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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Humans
*Mental Disorders
*Biomedical Research

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Humans
*Mental Disorders/diagnosis
*Psychopathology/methods

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

@article {pmid42149283,
year = {2026},
author = {Dey, A and Baumeister, TR and Evans, KC and Koppelmans, V and Luk, C and McLaren, DG and Parnianpour, P and Seres, P and , and Kalra, S},
title = {Correction: Data-driven disease subgrouping in ALS: a multicenter cerebral functional connectivity study.},
journal = {Journal of neurology},
volume = {273},
number = {6},
pages = {},
doi = {10.1007/s00415-026-13768-3},
pmid = {42149283},
issn = {1432-1459},
}

@article {pmid42149299,
year = {2026},
author = {Morimoto, S and Takahashi, S and Okano, H},
title = {Human iPSC‑based translational and reverse translational research for neurodegenerative diseases: emphasis on ALS and key advances.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {42149299},
issn = {1867-108X},
support = {JP21H05278, JP22K15736, JP25H00007//Japan Society for the Promotion of Science/ ; JP26K10434//Japan Society for the Promotion of Science/ ; JP26H02431//Japan Society for the Promotion of Science/ ; JP23bm1123046, JP23kk0305024, JP25ek0109811//Japan Agency for Medical Research and Development/ ; JP21wm0425009, JP22bm0804003, JP22ek0109616, JP23bm1423002, JP25wm0625519//Japan Agency for Medical Research and Development/ ; UBE Academic Foundation//UBE Academic Foundation/ ; the Kato Memorial Trust for Nambyo Research//the Kato Memorial Trust for Nambyo Research/ ; 2024A04//Japan Intractable Diseases Research Foundation/ ; Inamori Foundation//Inamori Foundation/ ; Kanagawa Institute of Industrial Science and Technology (KISTEC)e and Technology//Kanagawa Institute of Industrial Science and Technology (KISTEC)e and Technology/ ; Ono Medical Research Foundation//Ono Medical Research Foundation/ ; Nakatomi Foundation//Nakatomi Foundation/ ; },
abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) cause progressive loss of specific neuronal populations and currently lack curative therapies. Animal models and immortalized cell lines incompletely recapitulate human pathology and genetic heterogeneity, limiting drug discovery. Human induced pluripotent stem cells (iPSCs) provide a patient‑specific platform for disease modelling, drug screening and studying individual responses. Translational research (TR) uses iPSC models to identify candidate therapies that are subsequently tested in clinical trials, while reverse translational research (rTR) feeds clinical observations back to the bench by analyzing iPSCs derived from trial participants and integrating molecular data with patient phenotypes. This review summarizes recent advances in iPSC‑based TR and rTR for ALS and extends the discussion to other neurodegenerative diseases. Key clinical trials launched from iPSC screens-ropinirole, retigabine and bosutinib-are reviewed alongside emerging rTR efforts that use patient‑derived iPSCs to identify biomarkers and therapeutic mechanisms. We also survey iPSC models for AD, PD and HD, highlighting applications of three‑dimensional (3D) brain organoids and gene‑editing technologies. Finally, we discuss future directions for precision medicine, multimodal integration and technological challenges, with particular attention to how imaging biomarkers may complement iPSC-based TR/rTR frameworks in neurodegenerative diseases.},
}

@article {pmid42149483,
year = {2026},
author = {Ozimac, KM and Gonzalez, VV and Blaisdell, AP},
title = {Evidence of the conjunction fallacy in Rats (Rattus norvegicus) following two-lever choice training.},
journal = {Journal of comparative psychology (Washington, D.C. : 1983)},
volume = {},
number = {},
pages = {},
doi = {10.1037/com0000448},
pmid = {42149483},
issn = {1939-2087},
abstract = {The conjunction fallacy, a well-known cognitive bias, occurs when individuals erroneously judge the conjunction of 2 events as more probable than either event occurring independently (Tversky & Kahneman, 1983). Although this fallacy has been extensively studied in humans, recent research from our lab shows that nonhuman animals, such as rats, also demonstrate this bias (González, Sadeghi, et al., 2023). In González et al.'s study, rats were trained in a feature-positive/feature-negative go/no-go discrimination (A-/AX+; B+/BY-, where A and B were auditory cues and X and Y were visual cues, and + and-indicate that lever pressing was reinforced or not). At test, cues A and B were presented on probe trials with cues X and Y either unoccluded and off or occluded by a metal shield. Responding was low to A and high to B when the light was visible (and off). When the light was occluded, however, this pattern reversed, with high responding to A and low responding to B. This indicated a bias toward expecting the occluded light to be present rather than absent, consistent with a conjunction fallacy. In a go/no-go procedure, however, some trial types are rewarded, whereas others are unrewarded. This reward asymmetry may bias attention to the different cue conditions. Thus, the current study replicated this conjunction bias using a 2-alternative choice procedure where reinforcement was available on all trial types, removing this potential bias. Our demonstration of a strong conjunction fallacy replicated our prior results, setting the stage for parallel studies in rats and humans. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid42141072,
year = {2026},
author = {Cropper, HC and Mir, F and Liu, J and Dachet, F and Srivastava, VR and Ramizuddin, M and Kopecky, K and Mocanu, E and Jiang, QL and Soni, M and Valyi-Nagy, T and Mnatsakanova, D and Abrams, CK and Song, F and Loeb, JA},
title = {Axonal dying back of upper motor neurons in human ALS.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-52496-6},
pmid = {42141072},
issn = {2045-2322},
support = {T32AG057468/AG/NIA NIH HHS/United States ; },
abstract = {Patients with amyotrophic lateral sclerosis (ALS) typically present with arm, leg, or bulbar weakness. While genetics plays a clear role, it cannot explain why symptoms start focally or how upper (UMN) and lower motor neuron (LMN) systems are linked. In this clinicopathological case series, we examined the relationships between UMN/LMN disease in ten ALS patients. Detailed clinical assessments and motor cortex, brainstem, and spinal cord tissues were collected via rapid autopsy. Tissues were stained for UMN/LMN, myelin, axons, microglia, and pTDP43, and RNA-sequencing was performed. None of the patients had symptoms of frontotemporal dementia (FTD), but all had focal sites of clinical onset and both UMN/LMN involvement. LMN degeneration and microglial activation were highest at disease onset sites. UMN degeneration was present at all spinal cord levels through the medulla, regardless of onset site. Surprisingly, there was no evidence of UMN axonal degeneration above the brainstem. While extensive pTDP43 aggregates were seen in degenerating LMNs, no pTDP43 aggregates were seen in UMN cell bodies or their axons. RNA-sequencing implicated inflammatory pathways at sites of disease onset. Our findings suggest that some ALS patients without FTD have a dying back of UMN axons rather than a primary upper neuronopathy of neurons.},
}

@article {pmid42141160,
year = {2026},
author = {Hatano, Y and Nakahara, A and Tada, M and Kakita, A and Onodera, O and Ishihara, T},
title = {APOE ε4 influences the widespread TDP-43 pathological subtype in sporadic amyotrophic lateral sclerosis.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42141160},
issn = {1432-0533},
support = {23K14771//Japan Society for the Promotion of Science/ ; 21K07272//Japan Society for the Promotion of Science/ ; JPJS00420240016//JSPS J-PEAKS Program/ ; JP22jm0210097//the AMED-SICORP program/ ; JPMH23FC1008//the Ministry of Health, Labour and Welfare (Research on Rare and Intractable Diseases Program)/ ; JP24zf0127012//AMED MoonShot Program/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Male ; Female ; Aged ; Middle Aged ; *Apolipoprotein E4/genetics ; Aged, 80 and over ; Brain/pathology/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, most sporadic cases exhibiting TAR DNA-binding protein 43 (TDP-43) pathology. The anatomical distribution of TDP-43 pathology varies among patients; however, factors contributing to this heterogeneity remain unclear. Apolipoprotein E (APOE) ε4 is known to influence the spread of pathological protein in several neurodegenerative diseases, raising the possibility that it also modulates the pathological distribution of TDP-43 inclusions in ALS. We investigated this hypothesis in a cohort of 145 autopsy-confirmed sporadic ALS cases. ALS-associated TDP-43 pathology was classified into two subtypes: type 1 - largely restricted to motor regions - and type 2 - characterized by widespread cortical involvement. APOE genotypes and rare variants in known ALS-associated genes were determined by exome sequencing. Amyloid-β and tau pathologies were assessed neuropathologically using established staging systems. Structural equation modeling (SEM) was applied to disentangle direct and indirect relationships among APOE ε4, temporal clinical parameters, Alzheimer's disease-related pathologies, and ALS TDP-43 subtype. Furthermore, we also performed an unbiased evaluation using random forest model. APOE ε4 carriers showed a significantly higher proportion of type 2 pathology than non-carriers. Bayesian SEM demonstrated that APOE ε4 was directly associated with the type 2, widespread TDP-43 subtype, independent of amyloid-β and tau pathology, while also reproducing the canonical cascade linking APOE ε4 to amyloid-β and tau. Rare variants in ALS-associated genes showed no clear effect on TDP-43 subtype. These findings indicate that APOE ε4 modifies the anatomical distribution of TDP-43 pathology in sporadic ALS through mechanisms independent of classical Alzheimer's disease pathology. Incorporation of APOE genotype into ALS stratification may be informative for biologically grounded subtype-specific therapeutic approaches.},
}

Humans
*Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism
*DNA-Binding Proteins/metabolism/genetics
Male
Female
Aged
Middle Aged
*Apolipoprotein E4/genetics
Aged, 80 and over
Brain/pathology/metabolism

@article {pmid42141236,
year = {2026},
author = {Maxwell, K and Leung, S and Ozakinci, G},
title = {The psychological impact of using 3D printing and imaging technology for patient education: a scoping review.},
journal = {3D printing in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s41205-026-00327-9},
pmid = {42141236},
issn = {2365-6271},
abstract = {BACKGROUND: The way in which patient education is delivered during clinical consultations can have an impact on cognitive and emotional outcomes in patients. 3D printing and imaging can be used in patient education to improve understanding of the information and satisfaction with care. This scoping review sought to explore the psychological impact of using 3D models in patient education.

METHODS: Searches were conducted in PsycINFO, PsycARTICLES, PubMed, Medline and CINAHL. Levac et al.'s enhanced version of Arksey & O'Malley's methodological framework for conducting scoping reviews, and the PRISMA-ScR, were used to guide the screening and identification of relevant studies. Studies were included if they investigated the effect of using 3D models in patient education and explored psychological outcomes. Both quantitative and qualitative research were included.

RESULTS: Eleven studies were included in the review, including 2 qualitative studies. 3D models were most often used in educational consultations preceding a surgical procedure (n = 9). Psychological outcomes assessed were anxiety, quality of life, distress relief, and decisional conflict. The results were mixed, showing that using 3D models can have a positive as well as negative effect on psychological outcomes such as fear and disempowerment.

CONCLUSIONS: Using 3D models in patient education has the potential to improve patient anxiety and other psychological outcomes. However, more research is required to identify which patients and types of consultations 3D models are most useful for. For example, appointments involving important decision-making may benefit from the inclusion of 3D models. It is also essential to consider the communicative approach of the healthcare professional in the delivery of patient education with 3D models, as this factor is key to the outcomes of shared decision-making.},
}

@article {pmid42141322,
year = {2026},
author = {Slaghekke, HMJ and Govaarts, R and Mesarosova, L and Mühlebner, A and Beeldman, E and de Visser, M and van Es, MA and van den Berg, LH and van der Kooi, AJ and Pijnenburg, YAL and Aronica, E and Raaphorst, J},
title = {Associations of cognitive and behavioural impairment in ALS with brain pathology: pTDP-43 versus microglial activation.},
journal = {Journal of neurology},
volume = {273},
number = {6},
pages = {},
pmid = {42141322},
issn = {1432-1459},
support = {2013-19//Stichting ALS Nederland/ ; 023.012.055//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/complications/metabolism/psychology ; Male ; Female ; Middle Aged ; *Microglia/pathology/metabolism ; Aged ; *Cognitive Dysfunction/pathology/etiology/metabolism ; Frontotemporal Dementia/pathology/metabolism ; *Brain/pathology/metabolism ; Adult ; Gray Matter/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; },
abstract = {OBJECTIVE: Investigate associations between brain pathology (pTDP-43 inclusions and microglial activation) and cognitive and behavioural impairment in patients with amyotrophic lateral sclerosis (ALS).

METHODS: Based on comprehensive neuropsychological examination and behavioural assessment, 21 ALS patients of whom post mortem brain tissue was obtained, were classified as having 1) no cognitive and/or behavioural impairment (pure motor ALS), 2) mild cognitive and/or behavioural impairment (ALSci/bi), and 3) ALS with behavioural variant frontotemporal dementia (ALS-bvFTD). Immunohistochemical staining of pTDP-43 and HLA-DR-defined microglial activation was semi-quantitatively assessed in grey and/or white matter of the prefrontal cortex, thalamus, hippocampus, and motor cortex.

RESULTS: Fourteen patients had pure motor ALS, four patients had ALSci/bi, and three patients had ALS-bvFTD. pTDP-43 pathology in the grey matter of the prefrontal cortex and gyrus dentatus differed between groups, especially between pure motor ALS and ALS-bvFTD. For each extra-motor brain region, pTDP-43 severity was highest in patients with ALS-bvFTD and lowest in patients with pure motor ALS, with ALSci/bi in between. This pattern was not observed for microglial activation. Associations between white matter pTDP-43 severity and cognitive/behavioural impairment were less robust than those in grey matter.

CONCLUSION: Severity of cognitive and/or behavioural impairment in ALS is related to severity of pTDP-43 pathology, in particular in the grey matter of extra-motor brain regions; we did not detect a clear association with microglial activation.},
}

Humans
*Amyotrophic Lateral Sclerosis/pathology/complications/metabolism/psychology
Male
Female
Middle Aged
*Microglia/pathology/metabolism
Aged
*Cognitive Dysfunction/pathology/etiology/metabolism
Frontotemporal Dementia/pathology/metabolism
*Brain/pathology/metabolism
Adult
Gray Matter/pathology/metabolism
*DNA-Binding Proteins/metabolism

@article {pmid42141969,
year = {2026},
author = {Olesen, L and Moèll, SK and Knudsen, L},
title = {Living Outside the ALS Home - Everyday Experiences, Challenges and Needs of Adult Children with a Parent with ALS.},
journal = {Journal of social work in end-of-life & palliative care},
volume = {},
number = {},
pages = {1-27},
doi = {10.1080/15524256.2026.2672970},
pmid = {42141969},
issn = {1552-4264},
abstract = {Adult children of a parent with ALS may be highly burdened and in need of support, but studies of their experiences and needs are scarce. The aim of this study was to explore everyday experiences, challenges and needs of adult children living outside the home of a parent with amyotrophic lateral sclerosis (ALS). The design was qualitative using Interpretive Description methodology and Sense of Coherence as framework. Focus group interviews were conducted with 16 adult children. Participants experienced changes in relationship and roles with siblings and parents when ALS moved into the family. Their parents' disease evoked a need for understanding ALS and its trajectory as the disease raised questions, concerns, and sorrow. Furthermore, having a parent with ALS led to strong and mixed emotions and dilemmas like bad conscience, self-blame, gratitude and closeness and wanting to be there but also not being able to bear witnessing the deterioration of their parent. Adult children experience profound challenges and needs related to their parent's disease. They need information and support from professionals and peers as they struggle to balance the demands related to ALS and everyday life with family, work and leisure. Professionals should provide support for this vulnerable group who appear highly burdened practically and emotionally by the situation.},
}

@article {pmid42135015,
year = {2026},
author = {Bate, J and Fealey, J and Young, C and McArdle, A and Staunton, CA and Close, GL},
title = {Sport-related trauma and motor neurone disease: a scoping review of epidemiology, mechanisms and future directions.},
journal = {British journal of sports medicine},
volume = {},
number = {},
pages = {},
doi = {10.1136/bjsports-2025-111410},
pmid = {42135015},
issn = {1473-0480},
abstract = {OBJECTIVE: To map existing epidemiological evidence assessing the relationship of sport-related trauma and Motor Neurone Disease/Amyotrophic Lateral Sclerosis (MND/ALS), identify potential mechanistic pathways through which athletic exposures may influence disease risk and highlight gaps informing future research priorities.

DESIGN: Scoping Review. Online databases were used to retrieve data from available sources to 25 September 2025.

DATA SOURCES: Published and grey literature in English were identified through searches of ProQuest Central, Web of Science, Scopus, Sport Discus and PubMed. Studies were deemed eligible if they examined MND/ALS in the context of sport-related physical trauma.

METHODS: The scoping review was carried out in accordance with Preferred Reporting Items for Systematic reviews and Meta-analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. A three-step search strategy identified primary studies, secondary literature and grey literature. Following screening, data were extracted using a standardised charting tool to develop a descriptive analysis and thematic synthesis.

RESULTS: The search identified 3307 records, with 45 studies meeting inclusion criteria. General physical activity does not elevate MND/ALS risk; however, professional participation in high-impact sports, particularly those involving repetitive head impacts, has been associated with a 4-15-fold increased risk of MND/ALS. However, current evidence is largely descriptive, correlative and lacks mechanistic insights to verify causation.

CONCLUSION: This scoping review highlights a plausible association between repeated physical trauma in sport and MND/ALS, particularly in professional sports with high exposure to repeated head impacts. Future research should identify biological mechanisms linking trauma exposure with MND/ALS, integrating biomarker, experimental and longitudinal study designs to clarify causal mechanisms and inform risk mitigation in sport.},
}

@article {pmid42135109,
year = {2026},
author = {Yin, X and Zhang, H and Zhang, R and Xue, J and Hou, Y},
title = {Epigenetic noise in the aging brain: tuning neuronal vulnerability to neurodegeneration.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2026.04.006},
pmid = {42135109},
issn = {1878-108X},
abstract = {Aging is the predominant risk factor for neurodegenerative diseases, yet the mechanisms linking biological aging to selective neuronal degeneration remain incompletely understood. Accumulating evidence indicates that aging progressively disrupts epigenetic regulation, manifested as increased epigenetic noise in DNA methylation, histone modifications, and chromatin accessibility, which undermines transcriptional precision and the stability of neuronal identity. Recent advances in single-cell and spatial epigenomics further suggest that these age-associated epigenetic alterations are not merely correlative but can actively shape neuronal vulnerability across brain regions and cell types. In this review, we synthesize emerging evidence showing how epigenetic noise contributes to selective neurodegeneration across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, and discuss emerging strategies aimed at stabilizing the aging neuronal epigenome.},
}

@article {pmid42135512,
year = {2026},
author = {Zhang, Z and van Olst, L and Alessandrini, F and Wright, M and Edwards, AJ and Boles, J and Nalbandian, A and Forsyth, AV and Shepard, N and Watson, T and Kaspi, E and Mittal, A and Kuruvilla, J and Piehl, N and Ramakrishnan, A and Appel, S and Kiskinis, E and Gate, D},
title = {Integrated single-cell and spatial transcriptomic profiling in ALS uncovers peripheral-to-central immune infiltration and reprogramming.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42135512},
issn = {1546-1726},
support = {R01AG078713//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron (MN) degeneration in the brain and spinal cord. Although neuroinflammation is increasingly recognized as a hallmark of ALS, the precise molecular programs linking immune responses to MN pathology remain poorly defined. Using an integrated approach that combines single-cell and bulk RNA sequencing with spatial proteogenomics, we characterized both shared and distinct immune dynamics in peripheral blood and spinal cord tissues from patients with sporadic ALS and those carrying C9orf72 repeat expansions. Our analysis revealed broad immune remodeling in C9orf72 ALS, ALS subtype-specific and progression-associated differences in monocyte activation and antigen-experienced CD8 effector memory T cells with clonal features consistent with antigen-driven responses. Spatial mapping revealed complement activation and lipid-programmed myeloid states converging at sites of MN loss and TDP-43 pathology. Together, these findings connect peripheral and central immune alterations to ALS heterogeneity and highlight stratified immunomodulation as a potential therapeutic strategy.},
}

@article {pmid42135750,
year = {2026},
author = {Tamaki, Y and Kaneko, S and Urushitani, M},
title = {Maintenance and disruption of the physiological dimer structure of TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.},
journal = {BMC medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12916-026-04935-4},
pmid = {42135750},
issn = {1741-7015},
support = {24K18702//Japan Society for the Promotion of Science/ ; 23K24211//Japan Society for the Promotion of Science/ ; 25wm0625522h0001//Japan Agency for Medical Research and Development/ ; },
abstract = {BACKGROUND: Transactive response DNA-binding protein of 43 kDa (TDP-43) is an essential regulator of RNA metabolism, playing a pivotal role in splicing, transport, and stability. While its cytoplasmic aggregation is the pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), recent evidence suggests that the earliest pathogenic event is the disruption of its physiological homodimeric structure. Under healthy conditions, TDP-43 forms dimers via its N-terminal domain, a configuration that is crucial for its nuclear solubility and cooperative RNA binding. In this review, we propose the "Molecular Zipper" hypothesis to describe the maintenance of TDP-43 structural homeostasis. In this framework, the N-terminal domain acts as a stabilizing "NTD-mediated anchor" that keeps the protein in a functional, "zipped" dimeric state, effectively sequestering its aggregation-prone C-terminal regions. Pathogenic triggers-including genetic mutations, aberrant post-translational modifications such as phosphorylation and acetylation, and environmental stressors-can "unzip" this structure, leading to the formation of pathogenic monomers. These pathogenic monomers show increased propensity for cytoplasmic mislocalization and recruit wild-type protein into aggregates through a prion-like seeded aggregation mechanism, culminating in nuclear functional loss and cytoplasmic gain-of-toxicity. We further evaluate the emerging diagnostic landscape, focusing on methods to monitor the dimer-to-monomer ratio.

SHORT CONCLUSION: Integrating prior biochemical data on TDP-43 dimerization with structural modeling enables a more coherent account of the transition from the physiological dimer to pathological conformers. The Molecular Zipper framework offers a conceptual foundation for reconciling existing experimental findings and for guiding future studies on early structural changes in TDP-43 proteinopathy.},
}

@article {pmid42135847,
year = {2026},
author = {Sinha, IR and Atkinson, AL and Irwin, KE and Ling, JP and Wong, PC},
title = {TDP-43: [GU]-ardian of the transcriptome.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00944-2},
pmid = {42135847},
issn = {1750-1326},
abstract = {TDP-43 is a ubiquitously expressed, primarily nuclear DNA/RNA-binding protein implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). In this review, we examine the structure and regulation of TDP-43, how these features influence its localization and functional activity, and how their disruption may contribute to disease. Among TDP-43's diverse functions, splicing repression of nonconserved RNA sequences termed cryptic exons has emerged as especially central to human disease. TDP-43 nuclear depletion and cytoplasmic aggregation are well-established pathological features in affected neurons and glia of neurodegenerative diseases, and accumulating evidence suggests that loss of TDP-43-mediated splicing repression occurs presymptomatically in disease. Advances in RNA-sequencing have enabled systematic identification of cryptic exon inclusion as a sensitive marker of TDP-43 dysfunction. Here, we synthesize current knowledge of TDP-43 biology and curate datasets from human tissues and experimental models, focusing on cryptic splicing to provide a resource for leveraging cryptic exon biology to better understand, detect, and target TDP-43 dysfunction.},
}

@article {pmid42135897,
year = {2026},
author = {Kawazoe, T and Sugaya, K and Hayashi, K and Hino, K and Nakata, Y and Bokuda, K and Shimizu, T and Takahashi, K},
title = {Sex-Stratified Association of Regional Dopamine Transporter Binding With Disease Progression in Amyotrophic Lateral Sclerosis.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70432},
pmid = {42135897},
issn = {2328-9503},
support = {R051201013//Tokyo Metropolitan Hospital Organization/ ; },
abstract = {OBJECTIVE: To clarify the clinical relevance of dopamine transporter single-photon emission computed tomography (DAT-SPECT) abnormalities in amyotrophic lateral sclerosis (ALS), with a prespecified focus on sex-stratified associations with disease progression and short-term prognosis.

METHODS: Fifty-eight consecutive patients with ALS were prospectively enrolled and underwent [123]I-ioflupane DAT-SPECT, and DAT-SPECT data from 30 patients with essential tremor were analyzed as a reference group. We quantified the specific binding ratio (SBR) and the caudate-to-putamen binding ratio (BR-C/P) as age-adjusted Z-scores. Associations with functional decline (ΔALSFRS-R), respiratory function (forced vital capacity), neuropsychiatric measures, and a 6-month composite endpoint of death or ventilator support were examined using correlation and logistic regression analyses, with prespecified sex-stratified evaluation.

RESULTS: A significant sex difference in BR-C/P Z-scores prompted sex-stratified analyses. SBR Z-scores were not associated with clinical or neuropsychiatric variables in either sex. In women, lower BR-C/P Z-scores correlated with faster functional decline and were independently associated with a higher risk of death or ventilator support within 6 months (odds ratio per 1-unit increase, 0.31; 95% confidence interval, 0.12-0.83). In men, BR-C/P Z-scores correlated with forced vital capacity and respiratory decline. Exploratory voxel-based morphometry suggested limbic and striatal gray matter correlates in women with lower BR-C/P Z-scores.

INTERPRETATION: Regional dopaminergic imbalance captured by BR-C/P, rather than global SBR, demonstrated sex-stratified associations with disease progression in ALS. These findings support sex-specific interpretation of dopaminergic imaging biomarkers and suggest that BR-C/P may complement clinical measures for identifying higher-risk trajectories, particularly in women. Validation in larger, longitudinal cohorts is required.},
}

@article {pmid42135919,
year = {2026},
author = {Baird, LA and McQuown, H and Park, J and Teener, SJ and Webber-Davis, IF and Carter, AD and Jang, DG and Feldman, EL and Goutman, SA and Murdock, BJ},
title = {Peripheral Neutrophil Activation and Extracellular Trap Formation in Amyotrophic Lateral Sclerosis.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70431},
pmid = {42135919},
issn = {2328-9503},
support = {R01TS000339/ACL/ACL HHS/United States ; U01TS000351/ACL/ACL HHS/United States ; F31NS139629/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; R01NS120926/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; T32AI007413/NH/NIH HHS/United States ; //Richard Stravitz Foundation/ ; //Peter R. Clark Fund for ALS Research/ ; //Coleman Therapeutic Discovery Fund/ ; //Stanford Morris ALS Research Fund/ ; //Michael R. Johns Fund/ ; //Robert A. Epstein and Joan M. Chernoff-Epstein Emerging Scholar Fund/ ; //NeuroNetwork for Emerging Therapies/ ; //Scott Pranger ALS Center, the Dr. Randall Whitcomb Fund for ALS Genetics, the Coleman Therapeutic Discovery Fund, James and Margaret Hiller, Eric and Linda Novak/ ; },
abstract = {OBJECTIVES: Peripheral neutrophil levels in amyotrophic lateral sclerosis (ALS) inversely correlate with survival, suggesting a role for neutrophils in disease progression. Here, we characterize markers of several neutrophil activation pathways and evaluate their associations with survival to identify potential mechanisms of disease.

METHODS: Blood samples were obtained from participants at the University of Michigan ALS Clinic or from healthy controls. Ex vivo neutrophil extracellular trap (NET) formation was quantified via image analysis of primary neutrophils. Neutrophil function markers of general activation (calprotectin), migration (matrix-metalloproteinase 9 [MMP9]), and degranulation (neutrophil gelatinase-associated lipocalin [NGAL]) were then quantified in plasma via ELISA; NET formation (double-stranded DNA [dsDNA]) was assessed via fluorescence assay. These markers were then associated with ALS survival using Cox proportional hazard regression models, and analyses were stratified by sex.

RESULTS: Spontaneous ex vivo NET formation (N = 20 controls, 66 ALS) was increased in ALS (1.0% vs. 9.7%; p = 0.017). In plasma (N = 233 controls, 178 ALS), calprotectin (294 vs. 372 ng/mL; p < 0.001), MMP9 (106 vs. 152 ng/mL; p < 0.001), and NGAL (61 vs. 66 ng/mL; p = 0.01) were elevated in ALS. Calprotectin, MMP9, and NGAL levels were not associated with ALS survival; however, dsDNA was associated with poorer ALS survival but only in females (HR = 1.77 [95% CI, 1.20-2.61]; p = 0.004).

INTERPRETATION: Neutrophil function is altered in ALS, and NET formation is a potential mechanism by which neutrophils contribute to ALS, particularly in females.},
}

@article {pmid42136278,
year = {2026},
author = {Sharma, A and Mittal, V and Sharma, D and Deswal, G and Das, A and Guarve, K and Grewal, AS},
title = {Therapeutic Insights into Natural Products for Modulating Neurodegenerative Disease Pathways.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249405308251210104405},
pmid = {42136278},
issn = {1875-6166},
abstract = {INTRODUCTION: Neurodegenerative Disorders (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis (ALS), are chronic and progressive conditions marked by the gradual loss of neuronal structure and function. These disorders lead to cognitive, motor, and sensory decline, significantly reducing quality of life and posing a major global health burden due to rising healthcare costs and the absence of curative therapies. This review aims to comprehensively explore the therapeutic potential of natural products in targeting cellular and molecular mechanisms underlying NDs, highlighting their neuroprotective roles and potential for disease modification.

METHODS: A comprehensive literature review was conducted using databases including PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trials, and experimental studies were analyzed to evaluate the therapeutic potential of natural products and their bioactive compounds in the management of NDs.

RESULTS: ND pathogenesis involves oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation, ultimately leading to neuronal death. Current therapies largely provide symptomatic relief without altering disease progression. Natural products from plants, fungi, and marine sources demonstrate strong neuroprotective potential through multitargeted mechanisms. Bioactive compounds such as flavonoids, alkaloids, terpenoids, and polyphenols exhibit antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective activities. Key molecules, including curcumin, resveratrol, luteolin, quercetin, and catechins, modulate signaling pathways such as NF-κB, MAPK, PI3K/AKT, Nrf2, apoptosis, and autophagy, thereby reducing amyloid-beta aggregation, protecting dopaminergic neurons, improving mitochondrial function, and enhancing cognition in preclinical and clinical studies.

DISCUSSION: Natural products represent promising candidates for disease modification in NDs due to their multi-pathway actions and relatively low toxicity. However, major limitations, such as poor bioavailability, pharmacokinetic variability, and the lack of standardized formulations, hinder clinical translation. Innovative strategies, including advanced drug-delivery systems, structural modifications, and synergistic formulations, are needed to overcome these barriers.

CONCLUSION: Natural products hold significant therapeutic potential in managing neurodegenerative diseases by targeting multiple pathological mechanisms. Their integration into ND treatment could provide safer and more effective alternatives, but further well-designed clinical trials are essential to establish their efficacy and facilitate clinical application.},
}

@article {pmid42136293,
year = {2026},
author = {Ramesh, J and Jayanthi, B and Mohan, VK and Srinivasan, S and Vijayalakshmi, MK and Mohan, M},
title = {Targeted Nanotechnology Approaches to Bypass the Blood-brain Barrier in Neurodegenerative Disorders.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273444679260416064255},
pmid = {42136293},
issn = {1996-3181},
abstract = {Neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD) are a growing health burden across the world because of the progressive loss of brain cells and the ineffective nature of the available treatment. One significant challenge in the treatment of these conditions is the Blood- -Brain Barrier (BBB), a highly selective interface that limits the access of most therapeutic molecules to the central nervous system. Nanotechnology has become an attractive approach to addressing this difficulty, as it enables the delivery of drugs with high accuracy and actively engages in the repair of the BBB. This review provides an overall synthesis of focused nanotechnology solutions aimed at both circumventing and restoring BBB function in neurodegenerative illnesses. It discusses various nanoparticle (NP) platforms such as polymeric, lipid-based, micellar, metallic, and carbon-derived systems in the light of their physicochemical aspects, transport across the BBB, and therapeutic efficacy. Particular emphasis is put on the receptor-mediated transcytosis, neurovascular unit modulations, and the regulation of Wnt, Shh, and Tie-2 signalling pathways, which are BBB integrity pathways. The review incorporates mechanisms of BBB repair in combination with neuroprotective nanotherapies, rather than focusing solely on end repair. This review covers the role of targeted nanotechnology in the future of therapeutic approaches for neurodegenerative diseases. By connecting materials science, molecular neuroscience, and clinical innovation, it demonstrates how next-generation brain-targeted therapies can be developed using targeted nanotechnology.},
}

@article {pmid42136304,
year = {2026},
author = {Anjukandan, A and Kaliyaperumal, R},
title = {Challenges in Brain Drug Delivery for Neurodegenerative Disorders and Recent Trends: A Review.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273453002260416115852},
pmid = {42136304},
issn = {1996-3181},
abstract = {INTRODUCTION: Age-related disorders known as neurodegenerative illnesses are defined by uncontrolled neuronal loss that gradually impairs brain function. The majority of age-related neurodegenerative disorders are caused by dementias, in particular. Nowadays, the neurodegenerative disorders are not limited to age and are reported in all age groups. The drug delivery to treat the neurodegenerative disorders is challenging due to the presence of the blood-brain barrier (BBB).

METHOD: A critical literature review has been conducted across databases such as Scopus, Embase, Cochrane, and PubMed. Blood-brain barrier, neurodegenerative disorders, novel drug delivery system, and targeted drug therapy were the search terms.

RESULTS: Neurodegenerative Diseases (NDD) impact the peripheral nervous system, nerve cells, muscles, and the nerve-muscle junction. This term broadly encompasses cognitive disorders, such as Alzheimer's disease, Lewy body dementia, frontotemporal dementia, and vascular dementia. Additionally, other neurodegenerative conditions such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and spinocerebellar ataxias predominantly impair motor system function and nerves in the limbs. The existing therapeutic approaches to treat neurological diseases exhibit limited efficacy due to the BBB. This highly selective semipermeable membrane permits vital nutrients to enter the brain while blocking the potentially harmful toxins. It makes it very challenging to get medications into the brain. There are several effective approaches to deliver drugs to the brain (nanocarrier systems, intranasal administration, and focused ultrasound) to address the limitations of conventional treatments.

CONCLUSION: This review discusses neurodegenerative disorders, brain anatomy/physiology, barriers to drug delivery, and strategies to overcome these limitations.},
}

@article {pmid42136825,
year = {2026},
author = {Pan, J and Zhang, C and Li, J and Ma, L},
title = {Neurocritical progression in amyotrophic lateral sclerosis: pathological relevance and validation.},
journal = {Open life sciences},
volume = {21},
number = {1},
pages = {20251323},
pmid = {42136825},
issn = {2391-5412},
abstract = {Evidence from multiple clinical studies indicates that amyotrophic lateral sclerosis (ALS) frequently evolves into a condition requiring neurocritical care. In advanced stages or during acute complications, ALS can rapidly transition into a neurocritical state characterized by respiratory insufficiency, systemic dysfunction, and accelerated neurological decline. Although current management strategies for advanced-stage ALS are relatively well established, there remains a significant lack of targeted interventions aimed at preventing or attenuating neurocritical deterioration. This review systematically examines the pathophysiological mechanisms underlying neurocritical progression in ALS, including respiratory failure, metabolic imbalance, autonomic dysfunction, and multisystem involvement. We further evaluate emerging and potential therapeutic strategies designed to mitigate disease severity and stabilize critical neurological function. In addition, we analyze clinical and biological factors that increase susceptibility to neurocritical states and discuss evidence-based approaches to delay disease progression. By integrating clinical observations with mechanistic insights, this review aims to improve early recognition, optimize neurocritical management, and ultimately enhance outcomes for patients with ALS.},
}

@article {pmid42137032,
year = {2026},
author = {Miura, K and Nishimura, H and Ito, Y},
title = {Enhanced saccharification yields from rice straw by senescence-induced expression of a cytokinin biosynthesis gene in intragenic rice plants.},
journal = {Plant biotechnology (Tokyo, Japan)},
volume = {43},
number = {1},
pages = {145-149},
pmid = {42137032},
issn = {1342-4580},
abstract = {Controlling the digestibility of cellulosic biomass is important for its efficient use. We generated intragenic rice plants showing enhanced saccharification yield of rice straw. The rice cytokinin biosynthesis gene, LONELY GUY, under the control of the rice senescence-inducible STAY GREEN promoter, was introduced into the rice genome via particle bombardment. The rice-derived herbicide resistance gene ALS(G95A) was used as a selection marker gene. Regenerated intragenic rice plants with no foreign sequences showed enhanced saccharification yields from the leaves at harvest, whereas no significant differences were observed at the heading stage. Because the saccharification yields of rice straw are reduced after senescence, which is suppressed by cytokinin, we propose that the enhanced saccharification yields of intragenic rice plants are caused by the delay in senescence of the rice leaves due to the expression of the introduced cytokinin biosynthesis gene upon senescence.},
}

@article {pmid42137113,
year = {2026},
author = {Rong, P and Heidrick, L},
title = {An interpretable, clinically grounded framework for digital speech biomarker development in neurodegenerative diseases.},
journal = {Frontiers in digital health},
volume = {8},
number = {},
pages = {1794169},
pmid = {42137113},
issn = {2673-253X},
abstract = {INTRODUCTION: Communication ability-a key determinant of quality of life-is frequently affected and progressively declines in neurodegenerative diseases. Effective management of progressive communication disorders requires a personalized approach to deliver timely interventions tailored to the evolving profiles of communicative impairment, thereby supporting functional communication throughout the disease course. To this end, reliable tools capable of detecting and quantifying both disease-specific patterns of communicative impairment and within-disease phenotypic variability are urgently needed. This study leverages Artificial Intelligence and advanced data analytics to develop an acoustic-based framework for automated extraction of interpretable, clinically grounded speech markers to enable objective assessment and phenotyping of progressive communication disorders.

METHODS: Three groups of participants, including 14 individuals with amyotrophic lateral sclerosis (ALS) and 15 individuals with Parkinson's disease (PD), alongside 10 neurologically healthy controls, performed a standardized oral passage reading task, yielding 739 speech samples. Fifty acoustic features were extracted using an automated analytic pipeline and subsequently clustered into six interpretable composite markers. The clinical utility of these markers was evaluated with the recorded speech samples by examining their (1) associations with standardized metrics of cognitive, motor speech, and overall communicative functions, (2) efficacy for detecting and differentiating disease-specific communicative impairment patterns in ALS and PD using supervised machine learning, and (3) utility for within-disease phenotyping and stratification using unsupervised clustering analysis.

RESULTS: The markers effectively (1) detected subtle subclinical changes across multiple domains prior to substantial declines in functional communication outcomes; (2) differentiated disease-specific patterns of communicative impairment (multiclass area under the curve > 0.90); and (3) identified subgroups with distinct speech profiles within each disease.

DISCUSSION: The findings support the potential of the proposed framework as a clinically translatable, objective tool to facilitate early detection, differential diagnosis, and phenotyping of progressive communication disorders, ultimately advancing personalized, measurement-based care in neurodegenerative diseases.},
}

@article {pmid42139128,
year = {2026},
author = {Hong, J and Rao, P and Wang, W and Najafizadeh, L},
title = {EMBC Special Issue: ChatBCI-Assist: An Intent-Based P300 Speller with A Locally-Deployed LLM and Adaptive Stopping Strategy Enabling Record Online Spelling Performance.},
journal = {IEEE transactions on bio-medical engineering},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TBME.2026.3693965},
pmid = {42139128},
issn = {1558-2531},
abstract = {P300-based speller brain computer interfaces (BCIs) provide promising communication solutions for individuals with severe motor impairments such as those with amyotrophic lateral sclerosis (ALS). However, existing P300 spellers are constrained by slow typing speed and limited efficiency. Here, we present ChatBCI-Assist, an intent-based P300 speller that integrates a locally-deployed large language model (LLM), fine-tuned for the task at hand, with an adaptive stopping strategy for key selection and a graphical user interface (GUI) designed for efficient message composition, to achieve record-level online spelling performance. The LLM, trained on an ALS-specific communication corpus using low-rank adaptation (LoRA), produces context-aware, semantically coherent, and prefix-constrained word and phrase predictions in real time. The proposed GUI supports efficient, user-adaptive message composition, while the adaptive stopping strategy dynamically adjusts stimulus presentation based on each subject's classification performance. Combined with a subject specific stepwise linear discriminant analysis (SWLDA) classifier, ChatBCI-Assist enhances spelling efficiency. Results from online experiments demonstrate that ChatBCI-Assist achieves record performance, with an average information transfer rate (ITR) of 105.2 bits/min, an overall character-level mutual information rate (MIR) of 52.9 bits/min and characters per minute (CPM) of 19.7 in copy-spelling tasks, and 30.7 CPM in semantic spelling tasks. Evaluated using semantic ITR (SITR), a metric proposed to characterize semantic communication efficiency, ChatBCI-Assist achieved SITR of 147.1 bits/min. User experience evaluations further confirm reduced workload and higher usability from LLM-based semantic spelling configurations, compared to traditional copy-spelling paradigms (dictionary or LLM). This work demonstrates that integrating locally-adapted LLMs with intent driven design and subject-specific decoding optimization can substantially improve the speed, efficiency, and user experience of BCI-based communication systems.},
}

@article {pmid41922953,
year = {2026},
author = {Xing, Z and Cheng, Z and Yang, X and Hu, L and Wang, K and Wang, Y and Hu, D and Wang, YH and Du, J and Wang, L and Li, J},
title = {Integrated genomic and transcriptomic analysis reveals candidate genes underlying herbicide resistance in Sorghum.},
journal = {BMC plant biology},
volume = {26},
number = {1},
pages = {},
pmid = {41922953},
issn = {1471-2229},
support = {32372134//The National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Herbicide-resistant germplasms provide critical genetic resources for improving weed control and understanding resistance mechanisms in crops.

OBJECTIVE: To screen sorghum accessions for tolerance to ACCase and ALS inhibitor herbicides at the seedling stage, identify the major locus and strong candidate gene associated with feproxydim resistance, and verify the gene expression pattern and genetic variation by quantitative real‑time PCR (qRT‑PCR) and KASP genotyping.

METHOD: A total of 316 sorghum accessions were screened for seedling-stage herbicide tolerance using gradient herbicide treatments. Bulked segregant analysis sequencing (BSA-Seq) was performed on resistant and susceptible gene pools constructed from the F₂ population derived from IS1219 × RTx430. Transcriptome sequencing (RNA-Seq) was conducted on leaf tissues after feproxydim treatment to identify candidate genes within the mapped interval. KASP markers were developed for the functional variation site of the key candidate gene for genotyping validation. Quantitative real‑time PCR (qRT-PCR) was used to measure the relative expression level of the target gene and compare it with the susceptible control line. Protein sequence comparison was used to detect variations in the key candidate gene between resistant and susceptible lines.

RESULT: In the screening with the ACCase inhibitor 10% feproxydim, IS1219 exhibited high-level resistance. Preliminary screening under the ALS inhibitor mesosulfuron-methyl treatment identified only SJ304 with visible tolerance, which was not subjected to further mapping or validation. BSA-Seq identified a major feproxydim resistance QTL on chromosome 1. RNA-Seq revealed five co-expressed candidate genes in the target interval, among which Sobic.001G431500 (encoding carboxylesterase 17, an α/β‑hydrolase) was markedly upregulated in the resistant line IS1219 but not in the susceptible line RTx430. Quantitative real‑time PCR (qRT-PCR) analysis confirmed that Sobic.001G431500 was significantly upregulated in the resistant line IS1219 compared with the susceptible control. KASP genotyping demonstrated that the IS1219 allele cosegregated with feproxydim resistance. Protein sequence comparison showed that the IS1219 allele carried a missense mutation V300A and a deletion P301_P303 at and after position 300.

CONCLUSION: These findings identify a major QTL and a strong candidate gene Sobic.001G431500 associated with feproxydim resistance in the sorghum line IS1219, based on differential expression, genetic variation, and genotype–phenotype cosegregation. This study provides valuable genetic resources and functional markers for marker-assisted selection and breeding of feproxydim-tolerant sorghum varieties.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12870-026-08624-5.},
}

@article {pmid42126073,
year = {2026},
author = {Razlan, AN and Ma, W and Dickie, AC and Polgar, E and McFarlane, AG and Yadav, M and Cooper, AH and Strathdee, D and Watanabe, M and Bell, AM and Todd, AJ and Hachisuka, J},
title = {Characterisation of cold-selective lamina I spinal projection neurons in the mouse.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
pmid = {42126073},
issn = {2050-084X},
support = {10.35802/219433/WT_/Wellcome Trust/United Kingdom ; MR/V033638/1/MRC_/Medical Research Council/United Kingdom ; 10.35802/304005/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Mice ; *Cold Temperature ; TRPM Cation Channels/metabolism/genetics ; *Neurons/physiology ; Optogenetics ; Calbindins/metabolism ; Mice, Inbred C57BL ; *Spinal Cord/physiology/cytology ; Male ; },
abstract = {Skin cooling is detected by primary afferents that express the Trpm8 channel, but how this information is conveyed to the brain remains poorly understood. We have previously identified a population of lamina I projection neurons belonging to the anterolateral system (ALS) that receive numerous contacts from Trpm8-expressing primary afferents. Here, using a semi-intact somatosensory preparation, we provide evidence that these cells correspond to the cold-selective ALS neurons identified in previous physiological studies. We also confirm the presence of synapses from Trpm8 afferents onto these cells at the ultrastructural level and with optogenetics. Based on our previous transcriptomic findings, we identify calbindin as a molecular marker, and show that this can be used to target the cold-selective ALS neurons for anterograde tracing studies. We provide evidence that they project to brain regions that have been implicated in thermosensation: the rostralmost part of the lateral parabrachial area, the caudal part of the periaqueductal grey matter, and the posterior triangular and ventral posterolateral nuclei of the thalamus. Our findings provide important insights into the organisation of neuronal circuits that underlie thermoregulation and the perception of cold stimuli applied to the skin.},
}

Animals
Mice
*Cold Temperature
TRPM Cation Channels/metabolism/genetics
*Neurons/physiology
Optogenetics
Calbindins/metabolism
Mice, Inbred C57BL
*Spinal Cord/physiology/cytology
Male

@article {pmid42127155,
year = {2026},
author = {Sunindyo, WD and Anshori, I and Wiguna, KA and Kahari, MMH and Syafalni, I and Dwiyanti, L and , },
title = {Algorithm-assisted interpretation of cyclic and differential pulse voltammetry for cardiac troponin detection.},
journal = {PloS one},
volume = {21},
number = {5},
pages = {e0348348},
doi = {10.1371/journal.pone.0348348},
pmid = {42127155},
issn = {1932-6203},
mesh = {*Algorithms ; Humans ; *Electrochemical Techniques/methods ; Biomarkers/blood ; Electrodes ; Biosensing Techniques/methods ; *Troponin/analysis ; Reproducibility of Results ; },
abstract = {Cardiovascular disease remains a leading cause of mortality worldwide, and rapid identification of cardiac biomarkers is essential for early detection. Electrochemical voltammetry techniques, particularly cyclic voltammetry (CV) and differential pulse voltammetry (DPV), are widely used for detecting cardiac troponin; however, interpretation of raw voltammetric signals is often affected by baseline drift, signal noise, and operator-dependent analysis. This study proposes an algorithm-assisted analytical framework for automated interpretation of voltammetric data obtained from a screen-printed carbon electrode potentiostat. Polynomial fitting was applied for baseline correction in CV signals, while asymmetric least squares (ALS) was employed for DPV data. Peak-to-baseline current response was extracted as a quantitative indicator of biomarker presence. The proposed method successfully identified characteristic voltammetric peaks and distinguished samples with higher and lower cardiac biomarker responses relative to a predefined detection threshold. The analysis showed close agreement with reference electrochemical analysis software, demonstrating reliable peak detection and baseline estimation. By reducing manual interpretation and improving signal clarity, the framework enhances the reproducibility and accessibility of electrochemical biosensor measurements and supports early screening of cardiac biomarkers.},
}

*Algorithms
Humans
*Electrochemical Techniques/methods
Biomarkers/blood
Electrodes
Biosensing Techniques/methods
*Troponin/analysis
Reproducibility of Results

@article {pmid42127907,
year = {2026},
author = {Xu, W and Li, H and Zhang, W and Bai, G and Shen, C and Zhang, K},
title = {S-acylation of TDP43 regulates its condensation in amyotrophic lateral sclerosis.},
journal = {Molecular cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molcel.2026.04.016},
pmid = {42127907},
issn = {1097-4164},
abstract = {TDP43 inclusion bodies are widely present in the majority of patients with familial and sporadic amyotrophic lateral sclerosis (ALS). The mechanisms regulating TDP43 solubility remain incompletely understood. Here, we report that TDP43 undergoes S-acylation primarily at the Cys244 residue by the S-acyltransferase zDHHC23. This S-acylation maintains the liquid-like properties of TDP43 by reducing the aberrant interaction with poly(ADP-ribose) polymerase 1 (PARP1) and PARylated proteins, thereby countering the pathological condensation of TDP43. S-acylation-deficient TDP43 inclusions sequester the translational machinery and inhibit cytoplasmic protein translation, ultimately resulting in neurotoxicity. Importantly, TDP43 S-acylation is decreased in the familial ALS-associated TDP43 mutants as well as in SOD1-G93A mice and C9orf72-ALS induced pluripotent stem cell (iPSC)-derived neurons, suggesting the widespread involvement of TDP43 S-acylation in ALS pathogenesis. Our findings reveal an undescribed modification of TDP43 and provide deeper insight into the regulation of TDP43 pathological condensation in ALS.},
}

@article {pmid42129145,
year = {2026},
author = {Pulst, SM and Paul, S and Nguyen, H and Dansithong, W and Figueroa, KP and Gandelman, M and Bonini, NM and Scoles, DR},
title = {A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08830-x},
pmid = {42129145},
issn = {2041-4889},
support = {R21NS127028//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS137233//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS097903//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21NS128630//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R61/R33NS124965//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21NS128630//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35NS097275//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R56NS033123//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R37NS033123//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35NS127253//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R61/R33NS124965//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
abstract = {RNA-binding proteins (RBPs) play an essential role in development, normal functioning, and human disease. Staufen1 (STAU1) is an RBP that regulates mRNA degradation and subcellular localization, and is part of the ATXN2 protein complex. Previously, we showed that STAU1 is overabundant in patient fibroblasts and in mouse models of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 2 (SCA2), where it is associated with impaired autophagic flux due to STAU1-mediated upregulation of mTOR translation. STAU1 overabundance and impaired autophagy cause accumulation of biomolecular condensates and abnormal unfolded protein response (UPR). We generated a mouse model expressing the entire human STAU1 gene (hSTAU1) in a bacterial artificial chromosome (BAC) construct. hSTAU1 in these mice was expressed in cerebral hemispheres, cerebellum, and spinal cord, as well as cultured cortical neurons and cortical and spinal cord astrocytes, and microglia. Expression of hSTAU1 caused dysregulated gene expression, abnormal autophagy, glial activation, and changes in neuronal marker proteins. All of these were significantly improved by reducing STAU1 abundance by RNAi, but exacerbated in BAC-STAU1 mice crossed with Prp-TDP-43(Q331K) transgenic mice. Similar results were also obtained in eye phenotypes in ALS- and SCA2-relevant fly models upon changing staufen-1 dosage. Despite the molecular changes, we observed no overt behavioral changes in mice up to 55 weeks of age, suggesting that STAU1 may function as an epistatic modifier of neuronal degeneration. The BAC-hSTAU1 mouse will be useful for developing therapies targeting the human STAU1 gene.},
}

@article {pmid42130389,
year = {2026},
author = {Thurn, T and Chiò, A and Galvin, M and Stavroulakis, T and Anneser, J},
title = {Beyond the surface: Exploring differing aspects of wishes to hasten death in patients with amyotrophic lateral sclerosis.},
journal = {Palliative & supportive care},
volume = {24},
number = {},
pages = {e147},
doi = {10.1017/S1478951526102673},
pmid = {42130389},
issn = {1478-9523},
mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Cross-Sectional Studies ; Middle Aged ; Aged ; Longitudinal Studies ; Europe ; *Attitude to Death ; Quality of Life/psychology ; Surveys and Questionnaires ; Adult ; Aged, 80 and over ; },
abstract = {OBJECTIVES: This study investigates differing aspects of wishes to hasten death (WTHD) distinguished by the extent to which WTHD were linked to patients' agency: desire for hastened death (DHD), defined as general wishes for death to come sooner, and hastening death intentions (HDI), defined as thoughts about ending one's life. In particular, this study aims to examine the differences between DHD and HDI in patients with amyotrophic lateral sclerosis (pALS) and identify predictive factors for both.

METHODS: A cross-sectional nested study was conducted within a multi-center longitudinal study involving pALS from 5 European countries. Data collected included DHD (Schedule of Attitudes toward Hastened Death), HDI ("could you currently imagine ending your life?"), sociodemographic and clinical characteristics, psychological distress, quality of life, and social and spiritual-existential aspects.

RESULTS: In our sample of 121 pALS, 12.4% (15/121) expressed DHD, and 28.1% (34/121) expressed HDI. Of the 38 patients reporting any WTHD, only 11 experienced both DHD and HDI simultaneously. 23 patients reported HDI without DHD, while 4 patients expressed DHD without HDI. Multivariable logistic regression identified loneliness (OR = 1.33, 95% CI 1.03-1.71, p = 0.028) and reduced meaning in life (OR = 0.89, 95% CI 0.84-0.95, p < 0.001) as independent predictors of DHD. For HDI, independent predictors were female gender (OR = 3.31, 95% CI 1.37-7.98, p = 0.008) and lower spirituality (OR = 0.92, 95% CI 0.88-0.95, p < 0.001).

SIGNIFICANCE OF RESULTS: One in 3 pALS expressed WTHD. Our separate analysis of DHD and HDI supports the existence of distinct manifestations of WTHD and varying underlying factors. While DHD and HDI were associated with different predictors, our results point to the crucial role of spiritual-existential factors in the experience of WTHD, identifying these aspects as target points for intervention. This study highlights the importance of a nuanced understanding and communication regarding WTHD.},
}

Humans
Female
Male
*Amyotrophic Lateral Sclerosis/psychology/complications
Cross-Sectional Studies
Middle Aged
Aged
Longitudinal Studies
Europe
*Attitude to Death
Quality of Life/psychology
Surveys and Questionnaires
Adult
Aged, 80 and over

@article {pmid42131110,
year = {2026},
author = {Zhang, M and Su, L and Han, W and Song, F and Fu, Y and Chi, MB and Chen, X and Wu, YH and Gao, SJ},
title = {Single cell Raman spectroscopic profiles predict treatment responses in patients with de novo acute myeloid leukemia.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1767226},
pmid = {42131110},
issn = {2296-634X},
abstract = {INTRODUCTION: Leukemia is a clonal malignant proliferative disease originating from hematopoietic stem cells. Although its treatment strategy has gradually developed from traditional chemotherapy to a multimodal treatment system including novel targeted therapy and immunotherapy, primary drug resistance in particular remains the core clinical problem leading to poor patient prognosis. This clinical dilemma indicates that the traditional genotyping system based on genomics has not been able to fully resolve the molecular heterogeneity of acute myeloid leukemia (AML), and it is urgent to establish a precise stratified model that can dynamically reflect the functional status of tumor cells in the initial stage of treatment.

METHODS: In this study, Raman spectroscopy (RS) combined with machine learning algorithm was used to construct a metabolic prognosis prediction model for AML chemotherapy response. Bone marrow single cell Raman spectroscopy data of newly diagnosed AML patients were collected, and the molecular fingerprint was analyzed by principal component analysis linear discriminant analysis (PCA-LDA) and multivariate curve resolute alternating least square method (MCR-ALS).

RESULTS: The results showed that the PCALDA model achieved complete remission or non-remission (CR/NR) classification through 24 principal components (cumulative variance contribution of 90.1%), the accuracy of external validation was 94.8% (sensitivity 97.9%, specificity 92.0%), and the AUC reached 96.27%. Protein, lipid, nucleic acid and mixed components were decomposed by MCR-ALS, and lipid and nucleic acid metabolic pathways were enriched in NR group (P < 0.001).

DISCUSSION: Studies have shown that RS single-cell metabolic fingerprint can decode the metabolic reprogramming features associated with chemotherapy resistance in AML, providing a new marker-free and highly sensitive tool for real-time prognostic stratification and targeted intervention.},
}

@article {pmid42131159,
year = {2026},
author = {Dewan, L and Pal, S and Tibrewal, S},
title = {Letter to the Editor: Comment on Takai et al.'s "Age-Associated Differences in Optic Disc Findings of Leber's Hereditary Optic Neuropathy".},
journal = {Neuro-ophthalmology (Aeolus Press)},
volume = {50},
number = {3},
pages = {292-293},
pmid = {42131159},
issn = {0165-8107},
abstract = {This letter comments on the study by Takai et al examining age-related differences in acute phase optic disc morphology in Leber hereditary optic neuropathy. We highlight methodological considerations in subjective fundus photograph assessment, and discuss additional factors such as refractive status and timing of presentation that may influence the presence of optic disc edema. These points may aid in refining phenotypic interpretation in future LHON studies.},
}

@article {pmid42131356,
year = {2026},
author = {Macchietti, L and Carta, M and Delogu, F and Grepioni, F and Emmerling, F and Casali, L},
title = {Scaling up mechanochemical reactions: linking crystalline phase evolution studied via in situ PXRD with kinetics from MCR-ALS.},
journal = {Chemical science},
volume = {},
number = {},
pages = {},
pmid = {42131356},
issn = {2041-6520},
abstract = {This work addresses a key challenge in scaling up mechanochemical synthesis: deriving a kinetic model when unpredictable formation and intricate interaction of multiple crystalline phases occur during solid-state transformations. Reaction kinetics translate our understanding of chemical processes into mathematical rate expressions used for reactor design and evaluation, thus representing a challenge to be addressed for the scale up at the industrial level. Choosing co-crystallization of chloro-3-sulfamoylbenzoic acid (CSBA) and isonicotinamide (INA) as a model system, at first we employ time-resolved in situ powder X-ray diffraction (PXRD) and multivariate curve resolution-Alternating Least Squares (MCR-ALS) analysis to quantify and resolve the evolution of crystalline intermediates under varying methanol-assisted conditions. Our data show that even small changes in the amount of methanol can dramatically alter the kinetic profile, stabilise transient phases (including some that were previously unreported) and alter the overall reaction pathway. We then demonstrate the robust deconvolution of overlapping phases and the extraction of quantitative rate parameters that rationalize the observed behaviour by integrating kinetic modelling as a soft-hard constraint in the MCR-ALS workflow. The validation of the established MCR-ALS workflow is achieved by applying a phenomenological kinetic modelling tailored to rationalize the mechanochemical reaction rates. These results establish a broadly applicable platform for analysing and controlling the complex phase evolution, along with the derivation of a kinetic model instrumental to mechanochemical process development and scaling up, thereby supporting the transition of sustainable solid-state syntheses from the laboratory to industry.},
}

@article {pmid42133017,
year = {2026},
author = {Svihlik, J and Rusz, J},
title = {Screening speech disorders in progressive neurological diseases via long-term average spectrum.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42133017},
issn = {1435-1463},
abstract = {The long-term averaged spectrum (LTAS) may provide a universal method for capturing distinct patterns of dysarthria. This study aimed to evaluate the sensitivity of LTAS descriptors in a broad range of neurological diseases and various types and severities of dysarthria. Four spectral moments of spectral mean, spectral standard deviation, spectral skewness and spectral kurtosis based on LTAS were computed for reading passage collected from 461 speakers, including 306 healthy controls and 155 neurological patients secondary to Parkinson's disease (PD), progressive supranuclear palsy, multiple system atrophy (MSA), Huntington's disease, essential tremor, cerebellar ataxia (CA), multiple sclerosis (MS), and amyotrophic lateral sclerosis. Compared to controls, the spectral mean was significantly lower in PD and MS while elevated in CA. Significantly changed LTAS features were observed only in hypokinetic dysarthria and in mixed dysarthrias manifesting hypokinetic elements. Although LTAS features differed between controls and patients with varying degrees of dysarthria, there was no progressive increase in dysarthria severity. Our findings suggest that LTAS-based speech analysis may provide valuable cues to aid differential diagnosis among neurological diseases with overlapping clinical features. LTAS appears more informative when applied to specific diseases than to pooled dysarthria types arising from diverse neurological etiologies.},
}

@article {pmid42134656,
year = {2026},
author = {Vassallu, F and López, M and López Ambrosioni, F and Casal, J and Caltana, L and Igaz, LM},
title = {TDP-43 expression in the cytoplasm leads to early synaptic and mitochondrial abnormalities in an inducible mouse model of ALS/FTD.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106180},
doi = {10.1016/j.neuint.2026.106180},
pmid = {42134656},
issn = {1872-9754},
abstract = {TDP-43 proteinopathy is the primary pathology associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), indicating that these neurodegenerative diseases have common underlying mechanisms. We have previously shown that transgenic (Tg) mice conditionally overexpressing a cytoplasmic form of human TDP-43 protein (TDP-43-ΔNLS) in forebrain neurons replicate key features of FTD/ALS, including altered cognitive, motor and social behaviors. These behavioral phenotypes and changes in plasticity-related gene expression can be detected as early as 1 month after Tg induction, before overt neurodegeneration occurs. To assess early ultrastructural features in this model, we performed Transmission Electron Microscopy (TEM) analysis in the cortex (Ctx) and hippocampus (Hp) of Tg animals and their non-Tg controls. TEM evaluation of Ctx and Hp revealed that synaptic density was significantly decreased and synapse length was increased in both regions of Tg animals. Synaptic cleft thickness was increased and post-synaptic density thickness was decreased only in the Ctx of Tg mice, revealing differential regional effects in synaptic morphology. We analyzed mitochondrial density and we found an increase in the Ctx and a decrease in the Hp of Tg animals, with preserved individual mitochondrial area. Lastly, transcriptomic and proteomic analysis from both transgenic TDP-43-ΔNLS mice and human proteinopathy showed widespread decreased expression of synaptic structure and function genes. The alterations in synaptic density and architecture reported here, combined with the mRNA/protein expression data, suggest that TDP-43-ΔNLS mice may exhibit abnormal synaptic transmission and that ultrastructural changes play a role in the early behavioral deficits observed in this model.},
}