@article {pmid42942116,
year = {2026},
author = {Ramadan, S and Panza, E and Orlacchio, A},
title = {Beyond Monogenic Inheritance: Emerging Genetic Architecture of Amyotrophic Lateral Sclerosis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42942116},
issn = {1422-0067},
support = {JALSDGC project to A.O.//Italian research Foundation for ALS/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genetic Predisposition to Disease ; C9orf72 Protein/genetics ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by marked genetic and phenotypic heterogeneity. Although pathogenic variants in major ALS genes, including C9ORF72, SOD1, TARDBP, and FUS, have provided fundamental insights into disease pathogenesis, many familial and most sporadic cases remain without a molecular diagnosis, suggesting a genetic architecture extending beyond coding variants and monogenic inheritance. Advances in genomic technologies have revealed contributions from deep-intronic and regulatory variants, structural rearrangements, repeat expansions, and other forms of genomic variation incompletely captured by standard diagnostic approaches. Evidence also indicates that combinations of rare variants with moderate or incomplete penetrance may contribute to disease susceptibility and clinical variability, supporting a multilayer model of ALS genetics. Population-specific variation and convergence of genetically diverse defects on common molecular pathways further complicate variant interpretation and disease classification. This review examines emerging components of ALS genetic architecture, including non-coding variation, structural variants, repeat expansions, oligogenic burden, ancestry-related gaps, and convergent neurodegenerative pathways. Integrating these genomic layers with functional and transcriptomic evidence may improve variant interpretation, diagnostic yield, patient stratification, and the development of mechanism-based precision therapies.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
*Genetic Predisposition to Disease
C9orf72 Protein/genetics
RNA-Binding Protein FUS/genetics
Superoxide Dismutase-1/genetics

@article {pmid42944613,
year = {2026},
author = {Abbasi Dezfouli, S and Heidenreich, E and Shahrbaf, M and Khajeh, E and Ramouz, A and Klauss, M and Hellbach, K and Öcal, O and Loos, M and Mehrabi, A},
title = {Novel algorithm for the diagnosis and treatment of different types of bile leakage following liver surgery.},
journal = {BJS open},
volume = {10},
number = {5},
pages = {},
pmid = {42944613},
issn = {2474-9842},
mesh = {Humans ; *Anastomotic Leak/diagnosis/therapy/etiology ; *Hepatectomy/adverse effects ; *Algorithms ; Female ; Male ; Bilirubin/analysis/blood ; Aged ; Middle Aged ; Bile ; Anastomosis, Surgical/adverse effects ; Retrospective Studies ; Bile Ducts/surgery ; Drainage ; Postoperative Complications/diagnosis ; },
abstract = {BACKGROUND: Posthepatectomy bile leakage (PHBL) after liver resection with bilioenteric anastomosis may originate from the anastomosis (anastomotic leak (AL)) or the transection surface (surface leak), including leakage from isolated bile ducts (IBDLs). Differentiating these sources remains challenging, and standardized management guidelines are lacking.

METHODS: All patients undergoing liver resection with bilioenteric anastomosis from 2008-2023 were analysed. PHBL was classified by origin (AL, surface leak, IBDL) and timing (early versus late onset). Drain fluid bilirubin concentration, drain-to-serum bilirubin ratio, and daily bilirubin loss were evaluated by leak type. Outcomes of conservative, interventional, and surgical management were compared.

RESULTS: Among 2936 liver resections, 229 involved bilioenteric anastomosis. PHBL occurred in 96 patients, including 44 ALs (46%), 47 surface leaks (49%), and 5 IBDLs (5%). AL showed higher peak drain bilirubin than surface leak/IBDL (38.3 versus 18.6 mg/dl; P < 0.001). Receiver operating characteristic analysis identified cut-offs for AL diagnosis: drain bilirubin > 20.85 mg/dl, drain-to-serum ratio > 10.57, and bilirubin loss > 160.93 mg/day. Management success varied by type and timing: AL and IBDL responded best to reoperation (success rates 78% and 100%), whereas surface leak was more effectively managed without surgery (65%). In AL specifically, reoperation was more successful in early-onset leaks (65% versus 38% in late-onset; P = 0.069), whereas interventional therapy was more successful in late-onset leaks (58% versus 15% in early-onset; P = 0.003).

CONCLUSIONS: Distinct diagnostic thresholds help differentiate AL from other PHBL types. AL and IBDL benefit from reoperation, whereas surface leak is better managed without surgery. Timing influences therapeutic success, supporting a novel type- and timing-based management algorithm for PHBL.},
}

Humans
*Anastomotic Leak/diagnosis/therapy/etiology
*Hepatectomy/adverse effects
*Algorithms
Female
Male
Bilirubin/analysis/blood
Aged
Middle Aged
Bile
Anastomosis, Surgical/adverse effects
Retrospective Studies
Bile Ducts/surgery
Drainage
Postoperative Complications/diagnosis

@article {pmid42945473,
year = {2026},
author = {Salmon, K and de Majo, M and Basak, N and Crook, A and Cummings, C and Dratch, L and França, MC and Heckmann, J and Higgins, P and Knight, D and Koo, A and Nalini, A and Rouleau, G and Shahrizaila, N and Sokhi, DS and Son, B and Thomas, P and Trefiak, P and Van Damme, P and , and Roggenbuck, J and Harms, M and Al-Chalabi, A},
title = {Global best practice recommendations for genetic counselling and testing in amyotrophic lateral sclerosis.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag375},
pmid = {42945473},
issn = {1460-2156},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with substantial clinical and genetic heterogeneity. Advances in ALS genomics, emerging gene-targeted therapies, and genotype-specific clinical trials have increased the importance of genetic counselling and testing for individuals with ALS and their families. However, access to these services remains highly variable globally due to disparities in healthcare infrastructure, laboratory capacity, specialist availability, and funding. Existing guidance has largely been developed in high-resource settings and may not be feasible or equitable worldwide. The International Alliance of ALS/MND Associations convened an international, multidisciplinary Genetics Task Force to develop expert consensus recommendations for genetic counselling, genetic testing, and laboratory practice in ALS across diverse geographic and resource settings. Recommendations were developed through a structured, iterative consensus process incorporating clinical expertise, lived experience perspectives, published evidence, and global representation. Final recommendations were reviewed and approved through anonymous voting at an in-person consensus meeting. The resulting recommendations establish both minimum and aspirational best practices, emphasizing equitable access, informed decision-making, culturally responsive counselling, tiered genetic testing approaches, and context-appropriate laboratory standards. These globally informed recommendations provide a pragmatic framework to support clinicians, laboratories, policymakers, and advocacy organizations in improving access to high-quality ALS genetics services worldwide.},
}

@article {pmid42946239,
year = {2026},
author = {Dale, A and Sattler, R},
title = {TDP-43 dysfunction destabilizes glial homeostatic identity in ALS/FTD.},
journal = {Brain research},
volume = {},
number = {},
pages = {150618},
doi = {10.1016/j.brainres.2026.150618},
pmid = {42946239},
issn = {1872-6240},
abstract = {TAR DNA-binding protein 43 (TDP-43) pathology is a defining feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 dysfunction has traditionally been studied through a neuron-centric framework, increasing evidence demonstrates that astrocytes, microglia, and oligodendrocytes are also directly affected and actively contribute to disease progression. In this review, we examine how TDP-43 dysfunction disrupts lineage-specific glial homeostatic programs and promotes distinct pathological state transitions across major glial populations. In astrocytes, TDP-43 dysfunction impairs neurotransmitter regulation, metabolic and neuronal support, RNA homeostasis, and secretory signaling while promoting inflammatory and antiviral-like states. In microglia, altered TDP-43 disrupts inflammatory regulation, phagocytosis, lysosomal function, lipid metabolism, and stage-dependent protective responses. In oligodendrocytes, TDP-43 dysfunction compromises RNA processing, lineage maintenance, lipid metabolism, myelin integrity, and long-term axonal support. Together, these findings suggest that glial TDP-43 dysfunction cannot be reduced to a single generalized form of reactivity but instead reflects the breakdown of distinct cell type-specific identities required to maintain central nervous system homeostasis. A cross-glial framework integrating cell-autonomous dysfunction, non-cell-autonomous signaling, disease stage, and genetic context may therefore provide a more complete understanding of TDP-43 proteinopathy and its contribution to neurodegeneration across the ALS-FTD spectrum.},
}

@article {pmid42946847,
year = {2026},
author = {Raina, GS and Mehan, S and Das Gupta, G},
title = {Combined melatonin and edaravone therapy attenuates methylmercury-induced amyotrophic lateral sclerosis-like neurodegeneration through GLP-1 modulation and myelin preservation.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42946847},
issn = {1432-1912},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder characterized by the selective degeneration of upper and lower motor neurons, resulting in progressive muscle weakness, paralysis, and respiratory failure. Despite the availability of disease-modifying therapies, current treatment options provide only modest clinical benefits, highlighting the need for novel therapeutic strategies targeting multiple pathological mechanisms. Melatonin, a pleiotropic neuroprotective molecule with antioxidant, anti-inflammatory, and anti-apoptotic properties, has emerged as a promising candidate; however, its influence on glucagon-like peptide-1 (GLP-1)-associated neuroprotective signaling and related molecular events in ALS remains poorly understood. Therefore, the present study investigated the neuroprotective efficacy of melatonin in a methylmercury (MTMR)-induced rat model of ALS and explored its effects on GLP-1-associated molecular alterations, neuroinflammation, oxidative stress, apoptosis, neurotransmitter homeostasis, demyelination, and neuronal injury. Molecular docking analysis was performed to predict the interaction of melatonin with proteins implicated in ALS pathology. Adult Wistar rats were exposed to MTMR (5 mg/kg, p.o.) for 21 days to induce ALS-like neurodegeneration, followed by treatment with melatonin (5 or 10 mg/kg, i.p.), edaravone (3 mg/kg, i.p.), or their combination for an additional 21 days. Neurobehavioral performance, biochemical alterations, hematological parameters, molecular biomarkers, and histopathological changes were subsequently evaluated. MTMR administration produced profound motor deficits accompanied by reduced GLP-1 levels, neurotransmitter imbalance, increased neuroinflammatory and apoptotic markers, elevated neurofilament light chain (NEFL), skeletal muscle injury, methylmercury accumulation, and extensive myelin and neuronal damage. Melatonin treatment significantly attenuated these pathological alterations in a dose-dependent manner by increasing GLP-1 levels, improving antioxidant status, reducing inflammatory and apoptotic responses, restoring neurotransmitter balance, preserving myelin integrity, and improving neuronal morphology across multiple brain regions and the spinal cord. Molecular docking further predicted favorable interactions between melatonin and several proteins associated with ALS pathophysiology, supporting its potential as a multitarget therapeutic agent. In most outcome measures, combined treatment with melatonin and edaravone produced greater neuroprotective effects than either intervention alone. Collectively, these findings demonstrate that melatonin substantially attenuates methylmercury-induced ALS-like neuropathology through coordinated modulation of multiple pathological processes associated with neurodegeneration. Although the precise molecular mechanisms require further experimental validation, the observed restoration of GLP-1 levels together with improvements in oxidative stress, neuroinflammation, apoptosis, neurotransmitter homeostasis, and myelin integrity suggests that melatonin may represent a promising adjunctive therapeutic strategy for ALS.},
}

@article {pmid42946878,
year = {2026},
author = {Chen, Z and Mansikkaviita, J and Seitz, C and Yazdani, S and Lehikoinen, J and Deeba, E and Lovik, A and Keszei, M and Grönlund, H and Laaksovirta, H and Fang, F and Tienari, PJ and Ingre, C and Andersson, J},
title = {Persistent and compartmentalized T cell immunity in ALS.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {42946878},
issn = {1546-170X},
support = {802091//EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))/ ; 2023-02428//Vetenskapsrådet (Swedish Research Council)/ ; 2024-02262//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; FS-2023-ESC-S5//Target ALS (Target ALS Foundation)/ ; },
abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease increasingly linked to T cell responses, although the mechanisms driving T cell activation and disease progression remain unclear. Here we used single-cell RNA and T cell receptor sequencing, longitudinal immune profiling and imaging flow cytometry to identify long-lived intrathecal clonotypes and antigen-presenting cell-T cell complexes displaying features of immunological synapse formation, consistent with intrathecal antigen presentation. Higher frequencies of CD4[+] effector, CD4[+] regulatory and CD8[+] T cells in cerebrospinal fluid (CSF) were associated with slower disease progression, whereas increased circulating CD4[+] effector and regulatory T cells were associated with faster progression. T cell clonotypes shared between blood and CSF exhibited distinct transcriptional states. Finally, frequencies of cytomegalovirus-specific T cells in CSF and anticytomegalovirus serum antibodies were correlated with faster progression and shorter survival in sporadic amyotrophic lateral sclerosis. These findings reveal compartmentalized immune dynamics, largely contrasting protective intrathecal responses with harmful systemic activation.},
}

@article {pmid42946883,
year = {2026},
author = {Lillini, D and Basili, T and Migliorelli, L and Aironi, C and Gabrielli, L and Squartini, S},
title = {Improving dysarthric speech classification with generative AI-based data augmentation.},
journal = {Medical & biological engineering & computing},
volume = {},
number = {},
pages = {},
pmid = {42946883},
issn = {1741-0444},
abstract = {Dysarthria is a neurological speech disorder characterized by impaired motor control of speech production, resulting in reduced intelligibility. It commonly arises in the context of neurodegenerative conditions, including amyotrophic lateral sclerosis and cerebral palsy. The development of deep learning systems for dysarthria assessment is hindered by the scarcity of annotated data, which restricts the ability of models to generalize to unseen speakers. This study proposes a cross-corpus diffusion-based data augmentation strategy for improving automatic speech intelligibility classification from dysarthric speech. A Grad-TTS model is trained on dysarthric speakers from the TORGO dataset and used to synthesize the vocabulary of UA-Speech, producing speaker-conditioned samples intended to transfer pathological acoustic traits across corpora. The proposed strategy is evaluated both independently and in combination with conventional signal-level augmentation using ResNet-50 and ResNet-152 classifiers in binary and four-class intelligibility classification tasks. The results indicate that cross-corpus synthetic augmentation improves average performance and that, in most settings, its integration with conventional augmentation yields further gains, suggesting that the two strategies introduce complementary forms of variability.},
}

@article {pmid42947273,
year = {2026},
author = {Sigfridsson, I and Marklund, M and Andersen, PM and Zetterström, P and Marklund, SL and Brännström, T},
title = {Intracisternal injection of two human SOD1 aggregate strains induces templated aggregation and ALS in transgenic mouse model.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {42947273},
issn = {2051-5960},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; Mice, Transgenic ; *Superoxide Dismutase-1/administration & dosage/metabolism/genetics ; Humans ; Disease Models, Animal ; Spinal Cord/pathology/metabolism ; Mice ; *Protein Aggregation, Pathological/pathology ; Female ; Mutation ; Mice, Inbred C57BL ; },
abstract = {Cytosolic aggregates containing misfolded superoxide dismutase-1 (SOD1) protein is an established hallmark of ALS caused by mutations in the SOD1 gene. We have previously identified two structurally distinct strains of human (h) SOD1 aggregates (denoted A and B) in mice transgenic (Tg) for hSOD1. Strain A and B have both been shown to transmit templated aggregation and induce early-onset of fatal ALS-like disease when injected directly into the spinal cord or peripheral nerve of hSOD1 Tg mice. In contrast, peripheral administration of hSOD1 aggregates into the intraperitoneal cavity or skeletal muscle did not induce disease. Collectively, these studies provide insight on the spreading mechanism of SOD1. However, the complete map of propagation routes and underlying mechanisms utilized by SOD1 aggregates in ALS is not fully charted. Here, we investigated whether hSOD1 aggregates may spread to the central nervous system (CNS) via the cerebrospinal fluid (CSF). Mutant hSOD1 aggregate seeds or control samples prepared from spinal cords of hSOD1 Tg mice or non-Tg mice, respectively, were inoculated into the cisterna magna of adult 100-day-old Tg mice expressing the G85R mutated hSOD1 protein. Disease phenotyping as well as biochemical and immunohistochemical analyses were performed and compared across the experimental groups. The mice inoculated with hSOD1 seeds developed early signs of ALS by 90 days after inoculation and reached terminal stage approximately 180 days earlier than mice receiving control seeds. Additionally, both strain A and B were observed to initiate templated aggregation along the neuroaxis. The results show that hSOD1 aggregates are capable of transmitting from the CSF to the CNS where they induce ALS-like pathology and concomitant phenotype. Unraveling the propagation pathways utilized by SOD1 opens new avenues to assess treatment strategies against ALS.},
}

Animals
*Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism
Mice, Transgenic
*Superoxide Dismutase-1/administration & dosage/metabolism/genetics
Humans
Disease Models, Animal
Spinal Cord/pathology/metabolism
Mice
*Protein Aggregation, Pathological/pathology
Female
Mutation
Mice, Inbred C57BL

@article {pmid42947290,
year = {2026},
author = {Meyer, T and Grehl, T and Schumann, P and Weyen, U and Rödiger, A and Smesny, U and Ilse, B and Weydt, P and Bernsen, S and Fabian, R and Göricke, B and Petri, S and Lumi, R and Bjelica, B and Großkreutz, J and Cetin, H and Keritam, O and Haimberger, F and Korsukewitz, C and Löscher, W and Kohl, Z and Regensburger, M and Baum, P and Metelmann, M and Kettemann, D and Norden, J and Steinbach, R and Körtvélyessy, P and Lingor, P and McFarlane, R and Münch, C and Boentert, M and Maier, A},
title = {Anatomically Defined Motor Phenotypes Reveal Dissociated Trajectories of Progression, Neurofilament Profiles, and Survival in ALS.},
journal = {European journal of neurology},
volume = {33},
number = {11},
pages = {},
doi = {10.1111/ene.70798},
pmid = {42947290},
issn = {1468-1331},
support = {//Boris Canessa ALS Stiftung/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/blood/pathology/physiopathology/classification ; Disease Progression ; *Neurofilament Proteins/blood ; Female ; Phenotype ; Male ; Middle Aged ; *Motor Neurons/pathology ; Aged ; Cohort Studies ; },
abstract = {BACKGROUND: Clinical heterogeneity in amyotrophic lateral sclerosis (ALS) may reflect structured disease trajectories. This study investigated whether anatomically defined motor phenotypes capture reproducible patterns associated with progression, serum neurofilament light chain (NfL), and survival.

METHODS: In a multicenter cohort of 1307 ALS patients, motor phenotypes were classified by region of onset, timing of propagation to a vertically distant body region (early ≤ 12 months vs. later), and the degree of upper (UMN) and lower motor neuron (LMN) dysfunction. Intercenter consistency was assessed using the Friedman test and Kendall's W. Associations with ALS progression rate (ALSPR), NfL, and survival were analyzed using group comparisons and Cox regression models.

RESULTS: Phenotype classification was consistent across centers (Kendall's W 0.75-0.89). Onset phenotypes were significantly associated with ALSPR, NfL, and survival (p < 0.001). Trunk onset showed the lowest log(NfL/ALSPR), indicating dissociation between rapid progression and relative NfL elevation. Early propagation was the strongest marker of disease aggressiveness, with higher ALSPR, elevated NfL, and reduced survival (HR 2.93, p < 0.001). In early propagation, NfL disproportionally increased with progression indicating a relative uncoupling of NfL from functional decline. Phenotypes with balanced UMN/LMN and predominant LMN involvement were associated with shorter survival (HR 2.51, p < 0.001).

CONCLUSIONS: Anatomically defined motor phenotypes identify reproducible ALS trajectories with distinct clinical and neurofilament profiles. Early propagation provides an actionable risk marker of disease aggressiveness, while combined upper and lower motor neuron dysfunction or lower motor neuron predominance is prognostically unfavorable. These findings support integrating structured phenotyping into prognostic models and clinical trial stratification.},
}

Humans
*Amyotrophic Lateral Sclerosis/mortality/blood/pathology/physiopathology/classification
Disease Progression
*Neurofilament Proteins/blood
Female
Phenotype
Male
Middle Aged
*Motor Neurons/pathology
Aged
Cohort Studies

@article {pmid42947405,
year = {2026},
author = {Agarwal, S and Rehman, SAA and Muñoz, IM and Knebel, A and Hop, PJ and Gourlay, R and Brown, F and Macartney, T and Squires, I and Veldink, JH and Kenna, KP and Rouse, J and Mehta, AR},
title = {NEK1 autophosphorylation is disrupted by amyotrophic lateral sclerosis-associated missense variants: activity biomarkers and structural insights.},
journal = {Open biology},
volume = {16},
number = {10},
pages = {},
doi = {10.1098/rsob.260209},
pmid = {42947405},
issn = {2046-2441},
support = {//Greater Houston Community Foundation/ ; //UK Medical Research Council/ ; //National Institute for Health and Care Research/ ; MR/Z505535/1//Dementias Platform UK/ ; RGS/R2/252027//Royal Society/ ; },
mesh = {*NIMA-Related Kinase 1/genetics/metabolism/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Mutation, Missense ; Phosphorylation ; Humans ; Biomarkers/metabolism ; Models, Molecular ; },
abstract = {Rare variants in NEK1, encoding a serine/threonine kinase, are among the most consistently implicated genetic contributors to amyotrophic lateral sclerosis (ALS), reported in approximately 2-3% of cases. Yet, while recent studies have characterized the cell biological consequences of NEK1 loss-of-function, the biochemical effects of ALS-associated missense variants on kinase activity have not been directly investigated. This distinction is mechanistically important, because missense alleles encode mutant proteins rather than simply reducing protein dosage. Here, we provide the most comprehensive cell-based phosphoproteomic map of NEK1 phosphorylation to date, identifying 10 recurrent phosphorylation sites across independent expression and acquisition conditions. We experimentally assign pSer14, pThr156 and pSer418 as NEK1 autophosphorylation sites using kinase-dead controls, targeted extracted ion chromatogram analysis, phosphosite mutagenesis and phosphospecific antibodies. Leveraging activation-loop pThr156 as a read-out of NEK1 activity, we assessed nine ALS-associated missense variants spanning the major functional regions of the protein. Among catalytic-domain variants, R261C produced the most robust reduction in pThr156 autophosphorylation, R232C produced a smaller reduction, and R232H increased pThr156; the basic-region variant, A313T, also showed a smaller reduction. Structural modelling provides a mechanistic framework for understanding these variant-specific effects. Our study establishes the first activity-based framework for functional classification of NEK1 missense variants, and provides direct evidence that ALS-associated missense variants can alter NEK1 autophosphorylation through a mechanism distinct from simple haploinsufficiency. The phosphospecific antibodies, isogenic cell lines and curated phosphoproteomic datasets generated here provide a community resource for future studies of NEK1 regulation, variant interpretation and therapeutic target validation.},
}

*NIMA-Related Kinase 1/genetics/metabolism/chemistry
*Amyotrophic Lateral Sclerosis/genetics/metabolism
*Mutation, Missense
Phosphorylation
Humans
Biomarkers/metabolism
Models, Molecular

@article {pmid42947411,
year = {2026},
author = {Duffy, K and Gwathmey, K and Schneck, D and Arguedas, A and Xenopoulos-Oddsson, A and Heiman-Patterson, T and Ajroud-Driss, S and Arcila-Londono, X and Wymer, J and Olney, N and Hayat, G and Lunetta, C and Cerri, F and Al-Lahham, T and Sherman, A and Ghasemi, M and Cui, E and Fiecas, M and Walk, D},
title = {Time-to-Event Analysis of Clinical Milestones in the ALS Natural History Consortium Dataset.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70440},
pmid = {42947411},
issn = {1097-4598},
support = {FD-R01-007630/FD/FDA HHS/United States ; //Department of Neurology, University of Minnesota/ ; },
abstract = {INTRODUCTION/AIMS: Study of clinical milestones, particularly intermediate events like loss of ambulation, in large amyotrophic lateral sclerosis (ALS) cohorts is limited. Here, we leverage the ALS Natural History Consortium dataset to evaluate the time-to-event for several outcomes and prognostic factors that predict risk.

METHODS: Longitudinal data from 1950 participants were used in time-to-event analyses based on time from diagnosis. Outcomes were gastrostomy, loss of ambulation, loss of useful speech, non-invasive ventilation (NIV) usage, and death equivalent (death or mechanical ventilation). Median times-to-event were calculated along with Kaplan-Meier curves. Cox proportional hazards models for each outcome estimated (through adjusted hazard ratios [HR]) the impact of several prognostic factors, including sex, region of onset, age at diagnosis, and the initial rate of change (delta-FRS) in ALS Functional Rating Scale-Revised (ALSFRS-R) scores.

RESULTS: Estimated median times-to-event for clinical outcomes ranged from 1.44 to 6.21 years, with a median time to death equivalent of 2.12 years. A higher delta-FRS was the greatest risk factor for all outcomes (HRs between 2.01 and 3.05). Limb onset decreased risk of loss of speech, NIV use, gastrostomy, and death equivalent (HRs 0.41-0.78). Older age at diagnosis increased risk of gastrostomy, NIV use, and death equivalent (HRs 1.08-1.27).

DISCUSSION: These findings further inform expectations of time to various outcomes, especially rarely investigated intermediate events, and their risk factors. The importance of progression rate supports other recent findings, highlighting delta-FRS as a key prognostic factor with potential utility in clinical trial designs.},
}

@article {pmid42947522,
year = {2026},
author = {Sanghai, N and Vuong, B and Afridi, MSK and Leggett, S and Roghzai, H and Tranmer, GK},
title = {The Boron-Neuron Connection: The Potential of Boron-Containing Molecules for Treating Incurable Amyotrophic Lateral Sclerosis.},
journal = {ChemMedChem},
volume = {21},
number = {21},
pages = {},
doi = {10.1002/cmdc.70554},
pmid = {42947522},
issn = {1860-7187},
support = {202210PJT-495295//Canadian Institutes of Health Research (CIHR)/ ; RGPIN-2017-05938//Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; Reactive Oxygen Species/metabolism ; Animals ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; *Boron Compounds/chemistry/pharmacology/therapeutic use ; *Neurons/drug effects/metabolism ; Blood-Brain Barrier/metabolism/drug effects ; *Boron/chemistry/pharmacology ; Molecular Structure ; Oxidative Stress/drug effects ; },
abstract = {BACKGROUND: Boron (B), a group 13 metalloid, has emerged as a versatile element at the intersection of chemistry, biology, and medicine. Its electron-deficient nature and ability to reversibly interconvert between trigonal planar (sp[2]) and tetrahedral (sp[3]) geometries enable dynamic covalent interactions with biological nucleophiles, making boron-containing compounds (BCCs) attractive pharmacophores that selectively interact with reactive oxygen species (ROS) and are ROS-responsive for therapeutic development. BCCs possess antioxidant, anti-inflammatory, and metal-chelating properties that make them attractive candidates for neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS), a fatal and multifactorial motor neurodegenerative disorder, is characterized by oxidative stress, neuroinflammation, mitochondrial dysfunction, and metal dyshomeostasis, providing a strong rationale for exploring boron-based therapeutics.

METHODS: This review examines current literature on B chemistry, pharmacology, and translational applications, with emphasis on mechanisms relevant to ALS pathogenesis. This review focuses on ROS-responsive B scaffolds, blood-brain barrier (BBB) permeability, neuroprotective mechanisms, hormonal modulation, metal chelation, and emerging preclinical evidence supporting boron-based interventions.

CONCLUSIONS: BCCs represent a promising yet underexplored therapeutic platform for ALS and related neurodegenerative disorders. Their ROS-responsive, redox-modulating, and neuroprotective properties, combined with favorable CNS drug-like pharmacokinetics, offer a mechanistically distinct approach to disease modification. Emerging preclinical evidence strongly supports further translational investigation.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism
Reactive Oxygen Species/metabolism
Animals
*Neuroprotective Agents/chemistry/pharmacology/therapeutic use
*Boron Compounds/chemistry/pharmacology/therapeutic use
*Neurons/drug effects/metabolism
Blood-Brain Barrier/metabolism/drug effects
*Boron/chemistry/pharmacology
Molecular Structure
Oxidative Stress/drug effects

@article {pmid42933233,
year = {2026},
author = {Lehrer, S},
title = {ALS-associated cytoskeletal and glial gene expression: evidence consistent with developmental pathway re-engagement.},
journal = {Journal of the neurological sciences},
volume = {491},
number = {},
pages = {126231},
doi = {10.1016/j.jns.2026.126231},
pmid = {42933233},
issn = {1878-5883},
abstract = {BACKGROUND: We examined whether amyotrophic lateral sclerosis (ALS) is associated with cytoskeletal and glial transcriptional patterns compatible with developmental pathway re-engagement, while recognizing that similar patterns may arise from injury responses and altered cell composition.

METHODS: Postmortem RNA-sequencing data from the Target ALS Postmortem Tissue Core were analyzed using linear mixed-effects models accounting for repeated tissue samples within subjects. Models were adjusted for tissue source, age at death, sex, and postmortem interval. Composite scores represented Arp2/3 activity, SOX9/MEGF10 developmental-glial expression, and MYH10-associated transport imbalance.

RESULTS: ALS was associated with increased Arp2/3 expression (β = 0.399, P = 8.26 × 10[-9]), SOX9/MEGF10 expression (β = 0.643, P = 4.28 × 10[-6]), MYH10 expression (β = 0.308, P = 0.000801), and MYH10-KIF5C transport mismatch (β = 0.121, P = 0.00537); all remained significant after false-discovery-rate correction. The MYH10-Arp2/3 contractility index was not significant (β = -0.0909, P = 0.107).

CONCLUSIONS: ALS was associated with higher expression of selected cytoskeletal and glial genes in bulk postmortem tissue. These cross-sectional associations are compatible with, but do not demonstrate, developmental program reactivation, altered protein activity, or causation. Cell-resolved and functional studies are needed.},
}

@article {pmid42933234,
year = {2026},
author = {Cappelli, J and Hundal, S},
title = {Cost-effectiveness of multidisciplinary care compared with standard neurology care in Amyotrophic Lateral Sclerosis: A model-based cost-utility analysis.},
journal = {Journal of the neurological sciences},
volume = {491},
number = {},
pages = {126235},
doi = {10.1016/j.jns.2026.126235},
pmid = {42933234},
issn = {1878-5883},
abstract = {OBJECTIVE: To evaluate the cost-effectiveness of multidisciplinary clinic (MDC) care compared with standard general neurology care for adults with amyotrophic lateral sclerosis (ALS).

METHODS: A cost-utility analysis was conducted using a state-transition Markov model with monthly cycles over a 10-year horizon from the U.S. payer perspective. Health states comprised King's stages 1, 2, 3, 4 A, 4B, and death. Disease progression, mortality, utility, and cost inputs were derived from published literature (2005-2026). Transition probabilities were based on longitudinal data from the Pooled Resource Open-Access ALS Clinical Trials and permitted non-sequential progression. MDC-associated survival benefit was applied to stage-specific mortality across all King's stages. No additional utility benefit was assigned to MDC, while MDC-specific multipliers were applied to outpatient, inpatient, and emergency department costs. Outcomes included quality-adjusted life-years (QALYs), costs, cost per life-year gained, and incremental cost-effectiveness ratios (ICERs). Uncertainty intervals (UIs) were derived from sensitivity analyses.

RESULTS: MDC increased costs ($523,170 vs $378,171) and QALYs (0.73 vs 0.60), yielding 0.13 incremental QALYs (95% UI, 0.06-0.20) at an incremental cost of US$144,999 (95% UI, $53,784-$257,504). The ICER was US$1,158,673/QALY and cost per life-year gained was US$149,483. MDC was cost-effective in 0.1% of simulations at a willingness-to-pay threshold of $150,000/QALY.

CONCLUSION: MDC improved survival and quality-adjusted survival but at substantially higher cost. Its ICER remained well above commonly used U.S. willingness-to-pay thresholds across sensitivity analyses, including alternative utility valuations. These findings highlight the distinction between clinical benefit and cost-effectiveness and quantify the long-term economic consequences of survival gains associated with multidisciplinary ALS care.},
}

@article {pmid42933736,
year = {2026},
author = {Chakraborty, W and Anand, A and Kumar, S and Roy, KK},
title = {Circadian aging and neurodegeneration: the emerging role of the melatonin-cortisol axis in brain homeostasis, disease progression, and precision chronomedicine.},
journal = {Frontiers in neuroendocrinology},
volume = {83},
number = {},
pages = {101292},
doi = {10.1016/j.yfrne.2026.101292},
pmid = {42933736},
issn = {1095-6808},
abstract = {Circadian aging may promote neurodegenerative illnesses by dysregulating the melatonin-cortisol axis. Low nighttime melatonin synthesis, blunted cortisol circadian cycles, abnormal clock-gene oscillation patterns, and sleep-wake architecture undermine central and peripheral circadian equilibrium with age. Neuroendocrine alterations produce oxidative stress, mitochondrial failure, pervasive neuroinflammation (CNS immune function loss), and proteostasis. Increasing Alzheimer's, Parkinson's, ALS, Huntington's, frontotemporal dementia, Lewy body disease, PTSD, and vascular cognitive impairment due to impaired glymphatic axonal clearance/blood-brain barrier dysregulation/synaptic degeneration/pathoproteopathic protein We examine how clock genes, melatonin signaling, hypothalamic-pituitary-adrenal axis administration, microglia reactivity, and immune-mediated metabolic dysregulation affect dementia. New endocrine, transcriptomic, multi-omics, and wearable-derived digital biomarkers, chronopharmacology (including melatonin receptor agonists), bright-light therapy, time-restricted eating with exercise chronotherapy guidance/synchronization, sleep optimization, and gut microbiota modulation This study addressed inter-individual circadian variability, genetic susceptibility to therapy timing, biomarker standardization, and clinical trial design. The melatonin-cortisol axis may identify and treat age-related neurodegenerative diseases with tailored treatment.},
}

@article {pmid42933747,
year = {2026},
author = {Gray, EL and McGuiness, O and Menadue, C and Piper, A and Wong, K and Kiernan, MC and Yee, BJ},
title = {Diaphragm reserve utilisation in motor neurone disease: A novel ultrasound-derived physiological index.},
journal = {Respiratory physiology & neurobiology},
volume = {347},
number = {},
pages = {104667},
doi = {10.1016/j.resp.2026.104667},
pmid = {42933747},
issn = {1878-1519},
abstract = {INTRODUCTION: Respiratory involvement is a major determinant of prognosis in motor neurone disease (MND; or amyotrophic lateral sclerosis), yet conventional static respiratory measures provide limited information about how much available diaphragm thickening capacity is recruited during quiet breathing. We evaluated diaphragm reserve utilisation (RU), an ultrasound-derived ratio of tidal diaphragm thickening relative to maximal diaphragm thickening, as a novel physiological descriptor in MND.

METHODS: In a prospective observational study, 38 patients with MND and 20 healthy controls underwent right hemidiaphragm ultrasound to measure thickness at end-tidal expiration, peak tidal inspiration and peak maximal inspiration. Thickening fractions and RU were calculated. Between-group differences in diaphragm ultrasound indices were assessed. Secondary analyses examined relationships between RU, respiratory function and survival.

RESULTS: Tidal diaphragm thickening fraction was similar between patients with MND and controls, whereas maximal thickening fraction was lower in MND, resulting in higher RU in MND than controls. This pattern indicates that patients with MND maintained tidal diaphragm thickening while using a greater proportion of their available maximal thickening capacity. Higher RU was also associated with shorter survival, supporting its potential physiological and clinical relevance.

CONCLUSION: Diaphragm reserve utilisation describes the proportion of measured diaphragm thickening capacity recruited during tidal breathing. Patients with MND demonstrated preserved tidal thickening despite reduced maximal thickening capacity, resulting in higher RU than healthy controls. This supports RU as a novel physiological index of relative diaphragm thickening reserve utilisation. The relationship between RU and survival warrants validation in larger prospective cohorts.},
}

@article {pmid42934257,
year = {2026},
author = {Okoshi, K and Aoki, Y},
title = {Neuromuscular junction pathology in amyotrophic lateral sclerosis and emerging molecular therapeutic strategies.},
journal = {Journal of human genetics},
volume = {},
number = {},
pages = {},
pmid = {42934257},
issn = {1435-232X},
abstract = {Traditionally conceptualized as a soma-centric pathology, amyotrophic lateral sclerosis (ALS) is a fatal, heterogeneous neurodegenerative disease. The suboptimal outcomes of central nervous system (CNS)-directed therapeutic strategies have necessitated a shift in focus toward the dying-back hypothesis. This hypothesis contends that synaptic disconnection and axonal retraction at the distal neuromuscular junction (NMJ) are early pathological events that may antedate overt motor neuron loss. This review systematically examines the NMJ as an early vulnerable and therapeutically tractable peripheral niche in ALS pathogenesis, rather than merely a downstream consequence of proximal proteinopathy. Evidence from human clinical samples and ALS mouse models, particularly SOD1-G93A mice, collectively supports the early vulnerability of the NMJ, with the temporal precedence of denervation, synaptic retraction, and mitochondrial dysfunction most clearly demonstrated in experimental models. We highlight how the breakdown of the tripartite synapse-comprising the motor terminal, skeletal muscle, and terminal Schwann cells (tSCs)-may disrupt essential neurotrophic signaling and local metabolic homeostasis. Furthermore, we discuss how advancements in humanized in vitro NMJ models and spatial transcriptomics provide unprecedented resolution into localized RNA dysmetabolism and bioenergetic failure. Finally, we evaluate emerging therapeutic strategies specifically designed to stabilize or restore the NMJ, including MuSK agonists and other NMJ-directed approaches. By recontextualizing the NMJ as a critical early site of vulnerability, we propose that targeting the peripheral synaptic microenvironment may offer a promising strategy for modifying the progression of ALS.},
}

@article {pmid42934377,
year = {2026},
author = {Wu, Y and Zhang, X and Gao, C and Zhang, Z and Liao, X and Kang, Y},
title = {The cGAS-STING Pathway in Neuroinflammation and Neurological Disease: Mechanisms, Disease Contexts, and Periphery-to-Brain Communication.},
journal = {Cellular and molecular neurobiology},
volume = {46},
number = {1},
pages = {},
pmid = {42934377},
issn = {1573-6830},
support = {2024MZFS007//Research Grant of Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education/ ; 82272199//National Natural Science Foundation of China/ ; 2022YFC2504500//Key Technologies Research and Development Program/ ; },
mesh = {Humans ; Animals ; cGAS-STING Signaling Pathway ; *Nucleotidyltransferases/metabolism ; *Nervous System Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; *Neuroinflammatory Diseases/metabolism/pathology ; *Membrane Proteins/metabolism ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; STING Protein ; Signal Transduction ; Inflammation/metabolism/pathology ; },
abstract = {Neurodegenerative disorders involve a strong inflammatory component, yet the underlying inflammatory mechanisms may be heterogeneous across disease stage, cell type, and systemic context. A key unresolved question is how cellular and systemic stress is converted into sustained neuroinflammation. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an innate DNA-sensing hub that translates mislocalized self-DNA - derived from mitochondrial stress and mtDNA leakage, nuclear envelope instability, micronuclei formation, or impaired nucleic-acid disposal - into type I interferon, NF-kB, autophagy-related, and senescence-associated inflammatory programs. Rather than treating cGAS-STING as a universal disease-defining pathway, this review frames it as a context-dependent amplifier that becomes pathogenic when DNA-DAMP burden, defective mitochondrial quality control, neurovascular "leakage", and glial priming converge. We synthesize cell-type-specific evidence in microglia, astrocytes, neurons, and the neurovascular unit; compare mechanistic involvement across Alzheimer's disease, Parkinson's disease dementia and Lewy body disease, amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), vascular and acute brain injury, and systemic inflammatory encephalopathies; and organize periphery-to-brain communication axes using an explicit evidence-grading framework. A distinctive contribution of this review is a two-hit model in which systemic inflammatory stressors and barrier dysfunction first lower cognitive resilience, followed by brain-resident mitochondrial/DNA damage programs that lock in complement-linked synaptopathy. We also evaluate pharmacological and lifestyle-based modulation, emphasizing biomarker-enriched trial design, CNS exposure, compartment-specific target engagement, and immune-safety constraints. This framework aims to clarify when, where, and in whom cGAS-STING modulation may preserve synapses and cognition without unacceptable immune trade-offs.},
}

Humans
Animals
cGAS-STING Signaling Pathway
*Nucleotidyltransferases/metabolism
*Nervous System Diseases/metabolism/pathology
*Brain/metabolism/pathology
*Neuroinflammatory Diseases/metabolism/pathology
*Membrane Proteins/metabolism
Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
STING Protein
Signal Transduction
Inflammation/metabolism/pathology

@article {pmid42934615,
year = {2026},
author = {Bakhshi, F and Ashkezari, AD and Heydari, S},
title = {Design and protocol of a randomized assessor-blinded controlled trial evaluating an educational escape room for individual and team cardiopulmonary resuscitation skills among nursing students.},
journal = {BMC nursing},
volume = {25},
number = {1},
pages = {},
pmid = {42934615},
issn = {1472-6955},
support = {18765//Shahid Sadoughi University of Medical Sciences/ ; },
abstract = {BACKGROUND: High-quality cardiopulmonary resuscitation (CPR) depends not only on technical competence but also on effective communication, role clarity, leadership, and coordinated team performance under pressure. However, conventional CPR instruction may not adequately reproduce the collaborative and time-sensitive demands of real resuscitation. Educational escape rooms (EERs), as simulation-based gamified learning strategies, may provide a more immersive and learner-centered approach to strengthening both cognitive and teamwork-related aspects of CPR training. This study protocol was developed to evaluate the effect of a team-based CPR educational escape room (CPR-EER) integrated into advanced life support (ALS) training for undergraduate nursing students.

METHODS: This study was designed as a two-arm, parallel-group, assessor-blinded randomized controlled trial with a 1:1 allocation ratio. Participants were seventh-semester undergraduate nursing students at Shahid Sadoughi University of Medical Sciences, Yazd, Iran. All participants first received a standardized 8-hour CPR refresher workshop to establish a common educational baseline. The intervention group then participated in a structured CPR-EER delivered in fixed six-member teams in a simulated in-hospital cardiac arrest environment, whereas the control group continued with the routine curriculum during the primary comparison phase and received the intervention after post-test assessment. The primary outcome was team coordination during CPR, assessed using a Team Objective Structured Clinical Examination (TOSCE). Secondary outcomes included role-specific performance, CPR knowledge, and learner satisfaction. Outcomes were assessed at baseline and one month after the intervention. Data analysis was prespecified using a per-protocol framework and distribution-appropriate statistical tests.

DISCUSSION: This protocol provides a methodologically explicit and pedagogically grounded model for evaluating a gamified, team-based CPR-EER training strategy in undergraduate nursing education. By aligning intervention design, educational objectives, and outcome assessment, it may contribute to the development of more immersive, competency-oriented, and reproducible approaches to resuscitation training.

TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT), registered on 16 October 2024, IRCT20240815062770N1. Available at: https://irct.behdasht.gov.ir/ .},
}

@article {pmid42934968,
year = {2026},
author = {Seyam, M and Thompson, R and Luo, J and Skelly, J and Waheed, W and van den Berg, L and Tandan, R},
title = {Respiratory Phenotypes for Stratifying and Predicting Survival in ALS.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70443},
pmid = {42934968},
issn = {1097-4598},
abstract = {INTRODUCTION/AIMS: Phenotypic heterogeneity in amyotrophic lateral sclerosis (ALS) is an obstacle to stratification and survival prediction and is not sufficiently accounted for in clinical practice or trial design. We aimed to identify respiratory phenotypes to allow stratification and survival prediction in ALS.

METHODS: We retrospectively analyzed 292 ALS patients. Data included demographics, disease-related characteristics, and respiratory measurements (initial predicted forced vital capacity [FVC] and 3-month decline slope). Survival analysis was performed using Kaplan-Meier estimates and Cox regression. We defined four respiratory phenotypes based on dichotomized predicted FVC at the initial visit and its 3-month decline slope: (1) initial high, slow decline (IHSD), (2) initial high, fast decline (IHFD), (3) initial low, slow decline (ILSD), and (4) initial low, fast decline (ILFD).

RESULTS: Patients with an initial predicted FVC above the median had a median survival of 33 months, compared to 15 months for those below the median (p < 0.0001). The highest quartile had an almost threefold survival advantage over the lowest quartile (37 vs. 13 months, p < 0.0001). A 3-month slope at or above the median predicted longer survival (33 vs. 14 months, p < 0.0001). Survival varied across respiratory phenotypes, ranging from 41 months in IHSD to 11 months in ILFD-with all comparisons being significant (p ≤ 0.0012) except for ILSD vs. IHFD.

DISCUSSION: Defining respiratory phenotypes in ALS may allow tailored research within those subgroups, biomarker correlations, more accurate prognostication, and stratification in clinical trials based on phenotype-specific disease progression.},
}

@article {pmid42937037,
year = {2026},
author = {Calvo, A and Moglia, C and Canosa, A and Manera, U and Zucchi, E and Gianferrari, G and Martinelli, I and Mora, G and Cabras, S and Palumbo, F and Matteoni, E and Pellegrino, G and Minerva, E and Pascariu, D and Callegaro, S and D'Ovidio, F and Vasta, R and Mazzini, L and De Marchi, F and Mandrioli, J and Chiò, A},
title = {Rate and Shape of Functional Decline in Amyotrophic Lateral Sclerosis Identify Clinically Distinct Amyotrophic Lateral Sclerosis Phenotypes.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78394},
pmid = {42937037},
issn = {1531-8249},
abstract = {OBJECTIVE: The ALS Functional Rating Scale-Revised decline rate compresses trajectory shape into a single number, potentially missing distinct phenotypes. We tested whether shape identifies phenotypes that rate does not distinguish, and whether post-hoc analysis recovers a hidden ultrarapid subgroup.

METHODS: From the Piemonte and Valle d'Aosta register (2000-2022), we applied 2 models to 1,686 amyotrophic lateral sclerosis patients: a Gaussian mixture model (GMM; rate axis) and a latent-class mixed model (LCMM) with cubic splines (shape axis). Concordance, prognostic performance, calibration, and clinical utility were assessed at 24 months. External validation used the Emilia-Romagna register.

RESULTS: The rate model identified 4 classes (GMM-Slow 31%, GMM-Inter-slow 46%, GMM-Inter-fast 17%, GMM-Catastrophic 6%; slopes -0.44 to -3.52 points/month); the shape model 4 (LCMM-SlowLinear 46%, LCMM-PlateauFall 23%, LCMM-LateDecline 15%, LCMM-RapidEarly 16%). Concordance was modest (kappa = 0.273). Adding shape to rate changed discrimination negligibly (C-index 0.761 vs 0.755), but separated subgroups within rate classes (within GMM-Catastrophic, 30.1 vs 12.0 months). LCMM-LateDecline combined moderate early decline with reduced respiratory reserve (median forced vital capacity 83.5%) and 22.7-month median survival. The combined model gave the greatest net benefit for the composite outcome. Of 945 patients excluded for sparse sampling, 367 were ultrarapid progressors with shorter survival than LCMM-RapidEarly; findings replicated in the Emilia-Romagna register.

INTERPRETATION: Rate and shape describe partially overlapping aspects of the disease. LCMM-LateDecline, with moderate early decline yet occult respiratory compromise, is clinically challenging, and the 3-visit criterion hides over half of ultrarapid patients. Rate predicts the overall burden of progression, whereas shape predicts the timing of deterioration. ANN NEUROL 2026.},
}

@article {pmid42938002,
year = {2026},
author = {Huang, Z and Zhang, X and Song, WL and Wang, M and Yu, Z and Jiao, S},
title = {Deciphering Electrocatalytic Sulfur Reduction Reactions in Al-S Batteries via Single-Particle Electrodes.},
journal = {Journal of the American Chemical Society},
volume = {148},
number = {37},
pages = {39638-39646},
doi = {10.1021/jacs.6c08648},
pmid = {42938002},
issn = {1520-5126},
support = {52304318//National Natural Science Foundation of China/ ; 2023M740225//China Postdoctoral Science Foundation/ ; BX20230038//National Postdoctoral Program for Innovative Talents/ ; 24RCKA004//Science and Technology Program of Gansu Province/ ; },
abstract = {The kinetically sluggish sulfur reduction reaction (SRR) governs the performance of ultrahigh-capacity aluminum-sulfur batteries, while deciphering the SRR process is critical for rationally electrocatalyzing reaction kinetics to unlock their full energy output. To overcome this challenge, a single-particle electrochemical methodology has been developed to investigate the SRR process on a cobalt/nickel and nitrogen codoped graphene (CoNi-NG) electrocatalyst. The SRR process involves a major route of S8 → Al2S8 → Al2S4 → Al2S3 with a minor route of Al2S8 → Al2S6 → Al2S4, where Al2S4 conversion governs the overall SRR kinetics and Al2S4 contributes the most to the shuttle effect owing to its fastest generation and slowest consumption. The CoNi-NG raises the Co d-orbital energy level via Ni-to-Co electron transfer to accelerate cleavage of polysulfides, which doubles the exchange current density of rate-determining Al2S4 conversion. Consequently, the sulfur composite (S@CoNi-NG) electrode delivers a specific capacity of ∼1480 mAh gsulfur-1. Such a single-particle methodology for quantitatively deciphering electrocatalytic SRRs offers mechanistic guidance for rationally enhancing battery performance.},
}

@article {pmid42939346,
year = {2026},
author = {Alfaro-Rodríguez, A and Cortes-Altamirano, JL and Reyes-Long, S and Bonilla-Jaime, H and Avila-Camacho, FJ and Moreno-Villalba, LM and Herrera-López, ME and González-Maciel, A and Pérez-Guille, B and Soriano-Rosales, RE and Calderon-Guzman, D and Juaréz-Olguín, H},
title = {Glial Contributions to Pain in Neurodegenerative Disease Models: A Systematic Review of Microglial and Astrocytic Evidence.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939346},
issn = {2076-3425},
abstract = {Background/Objectives: Pain is a common and disabling non-motor manifestation of neurodegenerative disorders, but the contribution of glial cells to nociceptive processing remains incompletely understood. This systematic review evaluated evidence from preclinical models of neurodegenerative diseases linking microglial and astrocytic activity to pain. Methods: The protocol was prospectively registered in PROSPERO (CRD420251084310), and reporting followed PRISMA 2020. We conducted the original electronic search in PubMed/MEDLINE; during major revision, we conducted supplementary searches in Scopus and Web of Science Core Collection. Across the three sources, we identified 2248 records. After hierarchical deduplication by DOI, PMID, and normalized title, 1567 unique records were screened. Eligible in vivo studies assessed microglial and/or astrocytic alterations together with pain- or nociception-related outcomes. Risk of bias was independently evaluated by two investigators using the SYRCLE tool, and findings were synthesized qualitatively. Results: Twenty-six studies met the eligibility criteria: sixteen examined multiple sclerosis/experimental autoimmune encephalomyelitis (61.5%), seven Parkinson's disease (26.9%), two Alzheimer's disease-related models (7.7%), and one Huntington's disease model (3.8%); no eligible amyotrophic lateral sclerosis study was identified. Pain-related alterations involved inflammatory, neuroimmune, synaptic, and astrocyte-associated pathways, but the evidence was strongly model-dependent. Findings based on individual studies, including early astrocytic contributions in experimental autoimmune encephalomyelitis and altered inflammatory allodynia in an Alzheimer's disease model, are interpreted as study-specific observations requiring replication. Conclusions: The available evidence supports context-dependent associations between glial responses and nociceptive processing; however, marker specificity, EAE predominance, sex and age imbalance, and incomplete reporting of bias control procedures limit causal and cross-disease generalization.},
}

@article {pmid42939372,
year = {2026},
author = {Swindell, WR and Ali, A and Iacoangeli, A and Bhai, S},
title = {Meta-Analysis of ALS Post-Mortem Cerebral Cortex Transcriptome Studies Identifies Robust Shifts in Gene Expression Despite Significant Between-Study Heterogeneity.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939372},
issn = {2076-3425},
abstract = {Background: ALS is characterized by motor neuron failure with potential neurocognitive comorbidity. Cortical neurons, and their support cells, exhibit pathologic features, some of which have been identified in post-mortem transcriptome studies of the cortex from ALS patients and control subjects. These studies, however, have utilized varying technologies with few attempts to reconcile findings. Methods: This study used meta-analysis to evaluate differential gene expression (ALS vs. control) from 16 prior transcriptome studies utilizing multiple technologies (microarray, bulk RNA-seq or snRNA-seq). Normalization with GC content correction was used to mitigate downstream biases impacting differential expression. Results: Approximately one-third of protein-coding genes (5930 of 16,579) exhibited significant between-study effect size heterogeneity (FDR < 0.05), which was frequently associated with variation in average post-mortem interval. Nonetheless, we identified 269 and 273 differentially expressed genes (DEGs) with relatively consistent increased or decreased expression in the ALS cortex, respectively (FDR < 0.05 with SMD ≥ 0.20 or SMD ≤ -0.20). ALS-increased DEGs were associated with transcription (RNA polymerase), cell signaling (TGF-beta, PI3K), interneurons, microglia, endothelial cells, and deep laminar layers (L5, L6). ALS-decreased DEGs were associated with transcription (RNA polymerase), glial cells (astrocytes, oligodendrocytes) and the L1 layer. There was significant overlap between DEGs from the ALS cortex and those previously identified from ALS spinal cord and blood. Conclusions: These findings highlight signaling pathways, cell types and cortical layers associated with robust changes in ALS cortex gene expression. Our results illustrate the importance of meta-analysis as a tool for understanding between-study heterogeneity and identifying repeatable findings across technologies.},
}

@article {pmid42939724,
year = {2026},
author = {Hutchison, LL and Parkes, MM and Pioro, EP},
title = {Serotonergic Dysfunction and the Interacting Role of TAR DNA-Binding Protein 43 in the Progression of Amyotrophic Lateral Sclerosis: A Scoping Review.},
journal = {Biomolecules},
volume = {16},
number = {10},
pages = {},
pmid = {42939724},
issn = {2218-273X},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/physiopathology ; *DNA-Binding Proteins/metabolism ; *Serotonin/metabolism ; Animals ; Disease Progression ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons and widespread neural dysfunction. Loss of serotonin (5-HT) signaling and TAR DNA-binding protein 43 (TDP-43) dysfunction have both been identified as contributing factors to disease progression, although their relationship has yet to be fully defined. The objective of this review was to assess whether any mechanistic links exist between serotonergic dysfunction and TDP-43 proteinopathy in ALS. A scoping review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Databases were queried for the peer-reviewed literature concerning ALS pathophysiology, 5-HT, and TDP-43 (1946 to January 2026). Articles were screened and data independently extracted by two reviewers, which were subsequently synthesized qualitatively (n = 14). The current literature suggests that serotonergic dysfunction can be identified early in ALS pathology, indicated by decreased 5-HT concentration, degeneration of raphe projections, and changes in receptor activity. TDP-43 proteinopathy is a defining characteristic of ALS progression, characterized by cytoplasmic mislocalization and aggregation of TDP-43. Additionally, studies have identified bidirectional links between these dysfunctions: TDP-43 impairs serotonergic transmission, and 5-HT deficiency may drive pathological TDP-43 aggregation. Many mechanisms affected by both serotonergic and TDP-43 dysfunction are associated with disease progression including excitotoxicity, metabolic disturbances, and network hyperexcitability. Despite this, there is a lack of direct experimental evidence elucidating connections between these pathologies. Serotonergic dysfunction and TDP-43 proteinopathy may be linked by shared mechanisms in ALS, though specific causality has not been identified. Further research should aim to clarify the connection between these processes and discover therapeutic targets.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/pathology/physiopathology
*DNA-Binding Proteins/metabolism
*Serotonin/metabolism
Animals
Disease Progression

@article {pmid42939744,
year = {2026},
author = {Mohamed, YK and Yan, LJ},
title = {Edaravone for Potential Mitigation of Oxidative Stress and Inflammation in Kidney Disease.},
journal = {Biomolecules},
volume = {16},
number = {10},
pages = {},
pmid = {42939744},
issn = {2218-273X},
mesh = {Humans ; *Oxidative Stress/drug effects ; *Edaravone/therapeutic use/pharmacology ; Animals ; *Inflammation/drug therapy/metabolism ; *Kidney Diseases/drug therapy/metabolism/pathology ; Anti-Inflammatory Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Free Radical Scavengers/therapeutic use/pharmacology ; },
abstract = {Edaravone (EDA) is a synthetic free-radical scavenger FDA-approved for amyotrophic lateral sclerosis (ALS) treatment in the United States and is used clinically for treatment of acute ischemic stroke in Japan and other countries. While its antioxidant activity has been the primary focus of investigation in the mitigation of oxidative-stress-related injury, EDA exhibits anti-inflammatory, anti-fibrotic, anti-apoptotic, and anti-necrotic effects in animal models. These properties make it a potentially attractive therapeutic agent for kidney disease, where oxidative stress and inflammation contribute to renal cell injury, mitochondrial dysfunction, and progression of disease. In this review, we cover the underlying mechanisms of oxidative stress and inflammation in renal injury, and pharmacological and free-radical-scavenging mechanisms of EDA. Preclinical evidence in several kidney diseases, including ischemic/reperfusion injury, nephrotoxin-induced disease, and diabetic kidney disease, has been used to assess EDA for efficacy. In addition, we explore the modulatory roles of key signaling pathways, such as Nrf2 and NF-κB, in protective effects of EDA against oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, necrosis, and fibrosis. Finally, we highlight the potential of EDA as a therapy in future clinical applications for various kidney diseases such as acute kidney injury (AKI) and chronic kidney disease (CKD). It should also be emphasized that as EDA's renal efficacy evidence described in this review is largely limited to animal studies, robust human clinical data are lacking. Therefore, additional clinical studies are still needed to fully elucidate the efficacy, safety, and benefits of EDA for prevention and treatment of human kidney disease.},
}

Humans
*Oxidative Stress/drug effects
*Edaravone/therapeutic use/pharmacology
Animals
*Inflammation/drug therapy/metabolism
*Kidney Diseases/drug therapy/metabolism/pathology
Anti-Inflammatory Agents/therapeutic use/pharmacology
Signal Transduction/drug effects
Free Radical Scavengers/therapeutic use/pharmacology

@article {pmid42940139,
year = {2026},
author = {Carata, E and Mariano, S and Tenuzzo, BA and Panzarini, E},
title = {Advancing the Translational Pipeline: From In Vivo and In Vitro 2D Models to Next-Generation Cell Culture Models for Amyotrophic Lateral Sclerosis Modelling and Drug Discovery.},
journal = {Biomedicines},
volume = {14},
number = {10},
pages = {},
pmid = {42940139},
issn = {2227-9059},
abstract = {Background: Amyotrophic lateral sclerosis (ALS) is still a global health challenge, as there is no effective treatment due to the inadequacy of conventional experimental platforms for comprehending pathogenic mechanisms and developing therapy. Objectives: This review details the recent progress and clinical utility of next-generation iPSC-derived 3D in vitro systems integrated with microfluidics, CRISPR-Cas9 gene editing, multi-omics readouts, and AI-based machine learning, which are emerging as transformative platforms for recapitulating key ALS pathological hallmarks. Methods: A literature search was performed using PubMed and Web of Science, including only English-language publications. All the published papers collected covered the period from January 2015 to June 2026. Results: Human induced pluripotent stem cell (iPSC) cerebral organoids, assembloids, and organ-on-a-chip technologies are revolutionizing research into ALS by providing a way to model the complex spatial organization, cellular heterogeneity, and neural network dynamics of the human brain. Moreover, recent bioengineering advancements enable the inclusion of functional neurovascular units, the integration of resident immune cells (microglia), and the use of 3D bioprinting to accelerate the functional maturation of age-related phenotypes. CRISPR-Cas9 genome editing, OMICS, and machine learning improve tools for studying ALS and identifying therapeutic targets. Conclusions: Novel cell culture models may bridge the gap between preclinical animal models and human clinical trials and reduce the duration and costs of translation. Future work is likely to integrate bioprinting with organ-on-chip microfluidics, CRISPR-based genetic editing, and multi-omics readouts to build increasingly faithful, patient-specific ALS models for both basic research and precision therapeutics.},
}

@article {pmid42941452,
year = {2026},
author = {Gołąb-Janowska, M and Wełnicka-Wesołowska, A and Baumert, B and Machowska-Sempruch, K and Meller, A and Sobuś, A and Paczkowska, E and Kotlęga, D and Nowacki, P and Machaliński, B},
title = {Functional Status, Quality of Life and Survival After Repeated Intrathecal Administration of Autologous Lineage-Negative Cells in Amyotrophic Lateral Sclerosis.},
journal = {Journal of clinical medicine},
volume = {15},
number = {20},
pages = {},
pmid = {42941452},
issn = {2077-0383},
support = {STRATEGMED1/234261/2/NCBR/2014//National Centre for Research and Development/ ; },
abstract = {Background/Objectives: Adjuvant cell-based strategies are still being explored in amyotrophic lateral sclerosis (ALS). Materials and Methods: In this open-label, single-arm study of intrathecal autologous bone marrow-derived lineage-negative (LIN[-]) cells, we report functional status, quality of life, and survival after three administrations at six-week intervals. A total of 45 patients with sporadic ALS were qualified: 42 received all three administrations and 23 completed the 24-week assessment schedule, while 19 stopped attending because of deterioration. Results: In the 23 completers, Norris scale scores were stable until week 13 and then declined (p = 0.00004), and the Amyotrophic Lateral Sclerosis Assessment Questionnaire 40 (ALSAQ-40) followed the same pattern (p = 0.0019), whereas the ALS Functional Rating Scale-Revised (ALSFRS-R) declined at a constant 0.5 points per month. In all 42 treated patients the Norris score fell during treatment (0.95 points per month; 95% CI 0.52-1.38), so the plateau was confined to completers, who had milder baseline disease. Dose-related differences in quality of life were confounded by baseline imbalance; survival analyses were exploratory. Cell number did not correlate with cerebrospinal fluid brain-derived neurotrophic factor (BDNF) after the third administration in the 39 patients with paired samples (ρ = 0.14). No adverse event was recorded in 126 procedures, but harms were not graded systematically. Conclusions: These exploratory findings do not demonstrate efficacy; a sham-controlled trial with blinded raters is required.},
}

@article {pmid42941856,
year = {2026},
author = {Gómez-Pérez, CA and Ramírez-García, MÁ and Yescas-Gómez, P},
title = {The Role of SOD1 and Oxidative Stress in Amyotrophic Lateral Sclerosis: An Overview.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42941856},
issn = {1422-0067},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; *Oxidative Stress ; Animals ; Reactive Oxygen Species/metabolism ; Mutation ; Motor Neurons/metabolism/pathology ; Signal Transduction ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder that selectively affects motor neurons. The median survival time after diagnosis is 2 to 5 years. Oxidative stress (OS), driven mainly by reactive oxygen species (ROS), plays a central role in motor neuron (MN) degeneration. In this narrative review, we analyse the pathogenic role of SOD1 variants and their contribution to OS in ALS. SOD1 mutations alter the Cu/Zn superoxide dismutase enzyme, thereby promoting oxidative damage and triggering neuroinflammatory cascades via the MAPK, NF-κB and Nrf2/ARE signalling pathways. We also discuss emerging proteomic and machine-learning biomarkers, as well as the current therapeutic landscape. Riluzole and edaravone are approved treatments, while AMX0035 was approved in 2022 but withdrawn in 2024. Masitinib and EPI-589 remain investigational. In the realm of genetic therapies, the antisense oligonucleotide tofersen received accelerated FDA approval in 2023 for SOD1-ALS, primarily due to its ability to reduce plasma neurofilament light chain levels. However, the clinical benefit remains modest. RNA interference has reached human trials, while CRISPR/Cas9 remains in the preclinical stage. Both approaches have shown promising results in experimental models. Further research into ALS pathogenesis is needed to develop treatments that integrate antioxidant, anti-inflammatory, and gene-editing strategies.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology
*Superoxide Dismutase-1/genetics/metabolism
*Oxidative Stress
Animals
Reactive Oxygen Species/metabolism
Mutation
Motor Neurons/metabolism/pathology
Signal Transduction

@article {pmid42941925,
year = {2026},
author = {Gómez-Pérez, CA and Ramírez-García, MÁ and Ruiz-Sánchez, E and Romero-Hidalgo, S and Ochoa-Morales, A and Jara-Prado, A and Méndez-Armenta, M and Nava-Ruiz, C and Yescas-Gómez, P},
title = {Identification of SOD1 Gene Variants in Mexican Patients with Amyotrophic Lateral Sclerosis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42941925},
issn = {1422-0067},
support = {262111//Secretariat of Science, Humanities, Technology, and Innovation (SECIHTI)/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *Superoxide Dismutase-1/genetics ; Mexico/epidemiology ; Female ; Mutation ; Male ; Middle Aged ; Aged ; Gene Frequency ; Genetic Variation ; Adult ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressing, fatal neurodegenerative disorder that selectively affects motor neurons. Clinical manifestations include progressive muscle weakness, amyotrophy, fasciculations, dysphagia, and fatal respiratory failure. The median survival after symptom onset is typically 2 to 5 years. Despite its severity, the epidemiological profile and genetic landscape of ALS in Latin American populations, particularly in Mexico, remain unclear. In this study, we evaluated the mutational spectrum of the SOD1 gene in a Mexican cohort of 156 ALS patients. Using high-resolution melting (HRM) analysis and Sanger sequencing, we identified 22 SOD1 variants in 42 of 156 patients (overall variant carrier frequency, 26.92%). Pathogenic or likely pathogenic (P/LP) variants were found in 21 patients (13.5%). Notably, 5 of the 22 variants were novel, expanding the spectrum of SOD1 variants. The variant carrier frequency identified in this study is higher than that reported for European populations but similar to frequencies observed in Asian populations. Our results highlight the distinct genetic heterogeneity of ALS in Mexico and demonstrate that HRM is a rapid and effective method for identifying SOD1 gene variants.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/epidemiology
*Superoxide Dismutase-1/genetics
Mexico/epidemiology
Female
Mutation
Male
Middle Aged
Aged
Gene Frequency
Genetic Variation
Adult

@article {pmid42942089,
year = {2026},
author = {Lv, X and Huang, M and Long, W and Li, X and Hu, Z and Feng, Y and Du, J and Long, Q and Chen, Y and Shi, M and Qin, D},
title = {Epigenetic Mechanisms in Neurodegenerative Diseases: From Genetic Regulation to Therapeutic Potential.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42942089},
issn = {1422-0067},
support = {YPKLS2025-029//Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Dis-ease in Prevention and Treatment/ ; KUST-KH2022017Y//Kunming University of Science and Technology & the First People's Hospital of Yunnan Province Joint Special Project on Medical Research/ ; 202401AY070001-135//Yunnan Provincial Department of Science and Technology-Kunming Medical University Joint Special Project/ ; },
mesh = {Humans ; *Epigenesis, Genetic ; *Neurodegenerative Diseases/genetics/therapy/metabolism ; Animals ; DNA Methylation ; Gene Expression Regulation ; RNA Methylation ; Biomarkers/metabolism ; Histones/metabolism ; Epitranscriptome ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are multifactorial disorders in which genetic susceptibility alone cannot account for sporadic onset, clinical diversity, or age-dependent progression. Epigenetic mechanisms-DNA methylation, histone modifications, non-coding RNAs, and m6A RNA methylation-bridge environmental and intracellular cues to stable gene expression changes. Emerging evidence associates epigenetic dysregulation with amyloid-β/tau pathology in AD, α-synuclein pathology in PD, and TDP-43/C9orf72-associated toxicity in ALS, while functional studies suggest that selected epigenetic alterations may contribute to these processes. In this narrative review, we distinguish associative, functional, and mechanistic evidence using claim-specific criteria based on experimental perturbation, direct molecular assessment, and pathway-dependence or rescue testing, while considering the study system. We further evaluate the translational promise of epigenetic biomarkers in liquid biopsies, while emphasizing the major barriers that separate bench findings from bedside application, including poor target specificity, limited blood-brain barrier penetration, and the absence of biomarker-guided patient stratification. By integrating pathological mechanisms, biomarker development, and therapeutic strategies, this review argues that future epigenetic research in neurodegeneration must prioritize causal validation, CNS-penetrant drug development, and prospective trials integrating epigenetic profiling to achieve meaningful clinical impact.},
}

Humans
*Epigenesis, Genetic
*Neurodegenerative Diseases/genetics/therapy/metabolism
Animals
DNA Methylation
Gene Expression Regulation
RNA Methylation
Biomarkers/metabolism
Histones/metabolism
Epitranscriptome

@article {pmid42927744,
year = {2026},
author = {Mishchenko, TA and Grechukhina, AA and Kulikov, SS and Olajide, OJ and Mitroshina, EV and Krysko, DV and Vedunova, MV},
title = {When the Brain Signals Danger: Roles of Calreticulin and HMGB1 in Cell Death Mechanisms in Neurooncology and Neurodegeneration.},
journal = {Biochemistry. Biokhimiia},
volume = {91},
number = {10},
pages = {1822-1841},
doi = {10.1134/S0006297926601565},
pmid = {42927744},
issn = {1608-3040},
mesh = {Humans ; *HMGB1 Protein/metabolism ; *Calreticulin/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; Cell Death ; Signal Transduction ; Alarmins/metabolism ; },
abstract = {Contrary to the classical paradigm of brain immune privilege, damage-associated molecular patterns (DAMPs) act as key mediators in the dialogue between CNS cells and the immune system, determining pathways of immune response development. This review examines the role of key DAMPs - calreticulin (CRT) and high-mobility group box 1 protein (HMGB1) - in the functioning of CNS under normal conditions and during the development of neuropathologies, particularly oncological and neurodegenerative processes. Under normal conditions, CRT and HMGB1 ensure functioning of the brain, acting as necessary effectors of neurogenesis and homeostatic plasticity. In neurooncology, exposure of CRT on the surface of dying cells and release of HMGB1 serve as powerful adjuvant signals for antigen-presenting cells, inducing immunogenic cell death (ICD). Particular attention is given to the mechanisms of passive HMGB1 release during various types of regulated cell death (apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis), as well as to the role of redox modifications of the protein, which determine its pro-inflammatory, immunogenic, or tolerogenic properties. In neurodegeneration (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), excessive DAMP release exacerbates the development of chronic neuroinflammation, disrupts integrity of the blood-brain barrier (BBB), and forms a vicious cycle of pathological changes. Detection of CRT and HMGB1 in biological fluids or brain tissues has important prognostic potential, and regulation of their signaling pathways opens promising approaches for overcoming tumor resistance or inhibiting progressive neurodegenerative changes in the brain.},
}

Humans
*HMGB1 Protein/metabolism
*Calreticulin/metabolism
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Brain/metabolism/pathology
Cell Death
Signal Transduction
Alarmins/metabolism

@article {pmid42927931,
year = {2026},
author = {Luan, J and Yun, Y and Jiao, Y and Wang, Y and Ma, M and Shan, D and Wang, H and Ji, X and Tang, Y and Li, J and Zhan, Z and Sun, X and Gao, N and Lin, P and Yan, C and Sun, X and Yu, D and Liu, S and Liu, F},
title = {Cortical Motor Hierarchy Disruption Is Associated With Functional Status in Early Amyotrophic Lateral Sclerosis.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {17},
number = {5},
pages = {},
doi = {10.1002/jcsm.70411},
pmid = {42927931},
issn = {2190-6009},
support = {2025CXPT133//the Key R&D Program of Shandong Province/ ; 2022ZLGX03//the Key R&D Program of Shandong Province/ ; ZR2023MH180//the Natural Science Foundation of Shandong Province/ ; 20201125//the Qilu Young Scholarship of Shandong University/ ; ZR2023ZD14//the Shandong Provincial Natural Science Foundation Major Basic Research Project/ ; 2025M782111//the China Postdoctoral Science Foundation/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Female ; Male ; Middle Aged ; Magnetic Resonance Imaging ; *Motor Cortex/physiopathology/pathology ; Aged ; Cross-Sectional Studies ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterised by progressive muscle wasting and functional decline. Although cortical motor network disruption is a hallmark of ALS, the large-scale functional hierarchy alterations and their underlying molecular mechanisms in the early stage of the disease (ALS-ES) remain poorly understood. We aimed to characterise cortical gradient changes in early-stage ALS and to examine their neurochemical and transcriptomic correlates, as well as their cross-sectional associations with clinical functional status.

METHODS: We recruited 97 patients with early-stage ALS, all at King's stage 1 and 94 healthy controls with comparable age and sex distributions. The ALS-ES group included 65 women and had a median ALSFRS-R score of 40 (IQR, 37-44). Resting-state fMRI was used to construct the principal functional gradient. We integrated neurochemical maps of 19 neurotransmitter receptors/transporters, and transcriptomic data from the Allen Human Brain Atlas. Partial least squares (PLS) regression and cell-type enrichment analysis were employed to identify molecular correlates of gradient alterations.

RESULTS: Compared with HCs, ALS-ES patients exhibited a significant spatial contraction of the principal gradient. Specifically, gradient values significantly increased in the somatomotor network (SMN; t = 3.670, pFDR = 0.001) and decreased in the default mode network (DMN; t = -4.124, pFDR < 0.001). Within the ALS-ES group, higher SMN gradient values were associated with lower ALSFRS-R scores, whereas higher DMN gradient values were associated with higher ALSFRS-R scores. These macroscale alterations showed spatial correspondence with normative 5-HT4 receptor and norepinephrine transporter maps. PLS analysis identified a primary gene set (PLS1+) enriched in oligodendrocytes and mitochondrial functions (pFDR < 0.05), whereas the negative set (PLS1-) was associated with astrocytes, GABAergic neurons and RNA splicing pathways. Chromosome-level analysis revealed significant enrichment of PLS1- genes on chromosomes 5 and 16 (p < 0.05).

CONCLUSIONS: Early-stage ALS is characterised by a collapsed cortical functional hierarchy centred on the motor-somatosensory axis. These alterations were spatially associated with normative neurochemical maps and distinct transcriptomic annotations related to energy metabolism and RNA processing. These findings identify cross-sectional cortical functional-hierarchy alterations associated with functional status in early-stage ALS and provide a multi-scale framework for investigating their neurochemical and transcriptomic correlates.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/pathology
Female
Male
Middle Aged
Magnetic Resonance Imaging
*Motor Cortex/physiopathology/pathology
Aged
Cross-Sectional Studies

@article {pmid42927993,
year = {2026},
author = {Clarysse, M and Korsos, S and Cuypers, C and Raes, E and Vlaminck, L},
title = {Chirurgische behandeling van unilateraal geïmpacteerde maaltanden in de bovenkaak bij een paard.},
journal = {Journal of veterinary dentistry},
volume = {},
number = {},
pages = {8987564261493278},
doi = {10.1177/08987564261493278},
pmid = {42927993},
issn = {2470-4083},
abstract = {Impactie van permanente maaltanden bij het paard wordt voornamelijk gerapporteerd ter hoogte van de mandibula, terwijl betrokkenheid van de maxilla zeldzaam is. Dit rapport beschrijft een ongewone presentatie van congenitale impactie van drie opeenvolgende maxillaire molaren bij een 4-jarige merrie. Computertomografie toonde complexe ruimtelijke verhoudingen tussen de geïmpacteerde elementen, de sinusbodem en de aangrenzende structuren, deze werden op conventionele radiografie niet volledig onderkend en waren essentieel voor de chirurgische planning. Chirurgische extractie via een botflap van de sinus maxillaris liet gecontroleerde sectionering en aansluitende verwijdering van alle aangetaste elementen toe. Histopathologisch onderzoek van botstalen uit de sinusbodem toonde reactieve osteosclerose, wat veroorzaakt kan worden door chronische druk en/of sinusitis. Als postoperatieve complicaties ontstonden een oromaxillaire communicatie en een secundaire sinusitis na verlies van de polysiloxaanplug; deze werden behandeld door herhaardelijk debrideren en sinoscopische lavage. Op lange termijn resulteerde de behandeling in een bevredigend functioneel herstel en behoud van oraal comfort, niettegenstaande het verlies van meerdere maaltanden in de bovenkaak.},
}

@article {pmid42929812,
year = {2026},
author = {Zhang, N and Freeman, DD and Polster, BM},
title = {BAX, VDAC, Gasdermin, and Permeability Transition Pores in Inflammatory Mitochondrial DNA Release: Is This the "Hole" Story?.},
journal = {Cells},
volume = {15},
number = {20},
pages = {},
doi = {10.3390/cells15201839},
pmid = {42929812},
issn = {2073-4409},
support = {R01NS112212/NS/NINDS NIH HHS/United States ; R21NS133527/NS/NINDS NIH HHS/United States ; R21 NS133527 (B.M.P.)./NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *DNA, Mitochondrial/metabolism ; Animals ; *bcl-2-Associated X Protein/metabolism ; *Mitochondrial Permeability Transition Pore/metabolism ; *Voltage-Dependent Anion Channels/metabolism ; Mitochondria/metabolism ; *Inflammation/metabolism ; },
abstract = {Disease-modifying neuroprotective therapies for traumatic brain injury (TBI), stroke, and age-related neurodegenerative disorders have proven elusive. Interest in mitochondrial outer membrane permeabilization mechanisms as a drug target evolved from the 1990s discovery of BAX/BAK-mediated mitochondrial cytochrome c release as an apoptotic cell death trigger. However, enthusiasm waned as subsequent findings revealed that apoptosis is not the dominant cell death mechanism in the mature brain. The more recent discovery of mitochondrial DNA (mtDNA) as an inflammatory trigger produced renewed interest in mitochondrial permeability pathways. In particular, the DNA-sensing molecule cGAS and its downstream effector STING were implicated in the pathogenesis of several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and TBI. Nevertheless, these findings raised a puzzling question: how does mtDNA, which resides in the mitochondrial matrix surrounded by double membranes, escape to initiate inflammatory responses without triggering cytochrome c-dependent cell death? Here, we review the many proposed mechanisms for mtDNA release, including several that do not require mitochondrial membrane holes, and discuss advances toward pharmacological targeting of these pathways. Identification of the specific mtDNA efflux pathway(s) proximal to maladaptive neuroinflammatory responses may yield new treatment strategies for AD, TBI, and other neurological diseases.},
}

Humans
*DNA, Mitochondrial/metabolism
Animals
*bcl-2-Associated X Protein/metabolism
*Mitochondrial Permeability Transition Pore/metabolism
*Voltage-Dependent Anion Channels/metabolism
Mitochondria/metabolism
*Inflammation/metabolism

@article {pmid42929861,
year = {2026},
author = {Gong, X and Wei, H and Shen, L and Wang, Q and Wu, J and Wang, W and Xu, T},
title = {Single-Dose Intrathecal rAAV2-Retro Delivering Anti-hSOD1 miRNA Confers Robust Neuroprotection in Adult ALS Mice.},
journal = {Cells},
volume = {15},
number = {20},
pages = {},
doi = {10.3390/cells15201890},
pmid = {42929861},
issn = {2073-4409},
support = {22ZR1414500//Natural Science Foundation of Shanghai/ ; 21ZR1407700//Natural Science Foundation of Shanghai/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology ; *MicroRNAs/genetics/metabolism/administration & dosage ; *Superoxide Dismutase-1/genetics/metabolism ; Injections, Spinal ; *Dependovirus/genetics/metabolism ; Mice ; Humans ; Insulin-Like Growth Factor I/metabolism ; *Neuroprotection ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Gene Silencing ; Genetic Vectors ; Spinal Cord/metabolism/pathology ; Mice, Inbred C57BL ; },
abstract = {Amyotrophic lateral sclerosis (ALS) kills within a few years of onset, and the drugs licensed for treatment change that course only marginally. Silencing SOD1 has become a credible treatment route, but two gaps hold this approach back: an efficient vector platform for spinal cord transduction with limited peripheral transduction and evidence on whether adding neurotrophic support to gene silencing has any effect. We built an rAAV2-retro platform for intrathecal delivery. One intrathecal dose of an eGFP-expressing vector transduced all spinal cord segments and several brain regions, with a clear preference for spinal motor neurons and low expression in the liver and heart. Side by side in adult mice, we then used this platform to compare miRNA-mediated silencing of human SOD1, overexpression of IGF1, and the two together in SOD1[G93A] animals. A single injection of rAAV2-retro carrying an anti-hSOD1 miRNA extended median survival by 25 days, improved motor performance, protected neuromuscular junctions, spared α-motor neurons, and damped gliosis and apoptosis. IGF1 on its own also lengthened survival and limited neuronal loss, but it left motor performance unchanged. The benefit of IGF1 over miRNA alone was observed on most endpoints under the conditions tested; a modest, nominally significant improvement in hindlimb clasping was observed, which should be interpreted as exploratory given the number of comparisons performed. Silencing of hSOD1 therefore accounts for most of the benefit, and no statistically detectable additional benefit was observed for IGF1 on top of hSOD1 silencing under the conditions tested. A single intrathecal dose of rAAV2-retro-miRNA is thus an effective gene silencing approach in the SOD1[G93A] mouse model, with limited peripheral transduction in the liver and heart observed in C57BL/6J mice. However, these data also show the difficulty of achieving additional benefit by adding IGF1 under the conditions tested.},
}

Animals
*Amyotrophic Lateral Sclerosis/genetics/therapy/pathology
*MicroRNAs/genetics/metabolism/administration & dosage
*Superoxide Dismutase-1/genetics/metabolism
Injections, Spinal
*Dependovirus/genetics/metabolism
Mice
Humans
Insulin-Like Growth Factor I/metabolism
*Neuroprotection
Disease Models, Animal
Motor Neurons/metabolism/pathology
Gene Silencing
Genetic Vectors
Spinal Cord/metabolism/pathology
Mice, Inbred C57BL

@article {pmid42930312,
year = {2026},
author = {Nguyen, TT and Wang, L and Dao, TK},
title = {Biomimetic Coverage Optimization in WSNs via an Enhanced Spider-Wasp Optimizer with Adaptive Learning and Dual-Median-Point Guidance.},
journal = {Biomimetics (Basel, Switzerland)},
volume = {11},
number = {10},
pages = {},
doi = {10.3390/biomimetics11100760},
pmid = {42930312},
issn = {2313-7673},
support = {FITGR20250//Fuzhou Institute of Technology/ ; },
abstract = {Coverage optimization in wireless sensor networks (WSNs) is a non-convex deployment problem on which population-based optimizers often converge prematurely and lose diversity. This paper proposes the Enhanced Spider-Wasp Optimizer (ESWO), an extension of the Spider-Wasp Optimizer (SWO) conceptually inspired by the foraging and nesting behavior of Pompilidae wasps. ESWO integrates (i) an Adaptive Learning Strategy (ALS) that uses four types of positional gaps among individuals to sustain diversity, (ii) a dual-median-point guidance (DMPG) mechanism that steers exploitation towards the midpoint of two elite solutions, and (iii) a position-update rule with nest-overlap avoidance. Coverage is evaluated on a discretized target grid with a Euclidean binary-disk sensing model and an energy-penalized fitness. In four scenarios (25-65 nodes; 50 × 50 to 165 × 165 m[2]), ESWO was compared with seven algorithms, including SWO. It achieved coverage rates of 81%, 88%, 92% and 85%, the highest in every scenario (tied with MGWO at 81% in the smallest). In the 100 × 100 m[2] scenario it reached 85% coverage after 523 iterations, against 601-698 for the competitors, although final convergence iteration counts were not uniformly the lowest. Over 15 runs, ESWO obtained a mean coverage of 90.2% (SD 1.2), a 95% success rate and the lowest estimated energy consumption (175.3 J).},
}

@article {pmid42931148,
year = {2026},
author = {Giecko, M and Bossowski, F and Bossowska, M and Moniuszko-Malinowska, A and Chorąży, M and Sarnowska, M and Grygorczuk, S},
title = {Amyotrophic Lateral Sclerosis in a Patient Treated for Neurosyphilis: A Case Report.},
journal = {Neurology international},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/neurolint18100193},
pmid = {42931148},
issn = {2035-8385},
abstract = {BACKGROUND/OBJECTIVES: Neurosyphilis is a recognized treatable mimic of amyotrophic lateral sclerosis (ALS); syphilis serology is commonly included in the work-up of suspected motor neuron disease. We describe the converse situation: neurosyphilis that delayed recognition of coexisting ALS.

METHODS: A 46-year-old man with type 2 diabetes mellitus and degenerative spine disease presented with a six-month history of progressive limb weakness and gait disturbance. Serum syphilis serology was reactive (Venereal Disease Research Laboratory [VDRL] titer 1:32; Treponema pallidum hemagglutination assay [TPHA] titer 1:20,480), and cerebrospinal fluid (CSF) showed a mild mononuclear pleocytosis with raised protein and immunoglobulin G. Neurosyphilis was diagnosed and treated with a 14-day course of intravenous penicillin. The subsequent course was followed with neuroimaging and electrodiagnostic studies.

RESULTS: Despite treatment and resolution of the CSF pleocytosis, weakness and wasting progressed and bulbar involvement developed. Examination showed combined upper and lower motor neuron signs, electromyography showed an anterior horn cell pattern with widespread fasciculations, and cervical spine imaging showed degenerative changes without spinal cord compression. ALS was diagnosed at a later neurological admission.

CONCLUSIONS: Identifying a treatable mimic does not close the diagnostic process. Combined upper and lower motor neuron signs that continue to progress despite adequate treatment of neurosyphilis should prompt early electrodiagnostic evaluation for ALS, even though the relative contribution of each condition may remain uncertain.},
}

@article {pmid42926632,
year = {2026},
author = {Barbier, M and Ichalalen, M and Amador, MD and De Houwer, JFH and Suh, E and Lejeune, FX and Bieth, T and Reyes, C and Henry, E and Hinks, AE and Martin-Hardy, P and Rinaldi, D and Araktingi, L and Seelaar, H and Roué-Jagot, C and , and Lagarde, J and Sarazin, M and Salachas, F and Bruneteau, G and Teichmann, M and Levy, R and Bernard, E and Kaat, LD and Van Deerlin, V and Haase, G and van Swieten, J and Rapinat, A and Gentien, D and Le Ber, I},
title = {Somatic instability of the C9orf72 repeat expansion in blood differs between patients with amyotrophic lateral sclerosis or frontotemporal dementia.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.06.26364580},
pmid = {42926632},
abstract = {Individuals carrying a G4C2 repeat expansion in C9orf72 can develop amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD), at various and unpredictable ages. The contribution of the expansion to this extreme clinical variability remained a matter of debate. In this work, we validated the use of optical genome mapping to efficiently size this expansion from blood and applied this method to a cohort of 54 repeat expansion carriers including patients with FTD (n = 23), ALS (n = 22) and presymptomatic individuals (n = 9). Despite the high variability in expansion profiles, distinct groups can be inferred. Although consensus repeat profiles were similar between FTD and ALS patients, relationships between repeat number, indexes of repeat instability, and the age at sampling differed between clinical conditions. An age at sampling-dependent increase of repeat instability in blood was observed in presymptomatic carriers and FTD patients (p = 0.01 and p = 0.04 respectively), in contrast to patients with ALS (p = 0.9). The proportion of shorter repeats ([500-1500 repeats]) increased with the age at sampling in ALS patients but decreased in presymptomatic and FTD cohorts, while the proportion of larger repeats (>2000 G4C2), in particular those exceeding 4000 repeats, increased along with the age at sampling in presymptomatic carriers and FTD cases (p <1.10 [-e4] and p = 0.006 respectively) conversely to patients with ALS (p = 0.98). In conclusion, this work strongly supports different dynamics of repeat instability of the C9orf72 pathogenic expansion in blood linked to the clinical evolution. These findings provide new insights into the relationship between expansion profiles and clinical variability.},
}

@article {pmid42926777,
year = {2026},
author = {Ding, YN and Bahati, M and Li, MQ and Guan, PP and Wang, P},
title = {A CNS-targeted atovaquone nanotherapy mitigates complement activation and neuromuscular degeneration in ALS.},
journal = {Materials today. Bio},
volume = {41},
number = {},
pages = {103738},
pmid = {42926777},
issn = {2590-0064},
abstract = {Complement-mediated glial inflammation and synaptic injury are increasingly implicated in amyotrophic lateral sclerosis (ALS), but clinically translatable complement-modulating therapies remain limited. Atovaquone (ATQ) is an approved, poorly water-soluble small molecule with reported immunomodulatory activity. We investigated whether ATQ could modulate C1qb or C5aR1-associated pathology and whether lactoferrin (Lf)-derived nanomicelles could improve delivery to the spinal cord. ALS spinal-cord single-cell transcriptomic and pathway-enrichment analyses were combined with screening of an FDA-approved drug library, molecular docking and surface plasmon resonance (SPR). Lf-ATQ nanomicelles were characterised by dynamic light scattering, transmission electron microscopy and fluorescence distribution studies. Complement/inflammasome responses were examined in microglial and motor-neuron-microglia models. Therapeutic effects were evaluated in mice expressing the human superoxide dismutase 1 G93A variant (SOD1[G93A]) by motor testing, compound muscle action potential recording, histology, immunostaining, western blotting and proteomics. Complement genes, particularly C1qb and C5aR1, were enriched in microglia, whereas glutamatergic-synapse and axon-guidance programmes were negatively enriched. In cellular models and SOD1[G93A] spinal cord, Lf-ATQ reduced C1qb, NLRP3 and multiple inflammatory mediators, attenuated glial reactivity and altered autophagy-related proteins. Treatment preserved rotarod performance, grip strength, gait parameters, compound muscle action potential amplitude and gastrocnemius morphology. Proteomic analysis indicated remodelling of complement/coagulation, vesicular-transport and synaptic modules. These findings support Lf-ATQ as a central nervous system (CNS) -oriented, complement-regulating nanotherapy candidate for ALS. Direct functional target-inhibition assays, quantitative ATQ pharmacokinetics, long-term safety assessment and validation in non-SOD1 models remain necessary before translational conclusions can be drawn.},
}

@article {pmid42926935,
year = {2026},
author = {Celier, A and Lanore, A and Hesters, A and Hussein, S and Benchikh, R and Bruneteau, G and Morélot-Panzini, C and Parfait, M and Piljan, M and Le Guennec, L and Weiss, N and Demeret, S and Mayaux, J and Marois, C},
title = {Outcomes of patients with amyotrophic lateral sclerosis admitted to the ICU for acute respiratory failure.},
journal = {Annals of intensive care},
volume = {16},
number = {},
pages = {100183},
pmid = {42926935},
issn = {2110-5820},
abstract = {BACKGROUND: Data on patients with amyotrophic lateral sclerosis (ALS) admitted to the intensive care unit (ICU) for acute respiratory failure are scarce, and early prognostic markers are lacking.

METHODS: We conducted a retrospective cohort study of consecutive patients with ALS admitted for acute respiratory failure to two ICUs of a tertiary referral center between 2016 and 2022. The primary outcome was 3-month mortality. Factors associated with 3-month mortality were assessed using multivariable Cox proportional hazards regression. Survival and functional outcomes were evaluated up to 12 months.

RESULTS: Among 139 patients [median age 66 (IQR 57-73) years, 61.2% being men], 109 (78.4%) patients presented with hypercapnia and 82 (59.0%) with hypoxemia (defined as PaO₂/FiO₂ ratio < 300) at ICU admission, with frequent overlap between both conditions. Non-invasive ventilation was used in 79.9% of patients, while 13.7% were intubated, and 2.2% underwent tracheostomy. Three-month mortality was 48.2%, increasing to 61.2% and 74.1% at 6 and 12 months respectively. In multivariable analysis, hypoxemia at ICU admission was independently associated with increased 3-month mortality (HR = 2.27, 95% CI: 1.28-4.01; P = 0.005), along with older age (HR=1.03 per year, 95% CI: 1.00-1.06; P = 0.035). Among patients alive at 3 months, a majority (79.2%) were living at home.

CONCLUSION: ICU admission for acute respiratory failure in ALS is associated with substantial short-term mortality, consistent with the poor prognosis inherent to the natural history of the disease. Hypoxemia at admission identifies a subgroup at particularly high risk of death and may help inform early prognostic assessment and shared decision-making. However, patients who survive the acute ICU phase frequently achieve favorable short-term outcomes, with most living at home at 3 months.},
}

@article {pmid42927514,
year = {2026},
author = {McHutchison, C and Wuu, J and Cosentino, S and Saldana, R and Vadella, E and Benacerraf, A and McBane, K and Gonzalez, AS and Stark, JH and Li, Y and Abrahams, S and Benatar, M},
title = {Mild cognitive impairment in presymptomatic amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {42927514},
issn = {1432-1459},
support = {4365//Muscular Dystrophy Association/ ; 172123//Muscular Dystrophy Association/ ; 2015//The ALS Association/ ; R01 NS105479/NS/NINDS NIH HHS/United States ; U54 NS090291//CReATe Scholarship funded by the National Institutes of Health/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/complications/physiopathology ; Female ; Male ; *Cognitive Dysfunction/etiology/genetics/physiopathology/diagnosis/epidemiology ; *Prodromal Symptoms ; Middle Aged ; C9orf72 Protein/genetics ; Aged ; Superoxide Dismutase-1/genetics ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are clinically and biologically related, and each may be preceded by a prodromal stage of disease. Mild cognitive and behavioural impairment (MCI/MBI) have also been observed in those with clinically manifest ALS. The primary aim of this study was to characterise MCI in presymptomatic ALS.

METHODS: Criteria for frontotemporal-related MCI (MCI-ft), which require evidence of subthreshold cognitive performance or decline, were adapted from existing frameworks for MCI in prodromal FTD, presymptomatic ALS and clinically manifest ALS. MCI-ft was characterised in 216 Pre-fALS participants (74 C9ORF72, 94 SOD1, 20 other pathogenic variant carriers and 28 non-carriers) with neuropsychological data at 807 study visits. All designations were reviewed by a research neuropsychologist, with consensus discussions as needed.

RESULTS: MCI-ft was observed in 15 (20%) C9ORF72, 12 (13%) SOD1 and 3 (%) of other carriers at one or more study visits, compared to 1 (4%) non-carrier. Most visits with MCI-ft showed impairment affecting both language and executive functioning. Fluctuations in MCI-ft status between assessments were common.

CONCLUSION: The observed frequency and temporal course of MCI-ft in presymptomatic ALS, using criteria based on subthreshold cognitive performance and decline, expands understanding of this phase of disease. These findings help to inform future research examining the risk of phenoconversion to clinically manifest disease and aid the design of disease prevention trials.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/complications/physiopathology
Female
Male
*Cognitive Dysfunction/etiology/genetics/physiopathology/diagnosis/epidemiology
*Prodromal Symptoms
Middle Aged
C9orf72 Protein/genetics
Aged
Superoxide Dismutase-1/genetics
Neuropsychological Tests

@article {pmid42924853,
year = {2026},
author = {Regazzetti, M and Kiper, P and Merico, A and Rossi, S and Bulcão Visco, D and Luque Moreno, C and Baba, A},
title = {Feasibility and apparent safety of functional electrical stimulation-assisted cycling in amyotrophic lateral sclerosis and primary lateral sclerosis: a single-arm longitudinal pilot feasibility study.},
journal = {European journal of translational myology},
volume = {},
number = {},
pages = {},
doi = {10.4081/ejtm.2026.16025},
pmid = {42924853},
issn = {2037-7452},
abstract = {Functional electrical stimulation-assisted cycling may be relevant in motor neuron disease, but its feasibility and safety in amyotrophic lateral sclerosis and primary lateral sclerosis remain unclear. The authors aimed to assess feasibility, apparent safety, and exploratory pre-post clinical changes of a three-week functional electrical stimulation-assisted cycling protocol in ambulatory inpatients with amyotrophic lateral sclerosis or primary lateral sclerosis. Fifteen patients were assessed; 11 were enrolled (5 ALS, 6 PLS) and received 15 supervised 30-minute FES-cycling sessions over three weeks in addition to conventional neuromotor rehabilitation. Bilateral eight-channel stimulation targeted quadriceps, tibialis anterior, hamstrings, and gastrocnemius during active or active-assisted cycling. Feasibility outcomes were enrollment, completion, tolerance, adverse events, and pre-post data availability. Clinical outcomes were analyzed descriptively. Eleven of 15 assessed patients were enrolled (73.3%; 5 ALS, 6 PLS). All enrolled participants completed the protocol, no adverse events were documented, and complete pre-post data were available. Exploratory outcomes showed favorable short-term changes in mobility, walking, strength, and spasticity. This protocol appears feasible and apparently safe in selected ambulatory inpatients. Findings are hypothesis-generating and support a prospective controlled feasibility trial before efficacy is tested.},
}

@article {pmid42925434,
year = {2026},
author = {Shah, A and Godad, A and Bagwe Parab, S},
title = {Unlocking therapeutic potential of Wnt signaling pathway in neurodegenerative diseases.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42925434},
issn = {1573-7365},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Wnt Signaling Pathway/drug effects/physiology ; Animals ; Blood-Brain Barrier/metabolism/drug effects ; },
abstract = {The Wnt Signaling pathway is a regulatory network that is highly conserved in the central nervous system and is essential for the survival of neurons, synaptic plasticity, and the blood-brain barrier's integrity. The pathophysiology of major neurodegenerative and neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury (TBI), is highly influenced by canonical and non-canonical Wnt Signaling dysregulation, according to increasingly compelling evidence. In addition to emphasising common molecular events such as GSK-3β overactivation, β-catenin destabilisation, neuroinflammation, synaptic dysfunction, and BBB disruption, this study offers a comparative and mechanistic overview of Wnt pathway changes across various illnesses. This article identifies overlapping treatment targets, such as GSK-3β, DKK1, LRP5/6, and Wnt ligands, by integrating common and disease-specific Wnt-associated pathways, in contrast to traditional disease-specific reviews. Furthermore, new translational approaches involving natural substances, Wnt modulators, and pathway-targeted treatments are critically examined. All things considered, this study presents Wnt Signaling as a potential neuroprotective and regenerative target for upcoming precision-based treatments in neurodegenerative disorders.},
}

Humans
*Neurodegenerative Diseases/metabolism/drug therapy
*Wnt Signaling Pathway/drug effects/physiology
Animals
Blood-Brain Barrier/metabolism/drug effects

@article {pmid42925563,
year = {2026},
author = {Niu, Y and Zhang, D and Gong, T and Guo, G and Zhang, H and Gao, C and Yang, J},
title = {Constructing functional neural circuits to model amyotrophic lateral sclerosis with induced pluripotent stem cell-derived brain organoids.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRRONLINE-D-26-00781},
pmid = {42925563},
issn = {1673-5374},
abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons. Recent advances in human-induced pluripotent stem cell-derived brain organoids offer an innovative platform to model amyotrophic lateral sclerosis in a human-specific context. These three-dimensional organoid systems allow for the study of neuronal circuit-level dysfunction, which is central to amyotrophic lateral sclerosis pathogenesis, by incorporating multiple neuronal subtypes and supporting glial populations. In particular, the integration of region-specific brain organoids into assembloid models has enabled the reconstruction of functional long-range projections and cortico-motor circuits, closely resembling human neural connectivity. This review summarizes the generation and application of human induced pluripotent stem cell-derived brain organoids for amyotrophic lateral sclerosis research, with a focus on the reconstruction of neural circuits, multi-omics profiling, and functional assays. We also discuss how organoid systems can be leveraged for drug discovery and personalized medicine in amyotrophic lateral sclerosis, highlighting their potential to unveil human-specific disease mechanisms. Lastly, we address the current challenges and future directions for improving the physiological relevance of organoid models in amyotrophic lateral sclerosis research.},
}

@article {pmid42925619,
year = {2026},
author = {Moreira, JVA and Pinheiro, CVA and de Souza, RF and Chiappa, GR and Ramos, SC and da Silva de Magalhães, MJ and de Aguiar, DR and Dos Santos, DF},
title = {The clinical spectrum of suicide-related outcomes in amyotrophic lateral sclerosis: A systematic review and meta-analysis.},
journal = {General hospital psychiatry},
volume = {103},
number = {},
pages = {204-212},
doi = {10.1016/j.genhosppsych.2026.10.002},
pmid = {42925619},
issn = {1873-7714},
abstract = {OBJECTIVE: To synthesize clinically distinct suicide-related outcomes in amyotrophic lateral sclerosis (ALS) and comparative suicide risk without pooling non-equivalent constructs.

METHODS: We searched MEDLINE, Embase, Scopus, PsycINFO, the Virtual Health Library, and SciELO through March 17, 2026, and updated all searches for March 18 through October 9, 2026. We included observational reports of predefined suicide-related outcomes. Outcomes with at least 3 independent studies were pooled using random-effects generalized linear mixed models for proportions and a Hartung-Knapp model for comparative estimates. We used Joanna Briggs Institute tools and adapted GRADE.

RESULTS: Twenty-eight reports representing 26 independent cohorts were included; 21 cohorts contributed quantitative data. Active suicidal ideation was 43% (23/53; 95% CI, 30%-58%) in an end-stage cohort and 14% (10/71; 95% CI, 7%-24%) in a general clinic cohort; these estimates were not pooled. Hypothetical consideration of assisted dying was 50% (95% CI, 41%-59%; I[2] = 49%; 95% prediction interval, 21%-79%; 4 studies). Crude suicide mortality rates were 0.16 and 0.36 per 100 person-years in 2 cohorts. Three registry or administrative cohorts yielded a relative suicide-risk estimate of 4.6 (95% CI, 2.5-8.5; 95% prediction interval, 0.4-53.6). Certainty was low or very low.

CONCLUSIONS: Suicide-related experiences in ALS are clinically distinct. Clinicians should clarify meaning, assess intent and immediacy, evaluate decision-making capacity and treatable psychiatric symptoms, and address palliative and psychosocial needs. A death wish or assisted-dying preference should not be assumed to indicate active suicidal intent.},
}

@article {pmid42925692,
year = {2026},
author = {Ocampo, DEM and Martínez, SS},
title = {Dynamic UV-Vis monitoring of ternary pharmaceutical photodegradation using multivariate curve resolution and predictive modeling.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {367},
number = {Pt 2},
pages = {129014},
doi = {10.1016/j.saa.2026.129014},
pmid = {42925692},
issn = {1873-3557},
abstract = {Ultraviolet (UV) photodegradation of multicomponent pharmaceutical systems generates complex spectral signals due to overlapping absorption bands and transient intermediates, limiting conventional quantitative approaches. To address this challenge, an integrated chemometric strategy was developed to predict concentration profiles in dynamic ternary mixtures of paracetamol (PAR), naproxen sodium (NPX), and diclofenac sodium (DIC) in spiked river water using Ultraviolet-visible (UV-Vis) spectroscopy. UV-Vis spectra from individual photolysis experiments were analyzed by Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to estimate concentration profiles of the parent pharmaceuticals. These profiles were associated with ternary mixture spectra reconstructed by linear combination of the spectral data obtained from the individual photolysis experiments. The combined spectral data, together with experimentally acquired calibration data, served as input to develop a linear Partial Least Squares (PLS) and non-linear Artificial Neural Network (ANN) models, enabling simultaneous prediction of component concentrations. The degree of nonlinearity in the calibration datasets was first assessed using the Non-Linearity Degree (NLD), yielding values of 0.248, 0.398, and 0.214 for PAR, NPX, and DIC, respectively. These results exceeded the 0.05 threshold, indicating significant non-linear behavior in the calibration datasets. Accordingly, the linear PLS model showed limited predictive performance, particularly for DIC. In contrast, the non-linear ANN model achieved higher predictive accuracy, demonstrating its superior suitability for the dynamically evolving multicomponent systems.},
}

@article {pmid42926444,
year = {2026},
author = {Bennett, A and Johnson, EK and Benjamin, KJM},
title = {IsoGraph resolves coordinated transcript choice and gene abundance in the aging human brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.04.756439},
pmid = {42926444},
issn = {2692-8205},
abstract = {Relative transcript usage can change without a corresponding change in total gene expression, but resolving coordinated transcript choice across genes while separating it from abundance remains challenging. We present IsoGraph, a gene-centered framework that represents isoform usage and abundance as paired network channels, identifies gene modules, and quantifies their channel-specific contributions. In synthetic benchmarks, IsoGraph preferentially recovered network structure when coordinated transcript usage carried the planted signal, whereas abundance-based representations were more informative in abundance-dominated and RNA-degradation settings. Applied to BrainSEQ and GTEx adult brain transcriptomes, IsoGraph identified age-associated transcript-usage signals that persisted after conditioning on gene abundance and, in a region-dependent manner, after adjustment for estimated cellular composition. Modules were stable across donor subsets, and frozen module axes retained age associations across cohorts even when exact gene partitions differed. IsoGraph module context captured predictive information about held-out differential transcript usage beyond gene-wise evidence and conventional co-expression. Convergent evidence from structural annotation, short-read junction usage, independent long-read sequencing, and within-donor allelic analyses supported constituent transcript events. Disease colocalization further prioritized candidate isoform events at neurological and psychiatric disease loci, including an alternative terminal-exon event at PRDM2 associated with amyotrophic lateral sclerosis. Together, these results establish coordinated transcript usage as a reproducible component of transcriptomic organization and provide a framework for resolving its contribution alongside gene abundance and for tracing network-level signals to candidate transcript events.},
}

@article {pmid42926625,
year = {2026},
author = {Bhandary, P and Wang, Y and Omar, M and Moore, JH and Wang, ZP},
title = {CCT2 expression marks a translation-activated state in sporadic ALS motor neurons and is associated with functional decline.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.06.757033},
pmid = {42926625},
issn = {2692-8205},
abstract = {Sporadic disease accounts for about 90% of amyotrophic lateral sclerosis (ALS) cases, and its biological heterogeneity is a major contributor to the failure of trials that enroll patients under a single diagnosis. Because sporadic ALS lacks a shared genetic anchor, identifying biological signals is critical for effective patient stratification. We analyzed induced pluripotent stem cell-derived motor neurons from 619 AnswerALS participants using transcriptomics, proteomics, and whole-genome sequencing and identified CCT2 as the first single-gene marker of a molecular state within sporadic ALS, providing a measurable basis for trial enrollment according to biology. We first anchored the analysis in known ALS genotypes. C9orf72 and SOD1 motor neurons did not converge on a common signature but retained genotype-specific differences that bulk postmortem tissue compresses. Scoring 391 sporadic patients along three transcriptomic axes (bioenergetic stress, cell cycle, and inflammation) resolved three states. One state was marked by CCT2, a TRiC chaperonin subunit, which distinguished it from the quiescent state with an area under the curve of 0.892. CCT2 was also elevated at the protein level and associated with the rate of ALSFRS-R decline, although this association weakened after adjustment for culture composition. Upstream regulator analysis placed this state downstream of MYC and mTORC1 activation. No germline test across 360 whole genomes explained these states. Validation using Target ALS data showed that the relationship between CCT2 and the cell cycle program was also present in postmortem cortex enriched for layer 5b projection neurons.},
}

@article {pmid42907117,
year = {2026},
author = {Blinker, EJ and Amoh, GKA and Ankamah, S and Agyemang, C and Omech, B and Beune, E and Wekesah, FM and Azumah, M and Munneke, W},
title = {Implementation strategies, outcomes and determinants of integrated care for cardiometabolic conditions and mental, neurological and substance use disorders: protocol for a mixed-methods systematic review.},
journal = {BMJ open},
volume = {16},
number = {10},
pages = {e125828},
pmid = {42907117},
issn = {2044-6055},
abstract = {ΙNTRODUCTION: The co-occurrence of cardiometabolic diseases and mental, neurological and substance use disorders health conditions represents a growing global health burden, particularly in low- and middle-income countries. Although integrated, people-centred multimorbidity care is increasingly recognised as essential across settings, evidence remained limited on how these models are operationalised in routine practice and which implementation strategies are most effective to support their delivery. This protocol outlines the methods for a systematic review aiming to identify implementation strategies used to integrate care for cardiometabolic conditions and mental, neurological and substance use (MNS) disorders, examine associated implementation outcomes and explore contextual determinants influencing implementation across settings.

METHODS AND ANALYSIS: This protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines. A comprehensive search will be conducted in PubMed, CINAHL, APA PsycINFO, Scopus and Web of Science and relevant grey literature sources. Eligible studies include randomised controlled trials, quasi-experimental studies, mixed-methods studies, qualitative studies and implementation evaluations reporting on integrated care models addressing both cardiometabolic conditions and MNS disorders. To be included in this Systematic Review, studies must detail strategies or models integrating care for at least one cardiometabolic condition and one MNS disorder and provide data on implementation outcomes or contextual determinants. Title/abstract screening, full-text screening, data extraction and data synthesis will be conducted independently by at least two researchers following pilot testing. A formal risk of bias assessment will be performed using the Mixed Methods Appraisal Tool. A mixed-method, framework-based synthesis will be undertaken. Implementation strategies will be coded using the Expert Recommendations for Implementing Change taxonomy, implementation outcomes using Proctor et al’s taxonomy, and contextual determinants using the Consolidated Framework for Implementation Research. Quantitative data will be summarised descriptively using frequencies, proportions and summary tables, with findings stratified by country income level, setting and type of integrated care model where possible. Qualitative data will be analysed using inductive coding and deductive mapping to implementation science frameworks.

ETHICS AND DISSEMINATION: Ethical approval is not required as no primary data will be collected. The findings of this study will be disseminated through peer-reviewed publications, conference presentations, and stakeholders’ engagement in the field.

REGISTRATION DETAILS: The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 6 April 2026 (registration number CRD420261321825).},
}

@article {pmid42918614,
year = {2026},
author = {Speranza, J and Gale-Rogers, C and Stretch, AC and West, RJH},
title = {Drosophila Models of Human Neurodegenerative Diseases.},
journal = {Current opinion in insect science},
volume = {},
number = {},
pages = {101639},
doi = {10.1016/j.cois.2026.101639},
pmid = {42918614},
issn = {2214-5753},
abstract = {In his book Insects and the Life of Man: Collected Essays on Pure Science and Applied Biology, Sir V. B. Wigglesworth examined how a fundamental understanding of insect physiology and biology can be applied to some of society's greatest challenges, including human health. Here we reflect on how, in the 50 years since his book's publication, Drosophila melanogaster have played a critical role in advancing our understanding of human neurodegenerative diseases. Focusing on Parkinson's disease, Huntington's disease, and the frontotemporal dementia / amyotrophic lateral sclerosis spectrum, we examine the role Drosophila have played in elucidating fundamental mechanisms of neurodegeneration, identifying therapeutic targets, and dissecting the complex interplay that exists between genetics and environmental factors. Together these studies highlight how Drosophila models continue to provide critical insight into the molecular mechanisms underpinning neurodegeneration and provide a fundamental pre-clinical model in which we can accelerate research into human neurodegenerative conditions.},
}

@article {pmid42918778,
year = {2026},
author = {Abu-Rumeileh, S and Großkopf, H and Guthknecht, A and Mensch, A and Osterloh, D and Ratti, A and Conrad, J and Stapf, C and Krippner, J and Oeckl, P and Stoltenburg-Didinger, G and Maranzano, A and Steinacker, P and Weise, CM and Barba, L and D'Anna, L and Klafki, HW and Wiltfang, J and Silani, V and Froelich, L and Ticozzi, N and Hausner, L and Thal, DR and Weishaupt, JH and Lachmann, I and Verde, F and Otto, M},
title = {Tau isoform mapping across tissues and biofluids reveals a signature distinguishing Alzheimer's disease from amyotrophic lateral sclerosis.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42918778},
issn = {2041-1723},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/blood/metabolism ; *tau Proteins/blood/metabolism ; *Alzheimer Disease/diagnosis/blood/metabolism ; Female ; Protein Isoforms/metabolism/blood ; Male ; Biomarkers/blood/metabolism ; Brain/metabolism ; Aged ; Phosphorylation ; Spinal Cord/metabolism ; Mass Spectrometry ; Middle Aged ; Diagnosis, Differential ; Aged, 80 and over ; Immunoprecipitation ; Case-Control Studies ; },
abstract = {Blood phosphorylated tau 217 (p-tau217) accurately detects Alzheimer's disease (AD) pathology but is also elevated in amyotrophic lateral sclerosis (ALS), likely reflecting peripheral (big) tau released from muscle. Assays selectively measuring brain-derived (BD-) tau and BD-p-tau217 are therefore needed. We analysed serum BD-tau and p-tau217 in ALS (n = 139), AD (n = 101) and controls (n = 75) using direct immunoassays and after BD-Tau immunoprecipitation (BD-Tau-IP), and tau species in brain (n = 16), spinal cord (n = 11) and muscle (n = 10) by targeted mass spectrometry. With the direct immunoassays, BD-tau and p-tau217 were increased in AD and ALS versus controls. After BD-Tau-IP, BD-tau and BD-p-tau217 were elevated in AD only, improving diagnostic accuracy. Mass spectrometry revealed a central-to-peripheral shift from BD-tau to big tau predominance, with exclusively big p-tau217 detected in muscle. Selective detection of BD-tau species improves the specificity of blood AD biomarkers by reducing peripheral tau confounding.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/blood/metabolism
*tau Proteins/blood/metabolism
*Alzheimer Disease/diagnosis/blood/metabolism
Female
Protein Isoforms/metabolism/blood
Male
Biomarkers/blood/metabolism
Brain/metabolism
Aged
Phosphorylation
Spinal Cord/metabolism
Mass Spectrometry
Middle Aged
Diagnosis, Differential
Aged, 80 and over
Immunoprecipitation
Case-Control Studies

@article {pmid42919527,
year = {2026},
author = {Jiang, M and Ning, J and Wang, J and Hu, W and Sun, P and Zhao, N and Cao, H and Liao, M},
title = {Metabolic nontarget-site mechanism confers dual resistance to cyhalofop-butyl and imazamox in Leptochloa chinensis from China.},
journal = {Pesticide biochemistry and physiology},
volume = {224},
number = {},
pages = {107324},
doi = {10.1016/j.pestbp.2026.107324},
pmid = {42919527},
issn = {1095-9939},
mesh = {*Herbicides/pharmacology/toxicity ; *Imidazoles/pharmacology/toxicity ; *Herbicide Resistance/genetics ; *Poaceae/drug effects/genetics/metabolism ; China ; *Nitriles/pharmacology/toxicity ; *Oximes/pharmacology ; *Butanes/pharmacology ; Plant Proteins/genetics/metabolism ; },
abstract = {Chinese sprangletop (Leptochloa chinensis (L.) Nees) has emerged as a dominant grass weed in rice fields, representing a serious risk to crop productivity because of its rapidly increasing resistance to herbicides. A putative resistant population, MASHS7 (R), was collected from an imidazolinone-tolerant rice field, where it had survived applications of cyhalofop-butyl (CYB) and imazamox (IMA) at the field-recommended rates. Dose-response assays indicated that compared with the susceptible (S) population, the R population developed resistance to CYB (26.29-fold) and IMA (5.50-fold). Additionally, both the cytochrome P450 (P450) inhibitor malathion and the glutathione S-transferase (GST) inhibitor 4-chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) partially reversed the resistance of the R population to CYB and IMA. Target-site resistance mechanism analysis revealed that the R plants carried a Trp-to-Cys mutation at codon 1999 of ACCase, with no mutations in the ALS gene, and exhibited no overexpression of any target gene. Compared with the S plants, the R plants metabolized CYB, cyhalofop acid (CYA) and IMA faster. RNA sequencing analysis and quantitative real-time PCR (qPCR) validation confirmed that two P450s (CYP709B2 and CYP81Q32b) and one GST (GST4) gene were constitutively upregulated in the R plants. Molecular docking results predicted favorable binding interactions of these enzymes with CYA and IMA.},
}

*Herbicides/pharmacology/toxicity
*Imidazoles/pharmacology/toxicity
*Herbicide Resistance/genetics
*Poaceae/drug effects/genetics/metabolism
China
*Nitriles/pharmacology/toxicity
*Oximes/pharmacology
*Butanes/pharmacology
Plant Proteins/genetics/metabolism

@article {pmid42919989,
year = {2026},
author = {Rossini, E and Garibaldi, M and Hanna, MG and Pitceathly, RDS and Pizzamiglio, C},
title = {Mitochondrial dysfunction in neurology: biomarkers and clinical implications.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42919989},
issn = {1759-4766},
abstract = {Mitochondrial dysfunction is increasingly recognized as a shared downstream pathogenic mechanism across a wide spectrum of neurological disorders, ranging from primary mitochondrial diseases to conditions including amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease, multiple sclerosis, hereditary ataxias and idiopathic inflammatory myopathies. This Review examines the role of mitochondrial biomarkers in improving diagnostic accuracy, patient stratification and monitoring of disease progression and therapeutic response. Primary mitochondrial diseases are presented as proof-of-concept models of impaired oxidative phosphorylation, providing a framework for biomarker identification and validation with translational relevance to other neurological diseases. Mitochondrial biomarkers can be broadly categorized into four domains: fluid biomarkers, reflecting metabolic alterations and stress signalling; genetic biomarkers, capturing mitochondrial DNA integrity and dynamics; multi-omics approaches, integrating transcriptomic, proteomic and metabolomic signatures; and imaging biomarkers, enabling in vivo assessment of structural and functional consequences of mitochondrial dysfunction. Across disorders, these biomarkers reveal shared disturbances in bioenergetics, redox homeostasis, mitochondrial genome maintenance and inflammatory signalling. However, clinical implementation remains limited by methodological heterogeneity, biological variability and reduced disease specificity. Integrated, multimodal biomarker strategies, combined with longitudinal validation, will be essential for supporting precision medicine and guiding the development of therapies to target mitochondrial pathways in neurology.},
}

@article {pmid42920457,
year = {2026},
author = {Malik, A and Ferdousi, M and Azmi, S and Malik, RA},
title = {Corneal Confocal Microscopy (CCM) in Patients With Central Neurodegenerative Disease.},
journal = {Cureus},
volume = {18},
number = {9},
pages = {e116756},
pmid = {42920457},
issn = {2168-8184},
abstract = {Corneal confocal microscopy (CCM) is a rapid, non-invasive ophthalmic imaging technique that enables detailed visualization and quantification of small corneal nerve fibres. Although initially developed for the assessment of diabetic neuropathy, its application has broadened substantially, with increasing evidence supporting its value in a range of central neurodegenerative diseases. This narrative review synthesizes current findings on the use of CCM in dementia, multiple sclerosis, stroke, burning mouth syndrome, amyotrophic lateral sclerosis, trigeminal neuralgia, migraine and Parkinson's disease. Across these conditions, CCM consistently identifies measurable alterations in corneal nerve fibre density, length, branching and morphology, as well as changes in corneal immune cell populations. These structural abnormalities frequently correlate with disease severity, functional decline and clinical progression. In some disorders, CCM demonstrates diagnostic performance comparable to or exceeding existing biomarkers, and offers distinct advantages as a non-invasive, repeatable and objective measure that can detect early or subclinical neurodegeneration. Corneal confocal microscopy also shows potential as a prognostic and monitoring tool, particularly in conditions with limited reliable biomarkers. It may help stratify risk, track therapeutic response, and provide surrogate endpoints for clinical trials. Despite these strengths, several limitations remain, including modest sample sizes in some studies, variability in image interpretation, and difficulties differentiating between neurodegenerative conditions with overlapping patterns of nerve loss. Emerging automated analysis methods and artificial intelligence-based algorithms may help address these challenges by improving accuracy, reproducibility, and scalability. Overall, CCM represents a promising technique that bridges ophthalmology and neurology. A growing body of literature supports its utility across multiple neurodegenerative diseases, and further large-scale, longitudinal studies may help establish its role within routine clinical assessment and research.},
}

@article {pmid42921272,
year = {2026},
author = {He, Z and Zeng, J and Wang, G and Li, Y and Zhang, F},
title = {Neurodegenerative Diseases: Epidemiology, Risk Factors, Classification, Pathophysiology, Clinical Features, Diagnosis, and Therapeutic Strategies.},
journal = {MedComm},
volume = {7},
number = {11},
pages = {e71090},
doi = {10.1002/mco2.71090},
pmid = {42921272},
issn = {2688-2663},
abstract = {Neurodegenerative diseases are a growing cause of disability worldwide, particularly as populations age. Although these disorders differ in etiology and clinical presentation, advances in genetics, neuropathology, and biomarker research have identified shared disturbances in protein homeostasis, mitochondrial function, and immune regulation. These processes may contribute to selective neuronal vulnerability and neural circuit dysfunction. These findings are refining disease classification and diagnosis, yet effective disease-modifying therapies remain limited. Disease-specific abnormalities remain essential to clinical interpretation and treatment selection. Existing reviews often focus on individual disorders or isolated mechanisms, leaving the links between shared biology and disease-specific phenotypes insufficiently clear. We synthesize evidence on the epidemiology, risk factors, classification, and pathophysiology of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, frontotemporal dementia, Friedreich's ataxia, and multiple sclerosis. We compare their clinical manifestations and diagnostic approaches, including the evolving role of biomarkers, and critically assess established and emerging therapies. By distinguishing shared mechanisms from disease-specific abnormalities, we identify key translational gaps and explore how common biological disturbances may lead to distinct clinical trajectories. This cross-disease perspective may inform diagnostic reasoning, treatment development, and future comparative research.},
}

@article {pmid42922081,
year = {2026},
author = {Adorinni, S and Grieco, I and Morasso, S and Fornasier, M and Novello, G and Salmaso, V and Martínez-González, L and Cescon, E and Bassani, D and Bassan, GA and Gianferrara, T and Prencipe, F and Kost, V and Da Ros, T and Storici, P and Martinez, A and Spalluto, G and Moro, S and Federico, S},
title = {Riluzole-Derived Benzo[d]thiazoles as CK1δ Inhibitors for Amyotrophic Lateral Sclerosis-Related Neurodegeneration.},
journal = {ChemMedChem},
volume = {21},
number = {20},
pages = {},
pmid = {42922081},
issn = {1860-7187},
support = {PRIN 20227K7YJS//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Humans ; *Riluzole/chemistry/pharmacology ; Structure-Activity Relationship ; *Casein Kinase Idelta/antagonists & inhibitors/metabolism ; *Protein Kinase Inhibitors/chemistry/pharmacology/chemical synthesis ; Animals ; *Benzothiazoles/chemistry/pharmacology/chemical synthesis ; Molecular Docking Simulation ; *Neuroprotective Agents/chemistry/pharmacology/chemical synthesis ; Molecular Structure ; },
abstract = {Riluzole-derived benzo[d]thiazoles were investigated as metabolite-inspired CK1δ inhibitors, a kinase involved in TDP-43 phosphorylation and therefore relevant to amyotrophic lateral sclerosis (ALS). Starting from the known CK1δ activity of riluzole, we examined whether its major hydroxylamine metabolite could preserve target recognition and provide a rational entry point for scaffold optimisation. The metabolite retained CK1δ inhibition, but its limited chemical stability and toxicity in neuronal cells identified the hydroxylamine group as a critical liability. Replacement of this functionality with a hydrazine converted the fragile metabolite-derived structure into a more potent and tractable CK1δ inhibitor series. Structure-activity relationship studies revealed that the hydrazine moiety accommodates broader substitution than the hydroxylamine counterparts, with branched alkyl and benzyl groups giving the most balanced profiles. Docking and molecular dynamics suggested that the improvement could be attributed to an additional hydrogen-bond with Gly86 in the hinge region. The best derivative combined submicromolar CK1δ inhibition with passive blood-brain barrier permeability, short-term cellular tolerance, ATP competitive inhibition, direct target engagement, and preliminary selectivity over GSK3β. Although this compound did not result neuroprotective in an oxidative stress model, it paves the way for a focused benzo[d]thiazole platform for probing CK1δ biology in ALS.},
}

*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology
Humans
*Riluzole/chemistry/pharmacology
Structure-Activity Relationship
*Casein Kinase Idelta/antagonists & inhibitors/metabolism
*Protein Kinase Inhibitors/chemistry/pharmacology/chemical synthesis
Animals
*Benzothiazoles/chemistry/pharmacology/chemical synthesis
Molecular Docking Simulation
*Neuroprotective Agents/chemistry/pharmacology/chemical synthesis
Molecular Structure

@article {pmid42922691,
year = {2026},
author = {Grycz, K and Jan, C and Zawistowski, P and Wasicki, B and Özkan, B and Aousji, O and Sirtori, R and Fallini, C and Caron, G and Danner, SM and Roselli, F and Zytnicki, D and Bączyk, M},
title = {Defective synapto-nuclear signaling contributes to motoneuron vulnerability in SOD1-ALS.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.01.748568},
pmid = {42922691},
issn = {2692-8205},
abstract = {Glutamatergic excitatory synapses not only shape spiking activity and neuronal communication but also initiate activity-dependent signaling pathways that trigger transcriptional programs. Since glutamatergic excitatory synapses onto spinal motoneurons (MNs) are impaired presymptomatically in Amyotrophic Lateral Sclerosis, we investigated whether synapto-nuclear coupling is disrupted in MNs from mSOD1 mice and whether restoring it mitigates pathology. We developed an in vivo approach to selectively investigate the coupling between synaptic excitation and nuclear CREB phosphorylation in spinal MNs. Specific activation of Ia-MN synapses induces CREB phosphorylation in wild-type MNs but not in mSOD1 MNs at P50, indicating presymptomatic synapto-nuclear uncoupling. Enhancing cAMP/PKA signaling by pharmacological inhibition of cAMP degradation restored synapto-nuclear coupling, reduced misfolded SOD1, and slowed neuromuscular-junction denervation. Thus, activity-dependent synapto-nuclear signaling is impaired yet pharmacologically rescuable in mSOD1 MNs, supporting synapto-nuclear signaling as a determinant of MN resilience.},
}

@article {pmid42922848,
year = {2026},
author = {Gorenshtein, A and Omar, M and Jia, E and Adiniaev, Y and Daniel, O and Kruskal, J and Ahmed, M and Brook, O and Klang, E and Barash, Y},
title = {Limits of Trial-Adaptive Neural-Language Fusion Across Large Language Models in P300 Brain-Computer Interfaces.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.30.26361777},
pmid = {42922848},
abstract = {OBJECTIVE: Published P300-speller fusion schemes fix prior trust regardless of trial reliability; we tested whether a reliability estimate improves on it.

METHODS: We reanalyzed 3,373 archived P300-speller selections from 47 people with ALS (BigP3BCI). A fair, matched-search-space comparison, tuning both a fixed weight and an adaptive policy out-of-fold, was evaluated across 22 evaluable language-model priors up to 46.7B parameters. Two representative priors, GPT-2 and a classical 5-gram, additionally received detailed naive and mechanistic analyses.

RESULTS: No prior's 95% CI favored adaptive fusion under the fair comparison, despite unexploited oracle headroom at every scale. Under GPT-2, the naive comparison was significantly worse for adaptive fusion; both anchors converged to a degenerate or near-degenerate fair-comparison solution. For the representative anchors, three further controllers failed to convert that headroom into benefit; the fixed-fused posterior's output probability outperformed the best controller for flagging errors (2.8- to 3.8-fold enrichment).

CONCLUSION: A tuned fixed weight is a difficult-to-beat default across the tested scale range; reliability estimation gave no deployable adaptive advantage.

SIGNIFICANCE: Adaptive weighting should be validated against a fairly tuned baseline across model families and scales; in this dataset, the fused output's confidence identified high-risk selections better than the tested purpose-built ranker.},
}

@article {pmid42922986,
year = {2026},
author = {Yang, SH and Han, SK and Koo, Y},
title = {CRISPR/Cas9-mediated editing of SlALS1 enhances fruit sweetness in tomato.},
journal = {Frontiers in plant science},
volume = {17},
number = {},
pages = {1927332},
pmid = {42922986},
issn = {1664-462X},
abstract = {Fruit sweetness is a primary determinant of consumer preference and market value in tomato (Solanum lycopersicum), yet increasing sugar content without negatively affecting plant performance remains a major challenge in breeding programs. In this study, we targeted Acetolactate synthase 1 (SlALS1), a key enzyme in branched-chain amino acids (BCAAs) biosynthesis, to investigate whether modulation of primary metabolism could enhance fruit sugar accumulation. Tomato contains two ALS homologs, SlALS1 and SlALS2. Using CRISPR/Cas9-mediated genome editing, we generated SlALS1 knock-out lines in the Micro-Tom background. Loss of SlALS1 function led to a significant reduction in the levels of valine, leucine, and isoleucine in fruit tissues, confirming disruption of the BCAA biosynthetic pathway. Notably, soluble sugar content was markedly increased in the mutant lines, with glucose and fructose levels elevated by approximately 1.3-fold compared with wild-type fruits, resulting in a significantly higher Brix index. Metabolic profiling indicates that reduced BCAA biosynthesis may influence carbon allocation toward soluble sugar accumulation in fruit tissues, revealing an association between amino acid metabolism and carbohydrate accumulation during fruit development. Our findings demonstrate that precise editing of a central metabolic enzyme can enhance tomato fruit sweetness and suggest that SlALS1 may represent a promising target for genome editing aimed at improving fruit quality traits. However, further evaluation of agronomic traits, including plant growth and fruit yield, will be necessary to assess its potential for practical breeding applications.},
}

@article {pmid42923269,
year = {2026},
author = {Shen, C and Wu, XT and Yin, H and Zuo, JL and Zhang, CH and Cao, F and Zhang, Y and Tian, ZY and Robinson, N and Liu, JP},
title = {Selected traditional Chinese medicines for treating amyotrophic lateral sclerosis: a Bayesian network meta-analysis based on randomised controlled trials.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1706211},
pmid = {42923269},
issn = {1663-9812},
abstract = {OBJECTIVE: To assess the effectiveness of specific Traditional Chinese Medicine (TCM) therapies for Amyotrophic Lateral Sclerosis (ALS) using Bayesian network meta-analysis.

METHODS: PubMed, the Cochrane Library, EMBASE, Web of Science, and four Chinese databases up to 15th December 2024 was searched, including RCTs on adult Amyotrophic Lateral Sclerosis patients treated with TCM therapies (Chinese herbal medicine, preparations, non-pharmacological treatments) alone or combined with conventional treatments. Controls included no intervention, placebo, conventional treatments, or combinations. Primary outcomes were functional status (ALSFRS, ALSFRS-R, AALSS, m-Norris scales). Bayesian network meta-analysis compared treatment effects and calculated SUCRA values.

RESULTS: Thirty-five RCTs involving 27 TCM therapies were included. No significant differences in functional status or quality of life were found among TCM therapies, ICT, Riluzole alone, and Riluzole plus placebo. For functional status, Shenmai injection + ICT (SUCRA 0.735 for ALSFRS, 0.870 for ALSFRS-R), Jiweiling injection + placebo (SUCRA 0.868 for ALSFRS), Jiawei Sijunzi decoction alone (SUCRA 0.739 for ALSFRS-R), Acupuncture + rehabilitation exercises + Riluzole (SUCRA 0.928 for AALSS, 0.863 for m-Norris) and Shenzhe Jiangqi powder + placebo (SUCRA 0.860 for m-Norris) had the highest probabilities of being superior treatment. For quality of life, Thunder fire moxibustion + Riluzole and Jiweiling injection + placebo for ALSAQ-40 were favorable.

CONCLUSION: Despite no significant differences in functional status among TCM therapies, ICT, Riluzole alone, and Riluzole plus placebo, Jiweiling injection, Shenmai injection, Jiawei Sijunzi decoction, and Shenzhe Jiangqi powder may be regarded as candidate preparations for ALS patients. Future research should focus on real-world data to explore long-term effects and practical benefits.

https://inplasy.com/inplasy-2024-8-0050/, identifier INPLASY202480050.},
}

@article {pmid42924413,
year = {2026},
author = {Vornetti, G and Punzetti, F and Vacchiano, V and Rochat, MJ and Cantoni, E and Rizzo, G and D'Angeli, D and Morandi, L and Manners, DN and Liguori, R and Lodi, R and Tonon, C},
title = {Cerebellar involvement in sporadic amyotrophic lateral sclerosis: a magnetic resonance spectroscopy study.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag382},
pmid = {42924413},
issn = {2632-1297},
abstract = {Amyotrophic lateral sclerosis is increasingly recognized as a multisystem neurodegenerative disorder, and recent evidence suggests that the cerebellum may contribute to disease pathology, although cerebellar metabolic alterations have not previously been demonstrated in vivo. This study investigated cerebellar metabolic and structural changes using proton magnetic resonance spectroscopy ([1]H-MRS) and volumetric imaging. Thirty patients with amyotrophic lateral sclerosis (21 M, mean age 59.7 ± 7.6 years), 22 healthy controls (HC, 10 M, mean age 59.8 ± 9.6 years) and 16 individuals with hereditary spastic paraplegia type 4 (8 M, mean age 50.8 ± 12.5 years), a potential clinical mimic, underwent 3T MRI and [1]H-MRS with a single-voxel positioned in the left cerebellar hemisphere. Patients with amyotrophic lateral sclerosis showed significant reductions in myo-inositol/creatinine (P = 0.01) and glutathione/creatinine (P = 0.005), compared with HC, together with selective volume loss in cerebellar lobules I-IV, V, VI, and Crus I. Among metabolites, glutathione/creatinine had the highest discriminative accuracy for amyotrophic lateral sclerosis versus both HC and spastic paraplegia type 4, with areas under the curve of 0.80 and 0.71, respectively. These findings reveal distinct cerebellar metabolic alterations in amyotrophic lateral sclerosis, providing further evidence for cerebellar involvement in disease pathology and highlighting cerebellar [1]H-MRS as a potential adjunct to diagnostic evaluation.},
}

@article {pmid42906263,
year = {2026},
author = {Hawas, Y and Abo-Elnour, DE and Al-Hawari, NEM and Gahlan, S and Winkelman, JW},
title = {Restless legs syndrome and other neurological disorders: A systematic-narrative hybrid literature review with exploratory meta-analysis.},
journal = {Sleep medicine reviews},
volume = {90},
number = {},
pages = {102390},
doi = {10.1016/j.smrv.2026.102390},
pmid = {42906263},
issn = {1532-2955},
abstract = {Restless legs syndrome (RLS) is a sleep-related sensorimotor disorder affecting approximately 3% of adults worldwide. This review aims to synthesize current evidence on associations between RLS and major neurological conditions, provide an exploratory quantitative synthesis summarizing association patterns and heterogeneity, and identify priority mechanistic and clinical research gaps. Databases were searched from inception until August 2026. In our exploratory synthesis of 119 unique studies, RLS was significantly associated with Parkinson's disease (case-control OR 3.22, 95% CI 2.35-4.41; cohort RR 1.74, 95% CI 1.02-2.95), multiple sclerosis (OR 4.04, 95% CI 3.26-5.00), neuromyelitis optica spectrum disorder (OR 2.91, 95% CI 1.45-5.84), migraine or headache disorders (forward OR 2.72, 95% CI 2.19-3.38; reverse adjusted OR 1.53, 95% CI 1.36-1.73), peripheral neuropathy (OR 3.82, 95% CI 2.49-5.83), epilepsy (OR 2.11, 95% CI 1.58-2.82), and amyotrophic lateral sclerosis (OR 7.69, 95% CI 2.74-21.59). This work is an evidence-mapping review with exploratory pooling and is not intended as a definitive evidence synthesis. RLS is likely associated with neurodegenerative and other specific neurological conditions. Recognition of these associations may support earlier identification of comorbid conditions and targeted management strategies. However, the current evidence remains observational and heterogeneous.},
}

@article {pmid42907506,
year = {2026},
author = {Lee, HJ and Doğan, C and Koyuncu, S and Wehrmann, M and Artan, M and Petrovic, D and Loureiro, R and Sahu, AK and Schnubel, J and Grobushkin, P and Prymidis, D and Georgomanolis, T and Sokol, A and Yang, M and Hoppe, T and Frezza, C and Vilchez, D},
title = {Cold activates a BH2 metabolic network promoting longevity and proteostasis.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {42907506},
issn = {1476-4687},
abstract = {Moderately cold temperatures extend lifespan and promote health across species[1-3], yet the molecular mechanisms underlying these benefits remain unclear. Here we define a metabolite-driven, multi-tissue signalling system that links cold temperature to enhanced longevity and proteostasis in Caenorhabditis elegans. Cold temperature upregulates the biopterin-synthesis enzyme CAT-4 (GCH1 in humans), increasing production of dihydrobiopterin (BH2), a transportable reservoir for the bioactive cofactor tetrahydrobiopterin (BH4). BH2 is produced in muscle and transported to distal tissues, including the intestine and neurons, where it is converted into BH4 by the salvage enzyme DHFR-1. BH4 functions as an essential cofactor for phenylalanine hydroxylase PAH-1, promoting tyrosine synthesis and extending lifespan. This BH2-BH4 axis also prevents disease-related protein aggregation and subsequent neuronal dysfunction during ageing. Importantly, increasing BH2 synthesis specifically in muscle is sufficient to promote longevity and suppress pathological protein aggregation in distal tissues, even at normal or elevated temperatures. In human cells, BH2 or tyrosine supplementation reduces aggregation of polyQ-expanded proteins associated with Huntington's disease, as well as mutant variants of TDP-43 and FUS that cause amyotrophic lateral sclerosis. Together, these findings identify BH2 as a cold-induced metabolite of which the synthesis, intertissue transport and conversion into bioactive BH4 preserve organism-wide proteostasis and extend lifespan.},
}

@article {pmid42908777,
year = {2026},
author = {Wang, M and Mak, C and Li, X and Li, S and Cui, C and Cai, D and Liang, Z and Lu, T and Jia, Q and Shao, X and Ma, Y and Fan, G and Li, K and Mai, W and Mak, C and Liu, N},
title = {Case Report: Herbal nutritional intervention in a critically ill ALS patient with multidrug-resistant infection.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1912856},
pmid = {42908777},
issn = {2296-858X},
abstract = {We report a retrospective single case of a female patient with a 9-year history of amyotrophic lateral sclerosis (ALS) who presented with respiratory failure due to a multidrug-resistant organism (MDRO) infection, predominantly Klebsiella pneumoniae (KP), and who showed significant clinical improvement during a comprehensive treatment regimen that included an adjunctive herbal nutritional intervention. The objective of this retrospective single-case report was to describe the clinical course of this patient following a nutritional intervention with two herbal beverages: Sang Shen Pu Gong Ying (SSPGY) and Wu Zhi Mao Tao Hong Zao (WZMTHZ). The patient was admitted in critical condition and managed in three phases: initial antibiotics with occasional herbal beverages, daily herbal beverages, and a combination of herbal beverages with intermittent antibiotics. Retrospective analysis of clinical data revealed significant improvements post-intervention. Body weight increased from 26 kg to 35.5 kg at discharge and 39 kg at the 6-week follow-up. Vital signs normalized, with no detectable KP in the final hospital phase. Inflammatory markers, including C-reactive protein and white blood cell count, decreased markedly. Neurological status, as indicated by neurofilament light chain (NfL) levels, improved, and the patient showed respiratory autonomy and positional changes. Nutritional markers, total protein and creatinine, also improved. This case documents clinical improvements, including extended ventilator-free breathing periods, in an ALS patient with MDRO infection following a combined therapeutic approach. Although concurrent medical interventions were administered in real-world clinical practice, these findings suggest the potential value of this adjunctive intervention, warranting further systematic investigation. Clinical Trial Registration: identifier ITMCTR2024000322.},
}

@article {pmid42913489,
year = {2026},
author = {Huang, J and Zhang, S and Zhang, D and Yang, T and Li, C and He, M and Wang, J and Song, T and Wang, X and Lu, Y and Kong, Q and Tan, J and Zhang, J},
title = {Liquid-liquid phase separation in neurodegenerative diseases: Mechanisms, pathological transitions, and therapeutic opportunities.},
journal = {Science progress},
volume = {109},
number = {4},
pages = {368504261499190},
doi = {10.1177/00368504261499190},
pmid = {42913489},
issn = {2047-7163},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/genetics/therapy ; Phase Separation ; Animals ; Protein Aggregation, Pathological/metabolism ; Amyloid beta-Peptides/metabolism/chemistry/genetics ; DNA-Binding Proteins/metabolism/genetics ; Huntingtin Protein/genetics/metabolism ; tau Proteins/metabolism/genetics/chemistry ; alpha-Synuclein/metabolism/genetics/chemistry ; RNA-Binding Protein FUS/metabolism/genetics ; Biomolecular Condensates/metabolism ; },
abstract = {Liquid-liquid phase separation (LLPS) provides a biophysical framework for understanding biomolecular organization, yet its pathological relevance in neurodegeneration remains incompletely resolved. In this narrative review, we critically synthesize current evidence on LLPS in Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, focusing on mutant huntingtin, α-synuclein, amyloid-β, tau, TDP-43, and FUS. We first outline the molecular principles-including intrinsic disorder, multivalent interactions, and environmental sensitivity-that govern their phase behavior. We then examine how dynamic condensates may, under specific cellular contexts, transition toward less reversible oligomeric, gel-like, or solid assemblies, integrating evidence from in vitro, cellular, and in vivo studies. Importantly, current evidence does not support LLPS as a universal or obligatory precursor of pathological aggregation; rather, its biological consequences appear to depend on condensate composition, material properties, subcellular localization, and proteostasis capacity, while direct demonstration of disease-relevant condensates in vivo remains limited. We further discuss whether aberrant LLPS represents a cause, consequence, or context-dependent component of neurodegeneration and highlight emerging strategies that modulate condensate formation, maturation, or clearance while preserving physiological functions. Overall, this review defines both the mechanistic potential and current limitations of the LLPS framework and identifies key questions that must be addressed before pathological phase-state modulation can become a clinically actionable therapeutic strategy.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology/genetics/therapy
Phase Separation
Animals
Protein Aggregation, Pathological/metabolism
Amyloid beta-Peptides/metabolism/chemistry/genetics
DNA-Binding Proteins/metabolism/genetics
Huntingtin Protein/genetics/metabolism
tau Proteins/metabolism/genetics/chemistry
alpha-Synuclein/metabolism/genetics/chemistry
RNA-Binding Protein FUS/metabolism/genetics
Biomolecular Condensates/metabolism

@article {pmid42913510,
year = {2026},
author = {},
title = {Proceedings of the 25[th] Annual Meeting of the Northeast ALS Consortium.},
journal = {Muscle & nerve},
volume = {74 Suppl 2},
number = {},
pages = {S1-S112},
doi = {10.1002/mus.70436},
pmid = {42913510},
issn = {1097-4598},
}

@article {pmid42915077,
year = {2026},
author = {Ritchie, LM and Lester, MB and Sharma, AK and Patterson, JD},
title = {Quantified Interfacial Affinity of Hydrogen Sulfate and Sulfate Speciation in Model Marine Aerosol Particles.},
journal = {The journal of physical chemistry. A},
volume = {130},
number = {37},
pages = {7460-7468},
doi = {10.1021/acs.jpca.6c04034},
pmid = {42915077},
issn = {1520-5215},
support = {CHE-1708635//National Science Foundation/ ; CHE-2404123//National Science Foundation/ ; CHE-2404124//National Science Foundation/ ; },
abstract = {Heterogeneous reactions occurring in atmospheric aerosols are crucial components of multiple chemical reaction cycles. Sulfate species exert substantial influence on many heterogeneous reaction mechanisms due to their abundance and speciation. Despite the importance of sulfate species on heterogeneous reactions, quantitative descriptions of interfacial affinity and sulfate species partitioning at interfaces remain incomplete. Here, we quantify the interfacial properties of HSO4-, using cetyltrimethylammonium hydrogen sulfate (CTAHS) reverse micelles (RMs), as model marine aerosol particles. Infrared spectra (IR) of CTAHS RMs were collected and analyzed using multivariate curve resolution-alternating least-squares (MCR-ALS). MCR-ALS analysis reveals that four distinct species contribute to the observed IR spectra, which we assign as CTA+-HSO4- contact pairs (CPs), interfacial HSO4-, core HSO4-, and core SO42-. Computational studies reveal that the CTA+-HSO4- CPs exist in two distinct orientations at the interface. Spectral contributions from each chemical species are used to determine the quantitative interfacial affinity (χInt.) of HSO4-. Our observations indicate that the cationic charge of the interface alters the ionic distribution of sulfate species compared to air-water interfaces, placing H3O+ below HSO4-.},
}

@article {pmid42916114,
year = {2026},
author = {Milardi, D and Han, J and Lee, HJ and Ding, F and Miller, Y and Faller, P and Bush, AI and Crouch, PJ and Finkelstein, DI and Double, KL and Jeremic, A and Lim, MH and Ramamoorthy, A},
title = {Metal Ions and Protein Aggregation: Unraveling Molecular Interactions and Theranostic Prospects in Proteinopathies.},
journal = {Chemical reviews},
volume = {126},
number = {18},
pages = {10249-10333},
doi = {10.1021/acs.chemrev.5c00420},
pmid = {42916114},
issn = {1520-6890},
support = {R01AG048934/AG/NIA NIH HHS/United States ; R35GM13973/GM/NIGMS NIH HHS/United States ; R35GM145409/GM/NIGMS NIH HHS/United States ; R01DK132214/DK/NIDDK NIH HHS/United States ; NA//Florida State University/ ; NA//National High Magnetic Field Laboratory/ ; 2022PAAYZE//NextGenerationEU/ ; CUP: B53D23016440006//NextGenerationEU/ ; DP230101031//Australian Research Council/ ; GNT1194028//National Health and Medical Research Council/ ; GNT2019931//National Health and Medical Research Council/ ; RS-2022-NR070709//National Research Foundation of Korea/ ; RS-2022-NR073879//National Research Foundation of Korea/ ; RS-2024-00353015//National Research Foundation of Korea/ ; RS-2024-00411134//National Research Foundation of Korea/ ; MRF2007656//Medical Research Future Fund/ ; },
mesh = {Humans ; *Protein Aggregation, Pathological/metabolism/drug therapy ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Metals/chemistry/metabolism ; Animals ; Protein Aggregates ; },
abstract = {Protein aggregation is a pathological process associated with several human diseases termed proteinopathies, including neurodegenerative and metabolic disorders such as Alzheimer's disease, Parkinson's disease, type II diabetes, amyotrophic lateral sclerosis, and Huntington's disease. In these conditions, specific proteins misfold and accumulate into insoluble aggregates, disrupting normal cellular function and contributing to disease progression. Many studies have investigated the molecular mechanisms that underlie the aggregation pathways, the structure of aggregates, such as oligomeric intermediates and fibrils, and their cellular toxicity. Studies have also investigated the effects of cofactors like metals, lipids, other amyloid proteins, and small molecules. Recent research has increasingly emphasized the critical roles of metal ions such as copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn) in amyloid aggregation and toxicity. Alterations in metal ion transport, binding, or redox activity have been linked to the onset and progression of several amyloid-associated diseases. These metal ions can interact directly with amyloidogenic proteins, influencing their structural conformation, aggregation kinetics, and propensity to form toxic oligomers. This review aims to advance our understanding of how the regulation of metal ions within cells and their dysfunction contribute to the accumulation of harmful proteins, which is a key factor in proteinopathies. By examining the interactions between metal ions and key amyloidogenic proteins─including amyloid-β (Aβ), α-synuclein, tau, superoxide dismutase 1 (SOD1), human islet amyloid polypeptide (hIAPP), and insulin─we highlight both common and unique pathways through which metal ions influence protein aggregation. Additionally, this review explores the impact of metal ions on protein clearance mechanisms, such as autophagy and the ubiquitin-proteasome system, as well as emerging theranostic strategies. These include metal chelation therapies, metal-based imaging agents, and multifunctional compounds designed to restore metal balance while preventing aggregation and toxicity. By integrating biochemical, cellular, and therapeutic insights, this review contributes to a deeper understanding of the metallobiology of proteinopathies and supports the development of novel diagnostic and treatment approaches targeting metal-protein interactions.},
}

Humans
*Protein Aggregation, Pathological/metabolism/drug therapy
*Neurodegenerative Diseases/metabolism/drug therapy
*Metals/chemistry/metabolism
Animals
Protein Aggregates

@article {pmid42918320,
year = {2026},
author = {Nasb, M and Yang, D and Malik, TH and Xu, D and Dayoub, L and Zhou, J and Zhao, Y},
title = {State transitions in amyotrophic lateral sclerosis: mechanistic convergence and biomarker-guided stratification.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.10.036},
pmid = {42918320},
issn = {1873-7544},
abstract = {BACKGROUND: Biological heterogeneity is a major obstacle to therapeutic development in amyotrophic lateral sclerosis (ALS). Cross-sectional pathway labels do not show whether a mechanism is active or treatment-relevant in an individual patient.

METHODS: We conducted a structured critical narrative review informed by the Scale for the Assessment of Narrative Review Articles. MEDLINE, Embase, PubMed, and CENTRAL were searched for English-language literature published from 1 January 2015 to 7 August 2026; seminal earlier studies were identified by citation tracking. Human genetic, pathological, longitudinal biomarker, multi-omic, imaging, neurophysiological, and interventional evidence was prioritized. Evidence was appraised by human proximity, temporality, replication, mechanistic specificity, and treatment relevance.

RESULTS: Evidence supports interacting RNA/proteostasis, nucleocytoplasmic-transport, glial-inflammatory, and energetic-metabolic processes, but current evidence does not yet support the use of any candidate state for individual treatment assignment. The most mature temporal example is loss of TDP-43 splicing repression before neurofilament elevation in genetically at-risk individuals. Nucleocytoplasmic-transport evidence is strongest in C9orf72 disease; inflammatory and metabolic signals are confounded by disease burden and systemic illness; and the gut-brain axis remains a context-dependent amplifier. We propose prespecified transition rules, evidence grades, and biomarker-by-treatment interaction tests.

CONCLUSIONS: A state-transition model becomes clinically useful when longitudinal measurements add value beyond clinical predictors and injury markers and prospectively identify differential treatment benefit.},
}

@article {pmid42918387,
year = {2026},
author = {Verma, A and Goyal, A and Agrawal, N and Yadav, HN},
title = {Cellular senescence in ageing and neurodegenerative disorders: Molecular mechanisms, biomarkers, and therapeutic strategies.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111985},
doi = {10.1016/j.pnpbp.2026.111985},
pmid = {42918387},
issn = {1878-4216},
abstract = {Cellular senescence has been increasingly associated with neurodegenerative disorders, potentially linking ageing-related cellular impairment with mitochondrial dysfunction, chronic inflammation, and disrupted intercellular signalling. The present study aims to explore the increasing relevance of cellular senescence among key cell types, including neurons, astrocytes, neural progenitor cells, microglia and oligodendrocyte-lineage cells across neurodegenerative ailments such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. This review discusses the findings of pre-clinical and clinical studies which suggest that senescence-associated features may contribute to neurodegeneration. Further, it provides an overview of the biomarkers used in the identification of senescence in the CNS. Also, the review examines senotherapeutic treatment approaches, highlighting their actions on different CNS cell types and the growing clinical evidence. It also points out the challenges in translating these approaches to clinical application, such as targeting specific cell types and the lack of suitable biomarkers. Collectively, present findings suggest that senescence-associated alterations may contribute to neurodegeneration, although their effects appear to vary across cell types and diseases.},
}

@article {pmid42918426,
year = {2026},
author = {Kipanyula, MJ},
title = {Neurodegeneration in Sub-Saharan Africa: Intersections of Biological Ageing, Genomic Diversity and the Lifetime Exposome.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103429},
doi = {10.1016/j.arr.2026.103429},
pmid = {42918426},
issn = {1872-9649},
abstract = {Neurodegenerative diseases are emerging as an important consequence of population ageing in sub-Saharan Africa (SSA), but their scientific relevance extends beyond a projected rise in case numbers. SSA combines exceptional human genomic diversity with marked heterogeneity in vascular and metabolic risk, infection, nutrition, occupational exposures, air pollution, and access to health care. This combination creates an underused setting in which to study why biological ageing produces neurodegeneration in some individuals but relative resilience in others. This review critically synthesises evidence on Alzheimer's disease and related dementias, Parkinson's disease, amyotrophic lateral sclerosis/frontotemporal degeneration, Huntington's disease and related disorders, focusing on the intersection between hallmarks of ageing, disease-specific proteinopathies, ancestry and the lifetime exposome. Age-associated loss of proteostasis, mitochondrial dysfunction, impaired autophagy, chronic inflammation, neurovascular injury and genomic/epigenomic instability provide a mechanistic scaffold on which genetic susceptibility and cumulative exposures may act. Yet African evidence remains dominated by cross-sectional clinical phenotyping; neuropathology, longitudinal biomarkers, multi-omics and measured environmental exposures remain sparse. Recent African-ancestry Parkinson's disease genomics and emerging plasma biomarker studies demonstrate that ancestry-inclusive molecular neuroscience is feasible and can generate findings not predictable from European-ancestry datasets. The next phase should therefore move beyond documenting underdiagnosis toward longitudinal, biologically anchored cohorts that integrate phenotype, genomics, blood biomarkers, neuroimaging, exposomics, digital measures and health-system outcomes. This review proposes a research framework centred on biological ageing, gene-environment interaction and resilience. Such work would improve the validity of prevention, diagnosis and therapeutic translation in African populations while contributing globally to a more complete biology of neurodegenerative ageing.},
}

@article {pmid42902402,
year = {2026},
author = {Ufer, F and Rössling, R and Spottke, A and Németh, R and Schaprian, T and Coninck, NK and Gamez, A and Sterl, R and Naumann, P and Behr, N and Maier, A and Meyer, T and Weydt, P and Prüss, H},
title = {ABCD-Trial: study protocol for a randomized, double-blind, placebo-controlled study in patients with Amyotrophic lateral sclerosis for the evaluation of efficacy and safety of B-Cell Depletion with rituximab (ABCD).},
journal = {Trials},
volume = {27},
number = {1},
pages = {},
pmid = {42902402},
issn = {1745-6215},
mesh = {Humans ; *Rituximab/therapeutic use/adverse effects ; *Amyotrophic Lateral Sclerosis/drug therapy/immunology/diagnosis ; Double-Blind Method ; *B-Lymphocytes/drug effects/immunology ; Male ; Treatment Outcome ; Female ; Randomized Controlled Trials as Topic ; Disease Progression ; *Lymphocyte Depletion/methods/adverse effects ; *Immunologic Factors/adverse effects/therapeutic use ; Time Factors ; Middle Aged ; },
abstract = {BACKGROUND: The exact disease-causing mechanisms in ALS remain incompletely understood. A possible cause is inflammation of neurons. Compared to other neurodegenerative diseases, neuroinflammation is pronounced in ALS, presumably leading to disease progression and neuronal death. Patients with ALS can have neuronal autoantibodies and most notably antibody-producing cells in the cerebrospinal fluid. The CD20-binding therapeutic antibody rituximab targets these antibody-producing B-cells. Rituximab is a medication commonly used in neurology. Single patients with ALS have already been treated with rituximab, which was well tolerated. We therefore want to evaluate safety and efficacy of a treatment with rituximab in ALS patients in a double-blind placebo-controlled trial. With this trial we aim for slower disease progression and unveiling disease-causing mechanisms in ALS.

METHODS: A total of 52 male and female patients older than 18 years with active sporadic ALS and disease duration of less than 24 months who are on a stable dose of riluzole (50 mg BID) should be included. Patients requiring assisted ventilation of any kind or have a known intolerance to the study medication rituximab are excluded. The study medication rituximab or placebo should be administered over a period of 52 weeks at 4 distinct time points, followed by a follow-up period of 79 weeks with 4 visits. Treatment efficacy should be evaluated using the ALS functioning scale ALSFRS-R-SE at every study visit (except safety visits). Safety will be assessed through regular laboratory analyses, adverse event (AE) and serious adverse event (SAE) monitoring, and CD20+ B-cell kinetics. The primary endpoint is the change in the ALS Functional Rating Scale-Revised (ALSFRS-R-SE) from baseline to week 79. Trial sites will be at Charité/DZNE Berlin and DZNE Bonn.

DISCUSSION: ALS is a rapidly progressive neurodegenerative disease with limited treatment options. Recent preclinical in vivo studies suggest that B-cell-mediated autoimmunity contributes to disease progression. This trial will evaluate whether rituximab, which specifically depletes CD20+ B-cells, can slow ALS progression and provide insights into disease mechanisms.

TRIAL REGISTRATION: The trial was registered in the German WHO-recognized primary register Deutsches Register Klinische Studien DRKS (German Clinical Trials Register) on 3/07/2023 under registration number DRKS00030948.},
}

Humans
*Rituximab/therapeutic use/adverse effects
*Amyotrophic Lateral Sclerosis/drug therapy/immunology/diagnosis
Double-Blind Method
*B-Lymphocytes/drug effects/immunology
Male
Treatment Outcome
Female
Randomized Controlled Trials as Topic
Disease Progression
*Lymphocyte Depletion/methods/adverse effects
*Immunologic Factors/adverse effects/therapeutic use
Time Factors
Middle Aged

@article {pmid42902541,
year = {2026},
author = {Purvis, C and Patterson, EL and Burns, EE},
title = {Characterizing geographic diversity of acetolactate synthase resistance in US johnsongrass (Sorghum halepense) biotypes.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.71430},
pmid = {42902541},
issn = {1526-4998},
support = {//United Soybean Board/ ; },
abstract = {BACKGROUND: Acetolactate synthase (ALS)-inhibiting herbicides are widely used for Sorghum halepense weed control across agroecosystems. However, little is known about variation in resistance phenotypes and mechanisms among geographically diverse biotypes. This study surveyed S. halepense biotypes collected across the USA to quantify resistance to ALS inhibitors, identify target and non-target site mechanisms, and evaluate alternative herbicide options.

RESULTS: Dose response assays identified nicosulfuron resistance in 24% of evaluated biotypes, with resistant biotypes ED50 ranging from 66 to >4160 g ha[-1]. Among nicosulfuron resistant biotypes, 56% and 44% were also resistant to imazethapyr and thiencarbazone, respectively, demonstrating variability in resistance patterns among ALS herbicides of different chemical families. A novel primer set enabled simultaneous screening of all reported ALS resistance mutations across both ALS homeologs. Molecular screening identified the Trp574 substitution as the sole target-site resistance mechanism in 64% of resistant biotypes. Further, Trp574 mutation frequency varied among resistant biotypes, ranging from 21% to 91%, and was positively correlated with nicosulfuron resistance level. Resistant biotypes lacking target-site mutations exhibited over eightfold reductions in nicosulfuron ED50 following malathion pretreatment, suggesting involvement of cytochrome P450 non-target site resistance mechanisms. Despite the identification of these mechanisms, glyphosate and clethodim remained effective for S. halepense control in all but one biotype.

CONCLUSION: Overall, we demonstrated that ALS resistance in S. halepense varies across geographically diverse biotypes from the USA. Together, these findings provide important insight for resistance evolution and support development of management strategies for ALS resistant S. halepense biotypes. © 2026 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.},
}

@article {pmid42904191,
year = {2026},
author = {Quy, K and Doan, AT and Vu, TM and Nguyen, TM and Nguyen, D},
title = {Lower Motor Neuron Disease Misclassified As Inflammatory Myopathy in a Young Woman With Myositis-Specific Antibodies.},
journal = {Cureus},
volume = {18},
number = {9},
pages = {e116583},
pmid = {42904191},
issn = {2168-8184},
abstract = {A 30-year-old woman presented with slowly progressive neck and proximal limb weakness over three years. Initial evaluation showed moderate creatine kinase elevation, anti-Mi-2β and anti-glycyl-tRNA synthetase (EJ) positivity, and electrophysiological and muscle biopsy findings interpreted as inflammatory myopathy. She was diagnosed with polymyositis and received multiple immunosuppressive therapies without clinical improvement. Despite normalization of creatine kinase, weakness and muscle wasting progressed. Re-evaluation revealed profound generalized atrophy, hyporeflexia, widespread limb and tongue fasciculations, and preserved sensation. Nerve conduction studies showed markedly reduced motor amplitudes with relative preservation of sensory responses, while repeat muscle biopsy demonstrated severe chronic neurogenic atrophy. Genetic testing identified a heterozygous FIG4 p.Arg197Cys variant of uncertain significance. Lower motor neuron dysfunction was demonstrated in multiple anatomical regions, and the overall clinical and electrophysiological findings were consistent with the Gold Coast diagnostic framework for amyotrophic lateral sclerosis with a lower-motor-neuron-predominant phenotype. Immunosuppression was withdrawn, weakness continued to progress, and mechanical ventilation was required approximately six months later. This case highlights the need to reconsider the diagnosis when presumed inflammatory myopathy progresses despite biochemical improvement and adequate immunosuppressive therapy, particularly when neurogenic features emerge.},
}

@article {pmid42904327,
year = {2026},
author = {Paquet, A and Touzel-Deschênes, L and Roy, V and Brisson, JD and Mathieu, J and Dupré, N and Saikali, S and Gros-Louis, F},
title = {Cytoplasmic TDP-43 Accumulation in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-7},
doi = {10.1017/cjn.2026.10695},
pmid = {42904327},
issn = {0317-1671},
abstract = {BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare, early-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, spasticity and peripheral neuropathy. It is caused by biallelic mutations in the SACS gene, which encodes sacsin, a large protein involved in cytoskeletal organization and mitochondrial homeostasis, and protein quality control. Despite advances in understanding sacsin biology, the molecular mechanisms underlying neurodegeneration in ARSACS remain incompletely understood. Here, we report the first neuropathological evidence of pathological TAR DNA-binding protein 43 (TDP-43) accumulation in ARSACS.

METHODS: Available postmortem brain tissue from a genetically confirmed ARSACS patient homozygous for the Quebec founder mutation (SACS c.8844delT) was analyzed by immunohistochemistry, immunofluorescence and biochemical fractionation.

RESULTS: Neurons in the prefrontal cortex, motor cortex and cerebellum exhibited cytoplasmic phosphorylated dot-like TDP-43 (pTDP-43) aggregates with reduced nuclear localization. Biochemical fractionation further identified detergent-insoluble TDP-43 species in ARSACS tissue. Additional pathological features included increased neurofilament accumulation, vacuole-like neuronal changes, Purkinje cell loss and p62-positive cytoplasmic inclusions. Similar dot-like cytoplasmic pTDP-43 aggregates were observed in a second ARSACS case.

CONCLUSION: These findings identify pTDP-43 as a previously unrecognized pathological feature of ARSACS. While the patient exhibited no clinical or histopathological signs of amyotrophic lateral sclerosis, the presence of atypical pTDP-43 aggregates observed in ARSACS may represent a rare, secondary, early-stage or potentially underrecognized manifestation of TDP-43 pathology rather than a defining hallmark of the disease. Further studies in additional patients and experimental ARSACS models will be required to determine the prevalence and mechanistic basis of TDP-43 abnormalities in this disorder.},
}

@article {pmid42904407,
year = {2026},
author = {Dalkvist, M and Ersson, K and Bergström, S and Ekström, M and Emilsson, ÖI and Grote, L and Ingre, C and Kläppe, U and Lundström, S and Nygren, I and Sundh, J and Palm, A},
title = {End-of-life care of patients with amyotrophic lateral sclerosis and home mechanical ventilation: the national population-based DISCOVERY study.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/21678421.2026.2747563},
pmid = {42904407},
issn = {2167-9223},
abstract = {Background: Home mechanical ventilation (HMV), including noninvasive ventilation (NIV) and invasive ventilation (IV), is increasingly used in people with amyotrophic lateral sclerosis (pwALS), but its impact on end-of-life care remains unclear. Objective: To examine whether ventilation pathway (NIV or IV) influences symptom prevalence and relief during the final week of life in pwALS. Secondary objectives were to assess end-of-life discussions, place and cause of death, and anticipated death. Methods: This national, population-based retrospective cohort study included pwALS using HMV in the Swedish National Quality Registry for Respiratory Failure (Swedevox), cross-linked with the Swedish Register of Palliative Care, which contains staff-reported end-of-life data, and other national registries. Results: Among 652 pwALS, 609 received NIV (mean age 66 years, 42% female) and 43 IV (mean age 60 years, 42% female). Anxiety and breathlessness were more common in the NIV group (76% vs 48% and 72% vs 31%, both p < 0.001), while prevalence and relief of other symptoms were similar between groups. Most patients had end-of-life discussions (NIV 87%, IV 92%). NIV patients more often died in specialized palliative wards (22% vs 7%, p = 0.023). Most deaths were due to ALS (96%) and were anticipated (NIV 94%, IV 88%). Conclusions: In pwALS with HVM, NIV was associated with higher rates of anxiety and breathlessness in the final week of life, but the ventilation pathway did not influence overall symptom relief. End-of-life communications and cause of death were similar; place of death differed by ventilation pathway; however, most deaths were anticipated.},
}

@article {pmid42904859,
year = {2026},
author = {Zhang, L and Zhang, L and Zheng, Y and Zhuang, Z and Tang, L and Zheng, W and Xia, K and Ye, S and Yin, T and Huang, T and Fan, D},
title = {Plasma Lipidome Is Dysregulated in Amyotrophic Lateral Sclerosis and Associated With Life-Course Adiposity Polygenic Risk.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {17},
number = {5},
pages = {e70410},
doi = {10.1002/jcsm.70410},
pmid = {42904859},
issn = {2190-6009},
support = {82101490//National Natural Science Foundation of China/ ; 81873784//National Natural Science Foundation of China/ ; 82071426//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; //National Clinical Key Specialty Construction Program of China (2024)/ ; //Peking University Clinical Scientist Training Program/ ; 20250824//Young Elite Scientists Sponsorship Program of the Beijing High Innovation Plan/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics ; *Adiposity/genetics ; Female ; *Lipidomics/methods ; Genetic Risk Score ; Male ; Middle Aged ; Genetic Predisposition to Disease ; *Lipids/blood ; Lipid Metabolism ; Aged ; Risk Factors ; Biomarkers ; *Multifactorial Inheritance ; },
abstract = {OBJECTIVE: Although both pre-symptomatic adiposity and dysregulated lipid metabolism are implicated in amyotrophic lateral sclerosis (ALS), the mechanistic pathways linking adiposity to disease remain unclear. This study aimed to investigate how genetic predisposition to adiposity might influence ALS through specific lipid metabolic pathways.

METHODS: We conducted mass spectrometry-based quantitative lipidomics on plasma from 104 ALS patients and 78 age- and sex-matched controls. Life-course adiposity polygenic risk scores (PRS) for birth weight, body fat percentage, appendicular lean mass and whole-body fat-free mass were constructed. Associations and PRS-by-disease interaction effects on the lipidome were evaluated.

RESULTS: Compared to controls, ALS patients exhibited widespread lipid dysregulation. Seventy-eight lipid species were significantly altered (FDR  < 0.05, |Cohen's d| > 1.0), characterized by a predominant decrease in acylcarnitines (75% of species) and distinct shifts within sphingolipid and glycerophospholipid subclasses. A three-acylcarnitine candidate panel (C10:0, C12:0 and C18:2) using fivefold analysis with feature selection repeated within each training fold yielded an overall out-of-fold AUC of 0.958. Exploratory PRS-by-disease-status analyses identified 16 nominal interaction signals, including 13 acylcarnitines; no significant mediation effect of lipids between PRS and ALS risk was detected.

CONCLUSION: These findings identify robust ALS-associated plasma lipid alterations, and our exploratory findings suggest that genetic predisposition to adiposity may shape the pattern of lipid metabolic disruption in ALS, offering new insights into the disease's metabolic pathophysiology.},
}

Humans
*Amyotrophic Lateral Sclerosis/blood/genetics
*Adiposity/genetics
Female
*Lipidomics/methods
Genetic Risk Score
Male
Middle Aged
Genetic Predisposition to Disease
*Lipids/blood
Lipid Metabolism
Aged
Risk Factors
Biomarkers
*Multifactorial Inheritance

@article {pmid42905162,
year = {2026},
author = {Stapf, CD and Uzelac, Z and Iterbeke, L and Guthknecht, A and Barba, L and Strube, D and Kölsch, A and Kleeberg, K and Kendzierski, T and Roos, A and Steinacker, P and Abu-Rumeileh, S and Claeys, KG and Weishaupt, J and Mensch, A and Otto, M},
title = {Serum p-tau181 and p-tau217 levels in adolescents and adults with 5q spinal muscular atrophy.},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {42905162},
issn = {1432-1459},
support = {Clinician Scientist Programme n. CS25/01//Medical Faculty of Martin-Luther-University Halle-Wittenberg/ ; Clinician Scientist Programm No. CS22/06//Medical Faculty of Martin-Luther-University Halle-Wittenberg/ ; Clinician Scientist Programm No. CS26/01//Medical Faculty of Martin-Luther-University Halle-Wittenberg/ ; FTLDc 01GI1007A//German Federal Ministry of Education and Research/ ; D.3830//foundation of the state Baden-Württemberg/ ; },
mesh = {Humans ; Female ; *tau Proteins/blood ; Male ; Adolescent ; Biomarkers/blood ; Retrospective Studies ; Adult ; *Muscular Atrophy, Spinal/blood/drug therapy/physiopathology ; Middle Aged ; Phosphorylation ; Young Adult ; Amyotrophic Lateral Sclerosis/blood ; Alzheimer Disease/blood ; *Spinal Muscular Atrophies of Childhood/blood ; Aged ; Longitudinal Studies ; },
abstract = {BACKGROUND: Reliable blood biomarkers for longitudinal monitoring in adolescent and adult 5q spinal muscular atrophy (SMA) are lacking. Phosphorylated tau (p-tau) species are elevated in serum in amyotrophic lateral sclerosis (ALS), where they may reflect peripheral nerve and muscle pathology. We aimed to investigate serum p-tau181 and p-tau217 as longitudinal biomarkers in adolescent and adult SMA and assessed associations with clinical parameters.

METHODS: In this retrospective multi-centre study, we assessed serum p-tau181 and p-tau217 levels in adults with 5q SMA under treatment with nusinersen or risdiplam, comparing levels with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and non-neurodegenerative disease controls. Associations with motor function, respiratory capacity, creatine kinase (CK), and neurofilament light chain (NfL) were assessed using linear mixed-effects models adjusted for age and sex.

RESULTS: Serum p-tau181 was higher in SMA than in disease controls (β = -0.48, 95%-CI -0.81 to -0.15), but lower than in ALS (β = 0.99, 95%-CI 0.58 to 1.39) and AD (β = 0.56, 95%-CI 0.11 to 1.00). P-tau181 declined from baseline to FUP2 (Δ median -1.80 pg/mL, IQR -5.90 to 2.10); p-tau217 showed no longitudinal change. P-tau181 and p-tau217 were positively associated with motor function, functional status, respiratory capacity, and CK, with no association with NfL. In exploratory analyses, higher baseline p-tau181 was associated with greater HFMSE decline (β = 1.79, 95%-CI 0.59 to 2.99).

CONCLUSIONS: Serum p-tau181 and p-tau217 appear to reflect ongoing muscle turnover in adult SMA, declining as muscle mass decreases. Higher baseline p-tau181 was associated with subsequent functional deterioration, suggesting potential utility as a biomarker of active denervation and disease monitoring.},
}

Humans
Female
*tau Proteins/blood
Male
Adolescent
Biomarkers/blood
Retrospective Studies
Adult
*Muscular Atrophy, Spinal/blood/drug therapy/physiopathology
Middle Aged
Phosphorylation
Young Adult
Amyotrophic Lateral Sclerosis/blood
Alzheimer Disease/blood
*Spinal Muscular Atrophies of Childhood/blood
Aged
Longitudinal Studies

@article {pmid42905245,
year = {2026},
author = {Nowell, WB and McGale, N and Levy, O and Przydzial, K and Patel, N and Cleanthous, S and Andrews, JA and Rofail, D},
title = {Understanding Holistic Patient-Relevant Measurement in Amyotrophic Lateral Sclerosis: A Mixed-Methods Content Validity and Exploratory Rasch Analysis of Selected Clinical Outcome Assessments.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {42905245},
issn = {2193-8253},
abstract = {INTRODUCTION: Living with amyotrophic lateral sclerosis (ALS) has a profound impact on function and health-related quality of life (HRQoL). This mixed-methods study aimed to cognitively debrief selected ALS outcome measures to investigate their relevance and conduct exploratory Rasch Measurement Theory (RMT) analyses to assess targeting.

METHODS: Semi-structured interviews were conducted (January-September 2024) with people living with ALS (PLwALS) and clinicians to cognitively debrief selected patient- and clinician-reported outcome (PRO and ClinRO) measures. The PRO measures debriefed with PLwALS were Rasch Overall ALS Disability Scale (ROADS), 5-item ALS Assessment Questionnaire (ALSAQ-5), and Neurological Fatigue Index for Motor Neurone Disease (NFI-MND). ROADS and ClinRO ALS Functional Rating Scale-Revised (ALSFRS-R) were debriefed with clinicians. Interview transcripts were qualitatively analyzed; structured codes were used to compile data on item relevance and comprehensiveness. Exploratory RMT analysis was conducted using quantitative data from PLwALS responses to evaluate selected PRO psychometric properties.

RESULTS: Qualitative analysis of interviews with 31 PLwALS found that PROs were meaningful and relevant, and identified the relevance of individual items. Clinicians (n = 10) endorsed ALSFRS-R as a relevant and meaningful measure, and supported ROADS' conceptual coverage and response category. RMT analysis indicated evidence of good targeting, reliability, and item fit for the PROs, with some exceptions for ALSAQ-5.

CONCLUSION: This study supports the use of ALSFRS-R, ROADS, ALSAQ-5, and NFI-MND to measure meaningful aspects of ALS, with support for ALSAQ-5 qualified by its limited measurement precision. Scores from these measures can provide important insights into the lived experience of PLwALS, characterizing disease progression and HRQoL.},
}

@article {pmid42905272,
year = {2026},
author = {Tahedl, M and Toomey, A and Mandal, N and Mangan, S and Siah, WF and Tan, EL and Hardiman, O and Kleinerova, J and McKenna, MC and Hutchinson, S and Lope, J and Bede, P},
title = {Neurotransmitter-defined cerebral vulnerability patterns in frontotemporal lobar degeneration (FTLD).},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {42905272},
issn = {1432-1459},
support = {HRB JPND-Cofund-2025-3/HRBI_/Health Research Board/Ireland ; JPND - 2025 "Qual-Bulb-MND"//EU Joint Programme - Neurodegenerative Disease Research/ ; SFI SP20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; },
mesh = {Humans ; Female ; *Neurotransmitter Agents/metabolism ; Male ; *Frontotemporal Lobar Degeneration/diagnostic imaging/pathology/metabolism ; Middle Aged ; Aged ; Magnetic Resonance Imaging ; Atrophy ; Prospective Studies ; *Brain/diagnostic imaging/metabolism/pathology ; },
abstract = {BACKGROUND: Frontotemporal dementia syndromes encompass a genetically, clinically and radiologically heterogeneous set of conditions with distinctive clinical and imaging characteristics. The main FTD phenotypes exhibit strikingly different disease burden patterns with a predilection to specific brain regions and relative sparing of others. The apparent selectivity of cerebral involvement in FTD has not been fully elucidated.

METHODS: A prospective neuroimaging study has been undertaken with a uniform imaging protocol to characterise atrophy patterns in ALS-FTD, behavioural variant FTD, nonfluent variant primary progressive aphasia, and semantic variant primary progressive aphasia and evaluate associations with physiological neurotransmitter receptor expression maps. Anatomical correlations between focal volume loss and a large panel of neurotransmitters were systematically evaluated and associations ranked.

RESULTS: Associations were noted with GABAergic, opioid, cannabinoid, microglial and acetylcholine systems in ALSFTD-C9NEG. Correlations were observed with opioid, glutaminergic, and synaptic vesicle glycoprotein 2A receptor populations in ALSFTD-C9POS. Atrophy in bvFTD showed predilection to serotonergic, glutaminergic, opioid, GABAergic and cannabinoid circuits. Volume loss in nfvPPA colocalised with GABAergic, opioid, microglial, serotonergic, cannabinoid, acetylcholine, glutaminergic and dopaminergic networks. A multitude of neurotransmitter populations are implicated in svPPA including opioid, serotonergic, GABAergic, dopaminergic, and microglial systems.

DISCUSSION: The distinctive neuroimaging signatures of FTD phenotypes exhibit spatial associations with physiological neurotransmitter receptor density maps. The propensity of atrophy to specific brain regions in FTD subtypes may be defined by neurotransmitter populations. Our findings indirectly support the notion of neurotransmitter-system defined connectivity-based disease propagation in FTD.},
}

Humans
Female
*Neurotransmitter Agents/metabolism
Male
*Frontotemporal Lobar Degeneration/diagnostic imaging/pathology/metabolism
Middle Aged
Aged
Magnetic Resonance Imaging
Atrophy
Prospective Studies
*Brain/diagnostic imaging/metabolism/pathology

@article {pmid42905535,
year = {2026},
author = {Cheung, SW and Fogarty, MJ},
title = {Molecular signatures of selective motor neuron vulnerability in old age.},
journal = {Experimental physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/EP094279},
pmid = {42905535},
issn = {1469-445X},
support = {R01 AG086136/NH/NIH HHS/United States ; },
abstract = {Motor neuron (MN) death and impairment of fast-fatigable motor units is widely recognized in elderly humans and rats. However, the molecular signatures identifying vulnerable MNs remains underexplored. In murine models of amyotrophic lateral sclerosis, matrix metalloproteinase 9 (MMP-9) and chondrolectin (Chodl) decline with disease progression and have been considered molecular markers of fast-fatigable MNs. However, their expression in brainstem and lumbar MNs, in accordance with the 'size principle' (in which motor units are recruited in a size-dependent manner, with MNs of lower capacitance activated before those of greater capacitance) and their expression throughout the lifespan remain unclear. Here, we evaluated MMP-9 and Chodl in lumbar and hypoglossal MNs in young (6 months) and old (24 months) Fischer 344 (F344) rats. Longitudinal lumbar spinal cord transverse brainstem sections (the orientations providing maximal MN somal sizes for each pool) were immunolabelled for choline acetyltransferase, MMP-9 and Chodl. Expression was quantified using confocal microscopy in young and old rats (n = 5 females, n = 5 males per age). Overall, MMP-9 demonstrated a positive association with lumbar MN somal surface area in young rats. Paired within-animal analysis showed that in larger MNs, MMP-9 positivity was ∼70% greater than smaller MNs. The size-dependence of MMP-9 expression was absent in old lumbar MNs, suggesting either selective loss or downregulation of MMP-9 MN expression in ageing. No size-dependent change in Chodl was observed in lumbar or hypoglossal MNs, nor was MMP-9 associated with MN size in hypoglossal MNs. Collectively, these findings identify MMP-9 as a marker enriched within large lumbar MNs in young rats and suggest that age-related alterations in MMP-9 expression may reflect the selective vulnerability of the lumbar MNs.},
}

@article {pmid42901819,
year = {2026},
author = {Obara, K and Janelidze, S and Ito, D and Karlsson, L and Yamamoto, M and Mastrangelo, A and Tran, S and Tsujikawa, K and Nishio, Y and Ogi, T and Vacchiano, V and Liguori, R and Nakamura, R and Atsuta, N and Sobue, G and Nilsson, C and Parchi, P and Katsuno, M and Mattsson-Carlgren, N},
title = {Cerebrospinal fluid amyloid and neurodegeneration biomarkers in the diagnosis and prognosis of amyotrophic lateral sclerosis: a multicohort observational study.},
journal = {EBioMedicine},
volume = {},
number = {},
pages = {106511},
doi = {10.1016/j.ebiom.2026.106511},
pmid = {42901819},
issn = {2352-3964},
abstract = {BACKGROUND: Neurofilament light chain (NfL) is an established biomarker for amyotrophic lateral sclerosis (ALS). However, it remains unclear whether biomarkers reflecting amyloid-β metabolism (Aβ), tau (phosphorylated tau, pTau), and astrogliosis (glial fibrillary acidic protein, GFAP) can complement NfL in clinical applications. It is also unclear how Alzheimer's disease (AD) co-pathology affects disease progression in ALS.

METHODS: We studied 264 patients with ALS and 164 disease-control participants, analysing baseline cerebrospinal fluid (CSF) NfL, Aβ peptides, pTau181, pTau217, and GFAP. A two-step diagnostic strategy was examined in individuals with intermediate NfL values, using machine-learning models. Prognostic associations were evaluated using linear mixed-effects and Cox models adjusted for established predictors; survival was additionally examined in pooled analyses including an external ALS cohort (n = 153).

FINDINGS: Patients with ALS exhibited higher CSF NfL, Aβ38, Aβ40, Aβ42, pTau181, and pTau217 than controls, even within Aβ-negative subgroups. NfL discriminated ALS from controls with an AUC of 0.85 (0.82-0.88), which increased to 0.90 (0.88-0.92) in machine-learning models incorporating additional biomarkers. The machine-learning models maintained a high positive predictive value (0.90) for classifying cases with intermediate NfL values. Significant Aβ × NfL interactions were observed for longitudinal functional decline, and pooled survival analyses showed stronger associations between NfL and survival in the Aβ-positive ALS subgroup (14%) than in the Aβ-negative ALS subgroup (HR 4.02 [2.17-7.45] vs 1.62 [1.36-1.92]).

INTERPRETATION: Multiple biomarker assessments can reduce misclassification of individuals with intermediate NfL values. CSF Aβ positivity modified the association between baseline NfL and disease progression. Personalised diagnosis and prognosis based on fine-grained co-pathology evaluation may enhance clinical management of ALS.

FUNDING: This study was primarily supported by JST SPRING (JPMJSP2125). A complete list of funding organisations is provided in Acknowledgements.},
}

@article {pmid42901869,
year = {2026},
author = {Su, WM and Duan, QQ and Zhang, N and He, SY and Liu, RY and Wen, XJ and Gu, XJ and Wang, Y and Cao, B and Chen, YP},
title = {Plasma Proteomic Signatures Predict Incident Amyotrophic Lateral Sclerosis: A Prospective Study Stratified by C9orf72 Expansion.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {17},
number = {5},
pages = {e70405},
pmid = {42901869},
issn = {2190-6009},
support = {82371422//the National Natural Science Fund of China/ ; 2026NSFSC0510//the Science and Technology Bureau Fund of Sichuan Province/ ; 2022YFC2703101//the National Key Research and Development Program of China/ ; 2023HXFH032//the 1·3·5 project for disciplines of excellence Clinical Research Fund, West China Hospital, Sichuan University/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/epidemiology/diagnosis ; *C9orf72 Protein/genetics ; Prospective Studies ; *Proteomics/methods ; Male ; Female ; Biomarkers/blood ; Middle Aged ; Aged ; Incidence ; DNA Repeat Expansion ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder for which reliable preclinical biomarkers to predict disease onset are currently lacking. Plasma proteomics offers a promising avenue for early detection. The identification of plasma proteins and pathways associated with incident ALS holds potential to improve early diagnosis, enable risk stratification and provide insights into disease mechanisms.

METHODS: Employing the Olink Explore platform, we quantified 2920 plasma proteins within a prospective cohort of UK Biobank participants. Multivariate Cox proportional hazards regression was utilized to identify proteins associated with incident generalized ALS, C9-ALS (C9orf72-associated ALS) and non-C9-ALS. Enrichment analysis was conducted to delineate the biological pathways implicated by the identified proteins. Associations between plasma protein levels and the age at onset (AAO) of ALS were assessed via linear regression, while a multivariate Cox model was employed to evaluate the relationships between protein levels and ALS survival. We subsequently assessed potential causal relationships using Mendelian randomization (MR) and colocalization and analysed protein cross-sectional temporal patterns in ALS.

RESULTS: In this prospective cohort study, we followed 52 584 participants from the UK Biobank for a mean of 11.8 years. During this period, 291 (0.55%) incident cases of ALS were identified, among whom 34 individuals carried the C9orf72 hexanucleotide repeat expansion mutation. Nine proteins demonstrated associations with all-type ALS risk (FDR < 0.05): NEFL (HR: 2.897), CSRP3 (HR: 1.233), MYBPC1 (HR: 1.352), MEGF10 (HR: 1.744), MYOM3 (HR: 1.289) and THBS4 (HR: 1.570) were identified as risk factors, whereas EGFLAM (HR: 0.402), ITGAV (HR: 0.284) and CD248 (HR: 0.573) exhibited protective effects. NEFL (HR: 2.742) and three additional proteins were primarily associated with non-C9-ALS, while only NEFL (HR: 4.403) and COL5A1 (HR: 3.072) showed significant associations with C9-ALS. When combined with age and sex, these proteins yielded area under the curve (AUC) values exceeding 0.750 for predicting ALS at 3, 5 and 10 years. Furthermore, elevated NEFL levels were correlated with an earlier onset of non-C9-ALS and began to increase approximately 9.27 years prior to diagnosis, reaching a peak 1-2 years before clinical presentation in non-C9ALS cases via cross-sectional temporal analysis. Pathway analysis implicated muscle-related, extracellular matrix, energy metabolism and inflammatory pathways.

CONCLUSIONS: This investigation uncovers extensive alterations in plasma proteins associated with ALS risk, revealing potential novel biomarkers for both sporadic and C9orf72-linked forms of the disease. These results enhance our comprehension of early ALS pathogenesis and provide a foundation for subsequent biomarker identification and the development of targeted therapeutic strategies.},
}

Humans
*Amyotrophic Lateral Sclerosis/blood/genetics/epidemiology/diagnosis
*C9orf72 Protein/genetics
Prospective Studies
*Proteomics/methods
Male
Female
Biomarkers/blood
Middle Aged
Aged
Incidence
DNA Repeat Expansion

@article {pmid42896458,
year = {2026},
author = {Ozawa, M and Yoshimaru, D and Ishii, K and Okano, HJ and , },
title = {Data-driven progression trajectories across clinical subtypes of amyotrophic lateral sclerosis.},
journal = {Journal of the neurological sciences},
volume = {491},
number = {},
pages = {126224},
doi = {10.1016/j.jns.2026.126224},
pmid = {42896458},
issn = {1878-5883},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) exhibits substantial clinical heterogeneity; however, conventional classifications based on the predominant site of involvement may not fully capture patterns of disease progression. This study aimed to identify data-driven subtypes of ALS and reconstruct their temporal progression using item-level scores from the ALS Functional Rating Scale-Revised (ALSFRS-R).

METHODS: Baseline data from 3067 participants in the Pooled Resource Open-Access ALS Clinical Trials database were analyzed. Subtype and Stage Inference (SuStaIn) was applied to ALSFRS-R item scores to identify subtypes and infer their progression trajectories. Internal consistency was evaluated using complexity and sensitivity analyses. Longitudinal stability was assessed at 180 and 365 days. Associations with functional decline and survival were examined using adjusted statistical models.

RESULTS: Three clinically interpretable subtypes were identified, characterized by predominant upper-limb, lower-limb, or bulbar involvement. These subtypes exhibited distinct, consistent progression patterns across the analyses. Subtype stability was moderate short-term but limited longer-term; stage progression was largely monotonic. The bulbar subtype showed more rapid functional decline at both 180 and 365 days. Higher SuStaIn stage was associated with increased mortality. In an exploratory stage-stratified analysis, poorer survival was observed in the bulbar subtype than in the upper-limb subtype within the lower-stage group.

CONCLUSIONS: This study reconstructed ALS subtype-specific functional progression trajectories and inferred disease stage using a widely accessible clinical scale. SuStaIn-derived subtypes characterized patterns of functional heterogeneity, and higher stage was associated with increased mortality. Further prospective comparative validation is needed to establish the prognostic and clinical utility of this framework.},
}

@article {pmid42896567,
year = {2026},
author = {Gorenshtein, A and Adiniaev, Y and Liba, T and Barash, Y and Klang, E and Daniel, O},
title = {The calibration-to-accuracy mapping in P300 spellers does not transport across cohorts and was not restored by tested alignment or local recalibration.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/aeb62c},
pmid = {42896567},
issn = {1741-2552},
abstract = {Objective A calibration-derived score has been related to online P300-speller accuracy in the same session, always within the cohort measured. We evaluated whether a mapping from that score to expected accuracy transports to withheld cohorts. Approach Retrospective secondary analysis of BigP3BCI 1.0.0, the largest evaluation of this relationship to date: 18 of 20 studies contributed 271 participants, 739 session-condition records, and 19,611 character selections. The predictor was a decoder's cross-validated discriminability on calibration epochs, one study withheld from development. Between-cohort variation was summarised by the random-effects standard deviation tau. Main Results The association was positive in all 18 cohorts but varied widely (r 0.190 to 0.928; participant-level r = 0.714, p < 0.001), with 12 CIs excluding zero. Pooled estimation error was 0.098 (95% CI 0.091 to 0.107) against a benchmark of 0.146. Calibration did not transport: intercept tau 0.87 (unrepresented-cohort interval -1.97 to 1.85, log-odds); cohort-specific slopes varied more than tenfold (tau 0.43, interval 0.111 to 2.005). Neither alignment (signal- or score-space) nor either nonlinear boundary meaningfully reduced this heterogeneity. Local recalibration with up to 16 participants did not reliably improve on transporting; refitting both intercept and slope was significantly worse than transporting at the smallest sizes. Median time per selection, a stopping-rule proxy, accounted for 66% of between-cohort slope variance in meta-regression. The four ALS cohorts gave an uncorrected slope spread of 0.223, against 0.560 overall. Significance The evaluated score is a classifier's cross-validated discriminability on each session's calibration data rather than the source studies' undocumented online decoder. That score reproducibly signals within-session accuracy, but its mapping to accuracy is cohort-specific and supports ranking sessions after local validation rather than reporting accuracy elsewhere. The four-cohort ALS subgroup appeared more homogeneous than the full archive, illustrating how conclusions about transportability from a small cohort set can be fragile. .},
}

@article {pmid42898978,
year = {2026},
author = {Peng, S and Wang, L and Ouyang, J and Liu, R},
title = {The Role of Astrocytes in the Inflammatory Response in Neurodiseases.},
journal = {MedComm},
volume = {7},
number = {11},
pages = {e71069},
pmid = {42898978},
issn = {2688-2663},
abstract = {Astrocytes have emerged as central regulators of neuroinflammation, extending far beyond their traditional roles as structural and metabolic support cells. In neurological disorders, astrocytes undergo reactive remodeling that encompasses morphological, transcriptional, metabolic, and functional changes. Rather than fitting into a fixed A1/A2 dichotomy, reactive astrocytes exist along a disease-, region-, and stage-dependent continuum shaped by local pathology and intercellular crosstalk. This review summarizes how astrocytes contribute to neuroinflammatory processes in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, central nervous system injury, infection, multiple sclerosis, epilepsy, and autism spectrum disorder. We highlight convergent mechanisms, including cytokine and chemokine release, complement activation, glutamate and ion homeostasis disruption, oxidative stress, metabolic reprogramming, and blood-brain barrier regulation, while emphasizing disease-specific astrocytic programs. We further discuss astrocyte interactions with microglia, neurons, oligodendrocytes, endothelial cells, and peripheral immune cells, as well as key regulatory pathways, epigenetic remodeling, and lipid-dependent metabolic signaling. Finally, we evaluate current and emerging astrocyte-targeted therapeutic strategies, including metabolic modulation, receptor targeting, gene editing, nanodelivery, and gut-brain axis interventions. Defining functionally validated astrocyte states and developing biomarker-guided, stage-adaptive therapies may enable more precise intervention in neuroinflammatory and neurodegenerative diseases.},
}

@article {pmid42899523,
year = {2026},
author = {Campanella, B and Birindelli, L and Legnaioli, S and Lorenzetti, G and Consani, C and Ales, V and Benedetti, E and Bertozzi, MA and Bramanti, E},
title = {Task-Dependent Synergy between FTIR and Raman Spectroscopy for Sperm Quality Prediction.},
journal = {Analytical chemistry},
volume = {98},
number = {41},
pages = {29684-29699},
doi = {10.1021/acs.analchem.6c04960},
pmid = {42899523},
issn = {1520-6882},
mesh = {Humans ; Male ; *Spectrum Analysis, Raman/methods ; Spectroscopy, Fourier Transform Infrared/methods ; *Spermatozoa/cytology ; Sperm Motility ; Semen/chemistry ; Biomarkers/analysis ; *Semen Analysis/methods ; },
abstract = {Male infertility affects approximately 15% of couples worldwide, contributing to 40-50% of infertility cases in Western countries. Standard semen analysis remains the cornerstone of fertility assessment, yet conventional parameters (concentration, motility, morphology) have limited predictive value for fertilization success. Vibrational spectroscopy, particularly Fourier transform infrared (FTIR) and Raman spectroscopy, offers rapid, nondestructive chemical fingerprinting of biological samples. However, optimal strategies for integrating multimodal spectroscopic data remain unclear, and the value of fusion may depend on the biological end point. This study systematically compares FTIR and Raman spectroscopy, both independently and through multiple fusion strategies, for predicting rectilinear progressive sperm motility (binary classification) and normal morphology (continuous regression) in human seminal plasma. We determine whether complementary information exists, when fusion provides value, and which strategy optimally leverages multimodal data. Building on Raman-derived Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) concentration profiles, we further develop a clinical classifier based on four seminal plasma biomarkers (human serum albumin, glutathione S-transferase, transferrin, lysophosphatidylcholine), validated by leave-one-patient-out cross-validation and Firth's penalized logistic regression to address near-complete separation in this small-sample setting (n = 30). Our findings reveal technique-specific advantages: Raman spectroscopy substantially outperforms FTIR for binary motility classification, with feature-level fusion matching but not exceeding Raman's performance, indicating limited complementarity. Conversely, FTIR alone achieves superior predictive accuracy for continuous morphological outcomes. The clinical classifier based on MCR-ALS-derived biomarkers achieved AUC (Area Under the ROC Curve) = 0.855, accuracy = 86.7%, and BER (Balanced Error Rate) = 0.136, with model significance confirmed by permutation testing. Elevated human serum albumin and lysophosphatidylcholine emerged as the strongest negative predictors of high motility, consistent with seminal tract inflammation and sperm-cytotoxic phospholipid accumulation, while transferrin showed a positive association in line with its role in iron availability for sperm function. These results demonstrate that optimal spectroscopic approaches depend on the biological end point, with Raman's structural sensitivity favoring motility assessment and FTIR's compositional profiling better capturing morphological variation. The biomarker-based classifier is easier to interpret and complements whole-spectrum models by bridging chemometric analysis and biological interpretation.},
}

Humans
Male
*Spectrum Analysis, Raman/methods
Spectroscopy, Fourier Transform Infrared/methods
*Spermatozoa/cytology
Sperm Motility
Semen/chemistry
Biomarkers/analysis
*Semen Analysis/methods

@article {pmid42892382,
year = {2026},
author = {Fleshner, L and Chan, R and Klufas, T and Grant-Kels, JM and Zhou, AE},
title = {Reply to Botto et al's "Applicant interview metrics and preference signaling in dermatology: A serial cross-sectional study".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2026.09.134},
pmid = {42892382},
issn = {1097-6787},
}

@article {pmid42892517,
year = {2026},
author = {Xu, Z and Chen, X and Yi, W},
title = {Cryo-EM advances in TDP-43 amyloid fibrils structure determination.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107659},
doi = {10.1016/j.nbd.2026.107659},
pmid = {42892517},
issn = {1095-953X},
abstract = {TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein whose pathological aggregation characterizes a spectrum of neurodegenerative disorders known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and chronic traumatic encephalopathy (CTE). Recent breakthroughs in cryo-electron microscopy (cryo-EM) have revolutionized our understanding of these diseases by resolving the atomic structures of TDP-43 amyloid fibrils. These structural insights have been pivotal in elucidating the transition from functional liquid-liquid phase separation (LLPS) to irreversible solid-state aggregation. This review synthesizes key cryo-EM findings from 2019 to 2026, encompassing fibrils formed by the full-length low-complexity domain, disease-relevant core fragments, and filaments extracted directly from patient tissues, as well as the pathological implications of distinct structural polymorphs. These findings not only deepen our understanding of the brain science aspects of the pathogenesis of TDP-43 proteinopathies, but also provide an important structural basis for the development of specific conformational diagnostic methods and targeted therapeutic drugs.},
}

@article {pmid42894325,
year = {2026},
author = {Shadfar, S and Parakh, S and Perri, E and Jagaraj, CJ and Assar Kashani, S and Beyers, K and Ragagnin, AMG and Laird, AS and Atkin, JD},
title = {Protein disulphide isomerase protects against ALS/FTD phenotypes associated with cyclin F in zebrafish and cellular models.},
journal = {Redox report : communications in free radical research},
volume = {31},
number = {1},
pages = {2732775},
doi = {10.1080/13510002.2026.2732775},
pmid = {42894325},
issn = {1743-2928},
mesh = {Animals ; Zebrafish/metabolism ; *Protein Disulfide-Isomerases/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Cyclins/metabolism/genetics ; Humans ; *Frontotemporal Dementia/metabolism/genetics ; Phenotype ; Mutation ; Animals, Genetically Modified ; Apoptosis ; Endoplasmic Reticulum Stress ; },
abstract = {BACKGROUND: Mutations in CCNF, encoding cyclin F, cause a small proportion of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases. Mutant cyclin F mislocalises from the nucleus to the cytoplasm, impairs the ubiquitin proteasome system, disrupts endoplasmic reticulum (ER) to Golgi transport, and triggers ER stress and apoptosis. Protein disulphide isomerase (PDI), a redox-active ER chaperone of the thioredoxin superfamily, protects against ALS phenotypes induced by mutant SOD1, TDP-43, and FUS, but its activity against mutant cyclin F has not been examined.

OBJECTIVES: To test whether PDI overexpression prevents the cellular and behavioural phenotypes induced by the ALS/FTD-associated cyclin F[S621G] mutation.

METHODS: Neuro-2a cells were co-transfected with mCherry-tagged wild-type or mutant cyclin F[S621G] and V5-tagged PDI or empty vector. Subcellular localisation, XBP-1 and CHOP activation, proteasome reporter (GFPu) accumulation, nuclear morphology, and cleaved caspase-3 immunoreactivity were assessed by confocal microscopy. Transient transgenic zebrafish larvae generated by mRNA co-injection of cyclin F and PDI were assessed by photomotor response at 48 h post-fertilisation.

RESULTS: Mutant cyclin F[S621G] induced cytoplasmic mislocalisation, ER stress (assessed by XBP-1 and CHOP activation), proteasome dysfunction (indicated by GFPu accumulation), and apoptosis (assessed by nuclear condensation and caspase-3 activation), all of which were significantly attenuated by PDI co-expression. Zebrafish larvae expressing cyclin F[S621G] swam significantly shorter distances than uninjected or wildtype controls, and co-expression of PDI restored motor function to near-wildtype levels.

CONCLUSION: PDI protects against ALS/FTD-associated mutant cyclin F in both cellular and in vivo zebrafish models, identifying PDI as a redox-based therapeutic target for CCNF-linked ALS/FTD.},
}

Animals
Zebrafish/metabolism
*Protein Disulfide-Isomerases/metabolism/genetics
*Amyotrophic Lateral Sclerosis/metabolism/genetics
*Cyclins/metabolism/genetics
Humans
*Frontotemporal Dementia/metabolism/genetics
Phenotype
Mutation
Animals, Genetically Modified
Apoptosis
Endoplasmic Reticulum Stress

@article {pmid42894599,
year = {2026},
author = {Naseer, A and Iqbal, N and Bibi, I and Shah, SAR and Khalid, M and Khalid, A},
title = {Molecular recognition of axonal injury-associated candidate hub genes and predicted inhibitors across Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.},
journal = {In silico pharmacology},
volume = {14},
number = {3},
pages = {259},
pmid = {42894599},
issn = {2193-9616},
abstract = {UNLABELLED: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) have converging molecular pathologies such as neuroinflammation, mitochondrial dysfunction, and axonal degeneration, but do not have broadly effective disease-modifying therapies. A novel computational strategy was used in this study with an integrated in-silico pipeline to determine common candidate hub genes across AD, PD, and ALS and to computationally screen candidate inhibitors. The gene expression datasets were retrieved from the Gene Expression Omnibus database and analyzed with limma R package for blood-derived gene expression datasets for AD (GSE63060), PD (GSE99039) and ALS (GSE112680). A multi-dataset intersection analysis revealed 138 genes commonly upregulated and 0 commonly downregulated genes, which were functionally enriched in immune regulation, apoptotic signaling and mitochondrial instability pathways. Protein-protein interaction network analysis identified three key genes (MMP9, PTPN6 and TNFRSF1A) as high-confidence candidate hub genes for AD, PD, and ALS. The ZINC library of 34,853 compounds was screened for drug-like properties using QikProp to yield 16,466 drug-like compounds. Based on the comparative screening results, the structure of MMP9 (PDB ID: 8K5Y) was chosen for further analysis and two of the selected compounds ZINC04582833, ZINC00047690 were identified as the two highest ranked compounds with docking scores of - 10.4 and - 9.7 kcal/mol respectively. Both complexes were further evaluated by 100 ns MD simulations, showing RMSD profile stability, maintained secondary structure for both complexes. The results in this study make ZINC04582833 and ZINC00047690 computationally prioritized candidates for shared neurodegenerative targets for experimental validation.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00774-6.},
}

@article {pmid42894639,
year = {2026},
author = {Wang, Y and Fournier, L and Wymann, B and Talbot, K and Luisier, R and Patani, R},
title = {OGT regulates RNA-binding protein nucleocytoplasmic partitioning, but this fails in amyotrophic lateral sclerosis.},
journal = {iScience},
volume = {29},
number = {11},
pages = {117807},
pmid = {42894639},
issn = {2589-0042},
abstract = {O-linked N-acetylglucosamine transferase (OGT) catalyzes the O-linked β-N-acetylglucosamine (O-GlcNAc) modification to proteins and has been implicated in a range of diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and currently incurable neurodegenerative disorder. However, the precise mechanisms by which OGT influences ALS pathogenesis remain largely unresolved. In this study, we used human-induced pluripotent stem cell (hiPSC)-derived spinal motor neurons (hiPSC-MNs), the principal cell type that undergoes degeneration in ALS, to systematically reveal that OGT-related mechanisms regulate RNA-binding protein (RBP) nucleocytoplasmic compartmentalization. Using a combination of antisense oligonucleotide (ASO) technology and small molecular pharmacology, we reveal two distinct regulatory mechanisms of RBP compartmentalization, including by intron-retaining transcript-mediated sequestration and O-linked N-acetylglucosaminylation (O-GlcNAcylation)-mediated nuclear transport. We finally examine the tractability of manipulating OGT activity in the ALS context but demonstrate that the OGT-related mechanisms governing RBP localization in healthy hiPSC-MNs are impaired in the context of ALS-causing VCP and TARDBP mutations.},
}

@article {pmid42895147,
year = {2026},
author = {Chaudhary, S and Dhankhar, S and Saini, M and Singh, TG and Chauhan, S and Kumar, V},
title = {Mechanistic Evaluation of Psilocybin in Neurodegenerative Disorders: Relevance of 5-HT2A Receptors and Downstream Pathways.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273491538261009064612},
pmid = {42895147},
issn = {1996-3181},
abstract = {More than fifty million individuals worldwide are experiencing neurodegenerative disorders, which include Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and frontotemporal dementia. These disorders have a significant role in the gradual degradation of cognition and motor skills. Most current treatment approaches have little effect on changing the course of the disease and are largely symptomatic. Psilocybin, a naturally occurring tryptamine alkaloid from psilocybin mushrooms, has become a promising medicinal agent because of its hallucinogenic, neuroprotective, and neuroplastic properties. After being metabolically transformed into its active form, psilocin, it primarily activates serotonin 5-HT2A receptors. This modulates glutamatergic neurotransmission and neurotrophic signaling pathways such as BDNF/TrkB and mTOR, which regulate synaptic remodeling, dendritic complexity, neurogenesis, neuroinflammatory response, and default mode network connectivity, all of which are linked to depression and dementia. Preclinical research studies demonstrate that psilocybin increases hippocampal plasticity, restores dendritic complexity, lowers proinflammatory cytokine levels, and promotes fear extinction in experimental models of stress, ischemic stroke, and neurodegeneration. Emerging clinical studies also indicate that individuals with moderate cognitive impairment, early-onset Alzheimer's disease, and Parkinson's disease may see long-term decreases in anxiety and depression as well as improvements in cognitive function, frequently after a single dose administration. Additionally, psilocybin has demonstrated promise in treating mental comorbidities that often accompany neurodegenerative illness, such as treatment-resistant depression, drug use disorders, and obsessive-compulsive disorder. However, there are still significant obstacles to overcome, such as optimizing dosing schedules, assessing safety issues such as temporary perceptual abnormalities and cardiovascular consequences, and translating preclinical results into extensive phase -III clinical studies. This review incorporates the most recent data on psilocybin's chemistry, pharmacology, metabolism, and mechanistic actions; it highlights the drug's therapeutic potential across a variety of neurodegenerative diseases and emphasizes the necessity of carefully planned randomized controlled trials to determine clinical efficacy, long-term safety, and its place in multimodal treatment approaches.},
}

@article {pmid42895434,
year = {2026},
author = {Maccabeo, A and Cabras, S and Callegaro, S and Pateri, MI and Pili, F and Canosa, A and Manera, U and Palumbo, F and Matteoni, E and Pellegrino, G and Minerva, E and Ciravegna, A and Gianferrari, G and Puligheddu, M and Moglia, C and De Marchi, F and Mazzini, L and Mandrioli, J and Borghero, G and Chiò, A and Calvo, A and Vasta, R},
title = {Factors associated with post-tracheostomy survival in Amyotrophic Lateral Sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2026.2742815},
pmid = {42895434},
issn = {2167-9223},
abstract = {OBJECTIVE: To identify demographic and clinical factors associated with post-tracheostomy survival using three well-characterized cohorts of patients with Amyotrophic Lateral Sclerosis (ALS).

METHODS: ALS patients from the Piemonte and Valle d'Aosta ALS Register (PARALS) diagnosed between 1995-2019 interval who underwent tracheostomy were included. A multivariable Cox proportional hazards model was used to identify factors associated with post-tracheostomy survival. Significant findings were tested in two independent cohorts, the Emilia-Romagna Region ALS Register (ERRALS) and an incident ALS cohort from South Sardinia.

RESULTS: A total of 449 patients from PARALS underwent tracheostomy during the study period, with a median post-tracheostomy survival of 16.3 months (IQR 4.0-45.0). Younger age at tracheostomy was associated with longer survival (HR 1.03 per one-year increase, 95%CI1.01-1.05, p = 0.001), as being married/cohabiting (HR 0.78, 95%CI0.61-0.98, p = 0.033), a longer diagnosis-to-tracheostomy interval (HR 0.84 per one-year increase, 95%CI0.79-0.90, p < 0.001) and a lower ALS Functional Rating Scale slope from onset to tracheostomy (HR 1.13 per one-unit increase, 95%CI1.03-1.25, p = 0.012). These associations were replicated in the independent cohorts, when data were available. Additionally, discharge to nursing homes was associated with poorer survival in the Sardinian cohort (HR 4.23, 95%CI2.49-7.19; p < 0.001), whereas a more recent year of tracheostomy was associated with longer survival in the ERRALS cohort (HR 0.95, 95%CI0.90-0.99; p = 0.019).

DISCUSSION: We identified multiple factors associated with post-tracheostomy survival in ALS patients, encompassing clinical and demographic characteristics at tracheostomy as well as local factors influencing peri- and post-operative care. These findings may support decision-making and clinician-patient communication in the advanced stages of ALS.},
}

@article {pmid42895667,
year = {2026},
author = {Abu-Omar, K and Tcymbal, A and Messing, S and Gelius, P},
title = {[Physical activity and physical activity promotion among people with a migration background in Germany].},
journal = {Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz},
volume = {},
number = {},
pages = {},
pmid = {42895667},
issn = {1437-1588},
abstract = {Health equity has gained increasing importance in physical activity and health promotion and is firmly established as an important goal both internationally and in Germany. As social inequalities and multiple disadvantages influence physical activity behavior, population groups facing particular barriers to access-including people with a migration background-should receive greater consideration in physical activity promotion. This article provides an overview of the current state of research on physical activity and physical activity promotion among people with a migration background in Germany.Representative data indicate that people with a migration background are less physically active than people without a migration background. Key barriers reported include limited financial resources, language barriers, restricted opportunities for physical activity, and cultural factors. Different forms of social disadvantage, for example those related to gender, socioeconomic status, and migration background, may intersect and reinforce barriers to access. Using the project "Bewegung als Investition in Gesundheit" (BIG; "Physical Activity as an Investment in Health") as an example, this article illustrates how participatory and target-group-specific interventions can be used to reach, in particular, women with a migration background.In addition to participatory and target-group-specific interventions, equitable physical activity promotion requires structural conditions that facilitate access to opportunities for physical activity. The sustainable implementation and scaling-up of such interventions can contribute to reducing barriers to access and promoting health equity.},
}

@article {pmid42886553,
year = {2026},
author = {Gastaldo, D and Vito, S and Black, HH and Foreman, O and Yang, Z and Pham, V and Zhu, Y and Choi, M and Jovičić, A},
title = {Ataxin-2 downregulation rewires neuronal and astrocytic metabolism to protect against TDP-43 toxicity.},
journal = {Cell reports},
volume = {45},
number = {10},
pages = {118053},
doi = {10.1016/j.celrep.2026.118053},
pmid = {42886553},
issn = {2211-1247},
abstract = {Ataxin-2 (ATXN2) is a genetic modifier of TDP-43 toxicity and a promising therapeutic target in amyotrophic lateral sclerosis (ALS). However, the mechanisms underlying its neuroprotective effects remain poorly understood. Using global proteomic profiling in yeast and mouse TDP-43 models, we establish that pbp1/ataxin-2 (pbp1 is the yeast ataxin-2 ortholog) reduction confers neuroprotection by activating orthogonal stress-adaptive pathways in neurons and glia, rather than simply reversing TDP-43-induced damage. In neurons, ataxin-2 downregulation activates glycolysis and reductive glutamine carboxylation driven by IDH1, restoring ATP production independently of impaired mitochondria. In astrocytes, it upregulates cholesterol biosynthesis via HMGCS1, enhancing trophic support to neurons. Full neuroprotection requires both mechanisms: neuronal survival is only completely rescued when ataxin-2 is reduced in neuron-astrocyte co-cultures. Importantly, ataxin-2 downregulation protects against both TDP-43 gain- and loss-of-function toxicity, broadening its therapeutic relevance. Collectively, these findings establish ataxin-2 as a regulator of stress-adaptive metabolic resilience.},
}

@article {pmid42891488,
year = {2026},
author = {Boyce, D and Premasiri, A and Sullivan, S and Levine, B and Vieira, FG},
title = {Registry Forge: an open-source end-to-end pipeline for patient-directed SMART on FHIR registries.},
journal = {JAMIA open},
volume = {9},
number = {5},
pages = {ooag200},
pmid = {42891488},
issn = {2574-2531},
abstract = {OBJECTIVES: Patient-directed SMART on FHIR lets registries acquire longitudinal electronic health record data, but the payload requires substantial engineering before use. We present Registry Forge, an open-source pipeline that converts it into curation-ready outputs.

MATERIALS AND METHODS: Registry Forge parses C-CDA, HTML, RTF, PDF, and FHIR inputs, joins records to a canonical identifier, and emits a browser dashboard, an OMOP CDM v5.4 data set, GA4GH Phenopackets v2, a code inventory, and disease-specific narrative extractions.

RESULTS: Applied to the ALS Research Collaborative Study (94 participants, 56 US health systems), it processed 22 686 files and 1791 FHIR Bundles (109 599 resources); only 15.0% of files were full C-CDA XML; HTML (48.4%) and RTF (34.3%) predominated.

DISCUSSION: Payloads are far more heterogeneous than often assumed; the architecture is designed for extension, though generalizability remains to be demonstrated.

CONCLUSION: Registry Forge closes the gap between acquisition and curation-ready data with no server infrastructure and is openly available.},
}

@article {pmid42891860,
year = {2026},
author = {Wełnicka-Wesołowska, A and Łuczkowska, K and Nowacki, P and Paczkowska, E and Meller, A and Machowska-Sempruch, K and Machaliński, B and Gołąb-Janowska, M},
title = {Peripheral and cerebrospinal fluid inflammatory markers in sporadic amyotrophic lateral sclerosis an exploratory cross-sectional association study.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {11},
pages = {},
pmid = {42891860},
issn = {1590-3478},
support = {STRATEGMED1/234261/2NCBR/2014//Narodowe Centrum Badań i Rozwoju/ ; },
mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood ; Male ; Cross-Sectional Studies ; *Receptors, Tumor Necrosis Factor, Type I/cerebrospinal fluid/blood ; Biomarkers/cerebrospinal fluid/blood ; Middle Aged ; Tumor Necrosis Factor-alpha/cerebrospinal fluid/blood ; Aged ; C-Reactive Protein/metabolism/cerebrospinal fluid ; Fibrinogen/metabolism ; Inflammation/cerebrospinal fluid/blood ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with an ambiguous etiology, whose onset may be linked to innate immune system activation outside the central nervous system (CNS). We investigated the association between peripheral blood and CNS inflammatory parameters in 45 sporadic ALS patients compared to 30 controls, analyzing peripheral blood tests (C-reactive protein [CRP], blood count, fibrinogen) and cerebrospinal fluid (CSF) immunological measures (Tumor Necrosis Factor alpha [TNF-α], TNF receptor type 1 [TNFR-1], CRP) alongside clinical characteristics. Results revealed significantly higher concentrations of TNFR-1 in the CSF of ALS patients compared to the control group (1,029.5 ± 176.0 vs. 846.1 ± 167.5 pg/ml; p < 0.0001). This difference remained significant in multivariable logistic regression adjusting for age and sex (OR 1.82 per 100 pg/ml increment, 95% CI 1.26-2.63; p = 0.0015). In an exploratory ROC analysis, CSF TNFR-1 discriminated patients from controls with an AUC of 0.78 (95% CI 0.67-0.88). TNFR-1 correlated with age (R = 0.32, p = 0.038), associations with disease severity and a lower concentration in bulbar-onset disease were exploratory and not robustly significant. Plasma and CSF CRP concentrations did not differ significantly between groups, but strongly correlated with each other in both ALS (R = 0.83) and control (R = 0.82) cohorts, indicating a disease-non-specific relationship. CSF TNFR-1 is independently associated with sporadic ALS and warrants further investigation as a candidate disease-associated inflammatory biomarker. Given the limitations, our findings do not prove diagnostic accuracy or causality. Longitudinal studies with disease controls and blood-CSF barrier integrity measures are needed.},
}

Humans
Female
*Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood
Male
Cross-Sectional Studies
*Receptors, Tumor Necrosis Factor, Type I/cerebrospinal fluid/blood
Biomarkers/cerebrospinal fluid/blood
Middle Aged
Tumor Necrosis Factor-alpha/cerebrospinal fluid/blood
Aged
C-Reactive Protein/metabolism/cerebrospinal fluid
Fibrinogen/metabolism
Inflammation/cerebrospinal fluid/blood

@article {pmid42885660,
year = {2026},
author = {Bombaci, A and Iadarola, A and Giraudo, A and Fattori, E and Sinagra, S and Magnino, A and Falbo, M and De Marco, G and Calvo, A and Chiò, A and Cicolin, A},
title = {Salivary Dim-Light Melatonin Onset is Associated with Functional Decline, Respiratory Symptom Emergence, and Survival in Early Amyotrophic Lateral Sclerosis.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78398},
pmid = {42885660},
issn = {1531-8249},
abstract = {OBJECTIVE: Sleep-wake and circadian disturbances are increasingly recognized in people living with amyotrophic lateral sclerosis (plwALS), but endogenous circadian phase timing and its prognostic significance in early disease remain unclear. We assessed whether salivary dim-light melatonin onset (DLMO), an objective marker of central circadian phase, is altered in early plwALS and whether it provides prognostic information.

METHODS: In this prospective longitudinal observational study, plwALS within 18 months of symptom onset underwent home-based salivary melatonin sampling under dim-light conditions at 6 predefined time points around habitual sleep onset. Melatonin profiles were modeled using cubic smoothing splines, and DLMO was defined when the fitted curve first reached 3 pg/ml. Clinical, respiratory, and sleep assessments were collected at baseline (T0) and after 6 months (T6); a subgroup repeated saliva sampling at T6. Age- and sex-matched controls underwent melatonin profiling. Associations with disease progression, incident respiratory symptoms, and survival/tracheostomy were examined using regressions and survival analyses.

RESULTS: A total of 50 plwALS were enrolled. Compared with controls, plwALS showed an earlier DLMO (20:24 ± 1:18 vs 20:58 ± 0:50; p = 0.028) despite similar habitual sleep onset and chronotype. Within ALS cohort, a later baseline DLMO correlated with worse functional/motor status, faster progression of disease, incident dyspnea/orthopnea by T6 (adjusted OR 3.11; p = 0.019), and poorer survival/tracheostomy-free outcome. In the resampled subgroup (n = 28), DLMO and melatonin-derived metrics did not change over ~6 months.

INTERPRETATION: Circadian phase alterations are detectable in early ALS. Baseline DLMO showed exploratory associations with functional, respiratory, and survival outcomes. Larger independent cohorts are required before DLMO can be considered a validated prognostic biomarker. ANN NEUROL 2026.},
}