@article {pmid42739287,
year = {2026},
author = {Chen, M and Li, H and Jin, Q},
title = {Presymptomatic Amyotrophic Lateral Sclerosis: From Early Biomarker Detection to Phenoconversion Prediction.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {17},
pages = {},
pmid = {42739287},
issn = {2075-4418},
support = {81671117//National Natural Science Foundation of China/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) usually enters diagnostic pathways after motor symptoms emerge, by which time neural injury has been ongoing. Long-term hereditary ALS cohorts show that some pathogenic-variant carriers may show elevated neurofilament light chain (NfL), mild motor impairment (MMI), electromyographic abnormalities, or imaging changes before clinical manifestation. Since 2022, research has shifted from detecting presymptomatic abnormalities to identifying observable prodromal phenotypes and predicting phenoconversion timing. Operational MMI criteria, longitudinal imaging in chromosome 9 open reading frame 72 (C9orf72) expansion carriers, TAR DNA-binding protein 43 (TDP-43)-related fluid biomarkers, and plasma proteomic models spanning prediction horizons have broadened early identification. The ATLAS study, a trial of tofersen initiated in clinically presymptomatic carriers of superoxide dismutase 1 (SOD1) variants, incorporated specific SOD1 variants and within-person NfL increases into risk monitoring and used these criteria to select participants for the randomized treatment phase. Evidence remains concentrated in a few genetic subtypes, and no single marker accurately predicts individual phenoconversion. Identification requires genotype-specific natural history, serial clinical examinations and biomarker testing, with clinical utility validated in independent longitudinal cohorts and prevention trials.},
}

@article {pmid42740767,
year = {2026},
author = {Stern, C and Pollock, D and Barker, T and Holland, GM and Hasanoff, S and Shrestha, N and Semendric, I and Bulto, LN and Sharma, S and Fragkoudi, A and Facchin-Young, SC and Day-Sharman, AM and Stollery, L and Beasley-Hall, J and Schubert, C and Giles, L and Merlin, T and Vucic, S and Whitehouse, J and Munn, Z},
title = {Protocol for the Development of The Australian Motor Neurone Disease (MND) Guideline.},
journal = {Clinical and public health guidelines},
volume = {3},
number = {1},
pages = {e70055},
pmid = {42740767},
issn = {2836-3973},
abstract = {INTRODUCTION: Motor neurone disease (MND) is a rare but devastating neurodegenerative condition that results in progressive muscle weakness, disability, and eventual respiratory failure. In Australia, the impact of MND is significant, and there is a pressing need for a high-quality, locally relevant guideline to support equitable, person-centred care.

QUESTIONS: This guideline aims to address key clinical and care-related questions that arise across the MND trajectory. It will identify the most pressing topics and uncertainties in MND management through interest holder consultation and structured prioritisation.

METHODS: The guideline will be developed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and will align with standards set by the National Health and Medical Research Council (NHMRC) and the Guidelines International Network (GIN). Governance will include a multi-tiered structure with lived experience representation. Implementation planning and evaluation will be integrated throughout, with a planned transition to a living guideline model supported by an ongoing evidence surveillance strategy.},
}

@article {pmid42740795,
year = {2026},
author = {Imamura, K and Yoshioka, S and Kamizato, K and Oki, R and Hioki, H and Tsukita, K and Inoue, I and Shimizu, R and Takiguchi, M and Sakasai, T and Okusa, A and Shibukawa, R and Niki, T and Sakurai, S and Okunomiya, T and Kondo, T and Kato, T and Miyanohara, A and Kakinohana, M and Yamamoto, T and Marsala, M and Nishida, K and Izumi, Y and Inoue, H},
title = {Base editing rescues a hereditary motor neuron disease in mouse and patient-derived iPSC organoid models.},
journal = {Molecular therapy. Advances},
volume = {34},
number = {4},
pages = {201835},
pmid = {42740795},
issn = {3117-387X},
abstract = {In hereditary motor neuron diseases (MNDs), including forms of amyotrophic lateral sclerosis (ALS) caused by single-nucleotide variants, effective therapeutic strategies need to address both gain- and loss-of-function mechanisms. Genome editing-based gene therapy represents a promising approach for simultaneously targeting these mechanisms. To establish proof-of-concept for base editing in a hereditary MND, we targeted the P285L variant in the TRK-fused gene (TFG), which causes hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), a disorder that shares clinical and histopathological features with ALS. We identified the optimal adenine base editor by comparing candidate editors in HMSN-P patient-derived induced pluripotent stem cells (iPSCs). We then generated a transgenic mouse model expressing human TFG P285L and evaluated the selected editor by subpial delivery of adeno-associated virus (AAV) vectors to the spinal cord. AAV-mediated base editing prolonged survival, preserved motor neurons, and attenuated axon loss in ventral nerve roots. Treatment with the selected base editing vector reduced TFG aggregation and suppressed neuronal death in HMSN-P iPSC-derived neuromuscular organoids. Collectively, these findings support the therapeutic potential of base editing for hereditary MNDs.},
}

@article {pmid42740981,
year = {2026},
author = {Xie, G and Guo, Y and Wang, Z},
title = {Prevalence of and associated factors for sleep disorders in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1889217},
pmid = {42740981},
issn = {1664-2295},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/complications ; *Sleep Wake Disorders/epidemiology/etiology ; Prevalence ; },
abstract = {BACKGROUND: Sleep disorders stand as prevalent non-motor symptoms in individuals with amyotrophic lateral sclerosis (ALS) and may be linked to respiratory muscle weakness, neurodegenerative changes, and disruption of sleep architecture. Existing studies have reported considerable variability in the prevalence of sleep disorders in ALS patients, and findings regarding associated factors remain inconsistent. Therefore, this study intended to integrate the existing evidence through a meta-analysis to further clarify the prevalence of sleep disorders and their clinical relevant factors.

METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched from database inception to January 10, 2026. Cross-sectional, cohort, and case-control studies involving clinically diagnosed adult patients with ALS were included. A random-effects model was used to estimate the pooled prevalence of sleep disorders. Subgroup analyses were performed according to sex, site of onset, age, disease duration, body mass index (BMI), sleep disorder category based on the International Classification of Sleep Disorders, Third Edition, Text Revision (ICSD-3-TR), sleep-related treatment status, and assessment method (polysomnography [PSG] versus questionnaire-based assessment).

RESULTS: A total of 31 studies involving 2,762 patients with ALS were included. The pooled prevalence of sleep disorders was 50% (95% confidence interval [CI], 45-56%). Patients with sleep disorders were significantly older than those without sleep disorders (mean difference [MD] = 3.72 years, 95% CI, 2.39-5.05), whereas no significant associations were observed for sex, body mass index (BMI), disease duration, or site of onset. The prevalence did not differ significantly across the ICSD-3-TR categories (p = 0.7367), whereas questionnaire-based studies yielded a significantly higher pooled prevalence than PSG-based studies (p = 0.0367). Sensitivity analyses confirmed the robustness of the findings.

CONCLUSION: Approximately half of ALS patients have sleep disorders. Age may be related to the occurrence of sleep disorders, whereas no substantial relations were identified for sex, BMI, disease duration, or site of onset. Routine screening and early intervention for sleep issues should be strengthened in clinical management. Large-scale, multicenter prospective studies are still needed to further clarify the underlying mechanisms and clinical implications.

The publicly accessible registration URL is: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261287352. The systematic review was registered with PROSPERO (registration number: CRD420261287352).},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology/complications
*Sleep Wake Disorders/epidemiology/etiology
Prevalence

@article {pmid42741310,
year = {2026},
author = {Almeida, MR and Tábuas-Pereira, M and Matos, A and Santos, A and Teixeira, C and Baldeiras, I and Lima, M and Santana, I},
title = {The spectrum of C9orf72 repeat lengths in Portuguese frontotemporal dementia and amyotrophic lateral sclerosis patients: from pathogenic expansions to intermediate alleles.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1913909},
pmid = {42741310},
issn = {1662-4548},
abstract = {INTRODUCTION: Frontotemporal dementia and amyotrophic lateral sclerosis are clinically distinct disorders that share a common genetic etiology, with pathogenic hexanucleotide repeat expansions in the C9orf72 gene representing the most frequent genetic cause of both conditions. In this study we aim to determine the frequency of C9orf72 repeat expansions in patients with FTD and/or ALS and their at-risk relatives from central Portugal, and to analyze the distribution and repeat size of intermediate alleles within this cohort investigating their potential pathogenicity.

METHODS: Between January 2016 and January 2026, C9orf72 repeat expansions were assessed in 610 patients with the clinical presentation within the spectrum of FTD/ALS and in 63 asymptomatic relatives. C9orf72 repeat expansions were identified using a two-step PCR protocol comprising STR-PCR and RP-PCR, followed by repeat-length sizing with a commercial kit. Capillary electrophoresis traces were subsequently analyzed using AmplideX® PCR/CE Reporter software. Furthermore, carriers of intermediate alleles underwent comprehensive clinical, fluid-biomarker, and neuropsychological characterization to investigate the potential pathogenicity of these alleles.

RESULTS: Pathogenic C9orf72 expansions were identified in 11% of patients. The vast majority carried long expansions (>145 repeats), whereas three patients exhibited shorter expansions ranging from 38 to 78 repeats. Intermediate alleles were found in seven subjects with heterogeneous clinical presentations. Clinically, these individuals were indistinguishable from carriers of longer expansions.

DISCUSSION: C9orf72 hexanucleotide repeat expansions are a major genetic cause of FTD, ALS, and FTD-ALS in this cohort of patients, highlighting the importance of genetic testing for accurate counselling and clinical management. These findings support routine C9orf72 testing in all patients with these disorders, particularly those of European ancestry. Our findings also support the emerging view that intermediate C9orf72 repeat expansions may act as a genetic risk factors contributing to a broad spectrum of clinical phenotypes.},
}

@article {pmid42741938,
year = {2026},
author = {Zhang, B and He, Y and Su, T and Li, X and Zhang, X and Liu, R and Han, X and Zhang, R and Yang, C and Liu, X and Hou, Q and Zhang, Z and Xie, Y and Liu, G and Yang, X},
title = {UA-30 ameliorates motor deficits through RalA-mediated mitophagy in ALS mice.},
journal = {The Journal of clinical investigation},
volume = {136},
number = {18},
pages = {},
pmid = {42741938},
issn = {1558-8238},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; *Mitophagy/drug effects ; Mice ; Forkhead Box Protein O3/metabolism/genetics ; Mice, Transgenic ; Humans ; Disease Models, Animal ; Superoxide Dismutase-1/genetics/metabolism ; Motor Neurons/pathology/metabolism ; Male ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, skeletal muscle atrophy, paralysis, and eventually death. Mitochondrial dysfunction plays a pivotal role in ALS pathogenesis, although the precise pathogenic mechanisms remain elusive, and effective therapeutic strategies are extremely limited. In this study, we developed a small-molecule inhibitor, UA-30, which directly targets RalA, and explored its potential for the treatment of ALS. We found that when administered via oral gavage for 6 weeks following the onset of motor deficit, UA-30 extended lifespan and improved motor function of SOD1G93A mice, a model of ALS. UA-30 ameliorated motor neuron loss, neuroinflammation, fibrosis, and mitochondrial dysfunction, as evidenced by energy recovery, decreased oxidative stress, and enhanced mitophagy. Mechanistically, UA-30 inhibited RalA activity and thereby modulated ERK/FOXO3a signaling, which inhibited FOXO3a degradation via the ubiquitin-proteasome pathway; enhanced FOXO3a stability; and upregulated the expression of mitophagy-related genes in this ALS mouse model. The beneficial effects of UA-30 in ALS were abolished by overexpression of the constitutively active form of RalA (RalAG23V) or Mdivi-1 treatment. These findings support RalA inhibition as a therapeutic strategy for enhancing mitophagy and mitigating ALS-like pathology and support UA-30 as an orally active candidate for further preclinical development.},
}

Animals
*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology
*Mitophagy/drug effects
Mice
Forkhead Box Protein O3/metabolism/genetics
Mice, Transgenic
Humans
Disease Models, Animal
Superoxide Dismutase-1/genetics/metabolism
Motor Neurons/pathology/metabolism
Male

@article {pmid42736600,
year = {2026},
author = {Benatar, M and Wuu, J and Turner, MR and Macklin, EA},
title = {The diagnostic biomarker problem in amyotrophic lateral sclerosis.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag313},
pmid = {42736600},
issn = {1460-2156},
abstract = {In the effort to reduce the long diagnostic delay in amyotrophic lateral sclerosis, an often overlooked problem derives from confusion around the concept of diagnostic biomarkers and the type of data required to develop such tools. A useful diagnostic biomarker is one that can correctly differentiate individuals with, from those without, the disease of interest - and importantly, at a point in time when the diagnosis is otherwise uncertain. This requires a test with a high positive predictive value (the proportion of positive test results that are true positives), a high negative predictive value (the proportion of negative test results that are true negatives), or ideally both. Critically, positive and negative predictive values depend on the context of use for the diagnostic, which determines the prevalence of disease in the population in which the diagnostic test will be used. Almost all diagnostic biomarker studies in amyotrophic lateral sclerosis get this wrong - focusing on data and samples from patients for whom there is no diagnostic uncertainty. This Update distinguishes disease state biomarkers from diagnostic biomarkers; highlights the data required to clinically validate a diagnostic biomarker; underscores the critical importance of understanding the clinical context in which the diagnostic biomarker will be used; and outlines potential strategies for developing diagnostic biomarkers that might be clinically useful.},
}

@article {pmid42737027,
year = {2026},
author = {Musik, S and Zalewski, J and Jurkowska, J and Pędzimąż, W and Sasin-Kurowska, J and Panczyk, M},
title = {Leveraging Synthetic Clinical Data for Validation and Operational Readiness in Clinical Trials.},
journal = {Healthcare (Basel, Switzerland)},
volume = {14},
number = {17},
pages = {},
pmid = {42737027},
issn = {2227-9032},
support = {DWD/6/0494/2022//Ministry of Science and Higher Education/ ; },
abstract = {Background/Objectives: Obtaining timely access to detailed clinical trial data is not always straightforward. Privacy requirements, governance processes, and study-specific eCRF configurations can delay access, particularly during study start-up, when teams need realistic data to develop and test validation rules, reporting pipelines, and centralized monitoring tools. Methods: We developed SYNDATA, a modular framework that generates synthetic clinical trial datasets conforming to a target electronic case report form (eCRF). The framework combines study metadata from the Medidata Rave Architect Loader Spreadsheet (ALS) with selected empirical patterns learned from a closely matched reference study. It constructs patient-specific timelines from the ALS visit matrix, generates module-specific records using Bayesian networks for selected categorical dependencies and density-based methods for numeric and temporal variables, and applies postprocessing for counters, dictionary coding, and conditional missingness. A configurable Noise Tool injects controlled and reproducible data defects, including timeline inconsistencies, visit-window violations, numeric threshold exceedances, randomization or eligibility conflicts, and structural collisions, to stress-test downstream validation logic. Results: Synthetic and source data were compared descriptively using Jensen-Shannon distance, Cramér's V, and representative plots across selected domains. Several binary operational fields showed close descriptive agreement, whereas agreement was weaker for some more complex, multi-category safety- and medication-related variables. The evaluation covered a representative subset and does not establish uniform fidelity, formal statistical equivalence, or clinical validity across all generated domains. Conclusions: SYNDATA supports reproducible generation of ALS/eCRF-conformant datasets for operational validation, reporting development, and workflow testing before real trial data are available. Its demonstrated value is limited to the evaluated operational use case; fidelity is variable-specific, and more complex domains require further development and validation.},
}

@article {pmid42737854,
year = {2026},
author = {Ginanni, F and Nicoletti, F and Meoni, C and Becattini, L and Mancuso, M and Carlesi, C and Bianchi, F},
title = {Cognitive and Behavioural Profile of SOD1-ALS Across the ALS-FTD Spectrum: A Systematic Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {17},
pages = {},
pmid = {42737854},
issn = {1422-0067},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/psychology ; *Superoxide Dismutase-1/genetics ; *Frontotemporal Dementia/genetics/psychology ; *Cognition ; Mutation ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS) is increasingly recognized as a multisystem disorder. However, SOD1-associated ALS has traditionally been regarded as an exclusively motor phenotype. This systematic review challenges that paradigm by characterizing the cognitive and behavioural profiles of SOD1 mutation-related ALS. Following PRISMA guidelines, a systematic PubMed search identified 17 eligible studies. Across the included studies, encompassing 222 patients with SOD1 variants, three of the analyzed subjects fulfilled the diagnostic criteria for frontotemporal dementia (FTD), and a larger proportion exhibited multidomain cognitive deficits, including executive dysfunction, language impairment, and working memory decline. Behavioural disturbances, such as apathy, emotional lability, and mental rigidity, were also prominent. The historical assumption that SOD1 mutations completely spare cognitive networks likely reflects an under-recognition of subtle manifestations, compounded by the limited sensitivity of earlier screening tools. These findings indicate that cognitive and behavioural involvement can occur in SOD1-ALS, highlighting a highly heterogeneous phenotype. Encompassing varying degrees of severity-from subtle differences in neuropsychological test scores to formal FTD diagnoses-the current evidence points towards possible variant-specific phenotypes rather than a uniform cognitive syndrome. Routine multidomain cognitive screening is crucial in this population. Properly characterizing these non-motor features allows for more accurate disease staging, better monitoring of clinical progression, and the implementation of truly personalized care strategies.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/psychology
*Superoxide Dismutase-1/genetics
*Frontotemporal Dementia/genetics/psychology
*Cognition
Mutation

@article {pmid42738182,
year = {2026},
author = {Savov, V and Antov, P and Kostadinova-Slaveva, A and Todorova, E and Yusein, J and Ivanov, G and Dudeva, V and Ninikas, K and Petrin, S and Seng Hua, L},
title = {Influence of the Spent Coffee Ground-to-Ammonium Lignosulfonate Ratio on the Performance of Wood-Fiber Biocomposites.},
journal = {Materials (Basel, Switzerland)},
volume = {19},
number = {17},
pages = {},
pmid = {42738182},
issn = {1996-1944},
support = {BG16RFPR002-1.014-0015//European Union/ ; BG05SFPR001-3.004-0010//European Union/ ; НИС-Б-1397/16 May 2025//University of Forestry/ ; },
abstract = {Spent coffee grounds (SCGs) and ammonium lignosulfonate (ALS) are promising renewable constituents for wood-fiber biocomposites, but the effect of their relative proportion within the binder phase remains insufficiently understood. This preliminary study evaluated wood-fiber panels produced at a constant dry-matter matrix-to-fiber ratio of 50:50 while varying the SCG:ALS ratio from 70:30 to 30:70. The panels were hot-pressed and characterized for their physical and mechanical properties, while the corresponding SCG-ALS matrix formulations were evaluated by simultaneous TGA-DSC analysis. Increasing the SCG fraction generally improved dimensional stability and mechanical performance, whereas formulations containing 50% or more ALS showed a marked deterioration in water resistance. The SCG-rich 70:30 formulation provided the highest bending performance, with MOE and MOR values of 2156.5 and 12.83 N·mm[-2], respectively. Thermal analysis revealed ratio-dependent changes in mass loss and in the principal heat-flow event, which occurred between approximately 113 and 136 °C, confirming that the SCG:ALS ratio altered the early thermal behavior of the binder system. Overall, the SCG:ALS ratio was identified as a key formulation parameter, with SCG-rich systems providing the most favorable balance between mechanical performance, dimensional stability, and internal cohesion.},
}

@article {pmid42738680,
year = {2026},
author = {Strekalova, T and Gorlova, A and Munter, JPM and Chervinskaya, M and Deykin, A and Aladysheva, Z and Grigorieva, E and Lyundup, A and Askarova, S and Kostin, A and Pomytkin, I},
title = {Beneficial Effects of Putative Hydrogen Sulfide (H2S) Donor POM16 in a Genetic Model of Amyotrophic Lateral Sclerosis, FUS [1-359]-Transgenic Mice.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {17},
pages = {},
pmid = {42738680},
issn = {1420-3049},
support = {AP23485236//Ministry of Science and Higher Education of the R public of Kazakhstan/ ; FZWG-2024-0003//Ministry of Science and Higher Education of RF/ ; 101086453//European Union/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; *Hydrogen Sulfide/metabolism/chemistry ; Mice, Transgenic ; Disease Models, Animal ; Mice ; Spinal Cord/metabolism/drug effects/pathology ; Oxidative Stress/drug effects ; Motor Neurons/drug effects/metabolism/pathology ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by rapid motoneuron degeneration. Hydrogen sulfide (H2S), a signaling molecule that regulates post-translational modification, has recently been implicated in the pathophysiology of ALS. Our study aimed to design, synthesize, and investigate the potential effects of (2S)-2-aminopentanethioic S-acid (POM16), an isomer of the slow-releasing H2S donor thiovaline, in a genetic ALS model. FUS [1-359]-tg mice, which recapitulate ALS syndrome, and their wild-type (WT) littermates received POM16 (at a dose of 50/mg/kg) or standard ALS therapy riluzole (at a dose of 8 mg/kg/day) dissolved in drinking water, or vehicle, for six weeks starting at nine weeks of age. The onset of paralysis, physiological and motor functions, muscle atrophy, density of spinal cord motoneurons, gene expression of proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF), and concentration of oxidative stress marker malondialdehyde (MDA) in the spinal cord were studied. POM16-treated mutants displayed significant improvements in body weight, water and diet intake, as well as behavior in the rotarod, wire, and pole tests. The percentage of mice with paralysis on the 6th week of dosing was reduced from 48% in vehicle-treated mutants to 16% in POM16-treated FUS [1-359]-tg mice, while in the riluzole-treated group, it was 38%, not reaching significance. Notably, muscle weight was not significantly improved by the latter treatment, unlike the dosing with POM16. In comparison with vehicle-treated FUS [1-359]-tg mice, POM16-treated mutants had significantly higher motor neuron density in the spinal cord, lower MDA levels, and reduced muscle atrophy ranking. Thus, new compound POM16 has a therapeutic potential to counteract ALS pathology that is likely mediated via anti-oxidative stress mechanisms. Given that any effective treatment of this devastating disease is currently lacking, it is hoped that POM16 can be a promising therapy for ALS.},
}

Animals
*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology
*Hydrogen Sulfide/metabolism/chemistry
Mice, Transgenic
Disease Models, Animal
Mice
Spinal Cord/metabolism/drug effects/pathology
Oxidative Stress/drug effects
Motor Neurons/drug effects/metabolism/pathology

@article {pmid42738830,
year = {2026},
author = {Blair, K and Gosset, P and Martinez-Serra, R and Mórotz, GM and Martín-Guerrero, SM and Gomez-Suaga, P and Atherton, J and Mitchell, JC and Noble, W and Miller, CCJ and Markovinovic, A},
title = {Sigma-1 Receptor Stimulation Rescues FTD/ALS Mutant TDP43-Induced Disruption of the VAPB-PTPIP51 ER-Mitochondria Tethering Proteins via Inhibition of GSK3β.},
journal = {Cells},
volume = {15},
number = {17},
pages = {},
pmid = {42738830},
issn = {2073-4409},
support = {ARUK-PG2017B-3//Alzheimer's Research UK/ ; ARUK-DC2019-009//Alzheimer's Research UK/ ; MR/R022666/1/MRC_/Medical Research Council/United Kingdom ; MR/X021858/1/MRC_/Medical Research Council/United Kingdom ; AlzSoc-287/ALZS_/Alzheimer's Society/United Kingdom ; },
mesh = {*Receptors, sigma/metabolism/agonists ; Sigma-1 Receptor ; *Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors ; Humans ; *DNA-Binding Proteins/genetics/metabolism ; *Endoplasmic Reticulum/metabolism/drug effects ; *Mitochondria/metabolism/drug effects ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Mutation/genetics ; *Frontotemporal Dementia/genetics/metabolism ; *Mitochondrial Proteins/metabolism ; Animals ; Protein Binding/drug effects ; Mitochondria Associated Membranes ; Calcium/metabolism ; },
abstract = {Signalling between the ER and mitochondria regulates a number of key cellular functions that are damaged in frontotemporal dementia and related amyotrophic lateral sclerosis (FTD/ALS). This signalling involves close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 ER-mitochondria "tethering" proteins. A number of studies have shown that mutant genes which cause familial FTD/ALS disrupt the VAPB-PTPIP51 tethers and that this involves activation of GSK3β. TDP43 is one such mutant and altered TDP43 metabolism is central to FTD/ALS pathogenesis. Loss of Sigma-1 receptor function is also seen in FTD/ALS and there is evidence that Sigma-1 receptor agonists can repair damaged ER-mitochondria signalling. However, the underlying mechanisms are not properly understood. In this study, we show that the reference Sigma-1 receptor agonist PRE-084 stimulates VAPB-PTPIP51 binding and rescues FTD/ALS mutant TDP43-induced disruption to the VAPB-PTPIP51 interaction and linked ER-mitochondria Ca[2+] delivery. We also show that these effects involve inhibition of the kinase GSK3β, a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that ANAVEX2-73, a further Sigma-1 receptor agonist which is in clinical trials for Alzheimer's disease, also stimulates VAPB-PTPIP51 binding via GSK3β inhibition. Our findings provide novel insights into the mechanisms by which Sigma-1 receptor agonists influence defective ER-mitochondria signalling in FTD/ALS.},
}

*Receptors, sigma/metabolism/agonists
Sigma-1 Receptor
*Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors
Humans
*DNA-Binding Proteins/genetics/metabolism
*Endoplasmic Reticulum/metabolism/drug effects
*Mitochondria/metabolism/drug effects
*Amyotrophic Lateral Sclerosis/genetics/metabolism
*Mutation/genetics
*Frontotemporal Dementia/genetics/metabolism
*Mitochondrial Proteins/metabolism
Animals
Protein Binding/drug effects
Mitochondria Associated Membranes
Calcium/metabolism

@article {pmid42738833,
year = {2026},
author = {Ayupova, AI and Sidorova, AS and Luzina, EA and Sufianov, AA and Sufianova, GZ and Zaynutdinov, AM and Rizvanov, AA and Solovyeva, VV},
title = {Application of Mesenchymal Stromal Cells and Their Exosomes in Neurodegenerative Diseases and Lysosomal Storage Diseases.},
journal = {Cells},
volume = {15},
number = {17},
pages = {},
pmid = {42738833},
issn = {2073-4409},
support = {FZSM-2026-0022//The Ministry of Education and Science of the Russian Federation/ ; },
mesh = {Humans ; *Exosomes/metabolism ; *Neurodegenerative Diseases/therapy/metabolism ; *Mesenchymal Stem Cells/metabolism/cytology ; *Lysosomal Storage Diseases/therapy/metabolism ; Animals ; *Mesenchymal Stem Cell Transplantation/methods ; },
abstract = {Mesenchymal stromal cells (MSCs) have emerged as a promising therapeutic platform for central nervous system disorders, including neurodegenerative diseases and lysosomal storage disorders (LSDs). This review examines MSC mechanisms of action-paracrine activity, immunomodulation, antioxidant effects, TFEB-mediated autophagy regulation, and enzymatic cross-correction in LSDs-while critically assessing translational challenges. We provide a comparative analysis of MSC sources, administration routes, dosing regimens, and safety profiles, with emphasis on hemocompatibility and thrombotic risks. The evidence base for MSC efficacy in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and LSDs is systematically reviewed, highlighting both promising signals and limitations. MSC-derived extracellular vesicles are discussed as a cell-free alternative with improved safety and potential blood-brain barrier interaction. We propose an individualized monitoring framework integrating clinical scales, biomarkers, and neuroimaging. Despite preclinical promise, the field faces major hurdles: product standardization, optimal dosing, and the need for large, randomized controlled trials. The most rational path forward lies in combination strategies-MSCs as adjuncts to gene or enzyme replacement therapy-and engineered platforms for sustained delivery. This review provides a roadmap for translational decision-making and identifies critical gaps that must be addressed before MSC-based therapies can be integrated into routine neurological practice.},
}

Humans
*Exosomes/metabolism
*Neurodegenerative Diseases/therapy/metabolism
*Mesenchymal Stem Cells/metabolism/cytology
*Lysosomal Storage Diseases/therapy/metabolism
Animals
*Mesenchymal Stem Cell Transplantation/methods

@article {pmid42738864,
year = {2026},
author = {Ma, X and Liu, J and Guan, Y and Xu, C and Li, M and Zhang, X and Li, Z and Zhang, L and Wang, X and Zhang, H and Chen, Y},
title = {Lactate Metabolism and Signaling in Amyotrophic Lateral Sclerosis.},
journal = {Cells},
volume = {15},
number = {17},
pages = {},
pmid = {42738864},
issn = {2073-4409},
support = {No.82571627//National Natural Science Foundation of China/ ; No.82271483//National Natural Science Foundation of China/ ; No. ZR2024MH112//Shandong Province Natural Science Foundation of China/ ; 202402010641//Shandong Provincial Medical and Health Science and Technology Development Plan/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Lactic Acid/metabolism ; *Signal Transduction ; Animals ; Motor Neurons/metabolism/pathology ; Energy Metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons (MNs). Although the specific pathogenesis of ALS is not yet fully understood, there is increasing evidence that abnormal energy metabolism plays a key role in the onset and progression of the disease. Lactate has traditionally been considered a metabolic by-product of glycolysis and has received increasing attention in recent years. Research has shown that lactate is not only an important energy substrate but also a signaling molecule that regulates a variety of physiological processes, including neuron-glia metabolic coupling, neuroprotection and inflammatory responses. In ALS, abnormalities in lactate metabolism, dysfunction of the lactate shuttle, and dysregulation of lactate-related signaling pathways may jointly lead to neuronal energy deficits and increased neuroinflammation, thereby promoting MN degeneration. This review summarizes the latest advances in lactate metabolism and lactate-mediated signaling in ALS, with particular emphasis on their roles in neuronal energy regulation, neuroprotection and inflammatory regulation. In addition, we also discuss potential therapeutic strategies for lactate metabolism and its related pathways, aiming to provide new insights into the pathogenesis of ALS and the development of treatment methods for lactate-related metabolism.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/pathology
*Lactic Acid/metabolism
*Signal Transduction
Animals
Motor Neurons/metabolism/pathology
Energy Metabolism

@article {pmid42738890,
year = {2026},
author = {Wolozin, B and Best, M and Ellini, M and Ma, Y and Bok, S and Hwang, D and Filipponi, C},
title = {The Paradox of Tau and RNA-Binding Proteins: How Adaptive Stress Granule Regulation Becomes Pathological with Aging.},
journal = {Cells},
volume = {15},
number = {17},
pages = {},
pmid = {42738890},
issn = {2073-4409},
support = {AG080810, AG072577, AG082665, AG095773, AG096052 and AG064932/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Stress Granules/metabolism ; *tau Proteins/metabolism ; *RNA-Binding Proteins/metabolism ; *Aging/metabolism/pathology ; Animals ; Stress, Physiological ; DNA-Binding Proteins/metabolism ; Neurodegenerative Diseases/metabolism/pathology ; },
abstract = {RNA-binding proteins (RBPs) are a large class of proteins that form biological condensates to facilitate their functions. Chronic stress, such as occurs in neurodegenerative diseases, stimulates persistent accumulation of particular RBP condensates as part of the translational stress response, termed stress granules (SGs). These persistent SGs serve as a nidus for aggregation of RBPs to form pathologies that appear in neurodegenerative diseases, such as the occurrence of Tar DNA Binding Protein (TDP-43) in Amyotrophic Lateral Sclerosis. Many of the RBPs that accumulate in SGs are also associated with mutations that are linked to neurodegenerative diseases. The microtubule-associated protein tau is the major intracellular pathology that occurs in Alzheimer's disease. Tau is phosphorylated with stress, whereupon it functions to regulate SG biology; conversely, SGs serve as a crucible for the accumulation of toxic oligomeric tau. The regulation of stress by tau is an inherent part of biology that normally occurs during development and hibernation; however, with aging it becomes pathological, possibly because of the reduced proteostasis associated with aging.},
}

Humans
*Stress Granules/metabolism
*tau Proteins/metabolism
*RNA-Binding Proteins/metabolism
*Aging/metabolism/pathology
Animals
Stress, Physiological
DNA-Binding Proteins/metabolism
Neurodegenerative Diseases/metabolism/pathology

@article {pmid42738892,
year = {2026},
author = {Lysikova, E and Sitdikova, K and Makhambetova, A and Chaprov, K and Gorlova, A and Kostin, A and Novikova, P and Lyundup, A and Askarova, S and Kukharsky, MS and Deykin, A and Strekalova, T},
title = {Efficacy of Low Dose of Dihydroquercetin (DHQ) in Two Genetic Models of Neurodegeneration: Insights from FUS[1-359]-Tg and APPswe/PS1dE9 Paradigms.},
journal = {Cells},
volume = {15},
number = {17},
pages = {},
pmid = {42738892},
issn = {2073-4409},
support = {AP23485236, BR24992841//the Ministry of Higher Education and Science of the Republic of Kazakhstan/ ; FZWG-2021-0016 , FZWG-2024-0032, FZWG-2022-0023//and the Ministry of Science and Higher Education of RF/ ; Aqua-Synapse 101086453 EU//HORIZON EU/ ; },
mesh = {Animals ; *Quercetin/analogs & derivatives/pharmacology/therapeutic use/administration & dosage ; Mice, Transgenic ; Disease Models, Animal ; Mice ; *RNA-Binding Protein FUS/genetics/metabolism ; Alzheimer Disease/drug therapy/genetics/pathology ; Oxidative Stress/drug effects ; *Neurodegenerative Diseases/drug therapy/genetics ; Brain/pathology/drug effects ; Presenilin-1 ; Humans ; Male ; },
abstract = {Dihydroquercetin (DHQ), a powerful antioxidant and regulator of cellular metabolism, was proposed for therapy of neurodegenerative disorders. Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) are serious neurodegenerative disorders with oxidative stress as an overlapping feature and unmet therapeutic needs. To date, few studies have explored the efficacy of DHQ in animal models of genetically driven neurodegeneration. Here, APPswe/PS1dE9 (APP/PS1) mice and their wild-type (WT) littermates were orally administered DHQ (0.6 mg/kg/day) for four months, starting at eight months of age. At the age of 12 months, behavioral evaluation was performed, followed by brain staining with Congo red for amyloid plaque scoring and immunohistochemical analysis of GFAP-positive cells for the assessment of astrogliosis. Malondialdehyde (MDA) levels in the prefrontal cortex were studied as a marker of oxidative stress. Second, two-month-old FUS[1-359]-Tg mice, which recapitulate the hallmarks of ALS, received DHQ for 1.5 months and were investigated for general physiological parameters, the onset of paralysis, motor functions, and density of motor neurons in the spinal cord. DHQ-treated APPswe/PS1dE9 mutants displayed a decrease in amyloid plaque density of small size (≤100 μm) in the cortex and thalamus, had normalized MDA levels, improved conditioned taste aversion and Y-maze learning, and ameliorated anxiety measures, whereas their hippocampus-dependent step-down and pellet displacement performance remained impaired. In the second study, DHQ-treated FUS[1-359]-Tg mice showed rescued density of spinal cord neurons, normalized liquid and diet intake, and improved coat state, while the onset of paralysis and motor scores were not significantly ameliorated. Thus, chronic administration of low doses of DHQ exerted neuroprotective effects in both AD and ALS genetic models, which partially translated to reduced manifestations of these diseases.},
}

Animals
*Quercetin/analogs & derivatives/pharmacology/therapeutic use/administration & dosage
Mice, Transgenic
Disease Models, Animal
Mice
*RNA-Binding Protein FUS/genetics/metabolism
Alzheimer Disease/drug therapy/genetics/pathology
Oxidative Stress/drug effects
*Neurodegenerative Diseases/drug therapy/genetics
Brain/pathology/drug effects
Presenilin-1
Humans
Male

@article {pmid42739085,
year = {2026},
author = {Roscoe, SA and Allen, SP and McDermott, CJ and Stavroulakis, T},
title = {Serum Biomarkers for Nutritional Monitoring in Motor Neuron Disease: A Longitudinal Cohort Study.},
journal = {Nutrients},
volume = {18},
number = {17},
pages = {},
pmid = {42739085},
issn = {2072-6643},
support = {//University of Sheffield/ ; //Darby Rimmer ALS Foundation/ ; NIHR203321//NIHR Sheffield Biomedical Research Centre/ ; },
mesh = {Humans ; *Biomarkers/blood ; Female ; Male ; Longitudinal Studies ; *Motor Neuron Disease/blood/physiopathology/complications ; *Nutritional Status ; Middle Aged ; Aged ; Prospective Studies ; *Nutrition Assessment ; Inflammation/blood ; Disease Progression ; Body Composition ; Malnutrition/blood/diagnosis/etiology ; Severity of Illness Index ; Creatinine/blood ; },
abstract = {Background: Malnutrition and metabolic dysregulation are common in motor neuron disease (MND) and contribute to accelerated functional decline and reduced survival. Routine serum biochemical analytes can be used to assess nutritional status; however, their interpretation in MND is confounded by systemic inflammation and disease-related metabolic changes. This study investigated the relationship between serum biochemical analytes, inflammatory status, disease severity, progression, and body composition in people living with MND. Methods: In this single-centre, longitudinal prospective cohort study, 19 participants with confirmed MND were assessed at enrolment and at three-month intervals up to nine months. Serum concentrations of albumin, prealbumin, creatinine, transferrin, ferritin, retinol-binding protein, and lipid fractions were measured alongside routine inflammatory markers. Disease severity and progression were assessed using the revised ALS functional rating scale and King's College Staging System. Anthropometry included percentage weight change, body mass index, mid-upper arm circumference, triceps skinfold thickness, arm muscle area, and calf circumference. Participants with evidence of baseline inflammation were excluded from nutritional analyses. Results: Low-grade systemic inflammation was present in 9/19 (47%) of participants at enrolment, most commonly reflected by elevated fibrinogen. In the non-inflammatory sub-cohort (n/N = 10/19), serum creatinine was positively correlated with muscle-related functional subscores (p = 0.007) and declined between enrolment and three months (p = 0.02), showing predominantly negative trajectories by nine months. HDL cholesterol also declined over the nine-month follow-up (p = 0.03) and lipid fractions correlated positively with disease stage (p <0.001-0.02), suggesting evolving metabolic stress. Elevated serum retinol-binding protein was observed in 90% (n/N = 9/10) of participants without inflammation. Biochemical evidence of malnutrition (low transferrin and/or creatinine) was detected in one-third of participants, accompanied by weight loss and reductions in limb anthropometric parameters. Malnutrition risk was identified in 1/10 (10%) of the non-inflammatory sub-cohort using a modified ESPEN-based framework, and in 2/10 (20%) participants using GLIM criteria. Conclusions: Routine serum biochemical analytes provide complementary information on nutritional and metabolic status in MND when interpreted alongside inflammatory markers and anthropometry. Serum creatinine emerged as a longitudinal marker of muscle wasting, reflective of denervation and nutritional depletion, while lipid and retinol-binding protein alterations highlight non-nutritional disease mechanisms that may confound standard biomarker interpretation, informing more targeted nutritional assessments. These findings support a multimodal approach to nutritional monitoring in MND and emphasise the importance of accounting for inflammatory status in biomarker interpretation. Given the small sample size and the limited representation of non-ALS phenotypes, these findings should be regarded as hypothesis-generating and require confirmation in larger, multicentre cohorts with balanced phenotypic representation.},
}

Humans
*Biomarkers/blood
Female
Male
Longitudinal Studies
*Motor Neuron Disease/blood/physiopathology/complications
*Nutritional Status
Middle Aged
Aged
Prospective Studies
*Nutrition Assessment
Inflammation/blood
Disease Progression
Body Composition
Malnutrition/blood/diagnosis/etiology
Severity of Illness Index
Creatinine/blood

@article {pmid42739237,
year = {2026},
author = {Altay, FP and Polat, ŞB and Fakı, S and Karaahmetli, G and Akdoğan, L and Topaloğlu, O and Ersoy, R and Çakır, B},
title = {From Detection to Decision: A Single-Center Analysis of Preoperative Imaging, Surgical Indications and Postoperative Histopathological Findings in Adrenal Lesions.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {17},
pages = {},
pmid = {42739237},
issn = {2075-4418},
abstract = {Background/Objectives: The aim of this retrospective study was to characterize the preoperative hormonal, biochemical, and imaging features of adrenal lesions (ALs) and to assess differences in these features between benign and malignant lesions. Methods: This was a retrospective, single-center observational study conducted at the Endocrinology Clinic of Ankara Bilkent City Hospital. We reviewed the medical records of all patients referred to our clinic for the evaluation of an AL between February 2019 and August 2025. Demographic and clinical data and initial imaging were extracted from electronic medical records. Results: A total of 157 patients who underwent adrenalectomy were included in the analysis. Of these, 98 patients were female (62.4%) and 59 were male (37.6%). The mean age of the patients was 51.2 ± 12.54 years. Functionally, the findings were pheochromocytoma (n:44), overt Cushing syndrome (n:17), mild autosomal cortisol secretion (n:29), primary hyperaldosteronism (n:18), and non-functional (n:47). One patient had pheochromocytoma and mild autosomal cortisol secretion, and one patient had overt Cushing syndrome and primary hyperaldosteronism. Of the adrenal lesions, 70 (44.6%) were on the right, 71 (45.2%) on the left, and 16 (10.2%) were bilateral. 9% (7/79) of lesions measuring 4 cm and above, and 14% (4/28) of lesions measuring 6 cm and above were found to be malignant. The malignancy rate was 22% (4/18) in lesions located on the right and measuring 6 cm and above. All adrenocortical carcinomas were larger than 4 cm (8.3 ± 3.46) and all were on the right. The highest-grade malignant epithelial tumor was 12.9 cm and on the right. The malignant pheochromocytoma was 5.2 cm and on the left. It was determined that the frequency of right adrenal localization was significantly higher in the malignant group (85.7%) compared to the benign group (42.7%) (p = 0.045). Right tumor diameter (p = 0.002) and right and/or left tumor diameter (p < 0.001) were significantly higher in malignant lesions compared to benign lesions. Logistic regression analysis also supported a significant relationship between tumor size and malignancy. Conclusions: In our study, 9% (7/79) of lesions measuring 4 cm and above, and 14% (4/28) of lesions measuring 6 cm and above were found to be malignant. The malignancy rate in lesions on the right side measuring 6 cm and above was determined to be 22% (4/18). Although benign masses constituted the majority of lesions measuring 4 cm and above, all adrenocortical carcinomas were above 4 cm (8.3 ± 3.46). In light of the current findings, tumor size was observed to be associated with the distinction between malignant and benign adrenal lesions and may be considered an important descriptive characteristic in the clinical assessment of adrenal lesions.},
}

@article {pmid42723605,
year = {2026},
author = {Kimmelman, J},
title = {New oncology trial designs and equipoise: Commentary on Heynemann et al.},
journal = {Clinical trials (London, England)},
volume = {},
number = {},
pages = {17407745261471455},
doi = {10.1177/17407745261471455},
pmid = {42723605},
issn = {1740-7753},
abstract = {This essay responds to Heymemann et al.'s analysis of the applicability of clinical equipoise to emerging trial methods in cancer. Briefly, I argue that equipoise presses study designers to conduct trials at the point of maximum community uncertainty. Accordingly, equipoise encourages maximum information gain per patient enrolled (or inversel, minimal patient burden per gain in information). As such, equipoise is as much a condition for the ethical conduct of new study designs as it is for old ones. I close by suggesting that, whereas Heymemann et al. suggest new trial designs present a challenge to the operationalization of equipoise, I argue that equipoise presents a challenge for those wishing to operationalize new trial designs.},
}

@article {pmid42723774,
year = {2026},
author = {Wang, H and Sun, B and Wang, S and Pan, J and Du, R and Pang, X and Bai, J and Han, J and Feng, J},
title = {Integrated multi-omics identification of m6A-SNP-related diagnostic biomarkers in amyotrophic lateral sclerosis.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1914869},
pmid = {42723774},
issn = {1664-3224},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Polymorphism, Single Nucleotide ; Biomarkers ; Multiomics ; RNA Methylation ; Quantitative Trait Loci ; Epitranscriptome ; *Adenosine/analogs & derivatives ; Gene Expression Profiling ; Genetic Predisposition to Disease ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) lacks reliable and minimally invasive biomarkers for early diagnosis. m6A-associated single-nucleotide polymorphisms (m6A-SNPs) may influence RNA methylation and gene expression, offering opportunities to identify clinically relevant diagnostic markers.

METHODS: We integrated eQTLGen cis-eQTL data, RMVar m6A-SNP annotations, and ALS transcriptomic datasets to identify m6A-SNP-related genes. Random Forest and LASSO regression were combined to screen robust diagnostic markers. A nomogram was constructed and validated using independent cohorts. Immune infiltration, predicted m6A modification sites, and potential RBP-SNP interactions were assessed. Peripheral blood samples from ALS patients were used for exploratory validation of gene expression and global m6A levels.

RESULTS: We identified 109 ALS-associated m6A-SNP-related genes with cis-eQTL signals and narrowed these to seven candidate diagnostic markers (TMED5, OXR1, BRI3, FEM1C, SUZ12, EIF2AK4, and TJAP1). The seven-gene model outperformed the individual markers in the training cohort and retained moderate discrimination in the independent validation cohort. ALS samples showed differences in inferred immune-cell composition, including monocytes, neutrophils, and T-cell subsets. The selected SNP loci were located near predicted m6A sites and annotated RBP-binding regions. Exploratory clinical validation showed significant upregulation of FEM1C and SUZ12 at both mRNA and protein levels, accompanied by reduced global m6A modification.

CONCLUSIONS: Through multi-omics integration and exploratory clinical validation, this study identifies m6A-SNP-related candidate markers associated with ALS. The findings support further evaluation of m6A-related signatures for ALS discrimination and molecular characterization, while larger independent cohorts and additional calibration are required before clinical application.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/diagnosis
*Polymorphism, Single Nucleotide
Biomarkers
Multiomics
RNA Methylation
Quantitative Trait Loci
Epitranscriptome
*Adenosine/analogs & derivatives
Gene Expression Profiling
Genetic Predisposition to Disease

@article {pmid42724094,
year = {2026},
author = {Gomes-Duarte, A and Pascoal, S and Haselberg, R and Sogorb-Gonzalez, M and van Deventer, S},
title = {Correction: Targeting oxidized phosphatidylcholines in SOD1-associated ALS: therapeutic potential of PC-OxPL-VecTab[®].},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1960544},
doi = {10.3389/fnins.2026.1960544},
pmid = {42724094},
issn = {1662-4548},
abstract = {[This corrects the article DOI: 10.3389/fnins.2025.1620181.].},
}

@article {pmid42724165,
year = {2026},
author = {Alauddin, W and Srivastava, C and Goyal, P and Shukla, M and Garg, DK and Prajesh, BR and Singh, S and Shaikh, FI and Khairnar, S},
title = {Gut Microbiota, Neuroinflammation, and Autonomic Dysfunction in Neurodegenerative Diseases: A Systematic Review of Mechanistic and Translational Evidence.},
journal = {Cureus},
volume = {18},
number = {8},
pages = {e114312},
pmid = {42724165},
issn = {2168-8184},
abstract = {Neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, multiple system atrophy, and amyotrophic lateral sclerosis, are increasingly recognized as complex conditions arising from interactions among the gut microbiota, immune system, and autonomic nervous system. Growing evidence indicates that disruption of the intestinal microbial ecosystem may contribute to neuroinflammatory processes, autonomic impairment, and progressive neurodegeneration through the microbiota-gut-brain axis, although the underlying mechanisms and their translational implications remain incompletely understood. This systematic review was conducted in accordance with the PRISMA 2020 guidelines to comprehensively evaluate the evidence linking gut microbiota dysbiosis with neuroinflammation and autonomic dysfunction across neurodegenerative diseases. A systematic search of PubMed/MEDLINE, Scopus, Web of Science, EMBASE, EBSCOhost, CINAHL, PsycINFO, CENTRAL, Google Scholar, and major grey literature sources yielded 2,769 records. After duplicate removal and eligibility screening, 62 full-text reports underwent detailed assessment, of which 11 studies met the predefined eligibility criteria and were included in the qualitative synthesis. The evidence encompassed human observational, animal experimental, and in vitro approaches, with several studies integrating complementary clinical, microbiome, and experimental methodologies. Most included studies focused on Parkinson's disease and multiple system atrophy. Across studies, microbial dysbiosis was characterized by reduced abundance of short-chain fatty acid (SCFA)-producing bacteria alongside increased representation of pro-inflammatory microbial taxa. These microbial alterations were associated with disruption of intestinal barrier integrity, activation of inflammatory signaling pathways, microglial activation, elevated pro-inflammatory cytokine production, α-synuclein aggregation, and autonomic manifestations such as gastrointestinal dysmotility and cardiovascular autonomic dysfunction. Experimental studies provided biological support for the microbiota-gut-brain axis, whereas clinical investigations consistently demonstrated associations without establishing causality. Overall, current evidence suggests that gut microbial dysbiosis is closely associated with neuroinflammation and autonomic dysfunction in neurodegenerative diseases and may represent a promising avenue for biomarker discovery and therapeutic intervention. Nevertheless, the available literature is constrained by methodological heterogeneity, limited sample sizes, and the predominance of observational and preclinical studies. Future large-scale longitudinal investigations and rigorously designed randomized controlled trials are required to determine causal relationships and define the clinical utility of microbiome-targeted strategies.},
}

@article {pmid42725023,
year = {2026},
author = {Xiao, X and Cao, G and Hou, S and Yin, H},
title = {P2X7 Receptor in Rare Diseases: Shared Molecular Mechanisms and Therapeutic Implications.},
journal = {Journal of inflammation research},
volume = {19},
number = {},
pages = {613821},
pmid = {42725023},
issn = {1178-7031},
abstract = {Rare diseases (RDs) are individually uncommon but collectively affect a large global population, and the vast majority still lack effective disease-modifying therapies. With advances in genomics and data-sharing platforms, research has increasingly shifted from a single-disease perspective to the search for convergent molecular pathways that might be shared across clinically distinct entities. In this context, the purinergic P2X7 receptor (P2X7R) has emerged as a putative "shared molecular platform" due to its central role in inflammation amplification, cell death and immune regulation. P2X7R is an ATP-gated ion channel with unique structural and functional features: under high extracellular ATP, it not only forms a non-selective cation channel but can also dilate into a "large pore" permeable to macromolecules, thereby triggering Ca[2+]overload, NLRP3 inflammasome assembly, reactive oxygen species (ROS) production and apoptotic/necrotic-like cell death. This review briefly outlines the epidemiology of RDs and the structural-functional characteristics of P2X7R, then systematically summarizes current evidence linking P2X7R to multiple rare diseases, including Charcot-Marie-Tooth disease, Guillain-Barré syndrome, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and selected inflammatory and metabolic RDs (CAPS, familial Mediterranean fever, Systemic sclerosis, Dravet syndrome and Gaucher disease). By comparing P2X7R expression and functional alterations, downstream signaling pathways and pharmacological data from animal models across these conditions, we propose that a P2X7R-dependent network centered on a "Ca[2+]-NLRP3-inflammation/cell death axis" may constitute a common pathogenic backbone for diverse RDs. At the same time, disease-specific spatiotemporal expression patterns of P2X7R in central vs peripheral nervous systems and in immune vs target organ cells confer marked context dependence and "double-edged sword" properties. Finally, we discuss opportunities and challenges for P2X7R-targeted strategies, including the impact of disease stage and sex differences on therapeutic efficacy, and key bottlenecks in translating preclinical findings into clinical benefit. A deeper understanding of both shared and disease-specific roles of P2X7R may provide a conceptual framework and therapeutic entry point for precision stratification and multi-target interventions in rare diseases.},
}

@article {pmid42725432,
year = {2026},
author = {Wieland, CM and Wright, SE and Willey, S and Purwar, I and Grudzien, SJ and Krans, A and Laimon, EL and Asher, MJ and Isaacs, AM and Garner, AL and Todd, PK},
title = {Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation.},
journal = {Nucleic acids research},
volume = {54},
number = {17},
pages = {},
pmid = {42725432},
issn = {1362-4962},
support = {R01 NS086810/NS/NINDS NIH HHS/United States ; R01NS099280/NH/NIH HHS/United States ; I01BX004842-04/BX/BLRD VA/United States ; F31 NS113513/NS/NINDS NIH HHS/United States ; R35 GM153185/GM/NIGMS NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; R35 GM153185/NH/NIH HHS/United States ; //NGP/ ; T32 GM141840/NH/NIH HHS/United States ; P50 HD104463/HD/NICHD NIH HHS/United States ; P50HD104463/NH/NIH HHS/United States ; F31NS113513/NH/NIH HHS/United States ; T32 GM141840/GM/NIGMS NIH HHS/United States ; //UM MSTP/ ; R01NS086810/NH/NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; },
mesh = {*Neurons/metabolism ; *Codon, Initiator ; Animals ; Humans ; RNA Caps/metabolism/genetics ; C9orf72 Protein/genetics ; *Peptide Chain Initiation, Translational ; *Protein Biosynthesis ; DNA Repeat Expansion ; Eukaryotic Initiation Factor-4E/antagonists & inhibitors ; RNA, Messenger/metabolism/genetics ; Guanosine/analogs & derivatives/metabolism ; },
abstract = {Intronic GGGGCC repeat expansions in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This expansion supports a non-canonical form of translational initiation known as repeat-associated non-AUG (RAN) translation to produce toxic dipeptide repeat proteins that contribute to neurodegeneration. Here, we find that the efficiency of RAN translation and its dependency on the 5' 7-methylguanosine mRNA cap are variable across cell types, with both rodent neurons and human iNeurons favoring cap-independent RAN translation from two distinct repeats (CGG and GGGGCC) across multiple reading frames. Treatment with an eIF4E inhibitor that blocks cap-dependent translation enhances RAN translation specifically in neurons. Intriguingly, cap-independent RAN translation exhibits less reliance on near-cognate codons for initiation than cap-dependent RAN translation. This finding led us to identify a surprising global alteration in neuronal start codon stringency as a contributor to the relatively higher cap-independent RAN translation in this cell type. This effect correlates with cytoplasmic redistribution of eIF1 in neurons and is reversed with overexpression of the eukaryotic initiation factor eIF5, which relaxes start codon stringency and preferentially enhances cap-dependent RAN translation. Together, these findings reveal several neuron-specific features of translational regulation that favor cap-independent RAN translation with implications for nucleotide repeat expansion disorder pathogenesis.},
}

*Neurons/metabolism
*Codon, Initiator
Animals
Humans
RNA Caps/metabolism/genetics
C9orf72 Protein/genetics
*Peptide Chain Initiation, Translational
*Protein Biosynthesis
DNA Repeat Expansion
Eukaryotic Initiation Factor-4E/antagonists & inhibitors
RNA, Messenger/metabolism/genetics
Guanosine/analogs & derivatives/metabolism

@article {pmid42725564,
year = {2026},
author = {Peng, L and Ma, S and Liu, Y and Liu, S and Tang, L},
title = {Artificial liver support therapy alters TNFα and CD4+ T cell counts in liver failure: A pilot self-controlled study.},
journal = {The International journal of artificial organs},
volume = {},
number = {},
pages = {3913988261479971},
doi = {10.1177/03913988261479971},
pmid = {42725564},
issn = {1724-6040},
abstract = {BACKGROUND: Artificial liver support therapy (ALS) is increasingly used in liver failure, but its immunomodulatory effects remain incompletely understood. This pilot study aimed to investigate changes in plasma cytokines and T lymphocyte subsets following ALS.

METHODS: Twenty-seven patients with liver failure who received ALS were enrolled. Plasma levels of TNFα, IL-4, IL-6, IL-10, IL-17, IL-2, and IFN-γ, as well as T lymphocyte subsets (CD4+ T cell absolute count, CD4+/CD8+ ratio), were measured before and after treatment. Paired t‑tests were used for comparisons. Patients were dichotomized by median pre-treatment TNFα level to compare clinical outcomes.

RESULTS: After ALS, TNFα levels decreased significantly (2.537 ± 1.519 vs 1.522 ± 0.749 pg/mL, p = 0.004). IL-4 also showed a significant reduction (1.463 ± 1.165 vs 0.893 ± 0.648 pg/mL, p = 0.031). CD4+ T cell absolute count increased significantly (430.85 ± 220.15 vs 636.63 ± 429.27 cells/μL, p = 0.034). Total T cell count showed an increasing trend (788.70 vs 1093.63 cells/μL, p = 0.064). Patients with low pre-treatment TNFα levels (below median) had a significantly higher improvement rate compared to those with high TNFα levels (100% vs 71.4%, p = 0.036).

CONCLUSION: ALS therapy is associated with a significant reduction in TNFα and a significant increase in CD4+ T cell absolute count, suggesting potential anti‑inflammatory and immune‑restorative effects. Lower baseline TNFα levels may predict favorable short‑term outcomes.},
}

@article {pmid42725680,
year = {2026},
author = {Milone, M and Nicolau, S and Niu, Z and Liewluck, T and Sorenson, EJ and Shen, XM and Harper, CM and Litchy, WJ},
title = {TUBA4A Pathogenic Variant Manifesting With Adulthood-Onset Genetic Myasthenic Syndrome, Myopathy, and Infertility.},
journal = {European journal of neurology},
volume = {33},
number = {9},
pages = {e70753},
pmid = {42725680},
issn = {1468-1331},
support = {MDA Award ID: 497263//Muscular Dystrophy Association/ ; },
mesh = {Humans ; Female ; Middle Aged ; *Muscular Diseases/genetics/physiopathology/complications ; *Infertility, Female/genetics ; },
abstract = {OBJECTIVES: TUBA4A pathogenic variants are associated with ALS, frontotemporal dementia, spastic ataxia, spasticity, ataxia, Parkinson's disease, female infertility, macrothrombocytopenia, and myopathy. Four recently reported patients with TUBA4A neonatal/childhood onset myopathy had also a decrement on repetitive nerve stimulation (RNS), but such a finding was not further characterized. We describe a patient with a TUBA4A pathogenic variant with adulthood-onset genetic myasthenic syndrome accompanied by myopathy and infertility to highlight the neuromuscular junction defect as the main feature of the patient's phenotype.

METHODS: We reviewed the patient's clinical and laboratory findings and performed transcriptomic analysis on the patient's muscle.

RESULTS: A 53-year-old woman with infertility of unknown etiology manifested fatigability and proximal upper limb muscle weakness in her mid-30s, followed by lower limb involvement. Her examination showed proximal muscle weakness and fatigability but spared facial muscles. CK values were mildly elevated. Anti-AChR, MuSK, P/Q-type calcium channel, and LRP4 antibodies were absent. 2 Hz RNS showed decrement (-14% to -48%) in limb muscles that improved with 3,4-dyaminopyridine (3,4-DAP). Facilitation (231%) occurred in the trapezius. Muscle biopsy showed patchy loss of oxidative enzyme reactivity and no C5b9 or IgG at neuromuscular junctions. Whole genome sequencing identified a heterozygous known TUBA4A pathogenic variant (c.850G>A, p.Glu284Lys). Patient improved with 3,4-DAP and albuterol.

DISCUSSION: TUBA4A p.Glu284Lys can lead to treatable myasthenic syndrome with postsynaptic and likely presynaptic involvement, as suggested by the patient's electrophysiological findings and response to therapy. This patient expands the TUBA4A-disorder spectrum to include overlapping myasthenic syndrome-myopathy and shows that neuromuscular disease and infertility can occur within the same patient.},
}

Humans
Female
Middle Aged
*Muscular Diseases/genetics/physiopathology/complications
*Infertility, Female/genetics

@article {pmid42727268,
year = {2026},
author = {Aldrich, L and McDonough, KL and Timmermans, B and Bach, P},
title = {Visual perspective-taking and image-like representations: we can see it.},
journal = {Cognition},
volume = {278},
number = {},
pages = {106699},
doi = {10.1016/j.cognition.2026.106699},
pmid = {42727268},
issn = {1873-7838},
abstract = {Visual perspective taking describes the ability to represent how others see the world. It is presumed to be crucial for social reasoning and may underpin the development of theory of mind. Yet, a recent series of experiments by Samuel et al. (2021) purports that people are entirely incapable of representing another person's view. In these experiments, participants were asked to judge which of two parallel and vertical lines would appear larger from another person's perspective. Results indicated a lack of basic awareness that the line closer to the other person would appear larger to them. Due to potential issues with key features of the task however, Samuel et al.'s (2021) conclusion of perspective taking inability may be premature. Specifically, features of how the critical question was phrased, how the stimuli were created, and the way in which participants responded, likely obscured an underlying capacity for visual perspective taking. Over two experiments, we first demonstrate that minor adjustments to the original paradigm enables participants to reliably report another person's perspective. Second, by using a novel multi-trial adaptation of the paradigm, we show a large proportion of participants can make highly accurate judgements that closely track how another person's visual experience changes with location.},
}

@article {pmid42727710,
year = {2026},
author = {Inoue, Y and Tanaka, M and Oguchi, T and Sasaki, A and Saito, K and Inoue, A and Otsuka, N},
title = {Selective neuroprotection in the ALS-FTD spectrum: Mechanisms of neuronal resilience and translational perspectives.},
journal = {Brain research bulletin},
volume = {245},
number = {},
pages = {112111},
doi = {10.1016/j.brainresbull.2026.112111},
pmid = {42727710},
issn = {1873-2747},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is increasingly recognized as part of a broader clinico-pathological continuum encompassing frontotemporal dementia (FTD). Despite progressive degeneration across motor and cognitive neural systems associated with TDP-43 pathology, specific neuronal populations-including the oculomotor and abducens nuclei, Onuf's nucleus, and sensory dorsal column pathways-remain relatively preserved.

OBJECTIVE: Selectively preserved neuronal structures in ALS have largely been described as isolated neuropathological observations without sufficient mechanistic integration. This review aims to synthesize candidate intrinsic and microenvironmental mechanisms that may contribute to selective neuronal preservation and propose a translational framework for understanding neuronal resilience in the ALS-FTD spectrum.

METHODS: We conducted a comprehensive critical review of the literature addressing selective neuronal vulnerability and resistance in ALS-FTD, integrating comparative observations from related neurodegenerative and neuromuscular disorders. Particular emphasis was placed on candidate mechanisms associated with neuronal resilience, including Nrf2/ARE signaling, calcium homeostasis, glutamatergic receptor composition, glial-mediated neurotrophic support, and emerging transcriptomic evidence relevant to selective neuronal vulnerability.

RESULTS: Selective preservation of specific neuronal populations represents a distinctive biological characteristic of the ALS-FTD spectrum. Current evidence suggests that enhanced antioxidant defense, tightly regulated intracellular calcium dynamics, protective microenvironmental interactions, and other stress-response pathways may collectively contribute to resistance against TDP-43 proteinopathy. These findings may provide a mechanistic framework for understanding selective neuronal resilience and suggest potential avenues for future neuroprotective therapeutic development.

CONCLUSIONS: Integrating mechanisms of selective neuroprotection with translational neurobiological perspectives may provide a conceptual framework for ALS research. Leveraging preserved neural systems may not only inform biologically grounded supportive care strategies but also help identify mechanistically relevant targets for future disease-modifying interventions.},
}

@article {pmid42727824,
year = {2026},
author = {Li, X and Zhang, S and Liu, Y and Yu, X and Han, L and Liu, Y},
title = {Exploring the toxicological impact of BDE-209 on neurodegenerative diseases through network toxicology, molecular docking, molecular dynamics simulation and in-vitro study.},
journal = {Toxicology and applied pharmacology},
volume = {516},
number = {},
pages = {118034},
doi = {10.1016/j.taap.2026.118034},
pmid = {42727824},
issn = {1096-0333},
abstract = {Decabromodiphenyl ether (BDE-209) is a persistent flame retardant associated with neurotoxicity, but its potential links to neurodegenerative diseases remain unclear. We integrated network toxicology, molecular docking, molecular dynamics (MD) simulations, and in vitro experiments to investigate BDE-209 in Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Network analysis identified 90 shared targets, enriched in lipid metabolism, oxidative stress, and inflammatory pathways, including IL-17 and TNF signaling. Docking prioritized the FKBP12-mTOR complex as a candidate binding system, with a score of -8.6 kcal/mol. MD simulations supported the stability of the predicted pose, which was dominated by van der Waals and hydrophobic interactions involving PHE-128 and TRP-190. In differentiated PC12 cells, BDE-209 increased p-mTOR at 10 μM and IL-1β at 20 μM without overt cytotoxicity. Rapamycin attenuated the p-mTOR response, supporting mTOR involvement, although mTOR dependence of IL-1β induction was not established. At 40 μM, BDE-209 reduced viability, potentially confounded by precipitation or aggregation. These findings implicate mTOR dysregulation in BDE-209 cellular responses, but direct binding, chronic exposure, and in vivo disease relevance require further validation.},
}

@article {pmid42728797,
year = {2026},
author = {Sanghai, N and Pierce, K and Sharma, N and Leggett, S and Yadav, TC and Masrori, P and Atukorallaya, D and Palaniyandi, S and Marcogliese, PC and Tranmer, GK},
title = {Recent Advancements in Drug Delivery Across the Blood-Brain Barrier in Amyotrophic Lateral Sclerosis (ALS).},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {9},
pages = {e71078},
pmid = {42728797},
issn = {1755-5949},
support = {RGPIN-2017-05938//Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant/ ; 202210PJT-495295/CAPMC/CIHR/Canada ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Blood-Brain Barrier/drug effects/metabolism ; Animals ; *Drug Delivery Systems/methods/trends ; Blood-Spinal Cord Barrier/drug effects/metabolism ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neurodegenerative disease with limited therapeutic options. The blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) present major obstacles to central nervous system (CNS) drug delivery, restricting the effectiveness of many potential therapies. Increasing evidence suggests that BBB and BSCB dysfunction are not only barriers to treatment but also important contributors to ALS pathophysiology.

OBJECTIVE: To examine current evidence regarding BBB and BSCB dysfunction in ALS and evaluate the implications of stage-dependent barrier alterations for CNS drug delivery and therapeutic outcomes.

METHODS: Recent mechanistic, pathological, preclinical, and clinical studies examining BBB and BSCB alterations in ALS were reviewed. Evidence on tight junction disorganization, endothelial dysfunction, vascular leakage, altered transporter activity, and emerging therapeutic and drug delivery strategies was analyzed.

RESULTS: Converging evidence indicates that BBB and BSCB dysfunction are intrinsic and progressive features of ALS pathophysiology rather than passive consequences of neurodegeneration. Barrier impairment emerges early in the disease course and evolves across clinical stages. Disruption of barrier integrity may increase motor neuron vulnerability while modulating CNS drug exposure. Emerging strategies that bypass, exploit, or restore barrier function hold promise for enhancing CNS bioavailability and improving therapeutic outcomes.

CONCLUSIONS: Improved understanding of barrier alterations may facilitate development of more effective CNS-targeted therapies and improve therapeutic outcomes in ALS patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology
*Blood-Brain Barrier/drug effects/metabolism
Animals
*Drug Delivery Systems/methods/trends
Blood-Spinal Cord Barrier/drug effects/metabolism

@article {pmid42729071,
year = {2026},
author = {Subramaniam, AG and de Andrade Gensas, LK and Gradus-Pery, T and Perlson, E},
title = {Quantitative Analysis of Axonal Degeneration and TDP-43 Aggregation in Compartmentalized Human iPSC-Derived Motor Neuron-Myotube Co-cultures.},
journal = {Bio-protocol},
volume = {16},
number = {17},
pages = {e5801},
pmid = {42729071},
issn = {2331-8325},
abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by early and spatially restricted pathology in motor axons, including distal degeneration and accumulation of aggregation-prone proteins such as TDP-43. However, a major limitation in the field has been the lack of approaches that enable robust, quantitative, and compartment-specific analysis of these early axonal events, particularly in human-relevant systems. Here, we describe an integrated experimental and analytical framework that enables quantitative dissection of axonal degeneration and protein aggregation, specifically within distal motor axons. By combining compartmentalized human co-cultures with a dedicated image analysis strategy, this approach enables selective and quantitative analysis of pathological processes specifically within axons, independent of surrounding tissues such as muscle and other cellular compartments. This framework captures both structural degeneration and protein aggregation dynamics at subcellular resolution, enabling spatially resolved quantitative analysis of disease-relevant changes along axons. Importantly, the analytical framework is not limited to TDP-43 but is broadly applicable to diverse aggregation-prone proteins, thereby providing a generalizable platform to study axonal pathology across neurodegenerative diseases. Together, this work provides a scalable approach for investigating axonal pathology as an early and measurable feature of neurodegeneration, with potential applications in mechanistic studies and therapeutic targeting in ALS and related disorders. Key features • Compartmentalized human induced pluripotent stem cell (iPSC)-derived motor neuron-myotube co-cultures for modeling distal axonal pathology. • Microfluidic separation of somatic and distal axonal compartments enabling spatial perturbation and analysis. • Quantitative imaging of neurofilament heavy chain (NFH)-associated axonal degeneration and pTDP-43 accumulation. • Semi-automated workflow for a reproducible, scalable, and modular pipeline for image quantification.},
}

@article {pmid42730941,
year = {2026},
author = {Xie, J and Xie, H and Li, Y and Jiang, W and Wang, X and Xie, Q and Song, X and Fan, D and Li, HF and Deng, B},
title = {Atherosclerotic Cardiovascular Diseases Increase ALS Risk by 82% While Optimal Cardiovascular Health Halves It: A 0.5-Million Prospective Cohort Study.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78321},
pmid = {42730941},
issn = {1531-8249},
abstract = {OBJECTIVE: The objective of this study was to determine whether prevalent atherosclerotic cardiovascular diseases (ASCVDs) increase the risk of amyotrophic lateral sclerosis (ALS) and whether high cardiovascular health (CVH) can offset this risk.

METHODS: We prospectively analyzed 502,279 UK Biobank participants (37-73 years) with linked electronic health records. Prevalent ASCVD (coronary artery disease [CAD], ischemic stroke [IS], and peripheral artery disease [PAD]) was ascertained at baseline. CVH was quantified using Life's Essential 8 and categorized as low, moderate, or high. Cox models, joint analyses, and Mendelian randomization were applied.

RESULTS: Over a median follow-up of 13.74 years, 675 incident ALS cases were documented. A history of ASCVD was associated with a 43% higher risk of ALS (hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.16-1.78, p = 0.001), primarily driven by CAD and IS. Conversely, high CVH was associated with a lower risk of ALS compared with low CVH (HR = 0.52, 95% CI = 0.33-0.81, p = 0.004). Joint analysis revealed that individuals with low CVH and pre-existing ASCVD exhibited the highest ALS risk. Mendelian randomization analyses provided supportive evidence consistent with the observational associations among CAD, IS, and ALS. The inverse association between CVH and ALS risk was most pronounced among participants aged ≤65 years.

INTERPRETATION: Prevalent ASCVD was associated with a higher risk of ALS, whereas high CVH was associated with a lower risk of ALS. These findings support a potential link between CVH and ALS susceptibility, particularly among individuals aged ≤65 years. ANN NEUROL 2026.},
}

@article {pmid42731699,
year = {2026},
author = {Wang, X},
title = {Comment on Wei et al.'s "Association of primary tumor location with all-cause and cancer-specific mortality in cutaneous malignant melanoma patients".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2026.06.156},
pmid = {42731699},
issn = {1097-6787},
}

@article {pmid42732293,
year = {2026},
author = {Mikaelsson, Å and Tishelman, C and Noonan, K and Kowalski, L and Kleijberg, M and Johansson, T and Stenfors, T and Eriksson, LE and Goliath, I},
title = {Investigating effect versus impact in a participatory action research project: Building end-of-life communication competence in residential care facilities for older people.},
journal = {Palliative care and social practice},
volume = {20},
number = {},
pages = {26323524261488419},
pmid = {42732293},
issn = {2632-3524},
abstract = {BACKGROUND: Active involvement of residents, family members and staff in proactive end-of-life conversations remains uncommon in residential care facilities for older people, although these are common settings for the end-of-life. This study derives from a Participatory Action Research project with an intervention aimed at developing Death Literacy among residential care staff, to promote implementation of proactive end-of-life conversations.

OBJECTIVES: This article has a two-fold aim: (1) to investigate effects and forms of impact derived from this project intending to improve Death Literacy, and (2) to discuss challenges in this investigation and contribute to critical debate and further inform the use and development of the Death Literacy concept and related index (DLI).

METHODS: We combined quantitative analysis of pre-post intervention DLI survey data from staff and qualitative framework analysis of official documents along with transcribed interviews and workshop data from various staff groups. The framework was based on a matrix with Death Literacy features on one axis and forms of impact on the other.

RESULTS: The DLI showed no positive change over time. Effect evaluation was challenged by high baseline mean scores and ceiling effects on the DLI, and issues associated with the use of a participatory research approach, e.g. baseline differences between groups related to recruitment strategies. However, qualitative findings indicated all three forms of impact described in Kleijberg et al.'s model: impact on individual and group development, action-oriented impact, and strategy-oriented impact. These were seen to be related to all Death Literacy features, most notably experiential learning and social action.

CONCLUSION: Features of Death Literacy were relevant in understanding impact, although the usefulness of the DLI to measure change over time was limited in this study. A matrix framework provided nuanced insight beyond either model alone. Congruence of different methodological assumptions should be carefully considered when designing investigations of effect and impact of complex interventions with limited researcher control.},
}

@article {pmid42732704,
year = {2026},
author = {Riva-Rovedda, F and Calvo, A and Clari, M and Picciaiola, MV and Godono, A and Manera, U and Canosa, A and Palumbo, F and Moglia, C and Chiò, A and Rinaldo, RF and Tabbia, G and Solidoro, P and Dimonte, V},
title = {Time-dependent adherence to non-invasive ventilation in amyotrophic lateral sclerosis: an observational cohort study.},
journal = {Heart & lung : the journal of critical care},
volume = {80},
number = {},
pages = {102952},
doi = {10.1016/j.hrtlng.2026.102952},
pmid = {42732704},
issn = {1527-3288},
abstract = {BACKGROUND: Non-invasive ventilation (NIV) improves survival and quality of life in amyotrophic lateral sclerosis (ALS). However, adherence is frequently suboptimal and longitudinal outpatient data are limited.

OBJECTIVE: We assessed NIV adherence during the first year of outpatient adaptation, factors associated with time-dependent adherence, and the relationship between adherence and survival.

METHODS: We conducted a retrospective cohort study including individuals with ALS prescribed with NIV between January 2022 and June 2024 at the outpatient clinic of an Italian referral centre. Functional status, adherence, and device-related complications were recorded at 1, 3, 6, and 12 months. Data about deaths and tracheostomy events were collected.

RESULTS: Complete adherence data were available for 73 patients. Mean NIV use increased; nevertheless, approximately 30% of patients were non-adherent at 6 and 12 months. NIV-related complications ranged between 30-44%, though they were not significantly associated with adherence. Higher ALSFRS-R respiratory subscore (OR=0.78, 95% CI 0.64-0.95) and having a male caregiver (OR=0.19, 95% CI 0.04-0.96) were associated with reduced adherence. Time-dependent adherence was not significantly associated with survival, whereas older age at diagnosis and PEG placement were associated with a 5% and more than threefold higher risk of death/tracheostomy, respectively (HR 1.05, 95% CI 1.01-1.09; HR 3.42, 95% CI 1.54-7.59).

CONCLUSION: NIV adherence and NIV-related complications showed dynamic patterns over time. One-third of patients were non-adherent at 6 and 12 months, highlighting the need for tailored interventions throughout follow-up. Although time-dependent adherence was not independently associated with survival, period-averaged adherence appeared to produce a more favourable survival estimate than time-dependent adherence.},
}

@article {pmid42734068,
year = {2026},
author = {Villarroel-Campos, D and Sleigh, JN},
title = {Hyperactive KIF5A in Neurodegeneration.},
journal = {Cytoskeleton (Hoboken, N.J.)},
volume = {},
number = {},
pages = {e70204},
doi = {10.1002/cm.70204},
pmid = {42734068},
issn = {1949-3592},
support = {MR/Y010949/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {The highly polarised morphology of neurons and the sheer length of their axons make transport of cargoes throughout the cell a formidable task. Decades of evidence obtained from genetic studies on patients and animal models highlight deficits in axonal transport as a recurrent cause, or early contributing factor, in a plethora of neurodegenerative diseases. Axonal transport abnormalities usually manifest as a slowing of cargo trafficked by molecular motors along microtubules; however, hyperactivation of motors can also lead to disease. That is the case for the kinesin-1 protein KIF5A, in which hyperactive mutations are linked to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus (NEIMY). In this Perspective, we summarise the latest insights into the impact of KIF5A hyperactivity, such as loss of autoinhibition, aggregation, altered cargo binding and microtubule damage. We conclude by discussing possible strategies to counteract these disruptions, with an emphasis on the necessity of restoring axonal transport to physiological levels, a key requirement to maintain neuronal homeostasis.},
}

@article {pmid42734657,
year = {2026},
author = {Urusov, AE and Gorobets, MA and Aulova, KS and Timofeeva, AM and Toporkova, LB and Orlovskaya, IA and Ustyugov, AA and Nevinsky, GA},
title = {Autoimmune processes and production of catalytically active antibodies-abzymes in prone to amyotrophic lateral sclerosis FUS(1-359) mice.},
journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]},
volume = {75},
number = {1},
pages = {},
pmid = {42734657},
issn = {1420-908X},
mesh = {Animals ; *Antibodies, Catalytic/blood/immunology ; *Amyotrophic Lateral Sclerosis/immunology/blood/genetics/pathology ; Mice, Transgenic ; Mice ; Immunoglobulin G/blood/immunology ; Autoimmunity ; Female ; *RNA-Binding Protein FUS/genetics ; Disease Models, Animal ; },
abstract = {OBJECTIVE: It was shown previously that the development of not only many autoimmune (AIDs) but also neurological and neurodegenerative diseases (NDDs) including multiple sclerosis, tick-borne encephalitis, and schizophrenia in humans and experimental mice models occurs due to a specific destruction of the immune system. This error in the immune system leads to the formation of B lymphocytes producing adverse antibodies-abzymes possessing different catalytic activities.

METHODS: One of the earliest and statistically reliable index of developments of autoimmune reactions is the appearance in the blood abzymes that are absent in conditionally healthy donors. We investigated the in time changes catalytic activities of Abs-abzymes using standard methods of enzymology.

RESULTS: It was shown for the first time that, as in the case of various AIDs and NDDs, the early stages of ALS development in FUS(1-359) mice are also associated with the production of catalytic antibodies. CD-1 mice utilized for obtaining FUS(1-359) mice were also used. IgG samples were isolated from the blood of transgenic FUS(1-359) mice and their non-transgenic siblings (CD1) at different times. The first signs of ALS-like symptoms develop at the age of ≥ 2 months of life in FUS(1-359) mice, which was taken as zero time point, and then by ≥ 80 days of age, deep pathology was observed. It was shown for the first time that antibodies from the blood of FUS(1-359) mice exhibit DNase, amylase, phosphatase, and catalase catalytic activities beginning from 2 months of age. However, unlike non-transgenic siblings, the relative activity of mice IgGs was higher in FUS(1-359) mice. All activities of FUS(1-359) mice IgGs began to increase significantly starting from 20 to 30 days after beginning of experiments and achieved maximum upon reaching deep pathology.

CONCLUSIONS: The data obtained indicate that in the early stages of ALS development in FUS(1-359) mice containing genes associated with this pathology in humans, there is a disruption of the immune system and production of abzymes that destroy components of blood, cells and tissues. One cannot exclude that such autoimmune reactions are important for development of ALS in FUS(1-359) mice.},
}

Animals
*Antibodies, Catalytic/blood/immunology
*Amyotrophic Lateral Sclerosis/immunology/blood/genetics/pathology
Mice, Transgenic
Mice
Immunoglobulin G/blood/immunology
Autoimmunity
Female
*RNA-Binding Protein FUS/genetics
Disease Models, Animal

@article {pmid42734724,
year = {2026},
author = {Steger, L and Rothhammer, V and Zunke, F},
title = {Astrocytes in Neurodegeneration: Spatial States, Crosstalk, and Emerging Therapies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42734724},
issn = {1559-1182},
support = {S3- AstroFinder//Interdisziplinäres Zentrum für Klinische Forschung; IZKF, Erlangen/ ; 505539112//Deutsche Forschungsgemeinschaft/ ; },
mesh = {*Astrocytes/pathology/metabolism ; Animals ; Humans ; *Neurodegenerative Diseases/pathology/therapy/metabolism ; *Nerve Degeneration/pathology/therapy ; },
abstract = {Astrocytes are increasingly recognized as active drivers of neurodegeneration rather than passive responders. Single-cell and spatial transcriptomic analyses reveal that astrocytes occupy heterogeneous, regionally patterned states that align closely with selective neuronal vulnerability. Across Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease, and rare primary astrocytopathies, astrocytes consistently converge on dysfunction across four mechanistic axes: breakdown of glutamate homeostasis, impaired ion and water buffering, lysosomal, and autophagic insufficiency, as well as maladaptive inflammatory-stress signaling. Spatial multi-omics demonstrates that these disruptions are not uniformly distributed but instead map to discrete niches, including plaque-adjacent astrocytes in Alzheimer's disease, CD44-high fibrotic-like astrocytes in the substantia nigra in Parkinson's disease, and EAAT2-low ventral horn astrocytes in ALS, consistent with patterns of selective neuronal vulnerability. Primary astrocytopathies including Alexander disease, vanishing white matter disease, and megalencephalic leukoencephalopathy illuminate the causal power of perturbing individual astrocytic modules, revealing how isolated disruptions in proteostasis, translation control, or ion-water coupling can initiate widespread neurodegeneration. By integrating neuropathological, imaging, and transcriptomic evidence across studies, we derive a consensus-based regional framework of astrocytic vulnerability across neurodegenerative diseases. Together, these findings define a unifying framework in which astrocytes transition from homeostatic regulators to pathological amplifiers, highlighting astrocyte states as tractable, region-specific therapeutic targets and illustrating how integration of spatial atlases with mechanistic insights might help develop a framework for targeted astrocyte therapies.},
}

*Astrocytes/pathology/metabolism
Animals
Humans
*Neurodegenerative Diseases/pathology/therapy/metabolism
*Nerve Degeneration/pathology/therapy

@article {pmid42734825,
year = {2026},
author = {P Padhiyar, D and Butani, S and Patel, RJ},
title = {Optimization and characterization of lipid-based nanocarriers for intranasal delivery in amyotrophic lateral sclerosis.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42734825},
issn = {1432-1912},
abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder for which effective brain delivery of therapeutics remains challenging. Riluzole, a Biopharmaceutics Classification System class II drug used in the management of amyotrophic lateral sclerosis, exhibits low aqueous solubility and undergoes first-pass metabolism, which may limit its bioavailability. The present study aimed to develop and optimize riluzole-loaded nanostructured lipid carriers for intranasal delivery. Riluzole-loaded nanostructured lipid carriers were prepared by the melt-emulsification method and optimized using a four-factor, three-level Box-Behnken design. The effects of lipid composition ratio, surfactant concentration, sonication time, and stirring time on particle size, polydispersity index, and encapsulation efficiency were evaluated. The optimized formulation showed a particle size of 98.43 nm, a polydispersity index of 0.3, a zeta potential of -6.22 mV, an encapsulation efficiency of 89.4%, and a drug loading of 8.94%. Transmission electron microscopy demonstrated spherical nanoparticles, while differential scanning calorimetry and X-ray diffraction findings suggested reduced crystallinity and amorphization of riluzole within the lipid matrix. Fourier transform infrared spectroscopy indicated no significant drug-excipient incompatibility. The optimized formulation exhibited sustained drug release, with approximately 84% drug release over 24 h, and remained stable for 60 days at room temperature. These findings suggest that riluzole-loaded nanostructured lipid carriers are a promising lipid-based nanocarrier system for intranasal delivery and further biological evaluation for nose-to-brain drug delivery in amyotrophic lateral sclerosis.},
}

@article {pmid42734981,
year = {2026},
author = {Cho, M and Newman, DA and Tang, C and Alexander, L},
title = {Adverse impact, job performance, and diversity outcomes of applicant attraction: A simulation and paradox.},
journal = {The Journal of applied psychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/apl0001412},
pmid = {42734981},
issn = {1939-1854},
abstract = {Jones et al. (2022) specified conditions where applicant attraction on vocational interests would reduce adverse impact, by treating vocational interests as an attraction variable that can be related to both race and the predictor composite. We extend Jones et al.'s model of attraction and adverse impact to also include (a) job performance outcomes and (b) diversity (proportion of hires from the minority group), by comparing six generic applicant attraction scenarios. Using Monte Carlo simulations of a hiring process where applicants are attracted simultaneously based on minority/majority status (e.g., diversity recruiting) and/or on applicant qualifications (e.g., qualifications-based recruiting), prior to being screened on a selection predictor composite, we formalize the patterns of attraction effects on adverse impact, diversity, and job performance. Results reveal a paradox: No single attraction scenario improves all three outcomes (adverse impact, diversity, and job performance), although there exist applicant attraction conditions that can improve any two of the three. The pattern of attraction scenario results and the paradox persisted across a wide range of predictor composites. Counterintuitive implications for practice are discussed. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid42735486,
year = {2026},
author = {Cao, Q and Jiang, Z and Wang, Z and Wee, L and Dekker, A and Zhang, Z and Zhu, J},
title = {Corrigendum to "Minimum sample size calculation for radiomics-based binary outcome prediction models: tutorial and practical example based on Riley et al's theoretical framework" [Radiother. Oncol. 212 (2025) 111134].},
journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology},
volume = {224},
number = {},
pages = {111771},
doi = {10.1016/j.radonc.2026.111771},
pmid = {42735486},
issn = {1879-0887},
}

@article {pmid42735682,
year = {2026},
author = {Cousin, MA and Dagli, AI and Mignon, L and Shah, JS and Prudencio, M and Gendron, TF and Jain, A and Udine, E and van Blitterswijk, M and Middlebrooks, EH and Donahue, MH and Dagher, JE and Watzlawik, JO and Springer, W and Parekh, T and McEachin, ZT and Petrucelli, L and Oskarsson, B},
title = {N-of-1 investigational study of a novel antisense oligonucleotide drug in CHCHD10-related ALS shows early signs of efficacy.},
journal = {Med (New York, N.Y.)},
volume = {},
number = {},
pages = {101295},
doi = {10.1016/j.medj.2026.101295},
pmid = {42735682},
issn = {2666-6340},
abstract = {BACKGROUND: Pathogenic CHCHD10 variants cause a rare, dominantly inherited form of amyotrophic lateral sclerosis (ALS). Non-allele-selective CHCHD10 knockdown may mitigate a toxic gain-of-function mechanism. We evaluated nL-CHCHD-001 in one participant with the p.Arg15Leu variant.

METHODS: In this open-label N-of-1 study, 320-gapmer antisense oligonucleotides (ASOs) were screened, and a lead candidate was selected according to specificity and non-clinical safety criteria. Six intrathecal doses were administered over 12 months (three 50-mg doses followed by three 75-mg doses). Prespecified primary outcomes were 12-month changes in functional, cognitive, quality-of-life, respiratory, neurofilament light (NfL), and survival measures; secondary outcomes assessed were safety and tolerability. Analyses were descriptive.

FINDINGS: No serious adverse events occurred. Post-dose headache and fatigue were mild to moderate, and cerebrospinal fluid safety results were unremarkable. Plasma NfL decreased by approximately 50% from a mildly elevated pretreatment baseline and entered the laboratory reference range. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score increased from 33 to 36, vital capacity increased from 48% to 55% (as predicted), cognitive and quality-of-life scores remained stable, and the participant was alive at 12 months.

CONCLUSIONS: Individualized CHCHD10-directed treatment was feasible and well tolerated and was temporally associated with biomarker and clinical stability or improvement. This N-of-1 study demonstrates the feasibility of developing individualized ASO therapy for CHCHD10-related ALS and provides preliminary evidence of biomarker and clinical benefit. These findings support further evaluation of nL-CHCHD-001 and highlight NfL as a practical treatment-response biomarker for personalized therapeutics in ALS.

CLINICALTRIALS: gov: NCT06392126.

FUNDING: This study was supported by the n-Lorem Foundation, National Institutes of Health grants U01NS134684 and KL2 TR002379, and the Kevin Merszei Career Development Award.},
}

@article {pmid42736322,
year = {2026},
author = {Zussa, ZN and Smith, AN and van Vugt, JJFA and O'Shaughnessy, DS and Grima, N and Chan Moi Fat, S and Blair, IP and Rowe, DB and Pamphlett, R and Nicholson, GA and Kiernan, MC and van Rheenen, W and Veldink, J and , and Williams, KL and Henden, L},
title = {Characterising the motif composition and allele length distribution of ZFHX3 GGC repeat expansions in amyotrophic lateral sclerosis.},
journal = {Journal of human genetics},
volume = {},
number = {},
pages = {},
pmid = {42736322},
issn = {1435-232X},
support = {GNT2033019//Department of Health | National Health and Medical Research Council (NHMRC)/ ; },
abstract = {A pathogenic GGC repeat expansion in zinc finger homeobox 3 (ZFHX3), encoding a pure polyglycine (polyG) tract, causes spinocerebellar ataxia type 4 (SCA4). Intermediate expansions of other SCA loci have been implicated in amyotrophic lateral sclerosis (ALS), while repeat motif composition is recognised to influence pathogenicity in neurodegenerative diseases. Given the genetic pleiotropy between ALS and SCA, we evaluated whether ZFHX3 GGC expansions are associated with ALS and characterised repeat motif composition. ZFHX3 GGC repeat sizes were genotyped using ExpansionHunter in short-read whole-genome sequencing data from ALS cases and healthy controls of European ancestry. Repeat sizes were visually inspected using REViewer, and motif configurations were manually derived from a subset. Receiver operating characteristic analysis and Youden's J statistic identified a candidate repeat size threshold. Logistic regression tested associations of repeat length and motif composition with ALS, while regression models assessed clinical phenotypes. Across 5785 ALS cases and 7982 controls, no association was observed between ZFHX3 expansions and ALS risk. Longer alleles showed a nominal association with later disease onset, however this did not remain significant after Bonferroni correction. Among 802 ALS cases and 800 controls, 50 distinct motif compositions were identified, including 11 encoding pure polyG tracts characteristic of pathogenic SCA4 expansions; none were associated with ALS. Although no association with ALS was observed, this study established the dynamic nature of ZFHX3 repeat motif composition and configuration. Variation within and between repeat sizes, including pure polyG repeats, supports consideration of motif composition alongside allele length when evaluating neurodegenerative disease risk.},
}

@article {pmid42736511,
year = {2026},
author = {Soliman, AR and Guirguis, KJ and Kamal, NA},
title = {From fundus to filtration: AI-driven retinal phenotyping as a framework for non-invasive prediction of kidney pathological categories (the "virtual renal biopsy" concept)- a narrative review.},
journal = {International urology and nephrology},
volume = {},
number = {},
pages = {},
pmid = {42736511},
issn = {1573-2584},
abstract = {BACKGROUND: The burden of chronic kidney disease (CKD) continues to grow, affecting over 850 million individuals globally. Current methods to precisely and definitively classify CKD still rely on renal biopsy, a procedure with a 5.1% rate of major complications, and further cost and access complications in low-resource settings. The retina, containing the only accessible microvasculature for direct and non-invasive visualization, shares deep developmental and structural features with, and biologically plausible pathogenic overlap with, the kidney (see Sect. 3 for the distinction between established and hypothesized components of this relationship). Oculomics, an emerging discipline that incorporates AI to analyze retinal images to identify systemic disease, has shown promising results for binary CKD screening, with AUC scores of 0.83-0.93; this is distinct from, and should not be conflated with, the prediction of specific renal pathological categories discussed below. A 2025 study introducing the Kidney Intelligent Diagnosis System (KIDS) was among the first to demonstrate that specific renal pathological categories-IgA nephropathy, idiopathic membranous nephropathy, arterionephrosclerosis, diabetic nephropathy, and a combined idiopathic minimal change disease/focal segmental glomerulosclerosis category-could be predicted from retinal images using five separate binary prediction tasks, reporting AUC values of 0.790-0.932 (internal and, for a subset, external validation; hybrid image-plus-clinical-data models performed at the higher end of this range). This is best regarded as an early proof-of-concept for a non-invasive risk-stratification tool, conceptually described in this review as a 'virtual renal biopsy'-a metaphor for a proposed research framework, not a claim of diagnostic equivalence with tissue histopathology (Meng et al.'s DeepDKD model had earlier used retinal images to distinguish biopsy-defined diabetic from non-diabetic kidney disease, so KIDS is best described as an early multi-category model rather than the first retinal-AI study in this space).

AIM: This narrative review aims to consolidate various biological, technological, and clinical components of AI-driven retinal phenotyping and outline the path toward non-invasive prediction of kidney pathological categories. This includes the aspects of continuous progression from binary screening of CKD towards predicting specific histopathologies while considering the current state of explainability of AI, the performance metrics beyond AUC that are required for clinical deployment, and offering a detailed clinical research roadmap.

METHODS: Narrative synthesis was utilized to integrate data on CKD and deep learning, retinal vascular research, research on retinal-renal connections, AI explainability, and the KIDS model. A structured search of PubMed/MEDLINE, Embase, Scopus, and Google Scholar was performed for English-language, peer-reviewed original studies, systematic reviews, and clinical guidelines relevant to retinal-renal biology, oculomics, and AI-based renal pathology prediction; representative search terms, eligibility criteria, and the handling of preprints are detailed in Sect. 2. The data were organized by biological plausibility, evolution of modeling, integration of imaging technologies, metrics required for clinical validation, and research in translational barriers.

CONCLUSIONS: The combination of the biological plausibility of a retinal signature of renal injury, the advances in oculomics, AI, and early multi-category models such as KIDS lays a preliminary foundation for research toward non-invasive prediction of kidney pathological categories. In order to advance this research agenda, numerous multidisciplinary clinical studies are required along with the integration of different imaging technologies, rigorous reporting of calibration and clinically relevant performance metrics, and the creation of ethical and regulatory frameworks. The 'virtual renal biopsy' concept will not replace histopathology and is not yet supported by evidence sufficient for clinical deployment; if the underlying research agenda is executed rigorously, it may in time provide an adjunctive, non-invasive risk-stratification tool for the hundreds of millions of patients who do not have access to renal histopathological diagnosis.},
}

@article {pmid42721706,
year = {2026},
author = {Viljoen, S and Chaves, JCS and Peall, I and White, AR and Oikari, LE},
title = {Dysfunction of the blood-brain barrier and neurovascular unit in amyotrophic lateral sclerosis - From advanced human models to treatments.},
journal = {Journal of the neurological sciences},
volume = {490},
number = {},
pages = {126168},
doi = {10.1016/j.jns.2026.126168},
pmid = {42721706},
issn = {1878-5883},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, characterized by the degeneration of motor neurons, resulting in progressive and eventually complete loss of motor function. The phenotypical heterogeneity of ALS poses a challenge to early diagnosis and treatment, with currently available therapeutics only capable of relieving symptoms and slowing progression. While ALS is classified as a motor neuron disease (MND), research has identified significant impairment to the blood-brain barrier (BBB) and neurovascular unit (NVU) of ALS patients. The BBB along with supporting cells of the NVU selectively control the entry of substances into the central nervous system (CNS) and maintain brain homeostasis, with its many cellular components demonstrating impaired function, specifically relating to inflammation, oxidative stress and TDP-43 proteinopathy. The advent of more advanced in vitro techniques as well as use of patient-derived BBB cells has presented a promising alternative to recreate the in vivo structure of the BBB/NVU in a highly controlled platform. Such approaches have ranged from simple 2-dimensional (2D) cell culture to intricate 3-dimensional (3D) co-culture systems, as well as microfluidic systems and organoids, with a potential to investigate ALS associated BBB/NVU dysfunction and drug discovery. This review provides a comprehensive assessment of known BBB/NVU dysfunction in ALS and methods of investigating this using in vitro and in vivo platforms with a focus on inflammation, oxidative stress and pathological TDP-43 expression. This review also presents a future perspective to overcoming barriers to treatment of ALS using new patient-derived BBB/NVU model systems.},
}

@article {pmid42722039,
year = {2026},
author = {Morisaki, Y and Nomura, N and Matsuda, M and Ohshima, M and Fukuda, R and Komine, O and Okuda, T and Yamanaka, K and Misawa, H},
title = {Anti-LAG-3 antibody treatment initiated after symptom onset extends survival in ALS model mice.},
journal = {Neuroscience research},
volume = {231},
number = {},
pages = {105119},
doi = {10.1016/j.neures.2026.105119},
pmid = {42722039},
issn = {1872-8111},
abstract = {Immune checkpoint molecules have emerged as regulators of microglial function in neurodegenerative diseases. We previously demonstrated that LAG-3 shapes disease-associated microglial phenotypes in ALS and that germline LAG-3 deletion in SOD1[G93A] mice accelerated disease onset but extended duration, leaving survival unchanged. Here, we investigated the therapeutic efficacy of anti-LAG-3 antibody treatment starting after symptom onset. Anti-LAG-3 treatment extended survival, slowed neurological and motor decline, preserved body weight and motor neurons, and reduced microgliosis. Within microglia, the Axl[+] phagocytic-module fraction increased while the Dectin-1[+] inflammatory-module fraction decreased. These findings indicate that post-onset LAG-3 inhibition is a promising therapeutic strategy for ALS.},
}

@article {pmid42722112,
year = {2026},
author = {Butt, TH and Strait, M and Marcinczyk, L and Katz, G and Kalia, V and Jaafar, C and Saxena, R and Divjan, A and Saglimbeni, B and Munoz Umanes, ME and Tipps, E and Han, M and Mehta, P and Lee, I and Mitsumoto, H and Factor-Litvak, P and Shneider, NA and Kioumourtzoglou, MA and Re, DB},
title = {Astrocyte-derived extracellular vesicle phosphorylated TDP-43 as a blood-based biomarker for amyotrophic lateral sclerosis.},
journal = {Neurobiology of disease},
volume = {229},
number = {},
pages = {107601},
doi = {10.1016/j.nbd.2026.107601},
pmid = {42722112},
issn = {1095-953X},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by central nervous system (CNS) neuroglial TAR DNA-binding protein 43 (TDP-43) pathology in ∼90-95% of cases. Non-invasive biomarkers are critically needed to reduce diagnostic delay, enable patient stratification, and assess treatment efficacy in clinical trials. Astrocyte-derived extracellular vesicles (ADEVs) represent promising CNS liquid biopsy biomarkers, given astrocyte involvement in ALS pathogenesis and the ability of ADEVs to cross the blood-brain barrier and carry TDP-43. Here, we assessed the diagnostic performance of TDP-43 and its hyperphosphorylated pathological form, phospho-Ser409 (pTDP-43), quantified in ADEVs, for distinguishing ALS cases from matched healthy controls. ADEVs were immunoisolated from whole blood (n = 76) and plasma (n = 86) across three ALS biorepositories/cohorts. ADEV quality and enrichment were validated in accordance with minimal information for studies of extracellular vesicles guidelines, and protein levels were normalized by ratio to tetraspanin cluster of differentiation 81 (CD81). Diagnostic accuracy was evaluated by logistic regression and random forest models with cross-validation, adjusting for age and sex across 100 random seeds. Plasma ADEV pTDP-43/CD81 ratio best predicted ALS case status, with a mean AUC of 0.89 (95% CI: 0.75-0.99) from logistic models, corresponding to a mean sensitivity and specificity of 87% and 89%, respectively, and a mean AUC of 0.86 (95% CI: 0.82-0.90) from random forest models. Although the specificity of ADEV pTDP-43 relative to disease mimics and associations with disease progression require further investigation, these findings support its potential as a biomarker candidate for ALS and for patient stratification in TDP-43-targeted clinical trials.},
}

@article {pmid42723096,
year = {2026},
author = {Persico, M and Tuithung, S and Lorenzo, A and Crawford, D and Eleuteri, S and Simon, DK},
title = {Retromer-targeted therapy for neurodegenerative diseases.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {42723096},
issn = {1750-1326},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; *Vesicular Transport Proteins/metabolism ; *Endosomes/metabolism ; Mitochondria/metabolism ; Lysosomes/metabolism ; },
abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are neurodegenerative diseases characterized by dysfunction of the endosomal-lysosomal system (ELS). Four shared neurodegenerative mechanisms across ALS, PD and AD are regulated by the ELS, namely proteostasis and related protein misfolding, mitochondrial function, neurotransmission and neuroinflammation. These mechanisms are interconnected, contributing to neurodegeneration in a "snowball" manner. The retromer, a multimeric, evolutionarily conserved protein complex involved in intracellular protein trafficking, is at the crossroad of these neurodegenerative processes. This narrative review focuses on exploring the retromer structure, function as a master regulator of the ELS, and how this impacts proteostasis, mitochondrial biogenesis and homeostasis, neurotransmission and neuroinflammation across neurodegenerative diseases. We explore how alterations in retromer function can play an important role in neurodegeneration and discuss the impact of genetic and pharmacological manipulations of VPS35, one of the main retromer subunits. In vitro and in vivo studies have identified that the retromer enhances the activity of protein degradation pathways via the ELS, namely macroautophagy, chaperone-mediated autophagy, and the ELS itself, with concomitant reduction in misfolded protein levels. Also, in some model systems, when the retromer role is enhanced or restored, mitochondrial function is rescued, dysfunctional neurotransmission is restored, and the damaging effects of neuroinflammation are dampened. Lastly, we highlight the role of a novel pharmacological class of agents that enhance retromer function as a strategy for potentially slowing the progression of these neurodegenerative diseases in in vivo models of PD and ALS. We discuss the challenges in targeting the retromer, current limitations and potential off-target effects of retromer enhancement. Overall, the retromer regulates shared mechanisms across neurodegenerative diseases and retromer enhancers could represent a novel disease-modifying strategy in AD, PD and ALS.},
}

Humans
*Neurodegenerative Diseases/metabolism/drug therapy
Animals
*Vesicular Transport Proteins/metabolism
*Endosomes/metabolism
Mitochondria/metabolism
Lysosomes/metabolism

@article {pmid42723432,
year = {2026},
author = {Kohon, J and Tunalilar, O and Jespersen, B and Dys, S and Toda, E and Carder, P},
title = {Where the Wildfires Are: Correlates of Disaster Preparedness Among Oregon Assisted Living Communities.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {45},
number = {10},
pages = {1913-1923},
doi = {10.1177/07334648251414184},
pmid = {42723432},
issn = {1552-4523},
mesh = {Humans ; Oregon ; *Disaster Planning/organization & administration ; *Wildfires ; Geographic Information Systems ; *Assisted Living Facilities/organization & administration ; Aged ; Dementia ; },
abstract = {Assisted living communities (ALs) serve a growing population of older adults with long-term care needs, especially those with Alzheimer's and other dementias (ADRD), yet their capacity to prepare for hyper-complex climate-related disasters remains underexamined. Using geographic information systems (GIS), we mapped all licensed ALs with the Oregon Department of Forestry's wildfire hazard scores, and then assessed organizational correlates of preparedness with a representative sample of Oregon ALs (n = 321). ALs located in higher wildfire risk areas reported greater confidence in wildfire preparedness and were more likely to have received training and taken actions related to defensible space. However, communities serving residents with ADRD, as well as larger, nonprofit, and chain-affiliated ALs, expressed less confidence in engaging residents and implementing disaster protocols. These findings highlight important geographic and structural disparities in preparedness and underscore the need for tailored planning strategies that consider organizational characteristics and the increasing complexity of climate-related emergencies.},
}

Humans
Oregon
*Disaster Planning/organization & administration
*Wildfires
Geographic Information Systems
*Assisted Living Facilities/organization & administration
Aged
Dementia

@article {pmid42720979,
year = {2026},
author = {Huang, CS and Sanchez-Santos, C and Martinez-Gonzalez, L and Gil, C and Martinez, A},
title = {Innovative therapies under clinical development for ALS treatment. Part 2: biologics and natural products.},
journal = {Expert opinion on investigational drugs},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/13543784.2026.2729512},
pmid = {42720979},
issn = {1744-7658},
abstract = {INTRODUCTION: The clinical trial landscape for Amyotrophic Lateral Sclerosis (ALS) is rapidly expanding despite ongoing translational challenges. Following our 2022 analysis and as a continuation of Part 1, which focused on small molecules, this review provides a structured overview of biologics and natural products in the ALS clinical pipeline. Particular emphasis is placed on candidates that entered, advanced through, or completed clinical evaluation between 2022 and the end of 2025.

AREAS COVERED: Clinical trials for ALS registered in the United States (ClinicalTrials.gov) and the European Union (EU Clinical Trials Register/CTIS) were systematically reviewed and are summarized in this report.

EXPERT OPINION: Modern biotechnology, ethnopharmacology, and classical pharmacology are increasingly converging in ALS therapeutic development, making this one of the most active areas of neurodegenerative disease research. Nevertheless, major challenges remain, including central nervous system (CNS) penetration, long-term safety, interpatient variability, limited clinical evidence, and the need for reliable biomarkers. Emerging technologies, such as big data analytics and artificial intelligence, may help accelerate and optimize therapeutic development, as well as improve patient recruitment and stratification.},
}

@article {pmid42721110,
year = {2026},
author = {Alrabadi, B and Matar, HI and Bandak, N and Yaseen, S and Badwan, A and Alomari, O},
title = {Non-invasive brain stimulation in amyotrophic lateral sclerosis: a systematic review and meta-analysis of transcranial direct current stimulation and transcranial magnetic stimulation.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/17582024.2026.2731195},
pmid = {42721110},
issn = {1758-2032},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with limited disease-modifying treatments. Noninvasive brain stimulation techniques have been investigated as potential neuromodulatory interventions targeting cortical hyperexcitability in ALS.

OBJECTIVE: To systematically evaluate the clinical efficacy, neurophysiological effects, and safety of tDCS and TMS-based interventions in ALS.

METHODS: A systematic review and meta-analysis was conducted following PRISMA guidelines. PubMed, Scopus, Web of Science, and Cochrane Library were searched from inception to March 2026.

RESULTS: Thirty studies involving ALS patients were included. Pooled analyses showed no significant difference between active stimulation and sham in ALSFRS-R at 6 months (MD = 0.58, 95% CI - 0.16 to 1.31) or at end of follow-up (MD = 0.20, 95% CI - 0.49 to 0.89). No significant effect was observed for manual muscle testing. Considerable heterogeneity was noted across studies. However, several studies demonstrated modulation of cortical excitability and intracortical inhibitory circuits, particularly with repeated stimulation protocols. Both tDCS and TMS were consistently safe and well tolerated, with no serious adverse events reported.

CONCLUSION: Noninvasive brain stimulation in ALS does not significantly improve functional outcomes, but induces measurable neurophysiological changes with a strong safety profile. Further studies should optimize protocols and identify responsive subgroups.},
}

@article {pmid42719958,
year = {2026},
author = {Saito, M and Tsuzuki, H and Hosomi, A},
title = {Investigating Translocation Mechanisms of TDP-43 Into the Endoplasmic Reticulum Using Budding Yeast Models.},
journal = {Traffic (Copenhagen, Denmark)},
volume = {27},
number = {3},
pages = {e70054},
doi = {10.1111/tra.70054},
pmid = {42719958},
issn = {1600-0854},
support = {21K05502//Japan Society for the Promotion of Science/ ; 4-0012//Ohsumi Frontier Science Foundation/ ; },
mesh = {*Endoplasmic Reticulum/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Protein Transport/physiology ; Protein Sorting Signals ; Saccharomyces cerevisiae Proteins/metabolism/genetics ; *Saccharomyces cerevisiae/metabolism ; Glycosylation ; *Saccharomycetales/metabolism ; },
abstract = {Signal peptides direct secretory and membrane proteins to the endoplasmic reticulum (ER), but proteins lacking classical signal peptides can occasionally engage the ER translocation machinery. TDP-43 is a nuclear RNA-binding protein implicated in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 pathology has been linked to extracellular TDP-43 species, association with the ER luminal oxidoreductase PDI, and ER stress-related phenotypes, yet whether TDP-43 fragments can directly access the ER lumen remains unclear. Here, we used budding yeast to examine signal peptide-independent ER entry of TDP-43. C-terminal fragments of TDP-43 acquired N-glycans in ste24Δ cells, whereas full-length TDP-43 showed little detectable ER entry. Endo H digestion confirmed N-glycosylation of the fragments, and a protease protection assay supported ER luminal localization of TDP-43(Δ2-89). ER entry was reduced by sec61-41 and sec66Δ, indicating engagement of a Sec61/Sec66-dependent translocation pathway. Deletion analyses identified opposing sequence elements: residues 320-343 facilitated ER entry, whereas an N-terminal region upstream of the nuclear localization signal suppressed it. TDP-43(Δ2-89) also accessed the secretory pathway, and selected disease-associated variants caused Ire1-dependent growth vulnerability without increasing detectable ER translocation. These findings reveal a Ste24-suppressed route for noncanonical ER entry of TDP-43 fragments.},
}

*Endoplasmic Reticulum/metabolism
*DNA-Binding Proteins/metabolism/genetics
Protein Transport/physiology
Protein Sorting Signals
Saccharomyces cerevisiae Proteins/metabolism/genetics
*Saccharomyces cerevisiae/metabolism
Glycosylation
*Saccharomycetales/metabolism

@article {pmid42720086,
year = {2026},
author = {Benatar, M and Huey, ED and Onyike, CU and McHutchison, C and Tartaglia, MC and Barker, MS and Abrahams, S and De Vocht, J and Rhodes, E and Pijnenburg, YA and Turner, MR and van Damme, P and Lee, EB and Wuu, J and Benussi, A and Boeve, BF and McMillan, CT and Strong, MJ},
title = {Conceptualizing cognition and behaviour across amyotrophic lateral sclerosis and frontotemporal dementia.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag300},
pmid = {42720086},
issn = {1460-2156},
abstract = {Cognitive and behavioral dysfunction in frontotemporal dementia (FTD) evolves along a clinical continuum from a clinically silent stage of disease, through a prodromal period, often referred to as mild cognitive impairment (MCI) and/or mild behavioral impairment (MBI), and into a clinically manifest stage recognized by the syndromes of behavioral variant FTD and primary progressive aphasia (PPA). Similar cognitive and behavioral manifestations of varying severity are also encountered in individuals with amyotrophic lateral sclerosis (ALS). Notwithstanding this phenotypic overlap as well as a degree of shared genetic risk and underlying pathology, the approach to phenotypic characterization and description meaningfully differs between the ALS and FTD communities. The problem is particularly evident within the ALS community when describing impairment in the prodromal vs. clinically manifest disease stages. Pertinent considerations include the nature of cognitive and behavioral assessments, the nosology used to describe symptoms identified including those encompassed by the terms 'behavioral' and 'neuropsychiatric', the operationalized criteria that define prodromal syndromes and clinically manifest disease, and the extent to which these criteria rely on longitudinal (vs. cross-sectional) data. A multi-stakeholder workshop, held in London, Ontario (May 12-14, 2025), brought together neurologists, psychiatrists, neuropsychologists, neuropathologists, neuroscientists, and neurogeneticists studying ALS and FTD, to promote inter-disciplinary dialogue and to define a research agenda that might be jointly tackled to address these critical issues. A new nosology for classifying frontotemporal-related behavioral and neuropsychiatric dysfunction, which could be used to support empirical evidence collection, is proposed alongside a list of cognitive, language, behavioral and neuropsychiatric symptoms to be considered in the evaluation of individuals with ALS. Research priorities for each of the ALS and FTD communities, as well as initiatives that should be undertaken jointly, are highlighted. The long-term goal is to harmonize approaches to phenotypic characterization, the nosology used to describe symptoms, and the criteria used to define landmark stages along the clinical continua of the motor neuron and frontotemporal axes irrespective of clinical stage.},
}

@article {pmid42720300,
year = {2026},
author = {Li, S and Xia, X and Wei, Z and Wang, N and Lin, H and Niu, L},
title = {Generation of Herbicide-Resistant Alfalfa Germplasm via Prime Editing.},
journal = {Plant biotechnology journal},
volume = {},
number = {},
pages = {},
pmid = {42720300},
issn = {1467-7652},
support = {32325035//National Natural Science Foundation of China/ ; },
abstract = {Alfalfa (Medicago sativa) is the most widely cultivated forage crop worldwide, owing to its high protein content, balanced amino acid profile, and abundance of vitamins and minerals. However, weed infestation severely threatens alfalfa yield and quality. The lack of herbicide‑resistant cultivars, combined with the diversity of weed species, has made herbicide tolerance a key breeding objective. To address this challenge, we developed a highly optimized prime editing system and, for the first time, achieved prime editing in alfalfa by enhancing the expression efficiency of its components. Specifically, we introduced mutations in three target genes MsALS1, MsALS2 and MsACC1 to confer herbicide resistance: mutations in MsALS1 and MsALS2 were designed to confer resistance to ALS‑inhibiting herbicides (based on evidence from their rice homologs), while those in MsACC1 were targeted to confer resistance to aryloxyphenoxypropionate (APP) herbicides. Using the Csy4 nuclease system, we performed simultaneous prime editing of all three genes, ultimately generating alfalfa lines resistant to nicosulfuron and haloxyfop‑P‑methyl. This study represents the first successful multi‑gene prime editing in alfalfa, providing a novel tool and a valuable approach for alfalfa molecular breeding.},
}

@article {pmid42713005,
year = {2026},
author = {Belaidi, AA and Furtado, DL and Alves, F and Nisbet, RM and Ayton, S and Bush, AI},
title = {Engineering mRNA-LNP Medicines for the Ageing Brain: Opportunities and Challenges for Neurodegenerative Diseases.},
journal = {Exploration (Beijing, China)},
volume = {},
number = {},
pages = {70223},
pmid = {42713005},
issn = {2766-2098},
abstract = {Messenger RNA (mRNA) therapeutics delivered by lipid nanoparticles (LNPs) have advanced from concept to clinic at unprecedented speed, yet their promise for neurodegenerative diseases remains largely untapped. Currently intractable age-related proteinopathies such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis demand new therapies that combine molecular precision with scalable manufacturing. This review surveys recent advances in engineering LNPs that traverse the blood-brain barrier (BBB), evade innate immune surveillance, and achieve cell-selective expression in the ageing brain. We highlight emerging chemistries, including BBB-shuttling ionizable lipids, peptide-functionalized shells, and liver-detargeted formulations that enable systemic or minimally invasive delivery to the central nervous system (CNS) in animal models. Although no CNS-directed mRNA-LNP has yet reached clinical trials, first-in-human studies for rare metabolic disorders demonstrate favourable safety, manufacturability, and durable protein replacement. Drawing lessons from COVID-19 mRNA vaccines and ongoing liver-targeted programmes, we outline a translational roadmap for brain applications. Major hurdles that are critically assessed include efficient endosomal escape in aged neurons, heterogeneity of the senescent BBB, chronic-dose immunogenicity, and large-scale synthesis of next-generation lipids. Finally, we propose design rules and analytical standards to address outstanding knowledge gaps in expression durability and age-related BBB alterations. Together, these insights chart a path for engineering mRNA-LNP therapeutics capable of meeting the rising burden of neurodegenerative diseases in an ageing global population.},
}

@article {pmid42713279,
year = {2026},
author = {Kassubek, J and Müller, HP},
title = {Magnetic resonance imaging applications to amyotrophic lateral sclerosis beyond the central nervous system.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1849783},
pmid = {42713279},
issn = {1664-2295},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; },
abstract = {Traditionally, in amyotrophic lateral sclerosis (ALS) and other motor neuron disorders, the diagnostic and research focus in the domain of magnetic resonance imaging (MRI) has been targeted on the brain and spinal cord. Nevertheless, structures outside the central nervous system (CNS) are core structures of the pathological processes and are also assessible by imaging approaches. Advanced imaging of structures like bodyfat and muscles can considerably contribute to the pathophysiological understanding and disease monitoring of ALS. The multiparametric combination of MRI approaches that capture these changes could be very helpful in future studies, especially when machine learning algorithms are used. This review summarizes the current state of the art and the role of imaging beyond the CNS in ALS, examining its diagnostic and monitoring potential and how it might ultimately lead to improved management strategies for patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging
*Magnetic Resonance Imaging/methods

@article {pmid42713950,
year = {2026},
author = {Bernard, ME and Harrison, I},
title = {Dynamically biased microcanonical treatment of HCl dissociative chemisorption on Au(111) yields thermal associative desorption dynamics by detailed balance.},
journal = {The Journal of chemical physics},
volume = {165},
number = {10},
pages = {},
doi = {10.1063/5.0345352},
pmid = {42713950},
issn = {1089-7690},
abstract = {A dynamically biased microcanonical transition state theory model of HCl dissociative chemisorption on Au(111) was recently developed for Shirhatti et al.'s [J. Phys. Chem. Lett. 7, 1346 (2016)] non-equilibrium supersonic molecular beam experiments where normal translational energies varied over a 50-250 kJ/mol range. Model parameters include a relatively low threshold energy for reaction, E0 = 30.88 kJ/mol; an efficiency, εn = 0.26, for molecular normal translational energy to contribute to the active exchangeable energy capable of promoting reaction; and one surface oscillator, s = 1, involved in the local gas-surface collision complex wherein energy was taken as microcanonically exchangeable, although potentially subject to dynamical bias through efficiencies. To validate the model, detailed balance was used to predict the desorbing HCl product state distributions from thermal associative desorption of H(c) + Cl(c) on Au(111) that have been measured by Rettner and Auerbach [Science 263, 365 (1994)] while impinging a H atom beam onto a chlorinated Au(111) surface. Modeling of Rettner's [J. Chem. Phys. 101, 1529 (1994)] rovibrationally resolved HCl product state distributions allowed for the additional establishment of a rotational efficiency of εr = 0.23 that led to consistent prediction of both the thermal associative desorption and the supersonic molecular beam experimental results. The HCl(g) ⇄ H(c) + Cl(c) reactivity on Au(111) is thereby identified as a new benchmark system for gas-surface reactivity where highly detailed experimental data are available coming from both sides of the reaction barrier. The activation energy for thermal associative desorption was estimated as Ea,assoc = 5.6 ± 1.3 kJ/mol based on four independent kinds of measurement. The effect of dynamics on the thermal dissociative sticking coefficient, S(T), of interest in practical catalysis, was quantitatively assessed. As compared to a statistically behaving HCl/Au(111) system with Ea = 31 kJ/mol, dynamics reduced S(T) by a factor of 10 at 800 K, equivalent to an increase in activation energy of ΔEa = 15 kJ/mol.},
}

@article {pmid42716035,
year = {2026},
author = {Hardiman, O},
title = {HIMALAYA: learning from another negative phase 2 trial in ALS.},
journal = {The Lancet. Neurology},
volume = {25},
number = {10},
pages = {875-877},
doi = {10.1016/S1474-4422(26)00318-2},
pmid = {42716035},
issn = {1474-4465},
}

@article {pmid42716044,
year = {2026},
author = {Cudkowicz, ME and Shefner, J and van den Berg, LH and Chio, A and Fan, D and Großkreutz, J and Lunetta, C and Tsai, RM and Li, Y and Wallstroem, E and Xiong, L and Chen, Y and Atassi, N and , },
title = {Safety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.},
journal = {The Lancet. Neurology},
volume = {25},
number = {10},
pages = {900-910},
doi = {10.1016/S1474-4422(26)00277-2},
pmid = {42716044},
issn = {1474-4465},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Middle Aged ; Male ; Female ; Aged ; Adult ; Aged, 80 and over ; Young Adult ; Treatment Outcome ; Adolescent ; },
abstract = {BACKGROUND: RIPK1, a protein regulating inflammatory signalling and cell death, is implicated in amyotrophic lateral sclerosis (ALS) pathophysiology. SAR443820 is a selective, oral, CNS-penetrant, reversible RIPK1 inhibitor. We aimed to evaluate the safety, tolerability, and efficacy of SAR443820 in participants with ALS.

METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at 63 clinical sites in 13 countries (Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Spain, Sweden, the UK, and the USA). Adults (aged 18-80 years) with a diagnosis of possible ALS, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS, in accordance with the revised El Escorial World Federation of Neurology criteria, were randomly assigned (2:1) by use of a stratified block design (blocks of three) to receive either 20 mg SAR443820 orally twice per day or matching placebo in the 24-week double-blind period. Randomisation was done centrally using interactive response technology and stratified by geographical region of trial site, region of ALS onset, use of riluzole, use of edaravone, and use of the combination of sodium phenylbutyrate and taurursodiol. Participants, care providers, investigators, and outcomes assessors were masked to trial intervention. The primary outcome was a change in ALS Functional Rating Scale Revised (ALSFRS-R) total score from baseline to week 24 and was calculated for all participants who had an ALSFRS-R total score available at baseline and at week 24. Safety analyses included all randomly assigned participants receiving one dose or more of trial intervention. This trial is registered with ClinicalTrials.gov (NCT05237284) and was terminated early.

FINDINGS: Between April 13, 2022, and July 17, 2023, 397 participants were screened and 305 randomly assigned to SAR443820 (n=203) or placebo (n=102); six were excluded from the primary analysis due to missing baseline ALSFRS-R values. Mean age was 56·9 years (SD 11·5); 183 (60%) participants were male and 122 (40%) were female. Least squares mean change in ALSFRS-R from baseline to week 24 was -6·73 (95% CI -7·48 to -5·98) for SAR443820 group (n=169) and -6·32 (-7·36 to -5·27) for placebo group (n=87). There was no statistically significant difference between the study groups (least squares mean difference -0·41 [95% CI -1·71 to 0·88]). Participants in the SAR443820 group had higher incidence of adverse events (171 [85%] of 202 vs placebo 80 [78%] of 102) and treatment discontinuations (28 [14%] of 202 vs placebo five [5%] of 102), with elevated hepatic enzymes being the most common cause. Nine deaths occurred in the double-blind period (seven [3%] of 202 in the SAR443820 group and two [2%] of 102 in the placebo group); none was attributed to SAR443820.

INTERPRETATION: SAR443820 did not show clinical benefit and was associated with higher hepatic enzyme increase, indicating that further clinical development of SAR443820 in ALS is not warranted.

FUNDING: Sanofi.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy
Double-Blind Method
Middle Aged
Male
Female
Aged
Adult
Aged, 80 and over
Young Adult
Treatment Outcome
Adolescent

@article {pmid42716045,
year = {2026},
author = {Teunissen, CE and Vermunt, L and Barthélemy, NR and Benzinger, TLS and Graff-Radford, J and Verberk, IMW and Zetterberg, H and Schindler, SE and Jack, CR},
title = {Fluid biomarkers in the evolving care landscape of Alzheimer's disease and related disorders.},
journal = {The Lancet. Neurology},
volume = {25},
number = {10},
pages = {926-938},
doi = {10.1016/S1474-4422(26)00246-2},
pmid = {42716045},
issn = {1474-4465},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/blood ; tau Proteins/cerebrospinal fluid ; Animals ; },
abstract = {Fluid biomarkers for Alzheimer's disease have advanced rapidly during the past several years driven by breakthroughs including development of ultrasensitive and multiplexing technologies and high specificity antibodies. Blood-based biomarkers, such as neurofilament light for frontotemporal dementia and amyotrophic lateral sclerosis, and phosphorylated tau 217 for the diagnosis of Alzheimer's disease, are now being implemented in clinical practice, which is particularly timely because of the increasing clinical availability of amyloid-targeting treatments in Alzheimer's disease. Multiple fluid biomarkers are needed to capture the complexity of disease mechanisms for precise diagnosis and to measure the diverse pathologies that lead to dementia, such as vascular, α-synuclein, and TDP-43 pathologies. Moreover, fluid biomarkers can aid in capturing heterogeneity in treatment course between patients, probably due to copathologies or key intermediates, including microglia and astrocyte dysregulation. Increased focus on biomarker-pathology relationships in experimental models will likely accelerate biomarker development and further the understanding of their precise substrates. Future clinical implementation of biomarkers to capture the full complexity of pathologies will likely be facilitated by the expansion of diagnostic methods, development of point of care technologies, and remote sampling approaches.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
*Alzheimer Disease/cerebrospinal fluid/diagnosis/blood
tau Proteins/cerebrospinal fluid
Animals

@article {pmid42716967,
year = {2026},
author = {Mansour, SS and Mahmoud, AM and Moustafa, AA and Nashat, NW},
title = {"Green spectrophotometric determination of rupatadine, its toxic impurity, and methyl paraben: comparative AI-assisted univariate versus multivariate chemometrics".},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42716967},
issn = {2045-2322},
mesh = {*Parabens/analysis ; *Cyproheptadine/analogs & derivatives/analysis/chemistry ; Loratadine/analogs & derivatives/analysis ; Multivariate Analysis ; *Artificial Intelligence ; *Drug Contamination ; Spectrophotometry, Ultraviolet/methods ; Spectrophotometry/methods ; },
abstract = {Sensitive and selective green UV-spectrophotometric univariate and multivariate chemometric methods were developed to resolve the overlapped spectra of rupatadine fumarate (RUP), its impurity desloratadine (DES), and methyl paraben (MP). The univariate approach employed was the dual-wavelength (DW) method. Guided by artificial intelligence (AI) in the selection of the optimal wavelength pair, the determination of RUP was performed at 230 and 284.3 nm, and for MP at 236.6 and 253.8 nm. Among the multivariate methods, ANN demonstrated superior predictive accuracy (lowest RMSEP values), followed by PLS-1 and MCR-ALS, highlighting the power of machine learning for complex mixture resolution, particularly in the presence of the preservative MP. A three-factor, five-level experimental design was adopted to construct a calibration set comprising 25 mixtures with varying component ratios, along with 6 independent validation mixtures. The developed methods were successfully applied to pharmaceutical formulation containing the studied drug and were validated in accordance with International Conference of Harmonization (ICH) guidelines. The results obtained were reliable and reproducible, confirming the suitability of these methods for routine analysis and quality control in laboratories. Moreover, the GLANCE tool (Graphical Layout for Analytical Chemistry Evaluation) offered a clear visual summary of the twelve structured method attributes.},
}

*Parabens/analysis
*Cyproheptadine/analogs & derivatives/analysis/chemistry
Loratadine/analogs & derivatives/analysis
Multivariate Analysis
*Artificial Intelligence
*Drug Contamination
Spectrophotometry, Ultraviolet/methods
Spectrophotometry/methods

@article {pmid42717683,
year = {2026},
author = {Moody, L and Christoforidou, E and Joilin, G and Dilley, A and Hafezparast, M},
title = {Dysregulated microRNA-mRNA networks in SOD1G93A mouse skeletal muscle reveal metabolic impairments in ALS.},
journal = {Disease models & mechanisms},
volume = {},
number = {},
pages = {},
doi = {10.1242/dmm.052963},
pmid = {42717683},
issn = {1754-8411},
support = {Hafezparast/Oct19/897-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; Hafezparast/Apr21/880-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; //Sussex Neuroscience PhD Programme/ ; DOD/14/30-PF12794//My Name'5 Doddie Foundation/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a multi-system disease in which skeletal muscle actively contributes to pathology, yet the regulatory circuits that drive muscle dysfunction remain unclear. We examined microRNA (miRNA)-messenger RNA (mRNA) interactions in the gastrocnemius of hSOD1G93A mice across presymptomatic, early- and late-symptomatic stages, using RNA-seq, bioinformatics, and RT-qPCR. Compared with hSOD1WT and non-transgenic controls, hSOD1G93A muscle showed mutation-specific transcriptome reprogramming: 48 dysregulated miRNAs and 558 mRNAs at presymptomatic, and 64 miRNAs and 685 mRNAs at late-symptomatic stages. Functional enrichment pinpointed carbohydrate-handling pathways (glycolysis/gluconeogenesis, pentose-phosphate, fructose-mannose metabolism) as the dominant downregulated gene sets. Network analysis revealed clusters in which upregulated miRNAs converged on, and showed inverse expression patterns relative to metabolic transcripts. RT-qPCR confirmed inverse expression of 10 candidate miRNAs and 11 metabolic mRNAs, substantiating miRNA-guided repression of glycolytic enzymes and energy-sensing nodes. Collectively, we show that SOD1G93A drives an early, sustained miRNA signature that dampens glycolysis gene expression, which could promote the fast-to-slow fibre-type transition and exacerbate energy deficit in ALS muscle. Targeting these circuits offers a strategy to restore metabolic balance and slow disease progression.},
}

@article {pmid42717824,
year = {2026},
author = {Zarco-Martín, MT and Andreo-López, MC and Yagui-Beltrán, MS and Fernández-Soto, ML},
title = {Appendicular Skeletal Muscle Mass and Sarcopenia as Prognostic Markers in Amyotrophic Lateral Sclerosis.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {17},
number = {5},
pages = {e70378},
doi = {10.1002/jcsm.70378},
pmid = {42717824},
issn = {2190-6009},
support = {2024 Award for the Best Clinical Nutrition Research Project//Sociedad Española de Nutrición Clínica y Metabolismo/ ; 74-2022//Granada Biosanitary Research Institute (Ibs. Granada)/ ; },
mesh = {Humans ; *Sarcopenia/etiology/diagnosis/mortality/pathology ; *Amyotrophic Lateral Sclerosis/complications/mortality/diagnosis ; Female ; Prognosis ; *Muscle, Skeletal/pathology/physiopathology ; Male ; Aged ; Biomarkers ; Middle Aged ; Prospective Studies ; Hand Strength ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle wasting and functional decline. Prognostic assessment in clinical practice relies largely on functional scales and traditional anthropometric measures. The prognostic relevance of muscle mass, muscle strength and sarcopenia in ALS remains incompletely defined. This study evaluated the prognostic value of muscle mass, muscle function and sarcopenia in relation to mortality in patients with ALS.

METHODS: A prospective observational cohort study was conducted at the ALS Multidisciplinary Unit (UMELA), San Cecilio University Hospital in Granada. Sarcopenia was defined according to the European Working Group of Sarcopenia in Older People 2 (EWGSOP2) and malnutrition using the Global Leadership Initiative on Malnutrition (GLIM) criteria. Muscle status was assessed using bioelectrical impedance vector analysis (BIVA)-derived parameters, muscle ultrasound, handgrip strength (HGS) and physical performance (SPPB). Differences between survivors and nonsurvivors were analysed and logistic regression explored potential predictors of mortality. Receiver operating characteristic (ROC) curves were constructed for significant predictors. Survival was analysed using the Kaplan-Meier and Cox proportional hazards regression.

RESULTS: A total of 42 patients with ALS were included (mean age 66.1 ± 10.3 years, and 15 (36%) were female). During follow-up (mean survival 21.1 ± 10.5 months), 45% died. Survivors showed higher appendicular skeletal muscle mass index (ASMI) (6.94 ± 0.91 vs. 5.80 ± 0.98 kg/m[2], p = 0.001), body cellular mass index (BCMI) (8.92 ± 1.59 vs. 7.64 ± 1.87 kg/m[2], p = 0.034) and HGS (25.45 ± 11.11 vs. 17.67 ± 8.83 kg, p = 0.032), while BMI did not differ (p = 0.540). Sarcopenia was more prevalent in nonsurvivors (27.8% vs. 4.8%, p = 0.047). In multivariable analysis, ASMI remained associated with mortality after adjustment for age, onset type and ALSFRS-R (OR 0.33, 95% CI 0.11-0.81, p = 0.026), but this association was not statistically significant in the fully adjusted model including disease duration (p = 0.093). ASMI showed the highest discriminative ability (AUC 0.81), compared to BCMI (AUC 0.70) and HGS (AUC 0.71). ROC-derived cut-offs (ASMI 6.74 kg/m[2]; BCMI 7.2 kg/m[2]; HGS 21 kg) stratified survival. Higher ASMI (HR 7.53, p = 0.008), BCMI (HR 4.18, p = 0.005) and HGS (HR 4.02, p = 0.019) were associated with longer survival, whereas sarcopenia increased mortality risk (HR 15.53, p < 0.001).

CONCLUSIONS: Beyond BMI, skeletal muscle mass-particularly ASMI-was associated with survival in ALS. Sarcopenia identifies a subgroup of patients at particularly high risk of death. Sarcopenia assessment may improve prognostic stratification and support clinical management in ALS.},
}

Humans
*Sarcopenia/etiology/diagnosis/mortality/pathology
*Amyotrophic Lateral Sclerosis/complications/mortality/diagnosis
Female
Prognosis
*Muscle, Skeletal/pathology/physiopathology
Male
Aged
Biomarkers
Middle Aged
Prospective Studies
Hand Strength

@article {pmid42719214,
year = {2026},
author = {Mittal, D and Solanki, P and Jain, GK and Jhawat, V and Kesharwani, P and Dutt, R and Arora, S and Singh, RP},
title = {Herbal nanoparticles in the treatment of neurodegeneration: from molecular mechanisms to therapeutic translation.},
journal = {3 Biotech},
volume = {16},
number = {10},
pages = {420},
pmid = {42719214},
issn = {2190-572X},
abstract = {UNLABELLED: Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss involving multiple pathological mechanisms, including protein aggregation, oxidative stress, neuroinflammation, and mitochondrial dysfunction. Although conventional therapies provide symptomatic relief, they fail to halt disease progression and are limited by poor blood-brain barrier (BBB) penetration, off-target effects, and systemic toxicity. Likewise, several herbal bioactives, such as curcumin, resveratrol, quercetin, and epigallocatechin gallate, exhibit promising neuroprotective properties but suffer from poor aqueous solubility, low oral bioavailability, rapid metabolism, and inadequate brain delivery. Nanotechnology-based delivery systems have emerged as a promising approach to overcome these pharmacokinetic limitations by enhancing stability, controlled release, BBB transport, and brain accumulation of herbal therapeutics. This review critically summarizes recent advances in herbal nanoformulations, emphasizing disease-specific molecular targets, BBB-targeting strategies, comparative nanocarrier systems, pharmacokinetic optimization, intracellular trafficking, and translational challenges. Unlike previous reviews, it integrates recent evidence on nanotoxicology, manufacturing scalability, quality control, regulatory considerations, and emerging technologies, including biomimetic nanoparticles and extracellular vesicles. Despite encouraging preclinical outcomes, clinical evidence remains limited, and no herbal nanoformulation has yet demonstrated definitive efficacy or received regulatory approval for neurodegenerative diseases. Future clinical translation will require standardized formulations, rigorous safety evaluation, and well-designed clinical trials. Unlike previous reviews that primarily summarize individual nanocarrier systems or herbal therapeutics, the present review provides a comprehensive and critical synthesis of the current evidence by integrating disease-specific molecular mechanisms, herbal bioactives, nanocarrier design strategies, blood-brain barrier transport mechanisms, intracellular trafficking, pharmacokinetic considerations, translational barriers, regulatory challenges, clinical evidence, and emerging technologies. Furthermore, the review identifies major knowledge gaps and future research priorities to facilitate the successful clinical translation of herbal nanoformulations for neurodegenerative disorders.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13205-026-05048-8.},
}

@article {pmid42719350,
year = {2026},
author = {Imashuku, S},
title = {Literature review of pediatric Erdheim-Chester disease (ECD) and mixed histiocytosis (Langerhans cell histiocytosis/ECD).},
journal = {Annals of translational medicine},
volume = {14},
number = {4},
pages = {53},
pmid = {42719350},
issn = {2305-5839},
abstract = {BACKGROUND AND OBJECTIVE: Langerhans cell histiocytosis (LCH) and Rosai-Dorfman disease (RDD) are more commonly observed in childhood; however, Erdheim-Chester disease (ECD) predominantly affects adults, making pediatric ECD extremely rare. To find out the incidence and characteristics of ECD in children, a review article was prepared.

METHODS: A literature review was conducted to estimate the incidence of pediatric ECD and characterize its clinical features, using PubMed and Crossref, during 1990 to June 2026, with searched terms "Childhood or Pediatric", "Erdheim-Chester disease", "Mixed histiocytosis".

KEY CONTENT AND FINDINGS: A total of 28 pediatric ECD cases were collected, which compared with previously reported pediatric ECD case series (Pegoraro et al., n=21; Romano et al., n=16). Based on these reports, it was estimated that more than 30 pediatric ECD cases have been described to date. Pediatric ECD appears to be characterized by relatively high rates of central nervous system involvement (53-67%) and mixed histiocytosis (20-38%). In addition, ophthalmologic involvements in the Yeager et al.'s study in 45% (adult 30%) of pediatric ECD should be recognized as an important manifestation in the eyes even in children. Regarding prognosis, most pediatric patients with ECD were reported as alive with disease (AWD) at the time of publication, suggesting a more favorable outcome than that observed in adult cases.

CONCLUSIONS: Diagnosing ECD in children remains challenging; however, this rare entity should be considered in the differential diagnosis of pediatric histiocytosis, particularly in cases with central nervous system and ophthalmologic involvement.},
}

@article {pmid42719426,
year = {2026},
author = {Zambetti, E and Belli, S and Mucci, C and Greco, A},
title = {Living with Amyotrophic Lateral Sclerosis: Exploring what matters to patients and caregivers through their experiences.},
journal = {Palliative care and social practice},
volume = {20},
number = {},
pages = {26323524261474107},
pmid = {42719426},
issn = {2632-3524},
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disease the causes of which are not fully understood, that leads to early death. From the diagnosis, ALS significantly impacts the quality of life (QoL) for patients and their caregivers due to its unique characteristics. Both patients and their caregivers, formal and informal, increasingly feel the need to share their experiences, communicate their needs, and talk about what living with ALS entails.

OBJECTIVES: Given the few studies available in the literature on this topic, the study's aim is to explore the significance of ALS for patients and caregivers through their testimonies and to identify the collective representations and symbolic categories that influence their lives.

DESIGN AND METHODS: A total of 118 spontaneous written texts (67 produced by women) (81.752 tokens, TTR index=0.145; H% index=54.6%) collected from the web, from 67 ALS patients, 41 informal and 10 formal caregivers, were analyzed using the Emotional Text Mining (ETM) technique, with the T-Lab Software.

RESULTS: Four communication axes were identified: management of the disease (34.25%; physical vs. emotional), care (26.58%; technological vs. relational), support (21.39%; self-directed vs. social), and effort (17.78%; personal and institutional). The five clusters positioned in this factorial space relate to disease onset (12.29%), difficulties (30.78%), medical examinations (29.39%), coping strategies (14.79%), and needs (18.75%). There are differences between genders and groups.

CONCLUSION: The interpretation of the results enables an understanding of the cultural-symbolic system of ALS patients and caregivers, as well as the impact of the disease on their QoL. Through this, personalized interventions can be designed to promote resources and psychological well-being.},
}

@article {pmid42719847,
year = {2026},
author = {Tu, D and Riseman, J and Wei, Y and Ghosh, P and Raney, SG and Luke, MC and Evans, CL},
title = {Label-free quantification of topical drug permeation in skin using sparse spectral sampling stimulated Raman scattering imaging.},
journal = {Biophotonics discovery},
volume = {3},
number = {4},
pages = {043103},
pmid = {42719847},
issn = {3005-4745},
abstract = {SIGNIFICANCE: Stimulated Raman scattering (SRS) imaging has been used in evaluating topical drug product permeation. However, it has been mainly applied to a small group of active pharmaceutical ingredients (API) that have unique molecular bands which generate a prominent SRS signal against the background signal. The requirement of such unique molecular bands has been a large hurdle to generalizing SRS imaging to study a wide range of pharmaceutical molecules.

AIM: To overcome this barrier, an imaging method based on sparse spectral sampling stimulated Raman scattering (S4RS) microscopy and multivariate analysis was developed in this study.

APPROACH: Rather than relying on a single unique and strong peak, the API was specifically resolved using combined information from multiple wavenumbers across its spectrum. The workflow of applying this method to study APIs is demonstrated using metronidazole as an example. The sparse vibrational bands were first selected using Elastic-Net. Next, the metronidazole signal was unmixed from the compound signal of the skin-drug product mixture using multivariate curve resolution-alternating least squares (MCR-ALS).

RESULTS: The developed method demonstrated good capability in identifying the metronidazole signal in standard metronidazole-containing samples, including polymer films and skin samples treated with and without the drug product. This method enabled evaluation of the cutaneous pharmacokinetics (cPK) of metronidazole in ex vivo skin samples. Bioequivalence analysis was also completed for commercial drug products and laboratory-made control formulations containing metronidazole.

CONCLUSIONS: The developed method enables the study of APIs that lack a unique prominent peak, thereby bridging SRS imaging to a broader range of drug products.},
}

@article {pmid42707488,
year = {2026},
author = {Feyissa, GD},
title = {Serial Bogota bag tightening: A pragmatic advance in open abdomen management for resource-limited settings.},
journal = {World journal of gastrointestinal pharmacology and therapeutics},
volume = {17},
number = {3},
pages = {120768},
pmid = {42707488},
issn = {2150-5349},
abstract = {Open abdomen management poses unique challenges in resource-limited settings, where costly dynamic fascial traction techniques remain inaccessible. Balhara et al's prospective randomized trial published on the World J Gastrointest Pharmacol Ther introduces serial Bogota bag tightening, a bedside, negligible-cost method using urine bags and sutures, as an effective dynamic fascial traction alternative, achieving skin-to-skin distance ≤ 5 cm in 9.94 days vs 13 days in controls (P = 0.0003) and shortening hospital stays without added morbidity. This editorial appraises the study's strengths, contextualizes it against negative pressure wound therapy/mesh systems, and advocates its scalability for low- and middle-income countries, urging multicenter validation of long-term fascial closure.},
}

@article {pmid42707600,
year = {2026},
author = {Zhang, Z and Lu, Y and Yang, J and Li, M and Yang, M and Xu, Y and Ullah, MS and Wan, Q and Bao, B and Yu, W and Liu, X},
title = {Neurotoxic mechanisms of cadmium in neurodegenerative diseases.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1899381},
pmid = {42707600},
issn = {2296-634X},
abstract = {Cadmium (Cd) is a highly toxic, bioaccumulative heavy metal increasingly implicated in the pathogenesis of neurodegenerative disorders. This review systemically characterizes the molecular mechanisms underlying Cd-induced neurotoxicity, with particular emphasis on oxidative stress-mediated pathways that initiate interconnected processes including ferroptosis, mitochondrial impairment, disruption of calcium homeostasis, and chronic neuroinflammation. Evidence indicates that Cd exerts both convergent and disease-specific effects in neurodegenerative conditions. In Alzheimer's disease (AD), Cd exposure has been associated with enhanced amyloid-β (Aβ) deposition and increased tau hyperphosphorylation. In Parkinson's disease (PD), Cd disrupts metabolic homeostasis via the gut-liver-brain axis and promotes aberrant conformational changes and aggregation of α-synuclein (α-Syn). Within the amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum, Cd contributes to TDP-43 proteinopathy and impairs nucleocytoplasmic transport mechanisms. Therapeutic strategies targeting Cd-induced neurotoxicity are also explored, including upstream approaches like metal chelation and downstream interventions aimed at restoring autophagic flux, modulating the neuroimmune microenvironment, and enhancing neuronal repair. Although emerging platforms such as brain organoids provide valuable mechanistic insights, translating findings from in vitro models to real-world chronic exposure scenarios remains a significant challenge. This review provides a comprehensive framework for the development of early-warning systems and precision-based interventions for Cd-related neurodegeneration.},
}

@article {pmid42708447,
year = {2026},
author = {Gazal, NG and Castellanos-Montiel, MJ and Bruno, G and Franco-Flores, AK and Lépine, S and Gursu, L and Haghi, G and Maussion, G and Reintsch, WE and Stefani, FD and Anastasía, A and Bisbal, M and Gorostiza, EA and Durcan, TM and Unsain, N},
title = {BetaII-spectrin gaps and patches emerge from the patterned assembly of the actin/spectrin membrane skeleton in human motor neuron axons.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
pmid = {42708447},
issn = {2050-084X},
support = {ANPCyT-PICT-2021-GRF-II-00048//Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación/ ; IBRO-Collaboration Grants 2021//International Brain Research Organization/ ; },
mesh = {Humans ; *Spectrin/metabolism ; *Motor Neurons/metabolism ; *Axons/metabolism ; *Actins/metabolism ; Induced Pluripotent Stem Cells/metabolism ; *Cytoskeleton/metabolism ; },
abstract = {The actin/spectrin membrane-associated periodic skeleton (MPS) is a cytoskeletal structure that supports axonal integrity and function. Lower spinal motor neurons (MNs) are characterized by exceptionally long axons and are particularly susceptible to degeneration in a wide range of hereditary neuromuscular disorders, including amyotrophic lateral sclerosis. Using confocal and super-resolution imaging, we characterized the spatial distribution of βII-spectrin and the assembly pattern of the MPS in human MN axons derived from induced pluripotent stem cells. We discovered a striking gap-and-patch pattern in the medial axon, where sharply demarcated βII-spectrin gaps alternate with patches containing a well-organized MPS. The pattern is acutely induced by the kinase inhibitor staurosporine and pharmacological inhibition of actin polymerization prevents patch formation, indicating a requirement for actin nucleation in MPS assembly. Our data supports a model in which spectrin incorporation into nascent MPS patches depletes neighboring regions, producing long-range gaps-and-patches patterns.},
}

Humans
*Spectrin/metabolism
*Motor Neurons/metabolism
*Axons/metabolism
*Actins/metabolism
Induced Pluripotent Stem Cells/metabolism
*Cytoskeleton/metabolism

@article {pmid42709165,
year = {2026},
author = {Hamzeh, LH and Seyed, E and Elgendy, MA and Heib, D and Sadek, BI and Mohammed, COS and El Refaei, K and Soliman, YF and Eldmrdash, N and Abdelgalil, MS and Elsayed, MM},
title = {Efficacy and safety of memantine in adults with amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42709165},
issn = {1435-1463},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited disease-modifying treatment options. Memantine, an N-methyl-D-aspartate receptor antagonist, has been investigated in ALS, but its safety remains unclear. This study systematically assessed the safety of memantine in adults with ALS. A systematic review and meta-analysis was conducted following PRISMA 2020 guidelines, searching PubMed, Cochrane Library, Scopus, and Web of Science for randomized controlled trials of memantine in adults with ALS. Outcomes included ALSFRS-R and FVC decline, adverse neurological events, total and serious adverse events, treatment discontinuation, and all-cause mortality. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Because of heterogeneous reporting and missing variance estimates, ALSFRS-R and FVC outcomes were synthesized narratively; only safety outcomes were pooled quantitatively. Three randomized controlled trials (706 participants) met the inclusion criteria. Functional and respiratory outcomes could not be pooled because of heterogeneous reporting, and no consistent benefit was observed. Memantine showed lower headache incidence than placebo (RR 0.43; 95% CI 0.19-0.96), with no significant differences in constipation, falls, dizziness, treatment discontinuation, or all-cause mortality. Memantine showed a borderline increase in serious adverse events (RR 1.52; 95% CI 1.00-2.31) and a higher risk of total adverse events (RR 1.19; 95% CI 1.09-1.30). Memantine was associated with a small but significant increase in total adverse events and a trend toward more serious adverse events, without improving functional decline, respiratory function, or survival in ALS. Current evidence does not support its use as a disease-modifying or adjunctive therapy. Trial registration: PROSPERO CRD420261277874.},
}

@article {pmid42709218,
year = {2026},
author = {Sewell-Green, AR and Capstick, R and Holdom, CJ and Matthews-Rensch, K and Cameron, J and McCombe, PA and Henderson, RD and Ngo, ST and Steyn, FJ},
title = {Early weight loss predicts poorer prognosis and highlights limitations of predictive energy equations in amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {273},
number = {10},
pages = {},
pmid = {42709218},
issn = {1432-1459},
support = {2016-32//Wesley Medical Research/ ; CRG2025_01395//FightMND/ ; Higher Degree Research Scholarship//University of Queensland/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/metabolism ; *Weight Loss/physiology ; Prognosis ; Female ; Male ; Middle Aged ; Case-Control Studies ; Prospective Studies ; Aged ; *Energy Intake/physiology ; },
abstract = {BACKGROUND: Weight loss and malnutrition are associated with poorer outcomes in people living with amyotrophic lateral sclerosis (plwALS). This study investigated the prognostic relevance of early weight loss in plwALS and assessed whether existing energy equations provide useful guidance for nutritional management.

METHODS: In this prospective case-control and within-case comparison study (March 2016October 2024), 170 plwALS and 173 non-neurodegenerative disease controls completed baseline anthropometric and metabolic assessment. Participants with ALS were classified according to weight change during the first six months following study inclusion as Weight Gain, Stable Weight, or Weight Loss. Weight-change groups were compared for subsequent changes in anthropometry, functional capacity, and survival. In a nested cohort of 82 plwALS with reported energy intake and repeat assessments, we assessed whether the relationship between reported intake and equation-derived energy requirements was concordant with subsequent weight change.

RESULTS: Early weight loss was associated with continued loss of body weight, fat mass, and fat-free mass, faster functional decline, and increased risk of earlier death relative to Weight Gain (HR=4.78 [95% CI 2.68-8.53], p<0.001). Concordance between equation-derived energy requirements, reported energy intake and observed weight trajectory was low (17.3-32.1%). The IBW30(30) equation showed the greatest concordance among participants with Weight Loss, but no equation performed consistently across weight-change groups.

CONCLUSIONS: Early weight loss identifies plwALS at increased risk of subsequent weight and body-composition loss, functional decline and earlier death. Existing energy equations proposed for use in ALS show limited concordance with observed weight trajectories, particularly when applied at a single time point. These findings support serial monitoring of nutritional risk and individualized, phenotype-informed dietetic care in ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/metabolism
*Weight Loss/physiology
Prognosis
Female
Male
Middle Aged
Case-Control Studies
Prospective Studies
Aged
*Energy Intake/physiology

@article {pmid42709229,
year = {2026},
author = {Castro, J and Sá, V and Lopes, D and Alves, I and Oliveira Santos, M and de Carvalho, M},
title = {Phrenic nerve amplitude as an effort-independent prognostic biomarker of respiratory failure in amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {273},
number = {10},
pages = {},
pmid = {42709229},
issn = {1432-1459},
mesh = {Humans ; *Phrenic Nerve/physiopathology ; *Amyotrophic Lateral Sclerosis/complications/physiopathology/diagnosis ; Female ; Male ; Prognosis ; *Respiratory Insufficiency/etiology/diagnosis/physiopathology/therapy ; Nerve Conduction Studies ; Middle Aged ; Aged ; Noninvasive Ventilation ; Action Potentials/physiology ; Cohort Studies ; Biomarkers ; },
abstract = {OBJECTIVE: In amyotrophic lateral sclerosis (ALS), the effort-dependent respiratory metrics used to determine the timing of non-invasive ventilation (NIV) lose reliability as bulbar and/or cognitive impairment progresses. We tested whether the effort-independent phrenic nerve compound muscle action potential (CMAP) amplitude predicts the timing of NIV independently of forced vital capacity (FVC) and the revised ALS Functional Rating Scale (ALSFRS-R).

METHODS: Pre-registered analysis of a single-centre ALS cohort (n = 1,486) contributing 2968 serial phrenic nerve conduction studies. Amplitude was expressed as percentage of an age- and sex-predicted value (per 10% decrease), and time to NIV initiation was the primary outcome (death competing). We used cause-specific Cox models, time-dependent and bootstrap-validated discrimination, and a Bayesian joint longitudinal-survival model.

RESULTS: Lower amplitude predicted earlier NIV (adjusted hazard ratio [HR] 1.22 per 10% decrease, 95% CI 1.16-1.27; likelihood-ratio χ[2] = 77.6, p ≈ 10⁻1⁸). The association was concentrated in the first year (HR 1.31, 1.24-1.38) and attenuated thereafter. The optimism-corrected discrimination increment over the clinical model was +0.055 (0.034-0.073); below-normal amplitude approximately doubled 12-month NIV risk (62% vs 29%). In the joint model the current amplitude (HR 1.57, 1.46-1.69) and its rate of decline (HR 1.30, 1.20-1.44) were independently prognostic.

CONCLUSIONS: Phrenic nerve conduction studies, an effort-independent neurophysiological marker carried robust, near-term, incremental prognostic information for NIV beyond FVC and ALSFRS-R, establishing diaphragmatic motor amplitude as a candidate biomarker for objective respiratory prognostication in ALS. External validation and recalibration are required before clinical use.},
}

Humans
*Phrenic Nerve/physiopathology
*Amyotrophic Lateral Sclerosis/complications/physiopathology/diagnosis
Female
Male
Prognosis
*Respiratory Insufficiency/etiology/diagnosis/physiopathology/therapy
Nerve Conduction Studies
Middle Aged
Aged
Noninvasive Ventilation
Action Potentials/physiology
Cohort Studies
Biomarkers

@article {pmid42709336,
year = {2026},
author = {Colosimo, C},
title = {The Great Transatlantic Divide: The Case of Experimental Neuropharmacology.},
journal = {Clinical drug investigation},
volume = {},
number = {},
pages = {},
pmid = {42709336},
issn = {1179-1918},
abstract = {Despite substantial agreement between the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) on new drug approval in the past decades, a few new drugs for the treatment of some of the most prevalent and severe neurological disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as much rarer neurogenetic disorders, were handled differently by the two regulatory agencies. The possible reasons for the differing behaviors of the FDA and EMA are several and wide-ranging, and they will be examined in this opinion-based analysis. How patients' perceptions of the complex approaches to drug approval and commercialization may create disappointment and confusion will also be reappraised.},
}

@article {pmid42709471,
year = {2026},
author = {Chin, N and Zhang, Q and Zou, J and Cheng, KC and Zheng, W and Ye, Y},
title = {Cellular modifiers of TDP-43 phase transition and cytoplasmic aggregation.},
journal = {eLife},
volume = {15},
number = {},
pages = {},
pmid = {42709471},
issn = {2050-084X},
mesh = {*DNA-Binding Proteins/metabolism/genetics/chemistry ; Humans ; *Phase Transition ; Phase Separation ; *Cytoplasm/metabolism ; Active Transport, Cell Nucleus ; *Protein Aggregates ; Cell Nucleus/metabolism ; },
abstract = {RNA-binding protein TAR DNA-binding protein 43 (TDP-43) can form liquid-like nuclear assemblies whose phase behavior is thought to influence its aggregation propensity and neurotoxic activity. The mechanisms that govern the liquid-to-solid phase transition of TDP-43 remain poorly defined. Here, we combined chemical and genome-wide genetic screens to identify cellular factors that modulate the phase behavior of an RNA-binding-defective TDP-43 mutant. Our screens uncovered multiple cellular processes, including RNA splicing, protein translation, proteostasis imbalance, and nuclear export as TDP-43 phase regulators. We also developed a semi-permeabilized cell system that partially recapitulates the TDP-43 phase transition in vitro, and showed that nuclear export inhibition reshapes the nuclear environment to favor RNA-dependent liquid-liquid phase separation (LLPS) of TDP-43, which mitigates its aggregation. Nuclear export inhibition in a brain organoid model bearing an ALS-associated mutation reduces pathogenic phospho-TDP-43 accumulation. These findings identify multiple modulators of TDP-43 phase transitions in a sensitized model system and establish a framework for further dissecting the link between nuclear transport and TDP-43 phase dynamics.},
}

*DNA-Binding Proteins/metabolism/genetics/chemistry
Humans
*Phase Transition
Phase Separation
*Cytoplasm/metabolism
Active Transport, Cell Nucleus
*Protein Aggregates
Cell Nucleus/metabolism

@article {pmid42709996,
year = {2026},
author = {Davies, BJ},
title = {The floor, not the ceiling: industry ties across the cancer ecosystem.},
journal = {Journal of the National Cancer Institute},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnci/djag208},
pmid = {42709996},
issn = {1460-2105},
abstract = {Industry financial ties to the US cancer ecosystem are everywhere. Kim et al.'s systematic review and meta-analysis finds that financial conflicts of interest exceed 50% prevalence across most oncology domains. These relationships are not always benign. A robust body of health services research, including a 2021 systematic review of 36 studies, demonstrates that 83% of analyses identify a positive association between industry payments and prescribing behavior. Even a single industry-sponsored meal costing <$20 has been linked to significantly higher odds of prescribing the promoted drug. As federal National Institute of Health (NIH) funding faces cuts, industry's role in shaping the research agenda will only expand. Current US policy responses such as the disclosure through the Sunshine Act and dollar thresholds for guideline panelists have had minimal effectiveness in curtailing the money flowing to oncologists. This editorial argues for stronger structural reforms, specifically mandatory cooling-off periods for guideline committee members modeled on existing federal ethics statutes. Disclosure alone is insufficient, and some evidence suggests it may paradoxically license conflicted behavior. Meaningful progress requires moving beyond transparency toward policies that prevent conflicts from influencing clinical decision making.},
}

@article {pmid42710492,
year = {2026},
author = {Kage, F and Lee, M and Bramhe, S and McEwen, AG and Alpy, F and Higgs, HN},
title = {Phosphorylation-dependent interaction between VAP proteins and INF2 influences ER morphology.},
journal = {Current biology : CB},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cub.2026.08.031},
pmid = {42710492},
issn = {1879-0445},
abstract = {The endoplasmic reticulum (ER) interacts with virtually all other cellular organelles, and major players mediating these interactions are the ER-bound VAMP-associated protein (VAP) proteins VAPA and VAPB. Here, we show that VAP proteins interact with the actin polymerization factor INF2 in a phosphorylation-dependent manner. Similar to many other VAP-interacting proteins (the "VAPome"), an FFAT motif in INF2's C terminus interacts with the major sperm protein (MSP) domain of VAPs. Phosphorylation of a serine within the FFAT (S1100 in mouse; S1077 in human INF2) is necessary for high-affinity interaction both in cells and with purified proteins. The position of this phosphoserine, at position -1 of the FFAT consensus, is novel to the VAPome. Biochemical assays show that the phospho-FFAT binds both VAPA and VAPB, but not the related VAP family protein MOSPD2. Increased cytoplasmic calcium stimulates both INF2 phosphorylation and the INF2/VAP interaction. Amyotrophic lateral sclerosis (ALS)-associated mutations in the MSP disrupt the INF2/VAP interaction. Both major INF2 isoforms interact with VAPs: the INF2-CAAX isoform, which is constitutively ER-bound, and the INF2-nonCAAX isoform, which is predominantly cytosolic. For INF2-nonCAAX, VAP proteins cause ER recruitment in a phosphorylation-dependent manner. Disruption of INF2/VAP binding does not affect INF2-mediated actin polymerization but has a clear effect on ER morphology, causing the tubule/sheet balance to shift toward sheets. Cross-species evaluation suggests that only INF2 from placental mammals possesses an FFAT. These results suggest that interaction between VAP proteins and the actin polymerization factor INF2 plays a role in mediating ER morphology.},
}

@article {pmid42710553,
year = {2026},
author = {Babu, D and Le, TH and Liu, H and Raji, D and Tran, NH and Lockhart, S and Tran, P and Eldalal, O and Tonoyan, L and Siraki, AG},
title = {Edaravone as an antioxidant adjuvant to attenuate clozapine toxicity in vitro.},
journal = {Toxicology letters},
volume = {},
number = {},
pages = {113188},
doi = {10.1016/j.toxlet.2026.113188},
pmid = {42710553},
issn = {1879-3169},
abstract = {Despite being the gold-standard therapy for treatment-resistant schizophrenia, clozapine use remains constrained by the risk of rare but serious adverse drug reactions, including severe neutropenia and agranulocytosis. Neutrophil myeloperoxidase (MPO)-mediated bioactivation of clozapine to reactive metabolites has long been implicated in agranulocytosis. Although clozapine is metabolized by MPO, there are numerous other compounds that can also be metabolized by this enzyme. Edaravone is a drug used to treat amyotrophic lateral sclerosis and has potent antioxidant activity; we have previously shown that edaravone is metabolized by MPO. Therefore, we hypothesized that edaravone can attenuate early toxicological events associated with clozapine through MPO modulation. Using purified human MPO, MPO-rich human promyelocytic leukemia (HL-60) cells, and isolated human neutrophils, we evaluated clozapine oxidation, competitive intracellular uptake, protein adduct formation, and cytotoxicity. UV-visible spectroscopy demonstrated concentration-dependent inhibition of MPO-catalyzed clozapine oxidation by edaravone, with 100µM edaravone producing suppression comparable to 100µM 4-aminobenzoic acid hydrazide. LC-MS analysis showed that MPO/H2O2 reduced clozapine levels to 26.7 ± 2.9% of control, whereas co-incubation with edaravone preserved clozapine to 67.9 ± 16.2%. Under the same conditions, edaravone was almost completely consumed (0.03 ± 0.02% remaining), consistent with its sacrificial antioxidant activity. In HL-60 cells, edaravone attenuated MPO activity and did not significantly alter clozapine uptake after 30minutes (97.2 ± 7.6% of clozapine alone). Immunoblotting revealed that edaravone reduced clozapine-protein adduct formation in purified MPO, HL-60 cells, and neutrophils. Clozapine (75µM) induced marked HL-60 cytotoxicity after 24hours, whereas edaravone concentration-dependently restored viability, with 200µM fully preventing toxicity. These findings provide proof-of-concept that edaravone mitigates multiple mechanistic events linked to clozapine-induced hematological toxicity and may represent a potential strategy to improve clozapine safety.},
}

@article {pmid42710846,
year = {2026},
author = {Cunha, TA and Dourado, LC and Santana, GC and Yanagiura, MT and Galvão-Lima, LJ and Vale, SHL and Brandão-Neto, J and Dourado-Junior, MET and Leite-Lais, L},
title = {Evaluation of a self-administered version of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).},
journal = {Arquivos de neuro-psiquiatria},
volume = {84},
number = {9},
pages = {1-7},
doi = {10.1055/s-0046-1827063},
pmid = {42710846},
issn = {1678-4227},
support = {88887.824483/2023-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Reproducibility of Results ; Prospective Studies ; Female ; Middle Aged ; Male ; Severity of Illness Index ; Observer Variation ; Feasibility Studies ; Aged ; *Disability Evaluation ; Adult ; Surveys and Questionnaires ; },
abstract = {BACKGROUND: The Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is a standard tool for evaluating functional decline in patients with ALS. Despite its clinical value, administration by healthcare professionals can be time-consuming and resource intensive.

OBJECTIVE: To assess the reliability and feasibility of a self-administration version of the ALSFRS-R as an alternative for use in clinical and research settings.

METHODS: The present was an observational, analytical, prospective, single-center study involving ALS patients followed at the Neurology Outpatient Clinic of the Hospital Universitário Onofre Lopes (HUOL). Three independent assessments of the ALSFRS-R were conducted: one self-administered version and two interviewer-administered versions performed by different researchers during face-to-face consultations. Interrater reliability was assessed using intraclass correlation coefficients (ICCs), and agreement among the three versions was analyzed using Bland-Altman plots.

RESULTS: A total of 43 participants were included in the study, with a mean age of 57 ± 11.67 years. The ICCs indicated high reliability for both the total ALSFRS-R score and its functional domains. Linear regression analyses demonstrated strong agreement between the two researchers (R[2] = 0.98, p < 0.001), as well as between each researcher and the self-administered version (R[2] = 0.90 and 0.88, respectively). Bland-Altman analyses showed minimal bias and acceptable limits of agreement across all comparisons.

CONCLUSION: The self-administered version of the ALSFRS-R demonstrated high reliability and strong agreement with the researcher-administered versions, supporting its potential use for remote monitoring of ALS patients. Nonetheless, it should not replace professional assessments in clinical trial settings. Further research is warranted to validate its applicability in broader clinical contexts and diverse patient populations.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology
Reproducibility of Results
Prospective Studies
Female
Middle Aged
Male
Severity of Illness Index
Observer Variation
Feasibility Studies
Aged
*Disability Evaluation
Adult
Surveys and Questionnaires

@article {pmid42711836,
year = {2026},
author = {Nischal, SA and Kale, KM and Tourigny, K and Abuelem, M and Greene, G and Walsh, R and Molnár, Z},
title = {Neuroanatomy education through the years: Revisiting the teaching slides used by Sir Wilfrid Edward Le Gros Clark.},
journal = {Journal of anatomy},
volume = {},
number = {},
pages = {},
doi = {10.1111/joa.70235},
pmid = {42711836},
issn = {1469-7580},
support = {//Wellcome Trust History of Neuroscience Grant/ ; //Federation of European Neuroscience Societies History of Science Grants/ ; MR/W029073/1/MRC_/Medical Research Council/United Kingdom ; BB/X008711/1//BBSRC/ ; },
abstract = {Sir Wilfrid Edward Le Gros Clark (1895-1971) was a pioneering British anatomist, physician, and evolutionary biologist whose legacy spans the foundational development of twentieth century neuroanatomy, primate biology, and medical education. From his formative experiences as a young medical officer in the First World War to his later academic ascendancy at the University of Oxford, Le Gros Clark exemplified a rare fusion of clinical insight, anatomical precision, and philosophical curiosity. His tenure in Borneo, where he studied primates in their natural habitats, enriched his evolutionary perspective, while his later role in debunking the Piltdown Man fraud cemented his place as a steadfast defender of scientific integrity. At Oxford, Le Gros Clark assembled a singular collection of neuroanatomical teaching specimens, many of which remain preserved today within the Department of Physiology, Anatomy & Genetics, University of Oxford. Through detailed analysis of selected slides, including cases of tabes dorsalis, disseminated sclerosis, amyotrophic lateral sclerosis, syringomyelia, and the pineal gland's nervus conarii, we reflect on how Le Gros Clark's anatomical interpretations anticipated many of the concepts central to contemporary neuroscience, and on how his legacy has influenced generations of students and scientists. What emerges from these materials is that Le Gros Clark taught students not simply to memorize, but to observe, interpret, and understand the functional significance of anatomical structures in health and disease.},
}

@article {pmid42712067,
year = {2026},
author = {Baeza Robba, MJ and De Oliveira, G and Oropeza, T and Iriarte, E and Cianelli, R and Kim, K and De Santis, JP},
title = {"Support us, so we can rise": A qualitative exploration of Latinas' expectations of healthcare providers after intimate partner violence.},
journal = {Women's health (London, England)},
volume = {22},
number = {},
pages = {17455057261478478},
pmid = {42712067},
issn = {1745-5065},
mesh = {Humans ; Female ; *Hispanic or Latino/psychology ; *Intimate Partner Violence/psychology/ethnology ; Qualitative Research ; Adult ; *Survivors/psychology ; *Health Personnel/psychology ; *Help-Seeking Behavior ; *Patient Acceptance of Health Care/psychology ; Middle Aged ; Social Support ; Surveys and Questionnaires ; },
abstract = {BackgroundDue to multilevel factors, it is estimated that fewer than half of Latinas in the U.S who experience Intimate Partner Violence (IPV) access the resources they need. However, among those who do seek help, approximately 35% turn to a clinic or health center. This positions front-line healthcare providers (HCPs) as key actors in mitigating barriers to care. Delivering survivor-centered care, however, requires a nuanced understanding of Latina survivors' expectations of HCPs, grounded in their lived experiences and the structural contexts that shape their lives.ObjectivesThis study aimed to explore Latina survivors' expectations of healthcare providers during IPV disclosure and help-seeking.DesignA qualitative descriptive study guided by Liang et al.'s help-seeking theory.MethodsTwenty-five Latina IPV survivors living in South Florida were purposively recruited. Data collection included socio-demographic questionnaires and in-depth interviews (23 in Spanish, 2 in English/mixed). Interviews were transcribed and analyzed thematically in English by bilingual researchers. This study adheres to the SRQR Checklist.ResultsParticipants shared five key themes under the overarching concept "Support us, so we can rise", including 1) direct assessment, "If you ask us, we are going to tell"; 2) non-judgmental listening, "Create a supportive space"; 3) proactive referral and follow-up; 4) tailored support systems and social services; 5) delivery of educational interventions. Culturally responsive, empowering, and sustained provider engagement were seen as essential to fostering disclosure, resilience, and recovery.ConclusionFuture research should prioritize healthcare provider-led interventions and educational strategies that foster trust, safety, and empowerment while also facilitating a sustained help-seeking process. This includes proactive referrals and a thoughtful balance between follow-up care and respect for the survivor's autonomy. Incorporating a culturally specific perspective is critical to addressing the evolving needs of this population and advancing equity in care delivery.},
}

Humans
Female
*Hispanic or Latino/psychology
*Intimate Partner Violence/psychology/ethnology
Qualitative Research
Adult
*Survivors/psychology
*Health Personnel/psychology
*Help-Seeking Behavior
*Patient Acceptance of Health Care/psychology
Middle Aged
Social Support
Surveys and Questionnaires

@article {pmid42712181,
year = {2026},
author = {Mohajerin, B and Howard, R and Pincus, AL},
title = {A Response to Dimaggio et al.'s Commentary on Mohajerin et al. (2026).},
journal = {Clinical psychology & psychotherapy},
volume = {33},
number = {5},
pages = {e70332},
doi = {10.1002/cpp.70332},
pmid = {42712181},
issn = {1099-0879},
mesh = {Humans ; *Psychotherapy/methods ; Randomized Controlled Trials as Topic ; },
abstract = {Our randomized controlled trial comparing Unified Protocol (UP) and Schema-Focused Therapy (SFT) for grandiose and vulnerable presentations of narcissism has recently been critiqued in a commentary by Dimaggio et al. (2026). These authors raised concerns regarding the study's recruitment and subgroup classification, gender distribution, treatment response patterns, absence of dropouts, randomization, screening and recruitment procedures, trial registration, outcome assessment, supervision and treatment fidelity, treatment dose and duration, and disclosure of the NPD diagnosis. In this response, we clarify these methodological and procedural issues and provide additional information that was not fully described in the original article. We maintain that while both treatments were effective in ameliorating symptoms of narcissism, SFT was more effective in treating grandiose features, while UP was more effective in treating vulnerable features. Trial Registration: Iranian Registry of Clinical Trials identifier: IRCT20231106059970N3.},
}

Humans
*Psychotherapy/methods
Randomized Controlled Trials as Topic

@article {pmid42701950,
year = {2026},
author = {Morgillo, F and Digennaro, V and Panciera, A and Benvenuti, L and Carbone, N and Ferri, R and Zielli, SO and Faldini, C},
title = {Torsional deformities and anterior knee pain: a systematic review and clinical approach to miserable malalignment syndrome.},
journal = {Musculoskeletal surgery},
volume = {},
number = {},
pages = {},
pmid = {42701950},
issn = {2035-5114},
abstract = {Despite advancements in understanding and treating anterior knee pain linked to lower limb torsional deformities, a definitive consensus on diagnostic criteria, clinical indications, and therapeutic strategies for "miserable malalignment syndrome" remains elusive. This systematic review synthesizes current research to unify understanding of this complex condition. Findings highlight varied definitions and surgical approaches, underscoring standardization challenges. This systematic review aimed to synthesize current research to provide a more unified understanding of this complex condition. While studies report favorable anatomical correction and symptomatic relief, inconsistent clinical outcome scores and limited long-term follow-up hinder robust comparisons. Conservative measures are often ineffective due to underlying mechanical imbalance; surgical interventions, primarily derotational osteotomies of the femur and/or tibia, offer the most direct anatomical correction. However, optimal level, extent, and timing of these osteotomies-whether single or double level, staged or simultaneous-are debated. Liße et al.'s proposed diagnostic criteria offer a valuable step towards standardized identification of true miserable malalignment syndrome. Future research, particularly robust multi-center studies with standardized outcome measures, is critically needed to establish clearer, evidence-based guidelines, ultimately improving patient care and long-term outcomes for this challenging condition.},
}

@article {pmid42702895,
year = {2026},
author = {Uysal, SP and Dudley, KA and Sullivan, S and Brizzi, KT and Burke, KM and Hall, S and Pease, K and Goldstein, JN and Berry, JD and Ho, DT},
title = {Emergencies in Amyotrophic Lateral Sclerosis.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70398},
pmid = {42702895},
issn = {1097-4598},
abstract = {Emergencies are frequent in people living with amyotrophic lateral sclerosis (pALS), especially as the disease progresses, and can necessitate urgent evaluation and intervention. Progressive weakness in ALS inevitably increases fall risk, making discussion of fall prevention strategies integral to caring for pALS. Thromboembolic events and respiratory failure may present insidiously in ALS, requiring a high index of clinical suspicion, and management strategies differ from those for individuals without ALS. Bulbar impairment in ALS can give rise to aspiration, laryngospasm, and malnutrition leading to emergency department (ED) visits, underscoring the need for early consideration of gastrostomy tube placement. PALS face an increased risk of serious infections, making vigilant monitoring for any acute change essential. Tracheostomy and gastrostomy, although life-sustaining measures in ALS, may require ED care when complications arise. Proactive assessment and management are critical to prevent complications related to constipation, urinary dysfunction, cognitive and behavioral issues. Although serious adverse events from ALS treatments are very rare, potential immune-mediated neurologic complications are a consideration with tofersen use. Importantly, ALS emergencies should be viewed as potential indicators of disease progression, prompting timely serious illness discussions and reassessment of goals of care. Anticipation of potential complications and emergencies, combined with an understanding of appropriate evaluation and evidence-based management, constitute critical components of caring for pALS. Early recognition and proactive management of these emergencies can improve safety, reduce avoidable hospitalizations, and support goal-concordant, patient-centered care.},
}

@article {pmid42703939,
year = {2026},
author = {Sun, J and Vocht, J and Laroy, M and Stam, D and Lien, CH and Lamaire, N and D'Hondt, A and Peeters, R and Sunaert, S and Van Damme, P and Vandenbulcke, M and Van den Stock, J},
title = {Tracking Socio-emotional Brain Changes in Premanifest C9orf72 Repeat Expansion Carriers: A Structural and Functional 2-Year Longitudinal Magnetic Resonance Imaging Study.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78355},
pmid = {42703939},
issn = {1531-8249},
support = {//Foundation Thierry Latran/ ; //Alzheimer Research Foundation/ ; //Sequoia Fund for Research on Ageing and Mental Health/ ; 12AQF24N//FWO-Vlaanderen/ ; G0C0319N//FWO-Vlaanderen/ ; G030025N//FWO-Vlaanderen/ ; G019625N//FWO-Vlaanderen/ ; //KU Leuven,/ ; C24/18/095//KU Leuven Research Council/ ; C24/18/095; IDN/21/010//KU Leuven Research Council/ ; J1990130-233837//King Baudouin Foundation/ ; },
abstract = {OBJECTIVES: The C9orf72 hexanucleotide repeat expansion (C9RE) is the most frequent genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. Although structural alterations have been reported decades before symptom onset, the longitudinal evolution of socioemotional network dysfunction in premanifest C9RE carriers remains poorly understood.

METHODS: In this multimodal 2-year longitudinal study, we examined 21 premanifest C9RE carriers and 24 controls using structural magnetic resonance imaging (MRI), resting-state, and task-based functional MRI (fMRI), and multivariate pattern analysis. Participants completed facial emotion processing tasks during fMRI scanning, alongside behavioral assessments. We assessed regional activation, network connectivity, and voxel-wise structural integrity at baseline and follow up.

RESULTS: At baseline, premanifest C9RE carriers showed reduced emotion recognition efficiency, accompanied by bilateral thalamic atrophy, decreased activation in the anterior and posterior cingulate cortex, and increased activation in the posterior cerebellum, along with altered multivoxel activity patterns in the anterior cingulate and posterior cerebellum. Resting-state fMRI revealed decreased functional connectivity involving the thalamus, anterior, and posterior cingulate cortex. Longitudinal analyses indicated declining emotion-evoked responses in the posterior cingulate cortex and cerebellum, alongside further thalamic volume loss, whereas functional connectivity showed no significant change over time. Despite these progressive neural alterations, behavioral performance remained stable.

INTERPRETATION: Socioemotional circuit dysfunction emerges early in C9RE carriers and progresses over time, preceding overt clinical symptoms. Functional imaging, especially task-based fMRI combined with multivariate pattern analysis, captures early circuit-level alterations that may serve as sensitive biomarkers for premanifest neurodegeneration. ANN NEUROL 2026.},
}

@article {pmid42704422,
year = {2026},
author = {Demir, BS and Cicek, SO and Houran, MA and Azizoglu, ZB and Asan, M and Bas, H and Cetin, BS and Gumus, H and Erdem, S and Canatan, H and Unal, E and Hsieh, EW and Kısaarslan, AP and Eken, A},
title = {Clinical and immunological characterization of a child with a homozygous TBK1 kinase-domain truncation.},
journal = {Immunologic research},
volume = {74},
number = {1},
pages = {},
pmid = {42704422},
issn = {1559-0755},
support = {TSG-2023-10935 and TYG-2023-13110//Erciyes University Research Council (BAP Grants)/ ; },
mesh = {Humans ; *Protein Serine-Threonine Kinases/genetics/metabolism ; Homozygote ; *Arthritis, Juvenile/genetics/immunology/diagnosis ; *Encephalitis/genetics/immunology ; Cytokines/metabolism ; Mutation/genetics ; Phosphorylation ; Female ; Male ; Child ; },
abstract = {TBK1 is a serine-tyrosine kinase protein that transmits signals from pattern recognition receptors to the NF-κB pathway leading to production of Type 1 Interferons. Mutations in this protein have been associated with arthritis, vasculitis, herpes simplex encephalitis and amyotrophic lateral sclerosis. In the current study, we characterized the functional consequences of a TBK1-variant bearing a truncation in exon 4 and 5 in a patient with poly arthritis resembling juvenile idiopathic arthritis and necrotizing encephalitis. The truncation was associated with reduced TBK1 protein abundance and altered phosphorylation. The variant was associated with increased basal/and or Poly-I: C induced IL-6, TNFα, IL-1β and IL-18 and type 1 Interferon ex vivo. Our findings expand the phenotypic spectrum of TBK1 loss-of-function variants and may provide insight into the management of immune dysregulation in affected patients.},
}

Humans
*Protein Serine-Threonine Kinases/genetics/metabolism
Homozygote
*Arthritis, Juvenile/genetics/immunology/diagnosis
*Encephalitis/genetics/immunology
Cytokines/metabolism
Mutation/genetics
Phosphorylation
Female
Male
Child

@article {pmid42705614,
year = {2026},
author = {Fritsch, J and Wiesner, S and Guthmann, F and Richter, MF},
title = {[Pulmonale Hämorrhagie bei Frühgeborenen <1000 g (ELBW): Risikofaktoren und präventive Maßnahmen als Reaktion auf eine gestiegene Inzidenz].},
journal = {Klinische Padiatrie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2954-5687},
pmid = {42705614},
issn = {1439-3824},
}

@article {pmid42705992,
year = {2026},
author = {Nie, W and Jing, Z and Cheng, L and Li, LL and Bai, Y and Xu, F and Li, S and Lin, L and Dong, X and Yu, L and Cai, L and Pan, B and Han, H and Cheng, H and Wang, X},
title = {ROMO1 loss in cholinergic neurons induces mitochondrial ultrastructural damage and ALS-like neuromuscular degeneration.},
journal = {Science bulletin},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.scib.2026.08.063},
pmid = {42705992},
issn = {2095-9281},
}

@article {pmid42706741,
year = {2026},
author = {Grouls, A and Ubel, PA and Nguyen, M and Pathapati, N and Doerstling, S and Sloan, CE},
title = {Online Crowdfunding Campaigns for People Living With ALS Demonstrate Financial Burden and Unmet Needs.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70395},
pmid = {42706741},
issn = {1097-4598},
abstract = {INTRODUCTION/AIMS: People living with amyotrophic lateral sclerosis (ALS; pALS) have extensive care needs, from wheelchairs to feeding tubes to caregiving support. The financial impact of these needs on pALS and their caregivers (cALS) has not been fully explored. We aimed to explore the types of expenses for which pALS and cALS crowdfund, and the financial circumstances that lead them to resort to crowdfunding.

METHODS: We randomly selected 320 ALS-related crowdfunding campaigns posted on the GoFundMe platform from 2010-2020. We conducted a summative content analysis to categorize the expenses for which campaigns requested money and descriptions of financial burden.

RESULTS: We included 266 campaigns. Most campaigns were written by people who were not the pALS or cALS, such as children or coworkers (85.3%). Most campaigns fundraised for medication and treatment costs (21.4%), equipment (25.2%), accessibility needs for home (24.0%), and transportation (19.5%), and in-home caregiving services (18%). Multiple campaigns (22.9%) requested assistance with nonmedical expenses ranging from rent and utilities to personal travel and hobby goals. Many campaign writers (47.7%) described financial burden related to the pALS' diagnosis, including medical debt (4.5%) and job loss of the pALS (30.5%) and/or cALS (6.8%).

DISCUSSION: Our analysis of ALS-related crowdfunding campaigns highlights the breadth of medical and nonmedical care needs and quality of life goals for which people request additional financial support throughout the disease course. These findings provide important insights for ALS care teams into the expenses of pALS.},
}

@article {pmid42706758,
year = {2026},
author = {Zumbo, BD},
title = {Conditional Standard Error of Measurement as an Estimand of Individual Score Precision: Remarks on Pfadt et al. from an Operator-Theoretic Perspective.},
journal = {Psychometrika},
volume = {},
number = {},
pages = {1-7},
doi = {10.1017/psy.2026.10141},
pmid = {42706758},
issn = {1860-0980},
abstract = {This commentary supports Pfadt et al.'s (2026, Psychometrika, 2026, 1-35. https://doi.org/10.1017/psy.2026.10081) recommendation that individual score interpretation should rely on conditional standard errors of measurement rather than a single unconditional standard error. I argue, however, that this recommendation requires a sharper test-theoretic formulation. Conditional precision is not merely a computational refinement of the standard error of measurement; it is a different estimand, defined by the information structure relative to which score precision is interpreted. Using an operator-theoretic formulation of classical test theory, I treat the true score as a conditional expectation, the error score as a projection residual, and the standard error of measurement as the norm of that residual. From this perspective, conditional standard errors localize residual variation with respect to observed scores, score bands, persons, trait levels, or measurement contexts. This formulation clarifies why assumptions associated with particular estimation procedures should not be attributed to classical test theory itself, and why practices such as pooling sparse score groups change the estimand. The commentary concludes that responsible individual score interpretation requires identifying the relevant conditional-precision estimand before selecting an estimator or software procedure.},
}

@article {pmid42707250,
year = {2026},
author = {Unuakhalu, R and Purcell, A and Jindal, I and Wu, Y and Arnold, M and Dominick, KC and Shillington, A},
title = {The long road to diagnosis: recessive PMPCB deficiency hidden behind a dominant familial VCP defect.},
journal = {Molecular genetics and metabolism reports},
volume = {48},
number = {},
pages = {101350},
pmid = {42707250},
issn = {2214-4269},
abstract = {Multiple mitochondrial dysfunctions syndrome 6 (MMDS6), caused by biallelic likely pathogenic variants in PMPCB, is an extremely rare autosomal recessive childhood-onset neurodegenerative disorder, with only six reported cases to date, most resulting in early mortality. Pathogenic variants in VCP cause multisystem proteinopathy 1 (MSP1), an autosomal dominant adult-onset disorder encompassing inclusion body myopathy (IBM), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), typically presenting in mid-adulthood. We describe a 23-year-old female with two likely pathogenic variants presumed to be in trans in PMPCB and a co-occurring pathogenic VCP variant. She was misdiagnosed for over 20 years with early-onset VCP-related neurodegeneration due to a maternal family history of ALS. Her disease began at birth with microcephaly and progressed throughout childhood, including developmental regression, cerebellar and cerebral atrophy, optic atrophy, seizures, spasticity, dysarthria, and loss of ambulation. Initial genetic testing identified only the familial VCP variant. Updated genomic sequencing at age 23 revealed two likely pathogenic PMPCB variants, strong supporting a diagnosis of MMDS6. Her clinical features closely align with previously reported MMDS6 cases and are inconsistent with the typical adult-onset phenotype of VCP-associated disorders. While she shares overlapping features with VCP-related disease (limb-girdle weakness, spasticity, FTD), the timing and severity of her neurodevelopmental findings support MMDS6 as the primary diagnosis. Early mitochondrial dysfunction may predispose her to an accelerated or more severe future VCP-associated phenotype. This is the first report of combined likely pathogenic and pathogenic variants in PMPCB and VCP respectively, expanding the phenotypic spectrum of both disorders. The case underscores the necessity of periodic re-evaluation with advanced genetic testing, highlights important ethical and familial implications, and informs future diagnosis and management of patients with overlapping rare genetic conditions.},
}

@article {pmid42696637,
year = {2026},
author = {Guarino, AS and Wallace, J and Rohan, AM and Kroelinger, CD},
title = {Implementation Outcomes of 36 CDC-funded Statewide Perinatal Quality Collaboratives, 2023-2024.},
journal = {Journal of public health management and practice : JPHMP},
volume = {},
number = {},
pages = {},
pmid = {42696637},
issn = {1550-5022},
abstract = {CONTEXT: Maternal and infant morbidity and mortality remain high in the United States, and improving quality of clinical care is one strategy to improve outcomes. Perinatal Quality Collaboratives (PQCs) are statewide networks of teams working to improve maternal and infant health by supporting quality improvement (QI) initiatives. PQCs execute deliberate activities to support implementation of QI; implementation outcomes can be used to measure the execution of these activities.

OBJECTIVE: To examine PQC implementation outcomes to better understand implementation achievements.

DESIGN: We adapted Proctor et al.'s implementation outcomes framework to measure implementation outcomes using standardized annual PQC performance measures.

SETTING: US, October 2023 through September 2024.

PARTICIPANTS: Thirty-six Centers for Disease Control and Prevention-supported PQCs.

INTERVENTION: Developed implementation outcome definitions relevant for the standard PQC programmatic model and mapped outcomes to performance measures, assessing the execution of PQC activities. Descriptive PQC-reported data were summarized as counts and percentages.

MAIN OUTCOME MEASURE: Implementation outcomes (adoption, appropriateness, feasibility, fidelity, penetration, and sustainability).

RESULTS: PQCs reported moderate adoption, with an average of 67% of births in a state occurring in birthing hospitals that participated in PQC QI initiatives. PQCs also reported moderate appropriateness; among birthing hospitals serving populations most likely to experience adverse health outcomes, 67% participated with their PQC. An average of 85% of participating birthing hospitals submitted data to their PQC as required for QI initiatives (feasibility), and PQCs averaged 75% or higher on all fidelity measures (trainings, webinars, learning products, and convenings). For penetration, fewer than 50% of PQCs engaged in activities with community-based organizations, although 56% engaged with community members and 83% with patients/families. Most (78%) participating hospitals made lasting system changes (sustainability).

CONCLUSIONS: Findings suggest that PQCs implement QI initiatives with high feasibility, fidelity, and sustainability, moderate adoption and appropriateness, and varied penetration. Understanding PQC implementation outcomes can highlight areas of success and identify areas for PQC improvement.},
}

@article {pmid42697152,
year = {2026},
author = {Fernández-Beltrán, LC and García-Toledo, I and Javaloyes García, K and Jiménez-Coca, I and Jiménez-Rodríguez, J and Fernández-Bernal, A and Godoy-Corchuelo, JM and Portero-Otín, M and Corrochano, S},
title = {Pharmacological modulation with the LXR agonist T0901317 attenuates motor pathology in the SOD1[G93A] mouse model of ALS.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {5},
pages = {e01062},
doi = {10.1016/j.neurot.2026.e01062},
pmid = {42697152},
issn = {1878-7479},
abstract = {Dysregulation of cholesterol metabolism and neuroinflammation are critical drivers of Amyotrophic Lateral Sclerosis (ALS) pathology. Liver X receptors (LXRs) are master regulators of cholesterol homeostasis and immune responses. Here, we evaluated the therapeutic potential of chronic pharmacological modulation using the potent synthetic agonist T0901317 (T0) in the hSOD1[G93A] mouse model. To assess both long-term functional outcomes and the underlying molecular mechanisms, T0 was administered via two distinct experimental designs. In a longitudinal cohort treated from postnatal day 60 (P60) until the humane endpoint, T0-treated SOD1G93A mice exhibited delayed body weight loss and sustained improvements in neuromuscular strength and motor coordination. Critically, this continuous treatment preserved functional motor unit connectivity, delayed overall clinical progression, and significantly extended median lifespan. While protective in both sexes, the survival benefit was slightly more pronounced in females. Molecular characterization revealed that the early systemic T0 administration successfully engaged canonical LXR targets in the spinal cord, driving a significant transcriptional upregulation of cholesterol efflux pathways and suppressing pro-inflammatory signaling cascades. This response induced a lipid partitioning, evidenced by a significant accumulation of cholesterol esters within the central nervous system, potentially mitigating lipotoxicity. Taken together, these findings demonstrate that T0901317 treatment exerts a significant beneficial effect, highlighting the pharmacological modulation of these lipid and inflammatory networks as a promising therapeutic strategy for ALS.},
}

@article {pmid42697153,
year = {2026},
author = {Lo'pez-Blanch, R and Salvador-Palmer, R and Oriol-Caballo, M and Moreno-Murciano, P and Dellinger, RW and Estrela, JM and Obrador, E},
title = {Corrigendum to 'Nicotinamide riboside, pterostilbene and ibudilast protect motor neurons and extend survival in ALS mice'.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {5},
pages = {e01070},
doi = {10.1016/j.neurot.2026.e01070},
pmid = {42697153},
issn = {1878-7479},
}

@article {pmid42697379,
year = {2026},
author = {Mohammad, SI and Vasudevan, A and Oriquat, G and Gajjar, TB and Hanumanthayya, M and Shukla, SK and Tailor, NK and Baig, MR and Fadaam, O and Abdul, AS},
title = {Extracellular Vesicles in Neurodegenerative Diseases: A New Frontier in Diagnosis and Therapy.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116455},
doi = {10.1016/j.bbr.2026.116455},
pmid = {42697379},
issn = {1872-7549},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are among the progressive disorders of the nervous system that are characterized by the gradual destruction of neurons, the accumulation of misfolded proteins, and the limited effective therapeutic options. In recent years, numerous lines of evidence have emphasized the important role of extracellular vesicles (EVs) in the formation and progression of these diseases. These vesicles are membrane-bound nanoscale structures that are secreted by almost all cell types and play a role in cell-cell communication through the transfer of molecules such as proteins, lipids, and nucleic acids. In neurodegenerative disorders, EVs can facilitate the transport and dissemination of disease-related proteins, including amyloid-β, tau, α-synuclein, mutant huntingtin, SOD1, and TDP-43, thus contributing to the spread of pathological processes in different parts of the nervous system. On the other hand, the ability of these vesicles to cross the blood-brain barrier and reflect molecular changes occurring in the central nervous system makes them valuable candidates for the development of minimally invasive biomarkers. This review reviews the biogenesis, classification, isolation methods, and molecular content of EVs, and analyzes their role in the pathogenesis, diagnosis, and treatment of the most important neurodegenerative diseases. Also, the importance of EV-associated proteins, RNAs, and lipids as emerging diagnostic biomarkers, as well as the therapeutic potential of natural and engineered vesicles as drug delivery systems and regulators of neuroinflammation and neurodegenerative processes, is discussed.},
}

@article {pmid42697520,
year = {2026},
author = {Sharma, A and Jatana, N},
title = {Microbiota-derived metabolite-GPCR signalling in neurodegeneration.},
journal = {Neuroscience},
volume = {615},
number = {},
pages = {312-333},
doi = {10.1016/j.neuroscience.2026.09.001},
pmid = {42697520},
issn = {1873-7544},
abstract = {The gut microbiome acts as a primary regulator of host homeostasis, influencing the entire body through bidirectional communication along the gut-brain axis (GBA). Dysbiosis, which is defined as a state of microbial imbalance involving alterations in community composition and function, can disrupt the synthesis of important microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), bile acids and neurotransmitter precursors. This can lead to impaired essential host signalling pathways. There is growing evidence that metabolic alterations associated with dysbiosis contribute to the onset and progression of neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). In this context, G protein-coupled receptors (GPCRs) act as essential molecular transducers that link microbial metabolites to intracellular signalling networks. Aberrant GPCR activation, driven by altered metabolite profiles, modulates key downstream pathways including cAMP, MAPK, PI3K/Akt, NF-κB and Ca2 + signalling. This promotes neuroinflammation, oxidative stress, mitochondrial dysfunction and pathological protein aggregation - hallmark processes underlying neurodegeneration. By identifying convergent and disease-specific signalling pathways, the review highlights mechanistic nodes of therapeutic relevance and discusses GPCR-centric emerging and other microbiome-targeted strategies aimed at restoring metabolic and signalling homeostasis in neurodegenerative disorders.},
}

@article {pmid42697669,
year = {2026},
author = {Zhang, P and Liu, Y and Tian, X and Wang, H and Liu, R and Wang, G and Wu, Y},
title = {Overexpression of the cytochrome P450 gene CYP99A3 likely mediates mesosulfuron-methyl resistance in Lolium multiflorum from China.},
journal = {Pesticide biochemistry and physiology},
volume = {223},
number = {},
pages = {107300},
doi = {10.1016/j.pestbp.2026.107300},
pmid = {42697669},
issn = {1095-9939},
mesh = {*Lolium/genetics/drug effects/enzymology/metabolism ; *Sulfonylurea Compounds/pharmacology ; *Cytochrome P-450 Enzyme System/genetics/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; China ; *Plant Proteins/genetics/metabolism ; Acetolactate Synthase/genetics ; },
abstract = {Lolium multiflorum L. (Italian ryegrass) is a noxious weed causing severe yield losses in wheat production globally, and its rapid expansion across major wheat-producing regions in China poses an escalating agricultural threat. Recently, field-recommended doses of the acetolactate synthase (ALS) inhibitor mesosulfuron-methyl have failed to effectively control certain L. multiflorum populations. This study evaluated the resistance level and elucidated the underlying mechanisms in a suspected mesosulfuron-methyl-resistant L. multiflorum population (ZMHF-R) collected from China. Whole-plant bioassays demonstrated that the ZMHF-R population exhibited a high level of resistance (43.34-fold) to mesosulfuron-methyl. Replicate sequencing of the ALS gene revealed no known target-site mutations, thereby excluding target-site mutation-mediated resistance. Pretreatment with the cytochrome P450 inhibitors piperonyl butoxide (PBO) and malathion significantly synergized mesosulfuron-methyl toxicity in ZMHF-R, implicating P450 monooxygenases in the resistance phenotype. Comparative RNA-seq and RT-qPCR validation identified the constitutive overexpression of a specific P450 gene, LmCYP99A3, in the R population. Molecular docking simulations predicted favorable binding and potential metabolic activity of the LmCYP99A3 protein toward mesosulfuron-methyl. Furthermore, transgenic rice calli heterologously overexpressing LmCYP99A3 exhibited a distinct resistance phenotype against the herbicide. Taken together, this study functionally validates that LmCYP99A3 mediates mesosulfuron-methyl resistance in L. multiflorum, expanding our understanding of the metabolic basis of NTSR in this global weed species.},
}

*Lolium/genetics/drug effects/enzymology/metabolism
*Sulfonylurea Compounds/pharmacology
*Cytochrome P-450 Enzyme System/genetics/metabolism
*Herbicide Resistance/genetics
*Herbicides/pharmacology
China
*Plant Proteins/genetics/metabolism
Acetolactate Synthase/genetics

@article {pmid42698124,
year = {2026},
author = {Streicher, NS},
title = {Serum Neurofilament Light Chain and GFAP in Amyotrophic Lateral Sclerosis on a Commercial ECLIA Platform.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70397},
pmid = {42698124},
issn = {1097-4598},
abstract = {INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS), SIMOA-based studies show that baseline serum neurofilament light chain (NfL) predicts the revised ALS Functional Rating Scale (ALSFRS-R) decline rate and survival. The Roche Elecsys electrochemiluminescence immunoassay (ECLIA) reports values approximately six-fold lower; cross-platform comparison confirms comparable performance, but serial clinical-practice data remain limited. We assessed whether ECLIA NfL correlates with the ALSFRS-R decline rate under the sampling conditions of clinical practice, and whether GFAP or S-100B adds prognostic or disease-specific information.

METHODS: We retrospectively analyzed 58 patients with medical-record-confirmed ALS at an academic center (2022-2026). Serum NfL, GFAP, and S-100B were measured on the Roche Elecsys ECLIA. The NfL-ALSFRS-R correlation was assessed within matching windows; serial NfL was examined in patients with repeat draws.

RESULTS: First-per-patient NfL median was 7.06 pg/mL (IQR 4.06-17.30). NfL correlated strongly with the ALSFRS-R decline rate (Spearman r = 0.704, n = 31; r = 0.809 within 90 days, n = 17; both p < 0.0001). Fast progressors had 3.7-fold higher mean NfL than slow progressors (17.10 vs. 4.64 pg/mL). NfL showed no correlation with King's clinical stage (r = 0.00). GFAP correlated with age but not with progression rate or disease duration; S-100B showed no association with progression.

DISCUSSION: Serum NfL on a commercial ECLIA platform retained its strong correlation with progression rate despite unstructured sampling, replicating SIMOA-based findings at platform-specific values. NfL tracked the rate of decline rather than the accumulated disease state; GFAP and S-100B added no prognostic or disease-specific information.},
}

@article {pmid42698179,
year = {2026},
author = {Dhar, A and Sharar, AD and Papisetty, S and Bydon, M and Moinuddin, FM},
title = {The Therapeutic Potential of Purmorphamine Across Disease Models.},
journal = {Journal of cellular and molecular medicine},
volume = {30},
number = {17},
pages = {e71349},
pmid = {42698179},
issn = {1582-4934},
mesh = {Humans ; Animals ; *Purines/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Hedgehog Proteins/metabolism ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/therapeutic use ; Morpholines ; },
abstract = {Purmorphamine (PUR) is a trisubstituted purine compound that selectively activates Smoothened receptor, thereby initiating Sonic Hedgehog (Shh) signalling-a pathway critical for embryonic patterning, neuronal specification and tissue regeneration across multiple organ systems. Dysregulation of Shh signalling has been implicated in degenerative diseases yet therapeutic interventions targeting this pathway remain limited. PUR demonstrates broad therapeutic efficacy across diverse preclinical disease models by activating both canonical GLI-mediated transcription and non-canonical Shh pathways, resulting in neuroprotection, reduced neuroinflammation, enhanced blood-brain barrier integrity and tissue regeneration. In contrast to previous assumptions that Shh pathway activation requires endogenous ligand binding, PUR bypasses this requirement through direct Smoothened engagement, offering a pharmacologically tractable approach to pathway modulation. Preclinical studies demonstrate that PUR enhances motor neuron survival in amyotrophic lateral sclerosis models, protects dopaminergic neurons in Parkinson's disease, reverses behavioural abnormalities in autism spectrum disorder, promotes neurovascular repair following stroke, restores myelin integrity in multiple sclerosis models and drives osteogenic differentiation in bone tissue engineering applications. Beyond its established Smoothened agonist activity, recent evidence identifies PUR as a positive allosteric modulator of the secretin receptor, expanding its therapeutic scope to include cardiovascular applications such as hypertension management through enhanced nitric oxide bioavailability.},
}

Humans
Animals
*Purines/therapeutic use/pharmacology
Signal Transduction/drug effects
Hedgehog Proteins/metabolism
Disease Models, Animal
Neuroprotective Agents/pharmacology/therapeutic use
Morpholines

@article {pmid42698276,
year = {2026},
author = {Strong, MJ and Donison, N and Al-Chalabi, A and Boeve, B and Finger, EC and Holstege, H and Huey, ED and Lee, EB and Marzi, SJ and McHutchison, C and McMillan, CT and Otto, M and Petrucelli, L and Prudencio, M and Simuni, T and Tartaglia, MC and Turner, MR and Van Damme, P and Wolk, DA},
title = {Progress towards a biotypic biomarker profile for amyotrophic lateral sclerosis-frontotemporal spectrum disorders.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag297},
pmid = {42698276},
issn = {1460-2156},
abstract = {Determining the optimal timing of disease-modifying therapies for neurodegenerative disorders will necessitate identification of when the underlying pathobiological process becomes active, well in advance of the point at which clinical manifestions appear. Phenoconversion, the emergence of clinically manifest syndomes, may be preceded by years to decades of silent pathobiological activity that can only be mapped by an array of biomarkers. ALS and FTD, traditionally identified as distinct clinical syndromes, are increasingly recognized to exist along a spectrum of clinical syndromes with shared genetic risk and shared underlying pathology. This clinicopathological spectrum is underpinned by cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) as the common neuropathological hallmark. In contrast, the majority of neuropathologically-defined frontotemporal lobar degeneration (FTLD) is associated with alterations in either TDP-43 metabolism (FTLD-TDP) or of the microtubule associated protein tau (FTLD-tau), with a smaller percentage associated with either autosomal dominant genetic mutations or impairments in the ubiquitin proteasome system. As the field of neurodegenerative disorders increasingly shifts towards the frameworks of a pathobiological definition of disease, there is a growing imperative to develop biomarkers that reflect the varied pathobiologies that underly these disorders, and to determine the sensitivity of such biomarkers to detect the presence of these pathobiologies before phenoconversion. To that end, an international workshop was convened in London, Canada in 2025 to review the evidence for existing or evolving biomarkers suitable for (1) the detection of either ALS or FTD pathobiology prior to phenoconversion and/or (2) predict phenoconversion in at risk individuals. Such biomarkers might be conceptualized as "biotypic biomarkers", capturing their ability to describe an underlying pathophysiology whilst being agnostic to the emergent clinical manifestations. Whereas no single biotypic marker is yet able to predict the emergence of ALS, FTD or their intersection, a multimodal approach to developing a biotypic biomarker profile holds promise for the detection of relevant pathobiological processes. The strength of such an approach would be augmented by also addressing issues of resiliency/susceptibility both in terms of genetic risk susceptibility profiles and developing sensitive biomarkers of genomic and cellular aging. By including such nontraditional markers of disease, a more robust picture of not only the degenerative process but also of those factors that might potentially mitigate or drive a heightened probability of disease can be derived.},
}