@article {pmid42849148,
year = {2026},
author = {Freischmidt, A and Weishaupt, JH},
title = {Update on somatic mutations in major neurodegenerative diseases: mutational signatures in neurons and mosaicism.},
journal = {Current opinion in genetics & development},
volume = {101},
number = {},
pages = {102549},
doi = {10.1016/j.gde.2026.102549},
pmid = {42849148},
issn = {1879-0380},
abstract = {Somatic mutations in major neurodegenerative diseases are poorly understood, but research over the past 2 years provides valuable insights. Single-cell whole-genome sequencing of vulnerable neurons in Alzheimer's disease and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) revealed excess accumulation of single-nucleotide variant signatures and two-bp deletions independent of pathogenic protein aggregation. Increased oxidative DNA damage and possibly impaired DNA damage repair pathways may explain more pronounced signatures in patients. Ultra-deep sequencing of disease-associated genes in relevant tissues in ALS/FTD identified a subset of sporadic patients carrying mosaic variants that cause disease when present in the germline, but the pathogenicity of such mosaic variants at low allele frequencies is unclear. Research on somatic variants in Parkinson's disease remains underrepresented in the literature.},
}

@article {pmid42849176,
year = {2026},
author = {Zucchi, E and Niccolai, E and De Maio, F and Cuoghi Costantini, R and Quaranta, G and Guarnaccia, A and Bibbò, S and Martinelli, I and Gianferrari, G and Simonini, C and Nannini, G and Lulli, M and Baldi, S and Bartolucci, G and Vicini, R and Capasso, M and Bisogni, G and Conte, A and Brunori, P and Cammarota, G and Paganoni, S and D'Amico, R and Amedei, A and Masucci, L and Mandrioli, J and , },
title = {Immune effects of faecal microbiota transplantation in amyotrophic lateral sclerosis: a pilot multicentre, randomised, masked, sham-controlled, proof-of concept trial.},
journal = {EBioMedicine},
volume = {133},
number = {},
pages = {106509},
doi = {10.1016/j.ebiom.2026.106509},
pmid = {42849176},
issn = {2352-3964},
abstract = {BACKGROUND: The gut microbiota modulates peripheral immunity, which is altered in amyotrophic lateral sclerosis (ALS). Faecal microbiota transplantation (FMT) may exert immunological effects, but its impact in ALS remains unclear.

METHODS: FETR-ALS was a multicentre, randomised, masked, sham-controlled proof-of-concept trial conducted at four Italian ALS centres. Adults with ALS of 18 months duration or less and forced vital capacity of at least 70% predicted were randomly assigned (2:1) to receive FMT or a sham procedure (SP). The intervention consisted of two nasojejunal administrations of screened-donor faecal suspension at baseline and month 6, without antibiotic preconditioning. The primary endpoint was change in circulating Tregs among CD4[+] T cells at 6 months. Secondary endpoints included safety, ALS Functional Rating Scale-Revised slope, respiratory and nutritional measures, survival, and exploratory biomarker profiles. Analyses followed the intention-to-treat principle.

CLINICALTRIALS: gov identifier: NCT03766321.

FINDINGS: Between 2020 and 2024, 43 individuals were screened and 42 were enrolled and randomly assigned to FMT (n = 28; mean age 56.1 years [SD 8.2]; 14 [50%] male) or SP (n = 14; 59.6 years [9.1]; eight [57%] male). Overall, 29 participants completed the second procedure and 6-month follow-up, and Treg measurements were available for 28. The primary outcome was not met: at 6 months, 8/18 (44%) participant receiving FMT versus 2/10 (20%) receiving SP achieved a ≥20% increase in circulating Tregs (odds ratio [OR] 3.20, 95% CI 0.59-25.36; p = 0.21). Mean Treg increase was 2.36 percentage points higher with FMT (95% CI 0.19-4.55; p = 0.04). ALSFRS-R declined by -1.07 points/month in the SP group and -0.76 points/month in the FMT group, with a between-group difference in monthly decline of 0.31 points/month favouring FMT (95% CI 0.11-0.51; p = 0.002). Conversely, at month 6, the MRC score was lower in the FMT group than in the SP group (0.75 versus 0.89; mean difference -0.13, 95% CI -0.26 to 0.00; p = 0.042). FMT was associated with 32 adverse events (12.5% severe) versus 14 (28.6% severe) in SP, mostly gastrointestinal or infectious.

INTERPRETATION: In this exploratory trial, FMT was not associated with major safety concerns. Although the primary endpoint was not met, FMT was associated with a modest increase in circulating Tregs.

FUNDING: Italian Ministry of Health.},
}

@article {pmid42850388,
year = {2026},
author = {Kytöharju, M and Moilanen, JS and Martikainen, MH},
title = {Genetic testing and counselling of patients with monogenic amyotrophic lateral sclerosis in Northern Finland: a retrospective, single-centre study.},
journal = {European journal of human genetics : EJHG},
volume = {},
number = {},
pages = {},
pmid = {42850388},
issn = {1476-5438},
abstract = {Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease. Its aetiology is complex, but a subset is caused by single-gene pathogenic variants (monogenic ALS). The most common ALS-associated genes are SOD1 and C9orf72. We evaluated the implementation of genetic testing and associated genetic counselling for ALS at a Finnish tertiary-level university hospital. We used the electronic patient records of Oulu University Hospital (Oulu, Finland) to identify patients diagnosed with ALS between 2000 and 2023. Medical records were reviewed for neurological diagnosis and completion of genetic testing and counselling. We identified a total of 387 patients diagnosed with ALS. Of these, 225 patients (58%) were offered genetic testing, and 186 (83%) accepted. The offer for genetic counselling was given to 60 patients, of whom 46 (77%) attended counselling, whilst 13 did not. The proportion of patients who declined counselling did not differ between those with SOD1 and C9orf72 variants. Among the 143 patients tested for SOD1 variants, 36 (25%) were confirmed to harbor the ALS-associated p.Asp91Ala variant in SOD1; 31 were homozygous and 5 were heterozygous. In the 96 analyses of the C9orf72 hexanucleotide expansion, the diagnostic yield was 27 (28%) patients. A positive family history was more common in SOD1-ALS than in C9orf72-ALS (53% vs 33%). Nearly one fifth of patients declined testing and over one fifth of those with genetic ALS did not attend genetic counselling. The reasons for this warrant further investigation.},
}

@article {pmid42850529,
year = {2026},
author = {Reilich, P and Schöberl, F},
title = {[Amyotrophic lateral sclerosis: Specific considerations in palliative care].},
journal = {MMW Fortschritte der Medizin},
volume = {168},
number = {17},
pages = {51-54},
doi = {10.1007/s15006-026-6225-z},
pmid = {42850529},
issn = {1613-3560},
}

@article {pmid42850785,
year = {2026},
author = {Ozeloglu, İG and Akman Aydin, E},
title = {Gait-based neurodegenerative disease classification using multimodal temporal-spectral representations and a dual-branch CNN.},
journal = {Computer methods in biomechanics and biomedical engineering},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/10255842.2026.2736243},
pmid = {42850785},
issn = {1476-8259},
abstract = {Neurodegenerative diseases (NDDs) often cause gait impairments with overlapping motor symptoms, complicating multi-class discrimination. This study proposes a lightweight dual-branch convolutional neural network integrating recurrence plots and spectrogram representations of vertical ground reaction force signals to classify Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and healthy controls. Evaluated on the Gait in NDDs Dataset comprising 64 subjects, the proposed framework achieved 96.15% accuracy, outperforming recurrence-based (94.19%) and spectrogram-based (95.75%) single-branch models. The findings demonstrate that combining complementary temporal recurrence and spectral information improves discrimination of neurodegenerative gait patterns while maintaining low computational complexity.},
}

@article {pmid42851615,
year = {2026},
author = {Ohara, M and Ishigaki, S and Watts, JK and Yamada, K and Ikezu, T and Ikezu, S},
title = {Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {41},
pmid = {42851615},
issn = {3059-4944},
abstract = {Neurodegenerative disorders have diverse etiologies from monogenic mechanisms such as toxic gain-of-function mutation in subsets of amyotrophic lateral sclerosis (ALS) to multifactorial cascades exemplified by Alzheimer's disease (AD), which feature proteostasis failure, neuroinflammation, mitochondrial dysfunction, or age-associated cellular stress. While small molecules can modulate downstream pathways, nucleic acid therapeutics (NATs) target defined RNA sequences to directly reduce pathogenic gene expression, correct or shift isoform usage via splice modulation, and tune disease-relevant networks, positioning them as promising therapeutic modalities for neurodegenerative disorders. Recent clinical applications of NATs in the central nervous system (CNS) have made significant progress by optimized chemistries, improved tolerability, and established intrathecal administration routes, supporting sustained target engagement in relevant neural and glial compartments. This review summarizes three major NAT platforms-antisense oligonucleotides, small interfering RNAs, and aptamers-by highlighting their mechanisms of action, design principles to enhance their biodistribution, durability, and safety, and emerging novel delivery strategies for CNS targeting. We further discuss emerging translational opportunities across ALS, AD, polyglutamine disorders, prion diseases, and synucleinopathies by integrating disease biology with therapeutic rationale, and by summarizing regulatory approvals, ongoing clinical trials, and next generation NATs in preclinical development.},
}

@article {pmid42851749,
year = {2026},
author = {Li, M and Li, R and Deng, Z and Zhang, L and Lv, S and Shi, J and Ma, H and Guan, W and Zhang, H and Li, J and Teng, J},
title = {Traditional Chinese botanical medicines and plant-derived bioactive compounds in amyotrophic lateral sclerosis: mechanistic evidence, translational challenges, and therapeutic opportunities.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1918967},
pmid = {42851749},
issn = {1663-9812},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with limited therapeutic options, highlighting the need for multi-target interventions. Traditional Chinese botanical medicine (TCBM) interventions have attracted increasing attention as potential multi-target pharmacological candidates for ALS. In addition, a separate body of evidence derived from selected plant-derived bioactive compounds directly investigated in ALS-specific models provides complementary mechanistic insights into ALS-related pathways. However, the pharmacological mechanisms and translational potential of these two distinct evidence categories remain insufficiently summarized. This review systematically summarizes ALS-related pathological mechanisms and the molecular actions reported within these two distinct evidence categories, together with translational challenges and future research directions.

METHODS: A structured literature search was conducted in PubMed, Web of Science, and ScienceDirect up to May 2026. A total of 198 publications were retained, including 48 ALS-specific original intervention studies forming the core pharmacological evidence set.

RESULTS: ALS involves interconnected pathological processes, including neuroinflammation, oxidative stress, mitochondrial dysfunction, impaired proteostasis, excitotoxicity, and neuromuscular junction injury. Evidence across these two categories suggests modulation of multiple ALS-related pathological processes. Reported effects include regulation of inflammatory signaling, enhancement of Nrf2-mediated antioxidant responses, improvement of PGC-1α/MFN2-associated mitochondrial homeostasis, and promotion of protein clearance pathways.

CONCLUSION: Together, these distinct but complementary evidence categories highlight the potential for multi-target modulation of ALS-related pathology. However, current evidence remains predominantly preclinical, and clinical efficacy and translational feasibility require further validation.},
}

@article {pmid42851781,
year = {2026},
author = {Smeyers, J and Mordes, DA},
title = {Minding the gates: dual cell-autonomous and non-cell-autonomous mechanisms of TBK1 in ALS/FTD.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1941293},
pmid = {42851781},
issn = {1662-4548},
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comprise a neurodegenerative disease spectrum characterized by TDP-43 pathology and overlapping genetic risk factors. Loss-of-function variants in TBK1 (TANK-binding kinase 1) represent one of the most common genetic causes of ALS/FTD, highlighting haploinsufficiency for TBK1 as a major contributor to disease pathogenesis. Emerging evidence from iPSC and mouse models suggests that reduced TBK1 activity disrupts interconnected autophagy, endo-lysosomal, and innate immune pathways through both cell-autonomous and non-cell-autonomous mechanisms. In this review, we discuss the multifaceted role of TBK1 as a master regulator of proteostasis and inflammatory pathways, highlight its critical role in maintaining microglial homeostasis, and explore how these convergent functions inform therapeutic strategies for ALS/FTD.},
}

@article {pmid42852066,
year = {2026},
author = {Duarte, ML and Iared, W and Oliveira, ABS and Dos Santos, LR and da Silva, MSP},
title = {Comparison between ultrasound and electromyography for detection of fasciculations in amyotrophic lateral sclerosis: an updated systematic review and meta-analysis.},
journal = {Radiologia brasileira},
volume = {59},
number = {},
pages = {e20260011},
pmid = {42852066},
issn = {0100-3984},
abstract = {Fasciculations are a key manifestation of lower motor neuron dysfunction in amyotrophic lateral sclerosis (ALS). Al-though electromyography is considered the gold-standard method for the detection of fasciculations, its sensitivity for that purpose depends on the muscle sampled and the examination time. Muscle ultrasound has emerged as a dynamic, noninvasive technique with high sensitivity for detecting spontaneous muscle activity. This updated system-atic review compares ultrasound and electromyography in terms of their performance for the detection of muscle fas-ciculations in ALS, with stratification by muscle group and observation time. A comprehensive search of the literature identified studies evaluating both techniques. Data were synthesized descriptively and, when possible, quantitatively. Ultrasound demonstrated higher or comparable detection rates across most muscle groups, particularly in muscles that are large or deep, such as the biceps brachii, tibialis anterior, and vastus lateralis. Longer ultrasound observation times, especially 60 s, were associated with substantially higher detection rates without a loss of specificity. Although electromyography is still essential for electrophysiological characterization, ultrasound offers broader muscle cover-age, excellent reproducibility, and a noninvasive approach. These findings support muscle ultrasound as a valuable complementary tool for the detection and assessment of fasciculations in patients with motor neuron disease.},
}

@article {pmid42852085,
year = {2026},
author = {Öijerstedt, L and Lin, J and Singh, A and Yazdani, S and Saarinen, AM and Kläppe, U and Juto, A and Chamoun, S and Imrell, S and Fang, F and Lewandowski, SA and Ingre, C},
title = {Plasma cardiac troponin T as a marker of skeletal muscle involvement in amyotrophic lateral sclerosis.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag358},
pmid = {42852085},
issn = {2632-1297},
abstract = {Plasma cardiac troponin T (cTnT) is widely used as a marker of myocardial injury, yet recent studies suggest elevations in amyotrophic lateral sclerosis (ALS). Whether these elevations reflect disease-associated skeletal muscle remodelling remains unresolved. In this translational study, we analysed longitudinal plasma cTnT in a large clinical cohort comprising 496 patients with ALS and 84 with benign fasciculation syndrome (BFS). To investigate the biological origin of circulating cTnT, we examined publicly available skeletal muscle transcriptomes from patients with ALS (n = 28) and healthy controls (n = 17), and quantified troponin isoform expression in skeletal muscle from SOD1[G93A] mice and wild-type littermates. Plasma cTnT was significantly higher in ALS than in BFS (median 18 versus 6 ng/L, P = 3.6 × 10[-27]), with 57% of patients with ALS exceeding the cardiologic threshold of 15 ng/L. Diagnostic performance was high [area under the curve (AUC) 0.87], with excellent specificity (94%). Longitudinal modelling revealed a progressive increase in cTnT in ALS whereas levels remained stable in BFS. Skeletal muscle transcriptomics demonstrated robust upregulation of TNNT2, encoding cardiac troponin T, in ALS muscle, while other troponin isoforms were unchanged. In SOD1[G93A] mice, severely affected gastrocnemius muscle exhibited isoform-specific remodelling, including 20-fold upregulation of Tnnt2 and slow-fibre troponins, alongside downregulation of fast skeletal isoforms. Across clinical, transcriptomic, and experimental data, elevated plasma cTnT in ALS is best explained by disease-associated skeletal muscle remodelling rather than cardiomyocyte injury. Plasma cTnT emerges as a dynamic and accessible biomarker in ALS capturing muscle involvement. Prospective incorporation of cTnT into clinical trials and evaluation across broader neuromuscular differentials are warranted.},
}

@article {pmid42852552,
year = {2026},
author = {Choudhury, A and Prabha, S and Saeed, MU and Sulaimani, MN and Hassan, MI},
title = {Targeting protein misfolding and aggregation in neurodegenerative diseases: challenges for the identification and validation of targets for small molecules.},
journal = {Expert opinion on therapeutic targets},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728222.2026.2747518},
pmid = {42852552},
issn = {1744-7631},
abstract = {INTRODUCTION: Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and related proteinopathies are characterized by the misfolding, aggregation, and accumulation of specific proteins that disrupt neuronal homeostasis, leading to neuronal death. Despite major advances in structural biology and molecular neuroscience, identifying and validating druggable targets in neurodegenerative diseases remains challenging. Many involved proteins are intrinsically disordered, exhibit conformational heterogeneity, and form highly dynamic toxic species.

AREAS COVERED: This review summarizes the mechanisms of protein folding, misfolding, aggregation, and prion-like propagation in major neurodegenerative proteinopathies, including amyloid-beta and tau in Alzheimer's disease, alpha-synuclein in synucleinopathies, TDP-43 and FUS in ALS/FTLD, polyglutamine-expanded proteins, prion proteins, and rare hereditary amyloidosis. We also discuss major barriers to target identification and validation, including conformational flexibility, oligomer toxicity, blood-brain barrier penetration, and target engagement complexity. Finally, we highlight emerging strategies integrating structural biology, computational methods, and improved experimental models to discover small-molecule inhibitors for neurodegenerative diseases.

EXPERT OPINION: Effective therapeutic discovery will require moving beyond single-target models toward ensemble-based validation strategies. Integrating structural biology, advanced imaging, biomarkers, and computational approaches may improve the identification of druggable targets and support precision-medicine-based interventions for neurodegenerative diseases.},
}

@article {pmid42852819,
year = {2026},
author = {Sanjay, S and Chee, SP},
title = {Letter to the Editor: Comment on Yu X, et al's "Conjunctival Atypical Lymphoid Hyperplasia Associated with Cytomegalovirus Infection: A Case Report".},
journal = {Ocular immunology and inflammation},
volume = {},
number = {},
pages = {1-2},
doi = {10.1080/09273948.2026.2738015},
pmid = {42852819},
issn = {1744-5078},
abstract = {We comment on the report of bilateral conjunctival atypical lymphoid hyperplasia with cytomegalovirus (CMV) positivity by Yu et al. While the case is clinically valuable, we believe that the available findings do not establish active CMV infection or a causal relationship with lymphoid hyperplasia. We discuss the lack of tissue CMV PCR, discordant immunoglobulin heavy-chain clonality between eyes, diagnostic overlap with ocular adnexal lymphoma, and the need to consider lacrimal gland involvement and IgG4-related disease. We encourage cautious interpretation and longer clinicopathological follow-up.},
}

@article {pmid42853386,
year = {2026},
author = {Goebell, J and Bachhuber, F and Karmann, J and Klose, V and Kassubek, J and Müller, HP and Tumani, H and Ludolph, A},
title = {Neurofilaments support the differentiation of amyotrophic lateral sclerosis from degenerative cervical myelopathy.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42853386},
issn = {1435-1463},
abstract = {The differential diagnosis between degenerative cervical myelopathy (DCM) and early amyotrophic lateral sclerosis (ALS) is often clinically challenging; laboratory tests that support this distinction could be highly valuable. This study examined the concentrations of neurofilament light chain (NfL) and the phosphorylated neurofilament heavy chain (pNfH), in CSF and serum of carefully selected patients with DCM, spinal canal stenosis (SCS) and ALS, after exclusion of major neurological confounders. Patients were assigned to five groups according to MRI findings and ALS diagnosis. All patients were treated in the Department of Neurology, and were only included if a CSF or serum sample was available for retrospective measurement of neurofilaments. Z-scores were used for age-adjusted interpretation of NfL concentrations in CSF and serum. In addition, the albumin quotient (QAlb), as a marker for the integrity of the blood-CSF barrier, was investigated in the five patient groups. The levels of NfL and pNfH, including Z-score distributions, differed significantly. The groups with diagnosed ALS had elevated neurofilaments both in CSF and Serum. Comparison of neurofilament concentrations between patients with isolated spinal canal stenosis and patients with cervical myelopathy revealed no significant difference. The QAlb showed no clear correlation with elevated neurofilaments and provided limited value for differential diagnosis. In summary, we showed that NfL and pNfH in CSF and serum support the differential diagnosis of cervical SCS with and without myelopathy from ALS in carefully selected cohorts. However, since neurofilaments are not specific, they should be used in context with clinical assessment and imaging for individual diagnostic and treatment decisions.},
}

@article {pmid42853422,
year = {2026},
author = {Feole, M and Devoto, VMP and Dragišić, N and Čarna, M and Klosterman, K and Limbaek-Stokin, C and Forte, G and Moya, KL and Smith, RA and Svendsen, CN and Stokin, GB},
title = {Multiple motor proteins regulate TDP-43 anterograde axonal transport.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42853422},
issn = {1432-0533},
support = {LX22NPO5107//The European Union: Next Generation EU/ ; LM202305//The Ministry of Education, Youth, and Sports Czech Republic-EATRIS CZ/ ; },
mesh = {Humans ; *Axonal Transport/physiology ; *DNA-Binding Proteins/metabolism ; Kinesins/metabolism ; *Neurons/metabolism ; Synaptophysin/metabolism ; rab5 GTP-Binding Proteins/metabolism ; *Axons/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; },
abstract = {TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein essential for RNA metabolism. Under physiological conditions, it predominantly resides in the nucleus but is also expressed in the cytoplasm, where it regulates mRNA trafficking and local translation. In nearly 97% of amyotrophic lateral sclerosis (ALS) cases, TDP-43 undergoes nuclear depletion and cytoplasmic aggregation. While its nuclear functions are well characterized, its axonal roles remain poorly understood, despite axonal degeneration being a hallmark of ALS pathology. To address this gap, we investigated TDP-43 localization and transport dynamics in axons of H9-derived human neurons. We compared fluorescently labeled TDP-43 with three well-characterized axonal cargoes, ras-related protein Rab5, synaptophysin, and amyloid precursor protein, and examined protein-protein interactions between TDP-43 and the axonal transport machinery. Our analyses revealed that TDP-43 exhibits active anterograde axonal transport and interacts with multiple kinesin motor proteins, including all three KIF5 isoforms, through the adaptor KLC1, and the synaptic vesicles motor KIF1A. This multi-motor engagement suggests a flexible transport system that ensures mRNA delivery to distal axons. In ALS, where TDP-43 accumulates abnormally in the cytoplasm, this flexibility may become compromised, with multiple transport mechanisms simultaneously affected. This could contribute to progressive accumulation of non-functional TDP-43 granules, disrupting mRNA trafficking and local translation. Our findings provide a foundation for understanding how physiological TDP-43 transport mechanisms may be impaired during disease, highlighting axonal TDP-43 transport pathways as potential therapeutic targets.},
}

Humans
*Axonal Transport/physiology
*DNA-Binding Proteins/metabolism
Kinesins/metabolism
*Neurons/metabolism
Synaptophysin/metabolism
rab5 GTP-Binding Proteins/metabolism
*Axons/metabolism
Amyloid beta-Protein Precursor/metabolism
Amyotrophic Lateral Sclerosis/metabolism
Animals

@article {pmid42853426,
year = {2026},
author = {Liu, J and Ong, K and Meng, A and Stokin, GB and Loeb, JA and Ravits, J and Song, F},
title = {Lateral sclerosis in amyotrophic lateral sclerosis is an upper motor neuron distal axonopathy ("dying back"): a clinical-neuropathological study.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42853426},
issn = {1432-0533},
support = {NINDS P30NS047101//UCSD Microscopy Core grant/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Female ; Male ; *Motor Neurons/pathology ; Middle Aged ; *Axons/pathology ; *Pyramidal Tracts/pathology ; Aged ; Spinal Cord/pathology ; DNA-Binding Proteins/metabolism ; Nerve Degeneration/pathology ; Myelin Sheath/pathology ; Adult ; },
abstract = {The hallmark neuropathological feature of upper motor neuron (UMN) degeneration in amyotrophic lateral sclerosis (ALS) is the "sclerosis" of the lateral corticospinal tract (CST)-the major axonal pathway connecting UMNs to lower motor neurons (LMNs). However, few studies since Charcot's original descriptions in the nineteenth century have directly correlated clinical UMN phenotypes with corresponding neuropathological findings. We examined the pathology of the lateral CST at the cervical, thoracic, and lumbar levels of the spinal cord from ALS patients with predominantly UMN (UMN-p) phenotypes and compared it with that in patients with predominantly LMN (LMN-p) phenotypes. We assessed myelin loss, axonal degeneration, neuroinflammation, and TDP-43 pathology. Spinal cords from UMN-p ALS cases exhibited pronounced myelin loss in the lateral CST compared to LMN-p cases and controls, consistent with clinical phenotyping. Quantitative analysis revealed significant axonal loss across all axon diameter ranges in UMN-p ALS, which was more severe than in LMN-p ALS. Importantly, axonal loss was more pronounced in the lumbar than in the cervical spinal cord. We identified a distinct population of foamy, inflammatory microglia localized to regions of severe myelin and axonal loss in UMN-p ALS. TDP-43 was measurably increased in the UMN axons of the lateral and ventral CSTs. In summary, "lateral sclerosis" of ALS correlates to clinically imputed UMN degeneration. It consists of a combination of myelin loss, distal greater than proximal axonal degeneration, inflammatory microglial activation within the CSTs, and abnormally increased axonal TDP-43. The length-dependent gradient of motor axonal loss supports a "dying-back" process. A detailed comparison of "dying-forward" and "dying-forward" is provided in the Discussion. The association of loss of axons and myelin with abnormal microglial activity shows glio-axonal interactions in UMN axon degeneration, the latter CST (lateral sclerosis) across all three spinal cord levels in the ALS UMN-p samples but does not establish a causal relationship.},
}

Humans
*Amyotrophic Lateral Sclerosis/pathology
Female
Male
*Motor Neurons/pathology
Middle Aged
*Axons/pathology
*Pyramidal Tracts/pathology
Aged
Spinal Cord/pathology
DNA-Binding Proteins/metabolism
Nerve Degeneration/pathology
Myelin Sheath/pathology
Adult

@article {pmid42843275,
year = {2026},
author = {Adrita, N and Claassen, I and Huerta, M and Black, SM and Estevez, AG and Roberts, BR and Beckman, JS and Franco, MC},
title = {Tyrosine nitration: An emerging mechanistic landscape in neurodegeneration and cardiopulmonary disease.},
journal = {Redox biology},
volume = {97},
number = {},
pages = {104423},
doi = {10.1016/j.redox.2026.104423},
pmid = {42843275},
issn = {2213-2317},
abstract = {Protein tyrosine nitration is a post-translational modification associated with conditions of oxidative and inflammatory stress, driven by the production of reactive oxygen and nitrogen species (ROS and RNS). Once considered primarily a footprint of oxidative damage, tyrosine nitration is increasingly recognized as a selective modification that, in specific biological contexts, can alter protein structure, stability, enzymatic activity, and interaction networks. Mechanistically, nitration occurs through peroxynitrite-dependent and heme-peroxidase-dependent pathways and preferentially targets specific tyrosine residues based on local protein structure, solvent accessibility, and microenvironmental chemistry. Accumulating evidence has identified disease-specific nitration signatures across multiple pathological contexts. In neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, nitration of proteins such as tau, α-synuclein, manganese superoxide dismutase, ATP synthase, glyceraldehyde-3-phosphate dehydrogenase, heat shock proteins, and cytoskeletal components contributes to mitochondrial dysfunction, protein aggregation, metabolic failure, and neuronal loss. Similarly, in cardiovascular and pulmonary diseases, protein tyrosine nitration disrupts vascular and epithelial homeostasis by impairing endothelial signaling, fibrinolysis, lipid metabolism, and barrier integrity through modification of key regulatory proteins. By influencing phosphorylation-dependent signaling, enzymatic function, and protein-protein interactions, tyrosine nitration contributes to the connection between redox imbalance and progressive cellular and tissue dysfunction. This review summarizes current mechanistic insights into site-specific protein tyrosine nitration, highlights the emerging disease-associated nitroproteome, and discusses how advances in analytical and structural approaches are redefining nitration as a functional regulatory modification. Understanding the molecular determinants and consequences of tyrosine nitration may enable the development of targeted diagnostics and therapeutic strategies across diverse human diseases.},
}

@article {pmid42844074,
year = {2026},
author = {Portero-Campillo, E and Seghers-Carreras, C and Sayas-Catalán, J},
title = {Fooled by the Heartbeat: Cardioballistic Autotriggering in Amyotrophic Lateral Sclerosis.},
journal = {Archivos de bronconeumologia},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.arbres.2026.09.010},
pmid = {42844074},
issn = {1579-2129},
}

@article {pmid42844308,
year = {2026},
author = {Gandhi, SM and Patel, S and Haswani, NG and Wahab, S and Sabah, ZU and Kapoor, DU},
title = {RVG29-functionalized nanocarriers for brain-targeted therapy of neurodegenerative diseases: mechanisms, therapeutic advances, and translational perspectives.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42844308},
issn = {1432-1912},
abstract = {Neurodegenerative diseases (NDs) affect more than 55 million people worldwide, with this number projected to exceed 139 million by 2050 due to population aging. Alzheimer's disease (AD) accounts for 60-70% of dementia cases, while Parkinson's disease (PD) affects over 10 million individuals globally, highlighting the growing clinical and socioeconomic burden of these progressive neurological disorders. Effective treatment of AD, PD, amyotrophic lateral sclerosis (ALS), and related central nervous system disorders remains hindered by the blood-brain barrier (BBB), poor brain accumulation, rapid systemic clearance, and off-target toxicity. RVG29, a 29-amino-acid peptide derived from rabies virus glycoprotein, has emerged as a promising brain-targeting ligand because of its high affinity for nicotinic acetylcholine receptors expressed on neuronal and brain endothelial cells. This review critically examines the mechanisms underlying RVG29-mediated receptor-dependent BBB transcytosis, intracellular trafficking, and neuronal uptake. Furthermore, it comprehensively evaluates RVG29-functionalized lipid nanoparticles, polymeric nanoparticles, exosomes, biomimetic nanocarriers, micelles, inorganic nanostructures, and hybrid systems with respect to their physicochemical characteristics, targeting efficiency, therapeutic efficacy, and safety. Collectively, these nanocarriers demonstrate enhanced BBB penetration, increased drug accumulation in diseased brain regions, and efficient delivery of small molecules, genes, mRNA, and siRNA. By modulating oxidative stress, neuroinflammation, protein aggregation, ferroptosis, and mitochondrial dysfunction, RVG29-engineered nanocarriers provide significant neuroprotection with favorable biocompatibility and minimal immunogenicity. Despite these advances, challenges related to large-scale manufacturing, peptide stability, regulatory approval, and long-term biosafety must be addressed to facilitate their clinical translation as precision neurotherapeutics.},
}

@article {pmid42844425,
year = {2026},
author = {Stavrou, M and Heffernan, ÁB and Carter, RN and Dando, O and Jiwaji, Z and Burr, K and Nanda, J and Villarroel-Campos, D and Masoud Abdelhafid, A and Cholewa-Waclaw, J and Soong, D and Story, D and Schiavo, G and Hardingham, GE and Chandran, S and Selvaraj, BT},
title = {Astrocytes regulate axonal mitochondrial transport deficits in C9ORF72 amyotrophic lateral sclerosis motor neurons.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42844425},
issn = {1546-1726},
support = {(MR/T000708/1)//RCUK | Medical Research Council (MRC)/ ; (223022/Z/21/Z)//Wellcome Trust (Wellcome)/ ; },
abstract = {Disrupted axonal transport and astrocyte dysfunction are implicated in amyotrophic lateral sclerosis (ALS). Here we show these processes are linked-human-induced pluripotent stem-cell-derived astrocytes carrying the C9ORF72 mutation disrupt mitochondrial axonal transport and mitochondrial function in cocultured motor neurons (MNs). Conversely, isogenic gene-corrected astrocytes or boosting astrocytic mitochondrial bioenergetics rescue axonal mitochondrial transport deficits in C9ORF72 MNs. Our results delineate a non-cell-autonomous role for astrocytes in regulating mitochondrial transport along axons in ALS models.},
}

@article {pmid42845299,
year = {2026},
author = {Torres, P and Becerra, D and Astorga, JI and Fuentealba, M and Kauwe, G and Gonzalez, L and Diaz, G and Morales, V and Valenzuela, V and Wehrfritz, C and Ngwala, YY and Sepulveda-Quiñenao, C and Shah, S and Bons, J and Petrucelli, L and Tracy, TE and Schilling, B and Hetz, C},
title = {Oral administration of dibenzoylmethane (DBM) prevents cognitive decline in a C9ORF72-mediated FTD mouse model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.07.743573},
pmid = {42845299},
issn = {2692-8205},
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative disorders that display overlapping features. The hexanucleotide repeat expansion GGGGCC (G 4 C 2) in the C9ORF72 gene is the most common cause of ALS and FTD, which results in the accumulation of dipeptide-repeat protein aggregates. Regulation of protein synthesis at the level of the initiation factor eIF2α has been suggested as a transversal event contributing to neurodegeneration in ALS and FTD. eIF2α phosphorylation blocks protein synthesis to alleviate protein misfolding overload, but conversely it can reduce the expression of synaptic proteins resulting in neuronal dysfunction. Dibenzoylmethane (DBM) is a small molecule that reverses the translational attenuation mediated by eIF2α phosphorylation which has been shown to alleviate neurodegeneration in prion-infected mice and Tau transgenic animals. Here we investigated the efficacy of the oral administration of DBM in protecting a mouse model of C9ORF72 pathogenesis. Treatment of mice with 0.5% of DBM mixture in powdered food ad libitum was sufficient to prevent cognitive impairment in C9ORF72 mice. Unexpectedly, DBM treatment did not modify the content of poly(GA) and poly(GR) protein inclusion in the hippocampus and brain cortex. Proteomic profiling of brain tissue indicated that DBM administration corrected nearly 70% of the changes in gene expression triggered by expanded G 4 C 2 , where the main pathways modified by DBM were related to cytoskeleton organization, ALS, and metabolic processes. Most proteins corrected by DBM in our C9ORF72 model were also altered in the brain of human FTD/ALS patients. Overall, our results reinforce the idea that targeting protein synthesis with small molecules in patients carrying C9ORF72 mutations may result in improved cognitive capacity.},
}

@article {pmid42846340,
year = {2026},
author = {Garbey, M and Lesport, Q and Öztosun, G and Heidebrecht, M and Pirouz, K and Bayat, E},
title = {Correction: Feasibility study of noninvasive assessment of emotional state in patients with ALS.},
journal = {Frontiers in digital health},
volume = {8},
number = {},
pages = {1977072},
doi = {10.3389/fdgth.2026.1977072},
pmid = {42846340},
issn = {2673-253X},
abstract = {[This corrects the article DOI: 10.3389/fdgth.2026.1886561.].},
}

@article {pmid42847178,
year = {2026},
author = {Jernigan, B and Walters, HL and Corey, D and Garcia, A and Premasiri, A and Roddy, WT and Shearer, D and Thompson, TG and Tucker, J and Vieira, F and Boyce, D},
title = {Harmonizing ALS research data across multimodal data sets using the OMOP Common Data Model.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/21678421.2026.2738533},
pmid = {42847178},
issn = {2167-9223},
abstract = {Three nonprofit organizations-ALS Therapy Development Institute (ALS TDI), Answer ALS, and the Critical Path Institute (C-Path)-collaborated to harmonize distinct ALS research datasets using the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). This effort was designed to make otherwise separate ALS resources more comparable, enabling larger and more informative cross-cohort analyses. The teams coordinated vocabulary mapping, identified OMOP vocabulary gaps, and submitted new concepts to the Observational Health Data Science and Informatics (OHDSI) community for approval. Harmonized data from ALS TDI and Answer ALS were merged in the Neuromine data portal, while their clinical and digital health technology (DHT) datasets are also available through C-Path's Rare Disease Cures Accelerator-Data Analytics Platform (RDCA-DAP). This collaboration aligns with current regulatory priorities for data sharing and offers a model for harmonizing rare disease data. A robust, public GitHub repository was established to share real-time updates with the ALS research community.},
}

@article {pmid42847522,
year = {2026},
author = {Donlin-Asp, PG and Clayton, EL},
title = {Synaptic Proteostasis in Health and Disease.},
journal = {Journal of neurochemistry},
volume = {170},
number = {10},
pages = {e70565},
pmid = {42847522},
issn = {1471-4159},
support = {309570/Z/24/Z/WT_/Wellcome Trust/United Kingdom ; ARUK-SRF2022A-005//Alzheimer's Research UK/ ; //CureSynGAP/ ; 571/ALZS_/Alzheimer's Society/United Kingdom ; //Simons Initiative for the Developing Brain/ ; },
mesh = {Humans ; *Proteostasis/physiology ; *Synapses/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Autophagy/physiology ; *Neurons/metabolism/pathology ; Proteotoxic Stress ; },
abstract = {Neurons rely on tightly coordinated mechanisms of protein synthesis and degradation to maintain cellular homeostasis, a process known as proteostasis. Given their highly polarised and compartmentalised nature, regulation of proteostasis is especially important at neuronal synapses, which are spatially distant from the soma yet require rapid on-demand adaptation of the synaptic proteome. Neurons meet their demand for synaptic proteostasis through localised mRNA transport and translation, alongside specialised pathways for protein degradation. Recent advances reveal that thousands of transcripts localise to distal neuronal compartments and that their distribution may be shaped by RNA stability, RNA dynamics, and organelle-hitchhiking transport mechanisms. In parallel, processes such as synaptic autophagy and endolysosomal trafficking are crucial for maintaining synaptic structure and neurotransmission. Disruptions in these finely balanced mechanisms are a common underlying feature of various neurological disorders, including fragile X syndrome, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. This overview highlights key milestones and remaining questions in synaptic proteostasis, focusing on how local protein synthesis and degradation work together to preserve synaptic integrity and how their dysregulation can lead to disease.},
}

Humans
*Proteostasis/physiology
*Synapses/metabolism/pathology
Animals
*Neurodegenerative Diseases/metabolism/pathology
Autophagy/physiology
*Neurons/metabolism/pathology
Proteotoxic Stress

@article {pmid42847638,
year = {2026},
author = {Schneider, RB and Skibinski, G and Fiske, B and Kopil, CM and Merchant, K and Simuni, T},
title = {Considerations for therapeutic targets for clinical trials in biomarker-characterized prodromal Parkinson's disease populations.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X261493297},
doi = {10.1177/1877718X261493297},
pmid = {42847638},
issn = {1877-718X},
abstract = {Parkinson's disease (PD) is a growing public health problem and biologically targeted therapeutics (BTTs) that slow disease progression are urgently needed. However, the development of effective BTTs is challenging as PD is a clinically defined syndrome with pathobiological heterogeneity and the pathobiological process begins many years before the onset of clinically detectable motor symptoms. Testing BTTs in a biomarker-defined population at an earlier stage in the disease course, before a clinical PD diagnosis, may be the key to achieving this objective. The recent emergence of biological definitions of neuronal α-synuclein disease (NSD) and research frameworks for staging disease represent the first step towards testing BTTs in biomarker-defined prodromal populations. While biomarker-defined populations are essential for implementing precision therapeutic approaches, selecting and prioritizing BTTs for testing in early-stage populations is also critical, and requires consideration of biological relevance, safety, and operational feasibility. Here, in preparation for such studies, we review the landscape of publicly available PD BTTs organized by mechanistic pathways and targets, and summarize scientific, safety, and operational considerations relevant to early-stage, biomarker-defined trials targeting NSD participants prior to PD clinical diagnosis. Recognizing that there are shared biological mechanisms across neurodegenerative disorders, we complement this review of the PD therapeutic target landscape with a review of publicly available Alzheimer's dementia and amyotrophic lateral sclerosis BTTs and provide a comprehensive list of agents for reference.},
}

@article {pmid42847641,
year = {2026},
author = {De Lorenzo, A and Maranzano, A and Cocuzza, A and Gentile, F and Passaretti, M and Colombo, E and Torre, S and Aiello, EN and Calcagno, N and Gendarini, C and Olivero, M and Scheveger, F and Patisso, V and Spagliardi, J and Di Maio, A and Pierro, S and Treddenti, M and Gagliardi, D and Comi, GP and Corti, S and Pereira, JB and Agosti, P and Peyvandi, F and Messina, S and Doretti, A and Poletti, B and Morelli, C and Silani, V and Cinnante, CM and Verde, F and Ticozzi, N},
title = {White matter hyperintensity burden in amyotrophic lateral sclerosis: motor and survival correlates.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag347},
pmid = {42847641},
issn = {1460-2156},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration. Microvascular dysfunction has been implicated by recent research in ALS pathogenesis and motor neuron vulnerability. The aim of this study is to investigate whether MRI markers of white matter hyperintensities (WMHs), reflecting small-vessel disease, are associated with motor and cognitive impairment, disease staging and prognosis in ALS. In this retrospective cohort study MRI scans from 399 ALS patients were evaluated for periventricular and deep white matter hyperintensities (pvWMH and dWMH) using visual grading scales together with semi-automated volumetric quantification of relative WMH volume (WMHrv). The primary outcome was survival. Secondary outcomes included disease staging, functional impairment, motor and cognitive outcome measures. WMH burden was associated with more advanced King's topographic staging [pvWMH (P < 0.001), dWMH (P = 0.002)] and MiToS functional staging [pvWMH (P < 0.001), dWMH (P = 0.017)]. High pvWMH burden was associated with shorter survival [exp(β) = 3.503; 95% CI = 1.131, 10.832; P = 0.030] after adjustment for known prognostic factors. WMH measures correlated with greater functional impairment on ALSFRS-R score [pvWMH (P < 0.001), dWMH (P = 0.003), WMHrv (P = 0.008)]. WMH burden correlated with more severe lower, but not upper, motor neuron impairment, as measured with the MRC sum score [pvWMH (P = 0.002), dWMH (P = 0.024), WMHrv (p=0.030)] and lower motor neuron score [pvWMH (P < 0.001), dWMH (P = 0.001)]. WMH burden was also associated with cognitive deficits on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), as indicated by total [pvWMH (P = 0.007), dWMH (P = 0.009), WMHrv (P = 0.037)] and ALS-specific ECAS scores [pvWMH (P = 0.001), dWMH (P = 0.020), WMHrv (P = 0.022)]. This large-scale MRI study links small-vessel disease to clinical staging, survival and ALS-specific motor (distinctively LMN) and cognitive impairments. These results suggest that WMHs may reflect a diffuse neurovascular pathology spanning cortical and spinal regions and may be relevant to ALS progression. Routine MRI assessment of WMHs could aid patient stratification and inform trial designs. Longitudinal studies are needed to clarify causal relationships and neurovascular-targeted therapeutic implications.},
}

@article {pmid42848030,
year = {2026},
author = {Gaete, PV and Preciado, MP and Díaz, JJF},
title = {Contrasting clinical trajectories in two ALS patients with rare FUS variants: implications for variant interpretation, penetrance, and trial readiness.},
journal = {Neurogenetics},
volume = {27},
number = {1},
pages = {},
pmid = {42848030},
issn = {1364-6753},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *RNA-Binding Protein FUS/genetics ; Penetrance ; Phenotype ; Middle Aged ; Male ; Female ; Genetic Variation ; Mutation ; Genetic Association Studies ; Aged ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the motor system. A minority of cases are associated with a genetic variant. Variants in C9orf72, SOD1, TARDBP, and FUS are the most common. Compared with other forms of ALS, ALS presenting with FUS variants is relatively aggressive. However, phenotypic heterogeneity has been reported. We describe two cases of ALS with rare FUS variants with contrasting clinical courses. These cases highlight the importance of the different factors that influence ALS phenotypic presentation and the challenges of variant interpretation in ALS, as outlined in the ACMG Guidelines. It is essential to recognise specific genotype-phenotype relationships and environmental factors that could alter the clinical course of the disease and affect therapeutic agent selection.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
*RNA-Binding Protein FUS/genetics
Penetrance
Phenotype
Middle Aged
Male
Female
Genetic Variation
Mutation
Genetic Association Studies
Aged

@article {pmid42848219,
year = {2026},
author = {Vasta, R and Calvo, A and Moglia, C and Canosa, A and Manera, U and Gianferrari, G and Zucchi, E and Martinelli, I and Mora, G and Cabras, S and Palumbo, F and Matteoni, E and Maccabeo, A and Pellegrino, G and Minerva, E and Pascariu, D and Callegaro, S and D'Ovidio, F and Mazzini, L and De Marchi, F and Mandrioli, J and Chiò, A},
title = {Pre-diagnostic ALSFRS-R slope provides limited incremental information about the variability in subsequent functional decline in amyotrophic lateral sclerosis: a population-based study.},
journal = {Journal of neurology},
volume = {273},
number = {10},
pages = {},
pmid = {42848219},
issn = {1432-1459},
support = {RF-2016-02362405//Ministero della Salute/ ; 2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 20228N7573//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 259867//European Commission's Health Seventh Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101137074//Horizon 2020 Framework Programme/ ; project DIG-ALS//ARISLA/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/epidemiology ; Female ; Registries ; *Disease Progression ; Male ; Middle Aged ; Aged ; Longitudinal Studies ; Cohort Studies ; },
abstract = {BACKGROUND: The pre-diagnostic ALSFRS-R slope is frequently used in a clinical trial design and clinical practice under the implicit assumption that it reflects subsequent functional decline. We assessed the association between the pre-diagnostic ALSFRS-R slope and subsequent functional decline.

METHODS: The Piemonte and Valle d'Aosta ALS Registry (PARALS) was used as the primary cohort. The associations between pre- and post-diagnostic slopes at 6, 12, and 18 months were examined using correlation coefficients and multivariable linear regression. Linear and quadratic mixed-effects models used all ALSFRS-R assessments obtained during the first 18 months to evaluate longitudinal trajectories and quantify the incremental contribution of the pre-diagnostic slope. All analyses were replicated in the Emilia Romagna Registry for ALS (ERRALS).

RESULTS: A total of 2,222 patients from PARALS and 1,543 from ERRALS were included. In PARALS, the pre-diagnostic ALSFRS-R slope showed only a modest monotonic association with post-diagnostic functional decline (Spearman's ρ = 0.19-0.30) and explained 6.1% of its variance at 6 months, with this proportion decreasing thereafter. Quadratic mixed-effects models estimated that, at 12 months, the difference in ALSFRS-R change between patients in the highest and lowest pre-diagnostic slope quartiles was 2.04 points in PARALS (95% CI 1.25-2.83) and 2.47 points in ERRALS (95% CI 1.07-3.86). However, the linear and quadratic interactions together increased the marginal R[2] by only 0.43 percentage points in PARALS and 1.68 percentage points in ERRALS.

CONCLUSIONS: The pre-diagnostic ALSFRS-R slope identifies meaningful average differences in subsequent decline between patient groups but provides limited information for predicting individual trajectories.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/epidemiology
Female
Registries
*Disease Progression
Male
Middle Aged
Aged
Longitudinal Studies
Cohort Studies

@article {pmid42849018,
year = {2026},
author = {Rankin, J and Oltmann, C and Taylor, EP and Schachter, D and Lal, A},
title = {Early Palliative Care and Structured Serious Illness Communication in a Refugee Patient With Amyotrophic Lateral Sclerosis.},
journal = {The primary care companion for CNS disorders},
volume = {28},
number = {5},
pages = {},
doi = {10.4088/PCC.26cr04223},
pmid = {42849018},
issn = {2155-7780},
}

@article {pmid42833279,
year = {2026},
author = {Szeligowski, T and Ie, A and Kiraly, P and Hu, M and Ivanova, T and Jalil, A and Sergouniotis, P and Black, G and Wong, SC and Patel, CK and Henderson, R and Xue, K},
title = {Genetics, management and clinical outcomes in familial exudative vitreoretinopathy (FEVR): a multicentre retrospective cohort.},
journal = {Klinische Monatsblatter fur Augenheilkunde},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2962-8394},
pmid = {42833279},
issn = {1439-3999},
abstract = {in English Background Familial exudative vitreoretinopathy (FEVR) is a group of inherited retinal diseases characterised by abnormal retinal angiogenesis and peripheral non-perfusion. While over 10 genes have been implicated in FEVR, genotype-phenotype correlations and their clinical significance are incompletely understood. Here we describe a retrospective cohort of FEVR patients and assess the impact of defined genetic variants on protein structure, disease severity, inter-ocular variability, as well as treatment choices and visual outcomes. Methods Retrospective cohort of 51 patients with FEVR across three UK paediatric retina centres. All data was obtained from routine clinical records. Standard FEVR staging system was used throughout. Identified genetic variants were checked against genomic databases (ClinVar, GnomAD, UniProt), and their structural impact was examined using in silico algorithms (MutationTaster and PolyPhen2) to determine the likelihood of pathogenicity. Results 51 patients were included, with variants identified in FZD4 (n=16), LRP5 (n=13), TSPAN12 (n=11), KIF11 (n=6), NDP (n=4), and CTNNB1 (n=1). In silico analysis identified 11 variants not previously reported in FEVR, seven of which were classified as likely pathogenic. NDP variants were associated with the most severe and asymmetrical disease. Management included conservative monitoring (45 eyes), retinal laser photocoagulation (39 eyes), and surgical interventions (12 eyes), with the majority of patients achieving stable or improved visual acuity in all treatment groups. Conclusion This study demonstrates significant diversity among FEVR patients with regards to genetic variants, clinical presentation, and visual outcomes. Understanding genotype-phenotype correlations in FEVR may be crucial for developing novel treatment strategies. ABSTRACT in German Hintergrund Die familiäre exsudative Vitreoretinopathie (FEVR) ist eine Gruppe erblicher Netzhauterkrankungen, die durch eine abnorme retinale Angiogenese und eine periphere Minderperfusion gekennzeichnet ist. Obwohl mehr als 10 Gene mit FEVR in Verbindung gebracht wurden, sind Genotyp-Phänotyp-Korrelationen und deren klinische Bedeutung nur unvollständig verstanden. In dieser Arbeit beschreiben wir eine retrospektive Kohorte von FEVR-Patienten und untersuchen den Einfluss definierter genetischer Varianten auf die Proteinstruktur, den Krankheitsschweregrad, die interokuläre Variabilität sowie auf Behandlungsentscheidungen und visuelle Ergebnisse. Methoden Retrospektive Kohorte von 51 Patienten mit FEVR aus drei pädiatrischen Netzhautzentren im Vereinigten Königreich. Alle Daten wurden aus routinemäßigen klinischen Aufzeichnungen gewonnen. Durchgehend wurde das Standard-FEVR-Staging-System verwendet. Die identifizierten genetischen Varianten wurden mit genomischen Datenbanken (ClinVar, GnomAD, UniProt) abgeglichen, und ihre strukturelle Auswirkung wurde mittels In-silico-Algorithmen (MutationTaster und PolyPhen2) untersucht, um die Wahrscheinlichkeit einer Pathogenität zu bestimmen. Ergebnisse Es wurden 51 Patienten eingeschlossen, wobei Varianten in FZD4 (n=16), LRP5 (n=13), TSPAN12 (n=11), KIF11 (n=6), NDP (n=4) und CTNNB1 (n=1) identifiziert wurden. Die In-silico-Analyse identifizierte 11 zuvor nicht im Zusammenhang mit FEVR beschriebene Varianten, von denen sieben als wahrscheinlich pathogen eingestuft wurden. NDP-Varianten waren mit der schwersten und asymmetrischsten Erkrankung assoziiert. Das Management umfasste konservative Überwachung (45 Augen), retinale Laserphotokoagulation (39 Augen) und chirurgische Eingriffe (12 Augen), wobei die Mehrheit der Patienten in allen Behandlungsgruppen eine stabile oder verbesserte Sehschärfe erreichte. Schlussfolgerung Diese Studie zeigt eine erhebliche Vielfalt unter FEVR-Patienten hinsichtlich genetischer Varianten, klinischer Präsentation und visueller Ergebnisse. Das Verständnis der Genotyp-Phänotyp-Korrelationen bei FEVR könnte entscheidend für die Entwicklung neuartiger Behandlungsstrategien sein.},
}

@article {pmid42838501,
year = {2026},
author = {Knapp, J and Greif, R and Bathe, J and Wnent, J and Harding, U and Seewald, S and Fischer, M},
title = {Amiodarone After Conversion From a Non-shockable to a Shockable Rhythm in Out-of-Hospital Cardiac Arrest A Propensity Score-Matched Analysis from the German Resuscitation Registry.},
journal = {Resuscitation},
volume = {},
number = {},
pages = {111349},
doi = {10.1016/j.resuscitation.2026.111349},
pmid = {42838501},
issn = {1873-1570},
abstract = {BACKGROUND: Amiodarone should be administered after three shocks according the current ERC ALS guidelines. However, its effect in out-of-hospital cardiac arrest (OHCA) patients with an initial non-shockable rhythm who subsequently convert to a shockable rhythm is not established.

METHODS: We performed a retrospective observational cohort study using data from the German Resuscitation Registry. Adult patients with non-traumatic OHCA, having an initial non-shockable rhythm and subsequently received at least two defibrillations were included. Propensity-score-matched patient pairs (1:1) were analysed to compare outcomes between patients who received amiodarone during resuscitation and those who did not. The primary outcome was survival to hospital discharge. Secondary outcomes included hospital admission with return of spontaneous circulation (ROSC), 24-hour survival, survival to hospital discharge, and favourable neurological outcome at hospital discharge.

RESULTS: Of 5,535 patients included 3,181 received amiodarone and 2,354 did not. After propensity-score matching, 1,843 patients remained in each group. Amiodarone administration was associated with higher rates of hospital admission with ROSC (26.7% vs. 23.0%; OR 1.22, 95% confidence interval 1.05-1.42), 24-hour survival (21.4% vs. 14.7%; OR 1.58, 95% CI 1.33-1.87), and survival to hospital discharge (6.5% vs. 4.2%; OR 1.58, 95% CI 1.18-2.12). Favourable neurological outcome at hospital discharge was not statistically significant (3.7% vs. 2.9%; OR 1.31, 95% CI 0.91-1.89).

CONCLUSIONS: In OHCA patients with an initial non-shockable rhythm who subsequently converted to a shockable rhythm, amiodarone administration was associated with improved short-term and long-term survival, but not with a statistically significant improved favourable neurological outcome. Future controlled studies might define the proper (earlier) time of amiodarone administration.},
}

@article {pmid42839248,
year = {2026},
author = {Bublitz, SK and Bausewein, C and Detter, V and Feddersen, B and Graw, M and Klima, A and Klotz, P and Lorenzl, S and Gleich, S},
title = {Place and cause of death among people with chronic neurological diseases in Munich: a population-based study using death certificates.},
journal = {Neurological research and practice},
volume = {8},
number = {1},
pages = {},
pmid = {42839248},
issn = {2524-3489},
abstract = {INTRODUCTION: Access to palliative care is often delayed and fragmented for patients with chronic neurological diseases. This study aimed to characterize the place and cause of death among individuals with chronic neurological diseases to help identify potential gaps in palliative care provision.

METHOD: In this cross-sectional study, all death certificates from the city of Munich, Germany (2020-2023) were reviewed. Cases were included if malignant brain tumours, amyotrophic lateral sclerosis (ALS) or other motor neuron diseases, Parkinson's disease (PD), multiple sclerosis (MS) or other neurodegenerative or neuromuscular diseases were recorded as the cause of death or as a comorbidity.

RESULTS: Of 60,357 deaths, 2,536 individuals (4.2%) had at least one chronic neurological disease. The most common place of death was the hospital (43.8%), followed by nursing homes (25.9%) and the private home (25.0%), with variations among disease subgroups. Overall, the neurological disease was recorded as the immediate or underlying cause of death in 57.3% of cases, while in the remaining cases it was documented as a comorbidity, reflecting its presence without formal causal attribution to death.

DISCUSSION: This population-level analysis provides insight into the place and circumstances of death for a large cohort of patients with chronic neurological diseases in a major German metropolitan area and highlights substantial heterogeneity in end-of-life trajectories. The findings indicate that mortality statistics based on death certificates reflect structural limitations in cause-of-death attribution. Nevertheless, place of death remains a robust indicator, showing high hospital utilization and limited hospice use across most diagnostic groups, underscoring potential gaps in goal-concordant care.},
}

@article {pmid42839646,
year = {2026},
author = {Mercadante, S and Petronaci, A and , },
title = {One-Year Clinical Course of Patients With Amyotrophic Lateral Sclerosis Admitted to a Home Palliative Care Program: An Extension Study.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70429},
pmid = {42839646},
issn = {1097-4598},
abstract = {INTRODUCTION/AIMS: Longer term data on ALS patients receiving home palliative care are scarce. We extended follow-up of a 6-month cohort to 12 months to characterize the trajectory of function, symptoms, vital support (noninvasive ventilation [NIV], gastrostomy, and/or tracheostomy), and advance care planning (ACP).

METHODS: In this prospective, single-center study, 34 consecutive ALS patients in a home palliative care program (SAMOT, Palermo) were assessed at baseline, 2, 4, 6, and 12 months, using Karnofsky, ALS Functional Rating Scale-Revised (ALSFRS-R), Edinburgh Cognitive and Behavioural ALS Screen (ECAS), Edmonton Symptom Assessment Scale (ESAS), dysphagia, vital support, and advanced care planning (ACP).

RESULTS: Ten patients (29.4%) died over 12 months (70% at home); 26 completed the 12-month assessment. Karnofsky (34.4-27.7) and ALSFRS-R (27.1-21.7) declined significantly throughout (both p < 0.0005). Total ESAS rose from 15.7 to 23.7 (p < 0.0005); anxiety increased significantly between T4 and T12. NIV use rose from 20.6% to 50.0% (p = 0.014), while tracheostomy remained stable. Documented end-of-life decisions rose to 70.4% at 6 months but plateaued (69.2% at 12 months); no living wills were completed. Cognitive impairment on ECAS was present in about half of patients, unchanged over time. No patient was referred to or admitted to hospice.

DISCUSSION: Extending follow-up beyond 6 months shows continuous functional decline and rising symptom burden, and highlights late-onset anxiety and early-plateauing ACP. Despite progressive needs, this home palliative care model appeared to support most patients at home until death over 1 year, within this single-center, non-comparative cohort.},
}

@article {pmid42839768,
year = {2026},
author = {Iazzolino, B and Palumbo, F and Canosa, A and Callegaro, S and Passidomo, V and Manera, U and Vasta, R and Matteoni, E and Cabras, S and Pellegrino, G and Maccabeo, A and Moglia, C and Calvo, A and Chiò, A},
title = {Recalibration of the Frontal Behavioural Inventory Cut-Off for Behavioural Screening in Amyotrophic Lateral Sclerosis.},
journal = {European journal of neurology},
volume = {33},
number = {10},
pages = {e70778},
doi = {10.1111/ene.70778},
pmid = {42839768},
issn = {1468-1331},
support = {RF-2016-02362405//Ministero della Salute/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; 20228N7573//Ministero dell'Università e della Ricerca/ ; 259867//Seventh Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101137074//HORIZON EUROPE Framework Programme/ ; DIG-ALS//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/psychology ; Female ; Male ; Aged ; Middle Aged ; *Neuropsychological Tests/standards ; Sensitivity and Specificity ; Frontotemporal Dementia/diagnosis ; Reproducibility of Results ; },
abstract = {OBJECTIVE: The Frontal Behavioural Inventory (FBI) was validated in behavioural-variant frontotemporal dementia (bvFTD) with a cut-off of 25. We tested whether this threshold is appropriate in amyotrophic lateral sclerosis (ALS), where behavioural change is milder and partly confounded by motor pathology.

METHODS: We analysed 506 ALS patients with a valid FBI assessment. Behavioural impairment was defined using two complementary reference standards, to minimise dependence on any single behavioural instrument: a consensus rule (pathology on ≥ 2 of three independent instruments: Edinburgh Cognitive and Behavioural ALS Screen, Frontal Systems Behaviour Scale, Beaumont Behavioural Inventory) and Latent Class Analysis. ROC analysis identified the Youden-optimal cut-off; agreement was quantified by Cohen's κ; internal validity was assessed by stratified 5-fold cross-validation. Total and subscale scores were analysed separately.

RESULTS: Among 345 complete-case patients, 24.6% met criteria for behavioural impairment. The FBI total discriminated impairment well (AUC 0.855, 95% CI 0.806-0.898). The Youden-optimal cut-off was FBI ≥ 9 (sensitivity 0.87, specificity 0.74), whereas the legacy cut-off of 25 showed sensitivity 0.22. Subscale recalibration yielded cut-offs of FBI-Apathy ≥ 7 (AUC 0.808) and FBI-Disinhibition ≥ 4 (AUC 0.851).

CONCLUSIONS: In ALS, the bvFTD-derived threshold of 25 misses most patients with behavioural involvement. FBI ≥ 9 is a promising candidate ALS-specific screening threshold, with scores ≥ 15 indicating a higher probability of behavioural involvement; exploratory subscale thresholds of ≥ 7 for Apathy and ≥ 4 for Disinhibition are also proposed. These cut-offs substantially improve sensitivity while maintaining acceptable specificity, but require prospective external validation before replacing current practice.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/complications/psychology
Female
Male
Aged
Middle Aged
*Neuropsychological Tests/standards
Sensitivity and Specificity
Frontotemporal Dementia/diagnosis
Reproducibility of Results

@article {pmid42839902,
year = {2026},
author = {Bettoni, V and Nath, SR and Johnson, S and Oskarsson, B and Bojko, A and Salmaninejad, A and Tan-Arroyo, J and Cousin, MA and Staff, NP},
title = {Clinical and genetic characterization of FUS-associated ALS in a tertiary cohort.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/21678421.2026.2743446},
pmid = {42839902},
issn = {2167-9223},
abstract = {An understanding of FUS-related ALS is becoming increasingly actionable with the emergence of targeted therapies. We retrospectively reviewed patients with amyotrophic lateral sclerosis and reported FUS variants evaluated across all Mayo Clinic sites between January 2009 and June 2026. Variants were reevaluated according to ACMG/AMP criteria, and clinical and genetic data were abstracted from medical records. The primary cohort included 12 unrelated patients with pathogenic or likely pathogenic (P/LP) FUS variants; 6 patients with variants of uncertain significance were retained descriptively. Pathogenic variants clustered in the C-terminal region, including one previously unreported likely pathogenic frameshift variant, c.1491_1494dup. Patients with pathogenic variants showed early-onset, rapidly progressive disease with frequent bulbar or respiratory onset, predominant lower motor neuron findings, and short survival. Observed phenotypes were broadly consistent with previous variant-specific reports. These findings expand variant-specific natural history data in FUS-ALS and may inform prognosis, patient stratification, and the interpretation of emerging FUS-targeted therapeutic studies.},
}

@article {pmid42840349,
year = {2026},
author = {Morandi, L and Casadei, F and De Fanti, S and Bonan, L and Ravaioli, F and Palombo, F and Fiorentino, A and de Pasqua, S and Vacchiano, V and Avoni, P and Rizzo, G and Capellari, S and Ruggeri, E and Donadio, V and Castellani, G and Bacalini, MG and Lodi, R and Liguori, R and Carelli, V and Tonon, C},
title = {Nanopore sequencing combined with adaptive sampling and NanoExpansion enables accurate characterization of repeat expansion disorders.},
journal = {NAR genomics and bioinformatics},
volume = {8},
number = {4},
pages = {lqag117},
pmid = {42840349},
issn = {2631-9268},
mesh = {Humans ; *DNA Repeat Expansion ; *Nanopore Sequencing/methods ; Microsatellite Repeats ; Polymerase Chain Reaction ; Amyotrophic Lateral Sclerosis/genetics ; Sequence Analysis, DNA/methods ; Spinocerebellar Ataxias/genetics ; Myotonic Dystrophy/genetics ; },
abstract = {Expansion repeat disorders are caused by abnormal expansions of short tandem repeats (STRs). We evaluated targeted long-read nanopore sequencing for comprehensive characterization of STR expansions in 132 participants, including patients with myotonic dystrophy type 1 (DM1, n = 51) and DM2 (n = 3) already characterized by Southern blot, C9orf72-associated amyotrophic lateral sclerosis (ALS n = 11) evaluated by repeat primed polymerase chain reaction (RP-PCR; validation group), suspected spinocerebellar ataxia (SCA, n = 46), cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS; n = 13), Huntington's disease (1), Kennedy disease (1), Friedreich ataxia (FRDA, 2), and 4 healthy controls (test group). Native DNA was sequenced using adaptive sampling (AS) on Oxford Nanopore GridION or PromethION-2Solo platforms. Long-PCR sequencing was performed for comparison. We also developed NanoExpansion, a Python-based tool for sizing expanded alleles and detecting sequence interruptions. We correctly characterized all DM1, DM2, ALS, FRDA, Huntington's disease, and Kennedy disease cases, and identified eight SCA27B, two SCA37, three SCA31, one SCA3, and nine CANVAS cases. Compared with the AS approach, long-PCR underestimated alleles exceeding 800 repeats. Repeat interruptions were detected in 27/51 (52.9%) DM1 cases and 1/10 (10%) ALS, but not in CANVAS, FRDA, Huntington's disease, Kennedy disease, or SCA cases. This integrated sequencing analysis pipeline provides accurate, comprehensive characterization of repeat expansion disorders and has the potential to improve routine genetic diagnosis.},
}

Humans
*DNA Repeat Expansion
*Nanopore Sequencing/methods
Microsatellite Repeats
Polymerase Chain Reaction
Amyotrophic Lateral Sclerosis/genetics
Sequence Analysis, DNA/methods
Spinocerebellar Ataxias/genetics
Myotonic Dystrophy/genetics

@article {pmid42840744,
year = {2026},
author = {Mouraux, C and Santana, MM and Rosenthal, LS and Cortese, A and Santorelli, FM and Opal, P and Coarelli, G},
title = {The role of neurofilament light chain and other fluid biomarkers in cerebellar ataxias.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag313},
pmid = {42840744},
issn = {2632-1297},
abstract = {The genetic and phenotypic heterogeneity of hereditary ataxias complicates the design of clinical trials since each ataxia progresses at different rates. Consequently, robust biomarkers are urgently needed to monitor therapeutic efficacy and safety of potential therapeutic interventions. Neurofilament light chain has emerged as a leading candidate, serving as a sensitive pharmacodynamic biomarker of neuronal injury and treatment response in neurodegenerative disorders. This review explores the utility of neurofilament light chain across various ataxias, including polyglutamine spinocerebellar ataxias, Friedreich's ataxia, multiple system atrophy, and other genetic ataxias, such as ataxias associated with RCF1 and SPG7 genes. We synthesize evidence from recent studies that have used ultra-sensitive assays. These studies consistently demonstrate elevated neurofilament light chain levels in cerebrospinal fluid and blood, correlating with disease severity, progression and neuroimaging findings. Notably, neurofilament light chain levels rise during the presymptomatic stage in spinocerebellar ataxias, highlighting its potential for stratifying individuals for trial enrolment and tracking therapeutic effects. A treatment-induced reduction in neurofilament light chain could function as a surrogate endpoint for target engagement, analogous to its validated use in amyotrophic lateral sclerosis. Finally, we discuss the results of other studies conducted on other biomarkers, including glial fibrillary acidic protein, total tau and phosphorylated tau, which may reflect complementary aspects of neurodegeneration and glial activation. Glial fibrillary acidic protein may provide insights into astroglial reactivity and neuroinflammation. Similarly, alteration in total tau and phosphorylated tau levels may suggest dysfunction in neuronal cytoskeleton and axonal integrity. The review also focuses on target-engagement biomarkers, including polyglutamine-expanded ataxin proteins in spinocerebellar ataxias and frataxin in Friedreich's ataxia, as critical tools to complement the ataxia biomarker toolkit. The quantification of mutant ataxin proteins provides a mechanistic readout for emerging gene-silencing or protein-lowering therapies. In parallel, the measurement of frataxin levels serves as a pharmacodynamic marker in therapeutic strategies aiming to restore frataxin expression. These target-engagement biomarkers are valuable in early phases of clinical trials, which mainly aim to demonstrate the biological activity of a treatment before later-phase trials assessing clinical efficacy. Finally, we report on somatic instability in polyglutamine spinocerebellar ataxias as an emerging and highly relevant therapeutic target. CAG repeat mosaicism is gene specific and correlates with disease progression. Integrating measures of repeat instability with neurodegenerative biomarkers could provide a comprehensive monitoring approach in clinical studies. This overview underscores the potential of fluid biomarkers, particularly neurofilament light chain, in accelerating therapeutic development for hereditary ataxias.},
}

@article {pmid42841339,
year = {2026},
author = {Zhu, X and Qiao, X and Qin, N and Li, Z and Lv, Y and Lu, J and Guo, Z},
title = {Site-Selective Anion-Cation Regulation of Sulfide Electrolyte Enables Low-Pressure Dendrite-Suppressed All-Solid-State Lithium Metal Batteries.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e3893843},
doi = {10.1002/anie.3893843},
pmid = {42841339},
issn = {1521-3773},
support = {U25A20243//National Natural Science Foundation of China/ ; 2026C02A1252//Department of Science & Technology of Zhejiang Province/ ; },
abstract = {Achieving stable sulfide-based all-solid-state lithium batteries with Li metal anodes and high-capacity cathodes under low stack pressure is highly desirable for high-energy-density energy storage, but remains challenging because of unstable solid-solid interfaces and dendrite-induced short circuits. Here, we develop a site-selective anion-cation regulation strategy for argyrodite Li6PS5Cl electrolyte to couple framework stabilization with interphase chemistry, enabling long-term dendrite-suppressed cycling under low stack pressure. Al[3+] substitution for P[5+] forms AlS4 -related local units and strengthens local Al-S bonding, stabilizing the sulfide framework against redox decomposition. Cl[-] incorporation into the 4a/4d anion sublattice promotes Li[+] transport, delivering a high room-temperature ionic conductivity of 7.22 mS cm[-1]. More importantly, F/Cl regulation redirects the interfacial decomposition pathway from a Li2S-rich/LiCl interphase toward a LiF/LiCl-rich and Li2S-poor passivation layer, with exposed LiF/LiCl (200) planes that exhibit stronger interfacial adhesion with Li metal. Benefiting from this coupled framework-interphase regulation, Li | LAPSCF-Cl | Li symmetric cells cycle for over 8000 h at 0.5 mA cm[-2] at 3 MPa and support stable cycling of both NCM811 and sulfur cathodes paired with Li metal under a relatively low pressure of 30 MPa.},
}

@article {pmid42841866,
year = {2026},
author = {Anjum, A and Manai, AL and Noli, B and Borghero, G and Mascia, MM and Meloni, M and Kais, H and Figorilli, M and Puligheddu, M and Cocco, C},
title = {N-terminal proVGF modifications related to Amyotrophic Lateral Sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2026.2742817},
pmid = {42841866},
issn = {2167-9223},
abstract = {Objective: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor dysfunction, for which effective therapies and early diagnostic biomarkers remain limited. This study comprehensively investigated ALS-associated alterations in the N-terminal region of the proVGF precursor protein, evaluating their potential as novel diagnostic and prognostic biomarkers and exploring their precise correlations with clinical severity and plasma neurofilament light chain (NfL), an established indicator of neuroaxonal injury. Methods: N-terminal proVGF levels were quantified using a custom immunoassay using human plasma and lymphocytes as well as motor neuron-like NSC-34 cells subjected to oxidative stress. The clinical cohort comprised 49 ALS patients (28 early-stage, 21 advanced-stage) and 50 age-matched healthy controls. To assess disease specificity, plasma from patients with Parkinson's disease (PD, n = 50), idiopathic dystonia (n = 15), and idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD, n = 21) was analyzed alongside respective age-matched healthy controls (n = 26, 8, and 20). Furthermore, plasma NfL levels were measured and directly correlated with N-terminal proVGF concentrations. Results: N-terminal proVGF levels were significantly increased in both plasma and lymphocytes during the early and advanced stages of ALS. Plasma NfL levels were concomitantly elevated across all ALS patients. In advanced-stage patients, N-terminal proVGF concentrations significantly correlated with both ALSFRS-R scores and NfL levels. No significant N-terminal proVGF alterations were observed in PD, iRBD, or dystonia cohorts. Oxidative stress similarly upregulated N-terminal proVGF levels in vitro within NSC-34 cells. Conclusion: Alterations of the N-terminal region of proVGF are specific to ALS, highlighting their dual value as diagnostic and prognostic biomarkers.},
}

@article {pmid42842169,
year = {2026},
author = {Singh, RK and Banerjee, C and Mehan, S},
title = {Beyond Histamine Blockade: Clemastine Fumarate as a Promoter of Myelin Regeneration, Inflammatory Regulation, and Neuroimmune Modulation in CNS Disorders.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42842169},
issn = {1557-1904},
mesh = {Animals ; Humans ; *Clemastine/pharmacology/therapeutic use ; *Central Nervous System Diseases/drug therapy/immunology/metabolism ; *Myelin Sheath/drug effects ; *Neuroimmunomodulation/drug effects/physiology ; *Remyelination/drug effects/physiology ; Neuroinflammatory Diseases/drug therapy/immunology ; *Histamine H1 Antagonists/pharmacology/therapeutic use ; },
abstract = {Clemastine fumarate, a first-generation H1 antihistamine, has emerged as a promising candidate for drug repurposing in neurodegenerative and neuropsychiatric disorders owing to its ability to cross the blood-brain barrier and interact with multiple central nervous system targets. Experimental studies indicate that clemastine promotes remyelination by stimulating the differentiation of oligodendrocyte precursor cells into mature, myelin-producing oligodendrocytes, thereby restoring myelin integrity and improving axonal function in experimental models. In addition to its remyelinating properties, preclinical evidence suggests that clemastine may attenuate neuroinflammation by modulating microglial activation and suppressing pro-inflammatory signalling pathways. These effects have been associated with improved structural and functional outcomes in experimental models of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, and several neuropsychiatric disorders. Mechanistically, clemastine primarily acts through muscarinic M1 receptor antagonism to promotes remyelination, while additional pathways including PI3K/Akt, ERK1/2, autophagy-related signalling, inflammasome modulation, and sigma-1 receptor signalling have been proposed based on experimental evidence but remain incompletely understood and require further mechanistic validation. Among the neurological disorders investigated multiple sclerosis currently has the strongest clinical evidence with early clinical trials demonstrating modest remyelinating activity. In contrast, evidence supporting the use of clemastine in other neurological disorders remains largely confined to preclinical studies. Several translational challenges also remain unresolved including dose optimisation, treatment timing, long-term safety, sedative and anticholinergic adverse effects, and patient selection. Future research should focus on refining pharmacokinetic properties, optimising dosing strategies, evaluating rational combination therapies, and identifying predictive biomarkers to facilitate clinical translation. Although current evidence highlights the therapeutic potential of clemastine fumarate, its application beyond multiple sclerosis remains investigational and will require rigorous mechanistic studies together with well-designed clinical trials before broader clinical use can be established.},
}

Animals
Humans
*Clemastine/pharmacology/therapeutic use
*Central Nervous System Diseases/drug therapy/immunology/metabolism
*Myelin Sheath/drug effects
*Neuroimmunomodulation/drug effects/physiology
*Remyelination/drug effects/physiology
Neuroinflammatory Diseases/drug therapy/immunology
*Histamine H1 Antagonists/pharmacology/therapeutic use

@article {pmid42842441,
year = {2026},
author = {Chen, H and Qin, M and Zhu, R and Zhang, X and Lou, W},
title = {Large Language Models for Selecting Intraocular Lens Power Calculation Formulas: A Comparative Study.},
journal = {Journal of refractive surgery (Thorofare, N.J. : 1995)},
volume = {42},
number = {10},
pages = {e458-e467},
doi = {10.3928/1081597X-20260806-01},
pmid = {42842441},
issn = {1938-2391},
mesh = {Humans ; *Lenses, Intraocular ; *Large Language Models ; *Biometry/methods ; *Refraction, Ocular/physiology ; *Optics and Photonics ; Female ; Male ; Aged ; Lens Implantation, Intraocular ; Middle Aged ; Visual Acuity/physiology ; },
abstract = {PURPOSE: To evaluate refractive outcomes of large language model (LLM)-based selection of the optimal intraocular lens power calculator according to individual biometric parameters.

METHODS: Two hundred eight eyes undergoing routine cataract surgery were included. Ten leading LLMs (Gemini, Chat-GPT, Perplexity, Grok, DeepSeek, Kimi, Qwen, Doubao, ERNIE, and Hunyuan) were prompted to recommend "the single most appropriate formula" from Barrett Universal II (BUII), Cooke K6, EVO 2.0, Hill-RBF 3.0, Kane, and PEARL-DGS, based on axial length (AL), keratometry, anterior chamber depth, and lens thickness. Gemini was excluded because it consistently selected Kane. Precision (SD) and accuracy (absolute spherical equivalent prediction error [SEQ-PE]) were assessed with the Eyetemis Analysis Tool and compared with BUII and SRK/T, both overall and within AL subgroups.

RESULTS: Formula preferences varied markedly among LLMs. Overall, all LLMs and BUII demonstrated significantly greater precision than SRK/T, with Hunyuan, ChatGPT, and BUII showing highest precision and significantly improved accuracy compared to SRK/T (all P < .05). The leading percentages of eyes within the ±0.50 diopter (D) threshold were achieved by Perplexity (82.69%), ChatGPT (82.21%), Qwen (82.21%), and BUII (81.73%). Across AL subgroups, at least one LLM numerically outperformed BUII in both precision and accuracy; at the ±0.50 D threshold, certain models increased this percentage over BUII by approximately 3% when AL was ≤ 22 mm or ≥ 26 mm, and by 8% when 24.5 mm ≤ AL < 26 mm.

CONCLUSIONS: Compared with BUII, current LLMs exhibit limited capacity to improve refractive outcomes by selecting the optimal formulas for routine practice; however, certain LLMs show promise as adjunctive tools for personalized selection tailored to specific ALs.},
}

Humans
*Lenses, Intraocular
*Large Language Models
*Biometry/methods
*Refraction, Ocular/physiology
*Optics and Photonics
Female
Male
Aged
Lens Implantation, Intraocular
Middle Aged
Visual Acuity/physiology

@article {pmid42843091,
year = {2026},
author = {Venkatesan, A and Sinha, P and Basak, J and Bahadur, RP},
title = {Gene regulatory co-expression networks decipher potential lncRNA-miRNA-mRNA interactions modulating transcription regulation in neurodegeneration.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 2},
pages = {109462},
doi = {10.1016/j.compbiolchem.2026.109462},
pmid = {42843091},
issn = {1476-928X},
abstract = {Neurodegenerative diseases are complex disorders characterised by progressive neuronal loss and widespread transcriptomic dysregulation. However, understanding the molecular interactions among coding and non-coding RNAs, especially lncRNAs and miRNAs, contributing to disease progression remains elusive. In this study, RNA-Seq datasets from disease-relevant neuronal populations and different brain tissues representing Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS) are analysed using an integrative network-based framework. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) are combined to identify disease-associated modules and prioritise highly connected hub genes. They are subsequently integrated with curated RNA interaction databases to construct candidate lncRNA-miRNA-mRNA regulatory networks. Functional enrichment and UTR variant analyses are further incorporated to connect the regulatory network framework with biological processes and potential sequence variations. The novelty of the present study lies in the systematic integration of transcriptomic co-expression, post-transcriptional regulation, functional and sequence-level analyses within a single framework. This framework enables the identification of disease-specific and shared regulatory features, and links the candidate regulatory interactions with potential UTR sequence alterations. Across eight tissue-specific samples, 163 hub genes and 4869 candidate lncRNA-miRNA-mRNA interactions are identified. Additionally, we also identify 414 UTR variants associated with the hub genes. Pathways associated with hub genes including axonogenesis, synaptic organization, intracellular transport and RNA regulatory mechanisms are commonly found to be enriched in AD, PD and ALS. These findings provide a quantitative resource for prioritising regulatory interactions between candidate hub genes and associated UTR variants for future experimental validation.},
}

@article {pmid42833594,
year = {2026},
author = {Dahlhaus, R and Yalcin, I and Tischer, J and Braun, RJ},
title = {TDP-43 and ALS - what's wrong with my membranes?.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107630},
doi = {10.1016/j.nbd.2026.107630},
pmid = {42833594},
issn = {1095-953X},
abstract = {In recent years, multiple pathologies of the mRNA binding protein TDP-43 have been linked to the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS), in which almost 97% of all ALS patients exhibit TDP-43 abnormalities in affected neurons. Typically, neuronal degeneration first affects alpha motor neurons of the spinal cord and the lower brainstem, before the disease progresses to Betz cells, giant neurons of the primary motor cortex, and subsequently spreads into further brain regions. It is just the Betz cells though, which do not show cytosolic TDP-43 aggregation upon loss of nuclear TDP-43 expression, but instead display membrane defects in organelles such as the Golgi apparatus, the ER and the nuclear envelope. In this review, we will therefore examine connections between TDP-43 and inner membrane systems, with a particular focus on nuclear and the ER membranes. In doing so, we will summarize evidence suggesting that the disease may have an early onset, potentially even prenatally, and describe how interactions between TDP-43 and the lipid metabolism as well as connections with membrane components, may drive cells towards ALS as time goes by.},
}

@article {pmid42834122,
year = {2026},
author = {Sakai, S and Oiwa, K and Iguchi, Y and Akcay, IM and Watanabe, S and Komine, O and Nagata, N and Horiuchi, M and Sreedharan, J and Katsuno, M and Yamanaka, K},
title = {TBK1 eliminates aggregation-prone monomeric TDP-43 through an IFNβ-immunoproteasome pathway in ALS models.},
journal = {EMBO reports},
volume = {},
number = {},
pages = {},
pmid = {42834122},
issn = {1469-3178},
support = {JP22J23468//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP25K23745//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP18H02740//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP19KK0214//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP22H00467//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP22ek0109426//Japan Agency for Medical Research and Development (AMED)/ ; JP24wm0425014//Japan Agency for Medical Research and Development (AMED)/ ; JP26wm0625301//Japan Agency for Medical Research and Development (AMED)/ ; n/a//THE YUKIHIKO MIYATA MEMORIAL TRUST FOR ALS RESEARCH/ ; n/a//IKEDA RIKA Grant/ ; 221824/Z/20/Z//Wellcome Trust (WT)/ ; Sreedharan/Apr24/2362-791//Motor Neurone Disease Association (MNDA)/ ; },
abstract = {Loss-of-function mutations in TANK-binding kinase 1 (TBK1) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), characterized by cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43), known as TDP-43 pathology, but the mechanisms beyond impaired autophagy remain undefined. Here, we identify a TBK1-IFNβ-immunoproteasome axis as a novel autophagy-independent proteostatic pathway regulating TDP-43 clearance. TBK1 is activated by aggregation-prone monomeric TDP-43 via physical association, and this activation alleviates TDP-43 pathology in neuronal cells. TBK1 subsequently induces IFNβ expression, which upregulates the immunoproteasome to promote degradation of monomeric TDP-43 in neurons, including human iPSC-derived lower motor neurons. Importantly, IFNβ receptor expression is downregulated in spinal motor neurons from ALS patients with TDP-43 pathology. Furthermore, heterozygous Tbk1 deletion in SOD1[G93A] mice impairs immunoproteasome induction and increases polyubiquitinated protein accumulation in spinal cords, supporting the in vivo relevance of this pathway. Collectively, our findings reveal that impairment of the TBK1-IFNβ-immunoproteasome axis represents an autophagy-independent mechanism contributing to the development of TDP-43 pathology in ALS and FTD.},
}

@article {pmid42834925,
year = {2026},
author = {Piras, R and Bordini, S and Simi, RK and Consolo, I and Esposito, V and Cavaggion, C and Feder, M and Fossati, M and Grioli, G and Bicchi, A and Lunetta, C and Catalano, MG},
title = {Bridging stakeholder needs and technological capabilities to identify humanoid robot applications in rehabilitation: a case study in an ALS multidisciplinary care unit.},
journal = {Frontiers in robotics and AI},
volume = {13},
number = {},
pages = {1944029},
pmid = {42834925},
issn = {2296-9144},
abstract = {The integration of assistive service robots in healthcare has gained increasing attention for its potential to support clinical workflow and patient wellbeing. However, structured methodological approaches to identify clinically relevant applications for versatile robotic platforms before clinical implementation are still lacking. Moreover, the deployment of robots in these settings is often restricted to hyper-specialized tasks. To address these challenges, this study describes a stakeholder-driven process adopting a multidisciplinary co-design approach to adapt the Alter-Ego semi-anthropomorphic robot to the needs of a multidisciplinary neurorehabilitation unit for patients with Amyotrophic Lateral Sclerosis. We combined brainstorming, focus groups with healthcare professionals, patients and caregivers, and contextual observations to identify the real unmet needs and potential applications. The engineering team assessed the technological requirements and implementation readiness of each application. The clinical and engineering teams jointly reviewed the proposal, considering clinical, ethical, and infrastructural implications. This consensus-based process resulted in 12 use cases selected for the clinical protocol corresponding to 40 planned experimental sessions including autonomous or semi-autonomous tasks, as well as teleoperated activities for assistive and rehabilitation purposes. Furthermore, an exploratory pilot evaluated a subset of selected use cases, providing feedback to refine the platform and experimental protocol. Standardized assessments provided descriptive information on perceived workload, usability, and satisfaction. Participants generally reported a positive experience and manageable workload, while task-specific feedback identified aspects requiring further refinements. Overall, this experience offers preliminary insights into how clinical needs and technological capabilities can be jointly explored, providing a basis for subsequent clinical experimentation.},
}

@article {pmid42835448,
year = {2026},
author = {Zhu, R and Li, H},
title = {Global research architecture of RNA-binding proteins in neurodegenerative diseases: a web of science bibliometric study with PubMed record verification, 2001-2025.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1967205},
pmid = {42835448},
issn = {1663-4365},
abstract = {BACKGROUND: RNA-binding proteins (RBPs) connect RNA homeostasis to proteostasis and selective neuronal vulnerability, but the organization and evolution of this cross-disease research field remain unclear.

METHODS: We analyzed Web of Science Core Collection (WoSCC) records published through 2025. PubMed was used only to verify records by normalized DOI or exact normalized title; PubMed metadata were not pooled with WoS data, and all bibliometric analyses used WoS fields. Publication growth, contributors, collaboration, co-citation, bibliographic coupling, and conceptual evolution were examined using bibliometrix, VOSviewer, and CiteSpace-compatible workflows. A prespecified 43-concept dictionary preserved multiword biological entities in title/abstract networks. The study characterizes a query-defined and PubMed-verified literature corpus rather than estimating the relative biological importance of individual RBPs.

RESULTS: Of 2,454 records reported by the WoS search interface, 2,450 were available in the supplied exports and 2,309 met the year criterion. PubMed record verification retained 2,160 records (93.55%) in the analysis corpus; 149 records (6.45%) were not matched. Output increased from one publication in 2001 to 213 in 2025. Within this query-defined corpus, the mapped literature was concentrated around TDP-43 pathology, TARDBP/FUS genetics, and loss of RNA-processing function. The controlled concept network resolved three macro-communities, while recent temporal signals involved LATE, cryptic exons, and RNA transport. These findings describe the retrieved and verified corpus and are not presented as a search-independent ranking of the broader RBP field.

CONCLUSION: The maps document a WoS-derived and PubMed-verified literature corpus concentrated on TDP-43 and ALS/FTD and increasingly connected with cryptic RNA processing, condensate biology, nuclear transport, neuroimmune responses, and aging-related mixed proteinopathies. Because the corpus was conditioned by a title-level query containing named RBPs and by PubMed record verification, these patterns should not be interpreted as an unbiased ranking of RBP biology or as evidence of shared causality across diseases. Cross-disease translation should proceed through neuropathologically defined, age-stratified, and cell-type-resolved human cohorts, followed by causal perturbation and rescue in human disease models and multicenter longitudinal validation.},
}

@article {pmid42836993,
year = {2026},
author = {Al Khleifat, A and Malaspina, A and Kirby, J and Tree, T and Shaw, PJ and Leigh, PN and Al-Chalabi, A},
title = {TRICALS risk score augments but cannot replace neurofilament as a prognostic biomarker in ALS.},
journal = {Journal of neurology},
volume = {273},
number = {10},
pages = {},
pmid = {42836993},
issn = {1432-1459},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/drug therapy/diagnosis ; *Neurofilament Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Prognosis ; Female ; Male ; Middle Aged ; Aged ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with substantial clinical heterogeneity, complicating the design and interpretation of clinical trials. Two strategies have been proposed to address this variability: phenotype-based prognostic modelling and biomarker-based stratification using neurofilaments. We aimed to determine whether a widely used phenotype-based method, the TRICALS risk score, could substitute for neurofilament biomarkers in a clinical trial.

METHODS: We used data from the MIROCALS phase 2b randomised controlled trial of low-dose interleukin-2 in ALS (n = 220). The TRICALS risk score was calculated for each participant. The published biomarker model includes CSF phosphorylated neurofilament heavy chain (pNFH) and a pNFH × treatment interaction. We analysed the effects of replacing CSF pNFH with the TRICALS risk score and of adding TRICALS score as an additional covariate to the original model. Model performance was assessed using likelihood ratio χ[2] statistics and - 2 log likelihood (- 2LL). The primary outcome was survival.

RESULTS: TRICALS risk score was moderately correlated with CSF pNFH (r = 0.357), explaining 12.7% of shared variance. Substituting CSF pNFH with TRICALS score reduced model performance (- 2LL 928.25 vs 793.36). The TRICALS × treatment interaction was statistically significant (hazard ratio [HR] 0.72, 95% CI 0.54-0.96 p = 0.025), but contributed modestly to model fit (Δχ[2] = 4.76), compared with the pNFH × treatment interaction (Δχ[2] = 14.24). Incorporating the pNFH × treatment interaction significantly improved model fit and identified a treatment effect (HR 0.28, 95% CI 0.12-0.63; p = 0.002).

CONCLUSIONS: The TRICALS risk score does not substitute for CSF neurofilament biomarkers as a prognostic or stratification variable but provides complementary information.},
}

Humans
*Amyotrophic Lateral Sclerosis/cerebrospinal fluid/drug therapy/diagnosis
*Neurofilament Proteins/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Prognosis
Female
Male
Middle Aged
Aged

@article {pmid42837018,
year = {2026},
author = {de Azevedo, EM and Bernardo, VS and Lima, MMS and Eleutherio, ECA and Outeiro, TF},
title = {SOD1 co-pathologies in the brain: insights from neuropathological evidence and implications.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42837018},
issn = {1432-0533},
support = {001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 88887.169657/2025-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 88881.986154/2024-01//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 300367/2026-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 210.034/2026//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; },
mesh = {Humans ; *Superoxide Dismutase-1/metabolism ; *Brain/pathology/metabolism ; *Neurodegenerative Diseases/pathology/metabolism ; Animals ; Amyotrophic Lateral Sclerosis/pathology ; },
abstract = {Superoxide dismutase 1 (SOD1), originally regarded as an antioxidant enzyme, is now recognized as a multifunctional protein whose conformational instability and aggregation contribute to neurodegeneration. The emerging evidence suggests that SOD1 pathology extends beyond amyotrophic lateral sclerosis, supporting a role in multiple neurodegenerative diseases. This review summarizes current neuropathological evidence of SOD1 co-pathologies in the human brain, with particular emphasis on its associations with TAR DNA-binding protein 43 (TDP-43), tau, alpha-synuclein, amyloid-β, and other aggregation-prone proteins. We examine the distribution of pathological SOD1 species across neurodegenerative diseases, their coexistence in affected brain regions, and potential mechanisms underlying these interactions, including oxidative stress, impaired proteostasis, aberrant phase separation, and cross-seeding. We also discuss emerging observations of SOD1 pathology in neurological conditions beyond classical neurodegenerative diseases, raising the possibility that SOD1 misfolding represents a broader cellular response to neuronal injury. Collectively, the available evidence supports a shift from viewing SOD1 as a disease-specific protein to considering it a potential participant in interconnected proteopathic networks. Although the functional significance of SOD1 co-pathologies remains incompletely understood, elucidating the molecular basis of aggregation may provide new insights into disease onset and progression, improving our understanding of neurodegenerative mechanisms, and facilitating the development of biomarkers and the identification of therapeutic targets across diverse proteinopathies.},
}

Humans
*Superoxide Dismutase-1/metabolism
*Brain/pathology/metabolism
*Neurodegenerative Diseases/pathology/metabolism
Animals
Amyotrophic Lateral Sclerosis/pathology

@article {pmid42829893,
year = {2026},
author = {Lv, C and Zhu, W and Wen, X and Wang, Y and Xie, N and Liu, H and Jiang, Y and Zou, W and Liu, Q and Gou, J and Yu, X and Di, L and Lu, Y and Wang, M and Xu, M and Chen, H and Duo, J and Huang, Y and Da, Y},
title = {Cerebrospinal fluid inflammatory proteomic profiling identifies biomarkers linked to disease progression in amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {273},
number = {10},
pages = {},
pmid = {42829893},
issn = {1432-1459},
support = {82571595//National Natural Science Foundation of China/ ; ZDYN-2024-A-081//General Office of the National Administration of Traditional Chinese Medicine, the General Office of the National Health Commission, the Health Bureau of the Logistics Support Department of the Central Military Commission/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid ; Female ; *Disease Progression ; Male ; Biomarkers/cerebrospinal fluid ; Proteomics ; Middle Aged ; Aged ; Inflammation/cerebrospinal fluid ; Adult ; *Neuroinflammatory Diseases/cerebrospinal fluid ; },
abstract = {BACKGROUND: Neuroinflammation is a key component of amyotrophic lateral sclerosis (ALS), but its association with disease progression heterogeneity remains unclear. We aimed to identify CSF inflammation-related proteins associated with disease progression phenotype in patients with ALS.

METHODS: Patients with ALS were stratified into slow progressors (SP) and fast progressors (FP) according to the disease progression rate. CSF inflammatory proteins were measured using the Olink Target 96 Inflammation panel. Disease-associated biomarkers were identified using limma package and elastic net (EN) analysis. We assessed the discriminatory power of disease-associated biomarkers using receiver operating characteristic curve analysis and estimated the optimism-adjusted area under the curve (AUC) using the bootstrapping method.

RESULTS: Among 77 patients (SP: n=40; FP: n=37), limma analysis identified 11 differentially expressed proteins, with functional enrichment in chemokine signaling, TNF-related responses and NF-κB pathways. EN analysis identified 12 candidate proteins, among which CST5, CCL11, SIRT2, CD6, CCL4, MMP-1, TNFRSF9, CCL19, and MCP-4 showed positive associations with the SP phenotype. A model combining SIRT2, MMP-1, BMI, and site of onset yielded an apparent area under the curve of 0.769 (95% CI 0.662 to 0.876) and an optimism-corrected area under the curve of 0.729.

CONCLUSION: Our study uncovered a CSF inflammatory proteomic signature associated with slow disease progression in ALS. These findings indicate that specific CSF neuroinflammatory protein signatures reflect biological heterogeneity in ALS disease progression rather than non-specific neurodegeneration. SIRT2 and MMP-1 warrant further investigation as components of progression-stratification models, although validation in larger, longitudinal, and independent cohorts is required.},
}

Humans
*Amyotrophic Lateral Sclerosis/cerebrospinal fluid
Female
*Disease Progression
Male
Biomarkers/cerebrospinal fluid
Proteomics
Middle Aged
Aged
Inflammation/cerebrospinal fluid
Adult
*Neuroinflammatory Diseases/cerebrospinal fluid

@article {pmid42831014,
year = {2026},
author = {Dorça, AC and Morais, LA},
title = {A Novel Device for Pulmonary Expansion Under Simulated Healthy and Neuromuscular Conditions: A Bench Simulation Study.},
journal = {Medical devices (Auckland, N.Z.)},
volume = {19},
number = {},
pages = {626538},
pmid = {42831014},
issn = {1179-1470},
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) leads to a progressive decline in respiratory function, requiring volumetric expansion techniques to prevent hypoventilation. However, the mechanical performance of devices used for this purpose requires evaluation under controlled conditions in bench simulation studies. Devices, such as the manual resuscitator, are commonly used, but present limitations, including high pressures, variable flow, among others. A novel respiratory muscle training device designed to provide controlled flow and pressure (ILLIFE-T) was developed.

OBJECTIVE: To evaluate the behavior of the variables pressure, volume, and flow during the volumetric expansion technique, comparing the new device with the manual resuscitator and the manual resuscitator + Positive Expiratory Pressure (PEP), using simulated models of healthy and ALS affected lungs.

METHODS: This bench simulation study used the ASL 5000 simulator, configured with predefined respiratory profiles representing healthy and ALS respiratory conditions. Four repetitions of the volumetric expansion maneuver were performed for each device and simulated respiratory condition, with five insufflations per repetition. One recording was randomly selected from each repetition for analysis, resulting in four observations per device and simulated respiratory condition.

RESULTS: In the simulation with healthy respiratory conditions, the new device generated higher pressure (23.38±3.81 cmH2O), volume (1991.25 ±174.10 mL), and lower flow variability (-1.47±11.43 L/min) compared with the manual resuscitator (12.25±11.73 cmH2O; 1113.64±131.75 mL; 18.84±61.31 L/min) and the manual resuscitator with PEP valve (16.89±0.64 cmH2O; 1817.25±86.77 mL; -49.49±9.96 L/min), respectively. In ALS simulated models, the new device also achieved higher pressure (23.69±3.29 cmH2O) and volume (2235.28±264.74 mL) compared with the manual resuscitator (8.33±8.34 cmH2O; 563.45±212.03 mL, respectively) and the manual resuscitator with PEP valve (14.89±7.60 cmH2O; 1449.86±153.09 mL, respectively). Flow values were similar among devices: 15.10 ± 18.00 L/min for the new device, 19.28±56.03 L/min for the manual resuscitator, and 0.18±51.67 L/min for the manual resuscitator with PEP valve.

CONCLUSION: Pressure and volume were higher with the new device in both simulated models. Flow did not differ significantly among devices, although lower variability was descriptively observed with the new device.},
}

@article {pmid42831057,
year = {2026},
author = {Lehrer, S},
title = {Transient Activation of Developmental Cytoskeletal Remodeling Programs After Traumatic Brain Injury: A Multiple-Reactivation Model of Neurodegeneration.},
journal = {Cureus},
volume = {18},
number = {9},
pages = {e115789},
pmid = {42831057},
issn = {2168-8184},
abstract = {Background Traumatic brain injury (TBI) may transiently reactivate developmental cytoskeletal programs required for neural remodeling and repair. We hypothesized that, unlike the persistent embryonic pathway reactivation proposed in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), TBI produces transient reactivation followed by suppression during recovery. Methods Human transcriptomic datasets were analyzed to characterize Arp2/3-mediated cytoskeletal remodeling after TBI. Single-nucleus RNA sequencing was used to assess cell-type-specific expression, and longitudinal peripheral blood transcriptomic data were analyzed at day 1 (D1), day 7 (D7), and 6 months (M6). Arp2/3 pathway scores were evaluated using differential-expression, mixed-effects, and within-subject analyses. Results Acute TBI showed directionally increased neuronal Arp2/3 expression. Longitudinal analysis demonstrated strong temporal variation in Arp2/3 activity (p = 2.77×10[-7] in complete cases). Relative to D1, pathway activity declined at D7 (estimate -0.753, p = 0.0001) and M6 (-1.009, p < 0.0001). All 12 subjects with complete longitudinal measurements had lower M6 than D1 scores. Conclusions Acute human TBI brain tissue showed activation of Arp2/3-mediated cytoskeletal remodeling, while an independent longitudinal peripheral-blood cohort showed rapid attenuation and longer-term suppression of Arp2/3 pathway activity after injury. Together, these findings are consistent with, but do not establish, a transient reactivation-resolution model.},
}

@article {pmid42831407,
year = {2026},
author = {Frycz, S and WiĘcławski, W and Skotniczny, M and Binder, M},
title = {Assessing consciousness in end-stage ALS: response to young's commentary.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-2},
doi = {10.1080/21678421.2026.2739760},
pmid = {42831407},
issn = {2167-9223},
}

@article {pmid42831851,
year = {2026},
author = {Morozova, V and Hassieb, M and Ahmed, Z},
title = {Multisite Anodal Direct Current Stimulation Preserves Motor Function and Modulates Key Cellular Pathways in TDP-43 and SOD1 Mouse Models of Amyotrophic Lateral Sclerosis.},
journal = {Neuromodulation : journal of the International Neuromodulation Society},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurom.2026.08.007},
pmid = {42831851},
issn = {1525-1403},
abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by degeneration of upper and lower motor neurons and disruption of normal motor network excitability. This study aimed to determine whether multi-site direct current stimulation (DCS) can modulate spinal motor circuit excitability in an experimental model of ALS and to evaluate its potential as a neuromodulation approach for preserving motor pathway function.

MATERIALS AND METHODS: In an initial electrophysiological experiment, corticospinal-evoked muscle contractions were recorded using a force-displacement transducer to compare the effects of different multisite spinal electrode configurations on corticospinal output. Subsequently, two ALS mouse models, SOD1-G93A and TDP-43 A315T, underwent repeated in vivo multisite anodal DCS. Motor function was assessed using grid walking, hindlimb grip strength, and wire-hang tests across five time points. In the TDP-43 A315T model, motor neuron soma size was quantified using choline acetyltransferase immunostaining, whereas heat shock protein 70 (HSP70) expression and TDP-43/phosphorylated TDP-43 (p-TDP-43) aggregation were evaluated using western blotting and confocal imaging.

RESULTS: Multisite DCS produced the strongest suppression of corticospinal-evoked muscle contractions among all electrode configurations tested, indicating robust modulation of spinal excitability. In SOD1-G93A mice, repeated stimulation preserved motor performance across all behavioral assays, with the clearest differences emerging during later disease stages relative to unstimulated controls. In TDP-43 A315T mice, stimulation was associated with improved motor performance at the final testing point, preservation of motor neuron soma size, increased HSP70 expression, and significant reductions in both the number and size of cytoplasmic TDP-43 and pathological p-TDP-43 aggregates, consistent with enhanced proteostatic capacity and pathological protein clearance.

CONCLUSIONS: Multisite anodal DCS effectively modulates spinal excitability and preserves motor function in two mechanistically distinct mouse models of ALS. In the TDP-43 A315T model, these functional benefits are accompanied by preservation of motor neuron structure and molecular changes consistent with improved protein homeostasis. Together, these findings support multisite DCS as a promising neuromodulatory strategy for influencing disease-relevant mechanisms and slowing functional decline in ALS.},
}

@article {pmid42831972,
year = {2026},
author = {Rosenbohm, A and Herrera-Angeles, F and Huppertz, HJ and Haeusler, KG and Weishaupt, JH and Müller, HP and Kassubek, J},
title = {Neuroimaging signatures of facial onset sensory and motor neuronopathy (FOSMN).},
journal = {Journal of neurology},
volume = {273},
number = {10},
pages = {},
pmid = {42831972},
issn = {1432-1459},
mesh = {Humans ; Female ; Male ; Diffusion Tensor Imaging ; *Brain/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; Middle Aged ; *Neuroimaging ; *Facial Nerve Diseases/diagnostic imaging/pathology ; Atrophy ; Adult ; Image Processing, Computer-Assisted ; Aged ; *Motor Neuron Disease ; },
abstract = {Facial onset sensory and motor neuronopathy (FOSMN) is an exceptionally rare condition characterized by progressive facial paresthesia and the subsequent appearance of bulbar symptoms with rostro-caudal motor and sensory deficits sometimes extending to the hand muscles. The pathophysiological understanding of this disorder is very limited. In order to identify patterns of neuroanatomical involvement within the brain, we applied advanced magnetic resonance imaging-based techniques to a group of six patients with the diagnosis of FOSMN, using unbiased analysis techniques with atlas-based volumetry of volume-rendering T1-weighted data and whole brain-based spatial statistics of diffusion tensor imaging (DTI). The volumetric data showed significant global atrophy with prominent involvement of the medulla oblongata, while DTI demonstrated significant decreases in the right-hemispheric frontal lobe and bilaterally along the superior and inferior longitudinal fasciculi. In summary, this application of volumetry and DTI to a group of FOSMN patients demonstrated, beyond global brain atrophy as a correlate of a systemic disease process, regional atrophy in the brainstem/medulla oblongata, together with tract alterations of polymodal frontotemporoparietal interconnections. Future neuroimaging studies in larger patient groups of FOSMN are needed for detailed phenotype-neuroimaging correlations.},
}

Humans
Female
Male
Diffusion Tensor Imaging
*Brain/diagnostic imaging/pathology
Magnetic Resonance Imaging
Middle Aged
*Neuroimaging
*Facial Nerve Diseases/diagnostic imaging/pathology
Atrophy
Adult
Image Processing, Computer-Assisted
Aged
*Motor Neuron Disease

@article {pmid42832558,
year = {2026},
author = {Sui, Y and Zheng, DQ and Wang, Y and Zhao, SS and Li, KJ and Ye, C and Zhang, K},
title = {Decoupling metabolic defense: Mutational and recombinational chaos in Sod1-deficient cells.},
journal = {PLoS genetics},
volume = {22},
number = {10},
pages = {e1012326},
doi = {10.1371/journal.pgen.1012326},
pmid = {42832558},
issn = {1553-7404},
abstract = {Superoxide dismutase 1 (Sod1) is long recognized as a frontline antioxidant, yet its broader role in safeguarding the eukaryotic genome remains under-explored. Here, using a yeast model, we reveal that Sod1 is an indispensable guardian of genomic integrity. Its absence unleashes a genomic storm: whole-genome sequencing uncovered a dramatic surge in single nucleotide variations (13-fold), loss of heterozygosity (12-fold), chromosomal rearrangements (4-fold), and a staggering 48-fold increase in aneuploidy. Remarkably, this genomic instability was completely abolished under anaerobic conditions, identifying reactive oxygen species as the sole executioner. We demonstrate that Sod1 deficiency sculpts a unique mutational landscape dominated by C:G to A:T transversions-a molecular fingerprint of 8-oxoguanine overproduction. Mechanistically, these lesions are exacerbated by error-prone DNA polymerase ζ but mitigated by the concerted actions of Ogg1-mediated excision and DNA polymerase η. Critically, we show that Amyotrophic Lateral Sclerosis-associated variants are not created equal: the H48Q mutation shatters genome stability, whereas others (A4V, G36R, and G93A) remain benign in this context. Unlike yeast Sod1, human Sod1 is highly resistant to amino acid substitutions outside copper-binding sites, thus preventing the loss of enzyme function. Overall, our findings provide a mechanistically framework for understanding how Sod1 dysfunction drives genome instability in eukaryotic cells.},
}

@article {pmid42832702,
year = {2026},
author = {Batisse, E and Lloyd, M and Renoux, C and Ganji, A and Xu, J and Hatzopoulou, M and Weichenthal, S and Baumgartner, J},
title = {Long-term exposure to ultrafine particles and mortality from neurodegenerative diseases: a population-based cohort study.},
journal = {Epidemiology (Cambridge, Mass.)},
volume = {},
number = {},
pages = {},
doi = {10.1097/EDE.0000000000002054},
pmid = {42832702},
issn = {1531-5487},
abstract = {BACKGROUND: Transportation and industrial activities emit large quantities of air pollutants, including unregulated ultrafine particles (UFP, <0.1 um), which may adversely affect brain health.

METHODS: We analyzed data from 2.1 million adults in the Canadian Census Health and Environment Cohorts (CanCHECs) living in Montreal and Toronto (2001-2019). Vital status and primary cause of death were obtained from the Canadian Vital Statistics- Death database. We assigned high-resolution estimates of UFP number concentrations and UFP size to participants' residential postal codes using three-year moving averages. Cox proportional hazards models were used to estimates hazard ratios (HRs) between long-term outdoor UFP number concentrations and mortality from dementia, Parkinson's disease, and amyotrophic lateral sclerosis. We further examined associations by dementia sub-types including Alzheimer's disease, vascular dementia and unspecified dementia. Models were used with and without inverse probability of censoring weights for competing events, and adjusted for UFP size, sociodemographic factors, and co-pollutants.

FINDINGS: Over 19 million person-years, we identified 20,560 deaths from neurodegenerative diseases. Each 10,000 particle/cm 3 increase in UFP number concentrations was associated with increased dementia mortality (HR = 1.22, 95% CI: 1.17-1.27), with stronger associations observed after adjusting for UFP size. Positive associations were observed for all dementia subtypes, with the largest for vascular dementia (HR = 1.49, 95% CI: 1.27-1.76). We did not observe effects of UFP on mortality from Parkinson's disease or amyotrophic lateral sclerosis.

INTERPRETATION: Long-term exposure to outdoor UFPs may contribute to mortality from specific neurodegenerative diseases, particularly dementia. Reducing population exposures to these unregulated pollutants could help mitigate the burden of neurodegenerative mortality.},
}

@article {pmid42833128,
year = {2026},
author = {Basanth, S},
title = {Enzymatic N-deacylation is the predicted membrane-disruption switch for sphingomyelin: a falsifiable in-silico framework for sphingolipid vulnerability in ALS.},
journal = {Journal of molecular graphics & modelling},
volume = {149},
number = {},
pages = {109570},
doi = {10.1016/j.jmgm.2026.109570},
pmid = {42833128},
issn = {1873-4243},
abstract = {Sphingolipid dysregulation is an emerging feature of amyotrophic lateral sclerosis (ALS), but no systematic method separates species that may worsen axon-myelin membrane integrity from matter that may counteract it. We present an in-silico framework classifying sphingolipids and designed derivatives as candidate membrane-disruptive or candidate protective species, scored against real biological referents using externally published tools rather than a bespoke composite. Its central finding concerns a single, chemically defined difference in lipid state. In coarse-grained (MARTINI 3) molecular dynamics with three independent replicates per system, intact palmitoyl-sphingomyelin is indistinguishable from a pure-POPC bilayer (leaflet-mean Δ thickness + 0.001 nm, 95% CI brackets zero), whereas the modeled N-deacylated form thins it in every replicate (Δ=-0.043 nm, [- 0.046, - 0.041]), tracking a lyso-phosphatidylcholine detergent control (-0.083 nm, [- 0.087, - 0.080]) on two concordant estimators. Because only one lyso-sphingolipid is parameterized in public MARTINI 3, N-deacylation is not established here as a class-wide effect. Across eleven ALS studies (2021-2026), six report elevated serine-palmitoyltransferase (SPT) pathway sphingolipids, all in monogenic SPTLC1/SPTLC2 cohorts, whereas sporadic cohorts show disturbance without a shared direction. Because the simulations do not address whether this species is produced, accumulates, or reaches pathological concentrations in ALS tissue, we present the ALS connection as hypothesis-generating rather than direct evidence. Separately, an explicitly exploratory arm reports two designed modulators with predicted target engagement (Boltz-2) and an ADMET triage of their liabilities. The primary contribution is the membrane result with a wet-lab panel that makes it falsifiable.},
}

@article {pmid42833496,
year = {2026},
author = {Navarrete-Dechent, C and Pietkiewicz, P and Voloshynovych, M and Anriot, J and Marghoob, AA},
title = {Authors' response to Michelerio and Farnetani "Response to Navarrete-Dechent et al's 'Ultraviolet-induced fluorescent dermoscopy for the diagnosis of skin tumors: A multicenter study'".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2026.09.117},
pmid = {42833496},
issn = {1097-6787},
}

@article {pmid42828230,
year = {2026},
author = {Guo, X and Li, X and Chen, J and Bai, L and Yu, H and Cui, H},
title = {AHAS structural changes caused by mutations result in differences in binding affinity and resistance to two herbicides in Cyperus difformis L.},
journal = {Frontiers in plant science},
volume = {17},
number = {},
pages = {1932845},
pmid = {42828230},
issn = {1664-462X},
abstract = {As a malignant weed in paddy systems, Cyperus difformis L. (C. difformis) has evolved resistance to acetohydroxyacid synthase (AHAS, EC 2.2.1.6), also known as acetolactate synthase (ALS), inhibiting herbicides such as pyrazosulfuron-ethyl and bensulfuron-methyl due to prolonged selection pressure. This study systematically investigated the interaction mechanisms between mutated AHAS and these herbicides through biochemical and structural approaches. In this study, purified AHAS proteins of five mutated types and the wild type were obtained via prokaryotic expression, and their sensitivity and affinity for pyrazosulfuron-ethyl and bensulfuron-methyl were determined. The structural differences in different binding of AHAS binding to the two herbicides were identified via homology modeling and molecular docking. The sensitivity determination of purified AHAS indicated that AHAS with site 197 mutations had higher GR50 and I50 values for pyrazosulfuron-ethyl (25.60-74.78 μM) than for bensulfuron-methyl (6.62-38.32 μM). The AHAS with a site 376 mutation had higher GR50 and I50 values for bensulfuron-methyl than for pyrazosulfuron-ethyl, while the GR50 and I50 values of the AHAS with a site 574 mutation were the highest. The affinity of purified AHAS for the substrate revealed that all the mutations increased the affinity except for the Pro-197-Arg mutation. In addition, all the AHAS mutants had greater affinity for bensulfuron-methyl than for pyrazosulfuron-ethyl. Molecular docking results revealed that AHAS formed hydrogen bonds, π-π bonds, and hydrophobic interactions with pyrazosulfuron-ethyl and bensulfuron-methyl. The total number and types of interactions with pyrazosulfuron-ethyl and benzosulfuron-methyl were obviously different between the mutant AHAS and wild-type AHAS. Therefore, in this study, different mutations in AHAS induced distinct structural alterations, which reduced the affinity of the enzyme for herbicides, consequently leading to the development of weed resistance. The difference in affinity between the same mutant and the two herbicides led to a difference in resistance to the two herbicides. The results of this study are helpful for understanding the causes of weed resistance to herbicides at the structural level.},
}

@article {pmid42829678,
year = {2026},
author = {Ottu Para, NK},
title = {When the Electromyography (EMG) and the Patient Disagree: Unraveling a Motor Neuron Disease Mimic With Small-Fiber Dysfunction.},
journal = {Cureus},
volume = {18},
number = {9},
pages = {e115700},
pmid = {42829678},
issn = {2168-8184},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by upper and lower motor neuron dysfunction. Electromyography (EMG) is central to its evaluation, but neurogenic abnormalities and fasciculations are not specific to ALS and must be interpreted within the clinical phenotype and disease trajectory. This study reports a 52-year-old man with an approximately eight-year history of intermittent muscle twitching, bilateral upper-limb tremor, muscular tightness and warmth, and asymmetric cutaneous hypersensitivity. An initial electrodiagnostic evaluation raised concern for diffuse motor neuron disease, despite preserved strength, normal gait, absence of muscle wasting, and lack of clear upper motor neuron signs. Extensive evaluation for inflammatory, autoimmune, metabolic, toxic, infectious, paraneoplastic, neuromuscular junction, and peripheral nerve hyperexcitability disorders was unrevealing. Serum creatine kinase was mildly and variably elevated, while aldolase and a comprehensive myositis panel were normal. Brain magnetic resonance imaging (MRI) demonstrated no supportive features of ALS. Sudomotor testing showed reduced electrochemical skin conductance (ESC) in the hands, supporting small-fiber/autonomic dysfunction in the context of prominent sensory symptoms. Repeat EMG, performed after interval follow-up with broad muscle sampling, demonstrated focal neurogenic abnormalities involving bilateral ulnar distributions and left L5-S1 radiculopathy but found no electrophysiological evidence of a neurodegenerative disorder. The patient was treated symptomatically with gabapentin and vitamin E and reported approximately 80% improvement after six weeks. This case highlights the importance of clinicophysiological correlation, disease trajectory, sensory phenomenology, and repeat electrophysiology when an initial EMG suggests motor neuron disease but the longitudinal clinical picture is discordant. It also illustrates how small-fiber dysfunction and focal neurogenic abnormalities may coexist and mimic a progressive motor neuron syndrome.},
}

@article {pmid42826761,
year = {2026},
author = {Shai, Y and Alam, M and Dong, X and Zhang, Y and Hu, Y and He, Z and Feng, J and Chen, Y and Zhou, Z and Jiang, H},
title = {Mdivi-1 regulates mitochondrial fission and function via the CaMK2/Drp1 pathway in amyotrophic lateral sclerosis.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.10.002},
pmid = {42826761},
issn = {1873-7544},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive motor neuron loss. Given the high energy reliance of motor neurons, mitochondrial dysfunction especially excessive fission critically contributes to disease pathogenesis. Mitochondrial division inhibitor-1 (Mdivi-1), an inhibitor of the fission protein Drp1, has shown neuroprotective potential, but its mechanism of action on mitochondrial quality control in ALS remains unclear. Here, we examined the effects of Mdivi-1 on mitochondrial dysfunction and cell injury in NSC34 cells expressing mutant SOD1^G93A and in SOD1^G93A transgenic mice. ALS models exhibited increased reactive oxygen species accumulation, reduced mitochondrial content, loss of mitochondrial membrane potential, enhanced apoptotic signaling, and increased phosphorylation of CaMK2 and Drp1. Mdivi-1 treatment improved cell viability, reduced oxidative stress, restored mitochondrial integrity and membrane potential, and suppressed apoptosis. In addition, Mdivi-1 decreased Drp1 phosphorylation, whereas co-treatment with the CaMK2 activator DCP-LA partially reversed these effects. Furthermore, direct inhibition of CaMK2 with KN93 reduced CaMK2 and Drp1 phosphorylation, providing additional evidence that CaMK2 regulates Drp1 activation in SOD1^G93A cells. These findings indicate that pharmacological modulation of the CaMK2/Drp1 pathway can attenuate aberrant mitochondrial fission and associated cellular dysfunction in ALS models.},
}

@article {pmid42823255,
year = {2026},
author = {Corcia, P and Erazo, A and Couratier, P},
title = {Towards the integration of open-label extension and real-world evidence in ALS therapeutic evaluation?.},
journal = {Revue neurologique},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurol.2026.09.004},
pmid = {42823255},
issn = {0035-3787},
}

@article {pmid42823490,
year = {2026},
author = {Hatano, Y and Ishihara, T and Tada, M and Li, Y and Hirokawa, S and Uemura, M and Ando, S and Yokoseki, A and Kakita, A and Onodera, O},
title = {Insertion or deletion variants in TAF15 exon 15 are genetic factors impacting the prognosis of amyotrophic lateral sclerosis in a Japanese cohort.},
journal = {European journal of human genetics : EJHG},
volume = {},
number = {},
pages = {},
pmid = {42823490},
issn = {1476-5438},
support = {24K10506//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23K14771//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; },
abstract = {The influence of genetic factors on the prognosis of amyotrophic lateral sclerosis (ALS) has attracted considerable attention, with numerous studies exploring this relationship in clinically diagnosed patients. The present study attempted to clarify the precise impact of genetic factors on prognosis in patients with pathologically confirmed sporadic ALS. We conducted exome analysis on 137 consecutively autopsied patients with sporadic ALS exhibiting TDP-43 pathology, screening for non-synonymous or splice-site rare variants (RVs) in ALS-related genes. The impact of these variants on ALS prognosis was subsequently assessed. The exome analysis identified 31 RVs in 27 of the 137 patients, including TAF15 exon 15 insertion/deletion mutations (TAF15-15 indels) in 9 patients. Patients harboring RVs had significantly shorter survival times (median 18.0 months) than those without RVs (28.5 months), as determined by log-rank test (p = 0.02). Notably, the 9 cases with TAF15-15 indels demonstrated a significantly poorer outcome (15.0 months, p = 3e-06). Lattice Simulation of Sticker-Spacer Interactions (LASSI) simulations revealed stronger negative sticker-sticker interactions, and a tendency toward lower saturation concentration and higher dense-phase concentration in TAF15-15 indel proteins, suggesting enhanced condensation. The present analysis of pathologically diagnosed ALS patients has yielded genetic factors that could potentially aid more accurate diagnosis and prognostication. The frequent identification of TAF15-15 indels among ALS cases, and their association with significantly poorer outcome, suggests that this type of mutation could be prognostically significant in ALS. Furthermore, the mechanism by which TAF15-15 indels influence the course of ALS could be a promising target for future treatments.},
}

@article {pmid42825398,
year = {2026},
author = {Davias, A and Hansen, J and Akdis, CA and Weisskopf, MG},
title = {Associations Between Prediagnosis Plasma Neurofilament Light Polypeptide and Amyotrophic Lateral Sclerosis Risk in the Danish EPIC Cohort.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78382},
pmid = {42825398},
issn = {1531-8249},
abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a rapid time from symptoms onset to diagnosis. Elevated neurofilament light polypeptide (NfL) is well-established in symptomatic ALS and up to 5 years prediagnosis, but earlier timeframes remain understudied. We aimed to assess plasma NfL levels up to 23 years before ALS diagnosis and the relation to ALS risk.

METHODS: We conducted a nested matched case-control study within the Danish EPIC cohort (baseline 1993-1997) including 166 ALS cases (diagnosed 1997-2017) and 332 controls matched on birth year and sex. Plasma samples collected 0.4 to 23.2 years (median 14.1 years) prediagnosis were analyzed for NfL using Olink Target 96. Odds ratios were estimated using conditional logistic regression. Discriminatory performance was evaluated using receiver operating characteristic curves.

RESULTS: NfL levels were elevated in ALS cases relative to controls up to 14.6 years before diagnosis. Among those with blood samples collected <5, 5 to 14.6, and >14.6 years before diagnosis, the odds ratios (95% CI) for ALS per standard deviation increase in the normalized protein expression value of NfL were 3.8 (1.4-10.3), 1.7 (1.2-2.3), and 1.3 (0.9-1.7), respectively. The areas under the curve for ALS discrimination by NfL among those with blood collected <5 and 5-14.6 years before diagnosis were 0.78 and 0.63, respectively.

INTERPRETATION: Plasma NfL elevation may occur significantly earlier than previously reported, indicating a much longer ALS prodrome. Assuming other biomarker changes may also occur earlier, this raises the possibility of identifying at-risk individuals early that could benefit epidemiologic analyses, clinical trials, and prevention efforts. ANN NEUROL 2026.},
}

@article {pmid42825562,
year = {2026},
author = {Bromberg, MB},
title = {Amyotrophic Lateral Sclerosis.},
journal = {Continuum (Minneapolis, Minn.)},
volume = {32},
number = {5},
pages = {1529-1544},
doi = {10.1212/cont.0000000000001753},
pmid = {42825562},
issn = {1538-6899},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy/genetics/physiopathology ; Female ; Male ; Middle Aged ; },
abstract = {OBJECTIVE: This article describes the nerve loss underlying amyotrophic lateral sclerosis, its clinical manifestations, examination findings leading to the diagnosis, the expanding role of genetics, and available treatment and patient management.

LATEST DEVELOPMENTS: The cause of neuron death in patients with amyotrophic lateral sclerosis is not known, but many genes are strongly linked to the disease, in both patients with a family history and those with no history. A multistep pathologic process helps to explain the onset of symptoms later in life, even in patients with associated genes. Posttranslational and epigenetic changes are also important factors. Current clinical trials are based on putative pathologic mechanisms, and some newer therapies are gene-based.

ESSENTIAL POINTS: Amyotrophic lateral sclerosis has distinctive features and can be diagnosed largely from the history and examination, and true mimics are rare. While the cause of neuronal death is not known, pathogenic and risk factor gene variations are present in a number of patients, and posttranscriptional and epigenetic changes are likely major causative factors. Environmental factors likely contribute, but specific avoidable factors have not been identified. Drugs to slow the progress of the disease are currently limited, but trials for all patients with amyotrophic lateral sclerosis continue, including a focus on genetic factors. Patient management is optimized in multidisciplinary amyotrophic lateral sclerosis clinics, and interventions for nutrition with gastric feeding tubes and respiratory insufficiency by noninvasive ventilation enhance patient comfort.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/therapy/genetics/physiopathology
Female
Male
Middle Aged

@article {pmid42826575,
year = {2026},
author = {Tripathi, A and Yadav, AK and Kumar, N},
title = {AI-driven transcriptomics for neurodegenerative disease research: A systematic review.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 1},
pages = {109448},
doi = {10.1016/j.compbiolchem.2026.109448},
pmid = {42826575},
issn = {1476-928X},
abstract = {BACKGROUND: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS), present a growing global health challenge, with traditional diagnostic and therapeutic approaches facing significant limitations in early detection and mechanistic resolution.

OBJECTIVES: Innovations in transcriptomic technologies-spanning bulk RNA sequencing, single-cell RNA-seq (scRNA-seq), and spatially resolved transcriptomics-provide unprecedented insights into cellular heterogeneity and microenvironmental dysregulation. This systematic review synthesizes recent applications of artificial intelligence (AI), machine learning (ML), and deep learning (DL) across transcriptomic tiers to benchmark computational models for biomarker identification, disease diagnosis, patient subtyping, and drug repurposing.

METHODS & ELIGIBILITY: Following PRISMA 2020 guidelines for qualitative systematic reviews, literature published between 2016 and 2025 was systematically searched across PubMed/MEDLINE, IEEE Xplore, Google Scholar, and bioRxiv/medRxiv. Of 1058 records identified, 19 core empirical studies met all eligibility criteria and were synthesized in depth alongside contextual reference benchmarks.

SYNTHESIS & KEY FINDINGS: Traditional ML algorithms (SVM, RF, Elastic Net) demonstrate high diagnostic accuracy (AUC 0.72-0.98) in blood-based biomarker selection, while deep architectures (autoencoders, LSTMs, and Graph Neural Networks) excel at modeling continuous disease trajectories and resolving spatial transcriptomic niches (e.g., STAGATE, SpaGCN, cell2location). Emerging spatial deep learning models successfully localize disease-associated microglia (DAM) around amyloid plaques and trace axonal degeneration pathways.

LIMITATIONS & CONCLUSIONS: Key translational hurdles include data scarcity in rare NDD subtypes, lack of cross-platform spatial benchmarks, and the black-box nature of deep neural networks. Integrating explainable AI (XAI) and prospective multi-modal cohorts is essential for translating computational transcriptomics into clinical diagnostics and targeted therapeutics.},
}

@article {pmid42826598,
year = {2026},
author = {Rava, A and Di Trapano, M and Tse, C and Ji, L and Bid, HK and Trezza, V},
title = {Acidic cannabinoids in brain disorders: Neurobiological mechanisms, preclinical evidence, and translational challenges.},
journal = {Neuroscience and biobehavioral reviews},
volume = {191},
number = {},
pages = {107005},
doi = {10.1016/j.neubiorev.2026.107005},
pmid = {42826598},
issn = {1873-7528},
abstract = {Acidic cannabinoids, including tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), and related biosynthetic precursors, represent the predominant phytocannabinoid forms naturally produced by Cannabis sativa. Long considered pharmacologically inactive intermediates, these compounds are now increasingly recognized as bioactive molecules with potential therapeutic relevance for brain disorders. Compared with their decarboxylated counterparts, acidic cannabinoids exhibit distinct physicochemical, pharmacokinetic, and pharmacodynamic properties that may confer reduced psychotropic liability together with unique neurobiological effects. Emerging preclinical evidence indicates that acidic cannabinoids modulate multiple processes implicated in neurological and psychiatric disorders, including serotonergic and endocannabinoid signaling, neuroinflammation, oxidative stress, mitochondrial dysfunction, calcium dyshomeostasis, and synaptic transmission. In this review, we critically examine current knowledge regarding acidic cannabinoids in the context of brain disorders. We first summarize their biosynthesis, chemical stability, pharmacokinetic characteristics, and pharmacological differences from neutral cannabinoids. We then examine preclinical evidence supporting their potential therapeutic effects in epilepsy, anxiety, depression, psychosis-related conditions, and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We also discuss how artificial intelligence and computational approaches may support target identification, formulation optimization, pharmacokinetic modeling, and the development of personalized cannabinoid-based interventions. Finally, we highlight key methodological and translational challenges limiting the field and outline priorities for future research. Overall, acidic cannabinoids emerge as promising but still underexplored multitarget compounds with potential relevance for the treatment of brain disorders.},
}

@article {pmid42826647,
year = {2026},
author = {Esmaeili, H and Das, S and Rytel, K and Sidransky, E and Chen, Y},
title = {CRISPR screening in neurodegeneration and lysosomal biology: Uncovering disease mechanisms and genetic modifiers.},
journal = {Molecular genetics and metabolism},
volume = {149},
number = {3},
pages = {110265},
doi = {10.1016/j.ymgme.2026.110265},
pmid = {42826647},
issn = {1096-7206},
abstract = {Growing genetic and mechanistic evidence has highlighted substantial convergence between neurodegenerative disorders and lysosomal biology. Variants in lysosomal protein-encoding genes associated with lysosomal storage disorders (LSDs) have been implicated in common neurodegenerative diseases, suggesting that perturbations of lysosomal function represent a shared pathogenic mechanism. However, the low penetrance of neurodegenerative diseases in individuals carrying variants in these lysosomal genes suggests that additional genetic modifiers are involved as well. Advances in functional genomics, particularly clustered regularly interspaced short palindromic repeat (CRISPR)-based high-throughput screens, have opened new avenues to identify such modifiers and elucidate disease-associated pathways. These unbiased approaches have accelerated the discovery of molecular mechanisms underlying neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although to date few studies have applied CRISPR-based functional screens directly to LSDs, findings from neurodegenerative disease models provide a valuable framework for investigating lysosomal pathways and identifying genetic factors that influence phenotypic variability. In this review, we summarize recent advances in in vitro CRISPR-based screening approaches in neurodegenerative disorders and discuss their implications for understanding lysosomal biology and LSD-related mechanisms.},
}

@article {pmid42826718,
year = {2026},
author = {Cha, Y and Kim, KS},
title = {From patient cells to patient therapy: Twenty years of iPSC-based translation in neurodegenerative disease.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {103104},
doi = {10.1016/j.xcrm.2026.103104},
pmid = {42826718},
issn = {2666-3791},
abstract = {Twenty years after the discovery of induced pluripotent stem cells, the field has progressed from patient-specific disease modeling toward cell-based therapies for neurodegenerative disorders. Parkinson's disease has emerged as the leading model for neuronal replacement, whereas Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis require distinct combinations of circuit reconstruction, cellular support, immune modulation, and engineered therapeutic delivery. We discuss key determinants of clinical translation, including cell source, product identity, graft composition, graft-host interactions, manufacturing reproducibility, genomic integrity, and clinical evaluation. We propose that the interval between cell transplantation and long-term engraftment constitutes a biological "black box" in which graft fate and therapeutic outcome are determined. As regenerative medicine enters its third decade, future progress will depend not only on generating therapeutic cells but also on elucidating and engineering the biological processes that determine their fate after transplantation, marking a conceptual transition from stem cell biology toward transplantation biology.},
}

@article {pmid42826720,
year = {2026},
author = {Li, X and Cao, Z and Jiang, O and Wu, S and Zhou, B and Feng, Y and Chen, X and Wang, J and Zhou, J and Yan, R and Chen, M and Wang, S},
title = {Nitrate-responsive Sialin2 couples stress granule assembly and clearance to maintain neuronal homeostasis.},
journal = {Developmental cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.devcel.2026.09.001},
pmid = {42826720},
issn = {1878-1551},
abstract = {Stress granules (SGs) are phase-separated ribonucleoprotein condensates that support cellular adaptation to acute stress, but how extracellular signals coordinate their assembly and recovery-phase clearance remains unclear. Here, we show that nitrate-responsive Sialin2 coordinates SG homeostasis across the stress cycle. During acute stress, Sialin2 undergoes liquid-liquid phase separation and co-assembles with Ras GTPase-activating protein SH3-domain-binding protein (G3BP)-centered scaffolds to promote SG formation. During recovery, Sialin2 preserves liquid-like SG dynamics and promotes autophagy-linked clearance. Sialin2 loss delays SG resolution, promotes retention of amyotrophic lateral sclerosis (ALS)-linked fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43) variants, and enhances amyloid precursor protein (APP)-related amyloidogenic output. In an ALS mouse model, nitrate treatment reduces SG-like pathology and neuroinflammation, preserves neuronal integrity, and delays functional decline. Together, these findings define a nitrate-Sialin2 signaling module that couples SG assembly to recovery-phase clearance and links inorganic anion sensing to protection against neurodegeneration.},
}

@article {pmid42809873,
year = {2026},
author = {Fila, J and Quiroga, C and Di Gennaro, MS and Veloso, VI and Tripodoro, VA},
title = {[What to learn and teach to implement Shared Care Planning for people with Amyotrophic Lateral Sclerosis? Nominal Group Technique].},
journal = {Revista de la Facultad de Ciencias Medicas (Cordoba, Argentina)},
volume = {83},
number = {3},
pages = {e50160},
doi = {10.31053/1853.0605.v83.n3.50160},
pmid = {42809873},
issn = {1853-0605},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Patient Care Planning ; },
abstract = {BACKGROUND: Advance Care Planning (ACP) is crucial in neurodegenerative conditions such as Amyotrophic Lateral Sclerosis (ALS), yet its implementation in Latin America remains limited, partly due to the lack of specific professional training. The objective of this work is to identify, from the perspective of experienced professionals, the main barriers, tensions, and core contents for designing a training program in ACP for teams caring for people with ALS.

METHODS: A qualitative study using a participatory approach and Nominal Group Technique was conducted in Argentina in 2023. Seventeen professionals from clinical and psychosocial fields participated in the study. Thematic analysis was applied, with triangulation and consensus validation.

RESULTS: Implementation barriers and six thematic areas were identified. Key topics included ethical frameworks, communication tools, existential distress, and strategies for involving families. A cross-cutting axis was the influence of local culture, team emotional responses, and the prevailing biomedical model.

CONCLUSION: This study offers a conceptual and practical foundation for developing ACP training programs in the context of progressive neurological diseases. It represents a first step toward addressing a training gap in the region.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy
*Patient Care Planning

@article {pmid42816314,
year = {2026},
author = {Bryant, RJ and Marian, IR and Wolstenholme, J and Lamb, AD},
title = {Reply to Flavio L. Heldwein et al's Letter to the Editor re: Little M, Wolstenholme J, Landeiro F, Marian IR, Williams R, Francisco Lopez J, et al. Cost Effectiveness of Local Anaesthetic Transperineal Versus Transrectal Biopsy: Results from the TRANSLATE Study. Eur Urol Focus 2026;12:227-36.},
journal = {European urology focus},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.euf.2026.09.005},
pmid = {42816314},
issn = {2405-4569},
}

@article {pmid42817119,
year = {2026},
author = {Verma, A and Kushwaha, SKS and Kushwaha, N and Dutta, S and Nigam, P},
title = {Neuroinflammation and Autophagy in Neurodegeneration: Cellular Mechanisms and Therapeutic Strategies.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273459017260922073618},
pmid = {42817119},
issn = {1996-3181},
abstract = {Neurodegenerative diseases, including Huntington's disease, Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal dysfunction and loss, often accompanied by toxic protein aggregation and chronic neuroinflammation. Increasing evidence indicates that dysregulated autophagy and persistent inflammatory responses are central drivers of disease onset and progression. Autophagy, a fundamental cellular degradation and recycling process, is essential for maintaining neuronal homeostasis by removing damaged organelles and misfolded proteins through mechanisms such as macroautophagy and mitophagy. However, key regulators of this pathway, including ULK1, Beclin-1, LC3, and p62/SQSTM1, are frequently impaired in neurodegenerative conditions, leading to the accumulation of pathogenic proteins such as tau, α-synuclein, and amyloid-β. Concurrently, aberrant activation of microglia and inflammasomes promotes the sustained release of pro-inflammatory cytokines, creating a neurotoxic environment that exacerbates neuronal injury. This review examines the molecular crosstalk between autophagy and neuroinflammation, with particular emphasis on disease-specific mechanisms, including LC3-associated endocytosis (LANDO) in Alzheimer's disease, tau-mediated pathology, and dopaminergic neurodegeneration in Parkinson's disease. Importantly, this review introduces a unifying conceptual framework in which neuroinflammation and autophagy are integrated as a dynamic, stagedependent immune-autophagy axis that governs neurodegenerative disease progression and therapeutic responsiveness. In addition, emerging multimodal therapeutic strategies targeting both autophagic flux and immune modulation are discussed, including mTOR inhibitors, mitophagy enhancers, GLP-1 receptor agonists, and nanomedicine-based delivery systems. Advances in three-dimensional organoids, induced Pluripotent Stem Cell (iPSC) models, and biomarker-driven clinical trials are further enhancing translational potential. In conclusion, understanding the interplay between autophagy and neuroinflammation provides critical insights into the pathophysiology of neurodegeneration and offers promising avenues for the development of targeted, disease-modifying therapies.},
}

@article {pmid42817633,
year = {2026},
author = {Morley, JF},
title = {Proteostasis (in)action: the role of co-pathologies in neurodegenerative disease.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {381},
number = {1960},
pages = {},
pmid = {42817633},
issn = {1471-2970},
mesh = {*Proteostasis ; Humans ; *Neurodegenerative Diseases/physiopathology/pathology ; Animals ; Proteotoxic Stress ; Protein Folding ; },
abstract = {Clinically distinct neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), share in common progressive neuronal dysfunction and cell death associated with the accumulation of misfolded proteins. Central to these processes are the cellular and organismal proteostasis networks responsible for maintaining protein homeostasis through coordinated actions of molecular chaperones, the ubiquitin-proteasome system and autophagy-lysosomal pathways. As a consequence of ageing, genetic modifications and other disease-specific conditions, the proteostatic network becomes compromised, leading to the accumulation of toxic protein aggregates that disrupt neuronal function and lead to neurodegeneration. Specific misfolded proteins are associated with each neurodegenerative disease (i.e. α-synuclein in PD, amyloid-β/tau in AD and TAR DNA-binding protein 43/SOD in ALS). However, increasing evidence implicates more complex interactions of co-pathologies across these disorders, as Lewy bodies are common in AD brains and Alzheimer pathology is present in the majority of PD autopsy cases. These observations are consistent with the idea that disruption of proteostasis networks by one aggregation-prone protein could result in misfolding and aggregation of other neurodegeneration-related species. This review will examine the characteristics and consequences of co-pathologies in neurodegenerative disorders. Additionally, the review will outline emerging therapeutic strategies targeted at restoring proteostasis and mitigating the effects of co-pathological processes associated with neurodegenerative diseases. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.},
}

*Proteostasis
Humans
*Neurodegenerative Diseases/physiopathology/pathology
Animals
Proteotoxic Stress
Protein Folding

@article {pmid42817823,
year = {2026},
author = {Yanagi, KS and Lin-Moore, AT and Gordon, NC and Lins, JJ and Coyne, EM and Meininger, KL and Moy, SL and Stinson, LA and Walsh, MB and Gallati, M and Mahapatra, A and Aderogba, R and Jaworski, A and Hart, AC},
title = {A genetic screen for suppressors of neuron degeneration in a C. elegans sod-1G85R model of Amyotrophic Lateral Sclerosis.},
journal = {G3 (Bethesda, Md.)},
volume = {},
number = {},
pages = {},
doi = {10.1093/g3journal/jkag281},
pmid = {42817823},
issn = {2160-1836},
abstract = {Genetic variants in superoxide dismutase 1 (SOD1) cause the progressive neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). Treatments for this disease are limited, and the unique vulnerability of cholinergic and glutamatergic motor neurons to degeneration seen in ALS patients is not clearly understood. Identifying genetic modifiers of neurodegeneration can provide insight into the selective vulnerability of motor neurons in ALS and may accelerate identification of novel therapeutic targets. Here, we describe a forward genetic screen for suppressors of the stress-induced glutamatergic neuron degeneration in a single-copy C. elegans model of sod-1G85R. Used two different screening strategies, we identified 53 suppressor lines that decreased glutamatergic neuron degeneration to varying degrees. To rapidly identify suppressor genes, we sequenced suppressor lines and identified candidate suppressor genes based on frequency of de novo exonic mutations and previously published work. Two candidates were tested and excluded as suppressor genes: erh-1 and imph-1. For a subset of unidentified suppressor lines, we determined if cholinergic neurodegeneration was also suppressed; roughly one-third of suppressor lines showed no corresponding cholinergic neuron rescue, suggesting that mechanisms involved in cholinergic and glutamatergic degeneration are at least partially divergent. This study outlines the first unbiased genetic screen in a knock-in model of SOD1 neurodegeneration, describes a cohort of candidate suppressor lines with decreased SOD1-dependent neurodegeneration, excludes two candidates and discusses approaches for suppressor mutation isolation and gene identification.},
}

@article {pmid42817963,
year = {2026},
author = {Bidhan, V and Wynants, S and Swings, T and Vicente, CT and Küçükali, F and Van den Broeck, M and van Rooij, JG and Mol, MO and Donker Kaat, LL and Al-Sarraj, S and Bodi, I and King, A and Troakes, C and Proukakis, C and Schaeverbeke, J and Thal, DR and Vandenberghe, R and Vandenbulcke, M and Nguyen, AT and Reichard, RR and Kofler, J and Lopez, OL and White, CL and Boeve, BF and Graff-Radford, NR and Josephs, KA and Petersen, RC and Ghayal, NB and Murray, ME and Dickson, DW and van Swieten, JC and Sleegers, K and Seelaar, H and De Coster, W and Rademakers, R},
title = {Targeted single-nucleus sequencing of 39,800 neurons reveals extensive low-frequency somatic variants.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.21.753260},
pmid = {42817963},
issn = {2692-8205},
abstract = {Recent evidence implicates somatic mutations in disease-associated genes across multiple neurodegenerative disorders, including the identification of two somatic TARDBP variants as a putative cause of frontotemporal lobar degeneration with TDP-43 pathology type C (FTLD-TDP type C). However, these findings remain anecdotal. We performed single-nucleus amplicon sequencing of 39,800 neurons from the superior temporal gyrus of sporadic FTLD-TDP type C patients (34,738 neurons, 52 individuals) and non-demented controls (5,062 neurons, 26 individuals) using the Mission Bio Tapestri platform and investigated somatic variants in TARDBP and other FTLD-TDP-associated genes in a case-control setting. We uncovered an extensive landscape of ultra-low-frequency (<1%) somatic mutations across all analysed genes, including TARDBP . Rare somatic occurrences of known ALS/FTD-associated germline TARDBP variants, including p.N267S and p.M337V, were identified exclusively in patients. Among all targeted genes, TARDBP had the highest proportion of neurons harbouring a somatic variant, and this mutational burden was lower in individuals who died at an older age. Strikingly, the C-terminal domain of TDP-43, where most ALS/FTD germline pathogenic variants reside, exhibited a lower neuronal mutational burden than its other domains. This suggests that neurons harbouring damaging mutations may undergo progressive loss prior to autopsy, leaving only rare survivors at frequencies too low to detect by bulk or small-scale single-cell approaches. Together, our findings provide an unprecedented resolution into the somatic mutational landscape of post-mitotic neurons in FTLD-TDP type C and reveal a gene-specific layer of neuronal mosaicism that current single-cell WGS studies fail to detect.},
}

@article {pmid42818511,
year = {2026},
author = {Campisi, L and Terekhova, M and Melhem, R and Zeng, C and Martin, J and Joseph, TL and Bohacova, P and Jones, M and Nath, A and Benoit, N and Harmison, G and Wu, G and Sergushichev, A and Artyomov, M and Grunseich, C},
title = {Clonal CD8 T cells link peripheral and intrathecal immunity in ALS4 progression: a multiomics reference for ALS.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10810896/v1},
pmid = {42818511},
issn = {2693-5015},
abstract = {Dysregulated immune responses increasingly appear central to amyotrophic lateral sclerosis (ALS) pathology, but rapid progression and delayed diagnosis limit our understanding of how immune events evolve over the course of disease. By combining high parameter spectral flow cytometry with single cell RNA, TCR and BCR sequencing of peripheral blood and cerebrospinal fluid (CSF), we map the immune landscape in ALS4, a juvenile onset, slowly progressive ALS subtype, providing the first view of immune states spanning decades of disease progression. We identify an early emerging, progressively amplifying CD8 T cell program characterized by clonal expansion of peripheral GZMK[+] and GZMB[+] subsets and an abnormally high degree of TCR clonotype sharing between GZMK[+] CSF and GZMB[+] blood CD8 T cells. Our work defines a CD8 T cell trajectory that parallels clinical progression in ALS4 across CSF and blood and provides a reference for comparison with other ALS subtypes.},
}

@article {pmid42818787,
year = {2026},
author = {Koo, AS and Zhou, J and Méndez-Albelo, NM and Wei, Y and Xu, W and Zhao, X and Dewey, C and Tibbetts, RS},
title = {ALS-associated exitron splicing produces UBQLN2 isoforms with distinct properties.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.08.750250},
pmid = {42818787},
issn = {2692-8205},
abstract = {UNLABELLED: X-linked amyotrophic lateral sclerosis (ALS) implicated Ubiquilin 2 (UBQLN2) is expressed from a single exon. Here, we show that human UBQLN2 mRNA is alternatively spliced by virtue of a cryptic exonic intron (exitron) spanning the 5' untranslated region and the 5' end of UBQLN2 coding sequence. Splice-out of this exitron generates a spliced UBQLN2 (UBQLN2-Sp) transcript that is translated from codon M243 to produce an N-terminally truncated UBQLN2 isoform (UBQLN2-M243) with reduced stability, diminished proteasome targeting, and altered aggregation behavior following the introduction of ALS mutations. The RNA-binding proteins SRSF1 and PTBP1 control UBQLN2 splicing through binding to splice donor-proximal motifs, while TDP-43 was implicated as an indirect splicing repressor. UBQLN2 splicing was elevated and inversely correlated with UBQLN2 gene expression in the medial motor cortex of male ALS patients. These findings suggest that alternative splicing regulates UBQLN2 gene dosage and function, which may impact UBQLN2-ALS proteinopathy.

GRAPHICAL ABSTRACT: Created in https://BioRender.com.},
}

@article {pmid42821076,
year = {2026},
author = {Murasawa, S and Asanuma, Y},
title = {Determining the learning curve for anterolateral supine total hip arthroplasty: a retrospective analysis of six hundred and forty consecutive cases performed by a single surgeon.},
journal = {International orthopaedics},
volume = {},
number = {},
pages = {},
pmid = {42821076},
issn = {1432-5195},
abstract = {PURPOSE: To characterize the learning curve for single-surgeon performed anterolateral supine (ALS)-total hip arthroplasty (THA).

METHODS: We analysed 640 consecutive primary ALS-THAs performed between April 2017 and August 2024, including procedures performed with supervised assistance during 2017-2019. Operative time (OT), blood loss (BL), and complication rate (CR) were evaluated. Temporal trends in OT and BL were assessed using cumulative sum (CUSUM) analysis, and a data-driven single change-point analysis was performed for CR using 100,000 Monte Carlo permutations. Firth's penalised logistic regression assessed the association between continuous case numbers and complications after adjustment for age, sex, and American Society of Anesthesiologists (ASA) physical status.

RESULTS: OT and BL CUSUM curves peaked at cases 411 and 437, respectively. Mean OT decreased from 74.8 to 66.3 min and BL from 251.6 to 184.6 mL between 2022-2023 (both Holm-adjusted P < 0.001). Nine cases (1.4%) experienced 11 complication events. The estimated CR change point was case 281, with pre- and post-point CRs of 2.8% and 0.3%, respectively, but the permutation test was not significant (P = 0.1021). Increasing experience was associated with lower early complication odds after adjustment (odds ratio 0.64 per 100-case increase, 95% confidence interval 0.40-0.94; P = 0.023).

CONCLUSION: The ALS-THA learning curve varied by outcome, with operative efficiency improving after approximately 400 procedures. Increasing experience was associated with lower odds of early complications, supporting outcome-specific rather than single-threshold assessment.},
}

@article {pmid42821610,
year = {2026},
author = {Parthasarathy, N and Soetedjo, J and Panchavati, S and Parthasarathy, N and Lee, D and Arnold, C and Pouratian, N and Speier, W},
title = {Near-optimal P300 speller performance using large language models: A multi-model analysis with performance bounds.},
journal = {PloS one},
volume = {21},
number = {10},
pages = {e0349281},
doi = {10.1371/journal.pone.0349281},
pmid = {42821610},
issn = {1932-6203},
mesh = {Humans ; Large Language Models ; *Brain-Computer Interfaces ; *Event-Related Potentials, P300/physiology ; Electroencephalography ; *Amyotrophic Lateral Sclerosis/physiopathology ; },
abstract = {Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, severely impairs communication, requiring assistive technologies that restore interaction. The P300 speller brain-computer interface (BCI) enables communication by translating EEG responses into text; however, its practical adoption is limited by slow typing speed and the need for subject-specific calibration. Recent work has demonstrated that large language models (LLMs), such as GPT-2, can significantly improve the performance of the P300 speller by predicting words. However, it remains unclear whether these gains are model-specific or represent a broader trend across language models. Furthermore, the framework-specific performance bounds of LLM-assisted P300 spellers have not been systematically characterized within a unified decoding framework. In this study, we address these gaps through a systematic multi-model theoretical analysis framework. We evaluate a wide range of language models and introduce an idealized LLM to establish upper bounds on achievable performance. In addition, we incorporate cross-subject classifier training to reduce calibration requirements and assess generalization across subjects. Using extensive simulations on EEG data from 78 subjects, we demonstrate that the evaluated models consistently achieve substantial improvements in typing speed, with gains of up to ~45% (within-subject training) and ~75% (across-subject training) over conventional approaches. More importantly, we show that several high-performing models, despite architectural differences, operate within 5% of the theoretical performance bound, indicating diminishing returns from further model scaling. These improvements generalize across both within-subject and across-subject classifiers. Our results suggest that LLM-assisted P300 spellers are approaching oracle-based upper bounds within the considered decoding framework, shifting the primary bottleneck from language modeling to neural signal decoding. This work provides both a practical framework for improving BCI communication and a theoretical perspective on its achievable limits.},
}

Humans
Large Language Models
*Brain-Computer Interfaces
*Event-Related Potentials, P300/physiology
Electroencephalography
*Amyotrophic Lateral Sclerosis/physiopathology

@article {pmid42822337,
year = {2026},
author = {Zeng, Q and Zhu, Q and Jiang, Q and Zhou, J and Yue, L and Zhu, X and Zeng, X and Li, C and Qiao, G and Fu, Q},
title = {Core and bridge nodes between sleep quality and depression in Chinese patients with amyotrophic lateral sclerosis: A network analysis perspective.},
journal = {General hospital psychiatry},
volume = {103},
number = {},
pages = {108-117},
doi = {10.1016/j.genhosppsych.2026.09.014},
pmid = {42822337},
issn = {1873-7714},
abstract = {BACKGROUND: Sleep quality and depression are prevalent yet under-recognized non-motor symptoms (NMS) in amyotrophic lateral sclerosis (ALS), and the interplay between their symptom domains remains poorly characterized. This study applied network analysis to identify core and bridge nodes linking sleep quality and depression in Chinese ALS patients.

METHODS: A cross-sectional study was conducted among 372 ALS patients recruited from a tertiary hospital in Wuhan, China. Sleep quality and depressive symptoms were assessed using the Pittsburgh Sleep Quality Index (PSQI) and the Patient Health Questionnaire-9 (PHQ-9), respectively. A regularized Gaussian graphical model was estimated using the graphical LASSO algorithm. Node centrality metrics including strength, closeness, betweenness, and expected influence (EI) were calculated to identify core nodes, and bridge expected influence (BEI) was calculated to identify bridge nodes. A case-dropping bootstrap procedure was used to evaluate the stability of the network estimates.

RESULTS: Among all patients, 50.81% screened positive for poor sleep quality and 41.40% for depressive symptoms, with 28.49% screening positive for both. Subjective sleep quality showed the highest strength and EI, identifying it as the most central node. Daytime dysfunction exhibited the highest closeness and betweenness centrality and the largest BEI, emerging as the principal bridge node connecting the communities. The network demonstrated good stability, with CS-coefficients of 0.67 and 0.60 for EI and BEI, respectively.

CONCLUSION: The findings highlight subjective sleep quality and daytime dysfunction as potentially influential nodes within the sleep quality-depression network, representing candidate targets for future longitudinal and intervention studies that may inform strategies to support well-being in patients with ALS.},
}

@article {pmid42822436,
year = {2026},
author = {Guo, W and Ichida, JK},
title = {The accessory makes the drug: ASO-delivered siRNA enters the human CNS for ALS.},
journal = {Cell stem cell},
volume = {33},
number = {10},
pages = {1580-1581},
doi = {10.1016/j.stem.2026.09.004},
pmid = {42822436},
issn = {1875-9777},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/genetics ; *RNA, Small Interfering/metabolism/administration & dosage ; *Central Nervous System/metabolism ; Superoxide Dismutase-1 ; *Superoxide Dismutase/genetics/metabolism ; *Oligonucleotides, Antisense/therapeutic use ; Animals ; },
abstract = {In a recent article in Nature Medicine, Chen et al. describe a first-in-human study using an ASO tag to deliver a SOD1 siRNA to the central nervous system (CNS), potentially achieving faster, more extensive, and better-tolerated SOD1-lowering in ALS patients.[1].},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/genetics
*RNA, Small Interfering/metabolism/administration & dosage
*Central Nervous System/metabolism
Superoxide Dismutase-1
*Superoxide Dismutase/genetics/metabolism
*Oligonucleotides, Antisense/therapeutic use
Animals

@article {pmid42809650,
year = {2026},
author = {Tabone, S and Cacciottolo, R and Cauchi, RJ},
title = {Motor dysfunction phenotypes in a drosophila model validate DAO as an ALS gene.},
journal = {Human molecular genetics},
volume = {35},
number = {20},
pages = {},
doi = {10.1093/hmg/ddag093},
pmid = {42809650},
issn = {1460-2083},
support = {//University of Malta Research Seed Fund/ ; REP-2023-018//Xjenza Malta Fusion R&I Research Excellence Programme 2023/ ; RNS-2026-0030//Xjenza Malta Research Networking Scheme 2026/ ; //Tertiary Education Scholarship Scheme/ ; //Reach High II Scholarship/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology/metabolism ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Phenotype ; Humans ; *D-Amino-Acid Oxidase/genetics/metabolism ; Neuromuscular Junction/metabolism/pathology/genetics ; *Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/genetics ; Serine Racemase ; Racemases and Epimerases/genetics ; Animals, Genetically Modified ; Drosophila/genetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by progressive motor neuron (MN) loss. Although rare pathogenic variants in the D-amino acid oxidase (DAO) gene have been proposed to cause familial ALS, inconsistent findings across mammalian models have hindered functional validation. Here, we establish and characterise a Drosophila model of DAO loss-of-function by targeting its highly conserved orthologue, Daao1. Constitutive Daao1 knockdown caused early developmental lethality, while surviving adult escapers exhibited profound flight and climbing impairments. Contrary to expectations, Daao1 deficiency did not elevate D-serine levels in larval or adult brains, and simultaneous knockdown of serine racemase (Srr), the enzyme responsible for D-serine synthesis, failed to rescue locomotor phenotypes. Tissue-specific silencing revealed that Daao1 is essential within both MNs and muscles, but not glia, for maintaining motor performance. RNA-seq of Daao1-deficient flies uncovered widespread transcriptional dysregulation affecting metabolism, peptide transport, immune activation and developmental pathways, accompanied by alternative splicing changes in genes required for neuronal morphology and synaptic organisation. Consistent with these molecular alterations, neuromuscular junctions (NMJs) displayed reduced axonal branching and bouton numbers, indicating disrupted neuromuscular connectivity. Remarkably, ubiquitous expression of human DAO rescued lethality and motor defects, demonstrating functional conservation and supporting a role for DAO in maintaining neuromuscular health. Together, our findings reveal a previously unrecognised, D-serine-independent role for DAO in neuromuscular integrity and provide functional evidence connecting DAO dysfunction to ALS-relevant phenotypes. The DAO-ALS Drosophila model provides a powerful platform for mechanistic studies and for evaluating human DAO variants of uncertain significance in ALS.},
}

Animals
*Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology/metabolism
Disease Models, Animal
Motor Neurons/metabolism/pathology
Phenotype
Humans
*D-Amino-Acid Oxidase/genetics/metabolism
Neuromuscular Junction/metabolism/pathology/genetics
*Drosophila Proteins/genetics/metabolism
Drosophila melanogaster/genetics
Serine Racemase
Racemases and Epimerases/genetics
Animals, Genetically Modified
Drosophila/genetics

@article {pmid42811035,
year = {2026},
author = {Marzok, A and Mapletoft, JP and Ahmed, I and Cowbrough, B and Celeste, DB and D'Agostino, MR and Ang, JC and Chen, AT and Surendran, V and Tugg, Y and Li, H and Wong, K and Dvorkin-Gheva, A and Zhang, A and Stacey, HD and Lam, M and Kollar, Y and Milnes, KR and Afkhami, S and Miller, MS},
title = {Acute viral infection accelerates neurodegeneration in a mouse model of ALS.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42811035},
issn = {2041-1723},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/virology/pathology/genetics/immunology/drug therapy ; Disease Models, Animal ; Mice ; Superoxide Dismutase-1/genetics/metabolism ; *Virus Diseases/complications ; Mice, Transgenic ; Disease Progression ; Gliosis/virology/pathology ; Humans ; Female ; Superoxide Dismutase/genetics ; Spinal Cord/pathology ; Male ; },
abstract = {While several viral infections have been associated with amyotrophic lateral sclerosis (ALS), the mechanism(s) through which they promote disease remains elusive. Here we investigate the impact of common, acute viral infections on ALS disease onset and progression in the SOD1[G93A] mouse model. A single sublethal infection prior to onset of ALS clinical signs is associated with markedly accelerated ALS disease progression characterized by rapid loss of hindlimb function. Prior infection results in gliosis in the lumbar spine and upregulation of transcriptional pathways involved in inflammatory responses, metabolic dysregulation, and muscular dysfunction. Therapeutic suppression of gliosis with an anti-inflammatory small molecule, or administration of a direct-acting antiviral, is associated with significantly improved ALS clinical signs, akin to what is observed in uninfected animals. Our study provides causal and mechanistic evidence that the immune response elicited by acute viral infections may be an important etiological factor that alters ALS disease trajectory.},
}

Animals
*Amyotrophic Lateral Sclerosis/virology/pathology/genetics/immunology/drug therapy
Disease Models, Animal
Mice
Superoxide Dismutase-1/genetics/metabolism
*Virus Diseases/complications
Mice, Transgenic
Disease Progression
Gliosis/virology/pathology
Humans
Female
Superoxide Dismutase/genetics
Spinal Cord/pathology
Male

@article {pmid42811116,
year = {2026},
author = {Brooker, SM and Coukos, R and Krainc, D},
title = {Lysosomal dysfunction in neurodegenerative disease.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42811116},
issn = {1759-4766},
abstract = {Examination of genetic risk factors associated with neurodegenerative diseases has provided important mechanistic insights into the pathophysiology of these disorders, and it has implicated defects in lysosomal function as a key component of the neurodegenerative process. The lysosome has a primary role in mediating degradation of both intracellular contents and endocytosed material from the extracellular space. Aggregation of misfolded proteins is a pathological mechanism that is observed across neurodegenerative disorders, and aberrant lysosomal degradation of such proteins plays a pivotal part in driving neuronal dysfunction and cell loss. In addition to the crucial role of the endolysosomal system in degradation of intracellular constituents, lysosomes also serve as important nodes for intracellular signalling, participating in nutrient sensing, lipid metabolism, membrane repair and neuroinflammation. In this Review, we provide an overview of mechanisms of lysosomal dysfunction in neurodegenerative disease, with a particular focus on Parkinson disease, Alzheimer disease, frontotemporal dementia and amyotrophic lateral sclerosis.},
}

@article {pmid42811584,
year = {2026},
author = {Singh, R and Kumam, Y and Mahey, M and Patterson, E and Liu, S and Lancaster, S and Jugulam, M},
title = {Deciphering metabolic resistance to multiple herbicides in Amaranthus palmeri via transcriptome analysis.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.71345},
pmid = {42811584},
issn = {1526-4998},
support = {//Kansas Soybean Commission/ ; },
abstract = {BACKGROUND: Multiple herbicide resistance in Palmer amaranth (Amaranthus palmeri S. Watson) poses a serious threat to US crop production. A Palmer amaranth population (KCTR) from Kansas was found resistant to herbicides across six sites-of-action, including ALS-, PS II-, EPSPS-, PPO-, HPPD-inhibitors and synthetic auxins. Previous physiological and metabolic studies suggested that resistance in this population is predominantly associated with enhanced herbicide metabolism, possibly mediated by cytochrome P450 (P450) and/or glutathione S-transferase (GST) enzyme activity. The aim of this study was to identify candidate genes potentially associated with multiple herbicide resistance in KCTR Palmer amaranth population.

RESULTS: Differential gene expression analysis revealed 414, 129, 529, 152 and 688 genes differentially expressed in resistant plants as compared to susceptible, following chlorsulfuron, 2,4-D, atrazine, mesotrione and lactofen treatments, respectively. CYP72A219 paralogs, CYP704B1-like and GST-ct genes were constitutively up-regulated in resistant plants as compared to susceptible. Validated by qRT-PCR, CYP72A219 and CYP704B1-like were 3.4- to 6.6-fold and 5.9- to 12.4-fold up-regulated in resistant plants as compared to susceptible without any treatment.

CONCLUSIONS: Identifying genes associated with multiple herbicide metabolism is critical for understanding cross-resistance and evaluating new herbicides for resistance risk. These candidate resistance-associated genes serve as targets for functional validation studies in future to help develop molecular markers for screening broad-spectrum herbicide resistance. © 2026 Society of Chemical Industry.},
}

@article {pmid42812195,
year = {2026},
author = {Tao, R and Zheng, W and Peng, L and Lv, S and Wang, Q},
title = {Multistage pathogenesis and disease associations of Mycobacterium avium subsp. paratuberculosis.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1948490},
pmid = {42812195},
issn = {1664-3224},
mesh = {*Mycobacterium avium subsp. paratuberculosis/pathogenicity/immunology/genetics ; Animals ; *Paratuberculosis/microbiology/immunology/epidemiology/transmission ; Humans ; Macrophages/immunology/microbiology ; Host-Pathogen Interactions ; },
abstract = {Mycobacterium avium subsp. paratuberculosis (MAP) is the primary causative agent of Johne's disease (JD) in ruminants and bears potential public-health implications. Cumulative epidemiological and molecular evidence implies MAP may contribute to Crohn's disease (CD), whereas its links to multiple sclerosis (MS), type 1 diabetes mellitus (T1DM), and amyotrophic lateral sclerosis (ALS) remain associative without proven causality. This narrative review synthesizes MAP environmental distribution, strain genotyping, transmission routes, and multistage pathogenic mechanisms. MAP breaches the intestinal barrier via fibronectin attachment protein (FAP)-mediated invasion of microfold cells and establishes intracellular persistence within macrophages. It deploys virulence factors including protein kinase G (PknG) to inhibit phagosome-lysosome fusion, the stringent response regulator RelA for metabolic reprogramming, and the ESX-3 secretion system for iron acquisition, while subverting host immunity through M2 macrophage polarization and interleukin-10 (IL-10)/interleukin-6 (IL-6)-mediated anti-inflammatory responses, ultimately driving chronic granulomatous inflammation and tissue injury. We also critically assess diagnostic limitations-particularly the inability of polymerase chain reaction (PCR) to distinguish viable from non-viable organisms-and highlight major research challenges, including extrapolation of virulence mechanisms from other mycobacterial species. This work provides a theoretical framework for prevention, diagnosis, and targeted intervention of MAP-associated disorders.},
}

*Mycobacterium avium subsp. paratuberculosis/pathogenicity/immunology/genetics
Animals
*Paratuberculosis/microbiology/immunology/epidemiology/transmission
Humans
Macrophages/immunology/microbiology
Host-Pathogen Interactions

@article {pmid42813639,
year = {2026},
author = {Singh, AP and Prajapati, S and Yadav, S and Yadav, A},
title = {Lipid-based Nanocarriers for Neurodegenerative Disorders: Bridging Blood-brain Barrier Biology and Translational Drug Delivery.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026478560260909100922},
pmid = {42813639},
issn = {1875-5739},
abstract = {INTRODUCTION: Neurodegenerative disorders, including Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis, remain difficult to treat because the Blood-brain Barrier (BBB) severely restricts therapeutic access to the central nervous system. This review evaluates BBB biology and the potential of lipid-based nanocarriers to improve brain-targeted drug delivery and facilitate clinical translation.

METHODS: A structured narrative review of peer-reviewed preclinical and clinical literature published between 2000 and 2025 was conducted using PubMed, Scopus, and Web of Science. Evidence concerning BBB structure and transport mechanisms, lipid-based nanocarrier design, physicochemical characteristics, drug-release behavior, computational modelling, therapeutic applications, and translational challenges was critically synthesized.

RESULTS: Liposomes, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, and lipid-polymer hybrid nanoparticles demonstrated improved drug solubility, stability, controlled release, systemic circulation, and brain targeting. Preclinical evidence indicates enhanced brain bioavailability and therapeutic effects, including reductions in neuroinflammation, oxidative stress, and disease-associated pathological processes. However, clinical translation remains constrained by formulation complexity, scalability, long-term safety, and inconsistent clinical outcomes.

DISCUSSION: Integration of BBB transport biology with surface functionalization, receptormediated targeting, formulation engineering, and computational modelling may enable more rational nanocarrier development. Nevertheless, standardized characterization, reproducible manufacturing, comprehensive safety evaluation, and stronger clinical validation are required to bridge the gap between promising preclinical findings and therapeutic implementation.

CONCLUSION: Lipid-based nanocarriers represent promising platforms for overcoming biological and pharmacokinetic barriers in neurodegenerative disorders. Further optimization and rigorous translational validation are essential to establish their safety, reproducibility, and clinical effectiveness.},
}

@article {pmid42814295,
year = {2026},
author = {Chan, L and Shaikh, FA and Shah, P and Moriyama, H and Yokota, T},
title = {Development and Clinical Applications of Antisense Oligonucleotide Gapmers.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {3065},
number = {},
pages = {19-51},
pmid = {42814295},
issn = {1940-6029},
mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use/genetics/chemistry ; Animals ; *Genetic Diseases, Inborn/genetics/therapy ; *Genetic Therapy/methods ; },
abstract = {Antisense oligonucleotides (AONs) are synthetic oligonucleotides designed to bind target RNA and have opened new treatment possibilities for genetic diseases by regulating gene expression. AONs are often used to suppress the expression of mutated genes, which may interfere with essential downstream pathways. Since AONs have been introduced for clinical use, different chemistries have been developed to further improve efficacy, potency, and safety. One such chemistry is a chimeric structure of a central block of deoxyribonucleotides flanked by sequences of modified nucleotides. Referred to as a gapmer, this chemistry produced promising results in the treatment of genetic diseases. Tofersen is an example of a recently FDA-approved antisense oligonucleotide gapmer used for the treatment of amyotrophic lateral sclerosis. Many others are being tested in clinical trials or under preclinical development. This chapter will cover advancements in gapmer treatments for various diseases, including familial hypercholesterolemia, hereditary transthyretin amyloidosis, cancer, familial chylomicronemia syndrome, familial partial lipodystrophy, familial hypertriglyceridemia, Huntington's disease, myotonic dystrophy, prion diseases, and amyotrophic lateral sclerosis.},
}

Humans
*Oligonucleotides, Antisense/therapeutic use/genetics/chemistry
Animals
*Genetic Diseases, Inborn/genetics/therapy
*Genetic Therapy/methods

@article {pmid42814303,
year = {2026},
author = {Nakamura, Y and Moriyama, H and Yokota, T},
title = {Development of Antisense Oligonucleotide Gapmers for Amyotrophic Lateral Sclerosis.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {3065},
number = {},
pages = {161-170},
pmid = {42814303},
issn = {1940-6029},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/drug therapy ; Humans ; *Oligonucleotides, Antisense/genetics/therapeutic use/administration & dosage/chemistry ; Animals ; Superoxide Dismutase-1/genetics/metabolism ; Biomarkers ; },
abstract = {Advances in genetics and RNA biology have transformed the therapeutic landscape for neurodegenerative disease. Antisense oligonucleotide (ASO) therapies-particularly RNase H-activating "gapmers"-now enable sequence-specific suppression of pathogenic transcripts in the central nervous system. In amyotrophic lateral sclerosis (ALS), tofersen, a 2'-MOE-modified phosphorothioate ASO targeting SOD1 mRNA, has entered clinical use. By promoting RNase H-mediated degradation of SOD1 transcripts after intrathecal delivery, tofersen lowers SOD1 protein in cerebrospinal fluid and plasma neurofilament light chain, demonstrating robust target engagement and neurodegeneration biomarker improvement. Although pivotal trials did not meet primary functional endpoints (ALSFRS-R) at 28 weeks, longer-term and real-world observations suggest potential clinical benefit with earlier initiation, a hypothesis now being tested in presymptomatic SOD1 variant carriers. This chapter reviews the development of gapmer ASOs for ALS with a focus on tofersen-covering chemistry and mechanism, preclinical validation, clinical efficacy and safety, biomarker readouts, and ongoing trials-while outlining key challenges (CNS delivery, adverse event monitoring, endpoint sensitivity) and future directions, including earlier intervention guided by biomarkers and extension to additional genetic forms of ALS.},
}

*Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/drug therapy
Humans
*Oligonucleotides, Antisense/genetics/therapeutic use/administration & dosage/chemistry
Animals
Superoxide Dismutase-1/genetics/metabolism
Biomarkers

@article {pmid42814997,
year = {2026},
author = {Frisch, D and Fronstin, M and Zema, C},
title = {Agentic AI for Clinical Outcomes Research, Population Health Management Analyses With Large Administrative Databases, and Generating Epidemiological Estimates of Diseases: Feasibility and Validation Study.},
journal = {Journal of medical Internet research},
volume = {28},
number = {},
pages = {e100284},
doi = {10.2196/100284},
pmid = {42814997},
issn = {1438-8871},
mesh = {Humans ; Female ; Male ; *Artificial Intelligence ; Feasibility Studies ; Aged ; Middle Aged ; Adult ; *Databases, Factual ; Adolescent ; *Population Health Management ; Child ; Urinary Bladder Neoplasms/epidemiology ; Infant ; *Outcome Assessment, Health Care ; Young Adult ; Child, Preschool ; Huntington Disease/epidemiology ; Leukemia, Myeloid, Acute/epidemiology ; Prevalence ; Parkinson Disease/epidemiology ; Infant, Newborn ; United States/epidemiology ; },
abstract = {BACKGROUND: There is tremendous enthusiasm for the use of AI in health care because of the ability to analyze existing data for preventative, diagnostic, and treatment support. Agentic AI can feasibly provide access to large real-world datasets for the generation of real-world evidence for health care and clinical applications to health care providers, researchers, and administrators without access to large analytic programming resources.

OBJECTIVE: The objective of this study was to understand the feasibility of using agentic AI for clinical outcome research and population health management. Specifically, this study used an agentic AI evidence-generation platform to obtain epidemiological estimates of diverse medical conditions, with the results evaluated against existing AI frameworks.

METHODS: Prevalence estimates of 6 conditions (amyotrophic lateral sclerosis, acute myeloid leukemia, bladder cancer, Huntington disease, elevated lipoprotein (a), and Parkinson disease) were estimated using an agentic AI evidence-generation platform applied to an administrative claims database with representation from every US state. Gender-specific rates were calculated within the following age categories: 0 to 17, 18 to 24, 25 to 34, 35 to 44, 45 to 54, 55 to 64, and 65 to 74 years and 75 years and older. Period prevalence was estimated from January 1, 2020, to June 30, 2025, and annual prevalence rates for each year were estimated from 2020 to 2024. Continuous enrollment for 12 months was required during the study period for inclusion. Source code generated by the platform as part of the analysis was reviewed by an independent programmer for validation of methods and programming, and analyses were replicated using traditional programming methods. Results obtained throughout the process were evaluated against several existing AI application frameworks.

RESULTS: Regarding accuracy, epidemiological estimates obtained using the agentic AI platform were consistent with published estimates for all 6 conditions, as well as with estimates obtained from traditional programming methods. Regarding rigor, the agentic AI platform conducted the analysis with rigor by confirming acceptable methods in published literature for the type of data source used. Code lists used for the analysis were confirmed against existing algorithms when available. Appropriate statistical methods were used to compare differences in prevalence rates by age and gender. Regarding trust (explainability, transparency, replicability, traceability, and validation), the agentic AI platform generated all source code used for the analyses, which was reviewed and validated for accuracy and appropriateness. The analysis included a "human in the loop" to validate the research question, data extraction method, statistical analysis plan, and output plan prior to proceeding with each step.

CONCLUSIONS: With specific design considerations to ensure responsible use, agentic AI can be invaluable to increasing the accessibility of large datasets for applied clinical outcome research and population health management analyses.},
}

Humans
Female
Male
*Artificial Intelligence
Feasibility Studies
Aged
Middle Aged
Adult
*Databases, Factual
Adolescent
*Population Health Management
Child
Urinary Bladder Neoplasms/epidemiology
Infant
*Outcome Assessment, Health Care
Young Adult
Child, Preschool
Huntington Disease/epidemiology
Leukemia, Myeloid, Acute/epidemiology
Prevalence
Parkinson Disease/epidemiology
Infant, Newborn
United States/epidemiology

@article {pmid42815720,
year = {2026},
author = {Tazuma, T and Nakamori, M and Toko, M and Watanabe, T and Naito, H and Kanaya, Y and Agari, D and Shishido, T and Imamura, E and Imon, K and Nomura, E and Torii, T and Miyachi, T and Yamashita, H and Ohshita, T and Maruyama, H},
title = {Predictive Value of the Modified Controlling Nutritional Status Score for Critical Events in Patients with Amyotrophic Lateral Sclerosis.},
journal = {Clinical nutrition ESPEN},
volume = {},
number = {},
pages = {105162},
doi = {10.1016/j.clnesp.2026.105162},
pmid = {42815720},
issn = {2405-4577},
abstract = {BACKGROUND & AIMS: Amyotrophic lateral sclerosis (ALS) is associated with various clinical challenges and critical outcomes. Therefore, we established a regional registry and conducted the Chugoku ALS Retrospective and Prospective (CARP) study. The modified controlling nutritional status (m-CONUT) score holds the potential to comprehensively assess the condition of patients with ALS from aspects such as nutrition, metabolism, and inflammation. The present study used data from the CARP study to examine the relationship between the m-CONUT score and outcomes.

METHODS: Patients diagnosed with possible, probable, and definite ALS according to the Awaji criteria were enrolled between 2014 and 2023. A statistical analysis of data from patients enrolled within 2 years of ALS onset and followed for at least 6 months thereafter was performed. Patients were evaluated every 3 months, and missing values were supplemented by the last observation carried forward method.

RESULTS: This study included 36 patients. Eleven experienced critical events (ventilator placement or death), the majority of which were deaths. The m-CONUT score exhibited a worsening trend before the critical event occurred, as did the revised ALS functional rating scale score, body mass index, and forced vital capacity percentage. Critical events increased significantly with each 1-point increase in the m-CONUT score.

CONCLUSIONS: The m-CONUT score may have potential for predicting outcomes in patients with ALS.},
}

@article {pmid42816074,
year = {2026},
author = {Sriharan, A and Sullivan, T and Mitchell, C},
title = {Leading under uncertainty: a qualitative case study of crisis leadership in Canada's health system.},
journal = {BMJ open},
volume = {16},
number = {9},
pages = {e115820},
doi = {10.1136/bmjopen-2025-115820},
pmid = {42816074},
issn = {2044-6055},
mesh = {*Leadership ; Uncertainty ; Canada/epidemiology ; Humans ; Qualitative Research ; *COVID-19/epidemiology ; *Delivery of Health Care/organization & administration ; SARS-CoV-2 ; Pandemics ; },
abstract = {BACKGROUND: Prolonged public crises challenge leaders to make high-stakes decisions under conditions of uncertainty while sustaining organisational performance and public trust. Understanding how leaders navigate these complex demands is essential for strengthening health system preparedness and resilience.

OBJECTIVES: The goal was to explore and unpack lived leadership experiences during a public crisis situation and to unpack how contextual factors shape their behaviours under uncertainty and prolonged disruption.

DESIGN: This study was conducted in Canada during the middle phases of the COVID-19 pandemic (October 2020-March 2021). Canada's healthcare system operates within a federal-provincial framework, with public health responsibilities spanning national, provincial and local levels. 16 senior leaders with provincial or national responsibilities across healthcare delivery, government, academia and research participated in the study. Purposive sampling was used to achieve variation across organtional and geographic regions. A qualitative case study design was employed, with semistructured interviews serving as the primary data collection method and thematic analysis used to analyse the data. The analysis was informed by Sriharan et al's Crisis Leadership Framework and reported in accordance with the Standards for Reporting Qualitative Research.

METHODS: Videoconference interviews (40-50 min) explored leadership challenges, decision-making under uncertainty, communication, and contextual enablers and constraints. Transcripts were analysed using Braun and Clarke's six-phase approach with triangulation and reflexive documentation to enhance rigour.

RESULTS: Leaders described multifaceted roles that spanned clinical, administrative and advisory functions. Six leadership domains emerged from the analysis: adaptive leadership, learning-oriented leadership, systems thinking, psychological stewardship, implementation agility and strategic communication. Leadership enactment was shaped by structural integration and centralisation, which enabled real-time situational awareness and coordinated resource deployment. Rapid cycle decision-making was supported by emergency legislative flexibility, multidisciplinary evidence synthesis structures and peer learning networks. Constraints included systemic fragmentation, bureaucratic inertia, data sharing limitations and sustained workforce fatigue, all of which influenced leaders' ability to enact these domains under pressure.

CONCLUSIONS: Effective crisis leadership depended less on static competencies and more on dynamic enactment shaped by structural, operational and relational mechanisms. The findings extend the crisis leadership framework towards Dynamic Capability Leadership for Learning Health Systems, positioning leadership as a strategic capacity to sense emerging challenges, seize opportunities through rapid and accountable decision pathways and transform processes to sustain performance under uncertainty. These capabilities were enacted through adaptive and learning-oriented leadership, implementation agility, systems thinking, psychological stewardship and strategic communication, all amplified by structural integration and evidence-synthesis infrastructures. Overall, the findings highlight crisis leadership as a system property shaped by context, coordination and the ability to translate evolving knowledge into timely action.},
}

*Leadership
Uncertainty
Canada/epidemiology
Humans
Qualitative Research
*COVID-19/epidemiology
*Delivery of Health Care/organization & administration
SARS-CoV-2
Pandemics

@article {pmid42816153,
year = {2026},
author = {Gauld, N and Hikaka, J and Newsham, S and Frampton, C and Mylchreest, R and Brott, T and Buchanan, SM and Buetow, S},
title = {Caregiving and Respite for People With Motor Neurone Disease: A National Cross-Sectional Survey of Experiences and Challenges.},
journal = {Journal of clinical nursing},
volume = {},
number = {},
pages = {},
doi = {10.1111/jocn.70548},
pmid = {42816153},
issn = {1365-2702},
support = {23/987//Health Research Council of New Zealand/ ; //Motor Neurone Disease New Zealand/ ; //Natalie Gauld/ ; },
abstract = {AIMS: To ascertain care support for people with motor neurone disease encompassing formal and informal care (funded and unfunded care), residential respite utilisation, care tasks performed by family members, and experiences and challenges encountered in accessing funded care.

DESIGN: National cross-sectional survey.

METHODS: People with motor neurone disease, their family members, and bereaved family members were surveyed across New Zealand. Analysis included descriptive and multivariable statistical methods. Responses to open-ended questions were analysed thematically.

RESULTS: Data were available from 115 people with motor neurone disease, 89 family carers and 40 bereaved carers. Care hours data represented 189 unique individuals with motor neurone disease - 115 responses from people with motor neurone disease, 35 from family carers and 39 bereaved. Most (58%) reported needing funded care but only 50% received it (median 24 h/week), 51% reporting this was insufficient. Younger age, greater disease severity and slow (versus fast) progression rate were associated with greater likelihood of receiving funded care (all p < 0.05); fewer funded hours were associated with faster progression and age over 65 years (all p < 0.05). Most people with motor neurone disease (77%) received unpaid care (median 30 h/week), rising to 90% among bereaved respondents (median 80 h/week). Barriers to funded care included assessment delays, insufficient information and unmet eligibility criteria. Inadequate care funding affected family (e.g., exhaustion, safety issues), and the person with motor neurone disease (e.g., unmet needs and safety concerns), with additional financial impacts. Many family members reduced paid work during the illness. Residential respite was used by only 15%, with multiple reasons for non-use.

CONCLUSION: Inadequate funded care and residential respite provision in New Zealand impose a substantial burden on families to provide unpaid care, harming both people with motor neurone disease and family members.

IMPLICATIONS: Funded care needs to be more responsive to the needs of those with motor neurone disease and their caregivers.

IMPACT: Little is known about funded and unpaid care in motor neurone disease (MND), particularly the challenges of acquiring sufficient funding and arising from insufficient funding. This study found that many people with MND could not access the care hours they needed, leaving family members to provide high levels of unpaid care, while often reducing their own paid work. Resulting challenges included exhaustion for family, financial strain, unmet needs, and safety concerns for the person with MND. Insufficient care funding was associated with reduced life satisfaction for family members. The care funding system was hard to navigate and too slow, particularly where MND progresses fast. From a nursing perspective, this research highlights the critical importance of funded care that is flexible and responsive to rapidly changing needs. When funding systems are slow or difficult to navigate, the burden often falls on families, increasing stress and risk for the person with MND and their carers. This research should inform policy in New Zealand and internationally, demonstrating the need for care funding systems that are flexible, fast, and straightforward to use-findings relevant regardless of the funding model. Reporting method: this paper was informed by the STROBE checklist for cross-sectional studies.

The lead author has MND. Many people with MND and their family members were involved throughout the study, shaping its concept, scope, and methods. Two people with MND tested the survey in Qualtrics-one using eye gaze technology and one using voice to text. Four people with MND and three carers reviewed the questionnaire, providing feedback that resulted in rewording. One person with MND worked through every question with the lead author over three separate sessions to ensure all questions and response options were clear and meaningful.},
}

@article {pmid42806293,
year = {2026},
author = {Sanjay, S and Magliyah, MS},
title = {Letter to the Editor: Comment on Azeem S, et al's "Acute Retinal Necrosis-Associated Rhegmatogenous Retinal Detachment: A Systematic Review and Meta-Analysis".},
journal = {Ocular immunology and inflammation},
volume = {},
number = {},
pages = {1-2},
doi = {10.1080/09273948.2026.2737298},
pmid = {42806293},
issn = {1744-5078},
}

@article {pmid42807601,
year = {2026},
author = {Elmahgoub, S and Elshawa, A and Flannery, S},
title = {Anesthetic Management and Perioperative Outcome of Emergency Laparotomy in a Patient With Advanced Motor Neurone Disease: A Case Report.},
journal = {Clinical case reports},
volume = {14},
number = {10},
pages = {e73635},
pmid = {42807601},
issn = {2050-0904},
abstract = {Motor neurone disease (MND) presents significant perioperative challenges due to progressive respiratory muscle weakness, bulbar dysfunction, autonomic instability, and altered sensitivity to anesthetic agents. Emergency surgery further limits opportunities for optimisation and advance planning. We report the perioperative and anesthetic management of a patient with advanced MND undergoing emergency laparotomy for small bowel obstruction. A total intravenous anesthetic with cautious use of neuromuscular blockade was employed, and the patient was successfully extubated postoperatively. Despite an initially uncomplicated postoperative course, the patient subsequently developed progressive respiratory failure in the context of ongoing intra-abdominal pathology. Following multidisciplinary discussion and shared decision-making, care was transitioned to a comfort-focused approach. This case highlights the limitations of perioperative intervention in advanced MND and emphasizes the importance of goal-concordant care in emergency surgical settings.},
}

@article {pmid42807842,
year = {2026},
author = {Filser, PJ and Münchenberg, PS and Berger, E and Busse, R and Garcia, C and Kurth, T},
title = {Clinical and economic effectiveness of telehealth in home mechanical ventilation.},
journal = {ERJ open research},
volume = {12},
number = {5},
pages = {},
pmid = {42807842},
issn = {2312-0541},
abstract = {BACKGROUND: The number of patients requiring home mechanical ventilation is rising, while in-person follow-up is increasingly burdensome for patients and health systems. Telehealth may maintain clinical stability and improve care efficiency. This systematic review examined the clinical and economic effectiveness of telehealth in the management of home mechanical ventilation.

METHODS: The study protocol was registered a priori in PROSPERO. A systematic search was conducted in MEDLINE, Embase and Web of Science. The reporting of the systematic review was aligned with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. We included quantitative studies comparing telehealth-supported home ventilation with standard care, reporting clinical or economic outcomes.

RESULTS: From 356 identified studies, 11 met the inclusion criteria: nine randomised controlled trials, one cohort study and one retrospective analysis, mostly conducted in Europe, with a total of 1458 participants. The study populations included patients with, e.g. COPD, amyotrophic lateral sclerosis and obesity hypoventilation syndrome. Interventions involved telehealth-supported home ventilation management. Across studies, telehealth-supported care achieved clinical outcomes comparable to those of standard care. Arterial carbon dioxide tension (P aCO2) control and health-related quality of life were similar between groups, with one study reporting greater P aCO2 reduction with telemonitoring. Evidence on the number of hospitalisations and exacerbations was mixed. Mortality and survival rates showed nonsignificant trends towards benefit; one cohort study reported improved first-year survival. Economic outcomes varied: home initiation reduced costs, while long-term follow-up results were heterogeneous.

CONCLUSIONS: elehealth-supported home ventilation appears to be a comparable alternative to in-hospital management and often provides economic advantages. Future research should focus on standardised outcome measures, longer follow-up and health-system-specific cost-effectiveness analyses to guide sustainable implementation.},
}

@article {pmid42809516,
year = {2026},
author = {Jang, K and Morton, RL and Dennis, M and Nikolovski, J and Zhan, X and Ke, Y and Burns, B and Tran, AD},
title = {The cost-effectiveness and health equity of prehospital treatment strategies for out-of-hospital cardiac arrest patients: a systematic review.},
journal = {Prehospital emergency care},
volume = {},
number = {},
pages = {1-66},
doi = {10.1080/10903127.2026.2741269},
pmid = {42809516},
issn = {1545-0066},
abstract = {OBJECTIVES: Out-of-hospital cardiac arrest (OHCA) remains a major public health challenge, associated with substantial mortality and significant costs for health care system. This systematic review aimed to (i) synthesise economic evaluations of prehospital treatment strategies for OHCA from ambulance attendance through to hospital discharge; (ii) assess the methodological quality and reporting of the included studies; and (iii) evaluate the reporting of health equity-relevant data.

METHODS: We searched Medline, Embase, Scopus, EconLit, and CINAHL databases for records from database inception to 12 June 2026. The QHES and CHEERS checklists were used to assess the quality and reporting standards of included studies, and the review was reported according to the PRISMA checklist. The completeness of reporting health equity outcomes was reviewed using the PROGRESS (Place of residence, Race, Occupation, Gender, Religion, Education, Socioeconomic status and Social capital) - Plus framework.

RESULTS: Ten economic evaluations met eligibility criteria. Most studies were cost-utility analyses (n = 8, 80%) and used Markov models (n = 6, 60%). Most evaluations were 'very good quality' (≥80%) (n = 6, 60%). Early defibrillation and advanced life support (ALS) delivered by trained emergency medical technicians were cost-effective compared with no intervention, emergency physician-led ALS, standard emergency medical services or paramedic care (ICER range from £11,407 to USD $56,700 per QALY gained). Prehospital extracorporeal cardiopulmonary resuscitation (ECPR) was more cost-effective than in-hospital ECPR strategies (ICER range from AUD $27,323 to $44,000 per QALY gained). Termination-of-resuscitation (TOR) strategies were cost-effective compared with no TOR or other TOR strategies, including basic life support and ALS TOR, with estimates of $110,554 saved per QALY lost and USD $23,851 per QALY gained.Survival rate and neurological outcomes influenced cost-effectiveness results. Equity reporting was limited: almost all included studies addressed less than 40% of the PROGRESS-Plus equity criteria.

CONCLUSIONS: Most strategies that increased prehospital treatment intensity, avoided futile transport, or enabled earlier advanced care were cost-effective; however, the certainty of evidence, particularly for sub-groups, was limited by heterogeneous comparators and sparse equity reporting.},
}

@article {pmid42803299,
year = {2026},
author = {Shirakawa, T and Mikuriya, S and Inoue, Y and Murasaki, K and Salinas, F and Takegawa-Araki, T and Tamura, M},
title = {LRSAM1, an E3 ubiquitin ligase, modulates TDP-43 proteostasis in amyotrophic lateral sclerosis.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag334},
pmid = {42803299},
issn = {1460-2156},
abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by the cytoplasmic mislocalization, aberrant phosphorylation and pathological aggregation of TDP-43, a nuclear RNA-binding protein essential for RNA metabolism. Despite its central involvement in ALS pathogenesis, the molecular mechanisms that govern TDP-43 proteostasis remain incompletely understood. Here, we investigated the role of LRSAM1, an E3 ubiquitin ligase, in regulating TDP-43 localization and degradation. Postmortem spinal cord tissues from five patients with sporadic amyotrophic lateral sclerosis and five healthy controls were examined. Immunohistochemical analyses revealed that LRSAM1 preferentially colocalized with diffusely mislocalized cytoplasmic TDP-43 but not with dense cytoplasmic aggregates, suggesting a potential role in early-stage pathological processing. To model these effects in vitro, induced pluripotent stem cell-derived motor neurons from three patients with amyotrophic lateral sclerosis and four healthy control participants were used. Knockdown of LRSAM1 in induced pluripotent stem cell-derived motor neurons from patients with amyotrophic lateral sclerosis significantly increased cytoplasmic TDP-43 accumulation and phosphorylation, as measured by immunofluorescence imaging. Moreover, STMN2 mRNA splicing, a well-established TDP-43 functional readout, was disrupted upon LRSAM1 depletion. Conversely, overexpression of LRSAM1 ameliorated stress-induced TDP-43 mislocalization and phosphorylation in induced pluripotent stem cell-derived motor neurons from patients with amyotrophic lateral sclerosis but had minimal impact in control cells, indicating disease-specific vulnerability. Mechanistically, LRSAM1 interacted directly with the aggregation-prone C-terminal fragments of TDP-43 via the RRM2 domain of TDP-43 and promoted their proteasomal degradation. This selective interaction reduced the accumulation of toxic TDP-43 species and supported cytoplasmic proteostasis, particularly under conditions of cellular stress. In summary, our study identifies LRSAM1 as a novel modulator of cytoplasmic TDP-43 dynamics in amyotrophic lateral sclerosis. By facilitating degradation of pathogenic TDP-43 fragments, LRSAM1 preserves neuronal RNA processing and mitigates molecular hallmarks of amyotrophic lateral sclerosis. These findings enhance our understanding of post-translational control of TDP-43 and highlight LRSAM1 as a promising therapeutic target for modifying disease progression in amyotrophic lateral sclerosis.},
}

@article {pmid42803551,
year = {2026},
author = {Matsuoka, K and Ando, M and Nakashima, T and Takeyama, H},
title = {Sensitive and derivatization-free amino acid analysis using liquid chromatography-Raman spectroscopy.},
journal = {The Analyst},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6an00841k},
pmid = {42803551},
issn = {1364-5528},
abstract = {Liquid chromatography-Raman spectroscopy with post-column spotting and solvent evaporation achieved nanogram-level detection of amino acids without derivatization and demonstrated the feasibility of quantification at this level for phenylalanine and glutamine. All 20 amino acids were successfully detected regardless of chromophore presence. Lysine modifications were directly discriminated via distinct vibrational fingerprints. Co-eluting compounds were resolved by MCR-ALS-based spectral deconvolution, demonstrating that LC-Raman spectroscopy can add a spectral separation axis to chromatographic analysis. Furthermore, LC-Raman spectroscopy was also applied to quantitative analysis. For phenylalanine and glutamine, the calibration curves exhibited excellent linearity (R[2] = 0.9925 for phenylalanine, and R[2] = 0.9994 for glutamine). The quantitative results of these amino acids in the culture medium obtained via LC-Raman spectroscopy (65.9 ± 3.5 µg mL[-1] (n = 3, %RSD = 5.2%) for phenylalanine, and 576.3 ± 17.5 µg mL[-1] (n = 3, %RSD = 3.0%) for glutamine) were in good agreement with those determined by conventional detectors (66.1 µg mL[-1] for phenylalanine, and 584 µg mL[-1] for glutamine). This label-free approach establishes LC-Raman spectroscopy as a structural detection mode for LC, enabling chromatographic analysis to be coupled directly with molecular fingerprinting.},
}

@article {pmid42804712,
year = {2026},
author = {Avendaño-Arango, E and Salom-Palacio, I and Castillo-Támara, EE and Palacio-Villalba, B},
title = {Neuroepigenetics of the Environmental Exposome: Molecular and Clinical Implications in Neurodegeneration.},
journal = {The neurologist},
volume = {},
number = {},
pages = {},
doi = {10.1097/NRL.0000000000000694},
pmid = {42804712},
issn = {2331-2637},
abstract = {BACKGROUND: Neuroepigenetics studies the molecular mechanisms that regulate gene expression in the nervous system without altering the DNA sequence. The environmental exposome has emerged as a key factor influencing neuronal plasticity and brain homeostasis, contributing to vulnerability to neurodegeneration.

REVIEW SUMMARY: This narrative review analyzes the role of neuroepigenetic reprogramming as a central mechanism linking chronic environmental exposures with neurodegenerative diseases. Evidence indicates that alterations in DNA methylation, histone remodeling, and microRNA regulation contribute to mitochondrial dysfunction, oxidative stress, and chronic neuroinflammation. These mechanisms are critically involved in the pathogenesis of Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis.

CONCLUSIONS: Neuroepigenetics represents a central mechanistic axis in neurodegeneration by integrating environmental exposures with intrinsic biological processes. This framework offers new opportunities for the development of early biomarkers and targeted preventive and therapeutic strategies.},
}