, 4%). The publications covered a range of treatment modalities, including pharmacological, psychotherapeutic, neurostimulation, and lifestyle/complementary approaches. Elkin et al.'s NIMH Treatment of Depression Collaborative Research Program report (1,738 citations) and Unützer et al.'s IMPACT collaborative care RCT (1,837 citations) were the most referenced publications. Our results shed light on the conceptual framework of MDD treatment research, as current guidelines are shaped by significant randomized trials and systematic reviews. Precision-based and new treatments are growing the field, while traditional therapies continue to play a major role. Global applicability is limited by the geographic concentration of research, underscoring the need for diverse populations, assessment of new treatments, and incorporation of individual patient data to bolster the body of evidence.},
}

@article {pmid42164629,
year = {2026},
author = {Akan, T and Aishwarya, R and Bhuiyan, MS and Conrad, SA and Vanchiere, JA and Bhuiyan, MAN},
title = {Computational pathology with dynamic convolutional and adaptive kernels.},
journal = {Journal of pathology informatics},
volume = {21},
number = {},
pages = {100662},
pmid = {42164629},
issn = {2229-5089},
abstract = {Data processing and learning have become essential to the advancement of medicine, with pathology and lab medicine being no exception. Integrating scientific research with clinical informatics into clinical practice facilitates novel methodologies for patient care. Computational pathology is a burgeoning subspecialty in pathology that promises a better-integrated solution to histopathological images and clinical informatics. Deep-learning methods in computational pathology have demonstrated considerable advances in automated histopathological image analysis. However, convolutional neural networks (CNNs) face fundamental limitations when dealing with the significant morphological heterogeneity present in disease tissues. Conventional CNNs use fixed convolutional kernels, which restrict their effectiveness in adaptively extracting features from histopathological images that exhibit diverse pathological patterns, staining intensities, and tissue architecture. To address this substantial limitation, we present an optimized variant of Omni-Dimensional Dynamic Convolution (ODConv) networks for distinguishing diseased tissue from healthy tissue. Compared with prior dynamic convolution methods that attend to a single kernel dimension, ODConv applies multi-dimensional attention across spatial positions, input channels, output channels, and kernel candidates, enabling more flexible and adaptive feature extraction. We evaluated our approach on wheat-germ agglutinin-stained and hematoxylin and eosin-stained skeletal muscle images from multiple disease models, including G93A*SOD1 transgenic mice (amyotrophic lateral sclerosis) and Akita mice (Type I diabetes). ODConv, trained entirely from scratch without ImageNet pretraining, achieved competitive classification performance relative to seven fine-tuned pretrained architectures across both staining modalities, demonstrating the effectiveness of omni-dimensional dynamic kernels in learning discriminative morphological representations directly from domain data. The study reports strong statistical agreement metrics, proving effective class balance handling and stable decision boundaries. These findings confirm ODConv as a strong computational pathology framework that advances automated diagnosis of neurodegenerative and metabolic skeletal muscle disorders.},
}

@article {pmid42165374,
year = {2026},
author = {Fernández-Gómez, P and Tosat-Bitrián, C and Marugán, T and Fernández-Hernández, L and Cano, A and Martinez-Mulero, JA and López-Carbonero, JI and Pignatelli, J and Corrochano, S and Palomo, V},
title = {Lighting Up Mislocalized Proteins: Quantum Dot Probes for Multiplexed Cytoplasm-Selective Cell Profiling in Neurodegeneration.},
journal = {ACS sensors},
volume = {},
number = {},
pages = {},
doi = {10.1021/acssensors.5c01941},
pmid = {42165374},
issn = {2379-3694},
abstract = {Semiconductor quantum dots (QDs) provide unique stability, brightness, and multiplexed capacity for biomarker detection in complex diseases; however, their distinctive intracellular distribution has rarely been leveraged for spatially resolved diagnostics. Here, we show how QD-based sensors enable selective detection of cytoplasmic proteins and can quantify nucleo-cytoplasm protein mislocalization in patient-derived samples. We validated this approach labeling TAR DNA-binding protein 43 (TDP-43), a key mislocalized protein in amyotrophic lateral sclerosis (ALS). Spatial resolution is achieved in several patient-derived models and mouse brain tissue, underscoring the nanosensor's versatility across biological systems. Multiplexed QD-based immunolabeling, combined with confocal imaging and high-throughput flow cytometry, enables the detection of distinct cytoplasmic biomarker signatures that discriminate ALS patients from healthy controls. These signatures include variations in TDP-43 mislocalization and protein coexpression patterns, which were further modulated by pharmacological treatment. This work establishes QDs as spatially selective, multiplexable nanosensors capable of resolving subtle yet disease-relevant intracellular phenotypes in patient-derived samples. Compared to organic fluorophores, QDs enhance sensitivity, improve signal stability, and enable simultaneous spatially resolved biomarker quantification, broadening their potential for clinical diagnostics and personalized medicine. These findings establish QDs as powerful tools for neurodegeneration research, disease monitoring, and early biomarker discovery, with potential applications in translational neuroscience and precision medicine.},
}

@article {pmid42166253,
year = {2026},
author = {Fung, WY and Agustini, S and Amornvit, J and Chai, J and Damian, LF and Fadli, N and Pg Hj Mohd Yassin, DHN and Keovilayhong, S and Krishnan, D and Kulkantrakorn, K and Nguyen Tran, MD and Ng, K and Nghia, HTT and Ohnmar, O and Pengiran Tengah, DSNA and Prado, M and Remli, R and Rojana-Udomsart, A and Le Tuan, TQ and Yanuar, A and Shahrizaila, N},
title = {Strengthening care and research in ALS in Southeast Asia: a call for action.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/21678421.2026.2671159},
pmid = {42166253},
issn = {2167-9223},
abstract = {In Southeast Asia (SEA), healthcare resources, infrastructure, and access to therapies in amyotrophic lateral sclerosis (ALS) remain limited compared to other parts of the Asia-Pacific region. Many SEA countries continue to face delays in diagnosis, fragmented care pathways, and limited representation in international research. Beyond health system challenges, ALS in SEA may also differ biologically. Emerging studies suggest that genetic variants and clinical phenotypes in Asian populations are not fully mirrored in Western cohorts. In this report, the authors summarize their country-specific background and status of care in ALS as well as their consensus on future strategies and actions. Key short- and long-term strategies are proposed, highlighting the critical need for regional collaboration and patient engagement to advance ALS care and research in the region.},
}

@article {pmid42166260,
year = {2026},
author = {Liu, W and Li, Y and Sun, J and Wang, G and You, K and Xie, L and Chen, J},
title = {Data-Driven Internal Model Control for Output Regulation.},
journal = {IEEE transactions on cybernetics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TCYB.2026.3690605},
pmid = {42166260},
issn = {2168-2275},
abstract = {Output regulation is a fundamental problem in control theory, extensively studied since the 1970s. Traditionally, research has primarily addressed scenarios where the system model is explicitly known, leaving the problem in the absence of a system model less explored. Leveraging recent advances in Willems et al.'s fundamental lemma, data-driven control has emerged as a powerful tool for stabilizing unknown systems. This article tackles the output regulation problem for unknown single and multiagent systems (MASs) using noisy data. Many existing data-driven approaches rely on solving data-based output regulator equations (OREs), which become inadequate for achieving zero tracking error in the presence of noisy data. To overcome this limitation, we advocate the use of a classical tool from robust output regulation, namely, the internal model principle. We first apply this idea to linear time-invariant (LTI) systems and show that exact output regulation, that is, zero tracking error, can be achieved by solving a simple data-based linear matrix inequality (LMI). The framework is then extended to the $k$ th-order output regulation problem for nonlinear systems, followed by applications to both linear and nonlinear MASs. Finally, numerical tests validate the effectiveness of the proposed data-driven controllers.},
}

@article {pmid42166277,
year = {2026},
author = {De Los Reyes, A},
title = {Toward integrative, multisource, and multimodal approaches to assessing psychopathology intergenerationally and across the lifespan: Commentary on Caspi et al. (2026).},
journal = {Journal of psychopathology and clinical science},
volume = {135},
number = {4},
pages = {495-497},
doi = {10.1037/abn0001084},
pmid = {42166277},
issn = {2769-755X},
mesh = {Humans ; *Mental Disorders/diagnosis ; *Psychopathology/methods ; },
abstract = {Models of psychopathology contain constructs that cannot be directly observed. Assessing these constructs involves identifying specific behaviors that justifiably serve as "markers" of their presence, thus facilitating their precise and accurate measurement. Examples of these behavioral markers include the destruction of property for conduct disorder, the avoidance of unfamiliar people for social anxiety, and sleeping too much or too little for depression. These and other behavioral markers typify the measurement of both specific mental disorders as well as "p" as a transdiagnostic index of psychopathology. Importantly, researchers commonly implement measurement, methodological, and data-analytic practices that conflict with the data conditions that underlie psychopathology studies. For example, researchers often rely on one source to measure behavioral markers of psychopathology (e.g., self-report), even though 60 years of research indicate that the measurement source robustly dictates the conclusions of psychopathology studies. When researchers measure markers of psychopathology with multiple sources, they often integrate these multisource data using data-analytic strategies that misclassify valid data as measurement error; these misclassifications beget underpowered studies and, by logical extension, replication failures. These issues pertain to psychopathology research more broadly, but they also facilitate interpreting Caspi et al. (see record 2026-80066-001), and the foundation it sets for studying psychopathology both developmentally and intergenerationally. In this commentary, I highlight measurement, methodological, and data-analytic issues inspired by Caspi et al. and summarize work that supports their careful consideration. Caspi et al.'s findings call for developing integrative, multisource, and multimodal assessments that optimize the validity of psychopathology assessments intergenerationally and across the lifespan. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

Humans
*Mental Disorders/diagnosis
*Psychopathology/methods

@article {pmid41965692,
year = {2026},
author = {Vergano, M and Craxì, L and Zamperetti, N and Latronico, N},
title = {Sliding doors at the bedside: conditional outcomes and moral judgments in end-of-life care.},
journal = {Critical care (London, England)},
volume = {30},
number = {1},
pages = {},
pmid = {41965692},
issn = {1466-609X},
abstract = {BACKGROUND: Intensive care medicine has increasingly embraced shared decision-making and advance care planning as core components of good clinical practice. Nonetheless, clinical reasoning is sometimes implicitly framed as a linear, biologically driven process. In contexts of prognostic uncertainty, this framing risks obscuring a structural feature of decision-making: the constitutive role of value-based judgments in shaping prognosis and outcomes.

MAIN BODY: This paper introduces the concept of conditional outcomes to clarify a structural feature of certain clinical situations, in which survival or death does not follow from biology alone but is co-determined within the range of biologically possible trajectories by value-based choices made by patients, families, and clinicians regarding whether and how to intervene. Using the case of Mrs. Elizabeth, a woman with advanced amyotrophic lateral sclerosis, we show how an identical clinical state may be framed as either terminal or amenable to escalation, not because it is assessed differently, but because values and goals are interpreted and enacted differently. Even when shared decision-making is practiced, the way value judgments shape prognostic determinations often remains implicit. Making these assumptions explicit complements shared decision-making and advance care planning, clarifying how clinical outcomes are logically dependent on prior value-based commitments that shape judgments about benefit, burden, and the goals of care.

CONCLUSIONS: Making the conditional structure of outcomes explicit clarifies that value-based judgments are not ancillary to prognosis but structurally shape prognostic determinations and subsequent outcomes. Recognizing the conditional nature of prognostication strengthens clinical reasoning by integrating biological knowledge with ethical commitments in end-of-life care.},
}

@article {pmid42156174,
year = {2026},
author = {Su, X and Tan, X and Wang, Y and Liang, W and Wang, D and Huo, D and Wang, H and Qi, Y and Zhang, W and Han, L and Zhang, D and Wang, M and Xu, J and Wang, S and Wang, J and Feng, H},
title = {COMMD1 Induces Copper Deficiency of SOD1 by Inhibiting the Palmitoylation of CCS in ALS.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.1803-25.2026},
pmid = {42156174},
issn = {1529-2401},
abstract = {Mutations in superoxide dismutase 1 (SOD1) compromise its metal-binding capacity, resulting in protein misfolding and aggregation, which ultimately induces cellular apoptosis in amyotrophic lateral sclerosis (ALS). Copper metabolism domain containing 1 (COMMD1), a gene implicated in copper homeostasis, has not been thoroughly characterized in the context of ALS pathogenesis. In this study, we identified elevated COMMD1 expression in ALS, potentially contributing to diminished copper incorporation into SOD1. Knockdown of COMMD1 enhanced palmitoylation of the copper chaperone for SOD1 (CCS), facilitating its membrane translocation and promoting copper loading into SOD1, thereby conferring neuroprotection in ALS. Mechanistically, we established that COMMD1 knockdown augments CCS palmitoylation via activation of the hypoxia inducible factor 1 subunit alpha (HIF-1α)/fatty acid synthase (FASN) signaling axis. In vivo investigations utilizing male hSOD1[G93A] transgenic mice demonstrated that COMMD1 deficiency markedly ameliorated the deterioration of motor function and prolonged survival duration. These findings collectively suggest that COMMD1 represents a potential therapeutic target for ALS intervention.Significance Statement Superoxide dismutase 1 (SOD1) was the first identified mutant gene associated with amyotrophic lateral sclerosis (ALS). Mutations in SOD1 compromise its metal-binding function, resulting in neuronal apoptosis, a hallmark of ALS pathogenesis. Utilizing the SOD1[G93A] models of ALS, our findings revealed that COMMD1 deficiency significantly elevates copper incorporation into SOD1, consequently attenuating cellular apoptosis. These results suggest that targeted inhibition of COMMD1 could represent a potential therapeutic strategy for ALS treatment.},
}

@article {pmid42156213,
year = {2026},
author = {Nalepa, M and Skweres, A and Węgrzynowicz, M},
title = {Dysregulation of arginase and arginine pathways in neurodegenerative diseases: Metabolic and cellular dysfunction and therapeutic implications.},
journal = {Free radical biology & medicine},
volume = {252},
number = {},
pages = {559-579},
doi = {10.1016/j.freeradbiomed.2026.05.285},
pmid = {42156213},
issn = {1873-4596},
abstract = {Neurodegenerative diseases are increasingly recognized as disorders associated with metabolic dysfunction with arginine metabolism emerging as a significant contributor. Arginase, by regulating the balance between arginine and ornithine, is positioned at the crossroads of multiple arginine metabolic pathways, thereby controlling a variety of cellular processes essential for proper brain homeostasis. Chronic disruption of these pathways may lead to dysfunction of neurons and glia ultimately resulting in the induction of neurodegenerative processes. In this review, based on data from patients and experimental models, we synthesize and critically evaluate evidence demonstrating alterations in arginase isoenzymes and associated metabolic pathways in Alzheimer's Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis. We discuss mechanisms through which dysregulation of arginase and arginine metabolism may contribute to neurodegeneration, including disturbances in nitrogen metabolism, oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation. Based on this body of evidence, we propose therapeutic strategies targeting arginase-related pathways, with the aim of preserving cellular metabolic homeostasis to ameliorate disease progression. Finally, we outline directions for future research, emphasizing that a proper understanding of the physiological roles of arginase isoenzymes and their disease-, stage-, and cell-specific dysregulation will be essential for the development of effective metabolically targeted therapies against neurodegenerative diseases.},
}

@article {pmid42156505,
year = {2026},
author = {Kerins, C and Lieberam, I and Gentleman, E},
title = {ALS mutations do not alter perineuronal net formation in human stem cell-derived motor neurons.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-10244-6},
pmid = {42156505},
issn = {2399-3642},
support = {MR/N025865/1//RCUK | Medical Research Council (MRC)/ ; 218452/Z/19/Z//Wellcome Trust (Wellcome)/ ; },
abstract = {Perineuronal nets (PNNs) are extracellular matrix structures that stabilise synaptic inputs and play a role in regulating neuronal plasticity. Although PNN dysregulation is observed in several neurological disorders, their relevance to amyotrophic lateral sclerosis (ALS) remains unclear. In particular, the extent to which PNN alterations reported in ALS animal models are motor neuron (MN)-intrinsic is unknown. We investigated whether human pluripotent stem cell-derived MNs form PNN-like structures in vitro, and whether ALS-associated mutations alter this process. We show that PNN-like structures containing hyaluronan, tenascin-R, and aggrecan form in in vitro co-cultures of iPSC-derived MNs and astrocytes, and that their formation and gene expression were not altered by ALS mutations. To explore whether PNN dysregulation reflects contributions from other cell types or selective MN vulnerability, we conducted meta-analyses of transcriptomic datasets from pluripotent stem cell-derived astrocytes carrying ALS-associated mutations, as well as datasets comparing MN populations with differential susceptibility to ALS. These analyses revealed no consistent differences in PNN-related gene expression within human stem cell-derived MNs. In contrast, transcriptomic analyses of human post-mortem ALS tissues revealed dysregulation of PNN-related genes, including core PNN components. Taken together, these findings indicate that PNN-related alterations described in ALS animal models are not reproduced by ALS-associated mutations in MNs alone, and instead point to a role for additional cellular components within the central nervous system.},
}

@article {pmid42156779,
year = {2026},
author = {Shaw, TB and Al Najjar, A and Barth, M and Bollmann, S and Bourgeat, P and Chang, J and Dempsey-Jones, H and Fazlollahi, A and Fripp, J and Garden, N and Guo, CC and Henderson, RD and Kuan, E and Lv, J and McCombe, PA and Narayanan, A and Ngo, ST and Nguyen, V and O'Brien, K and Robinson, G and Robinson, S and Salvado, O and Stewart, A and Steyn, FJ and Bollmann, S},
title = {Multimodal ultra-high-field MRI, clinical, cognitive, and genetic profiles across the ALS-FTD spectrum.},
journal = {Scientific data},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41597-026-07461-3},
pmid = {42156779},
issn = {2052-4463},
support = {PDF2112//Motor Neurone Disease Research Australia/ ; TU2201//Motor Neurone Disease Research Australia/ ; APP2029871//National Health and Medical Research Council/ ; Boosting Dementia Research Leadership Fellowship (APP1135769)//National Health and Medical Research Council/ ; ECR-202503-01848//FightMND/ ; Mid-Career Research Fellowship//FightMND/ ; APP 1088419, DP250103627//National Health and Medical Research Council, Australia/ ; FT140100865, IC170100035, DP200103386, DP250103627//Australian Research Council/ ; DP250103627//Australian Research Council/ ; DP240102161//Australian Research Council/ ; Linkage Grant LP200301393//Australian Research Council, Australia/ ; RTP//University of Queensland Graduate School/ ; Research Development Grant//Brain and Mind Centre, University of Sydney/ ; Fudan Brain and Intelligence Science Alliance Flagship Research Program, Moyira Elizabeth Vine Fund for Research into Schizophrenia Program//University of Sydney/ ; 10.55776/PAT3786024//Austrian Science Fund/ ; 794298//Marie Sklodowska-Curie Actions, European Union/ ; },
abstract = {This dataset was acquired and curated to explore the spectrum of Motor Neuron Disease (MND) and Fronto-Temporal Dementia (FTD) with Ultra-High Field Magnetic Resonance Imaging (7 Tesla) and compare these to non-neurodegenerative disease controls (known colloquially as "The 7 T hEalthy Ageing study [7TEA]"). Twenty people living with neurodegenerative disease and 14 non-neurodegenerative controls underwent a comprehensive multimodal MRI protocol including structural, diffusion, quantitative MRI, resting state, and task fMRI, alongside cognitive testing and genetic screening. This dataset combines detailed imaging phenotypes with extensive clinical characterisations. It facilitates investigations into the spectrum of MND and FTD, has provided a basis for developing novel quantitative biomarkers, and supports the exploration of interactions between imaging features and clinical progression. The availability of this dataset supports various research avenues, from detailed hippocampal subfield analyses, network connectivity assessments, and multimodal genetic, cognitive, and imaging studies. The dataset is published on OpenNeuro (dataset ds007036) and is curated in the Brain Imaging Data Structure (BIDS) standard.},
}

@article {pmid42157222,
year = {2026},
author = {Bayer, PA and O'Bryan, SJ and Thomas, HJ and Del Vecchio, A and Jain, G and Farina, D and Ferri, A},
title = {The use of high-density surface electromyography in amyotrophic lateral sclerosis: a scoping review.},
journal = {Journal of neuroengineering and rehabilitation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12984-026-02022-6},
pmid = {42157222},
issn = {1743-0003},
support = {GNT2021176//National Health and Medical Research Council/ ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterised by progressive degeneration of motor neurons, resulting in muscle weakness and atrophy. This neuronal loss is partially compensated for by the collateral sprouting of surviving motor neurons, leading to the formation of enlarged motor units (MUs). These MU adaptations, together with hyperexcitability and altered descending messages from the brain, lead to altered characteristics of the MU action potential shape and discharge pattern, that can be captured using high-density surface electromyography (HDsEMG). The aim of this review is to survey all available literature, investigating how HDsEMG has been used in ALS, and highlight differences in methods and outcomes to allow comparison between studies.

METHODS: A systematic literature search was conducted using four databases (PubMed, Scopus, IEEE Xplore, and Academic Search Ultimate) to identify studies employing HDsEMG in individuals diagnosed with ALS. Eligible studies were reviewed to examine experimental protocols, hardware and software configurations and reported outcome measures.

RESULTS: Out of 168 identified articles, 26 were included in this review. High heterogeneity was observed in recording methods, analysis, and reporting strategies. Based on measurable features of MU behaviour and morphology, the outcomes reported in the studies were grouped into five main categories: fasciculations, MU properties, MU discharge characteristics, multiple discharges and number of MUs.

CONCLUSIONS: HDsEMG represents a promising non-invasive technique that allows for repeated, longitudinal measurements as well as the detection of multiple MUs and their individual analysis, the potential of which has not been fully explored. HDsEMG has a strong potential for clinical use in ALS, but its application should first be based on a clear understanding of disease pathophysiology. The findings of this review highlight the urgent need for a consensus on standardised protocols and reporting practices for the application of HDsEMG in ALS research, along with the development of methods that can sensitively indicate disease-specific physiological changes to improve comparability, reproducibility. This understanding will improve how HDsEMG findings are interpreted and support the translation of HDsEMG into a diagnostic tool.},
}

@article {pmid42158589,
year = {2026},
author = {Tran, CM and Reddy, N and Thomas, JK and Venugopal, V and Bowser, R},
title = {CHI3L1 (YKL-40) and Chit-1 expressing glia in the white matter of ALS, FTLD and AD: correlations to pathology and disease duration.},
journal = {BMJ neurology open},
volume = {8},
number = {1},
pages = {e001225},
pmid = {42158589},
issn = {2632-6140},
abstract = {BACKGROUND: Chitotriosidase (Chit-1) and chitinase-3-like protein 1 (CHI3L1) protein levels are increased in the cerebrospinal fluid (CSF) of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). Few studies have examined the spatial expression of chitinase-expressing cells with respect to neuropathologic hallmarks of disease.

METHODS: RNA sequencing was used to examine Chit-1 and CHI3L1 gene expression in the spinal cord and motor cortex. Immunohistochemistry was used to characterise the distribution of Chit-1 and CHI3L1 expressing cells in ALS, C9-ALS, FTLD, AD and non-neurologic disease controls. Immunofluorescence confocal microscopy was used to correlate distribution of Chit-1 and CHI3L1 expressing cells to TDP-43 pathology.

RESULTS: Chit-1 gene expression was increased in the spinal cord, and CHI3L1 expression was increased in both the spinal cord and motor cortex of patients with sALS and C9-ALS when compared with controls. Highest levels of Chit-1[+] glia were in cortical regions that contain hallmark neuropathology for each neurodegenerative disease. CHI3L1[+] glia were only significantly increased in sALS. Neither Chit-1[+] nor CHI3L1[+] glia was in close proximity to phosphorylated TDP-43 (pTDP) containing neurons in the motor cortex grey matter; however, there was a significant co-localisation of glial pTDP with Chit-1 and CHI3L1 in the motor cortex white matter.

CONCLUSIONS: Chit-1 and CHI3L1 expressing cells were most abundant in the white matter of cortical regions affected by each neurodegenerative disease and the spinal cord. Chit-1 or CHI3L1 expressing cells in the white matter often contained pTDP. We also observed correlations between levels of Chit-1 or CHI3L1 expressing cells in the white matter to disease duration.},
}

@article {pmid42159145,
year = {2026},
author = {Gray, M and Truong, MT},
title = {Invited Commentary on: Modi et al.'s "Development of a Structured Tool for Evaluation of Auricular Reconstruction for Microtia".},
journal = {Facial plastic surgery & aesthetic medicine},
volume = {},
number = {},
pages = {26893614261452864},
doi = {10.1177/26893614261452864},
pmid = {42159145},
issn = {2689-3622},
}

@article {pmid42159474,
year = {2026},
author = {Mueller, A and Vallejo, V and Panadés, MP and Hardiman, O and Danel-Brunaud, V and Ajroud-Driss, S and Couratier, P and Shefner, J and Gokey, A and DiCesare, M and Lennox, E and Praestgaard, J and Brujin, L and Allred, P and Miller, R},
title = {Evaluation of Digital Technologies for Home-Based Assessment in People With Amyotrophic Lateral Sclerosis.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70429},
pmid = {42159474},
issn = {2328-9503},
support = {//Novartis Pharma AG/ ; },
abstract = {OBJECTIVE: Digital technologies hold promise for transforming healthcare by enhancing personalized treatments and offer valuable opportunities to improve patient care. Here, we evaluated several novel, self-administered, home-based, digital endpoints for their association with corresponding conventional standard clinical measures (primary) in people living with Amyotrophic Lateral Sclerosis (ALS).

METHODS: This was a longitudinal study in people with ALS who were followed up to 9 months. A total of 33 participants were enrolled in the study. At each of six visits, participants were evaluated with a battery of conventional standard measurements to determine ALS disease progression and quality of life. Between visits, participants performed weekly home-based self-assessments with digital health technologies (DHT) and self-administered ALSFRS-R. Cross-sectional analysis of DHTs anchored to ALSFRS-R and longitudinal analyses were performed and compared to standard clinical measures.

RESULTS: Of the 33 participants, 20 completed the study, and 13 discontinued before completing the planned 9-month follow-up mainly due to disease progression. The distribution of various digital metrics in home-based assessments corresponded well with the sub-scores of ALSFRS-R in the cross-sectional analyses, with the strongest construct validity for digital speaking rate. In the longitudinal analysis, a weak but significant trend in most metrics was observed, with the strongest trend in the duration of the Timed Up and Go (high variability between participants).

INTERPRETATION: The findings from this study provide insights into the potential of digital endpoints to evaluate people living with ALS with the goal of reducing the burden of study participation and improving the efficiency of ALS clinical trials.},
}

@article {pmid42159475,
year = {2026},
author = {Sewak, A and Inácio, V and Wuu, J and Benatar, M and Hothorn, T},
title = {Likelihood-based modeling of covariate-specific time-dependent receiver operating characteristic curves.},
journal = {Statistical methods in medical research},
volume = {},
number = {},
pages = {9622802261445416},
doi = {10.1177/09622802261445416},
pmid = {42159475},
issn = {1477-0334},
abstract = {Identifying reliable biomarkers for predicting clinical events in longitudinal studies is important for accurate disease prognosis and for guiding development of new treatments. However, prognostic studies are often observational, making it difficult to account for patient heterogeneity. In amyotrophic lateral sclerosis (ALS), factors such as age, site of onset and genetic status influence both survival and biomarker levels, yet their impact on the prognostic accuracy of biomarkers over time remains unclear. While time-dependent receiver operating characteristic methods have been developed to handle censored time-to-event outcomes, most do not adjust for covariates. To address this, we propose the nonparanormal prognostic biomarker framework, which models the joint distribution of the biomarker and event time while accounting for covariates. This allows estimation of covariate-specific time-dependent receiver operating characteristic curves and related summary measures. We apply the NPB framework to evaluate serum neurofilament light as a prognostic biomarker in ALS, showing that its accuracy varies over time and with patient characteristics. By capturing these covariate-specific effects, the NPB framework supports more targeted risk stratification and can potentially improve the design of clinical trials for new ALS treatments.},
}

@article {pmid42149647,
year = {2026},
author = {Hui, LM and Yu, E and Chung, A and Kwan, BYM},
title = {Artificial intelligence for assessment in competency-based medical education: current practices and future directions.},
journal = {Postgraduate medical journal},
volume = {},
number = {},
pages = {},
doi = {10.1093/postmj/qgaf195},
pmid = {42149647},
issn = {1469-0756},
abstract = {BACKGROUND: Competency-Based Medical Education (CBME) relies on frequent, competency-focused assessments, which can be challenging to implement consistently. Artificial Intelligence (AI) holds promise to improve assessment efficiency, objectivity, and feedback in CBME, but its use remains in early stages with limited understanding of current practices and evaluation methods. This study aims to map existing AI applications in CBME assessments to guide future work.

METHODS: A comprehensive search was performed in MEDLINE (Ovid), EMBASE (Ovid), PsycINFO, and Scopus using tailored keywords and MeSH terms. Included studies focused on the deployment of AI for assessment within CBME, covering applications in generating, analyzing, or interpreting evaluation data across undergraduate, graduate, and continuing professional education. The PRISMA-ScR guidelines were used to ensure transparent reporting, and findings were synthesized following Levac et al.'s approach.

RESULTS: Of the 1002 search results, 32 studies met the inclusion criteria. Key findings indicate a wide application of AI from surgical or procedural skill assessment, to clinical note assessment, communication assessment, feedback generation, projected trainee performance, and analysis of narrative feedback from supervisors.

CONCLUSION: This review highlights potential advantages, such as timely evaluations, and challenges, such as lack of granularity, of AI integration. In conclusion, thoughtful integration of AI into competency-based medical education can complement traditional assessment methods and enhance learner outcomes, provided it is supported by robust infrastructure, ethical oversight, and collaborative policy development.},
}

@article {pmid42149655,
year = {2026},
author = {Kapitány-Fövény, M},
title = {A qualitative analysis of addiction components in rhinitis medicamentosa.},
journal = {Journal of behavioral addictions},
volume = {},
number = {},
pages = {},
doi = {10.1556/2006.2025.00530},
pmid = {42149655},
issn = {2063-5303},
abstract = {This commentary evaluates Lakatos et al.'s qualitative study on nasal spray addiction within rhinitis medicamentosa (RM), applying Griffiths' addiction component model. While evidence remains insufficient for formal diagnostic inclusion, the study identifies behavioral and psychological features paralleling core addiction criteria. Case reports and user narratives provide additional support, though counter-evidence persists. Conceptual and methodological challenges highlight the need for research addressing clinical relevance, theoretical embedding, and taxonomic plausibility. Despite limited empirical validation, the significant distress and functional impairment reported by affected individuals underscore the importance of recognizing and addressing this emerging issue.},
}

@article {pmid42151714,
year = {2026},
author = {Zwicker, J and Smith, IC and Bush, SH and Rice, J and Murphy, R and Breiner, A and Buenger, U and Zehrt, B and Warman-Chardon, J and Watt, CL},
title = {Lessons Learned From a Feasibility Study of Longitudinal Palliative Care for Patients With Amyotrophic Lateral Sclerosis.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70283},
pmid = {42151714},
issn = {1097-4598},
support = {//ALS Society of Canada/ ; //Eric Poulin Centre for Neuromuscular Disease/ ; //University of Ottawa/ ; INS-464765/CAPMC/CIHR/Canada ; 932196//Muscular Dystrophy Canada/ ; },
abstract = {INTRODUCTION/AIMS: The benefits of initial palliative care (PC) consultation for patients with amyotrophic lateral sclerosis (ALS) have been previously described. The aim of this study was to explore the evolution of PC needs of patients with ALS over time through analysis of PC follow-up visits.

METHODS: Patients followed at a multidisciplinary ALS clinic received PC consultations and follow-ups between October 2020 and April 2022. All patients who received at least one PC follow-up visit were included in this study. Physician documentation of the visits was analyzed for sub-themes and topics. Topics discussed during visits and visit frequency were examined in the context of patient variables.

RESULTS: The 26 patients had at least one PC follow-up visit (range 1-12 visits). Topics of discussion varied by individual rather than disease status and were often discussed repeatedly. Compared to initial consultations, follow-up visits featured more frequent discussion of sialorrhea and less frequent discussion of constipation, pain, and prognosis (all p < 0.05). Care coordination was discussed in 82% of follow-ups. Time between follow-up visits shortened as the disease progressed. Medical assistance in dying (MAID) was discussed by 31% of patients either at initial consultation or follow-up.

DISCUSSION: Each individual with ALS has unique PC needs. PC specialist resource planning should anticipate higher frequency visits for patients later in the disease course. Given the importance of care coordination and the scarcity of PC specialists, we recommend further study of effective models of care coordination. We recommend that PC specialists be comfortable counseling patients on MAID.},
}

@article {pmid42151746,
year = {2026},
author = {Best, JD and Landera, MA and Ma, R and Perry, BJ},
title = {Perceptions of Speech-Language Pathology Care in Amyotrophic Lateral Sclerosis: A Patient-Centered Exploratory Study.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70286},
pmid = {42151746},
issn = {1097-4598},
support = {K23NS123369/NH/NIH HHS/United States ; //MGH Institute of Health Professions/ ; },
abstract = {INTRODUCTION/AIMS: Given limited research on patient perspectives of speech-language pathology (SLP) services in ALS care, this study aimed to assess the satisfaction with, and understanding of, SLP services by people with ALS (pwALS) and to examine the alignment between services received and patient-reported impairments.

METHODS: A cross-sectional survey assessing pwALS' perceptions of SLPs was distributed from October 2024 to January 2025 through electronic mailing lists of relevant professional organizations. A questionnaire examined pwALS' understanding of the SLP role, satisfaction levels, alignment between patient-reported impairments and SLP interventions, and perceived gaps in care. Responses were analyzed using descriptive statistics, with open-ended items analyzed using qualitative analysis.

RESULTS: The 81 survey respondents consisted of pwALS (81.5%), caregivers (11.1%), family members (4.9%), and others (2.5%). Overall satisfaction with SLP care was high, though open-ended responses revealed gaps in understanding. Many were unaware of the full scope of SLP services; only 17.3% recognized cognitive evaluation and 8.6% cognitive therapy, compared with speech (77.8%) and swallowing (81.5%) evaluations. Reported services often did not align with communication and swallowing needs, but patients educated about a service were significantly more likely to use it.

DISCUSSION: Overall satisfaction with SLP care was high; however, open-ended responses revealed gaps in understanding, unmet needs, and limited awareness of the full scope of SLP services. This misalignment highlights the need for improved patient and caregiver education regarding the role and timing of SLP involvement to enhance engagement, appropriate service use, and outcomes in ALS care.},
}

@article {pmid42152795,
year = {2026},
author = {Hu, N and Qi, M and Su, N and Zhang, D and Zhang, J and Xu, Y and Wang, K and Xu, Y and Li, Z and Hu, B and Wang, L and Wu, B and Chu, L and Wang, Y and Jiang, H and Lu, Z and Wu, J and Fan, X and Han, F and Tian, F and Yuan, J and Liu, M and Zhu, Y},
title = {Quantitative Gait Analysis Reveals Distinct Patterns Associated With Pyramidal Involvement in Amyotrophic Lateral Sclerosis: A Cross-Sectional Study.},
journal = {Brain and behavior},
volume = {16},
number = {5},
pages = {e71498},
doi = {10.1002/brb3.71498},
pmid = {42152795},
issn = {2162-3279},
support = {//National Science and Technology Major Project/ ; CIFMS 2021-I2M-1-003//CAMS Innovation Fund for Medical Sciences/ ; //Ministry of Industry and Information Technology of China/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; Male ; Female ; Middle Aged ; *Gait Analysis/methods ; Cross-Sectional Studies ; Aged ; *Gait Disorders, Neurologic/physiopathology/etiology ; *Gait/physiology ; Adult ; Machine Learning ; *Pyramidal Tracts/physiopathology ; Motor Neurons/physiology ; Severity of Illness Index ; },
abstract = {OBJECTIVE: To dissect specific gait abnormalities associated with upper motor neuron (UMN) dysfunction in amyotrophic lateral sclerosis (ALS) by controlling for overall disease severity and to develop a multivariate classification model.

METHODS: We performed 3D gait analysis on 118 ALS patients and 1796 healthy controls (HC). ALS patients were categorized into those with ALS with UMN dysfunction((ALS-UMN), n = 70) and those without ALS without UMN signs ((ALS-Numn), n = 48) lower limb UMN signs based on neurological examination. Gait parameters were compared, and their association with UMN involvement was analyzed using partial correlation (controlling for ALSFRS-R score) and machine learning models (Random Forest and Least Absolute Shrinkage and Selection Operator (Lasso) regression).

RESULTS: Compared with HC, ALS patients exhibited widespread gait deterioration (e.g., reduced speed, increased step width, p < 0.001). After controlling for ALSFRS-R, specific parameters, including reduced stride, increased step width, prolonged double support, and elevated gait cycle time asymmetry, remained independently associated with UMN severity (PENN score, p < 0.01). A multivariate model incorporating key features demonstrated fair discriminative ability for identifying ALS-UMN patients, with an area under the curve (AUC) of 0.690, a sensitivity of 0.816, and a specificity of 0.418.

CONCLUSION: Quantitative gait analysis reveals a distinct spatiotemporal pattern linked to UMN dysfunction in ALS. A model based on gait features shows potential, particularly high sensitivity, for identifying patients with pyramidal signs, supporting the exploratory utility of objective gait metrics for motor phenotyping in ALS, pending external validation.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/complications
Male
Female
Middle Aged
*Gait Analysis/methods
Cross-Sectional Studies
Aged
*Gait Disorders, Neurologic/physiopathology/etiology
*Gait/physiology
Adult
Machine Learning
*Pyramidal Tracts/physiopathology
Motor Neurons/physiology
Severity of Illness Index

@article {pmid42152867,
year = {2026},
author = {Cho, Y and Won, SY and Kim, H and Lee, HK and Cho, SR},
title = {The effects of a mobile healthcare application on speech and swallowing in amyotrophic lateral sclerosis.},
journal = {Digital health},
volume = {12},
number = {},
pages = {20552076261452405},
pmid = {42152867},
issn = {2055-2076},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) impairs oral motor function, negatively affecting patients' speech and swallowing abilities, as well as quality of life.

OBJECTIVE: This study aims to evaluate the effectiveness of A Successful Swallowing with Effortful Training (ASSET) program, included in the 'The 365 Healthy Swallow Health Coach application' in preserving speech and swallowing abilities in ALS patients through self-training.

METHODS: In this 8-week quasi-experimental study, 13 participants were allocated to either the app-guided ASSET training group (n=7; three sessions per day, five days per week) or a usual-care control group (n=6) based on their clinical visit schedules. To evaluate changes over time and compare the two groups, linear mixed models were employed. Changes in ALS severity scale (ALSSS), Diadochokinetic (DDK) task, speech intensity, Speech Handicap Index-15, Dysphagia Handicap Index, Swallowing Quality of Life (SWAL-QOL), and Brief Inventory of Swallowing Assessment-15 were assessed.

RESULTS: ALSSS speech scores was relatively preserved from 5.43 (95% CI 3.01-7.84) to 5.29 (95% CI 2.87-7.70) in the ASSET treatment group, but declined from 6.33 (95% CI 3.73-8.94) to 4.83 (95% CI 2.23-7.44) in the control group, with a significant group-by-time interaction (p=.017). DDK/tuh/and/kuh/were relatively preserved from 11.86 to 11.71 and from 12.29 to 11.57 respectively in ASSET group, but declined from 11.67 to 7.50 and from 11.83 to 7.17 in the control group, with significant interactions in/tuh/(p=.032) and/kuh/(p=.044). SWAL-QOL total score was relatively preserved from 155.86 to 149.71 in ASSET group, but declined from 154.67 to 125.17 in the control group, with a significant interaction (p=.011).

CONCLUSIONS: The findings suggest that ASSET program may help preserve speech and swallowing function in patients with ALS. Future research should validate the ASSET program with a larger, adequately powered sample size.},
}

@article {pmid42155171,
year = {2026},
author = {Czuba, M and Szafrańska, K and Kolaczkowski, M and Marcinkowska, M},
title = {Targeting lysosomal dysfunction with small-molecule TRPML1 ligands: Therapeutic opportunities in lysosomal storage disorders, neurodegeneration and beyond.},
journal = {European journal of medicinal chemistry},
volume = {315},
number = {},
pages = {118951},
doi = {10.1016/j.ejmech.2026.118951},
pmid = {42155171},
issn = {1768-3254},
abstract = {TRPML1, a lysosomal Ca[2+] channel, has emerged as a clinically relevant target due to its genetic and mechanistic links to lysosomal storage disorders and neurodegenerative diseases, including Gaucher disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. This evidence has prompted TRPML1 drug discovery efforts across academia and industry, with several small-molecule agonists advancing toward clinical development. In this review, we provide a comprehensive overview of the therapeutic potential of TRPML1 as a molecular target from a medicinal chemistry perspective. We summarize the structural basis of channel activation and inhibition, highlighting insights from recent cryo-EM studies that define the principal ligand-binding sites and mechanisms of allosteric modulation. We systematically survey the chemical space of TRPML1 ligands reported to date, including diverse agonist and antagonist chemotypes, and extend this analysis to encompass undisclosed or recently disclosed compounds emerging from industry pipelines. Furthermore, we discuss key determinants of ligand design and developability, including the challenges associated with targeting a deeply embedded, lipophilic binding pocket within the membrane. Overall, the available evidence positions TRPML1 as a promising target for small-molecule drug discovery and provides a framework for the rational design of next-generation lysosome-directed therapeutics.},
}

@article {pmid42155219,
year = {2026},
author = {He, L and Zhu, Z and Liu, W and Lan, J and Lin, S and Shang, J},
title = {A Y-γ segmented linear framework for non-equilibrium UV-Vis titration: stage-resolved exploratory analysis of a chemically evolving EGCG-iron system.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {361},
number = {},
pages = {128073},
doi = {10.1016/j.saa.2026.128073},
pmid = {42155219},
issn = {1873-3557},
abstract = {Non-equilibrium UV-Vis titration data are difficult to interpret when multiple processes overlap and strict equilibrium assumptions no longer hold. We propose a non-equilibrium titration framework that transforms UV-Vis matrices into reaction-progress space using a dimensionless γ and a volume-corrected absorbance Y. Under mass and proton-balance constraints, locally single-process intervals obey Yλ = aλ + bλγ; segmented linear regression then yields wavelength-dependent slope fingerprints (bλ) that delineate coordination stages. In the EGCG-iron system, the Y-γ analysis resolves a progression from low-coordination mononuclear species to higher-coordination complexes, multinuclear/bridged units, and iron-rich aggregates across metal-to-ligand ratios and pH. Single-wavelength initial-rate measurements and solid-state characterization support rapid deprotonation-coordination coupling and the formation of cross-linked multinuclear networks at high γ. To benchmark soft-modeling, we performed MCR-ALS decompositions under weak constraints (post-normalized closure) and strong constraints (iterative simplex projection plus monotonic decay-to-zero of the initial dominant component). Both fits achieve similar residual levels, yet the recovered spectra/concentration profiles differ, evidencing rotational ambiguity and emphasizing the dependence of chemometric solutions on constraint choice. In contrast, the Y-γ segmented linear model relies on explicit stoichiometric/proton-balance transformations, providing robust stage boundaries and compact spectral descriptors while remaining computationally simple. This combined hard/soft analysis offers a practical route to mechanistic interpretation of complex titration spectra and motivates future integration of Y-γ descriptors with advanced chemometrics and hybrid hard-soft modeling.},
}

@article {pmid42155417,
year = {2026},
author = {Simpson, J and Zarotti, N},
title = {Distress, not symptoms: Reframing psychological difficulties in neurodegenerative diseases of the motor system.},
journal = {Cortex; a journal devoted to the study of the nervous system and behavior},
volume = {200},
number = {},
pages = {262-271},
doi = {10.1016/j.cortex.2026.05.004},
pmid = {42155417},
issn = {1973-8102},
abstract = {Psychological distress is common among people living with neurodegenerative diseases of the motor system (NDMS) such as Parkinson's disease, motor neurone disease/amyotrophic lateral sclerosis, and Huntington's disease. Yet the way psychological difficulties are conceptualised in these populations is heavily shaped by medicalised language. Terms such as 'non-motor symptoms' and 'neuropsychiatric manifestations' were originally introduced to draw attention to difficulties beyond movement changes but they now risk positioning mood, anxiety, apathy, and related experiences solely as direct manifestations of neurological degeneration. This framing can obscure the rich psychosocial contexts in which distress arises, blur distinctions between emotional responses and disease processes, and reinforce deficit-based and disease-focused understandings that privilege biological explanations over person-centred ones. It may also influence clinical communication, treatment decisions, help-seeking behaviour, and access to psychological therapy and psychosocial interventions, contributing to inequities in care. This article argues that linguistic choices are not neutral: they construct the boundaries of what counts as legitimate knowledge, shape expectations about causality, and delimit the interventions considered appropriate. Without critical attention to these assumptions, individuals may experience distress as biologically inevitable and clinicians may overlook psychosocial contributors that are amenable to change. We propose that greater awareness of the power of language, coupled with empirical investigation into its effects, is essential for developing a linguistic reformulation of psychological distress in NDMS and more holistic, contextually grounded approaches to supporting psychological wellbeing.},
}

@article {pmid42142504,
year = {2026},
author = {Abd-Eldayem, AM and Mohammed, RA},
title = {Riluzole in neuroinflammation and neurodegeneration: Mechanistic insights and experimental validation.},
journal = {Current opinion in pharmacology},
volume = {88},
number = {},
pages = {102632},
doi = {10.1016/j.coph.2026.102632},
pmid = {42142504},
issn = {1471-4973},
abstract = {Neuroinflammation and neurodegeneration are tightly interconnected processes that drive the progression of multiple central nervous system (CNS) disorders. Riluzole, a benzothiazole derivative approved for amyotrophic lateral sclerosis (ALS), has been widely investigated for its broader neuroprotective potential. Its actions include modulation of glutamatergic transmission through presynaptic inhibition and upregulation of excitatory amino acid transporters. Additionally, Riluzole inhibits voltage-gated sodium channels, thereby reducing neuronal hyperexcitability and excitotoxicity. Its anti-inflammatory properties are mediated through the suppression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and the attenuation of microglial activation, while its antioxidant effects involve the activation of the nuclear factor erythroid 2-related factor 2/heme Oxygenase-1 (Nrf2/HO-1) pathway and the preservation of mitochondrial function. These mechanisms have been supported by preclinical evidence across models of ALS, Alzheimer's disease (AD), Huntington's disease (HD), and spinal cord injury (SCI), with emerging clinical data supporting its broader therapeutic relevance. Although clinical findings remain limited and disease-specific, the mechanistic breadth of Riluzole continues to motivate interest in its potential utility across neuroinflammatory and neurodegenerative conditions. This review synthesizes recent advances in Riluzole pharmacology and outlines key considerations for future mechanistic and translational research.},
}

@article {pmid42143042,
year = {2026},
author = {Ferrari, V and Tedesco, B and Cozzi, M and Pramaggiore, P and Gagliani, MC and Magdalena, R and Cornaggia, L and Casarotto, E and Chierichetti, M and Mohamed, A and Brodnanovà, M and Milioto, C and Piccolella, M and Galbiati, M and Crippa, V and Provenzani, A and Cortese, K and Rusmini, P and Cristofani, R and Poletti, A},
title = {VCP modulation ameliorates pathological features in C9orf72 models.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08856-1},
pmid = {42143042},
issn = {2041-4889},
support = {23236//AFM-Téléthon (French Muscular Dystrophy Association)/ ; 29514//AFM-Téléthon (French Muscular Dystrophy Association)/ ; 29514//AFM-Téléthon (French Muscular Dystrophy Association)/ ; GGP19128//Fondazione Telethon (Telethon Foundation)/ ; GMR25T1103//Fondazione Telethon (Telethon Foundation)/ ; PRIN-Progetti di ricerca di interesse nazionale n. 2022EFLFL8//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; National Center for Gene Therapy and Drugs Based on RNA Technology (CN3) CN00000041//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PRIN-Progetti di ricerca di interesse nazionale n. 2020PBS5MJ//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PRIN-Progetti di ricerca di interesse nazionale n.//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PRIN-Progetti di ricerca di interesse nazionale n. 2022KSJZF5//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PRIN-Progetti di ricerca di interesse nazionale n. P2022B5J32//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; piano di sviluppo della ricerca (PSR) UNIMI -linea B//Università degli Studi di Milano (Universitas Studiorum Mediolanensis)/ ; piano di sviluppo della ricerca (PSR) UNIMI -linea B//Università degli Studi di Milano (Universitas Studiorum Mediolanensis)/ ; piano di sviluppo della ricerca (PSR) UNIMI -linea B//Università degli Studi di Milano (Universitas Studiorum Mediolanensis)/ ; 2025-0708//Fondazione Cariplo (Cariplo Foundation)/ ; 2025-0708//Fondazione Cariplo (Cariplo Foundation)/ ; 2021-1544//Fondazione Cariplo (Cariplo Foundation)/ ; Grant 2020//Kennedy's Disease Association (KDA)/ ; Grant 2018//Kennedy's Disease Association (KDA)/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases linked by similar pathological mechanisms, which, in some familial forms, may be associated with the same genetic alterations. Among them, the most common is the C9ORF72 (C9) mutation. The C9 mutation consists in an aberrant expansion of the hexanucleotide repeat (G4C2)n that leads to the production and accumulation of toxic dipeptide repeat proteins (DPRs). Some of these C9-DPRs contribute to neuronal dysfunction and degeneration through different mechanisms. One of these involves alterations in the protein quality control (PQC) system, specifically in the autophagy-lysosomal pathway. Valosin-containing protein (VCP) is a critical component of the PQC system, assisting the degradation of misfolded proteins and damaged organelles and the maintenance of cellular homeostasis. In this study, we investigated the role of VCP in modulating pathological features associated with C9 mutation. Using neuronal cell models, we demonstrated that VCP overexpression significantly reduced C9-DPRs levels. This reduction is mediated by mechanisms involving both the ubiquitin-proteasome system (UPS) and autophagy. Additionally, we also observed that C9-DPRs induce lysosomal damage, which is counteracted by VCP overexpression, as indicated by decreased galectin-3 puncta and restored lysosomal pH. We then pharmacologically activated VCP-mediated clearance through SMER28, increasing the clearance of the most toxic DPR, the polyPR. We also determined that in this model, SMER28 activity is mediated by the UPS and is associated with the mitigation of DPR-induced lysosome damage. Additionally, using motor neurons derived from induced pluripotent stem cells (iPSC-MNs) from C9-ALS mutation carriers, we demonstrated that SMER28 treatment significantly decreased polyGA levels, a marker for C9-DPR accumulation. Moreover, SMER28 rescued C9-MNs commitment to differentiation and the alteration in the expression of autophagy-related genes. Taken together, our findings strongly support VCP as a modulator of C9 pathology and highlight its potential as a therapeutic target.},
}

@article {pmid42143268,
year = {2026},
author = {Lonn, H and Ndep, AO and Ekpenyong, BN and Cockburn, L and Chirac, AJ and Tchiaze, ATG and Jingkuo, GHM and Abua, EE and Isho, MC},
title = {Experiences and challenges of caregivers of children with cerebral palsy in Magba subdivision, Cameroon: a qualitative analysis.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-04976-5},
pmid = {42143268},
issn = {1471-2377},
abstract = {BACKGROUND: Cerebral palsy (CP) is one of the most common childhood neurodisability globally and disproportionately affects children in low- and middle-income countries. In Cameroon, limited epidemiological data, weak rehabilitation infrastructure, and entrenched sociocultural beliefs shape how CP is understood and managed. Children with CP often require lifelong support, placing substantial physical, emotional, and economic demands on family-caregivers, most commonly mothers. Understanding caregivers' lived experiences within specific cultural and resource-limited contexts is critical for informing inclusive and effective interventions. This study explored the lived experiences and challenges of family-caregivers of children with CP in Magba Subdivision, West Region of Cameroon.

METHOD: This study employed a qualitative exploratory design using in-depth interviews and inductive content analysis. Participants were family caregivers of children with CP, purposively recruited through community-based rehabilitation (CBR) services. In-depth, face-to-face interviews were conducted in English or local languages, audio-recorded, transcribed, and translated. Data were analysed using inductive content analysis following Elo and Kyngäs' approach. Findings were interpreted using Raina et al.'s multidimensional caregiving model.

RESULTS: All participants, aged 15-49 years, were family caregivers of children with CP, aged 4-15 years. Six interrelated themes emerged: (1) sociocultural challenges, including stigma, discrimination, and harmful spiritual beliefs framing CP as witchcraft, ancestral punishment, 'snake', or 'marine spirit'; (2) economic constraints arising from inability to engage in paid work and the absence of social protections; (3) physical caregiving burden characterised by exhaustion, chronic pain, and musculoskeletal strain; (4) inadequate specialized services and health information; (5) limited social/family support; and (6) limited access rehabilitation services. These challenges intensified caregiver isolation and emotional distress.

CONCLUSION: Caregiving for children with CP in Magba is shaped by intersecting sociocultural, economic, and systemic factors that extend beyond individual coping capacity. Strengthening culturally sensitive community-based rehabilitation, improving access to early diagnosis and rehabilitation, and implementing disability- and gender-responsive social protection policies are essential to reduce caregiver burden and promote inclusive child and family wellbeing in Cameroon.},
}

@article {pmid42143797,
year = {2026},
author = {Tribhuvan, M and Phatke, SN},
title = {Comment on "Head injuries as a risk factor for amyotrophic lateral sclerosis: A systematic review and meta-analysis".},
journal = {Clinical neurology and neurosurgery},
volume = {268},
number = {},
pages = {109480},
doi = {10.1016/j.clineuro.2026.109480},
pmid = {42143797},
issn = {1872-6968},
}

@article {pmid42145633,
year = {2026},
author = {Sonkar, KS and D'Ancona, VL and Cramp, J and Shilling, H and Giles, E and Howell-Bray, T and Fillingham, B and Cudkowicz, ME and Nath, A and Rothstein, JD and Bowser, R and Borroni, B and Padovani, A and Berry, JD and Vakili, GS and Buratti, E and Thrippleton, IP},
title = {Functional Activity of TDP-43: A Direct Biomarker for ALS.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.26352054},
pmid = {42145633},
abstract = {TDP-43 dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), yet no biofluid biomarker directly measures its functional activity. We developed a serum-based homogeneous time-resolved FRET (hTR-FRET) assay that quantifies TDP-43 RNA-binding activity using synthetic UU rich RNA probes. We analyzed 1,080 serum samples from controls, sporadic ALS, and genetic subgroups (C9orf72, SOD1) across multiple biorepositories. Cross-sectionally, TDP-43 ligation activity was elevated in ALS (mean 390 a.u.) versus controls (304 a.u.), yielding AUC = 0.79. Genotype means were 392 a.u. (sporadic), 382 a.u. (C9orf72), and 323 a.u. (SOD1); with a 366 a.u threshold achieved 95% specificity against controls. Longitudinally, Target ALS showed a modest but significant inverse correlation between TDP-43 activity and ALSFRS-R, while other cohorts exhibited similar non-significant trends. Elevated signal likely reflects increased extracellular, probe-competent TDP-43 species. This assay provides direct functional measurement of disease-relevant TDP-43 biology, supporting applications in diagnostic discrimination, genotype stratification, and progression monitoring in prospective studies.},
}

@article {pmid42145639,
year = {2026},
author = {Humphrey, J and Oku, A and Byrska-Bishop, M and Basile, AO and Evani, US and Corvelo, A and Tokolyi, A and Bp, K and Réal, A and Kim, Y and Bond, ML and Clarke, WE and Fu, R and Geiger, H and Chang, S and Naito, T and Jang, B and Musunuri, R and Dredge, WH and Al-Abri, R and Hoover, BN and Manaa, D and McClintock, J and Singh, FP and Pedersen, MH and Runnels, A and Propp, N and Fennessey, S and Won, HH and Zody, MC and Narzisi, G and Robine, N and Lappalainen, T and Fagegaltier, D and Gürsoy, G and Knowles, DA and Raj, T and , and Harms, MB and Phatnani, H},
title = {The New York Genome Center ALS Consortium resource integrates postmortem tissue transcriptomics and whole genome sequencing to empower biological discovery.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.29.26350889},
pmid = {42145639},
abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with substantial genetic and clinical heterogeneity that impedes therapeutic development. Large-scale multi-tissue genomic resources have transformed the study of neuropsychiatric and neurodegenerative diseases, but no equivalent resource exists for ALS. Here we present the full NYGC ALS Consortium dataset, combining whole-genome sequencing from 4,746 donors and bulk RNA-seq from 2,574 samples across 8 brain and spinal cord regions from 695 donors across the ALS disease spectrum. Our catalogue of small variants, structural variants, and short tandem repeats identified likely pathogenic mutations in 15.6% of ALS cases. Gene expression and mRNA splicing analysis across 5 major tissues reveals shared and region-specific features, highlighting microglial and T-cell dysregulation in the spinal cord. Mapping the genetic regulation of expression and splicing across tissues identified associations with 6 ALS risk loci, whereas allele-specific rare variant analysis detected expression effects for C9orf72 and OPTN . All data are immediately publicly available.},
}

@article {pmid42146463,
year = {2026},
author = {Chen, X and Yan, H and Wei, H and Sajadi, S and Hu, J and Vasconcellos, V and Kim, A and Shriram, T and Tan, H and Keum, K and Wu, J and Paukert, M and Yang, Y},
title = {Genetic suppression of myeloid receptor Clec7a attenuates microglia neuroinflammation and promotes microglial phagocytosis to delay disease progression in ALS models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.722437},
pmid = {42146463},
issn = {2692-8205},
abstract = {Microglial activation has been closely associated with accelerated ALS disease progression. However, specific microglial pathways that regulate microglial activation and ALS disease progression remain limitedly understood. Here, we determined the role of Clec7a (or Dectin-1), a core signature gene of disease-associated microglia (DAM) in ALS, in regulating microglial activation and ALS disease progression. Our spinal cord scRNA-Seq results found that Clec7a deficiency specifically attenuated microglial neuroimmune gene expression in SOD1G93A mice and human ALS. In addition, in vivo two-photon imaging of human (h) TDP43 phagocytosis by microglia in the cortex showed that Clec7a deficiency promotes microglial phagocytosis of pathological hTDP43 by enhancing microglial process dynamics. Subsequent survival analysis further showed that selective deletion of Clec7a in microglia mitigates motor neuron degeneration and delays disease progression in SOD1G93A ALS mice. Together, our results establish that Clec7a is a key regulator in shaping disease microglial functions and promotes disease progression in ALS.},
}

@article {pmid42146521,
year = {2026},
author = {Shahani, N and Banerjee, R and MacMullen, C and Sharma, N and Habibi, M and Wasserman, HD and Noyes, NC and Zhao, P and Elgendy, B and Cameron, MD and Bannister, TD and Hegazy, L and Finck, BN and Davis, RL},
title = {Pharmacological rescue of mitochondrial dysfunction, neurite degeneration, and premature death of ALS and AD iPSC-derived neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.722019},
pmid = {42146521},
issn = {2692-8205},
abstract = {UNLABELLED: Mitochondrial (MT) dysfunction is a key driver of ALS pathology. Without a healthy MT system, motor neurons (MN) function at sub-optimal levels and die. In addition, other effects of ALS, like axon/dendrite degeneration, may occur from a pathophysiological cascade spurred by MT dysfunction. A phenotypic screen identified Dipyridamole (DPM), an FDA-approved and safe drug, as having extraordinary effects on ALS patient induced pluripotent stem cell (iPSC)-derived MNs. The drug prevented MT fragmentation, loss of MT content, impaired MT bioenergetics, axon/dendrite degeneration, and premature MN death, extending neuronal survival by more than fivefold. Importantly, its efficacy extended across iPSC-derived neurons representing two different familial forms of ALS (C9orf72, TDP43) and Alzheimer's disease (PSEN1), implying broad neuroprotection across ALS forms and other neurodegenerative diseases. DPM increased MT respiration and pyruvate uptake in a mechanism requiring the Mitochondrial Pyruvate Carrier (MPC), mechanistically explaining its biological activities. Thus, DPM is a promising drug to repurpose or refine for treating neurodegenerative diseases or other diseases that would benefit by augmenting pyruvate uptake into MT.

TEASER: Dipyridamole, an FDA-approved drug, restores mitochondrial function and protects neurons in ALS and Alzheimer's disease.},
}

@article {pmid42147178,
year = {2026},
author = {Gough, E and Basu, S and Brubaker, J and DeNeraing, B and Sack, D and Bourgeois, AL and Walker, R and Harro, CD and Chakraborty, S},
title = {Influence of Gut Microbiota on Immune Responses and Protection in Volunteers Receiving the Live Attenuated Oral ETEC Vaccine ACE257 followed by Virulent ETEC H10407 Challenge.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9284363/v1},
pmid = {42147178},
issn = {2693-5015},
abstract = {Enterotoxigenic Escherichia coli (ETEC) remains a major cause of diarrheal morbidity with no licensed vaccines. Role of gut microbiota in vaccine immunogenicity and protection was investigated using 16S rRNA sequencing from the stool samples of 27 volunteers receiving two doses of the live attenuated oral ETEC vaccine ACE527 followed by virulent ETEC H10407 challenge. Systemic and mucosal IgG and IgA responses to heat-labile toxin-B (LTB) and colonization-factor-antigen-I (CFA/I) were quantified by ELISA in serum and antibody-in-lymphocyte-supernatant (ALS). Microbiome α-diversity, β-diversity, and taxa-immune associations were evaluated using regression models, MiRKAT, and relaxed LASSO. Vaccination increased (~ 25-30%) Eubacterium_brachy_group, Family_XIII_AD3011 and Actinomyces. Higher α-diversity (inverse-Simpson) was associated with reduced ALS anti-LTB and CFA/I IgA responses, whereas β-diversity correlated with increased serum anti-CFA/I IgA. Members of Anaerovoraceae, Peptostreptococcaceae, Oscillospiraceae, and Veillonellaceae enhanced immune responses and protection against severe diarrhea and ETEC colonization, while Ruminococcaceae, Sutterellaceae, Coriobacteria, Clostridia, and Actinobacteria showed antagonistic associations.},
}

@article {pmid42147445,
year = {2026},
author = {Arogundade, OA and Lam, KJK and Brown, KA and Jain, T and Issagholian-Lewin, PO and Huang, C and Rae-Hudson, T and Briseno, K and Wyman, SK and Krishnappa, N and George, CA and O'Dare, K and Wilson, RHC and van Eijk, P and Reed, SH and Giannikopoulos, P and Clelland, CD},
title = {Arrayed dual-gRNA CRISPR screening platform for C9orf72 repeat expansion excision in patient iPSCs.},
journal = {Molecular therapy. Advances},
volume = {34},
number = {2},
pages = {201741},
pmid = {42147445},
issn = {3117-387X},
abstract = {An intronic hexanucleotide repeat expansion in C9orf72 is the leading genetic cause of both frontotemporal dementia and amyotrophic lateral sclerosis (C9-FTD/ALS). We have previously demonstrated that CRISPR-Cas9 excision of the repeat expansion in patient iPSCs reverts pathological hallmarks of C9-FTD/ALS. Here, we aim to identify efficient and safe gRNAs for CRISPR-spCas9 dual-gRNA excision of the C9-repeat expansion. Utilizing novel ddPCR and single-molecule sequencing assays, we screened 120 gRNA pairs, comparing 64 bi-allelic, intronic excisions of the repeat region to 56 allele-specific excisions of the mutant allele in patient iPSCs, ranking them by efficiency. Bi-allelic excisions of the intronic repeat region were more efficient than excisions of the mutant allele. Single gRNA indel rates can nominate likely efficient gRNA pairs, but these pairs must be tested empirically. The length of the repeat expansion did not impact excision efficiency; rather, the activity of individual gRNAs drove excision efficiencies. Using whole genome sequencing and INDUCE-seq, we found only one detectable off-target of those nominated by Cas-OFFinder and CHANGE-seq across 4 of the most efficient gRNAs. This study advances the development of targeted therapies for C9-FTD/ALS and establishes a framework for dual-gRNA screening in patient iPSCs applicable to other repeat expansions.},
}

@article {pmid42148083,
year = {2026},
author = {Li, L and Wang, S and Duan, L and Zhang, L and Yan, H and Chen, X and Tao, L and Gao, Y},
title = {Ferroptosis-immune crosstalk in CNS diseases: mechanisms and translational insights.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1807104},
pmid = {42148083},
issn = {1664-3224},
mesh = {*Ferroptosis/immunology ; Humans ; Animals ; *Central Nervous System Diseases/immunology/metabolism/etiology/pathology ; Iron/metabolism ; },
abstract = {Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation, which plays a pivotal role in regulating the inflammatory-immune microenvironment of central nervous system (CNS) diseases. Mounting evidence indicates that dysregulated iron metabolism and an imbalance in antioxidant defenses can induce ferroptosis in neurons and glial cells while simultaneously remodeling immune cell function, thereby establishing a bidirectional feedback loop that amplifies neuroinflammation and tissue damage. In neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), pro-inflammatory cytokines such as TNF-α and IL-1β released by activated microglia upregulate neuronal iron transporters (e.g., DMT1 and TfR1), promoting iron accumulation and ferroptotic cell death. In turn, damage-associated molecular patterns released from ferroptotic cells further potentiate immune activation, forming a self-amplifying cycle. In contrast, within the glioma microenvironment, CD8[+] T cell-derived IFN-γ suppresses SLC7A11 expression in tumor cells, leading to glutathione depletion and glutathione peroxidase 4 inactivation, thereby triggering ferroptosis and modulating anti-tumor immunity. Although targeting ferroptosis or neuroimmune pathways has shown therapeutic promise in mitigating neurological deficits and enhancing anti-tumor responses, the underlying mechanisms governing ferroptosis-immune crosstalk remain inadequately characterized. Herein, this review systematically summarizes the key biological characteristics of ferroptosis and immune responses, with particular emphasis on their interplay across major CNS disorders (i.e., AD, PD, ALS, multiple sclerosis, stroke, and glioma). Furthermore, we discuss emerging therapeutic strategies encompassing small molecules, immunomodulatory approaches, and nanotechnology-based interventions, highlighting the ferroptosis-immune axis as a promising therapeutic target for CNS diseases.},
}

*Ferroptosis/immunology
Humans
Animals
*Central Nervous System Diseases/immunology/metabolism/etiology/pathology
Iron/metabolism

@article {pmid42148235,
year = {2025},
author = {Naserzadeh, E and Olfati, N and Akhlaghi, S and Emadzadeh, M and Rashidnezhad, A and Nafissi, S and Fatehi, F and Sarraf, P and Haghi-Ashtiani, B and Ziaadini, B and Ansari, B and Okhovat, AA and Basiri, K and Boostani, R},
title = {Translation and psychometric validation of the Persian version of amyotrophic lateral sclerosis cognitive behavioral screen (ALS-CBS) and revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R).},
journal = {Current journal of neurology},
volume = {24},
number = {1},
pages = {16-22},
pmid = {42148235},
issn = {2717-011X},
abstract = {Background: The Amyotrophic Lateral Sclerosis Cognitive Behavioral Screen (ALS-CBS) and the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) are widely recognized tools for evaluating cognitive, behavioral, and functional changes in patients with amyotrophic lateral sclerosis (ALS). Given the increasing number of ALS cases in Persian-speaking communities, there is a critical need for culturally and linguistically adapted versions of these instruments. The objective of this study was to translate the ALS-CBS and ALSFRS-R into Persian and evaluate their validity and reliability to ensure their applicability in clinical practice and research. Methods: The Persian versions of the ALS-CBS and ALSFRS-R questionnaires were developed using the translation-back translation method. The translated questionnaires were administered to 36 individuals diagnosed with ALS. To assess content validity, neuromuscular specialists evaluated each item based on relevance, clarity, simplicity, necessity, and comprehensiveness, using content validity ratio (CVR) and content validity index (CVI) measures. Internal consistency reliability was assessed using Cronbach's alpha coefficient. Test-retest reliability was evaluated using the intra-class correlation coefficient (ICC). Statistical analysis was conducted using SPSS software. Results: All questionnaire items demonstrated satisfactory face validity after expert-guided revisions. The minimum acceptable values for CVI (≥ 0.78) and CVR (≥ 0.62) were achieved by correcting items that initially scored below the threshold. Reliability analysis revealed ICC values of 0.969 and 0.816 for the cognitive and behavioral sections of the ALS-CBS, respectively, and 0.909 for the ALSFRS-R. Cronbach's alpha coefficients were 0.791 for the ALS-CBS behavioral section and 0.825 for the ALSFRS-R, indicating acceptable internal consistency. Conclusion: The Persian versions of the ALS-CBS and ALSFRS-R have been shown to be both valid and reliable. These adapted tools provide valuable resources for assessing the cognitive, behavioral, and functional status of patients with ALS in Persian-speaking populations, ultimately supporting more accurate diagnosis, monitoring, and disease management.},
}

@article {pmid42148602,
year = {2026},
author = {Du, W and Wu, T and Fan, Y and Zhao, M},
title = {When copper turns killer: Decoding copper dyshomeostasis and cuproptosis in neurodegenerative pathogenesis and precision metal interventions.},
journal = {Neural regeneration research},
volume = {21},
number = {9},
pages = {3964-3976},
doi = {10.4103/NRR.NRR-D-25-00808},
pmid = {42148602},
issn = {1673-5374},
abstract = {Copper is an essential cofactor for neuronal metabolism, enzymatic functions, and neurotransmission. However, copper dyshomeostasis-induced redox activity makes the brain vulnerable to oxidative and proteostatic stress. Cuproptosis, a recently characterized form of programmed cell death, is triggered by copper binding to lipoylated enzymes of the tricarboxylic acid cycle, resulting in proteotoxic stress, mitochondrial dysfunction, and cell death. Given that mitochondria are central to copper handling and the primary site of cuproptosis, we examine mitochondrial pathways and key cuproptosis-related genes. We also assess disease-specific signatures of copper imbalance. In Alzheimer's disease, excess copper binds to amyloid-β, promoting aggregation and neurotoxicity. In Parkinson's disease, copper-bound α-synuclein fosters aggregation, while copper-driven redox cycling elevates reactive oxygen species. Cuproptosis worsens mitochondrial vulnerability in Parkinson's disease and impairs cellular stress responses in Huntington's disease. In amyotrophic lateral sclerosis, superoxide dismutase 1-related defects compromise antioxidant defenses alongside copper-dependent mitochondrial dysfunction. In prion diseases, copper facilitates prion protein misfolding and toxicity. Across these disorders, common features include mitochondrial dysfunction and cuproptosis hallmarks-such as enhanced protein lipoylation, elevated reactive oxygen species, impaired electron transport chain activity, fragile Fe-S clusters, and increased reliance on the tricarboxylic acid cycle-which collectively increase neuronal susceptibility to copper dyshomeostasis. Clarifying and understanding the critical roles of copper metabolism not only elucidates the pathogenesis of neurodegenerative diseases but also offers alternative therapeutic strategies. This review uniquely integrates the mitochondria-centered cuproptosis axis with copper dyshomeostasis across Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases, mapping convergent vulnerabilities to mechanism-grounded interventions and outlining testable translational routes.},
}