@article {pmid43015100,
year = {2026},
author = {Ackerman, SD and Fontenas, L},
title = {Glial Regulation of Motor Circuit Formation, Function, and Regeneration.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {46},
number = {45},
pages = {},
pmid = {43015100},
issn = {1529-2401},
support = {R01 NS144659/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; *Neuroglia/physiology ; Humans ; *Nerve Regeneration/physiology ; *Nerve Net/physiology ; *Motor Neurons/physiology ; },
abstract = {From simple planaria to humans, proper assembly and maintenance of motor circuits is key to organismal survival. Each year, ∼250,000-500,000 individuals suffer a spinal cord injury with little hope of successful recovery. Moreover, motor circuits are a primary target of prevalent neurodegenerative conditions like ALS and Parkinson's disease. Thus, understanding the mechanisms that build, maintain, and rebuild motor circuits is of substantial clinical interest. Recent data indicate that glia, a heterogeneous group of non-neuronal cells within the nervous system, directly communicate with neurons to tune motor circuit dynamics. We now know glia are often active drivers of neural development and pathology, rather than passive bystanders. This mini-review will highlight recent advances in our understanding of how diverse glial cell types promote proper construction, function, and deconstruction of the key circuits that drive motor behavior.},
}

Animals
*Neuroglia/physiology
Humans
*Nerve Regeneration/physiology
*Nerve Net/physiology
*Motor Neurons/physiology

@article {pmid43015463,
year = {2026},
author = {Keuss, MJ and Harley, P and Ryadnov, E and Jackson, RE and Boll, M and Zanovello, M and Wilkins, OG and Barattucci, S and Ilic, D and Simkin, RL and Chien, MZYJ and Cammack, AJ and Šoltić, D and Mehta, PR and Ling, YT and Kowald, M and Morrie, RD and Miller, G and Oliveira, MG and Duddy, G and Wood, S and Parkes, JE and Sinha, A and Correa-Sánchez, AF and Isaacs, AM and Oliver, PL and Hamid, F and Green, EM and Fisher, EMC and Davies, B and Schiavo, G and Shah, M and Lipstein, N and Burrone, J and Fratta, P},
title = {UNC13A splice correction rescues synaptic dysfunction induced by TDP-43 loss.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {43015463},
issn = {1476-4687},
abstract = {TDP-43 nuclear depletion is a defining pathological feature of amyotrophic lateral sclerosis and frontotemporal dementia that induces widespread cryptic splicing defects in hundreds of transcripts[1-8]. Despite this, whether TDP-43 loss affects synaptic function has remained unclear. Here we show that TDP-43 loss induces a predegenerative state in which neurons remain structurally intact but suffer a substantial breakdown in synaptic communication. Genetic correction of a single cryptic splicing event in UNC13A was sufficient to rescue these deficits. We developed splice-switching antisense oligonucleotides that correct UNC13A cryptic splicing in human cortical and spinal motor neurons and in a humanized mouse model. In human neurons this intervention restored spontaneous and evoked synaptic vesicle release, release probability at individual synapses and wider network synchrony. Together, this establishes UNC13A splice correction as a mechanistically defined and genetically validated therapeutic strategy relevant to roughly 97% of patients with amyotrophic lateral sclerosis and roughly 50% of patients with frontotemporal dementia with TDP-43 pathology.},
}

@article {pmid43015714,
year = {2026},
author = {Pérez-de la Cruz, S},
title = {From technique to sensitivity: the transformation of clinical and ethical reasoning in physiotherapy students in the context of chronic neurodegenerative diseases.},
journal = {BMC medical education},
volume = {26},
number = {1},
pages = {},
pmid = {43015714},
issn = {1472-6920},
mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Physical Therapy Specialty/education/ethics ; Qualitative Research ; *Clinical Reasoning ; Male ; Female ; Spain ; *Physical Therapists/education ; Attitude of Health Personnel ; Chronic Disease ; Curriculum ; },
abstract = {BACKGROUND: The evolution of Physiotherapy requires a shift from the biomedical model towards bioethical and humanistic approaches. This study explores how final-year students perceive their professional role when dealing with patients with complex neurodegenerative conditions, where traditional technical success is challenged by the irreversibility of the deterioration.

METHODS: Qualitative research based on interpretative description. Thirty final-year students from the University of Almería (Spain) took part, divided into five working groups. Three training sessions and discussions were held on Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, stroke and Rett syndrome. The data were analysed using thematic analysis and triangulation by researchers external to the study, with reflexivity ensured through logbooks.

RESULTS: A shift in clinical reasoning was identified, with sensitivity taking precedence over technique. Students redefined therapeutic success in terms of "comfort" and support, valuing "microscopic achievements" such as the preservation of dignity and the alleviation of distress. Of particular note is the ability to adapt ethical principles according to the patient's cognitive integrity (autonomy in ALS versus protection in Alzheimer's) and the integration of the carer as an inseparable part of the therapeutic process.

CONCLUSION: Future physiotherapists perceive humanization and the empathetic interpretation of non-verbal cues as essential therapeutic tools. Unlike previous studies focused on clinical experience, this research explores pre-clinical ethical maturation, offering a unique perspective on the educational foundation and humanistic predisposition of future graduates prior to their immersion in the healthcare system. It is imperative that academic curricula formally integrate competencies in bioethics, palliative care and emotional management to prepare graduates for extreme vulnerability and prevent early professional burnout.},
}

Humans
*Neurodegenerative Diseases/therapy
*Physical Therapy Specialty/education/ethics
Qualitative Research
*Clinical Reasoning
Male
Female
Spain
*Physical Therapists/education
Attitude of Health Personnel
Chronic Disease
Curriculum

@article {pmid43016267,
year = {2026},
author = {Afridi, S and Choudhary, F and Sharma, P and Mustafa, M and Farooqi, H},
title = {Ubiquitin-Proteasome System: Key Insights into Neurological Disorder Mechanisms.},
journal = {Current aging science},
volume = {19},
number = {4},
pages = {406-420},
pmid = {43016267},
issn = {1874-6128},
mesh = {Humans ; *Proteasome Endopeptidase Complex/metabolism ; *Ubiquitin/metabolism ; Animals ; Ubiquitin-Protein Ligases/metabolism ; *Neurodegenerative Diseases/drug therapy/enzymology/physiopathology/pathology/metabolism ; Autophagy ; Proteostasis ; Proteolysis ; Proteotoxic Stress ; Signal Transduction ; },
abstract = {The ubiquitin-proteasome system (UPS) is crucial for maintaining protein homeostasis in the central nervous system. Dysfunction of the UPS leads to the accumulation of neurotoxic aggregates, including amyloid, tau, alpha-synuclein, SOD1, and TDP-43, which are hallmark features of various neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. Agerelated decline in the UPS and autophagy-lysosomal pathways results in compromised proteostasis and progressive neuronal damage. Current literature from diverse databases provides insights emphasizing the clinical relevance of UPS-targeted interventions. Strategies such as targeted degradation of misfolded proteins, modulation of PINK1/Parkin-mediated mitophagy, and the use of enzyme activators or allosteric modulators show potential in restoring brain homeostasis. This review discusses UPS-mediated proteolytic mechanisms, molecular disruptions associated with disease progression, and emerging therapeutic approaches aimed at enhancing protein clearance.},
}

Humans
*Proteasome Endopeptidase Complex/metabolism
*Ubiquitin/metabolism
Animals
Ubiquitin-Protein Ligases/metabolism
*Neurodegenerative Diseases/drug therapy/enzymology/physiopathology/pathology/metabolism
Autophagy
Proteostasis
Proteolysis
Proteotoxic Stress
Signal Transduction

@article {pmid43016791,
year = {2026},
author = {Cáceres-Palomo, L and Alfonso-Triguero, M and Belloso-Iguerategui, A and Santiago-Mujika, E and Mirón-Alcalá, M and Arranz, AM},
title = {Chimeric models of neurodegenerative diseases: from disease mechanisms to regenerative therapies.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {51},
pmid = {43016791},
issn = {3059-4944},
abstract = {Human-rodent chimeric CNS models provide a unique platform for investigating human-specific aspects of neurodegeneration within the physiological environment of the living CNS. These models are generated by transplanting human pluripotent stem cell-derived neurons, astrocytes, microglia, oligodendrocytes, or neural or glial progenitor cells into the CNS of permissive host animals. Following transplantation, human cells mature, functionally integrate within host tissue, and retain key species-specific molecular and cellular features. Here, we review recent advances in the use of chimeric models to investigate disease mechanisms in Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and demyelinating disorders. We highlight the unique insights these models have provided into human-specific cellular vulnerabilities, genotype-dependent phenotypes, glial responses, and neuroimmune interactions in vivo. We also discuss emerging translational applications, including cell replacement therapies, engineered glial delivery platforms, and remyelination strategies, some of which have progressed toward clinical translation. Finally, we outline the current limitations and future directions for developing next-generation multi-lineage humanized models with enhanced disease fidelity and translational potential.},
}

@article {pmid43016795,
year = {2026},
author = {Wölk, SA and Walter, U and Prudlo, J and Ruß, AK and Patejdl, R},
title = {Simultaneous evoked CMAP recording and sonography reveal a prolonged electromechanical delay in ALS patients.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1943566},
pmid = {43016795},
issn = {1664-2295},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Female ; Male ; Middle Aged ; *Muscle, Skeletal/physiopathology/diagnostic imaging ; Aged ; Nerve Conduction Studies ; Adult ; *Evoked Potentials, Motor/physiology ; Ultrasonography ; Electromyography ; Neural Conduction/physiology ; },
abstract = {Alterations in electromechanical coupling have been described in patients with amyotrophic lateral sclerosis (ALS) and may contribute to the pathophysiology of the disease. Regardless of this, few measurements of electromechanical delay (EMD) in ALS patients have been published. In this motor nerve conduction study, 28 patients with ALS were examined for changes in electromechanical coupling time compared to healthy individuals using sonoelectromyography, a novel dual-method approach combining simultaneous evoked compound muscle action potential (CMAP) recording following an ENG protocol with Doppler ultrasound. In the examination of four muscles (the abductor digiti minimi muscle, brachioradialis muscle, tibialis anterior muscle, and rectus femoris muscle) ALS patients exhibited prolonged electromechanical delay times. These results demonstrate alterations in the electromechanical properties of muscle fibers and provide further insight into muscle contractility in ALS. The findings support the advancement and wider utilisation of sonoelectromyography as an innovative tool for assessing muscle function and indicate that EMD could be incorporated into diagnostic and disease monitoring protocols in ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging
Female
Male
Middle Aged
*Muscle, Skeletal/physiopathology/diagnostic imaging
Aged
Nerve Conduction Studies
Adult
*Evoked Potentials, Motor/physiology
Ultrasonography
Electromyography
Neural Conduction/physiology

@article {pmid43019526,
year = {2026},
author = {Steyn, F and Pilkar, R and Sethi, N and Heller, L and Holdom, C and van Eijk, RPA and Straczkiewicz, M and Burke, KM and Berry, JD and Chandriani, S and Jewett, G and Hodson-Tole, E and Hovinga, C and Vieira, F and Guo, C},
title = {Rethinking Digital Outcome Measures for Amyotrophic Lateral Sclerosis Trials: Consensus Priorities for Actigraphy Harmonization, Validation, and Regulatory Readiness.},
journal = {Journal of medical Internet research},
volume = {28},
number = {},
pages = {e106677},
pmid = {43019526},
issn = {1438-8871},
mesh = {*Amyotrophic Lateral Sclerosis/therapy/physiopathology ; Humans ; *Actigraphy ; *Outcome Assessment, Health Care ; *Clinical Trials as Topic ; Consensus ; Digital Health ; },
abstract = {Amyotrophic lateral sclerosis (ALS) clinical trials need outcome measures that complement established end points while capturing how people function in daily life. In this viewpoint, we draw on our collective experience in ALS research, clinical trials, digital-measure development, and regulatory science, together with published evidence, a preliminary patient survey, stakeholder discussions, and experience from multisite actigraphy studies. We argue that the field now has a substantial base of longitudinal data and candidate measures, but lacks the coordinated framework needed to compare, prioritize, and validate them across studies. We identify 4 linked priorities: adopt fit-for-purpose measures in stages and within defined contexts of use; harmonize data collection and analysis; use data to shortlist and validate measures across cohorts; and prepare actigraphy methods for trial adoption through early industry and regulatory engagement. Across these priorities, actigraphy should complement rather than replace established clinical outcomes, with its integration guided by patient relevance, ALS phenotypic heterogeneity, participant, and caregiver burden, and the intended context of use. Our central message is that progress now depends less on generating additional isolated datasets or measures than on coordinating the evaluation of existing assets, and aligning future evidence generation.},
}

*Amyotrophic Lateral Sclerosis/therapy/physiopathology
Humans
*Actigraphy
*Outcome Assessment, Health Care
*Clinical Trials as Topic
Consensus
Digital Health

@article {pmid43020536,
year = {2026},
author = {Han, L and Hou, J and Zhang, D and Zhang, W and Wang, D and Huo, D and Su, X and Tan, X and Wang, M and Xu, J and Cheng, J and Wang, J and Feng, H},
title = {Combined γ-oryzanol and α-lipoic acid treatment suppresses inflammation and apoptosis in hSOD1[G93A] models of amyotrophic lateral sclerosis via the AKT/GSK3β pathway.},
journal = {Journal of pharmacological sciences},
volume = {162},
number = {4},
pages = {331-345},
doi = {10.1016/j.jphs.2026.10.004},
pmid = {43020536},
issn = {1347-8648},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; *Apoptosis/drug effects/genetics ; *Glycogen Synthase Kinase 3 beta/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Signal Transduction/drug effects/genetics ; *Phenylpropionates/pharmacology/administration & dosage/therapeutic use ; *Thioctic Acid/pharmacology/administration & dosage/therapeutic use ; Mice, Transgenic ; Disease Models, Animal ; Humans ; *Inflammation/drug therapy/genetics ; Drug Therapy, Combination ; *Neuroprotective Agents ; *Resorcinols/pharmacology/administration & dosage ; Mice ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with complex pathogenic mechanisms, and the efficacy of single-target interventions remains limited. γ-Oryzanol (Orz) and α-lipoic acid (ALA) exert neuroprotective effects individually, yet their combined effects and molecular mechanisms in ALS remain unclear.

AIM: To investigate the therapeutic effects and mechanisms of combined Orz and ALA treatment in ALS.

METHODS: Network pharmacology was used to identify potential targets shared by the compounds and ALS. Core targets and pathways were identified through protein-protein interaction (PPI) network analysis, molecular docking, and functional enrichment analysis, followed by experimental validation in hSOD1[G93A] cell and transgenic mouse models.

RESULTS: Six core targets (EGFR, AKT1, HSP90AA1, BCL2, SRC, HSP90AB1) were identified. In hSOD1[G93A] cells, combined treatment modulated mRNA expression and protein phosphorylation of the core targets and attenuated cellular injury. In hSOD1[G93A] transgenic mice, the combination delayed disease progression, prolonged survival, improved motor function, and reduced motor neuron loss. This combination alleviated inflammation and apoptosis by activating the AKT/GSK3β pathway.

CONCLUSION: Combined Orz and ALA treatment modulates core targets, activates the AKT/GSK3β pathway, and suppresses inflammation and apoptosis. This combination represents a promising therapeutic strategy for ALS.},
}

Animals
*Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology
*Apoptosis/drug effects/genetics
*Glycogen Synthase Kinase 3 beta/metabolism
*Proto-Oncogene Proteins c-akt/metabolism
*Signal Transduction/drug effects/genetics
*Phenylpropionates/pharmacology/administration & dosage/therapeutic use
*Thioctic Acid/pharmacology/administration & dosage/therapeutic use
Mice, Transgenic
Disease Models, Animal
Humans
*Inflammation/drug therapy/genetics
Drug Therapy, Combination
*Neuroprotective Agents
*Resorcinols/pharmacology/administration & dosage
Mice

@article {pmid43020712,
year = {2026},
author = {Okagaki, N and Tsuboi, T and Chihara, Y and Sumi, K and Hajiro, T and Maetani, T and Tanabe, N and Handa, T and Sato, S and Sato, A},
title = {Ventral Lung Injury and Pneumothorax in Patients With Amyotrophic Lateral Sclerosis Receiving Long-term Positive Pressure Ventilation.},
journal = {Archivos de bronconeumologia},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.arbres.2026.10.015},
pmid = {43020712},
issn = {1579-2129},
}

@article {pmid43020779,
year = {2026},
author = {de Jongh, R and Wiersema, AF and van Dijk, CH and Verdegaal, RC and Smulders, MMJ and Basak, O and van Os, J and Peeters, S and Olmedo-Martínez, L and Bloemenkamp, LM and Garner, KM and Da Cruz, S and Koppers, M and Iuliano, A and Pijnappel, WWMP and Kenna, KP and Pasterkamp, RJ},
title = {SLITRK2 knockdown rescues axonal and functional neuromuscular junction deficits in human iPSC-derived mutant FUS-ALS motor neurons.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {43020779},
issn = {2041-1723},
mesh = {Humans ; *Neuromuscular Junction/metabolism/pathology ; *Motor Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *Axons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Gene Knockdown Techniques ; *RNA-Binding Protein FUS/genetics/metabolism ; 3' Untranslated Regions/genetics ; *Nerve Tissue Proteins/genetics/metabolism ; Mutation ; Animals ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron (MN) loss caused by early axonal and synaptic changes. However, the mechanisms underlying these changes remain incompletely understood. Here, we exploit FUS-ALS to interrogate cell compartment-specific changes in RNA expression and regulation in human induced pluripotent stem cell (iPSC)-derived MN. This approach identifies compartment-specific 3' untranslated region (3'UTR) isoform expression in human healthy control MN axons. Further, it unveils altered 3' UTR isoforms in ALS in different cellular compartments in genes such as SNCA, previously linked to neurodegeneration. Expression of SLITRK2 is most strongly and consistently upregulated across multiple FUS-ALS models, and its knockdown normalizes axonal defects linked to FUS-ALS. Using a fully iPSC-derived neuromuscular microfluidics protocol, we show that SLITRK2 knockdown in FUS-ALS MN rescues neuromuscular junction (NMJ) signaling without affecting NMJ innervation or MN hypo-excitability. Our study provides insight into compartment-specific 3'UTR expression in ALS, presents a robust iNMJ-on-a-chip model, and links elevated SLITRK2 to axonal and synaptic defects in FUS-ALS.},
}

Humans
*Neuromuscular Junction/metabolism/pathology
*Motor Neurons/metabolism/pathology
*Induced Pluripotent Stem Cells/metabolism
*Axons/metabolism/pathology
*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology
Gene Knockdown Techniques
*RNA-Binding Protein FUS/genetics/metabolism
3' Untranslated Regions/genetics
*Nerve Tissue Proteins/genetics/metabolism
Mutation
Animals

@article {pmid43021253,
year = {2026},
author = {Nie, Y and Zhang, J and Zhang, Z and Zhou, J and Zhang, W and Zhao, Y and Li, M and Qiao, L},
title = {Amyotrophic lateral sclerosis coexisting with primary sjögren's syndrome: a clinical case series and exploratory transcriptomic analysis.},
journal = {BMC medical genomics},
volume = {19},
number = {1},
pages = {},
pmid = {43021253},
issn = {1755-8794},
support = {GZC20251435//China Postdoctoral Science Foundation/ ; 823B2037//the National Natural Science Foundation of China/ ; 82471829//the National Natural Science Foundation of China/ ; 2022-PUMCH-C-006//National High Level Hospital Clinical Research Funding/ ; 7232113//Beijing Natural Science Foundation/ ; },
mesh = {Humans ; *Sjogren's Syndrome/complications/genetics ; *Amyotrophic Lateral Sclerosis/complications/genetics ; Female ; *Gene Expression Profiling ; Middle Aged ; *Transcriptome ; Male ; Aged ; Retrospective Studies ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration, while primary Sjögren's syndrome (pSS) is a systemic autoimmune disease with prominent immune dysregulation. Although immune-related alterations have been implicated in ALS and autoimmune diseases, the clinical coexistence of ALS and pSS remains poorly characterized. We aimed to describe the clinical features of patients with concomitant ALS and pSS and to explore peripheral blood transcriptomic patterns in independent ALS and pSS cohorts.

METHODS: We retrospectively identified patients with both ALS and pSS through systematic electronic health record screening and multidisciplinary clinical review. Clinical characteristics, disease chronology, treatment exposure, and outcomes were summarized. In parallel, we performed an exploratory transcriptomic analysis using publicly available peripheral blood datasets from independent ALS and pSS cohorts. Differentially expressed genes and overlapping inflammatory signatures were evaluated, with additional sensitivity assessment performed using an independent ALS cohort.

RESULTS: Seven patients fulfilling diagnostic criteria for both ALS and pSS were identified. The temporal relationship between the two diseases was heterogeneous, with variable disease onset sequences and clinical trajectories. Immunomodulatory treatments were associated with transient improvement in systemic autoimmune manifestations in some patients, but no conclusions regarding modification of ALS progression could be established. Transcriptomic analyses identified overlapping upregulated genes between ALS and pSS cohorts, enriched in interferon- and NF-κB-related inflammatory signatures. However, these signatures represent commonly observed inflammatory responses across multiple disease contexts and should not be interpreted as evidence of ALS-pSS-specific biological convergence. Sensitivity assessment using an independent ALS cohort demonstrated partial reproducibility of selected non-specific inflammatory signatures across datasets.

CONCLUSIONS: Taken together, these findings present two independent, exploratory observations: a rare clinical co-occurrence and a non-specific systemic inflammatory signature identified in unrelated public datasets, both requiring sensitivity assessment and serving as hypothesis-generating baselines for future studies.},
}

Humans
*Sjogren's Syndrome/complications/genetics
*Amyotrophic Lateral Sclerosis/complications/genetics
Female
*Gene Expression Profiling
Middle Aged
*Transcriptome
Male
Aged
Retrospective Studies

@article {pmid43021426,
year = {2026},
author = {Karra, RD and Kaivola, K},
title = {Reconciling cryptic relatedness to drive gene discovery in amyotrophic lateral sclerosis/frontotemporal dementia.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag400},
pmid = {43021426},
issn = {1460-2156},
}

@article {pmid43021436,
year = {2026},
author = {Plessis-Belair, J and Sher, RB},
title = {Neuronal cell-cycle re-entry stratifies clinical trajectories in amyotrophic lateral sclerosis.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag391},
pmid = {43021436},
issn = {1460-2156},
abstract = {The clinical heterogeneity of Amyotrophic Lateral Sclerosis (ALS) remains a fundamental barrier to effective therapy. While cell cycle re-entry in post-mitotic neurons is a known precursor to neurodegeneration, its role in defining patient-specific outcomes has never been established. Here, we integrate large-scale transcriptomic profiling from the AnswerALS cohort with mechanistic studies in human iPSC-derived spinal motor neurons to define how cell-cycle re-entry shapes disease heterogeneity in ALS. We identify a transcriptionally distinct patient subgroup with the highest expression of G1 or G2-phase cyclins that exhibit significantly slower functional decline (ALSFRS-R), whereas the engagement of S-phase markers correlates with accelerated disease progression. Nucleocytoplasmic transport dysfunction, a hallmark of ALS and related disorders, disrupts the spatial distribution of key regulatory proteins and may contribute to maladaptive cell-cycle activation. Our recent evidence suggests that impaired nuclear import may initiate, rather than merely accompany, neuronal cell-cycle re-entry. Using iPSC-derived motor neurons, we show that impaired nuclear import initiates TDP-43 pathology and global nuclear/cytoplasmic mis-localization of key ALS-related proteins. This nucleocytoplasmic transport dysfunction triggers a transient wave of cell-cycle activity immediately preceding neuronal cell death. Crucially, we show that DNA-replication initiation is a pathological inflection point of no return, as neurons entering S-phase accumulate replication-associated DNA damage and undergo cell death. Selective inhibition of CDK4/6 prevents S-phase entry and confers potent neuroprotection. Our findings demonstrate that impaired nuclear import drives maladaptive cell-cycle reactivation in ALS and that the depth of cell-cycle engagement stratifies neuronal fate and patient trajectories.},
}

@article {pmid43021924,
year = {2026},
author = {Alessi, C and Sacchi, N and Fundarò, C and Ferrara, A},
title = {AS-ULDAR: a ROS 2-based collaborative robotic platform for upper-limb rehabilitation - systems integration and pilot usability evaluation in a clinical environment.},
journal = {Frontiers in robotics and AI},
volume = {13},
number = {},
pages = {1914367},
pmid = {43021924},
issn = {2296-9144},
abstract = {Robotic rehabilitation can increase the intensity and personalization of upper-limb therapy, but its clinical translation is hindered by the difficulty of integrating individually validated technical components into a single clinician-ready platform. This paper presents a platform which is intended to be an Auto-calibrating System for Upper Limb Disability Assessment and Rehabilitation (AS-ULDAR), a ROS 2-based platform built around a Franka Emika Panda robot that unifies motor/cognitive assessment, sensorless force estimation, and Cartesian and Human Joint-based Trajectory Tracking within a clinician-oriented GUI. While these functionalities were individually validated in prior work, the present contribution lies in their systems-level integration and in identifying the operational barriers that emerge when deploying such a platform in a real clinical workflow, targeting adult patients with chronic neurological conditions (stroke, Parkinson's, ALS, MCI) and mild-to-moderate upper-limb impairment. The platform was evaluated through a formative usability study: the standalone GUI by five naïve users, and the complete system by seven physiotherapists performing the full clinical workflow (no patients were involved; clinical efficacy is outside this scope). The system was technically stable throughout. Usability (SUS) was high for the GUI (87.5 ± 1.8) but markedly lower and more heterogeneous for the complete platform (54 ± 16), with feedback pointing to robot setup and workflow operation-not interface design-as the main friction points for clinical staff. These results show that integrating multiple rehabilitation functionalities is technically feasible, but that usability must be treated as a system-level property, and they provide concrete operational lessons for the clinical translation of cobot-based rehabilitation platforms.},
}

@article {pmid43022201,
year = {2026},
author = {Singaravel, V},
title = {Optogenetics in neurobiology and neurodegenerative disorders: from neural circuit mechanisms to precision neuromodulation.},
journal = {Frontiers in medical technology},
volume = {8},
number = {},
pages = {1958917},
pmid = {43022201},
issn = {2673-3129},
abstract = {Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis and stroke, are characterized by progressive neuronal dysfunction, synaptic impairment and neural circuit degeneration, leading to severe cognitive and motor deficits. Although considerable progress has been made in understanding their molecular pathology, the circuit level mechanisms driving disease onset and progression remain incompletely understood. Optogenetics, which combines microbial opsins, genetic engineering and optical stimulation, enables reversible, cell-specific control of neuronal activity with millisecond precision and has transformed neuroscience from observational analysis to causal investigation of neural circuits. This review summarizes recent advances in the molecular basis of optogenetics, microbial opsins, gene delivery strategies and optical stimulation technologies, together with their applications in basic neurobiology and neurodegenerative disease research. We discuss how optogenetics has advanced understanding of neural circuit organization, synaptic plasticity, memory, neurodevelopment, sleep regulation, protein aggregation, synaptic dysfunction, neuroinflammation, mitochondrial impairment, oxidative stress and regulated cell death. Although these studies have generated important mechanistic insights and demonstrated functional improvements in experimental models, translation into human therapies remains investigational due to challenges associated with gene delivery, long-term opsin expression, immune compatibility and optical accessibility. Emerging therapeutic strategies, including closed-loop neuromodulation, wireless photostimulation, artificial intelligence-assisted neural decoding, nanotechnology enabled light delivery and brain computer interfaces, are critically evaluated with emphasis on their current evidence status, translational challenges and limitations for clinical implementation. Collectively, optogenetics provides an unprecedented platform for deciphering disease mechanisms and evaluating circuit-based neuromodulation strategies, while continued technological and biological validation will determine its future role in precision therapies for neurodegenerative disorders.},
}

@article {pmid43022354,
year = {2026},
author = {Urbi, B and Sabet, A and Hughes, I and Bedlack, R and Russo, E and Broadley, SA},
title = {A phase II, randomised, placebo-controlled, double-blind trial of cannabis extract for amyotrophic lateral sclerosis: the EMERALD trial.},
journal = {BMJ neurology open},
volume = {8},
number = {2},
pages = {e001766},
pmid = {43022354},
issn = {2632-6140},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited disease-modifying treatment options. Preclinical and clinical data suggest that cannabinoid-based therapies may exert neuroprotective and symptomatic benefits. We conducted a trial to evaluate the effects of cannabis-based medicine extract (CBME) on disease progression in patients with ALS.

METHODS: This was a randomised, double-blind, placebo-controlled trial. Participants received CBME or placebo for 6 months. The primary outcome was the difference in ALS Functional Rating Scale-Revised (ALSFRS-R) scores at the end of treatment (EOT). Secondary outcomes included adverse events, forced vital capacity (FVC), pain and spasticity measures, weight loss, cognition and quality of life.

RESULTS: Due to COVID-19 restrictions and driving limitations, only 17 participants were enrolled (CBME: n=8; placebo: n=9), and 8 completed treatment (4 per group). At EOT, adjusted mean ALSFRS-R scores were 31.67 for CBME and 34.33 for placebo (difference: -2.66; 95% CI -7.25 to 1.92; p=0.18; n=8). No significant differences were observed in secondary outcomes. Post hoc analyses suggested potential effects of CBME on pain and cognition for further confirmation: usual pain intensity decreased by 2.52 points (95% CI -8.92 to 3.87, p=0.34; n=8), a decrease of 3 days in the number of pain days (95% CI -28.90 to 22.59, p=0.75; n=8), executive function improved by 7.71 points (95% CI 0.90 to 14.52; p=0.04; n=8) and a 5.68-point improvement in memory (95% CI -0.29 to 11.64; p=0.06; n=8).

CONCLUSION: This trial did not achieve the target sample size therefore was underpowered to demonstrate efficacy of cannabis in slowing ALS progression. However, exploratory analyses generated hypotheses regarding possible effects on pain and cognition which require confirmation in adequately powered studies.

TRIAL REGISTRATION NUMBER: (ID: NCT03690791) on 27 September 2018.},
}

@article {pmid43022413,
year = {2026},
author = {Shan, Q and Li, J and Wang, Y and Gupta, S and Song, L and Zhang, W and Su, F and Guo, Y},
title = {Brain-computer interfaces for neurodegenerative diseases: A comprehensive review of closed-loop systems from diagnosis to neural rehabilitation.},
journal = {iScience},
volume = {29},
number = {11},
pages = {118073},
pmid = {43022413},
issn = {2589-0042},
abstract = {Brain-computer interface (BCI) technology serves as an important bridge between the nervous system and external devices and has shown considerable promise for the diagnosis and treatment of neurodegenerative diseases, whose global burden continues to increase: in 2021, more than 57 million people were living with dementia worldwide, with Alzheimer's disease (AD) accounting for approximately 60-70% of cases, while an estimated 11.77 million people were living with Parkinson's disease (PD) in 2021, according to the Global Burden of Disease Study 2021. This growing disease burden, together with the progressive loss of cognitive, motor, and communicative functions, highlights the need for more precise approaches to early detection, functional assistance, and individualized intervention. Conventional diagnostic and therapeutic approaches remain poorly suited to early detection and timely intervention. This paper analyzes the development of BCI technology, from the first detection of electroencephalogram (EEG) signals to the parallel development of invasive and non-invasive systems, and outlines the basic principles of signal acquisition, processing, and decoding, together with the relative advantages and limitations of different approaches. It then focuses on the use of BCI in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), covering early diagnosis, functional reconstruction, and neuromodulation. The article also discusses the difficulties encountered by BCI technology in terms of technological realization, clinical translation, and ethical considerations, as well as several future research directions, including multimodal fusion, adaptive algorithms, closed-loop control systems, and personalized treatment so as to drive the applications of BCI in precision medicine and in neurological diseases.},
}

@article {pmid43022629,
year = {2026},
author = {Agarwal, S and Gourlay, R and Soares, RF and Mehta, AR},
title = {In-Gel Tryptic Digestion and HCD/EThcD LC-MS/MS for Mapping Autophosphorylation Sites.},
journal = {Bio-protocol},
volume = {16},
number = {21},
pages = {e5836},
pmid = {43022629},
issn = {2331-8325},
abstract = {This protocol describes a targeted workflow for identifying and quantitatively comparing kinase autophosphorylation sites, using in-gel proteolytic digestion, LC-MS/MS analysis, phosphosite localisation, and extracted ion chromatogram (XIC) analysis. The detailed protocol begins with an excised SDS-PAGE gel band containing the immunoprecipitated kinase of interest. Standard cell culture, expression, immunoprecipitation, and SDS-PAGE procedures can be used to generate this starting material according to the experimental system under investigation; the specific conditions used for NEK1 are described in our associated research article. Here, the protocol is applied to characterise phosphorylation sites on NEK1-a serine/threonine kinase implicated in amyotrophic lateral sclerosis (ALS)-using a homozygous NEK1 knockout cell background in which GFP-tagged wild-type or kinase-dead NEK1 constructs are re-expressed. This experimental system enables accurate assessment of kinase-dependent phosphorylation events in the absence of endogenous NEK1. A key methodological feature of the workflow is the use of two parallel MS2 fragmentation strategies: higher energy collisional dissociation (HCD) and electron-transfer/HCD (EThcD). EThcD generates complementary b/y and c/z ion series, providing superior localisation confidence for labile phosphorylation events that are difficult to resolve using HCD alone. Relative phosphopeptide abundance across conditions can be assessed using extracted ion chromatograms generated in FreeStyle, or using Skyline software with normalisation to the total ion current (TIC), as performed in the associated NEK1 study. Although demonstrated here using NEK1, the protocol is readily adaptable to other kinases amenable to immunoprecipitation and will be of interest to researchers studying kinase signalling, post-translational modification biology, and disease-associated phosphorylation events. Key features • Uses a homozygous NEK1 knockout cell background with re-expressed GFP-tagged constructs for discrimination of kinase-activity-associated candidate autophosphorylation events from background. • Parallel HCD and EThcD fragmentation runs per sample for complementary phosphosite localisation; EThcD is particularly advantageous for labile or multiply phosphorylated peptides. • Quantitative wild-type vs. kinase-dead comparison using extracted ion chromatograms normalised to reference peptides or total ion current, with worked m/z calculations and FreeStyle screenshots. • Readily adaptable to any kinase amenable to immunoprecipitation and for which a kinase-dead control construct can be generated.},
}

@article {pmid43023114,
year = {2026},
author = {Kim, SH and So, JH and Lee, Y and Park, NY and Park, JS and Kim, P and Bae, JE and Jo, DS and Park, HC and Cho, DH},
title = {OGS-MA114 ameliorates FUS mutant-associated ALS pathology by activating PINK1-dependent mitophagy.},
journal = {Animal cells and systems},
volume = {30},
number = {1},
pages = {644-656},
pmid = {43023114},
issn = {1976-8354},
abstract = {Mitochondrial dysfunction and impaired mitophagy are increasingly recognized as central contributors to pathogenesis of amyotrophic lateral sclerosis (ALS). In this study, we identified OGS-MA114 (C23H19ClN4O3S), as a compound that activates mitophagy through a bioactive chemical library screen in SH-SY5Y cells. OGS-MA114 significantly enhanced autophagic and mitophagic flux, increased Ser65-phosphorylated ubiquitin levels, and promoted Parkin recruitment to damaged mitochondria, indicating activation of the PINK1/Parkin pathway. In SH-SY5Y cells expressing the ALS-associated FUS[P525L] mutant, OGS-MA114 restored mitochondrial membrane potential, reduced cleaved caspase-3 levels, and improved cell viability under mitochondrial stress conditions. Furthermore, in a transgenic zebrafish model expressing mutant FUS[R521C], OGS-MA114 significantly improved locomotor activity and survival while reducing cell death in the spinal cord. These findings suggest that OGS-MA114 ameliorates ALS-associated pathological phenotypes by enhancing PINK1-dependent mitophagy. Thus, pharmacological modulation of mitophagy may provide a useful basis for further investigation of ALS and -related neurodegenerative disorders.},
}

@article {pmid43023372,
year = {2026},
author = {Morena, D and Piro, G and Crusco, P and Scopetti, M and Santurro, A and Turillazzi, E and Fineschi, V},
title = {Raman Spectroscopy for Forensic Pathology Applications: A Case Series and Narrative Literature Review.},
journal = {Current pharmaceutical biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892010511762261023050620},
pmid = {43023372},
issn = {1873-4316},
abstract = {INTRODUCTION: Forensic pathology benefits from analytical methods that can add molecular information while preserving tissue morphology and evidentiary material. Confocal Raman microspectroscopy provides non-destructive, spatially resolved chemical information with limited sample preparation. This study evaluated its complementary value in three representative forensic scenarios and contextualized the findings through a structured narrative review of Raman applications in forensic science.

METHODS: Confocal Raman microspectroscopy was applied to formalin-fixed, paraffin-embedded tissue sections from 73 judicial autopsy cases, comprising pulmonary fat embolism (n = 15), acute cocaine intoxication (n = 27), and firearm-related fatalities (n = 31), together with seven sudden cardiac death controls. Spectra were acquired in the fingerprint (660-1800 cm⁸¹) and highwavenumber (2500-3200 cm⁸¹) regions for biological tissue analysis, with additional lowwavenumber acquisition for inorganic gunshot-residue characterization. The spectroscopic analysis was exploratory and descriptive rather than a validated classification study. In parallel, a structured narrative review was conducted using PubMed/MEDLINE, Scopus, and Web of Science to summarize major forensic applications of Raman spectroscopy.

RESULTS: In pulmonary fat embolism, Raman spectra showed characteristic lipid-associated bands, including C-H stretching at 2851, 2928, and 3007 cm⁸¹ and an ester carbonyl band at 1746 cm⁸¹. In cocaine-related fatalities, MCR-ALS mapping demonstrated spatial differences in lipid- and protein-associated spectral contributions relative to controls, including bands around 700, 1000, 1450, and 1650-1690 cm⁸¹. In firearm fatalities, Raman microspectroscopy detected inorganic gunshot-residue particles at wound margins, including a mendipite-associated signature at approximately 148-152 cm⁸¹ and barium-containing spectral features. The narrative review further identified applications in biological fluid discrimination, bloodstain pattern analysis, skeletal and postmortem interval assessment, trace evidence, and chemometric classification.

DISCUSSION: The present findings support its role as an adjunct to established histopathological, toxicological, and trace-evidence methods rather than as a stand-alone diagnostic technique. Confocal Raman microspectroscopy provided complementary, spatially resolved molecular information across the three forensic case categories while preserving the analyzed tissue sections.

CONCLUSION: Standardized acquisition protocols, case-level quantitative validation, multicenter reproducibility studies, and shared forensic spectral libraries remain necessary before routine implementation.},
}

@article {pmid43023417,
year = {2026},
author = {Lu, JJ and Cheung, M},
title = {iPSC-based Approaches to Amyotrophic Lateral Sclerosis: from Drug Screening to Regenerative Medicine in Early Clinical Translation.},
journal = {Stem cells (Dayton, Ohio)},
volume = {},
number = {},
pages = {},
doi = {10.1093/stmcls/sxag064},
pmid = {43023417},
issn = {1549-4918},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by progressive loss of upper and lower motor neurons (MNs), with limited therapeutic options and modest benefit from currently approved drugs. Induced pluripotent stem cells (iPSCs) have emerged as a versatile platform for ALS research, enabling both regenerative medicine and phenotypic drug screening. iPSC-based transplantation strategies aim to replace lost cells or deliver neuroprotective support, while iPSC-derived MNs support drug discovery and repositioning. In the two decades since their discovery, iPSC technologies have progressed from concept to clinical translation, with both cell therapy products such as AstroRx and XS-228 entering trials and three screened drug candidates, Ropinirole, Bosutinib, and Ezogabine, advancing into clinical trials, underscoring their translational potential. In this review, we summarise iPSC-based approaches to ALS, focusing on cell therapies and drug discovery, highlight factors influencing transplantation success, and discuss ongoing clinical trials. We further discuss constraints that impede clinical trial progress, including limited understanding of ALS pathogenesis, absence of robust biomarkers to guide patient stratification and evaluate treatment response, and technical challenges related to the maturation of iPSC-derived neural cells. Finally, we advocate that advancing iPSC approaches requires both deeper understanding of ALS biology and technical innovation. Key priorities are refining iPSC differentiation protocols to improve neuronal maturity and implementing trial designs with adequate duration and rigorous patient stratification.},
}

@article {pmid43010486,
year = {2026},
author = {Li, Y and Hu, J and Lai, T and Wang, L and Shum, PP and Chen, GJ},
title = {A Simulation-Driven Deep Learning Approach for Artifact-Resistant Raman Spectral Unmixing.},
journal = {Analytical chemistry},
volume = {98},
number = {44},
pages = {30132-30140},
doi = {10.1021/acs.analchem.5c07805},
pmid = {43010486},
issn = {1520-6882},
support = {ZDSYS20220527171201003//Shenzhen Key Laboratory of Deep Subwavelength Scale Photonics/ ; G030230001//High-Level Special Funds/ ; G03034K004//High-Level Special Funds/ ; SGDX20211123114001001//Shenzhen Science and Technology Program/ ; 2024YFB3613400//National Key R&D Program of China/ ; 62220106006//National Natural Science Foundation of China/ ; 62361136584//National Natural Science Foundation of China/ ; 624B2061//National Natural Science Foundation of China/ ; 2021B1515120013//Guangdong Basic and Applied Basic Research Foundation/ ; },
abstract = {Raman hyperspectral imaging provides label-free chemical contrast, but quantitative analysis is limited by weak signals, fluorescence background, instrumental noise, and overlapping component spectra. Here, we present a simulation-driven cascaded attention U-Net (AU-Net) for Raman spectral denoising and targeted component unmixing directly from raw spectra. The training data were generated from measured pure-component references combined with randomized fluorescence baselines, nuisance Raman features, reference-spectrum perturbations, and mixed Poisson-Gaussian noise. This design provides paired raw inputs, denoised spectra, and component-level targets without requiring experimentally annotated mixture spectra. AU-Net was evaluated on simulated lipid-protein-DNA mixtures, sugar-mixture spectra, and HeLa-cell Raman hyperspectral images and was compared with NNLS, MCR-ALS, and an autoencoder-based Raman unmixing baseline under explicit preprocessing and reference-use assumptions. The benchmarks show that the raw-input neural workflow improves component recovery under the tested noise, baseline, and interference conditions, while additional stress tests define limitations under reference-spectrum variation, bilinear mixing, and changed target libraries. These results establish AU-Net as a reference-anchored workflow for repeated Raman analyses with a stable component library rather than a blind or universally transferable unmixing method.},
}

@article {pmid43011570,
year = {2026},
author = {Orsulik, D and Niccoli, T},
title = {Integrating single-cell transcriptomics into model systems to decode neurodegeneration in amyotrophic lateral sclerosis.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1911064},
pmid = {43011570},
issn = {1662-5102},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by motor neuron degeneration. Several genetic risk factors, including mutations in C9orf72, SOD1, TARDBP and FUS have been linked to disease. However, the precise cellular pathogenic mechanisms of ALS remain poorly understood, impeding the development of effective therapeutics. ALS model systems, ranging from Drosophila, mice to human induced pluripotent stem cells (hiPSCs), are powerful research platforms for decoding these mechanisms, with their high genetic tractability allowing for the tracking of disease across the life course. Recently, the application of single cell resolution approaches have allowed the dissection of the heterogenous nature of cellular response to disease in these models, revealing novel ALS pathogenic mechanisms and therapeutic targets. In this Review, we explore the unique benefits and challenges of using single-cell RNA-sequencing (scRNA-seq)/single-nucleus RNA-sequencing (snRNA-seq) analysis of in vivo and in vitro ALS model systems to identify disease pathways and drive our mechanistic understanding of ALS forward. By using single cell approaches in models of ALS, researchers can identify novel, druggable, cellular pathways acting across all disease stages that may be obscured in late-stage post-mortem tissue.},
}

@article {pmid43011830,
year = {2026},
author = {Lin, J and Zou, X},
title = {From intestinal barrier sensing to glial immune programming: a barrier-immune-glia relay in microbiota-associated neurodegeneration.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1956619},
pmid = {43011830},
issn = {1664-3224},
mesh = {Humans ; Intestinal Barrier Function ; Animals ; *Neurodegenerative Diseases/immunology/metabolism/microbiology/etiology ; *Neuroglia/immunology/metabolism ; *Gastrointestinal Microbiome/immunology ; Blood-Brain Barrier/immunology/metabolism ; *Intestinal Mucosa/immunology/metabolism/microbiology ; },
abstract = {The gut microbiota contributes to host homeostasis through metabolic, immunological, neural, and barrier-related pathways, and its role in the onset and progression of neurodegenerative diseases has received increasing attention. Patients with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis often exhibit alterations in gut microbial composition, microbial metabolic function, and peripheral inflammatory phenotypes. However, existing clinical evidence is derived predominantly from cross-sectional studies, and the direction of causality between microbiota alterations and disease pathology remains to be established. This review uses a "barrier-immune-glial relay" framework to systematically summarize the potential mechanisms through which gut microbiota-associated signals influence immune homeostasis in the central nervous system. First, alterations in microbial composition, short-chain fatty acids, bile acids, tryptophan derivatives, and lipopolysaccharide may act on the intestinal epithelial barrier, enteric nervous system, and intestinal mucosal immune cells, thereby affecting local immune tolerance and inflammatory responses. Second, intestinal macrophages, dendritic cells, innate lymphoid cells, T cells, and B cells may translate local microbial signals into circulating metabolites, inflammatory mediators, and immune cell-associated signals, which may in turn influence blood-brain barrier function and the central immune microenvironment. Furthermore, microglia and astrocytes, as key integrators within the central nervous system, can respond to gut-derived metabolites and peripheral immune signals. Their interaction network may determine whether neuroinflammation, synaptic injury, and neurodegenerative pathology are amplified or constrained. This review also evaluates the levels of evidence supporting these mechanisms in Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Although these disorders may share mechanistic nodes, including barrier impairment, immunometabolic dysregulation, and glial responses, their core pathologies, immune contexts, and temporal disease trajectories differ substantially. Finally, we propose that establishing a verifiable causal chain linking "microbial functional genes-metabolites-barrier and immune remodeling-glial cell states-neuropathology-clinical phenotypes" will provide a basis for biomarker development and precision interventions in neurodegenerative diseases.},
}

Humans
Intestinal Barrier Function
Animals
*Neurodegenerative Diseases/immunology/metabolism/microbiology/etiology
*Neuroglia/immunology/metabolism
*Gastrointestinal Microbiome/immunology
Blood-Brain Barrier/immunology/metabolism
*Intestinal Mucosa/immunology/metabolism/microbiology

@article {pmid43012292,
year = {2026},
author = {Eng, JH and Chong, AEY and Koh, RY and Ling, APK},
title = {Ferroptosis as a Therapeutic Target in Neurological Disorders: Pharmacological Advances and Translational Challenges.},
journal = {Current pharmaceutical biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892010520055261019113815},
pmid = {43012292},
issn = {1873-4316},
abstract = {Ferroptosis is an iron-mediated form of programmed cell death characterised by distinct features, including excessive iron accumulation, lipid peroxidation, and impaired antioxidant mechanisms. The susceptibility of the Central Nervous System (CNS) to ferroptosis has been reported, along with evidence that ferroptosis is associated with neurological disorders such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), stroke, and Multiple Sclerosis (MS). To date, major ferroptosis inhibitors encompass iron chelators, lipid-trapping antioxidants, and antioxidant modulators. Translational challenges in drug toxicity, selectivity, and delivery promote drug development in terms of improving pharmacokinetics through structural modification, alternative routes of administration, and nanoparticle encapsulation. In addition, research on identifying novel and promising ferroptosis inhibitors from natural products and known drug compounds is continuous, accompanied by ongoing drug optimisation and modification. Biomarkers of ferroptosis have been discussed given the emerging clinical interest in them for disease diagnosis or prognosis and patient stratification. Standalone anti-ferroptotic treatments for CNS disorders have been found to be difficult to achieve favourable clinical outcomes, thereby suggesting combination therapies that not only harness ferroptosis but also address diverse pathological pathways in the respective diseases as a prospect for managing CNS disorders. Thus, this article aims to review recent updates on clinically approved ferroptosis inhibitors as well as summarise the current drug development landscape and outline future directions to provide a better understanding of the contemporary development of ferroptosis inhibitors for neurological disorders.},
}

@article {pmid43012465,
year = {2026},
author = {Keerthipriya, MS and Nalini, A and Thomas, PT},
title = {Authors' Reply- Unfinished Breath: Caregivers' Perceptions of Terminal Events and Gaps in Amyotrophic Lateral Sclerosis Care in India.},
journal = {Annals of Indian Academy of Neurology},
volume = {},
number = {},
pages = {},
doi = {10.4103/aian.aian_1096_26},
pmid = {43012465},
issn = {0972-2327},
}

@article {pmid43013396,
year = {2026},
author = {Park, H and Kim, T and Kang, M and Ryu, JK and Lee, S},
title = {TNIP1 acts as an aggrephagy receptor that assembles clearance machinery for protein aggregate removal.},
journal = {Cell reports},
volume = {45},
number = {11},
pages = {118283},
doi = {10.1016/j.celrep.2026.118283},
pmid = {43013396},
issn = {2211-1247},
abstract = {Selective autophagy receptors recognize and recruit harmful intracellular components to autophagosomes for degradation, and their dysfunction is linked to neurodegeneration, metabolic disorders, and cancer. Here, we identified TNFAIP3 interacting protein 1 (TNIP1) as an aggrephagy receptor implicated in neurodegenerative diseases. TNIP1 accumulated at polyubiquitinated protein aggregates upon proteotoxic stress. Genetic depletion of TNIP1 reduced protein aggregate clearance and increased axonal degeneration under proteotoxic stress. Mechanistically, TNIP1 enhanced protein aggregate clearance by assembling aggrephagy receptors, such as SQSTM1/p62 and TAX1BP1, onto protein aggregates. Gene expression analysis revealed that TNIP1 expression levels are reduced in patients with amyotrophic lateral sclerosis (ALS) with TAR DNA-binding protein 43 (TDP-43) inclusion pathology. Additionally, an ALS-associated TNIP1 mutant exhibited impaired association with TDP-43 aggregates and failed to rescue their autophagy-mediated degradation. These findings establish TNIP1 as an aggrephagy receptor and reveal its potential role as a therapeutic target for ALS and other proteinopathies.},
}

@article {pmid43014974,
year = {2027},
author = {Lee, N and Roytman, M},
title = {Dementia and Neurodegenerative Disease: Movement Disorders.},
journal = {Neuroimaging clinics of North America},
volume = {37},
number = {1},
pages = {103-123},
doi = {10.1016/j.nic.2026.07.006},
pmid = {43014974},
issn = {1557-9867},
mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging ; *Movement Disorders/diagnostic imaging/complications ; *Dementia/diagnostic imaging/complications ; Brain/diagnostic imaging ; *Neuroimaging/methods ; Positron-Emission Tomography/methods ; },
abstract = {Movement disorders encompass a wide variety of neurodegenerative conditions that ultimately present with a combination of changes in movement, and in some cases, changes in cognition. The heterogeneity of movement disorders reflects several underlying pathologic processes and include relatively common entities, such as Parkinson's disease and normal pressure hydrocephalus, as well as less common entities, such as atypical Parkinsonian syndromes, Huntington's disease, Wilson's disease, and amyotrophic lateral sclerosis. Multimodal imaging techniques, including a variety of PET radiotracers, can facilitate an accurate diagnosis of neurodegenerative movement disorders, highlighting the critical role of radiologists in this field.},
}

Humans
*Neurodegenerative Diseases/diagnostic imaging
*Movement Disorders/diagnostic imaging/complications
*Dementia/diagnostic imaging/complications
Brain/diagnostic imaging
*Neuroimaging/methods
Positron-Emission Tomography/methods

@article {pmid43001357,
year = {2026},
author = {Han, X and Li, R and Zhang, H and Liu, Y and Loong, SK and Wei, S and Wang, Y and Pan, W and Dong, T},
title = {Amyotrophic lateral sclerosis treated with the modified Bu-Shen-Jian-Pi decoction (mBSJP): Multicenter study.},
journal = {International journal of clinical pharmacology and therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.5414/CP205054},
pmid = {43001357},
issn = {0946-1965},
abstract = {OBJECTIVES: To investigate whether the modified Bu-Shen-Jian-Pi decoction (mBSJP) is more efficacious than the hitherto used and promoted BSJP formula in the treatment of amyotrophic lateral sclerosis (ALS).

BACKGROUND: ALS is a fatal neurodegenerative disease with no satisfactory treatment option. Currently, there are few palliative care methods that can significantly delay the progression of the disease, and the efficacy of the herbal treatments used hitherto has also been unsatisfactory.

MATERIALS AND METHODS: A total of 165 patients with ALS who met the diagnostic criteria after screening were randomly allocated into two groups, a modified Bu-Shen-Jian-Pi decoction group referred to as the mBSJP group and the placebo group. Clinical efficacy and side effects were evaluated during a 16-week observation period. Primary outcomes included Amyotrophic Lateral Sclerosis Symptom Score in Integrative Treatment Scale (ALS-SSIT) and Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) scores, and secondary observation parameters were 36-Item Short-Form Health Survey Questionnaire (SF-36) and forced vital capacity (FVC).

RESULTS: A total of 73 patients in the mBSJP group and 71 patients in the placebo group completed the trial. At the end of the 16[th] week of treatment, there were significant statistical differences observed between the two groups in values for both the ALS-SSIT and the ALSFRS-R scores showing that mBSJP significantly delayed progression of the disease and appearance of symptoms compared to the administration of placebo.

CONCLUSION: Treatment of ALS with mBSJP delays disease progression and is recommended as a treatment option for ALS in regions where the use of traditional Chinese medicine is regulated and approved.},
}

@article {pmid43002167,
year = {2026},
author = {Sheenam, N and Gaur, R and Gonnade, NM and Abins, TK and Satyavna, F},
title = {Correspondence- The Unfinished Breath: Caregiver Perceptions of Terminal Events and Gaps in Amyotrophic Lateral Sclerosis Care in India - Methodological Considerations.},
journal = {Annals of Indian Academy of Neurology},
volume = {},
number = {},
pages = {},
doi = {10.4103/aian.aian_858_26},
pmid = {43002167},
issn = {0972-2327},
}

@article {pmid43003200,
year = {2026},
author = {Bernardo, BC and Russell, AP},
title = {Beyond neurones: cardiac involvement in motor neurone disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.11.011},
pmid = {43003200},
issn = {1873-7544},
abstract = {Motor neurone disease (MND) is a fatal neurodegenerative disorder defined by the progressive loss of upper and lower motor neurones. This degeneration leads to muscle wasting and weakness, most prominently affecting the upper and lower limbs, the bulbar musculature responsible for speech and swallowing, as well as the respiratory muscles (Feldman et al., 2022). As the disease advances, affected individuals experience profound functional decline, loss of independence, and ultimately respiratory failure, which remains the leading cause of death (Kiernan et al., 2021). Despite advances in understanding the molecular and cellular mechanisms of MND, effective disease‑modifying treatments are limited and there is no cure. Management therefore focuses largely on symptomatic treatment and multidisciplinary supportive care to maintain quality of life (Simon et al., 2015). The long-standing view of MND as a disease confined to the motor system is increasingly being challenged. Emerging evidence from human and rodent studies suggests that other organ systems, such as the heart, may also be affected, raising the possibility that cardiac involvement is a clinically relevant but under‑recognised feature of the disease.},
}

@article {pmid43003661,
year = {2026},
author = {Wu, FM and Spitters, SJ and Sidhu, MS and Smith, JA},
title = {A meso-level approach to quality improvement: a qualitative rapid evaluation of the role of integrated care boards in improving access to general practice in England.},
journal = {BJGP open},
volume = {},
number = {},
pages = {},
doi = {10.3399/BJGPO.2026.0142},
pmid = {43003661},
issn = {2398-3795},
abstract = {BACKGROUND: Commissioning and funding agencies have an increasing role in translating and implementing national policies to improve primary care access, whilst being sensitive to the needs of local contexts. Integrated Care Boards (ICBs) are meso-level commissioning organisations that sit in between national bodies and general practices in the National Health Service (NHS) in England.

AIM: In this study we examine the role of ICBs in facilitating improvements in access to general practice.

DESIGN & SETTING: Qualitative rapid evaluation in three English NHS districts (ICB areas) focused on the role of the ICB in supporting access-focused improvements to primary care services.

METHOD: The study included semi-structured interviews (n=32) with ICB and general practice staff and two focus groups with members of patient representative groups (n=14). We used Braun and Clarke's (2006) six phases of data engagement for data analysis. Our analysis was informed by Bate et al's (2008) framework of six challenges in organising for quality. Site workshops (n=3) with general practice staff supported refinement of findings as part of member validation.

RESULTS: ICBs were found to perform three key roles in facilitating and implementing access-related quality improvement: 1) translational work to contextualise national funding priorities and objectives to the local level; 2) relational work to build trustbased relationships with practices and system stakeholders including local government, at-scale primary care providers, and patient groups; and 3) developmental work to establish infrastructure to support quality improvement, including knowledge-sharing and data analytics capacity.

CONCLUSION: Commissioners play a critical role in bridging national and local contexts to support quality improvement in primary care. The capacity and capability of ICBs to carry out this role are however limited by ongoing organisational restructuring initiated by national policy makers and by constrained resources.},
}

@article {pmid43004356,
year = {2026},
author = {Peden, AE and Raman, M and Jackson, O and Lawton, B},
title = {A qualitative analysis of the impact of drowning prevention programs on belonging among international students.},
journal = {BMC public health},
volume = {26},
number = {1},
pages = {},
pmid = {43004356},
issn = {1471-2458},
support = {PS70229//Medibank Better Health Foundation/ ; PS70229//Medibank Better Health Foundation/ ; APP2009306//National Health and Medical Research Council/ ; },
mesh = {Humans ; *Drowning/prevention & control ; Qualitative Research ; Male ; Female ; *Students/psychology/statistics & numerical data ; Interviews as Topic ; Young Adult ; Swimming/psychology ; Universities ; Australia ; Adult ; },
abstract = {BACKGROUND: Australia has a reputation as a comparatively safe place for international students to study, yet this group is identified as facing increased drowning risk. This qualitative study explored how drowning prevention programs (Learn to Swim and Beach Ocean Safe) at a coastal university in Sydney, Australia, impacted international students' sense of belonging.

METHODS: Via one-on-one interviews with 18 international students, thematic analysis of interview transcripts compared student experiences and insights against Allen et al's four interrelated components from which belonging emerges: competencies for belonging (skills and abilities); opportunities to belong (enablers, removal/reduction of barriers); motivations to belong (inner drive); and perceptions of belonging (cognitions, attributions, and feedback mechanisms - positive or negative experiences when connecting).

RESULTS: We found students' experiences were overwhelmingly positive, fostering increased self-rated skills and confidence. This facilitated social and broader community interaction, minimising previously held feelings of being an outsider when visiting aquatic locations. Additional benefits included friendship facilitation and mental and physical health benefits.

CONCLUSIONS: These findings highlight the opportunity for universities to provide international students with swimming and water safety skills to both reduce drowning risk and foster student belonging. These dual benefits warrant consideration by tertiary education institutions and implementation and expansion of drowning prevention and water safety programs using evidence-based curriculum, teaching practices and evaluation.},
}

Humans
*Drowning/prevention & control
Qualitative Research
Male
Female
*Students/psychology/statistics & numerical data
Interviews as Topic
Young Adult
Swimming/psychology
Universities
Australia
Adult

@article {pmid43004989,
year = {2026},
author = {Sharma, R and Niranjan, N and Long, A and Sharma, R and Safieh, F and Kumar, P and Sund, P and Sellami, Z},
title = {Genome Editing of Mitochondrial Dysfunction in Neurological Disease: Progress and Translational Barriers.},
journal = {The Yale journal of biology and medicine},
volume = {99},
number = {3},
pages = {521-539},
pmid = {43004989},
issn = {1551-4056},
mesh = {Humans ; Animals ; *Gene Editing/methods ; *Mitochondria/genetics/metabolism/pathology ; *Nervous System Diseases/genetics/therapy ; *Mitochondrial Diseases/genetics/therapy ; DNA, Mitochondrial/genetics ; Neurodegenerative Diseases/genetics ; Translational Research, Biomedical ; },
abstract = {Mitochondrial dysfunction is increasingly recognized as a shared mechanism across neurological disease. Specifically, impaired oxidative phosphorylation, oxidative stress, and mitochondrial DNA damage are factors in primary mitochondrial disorders and major neurodegenerative diseases such as Parkinson, Alzheimer, and Huntington diseases, and amyotrophic lateral sclerosis. This review surveys the mechanisms driving mitochondrial dysfunction and evaluates the current landscape of gene-editing technologies developed to address them. We examine mitochondria-targeted editors and nuclear-targeted editors, examining the editing capability, delivery constraints, and off-target risk of each. Heteroplasmy-shifting nucleases currently offer the strongest in vivo evidence for mtDNA-directed therapy, while base editors extend correction to homoplasmic mutations at the cost of a narrower editing scope and off-target editing. Nuclear editing platforms avoid the mitochondrial gRNA import barrier entirely, allowing current technologies to achieve the most progress toward functional, behavioral rescue in animal models. Across all platforms, delivery efficiency, off-target specificity, and translation from rodent to primate models remain unresolved barriers to clinical application. Gene editing for mitochondrial dysfunction is highly creditable as a precision therapy for genetically defined disease subsets, including primary mitochondrial disease and other neurodegenerative disorders with a known nuclear driver, rather than as a universal strategy for sporadic neurodegeneration, where mitochondrial dysfunction arises from multifactorial and poorly localized causes.},
}

Humans
Animals
*Gene Editing/methods
*Mitochondria/genetics/metabolism/pathology
*Nervous System Diseases/genetics/therapy
*Mitochondrial Diseases/genetics/therapy
DNA, Mitochondrial/genetics
Neurodegenerative Diseases/genetics
Translational Research, Biomedical

@article {pmid43006766,
year = {2026},
author = {Via, G and Corradi, F and Tavazzi, G and Wong, A},
title = {Is cardiac arrest still a binary clinical diagnosis? Toward electro-mechanical-hemodynamic phenotyping in the era of point-of-care ultrasound.},
journal = {The ultrasound journal},
volume = {18},
number = {1},
pages = {19728},
doi = {10.5826/tuj.2026.19728},
pmid = {43006766},
issn = {2524-8987},
abstract = {BACKGROUND: Cardiac arrest (CA) remains operationally recognized through clinical signs of absent effective circulation and classified primarily by electrical rhythm. Point-of-care ultrasound (PoCUS) challenges this rhythm-pulse paradigm by directly revealing cardiac mechanical activity and, with Doppler, circulatory flow, exposing physiologically distinct states concealed within current CA categories.

METHODS: This physiology-based conceptual manuscript proposes an integrated electro-mechanical-hemodynamic framework for CA and translates it into PoCUS-consistent phenotyping, portraying CA presentations (CA phenotypes) as pathophysiological states that may transition from one to another along a spontaneous or treatment-modified continuum.

CLINICAL IMPLICATIONS: The framework distinguishes three principal phenotypes: shockable CA (ventricular fibrillation/pulseless ventricular tachycardia); zero-flow CA, encompassing Asystole and PEA without organized ventricular contraction (S-PEA) or with agonal mechanical activity (A-PEA); and severe low-flow CA (C-PEA), in which organized ventricular contraction persists despite absent palpable pulse, and may generate residual circulation. PoCUS can define mechanical states, identify reversible causes, contextualize diagnostic findings, reveal occult shockable activity, and track phenotype transitions. Doppler and invasive arterial-pressure monitoring further characterize spontaneous flow and pressure and may support phenotype-informed treatment.

CONCLUSIONS: Electro-mechanical-hemodynamic phenotyping extends established ALS classification by providing a standardized physiological language for distinct CA states, enabling more homogeneous research populations, phenotype-specific resuscitation research, and rigorous evaluation of PoCUS-informed management. Taken together, these physiological distinctions provide a rationale for reconsidering how cardiac arrest is characterized and how PoCUS-derived information could inform future research, evidence reviews, and resuscitation recommendations.},
}

@article {pmid43008331,
year = {2026},
author = {Wallner, J and Angrick, M and Luo, S and Candrea, D and Crone, N and Krusienski, DJ},
title = {Lower frequency ECoG features improve longitudinal stability of speech and hand-grasp detection in a patient with progressive ALS.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/aec049},
pmid = {43008331},
issn = {1741-2552},
abstract = {Achieving long-term decoding stability is a critical challenge for chronic intracranial brain-computer interfaces (BCIs). High-gamma (HG) activity from intracranial recordings is the standard signal for BCI control, and lower-frequency features can enhance HG decoding performance. This study evaluated the longitudinal stability of speech and hand-grasp detection models using individual and joint spectral features, and the local motor potential (LMP). Approach. Longitudinal data from a single participant implanted with two 64-channel ECoG arrays were used to evaluate the long-term stability of logistic regression models for speech and hand-grasp detection. Models were trained on individual frequency bands and on the LMP, a time-domain low-frequency feature, and evaluated over 21 months for speech and 13 months for grasp. The best-performing band features were then combined into multi-band models and analyzed for their spatial contributions. Main Results. The LMP yielded the most accurate single feature models in both tasks (speech 93.8%, grasp 99.4%) and showed little or no decline. Multi-band models combining HG with lower frequency bands were substantially more stable than HG-only models and outperformed the LMP models for speech but not grasp. HG accuracy degraded strongly for both tasks (speech:-4.3 percentage points per 100 days, or pp/100d, grasp:-3.4 pp/100d). HG+beta for speech showed a negligible decline (-0.5 pp/100d, 95.6% ±0.06% overall), and for grasp, delta alone showed remarkable stability (+0.5 pp/100d), while HG+beta+delta maintained 98.2 ±0.09% overall accuracy with flat performance (+0.0 pp/100d). The advantage of the multi-band models increased over time, reaching +20.6 pp for speech and +10.2 pp for grasp in the last 100 days. Significance. Incorporating lower-frequency neural activity yields more stable long-term speech and grasp detection than HG alone. These findings indicate that lower-frequency and multi-band features may reduce recalibration requirements for simple BCI tasks, and may complement the precision control provided by HG activity.},
}

@article {pmid43009466,
year = {2026},
author = {Malik, T and Jones, S and Ma, O and Mohan, S and Burger, RM and Babcock, DT},
title = {Autophagy induction mitigates FUS aggregate formation and early synaptic dysfunction at the NMJ in a FUS-ALS model.},
journal = {Cell death discovery},
volume = {12},
number = {1},
pages = {},
pmid = {43009466},
issn = {2058-7716},
support = {R01NS110727//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; SAP4100095607//Pennsylvania Department of Health (PDH)/ ; },
abstract = {Mutations in Fused in Sarcoma (FUS), an RNA binding protein, cause Amyotrophic Lateral Sclerosis (ALS). ALS is an aggressive neurodegenerative disease resulting in motor neuron degeneration. Defects in synaptic integrity precede neuronal loss in ALS, but the mechanisms responsible for these early synaptic defects are unclear. To investigate early synaptic defects associated with ALS, we expressed an ALS-linked variant of human FUS in adult motor neurons and assessed synaptic pathology at the neuromuscular junction (NMJ). Here, we highlight the accumulation of FUS-positive aggregates at synaptic terminals and subsequent reduction in microtubule stability. Autophagy induction via expression of Rab1 or Fragile-X Mental Retardation Protein 1 (FMR1), or treatment with rapamycin reduces aggregate formation and restores synaptic structure and function. These findings reveal the utility of inducing autophagy to address early synaptic dysfunction in an ALS model and demonstrate a potential therapeutic target to preventing later stages of disease progression.Teaser Maintaining synaptic integrity protects motor neurons in a model of ALS.},
}

@article {pmid43009540,
year = {2026},
author = {Lee, HJ and Lee, SJ},
title = {The neuro-inflammaging triangle: a self-amplifying circuit of protein pathology, senescence-associated secretory phenotype and innate immunity in neurodegenerative disease.},
journal = {Experimental & molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {43009540},
issn = {2092-6413},
support = {RS-2024-00336045//National Research Foundation of Korea (NRF)/ ; RS-2023-00266536//Ministry of Health and Welfare (Ministry of Health, Welfare and Family Affairs)/ ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, frontotemporal dementia and amyotrophic lateral sclerosis, share common pathological features, including abnormal protein aggregation, chronic neuroinflammation and progressive neuronal loss. Ageing is the strongest risk factor, accompanied by a chronic, mild inflammatory state called 'inflammaging,' partly due to senescent cells producing senescence-associated secretory phenotype (SASP) factors. Innate immune DNA- and danger-sensing pathways, most notably the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasomes, convert cellular injury into chronic neuroinflammation. Here, we propose that protein pathology, SASP, and innate immune activation form a self-amplifying triangular circuit leading to age-related neurodegeneration. We present the cellular and molecular basis of each part and how microglia, astrocytes, oligodendrocyte precursor cells and neurons contribute. We outline treatment strategies, including senolytics, senomorphics, innate immune pathway inhibitors and metabolic restoration, and identify unresolved questions, including the reversibility of post-mitotic neuronal senescence, the relative contribution of each cell type and the translational challenge of interrupting the cycle. Collectively, the neuro-inflammaging triangle theory shifts focus from individual pathogenic entities to the self-amplifying circuit that sustains them, offering a unified mechanistic model to advance our understanding and treatment of age-related neurodegeneration.},
}

@article {pmid43009624,
year = {2026},
author = {Rossi, MN and Attili, L and Cervelli, M},
title = {CircSMOX in muscle and neuronal physiology and disease.},
journal = {Amino acids},
volume = {58},
number = {1},
pages = {},
pmid = {43009624},
issn = {1438-2199},
mesh = {Humans ; Animals ; *RNA, Circular/genetics/metabolism ; *Muscle, Skeletal/metabolism ; *Neurons/metabolism/pathology ; MicroRNAs/genetics/metabolism ; *Neurodegenerative Diseases/metabolism/genetics ; Gene Expression Regulation ; },
abstract = {Circular RNAs (circRNAs) are single stranded RNA molecules with a covalently closed loop structure that confers remarkable stability. They are increasingly recognized as important regulators of gene expression, showing tissue- and stage-specific expression patterns. CircRNAs influence gene expression through several routes: many sequester microRNAs, others bind specific RNA-binding proteins, and some affect transcription or post-transcriptional control. A subset can even be translated into short peptides. They are particularly abundant in the nervous system and in skeletal muscle, where they contribute to processes such as neural development, synaptic function, neuronal plasticity, muscle formation, and tissue homeostasis. Disruptions in circRNA expression patterns have been linked to neurodegenerative conditions, muscle-wasting disorders, and other disease states. Among the known circRNAs, circSMOX-formed from exons 2 and 3 of the murine SMOX gene-has been found dynamically expressed during brain and muscle development and increased in models of ischemia, spinal cord damage, and muscle atrophy. During C2C12 myogenic differentiation, circSMOX expression parallels that of the linear SMOX transcript. In contrast, in dexamethasone-induced atrophy and in ALS mouse models (SOD1[G93A] and hFUS[+/+]), which exhibit progressive muscle atrophy, circSMOX is significantly upregulated. Mainly localized in the cytoplasm and less abundant than the linear isoform, circSMOX acts as a miR-340-5p sponge, influencing neuroinflammatory pathways. Despite these insights, the precise molecular mechanisms of circSMOX remain to be fully clarified, and the identification of a human ortholog will be important to broaden its therapeutic potential.},
}

Humans
Animals
*RNA, Circular/genetics/metabolism
*Muscle, Skeletal/metabolism
*Neurons/metabolism/pathology
MicroRNAs/genetics/metabolism
*Neurodegenerative Diseases/metabolism/genetics
Gene Expression Regulation

@article {pmid43009651,
year = {2026},
author = {Meyer, A and Semenkova, A and Wezel, S and Weber, M and Schweikert, K and Schläger, R and Wendebourg, J and Piguet, O and Berres, M and Braun, N and Lulé, D and Sollberger, M},
title = {Impaired discrimination of negative facial emotions in pure motor ALS.},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {43009651},
issn = {1432-1459},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/psychology ; Female ; Male ; Middle Aged ; *Emotions/physiology ; Cross-Sectional Studies ; Aged ; *Facial Expression ; *Facial Recognition/physiology ; *Discrimination, Psychological/physiology ; },
abstract = {BACKGROUND AND OBJECTIVES: Emotion recognition deficits in amyotrophic lateral sclerosis (ALS) remain debated. We investigated whether patients with pure motor ALS (without cognitive and behavioural disturbances) and without clinically relevant mood disturbances are impaired in discriminating negative facial emotions, using a test without ceiling effects.

METHODS: This cross-sectional study included 35 patients with pure motor ALS, based on the revised Strong criteria and operationalised using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), without clinically relevant mood disturbances, alongside 35 age-, sex-, and education-matched cognitively and psychiatrically healthy controls. All participants completed a shortened five-emotion version of the Facial Emotion Intensity Rating Test - Congruent and Incongruent and the Facial Sex Matching Task (FSMT), a brief screening measure of non-emotional facial discrimination.

RESULTS: Pure motor ALS patients showed poorer discrimination among negative facial emotions than healthy controls (p = 0.011, Cohen's d = 0.63). The group difference did not differ significantly across anger, fear, sadness, and disgust (p = 0.178). Similarly, the group difference in discrimination among negative emotions did not differ significantly from that in discrimination between negative emotions and happiness (p = 0.459). The two groups did not differ significantly on the FSMT.

CONCLUSION: Discrimination of negative facial emotions was impaired in patients with pure motor ALS, suggesting that classification based on ECAS screening may underestimate social-cognitive involvement. Our findings are compatible with the concept of an ALS-frontotemporal spectrum disorder. Whether impaired emotion discrimination relates to additional cognitive or behavioural impairment remains to be determined. The clinical utility and reliability of our measure require further study.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/complications/psychology
Female
Male
Middle Aged
*Emotions/physiology
Cross-Sectional Studies
Aged
*Facial Expression
*Facial Recognition/physiology
*Discrimination, Psychological/physiology

@article {pmid42999280,
year = {2026},
author = {Maita, N and Kim, SY and Kajino, Y and Kato, M},
title = {ALS-associated mutations reveal a conserved C-terminal self-assembly module in the TDP-43 low-complexity domain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.09.756561},
pmid = {42999280},
issn = {2692-8205},
abstract = {TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein whose low-complexity domain (LCD) mediates self-assembly, liquid-liquid phase separation, and pathological aggregation associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previous studies have established the central ultraconserved region (UCR) of the LCD as a major determinant of TDP-43 self-association. However, the contribution of the evolutionarily conserved C-terminal region remains poorly understood. To identify LCD residues required for self-assembly, we systematically analyzed 47 ALS-associated substitutions distributed throughout the TDP-43 LCD using hydrogel-binding and thioflavin T (ThT) assays. Several ALS-associated substitutions within the C-terminal conserved region (CCR) markedly reduced hydrogel incorporation and impaired fibrillization. Similar assembly defects were observed for methionine-to-serine substitutions at two conserved CCR residues, M405 and M414. Furthermore, CCR-containing C-terminal fragments encompassing residues 360-414 or 379-414 formed ThT-positive fibrillar assemblies in vitro . The assembly kinetics exhibited a characteristic lag phase followed by rapid fluorescence growth, consistent with the formation of cross-β-rich assemblies. These findings identify the CCR as an additional conserved self-assembly module within the TDP-43 LCD and expand the prevailing UCR-centered model of TDP-43 assembly. The observation that multiple ALS-associated substitutions reduce rather than enhance self-association further raises the possibility that disruption of normal TDP-43 assembly contributes to disease pathogenesis.},
}

@article {pmid42999738,
year = {2026},
author = {Wang, D and Xu, L and Liu, W and Xie, Z and Sun, Y and Fan, M and Wang, L and Ren, Q and Liu, Y and Liang, J and Wang, R},
title = {Muscle Organoids Frontier: Construction Strategies and Applications of Multi-lineage Muscle Organoids and Multi-organoid Systems.},
journal = {Phenomics (Cham, Switzerland)},
volume = {6},
number = {5},
pages = {757-772},
pmid = {42999738},
issn = {2730-5848},
abstract = {In recent years, multi-lineage muscle organoids have rapidly emerged as transformative research tools, providing high-fidelity models for deciphering skeletal muscle development and the pathological mechanisms of muscle diseases such as sarcopenia, amyotrophic lateral sclerosis, and myasthenia gravis. Primarily derived from pluripotent stem cells, these organoids integrate multiple functional lineages, such as skeletal muscle, neural, vascular, and skeletal components, thereby addressing the limitations of conventional single-tissue muscle models. In parallel, multi-organoid systems, such as assembloids and organ-on-a-chip platforms, further integrate distinct organoids (e.g., muscle, skeletal tissue, tendon, and hindbrain/cervical spinal cord) to reconstruct inter-organ communication and systemic physiology under physiologically relevant conditions. By recapitulating in vivo-like multi-tissue interactions, they serve as critical platforms for drug screening and therapeutic development. This review summarizes recent advances in multi-lineage muscle organoids and multi-organoid systems, outlining their cellular sources, construction strategies, and major applications in basic research, disease modeling, and drug discovery, and discusses current challenges and future directions to enhance their potential in muscle research.},
}

@article {pmid43000537,
year = {2026},
author = {Montanera, KN and Lee, AJ and Yun, W and Ialongo Del Prete, A and Yeh, SY and Jung, I and Rhee, HS},
title = {CREST functions as a molecular bridge between neuron-specific enhancers and epigenetic regulators in mature motor neurons.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {43000537},
issn = {2041-1723},
support = {202203PJT-183582//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; RGPIN-2018-0604//Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology)/ ; CFI37547//Canada Foundation for Innovation (Fondation canadienne pour l'innovation)/ ; },
mesh = {Animals ; *Motor Neurons/metabolism/cytology ; *Epigenesis, Genetic ; Mice ; *Enhancer Elements, Genetic ; *Transcription Factors/metabolism/genetics ; Cell Differentiation/genetics ; Histones/metabolism ; Neurogenesis/genetics ; Gene Expression Regulation, Developmental ; Embryonic Stem Cells/cytology/metabolism ; Nerve Tissue Proteins/metabolism/genetics ; DNA Helicases/metabolism/genetics ; },
abstract = {Motor neuron development requires precise transcriptional regulation mediated in part by BAF (BRG1/BRM-associated factor) chromatin remodeling complexes. The neuron-specific BAF subunit CREST is critical for neuronal function and is mutated in some cases of amyotrophic lateral sclerosis (ALS), yet its underlying genomic mechanisms remain unclear. Using mouse embryonic stem cell differentiation, we show that CREST is essential for motor neuron maturation by activating mature neuronal genes and repressing progenitor genes. Mechanistically, CREST interacts with the neuronal transcription factors ONECUT1 and NGN2, and the BRM ATPase to target pre-existing accessible enhancers of neuronal genes. CREST deletion selectively prevents CBP histone acetyltransferase recruitment, reducing histone H3K27 acetylation at these enhancers and downregulating target gene expression, without disrupting BRM binding, enhancer accessibility, or long-range chromatin architecture. Overall, our findings identify CREST as a crucial epigenetic mediator bridging lineage-specific transcription factors, BAF complexes, and CBP to activate enhancers and promote proper motor neuron development.},
}

Animals
*Motor Neurons/metabolism/cytology
*Epigenesis, Genetic
Mice
*Enhancer Elements, Genetic
*Transcription Factors/metabolism/genetics
Cell Differentiation/genetics
Histones/metabolism
Neurogenesis/genetics
Gene Expression Regulation, Developmental
Embryonic Stem Cells/cytology/metabolism
Nerve Tissue Proteins/metabolism/genetics
DNA Helicases/metabolism/genetics

@article {pmid43001128,
year = {2026},
author = {AlRuwaili, R and Alenzi, MH and Alenzi, MH and Alali, AOA and Aljohani, SN and Alenzi, RF and Abu Alsel, B and Fawzy, MS},
title = {Community awareness and knowledge of amyotrophic lateral sclerosis: a cross-sectional study in the Northern Border Region of Saudi Arabia.},
journal = {PeerJ},
volume = {14},
number = {},
pages = {e21710},
pmid = {43001128},
issn = {2167-8359},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Saudi Arabia ; Female ; Cross-Sectional Studies ; *Health Knowledge, Attitudes, Practice ; Middle Aged ; Adult ; Male ; Surveys and Questionnaires ; Young Adult ; Aged ; *Awareness ; Logistic Models ; },
abstract = {BACKGROUND: Public awareness of amyotrophic lateral sclerosis (ALS) is limited worldwide, with potential implications for timely recognition, care seeking, and social support. Data from the Northern Border Region of Saudi Arabia are lacking. This study aims to assess community awareness and knowledge of ALS and identify predictors of good awareness among adults in the Northern Border Region of Saudi Arabia.

METHODS: A cross-sectional survey of 1,277 adults used a structured self-administered questionnaire covering sociodemographic characteristics, general awareness, knowledge, attitudes, personal experience, and information sources. Awareness was scored from 16 knowledge items and categorized as good (≥ 60%) or poor (<60%). Descriptive statistics, chi-square tests with Cramér's V, and multivariable logistic regression were applied; model performance was assessed using the Hosmer-Lemeshow test and area under the receiver operating characteristic (ROC) curve (AUC).

RESULTS: Participants were mainly young to middle-aged, female, and university-educated, and most worked outside the health field. Although 45.2% had heard of ALS, 90.8% showed poor awareness, while only 9.2% showed good awareness. Uncertainty predominated regarding prognosis, risk groups, neuroanatomical involvement, non-motor symptoms, curability, and diagnostic difficulty. Age and occupation were associated with awareness in bivariate analyses but lost significance after adjustment. Never having heard of ALS markedly reduced the odds of good awareness (adjusted odds ratio (AOR) = 0.167, 95% confidence interval (CI) [0.097-0.288], p < 0.001), while using the internet and healthcare sources was associated with higher awareness. The model showed good calibration (Hosmer-Lemeshow p = 0.891) and discrimination (AUC = 0.820).

CONCLUSIONS: Community awareness and knowledge of ALS in this region are poor, underscoring the need for targeted digital and healthcare-based educational initiatives to improve ALS literacy.},
}

Humans
*Amyotrophic Lateral Sclerosis/psychology
Saudi Arabia
Female
Cross-Sectional Studies
*Health Knowledge, Attitudes, Practice
Middle Aged
Adult
Male
Surveys and Questionnaires
Young Adult
Aged
*Awareness
Logistic Models

@article {pmid42993774,
year = {2026},
author = {Demeyere, M and Dufourni, A and Verhaeghe, LM and Paulussen, E and Heirman, L and De Baere, S and Croubels, S and De Backer, T and van Loon, G and Decloedt, A},
title = {Blood serotonin, ionized magnesium, cardiac troponin I, N-terminal pro-brain natriuretic peptide concentrations, and mitral valve billowing in horses with mitral valve regurgitation.},
journal = {Journal of veterinary internal medicine},
volume = {40},
number = {6},
pages = {},
pmid = {42993774},
issn = {1939-1676},
support = {1SA2225N//Research Foundation Flanders/ ; FWO.HMZ.2022.0008.01//Research Foundation Flanders/ ; D25EQ-039//Morris Animal Foundation/ ; 01B05818//Special Research Fund Ghent University/ ; //Nova Biomedical/ ; },
mesh = {Animals ; Horses ; *Magnesium/blood ; *Troponin I/blood ; *Natriuretic Peptide, Brain/blood ; *Mitral Valve Insufficiency/veterinary/blood/diagnostic imaging ; *Serotonin/blood ; *Horse Diseases/blood/diagnostic imaging/pathology ; Female ; *Peptide Fragments/blood ; Male ; Cross-Sectional Studies ; Biomarkers/blood ; Prospective Studies ; Echocardiography/veterinary ; Mitral Valve Prolapse/veterinary/blood ; },
abstract = {BACKGROUND: Serotonin, ionized magnesium (iMg), cardiac biomarkers, and mitral valve prolapse are extensively investigated in humans and dogs with mitral valve regurgitation (MR), but not in horses.

HYPOTHESIS/OBJECTIVES: To investigate serotonin, iMg, cardiac troponin I (cTnI), and N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations and degree of mitral valve billowing (MVB) in horses with MR.

ANIMALS: Eighty controls (no/trivial MR), 122 horses with MR (92 mild, 24 moderate, 6 severe).

METHODS: Prospective cross-sectional observational study. All horses underwent echocardiography with MVB distance assessment and MR classification. Platelet-poor plasma serotonin and serum iMg, cTnI, and NT-proBNP concentrations were determined. Controls and horses with different MR grades, biomarker concentrations, and MVB distance were compared using (non-)parametric tests.

RESULTS: Ionized magnesium concentration was lower in MR compared to controls (mean difference, 0.03 mmol/L; 95% CI, 0.01-0.05; P = .01), but showed no correlation with billowing distance. The billowing distance was higher in horses with MR than in controls (septal: median difference, 0.2 cm; 95% CI, 0.1-0.3; P < .001; parietal: median difference, 0.3 cm; 95% CI, 0.2-0.3; P < .001), and in horses with a crescendo compared to a holosystolic MR jet (septal: median difference, 0.2 cm; 95% CI, 0.1-0.3; P = .003; parietal: median difference, 0.1 cm; 95% CI, 0.0-0.2; P = .01). No differences in serotonin, cTnI, and NT-proBNP concentrations were detected.

Mitral valve billowing is to some extent likely physiological. The association of serotonin and iMg in MVB and MR requires further investigation. Both cTnI and NT-proBNP showed limited use as biomarkers of MR severity.

ABSTRACT (DUTCH): Achtergrondinformatie: Serotonine, geïoniseerd magnesium (iMg), cardiale biomarkers en mitraalklep prolaps werden reeds uitgebreid onderzocht bij mensen en honden met mitraalklep regurgitatie (MR), in tegenstelling tot paarden met MR. Hypothese/Doelstelling: Het onderzoeken van de serotonine, iMg, cardiaal troponine I (cTnI) en N-terminal pro-brain natriuretic peptide (NT-proBNP) concentraties en de mate van bolling van de mitraalklep naar het linker atrium (MVB) bij paarden met MR. Studiepopulatie: Tachtig controle paarden (geen/triviaal MR), 122 paarden met MR (92 mild, 24 matig, 6 erg). Materiaal en methoden: Prospectieve cross-sectionele observationele studie. Alle paarden ondergingen echocardiografie, waarna de mate van MVB gemeten werd en MR classificatie uitgevoerd werd. De concentraties van serotonine in bloedplaatjesarm plasma en van iMg, cTnI en NT-proBNP in serum werden bepaald. Controle paarden en paarden met verschillende MR graden, biomarker concentraties en de mate van MVB werden onderling vergeleken aan de hand van (non-)parametrische testen. Resultaten: De concentratie iMg was lager bij paarden met MR in vergelijking met controle paarden (gemiddeld verschil, 0.03 mmol/L; 95% BI, 0.01-0.05; P = 0.01), maar vertoonde geen correlatie met de mate van MVB. De mate van MVB was hoger bij paarden met MR dan bij controle paarden (septaal: mediaan verschil, 0.2 cm; 95% BI, 0.1-0.3; P < 0.001; pariëtaal: mediaan verschil, 0.3 cm; 95% BI, 0.2-0.3; P < 0.001), en bij paarden met een crescendo MR jet in vergelijking met paarden met een holosystolische MR jet (septaal: mediaan verschil, 0.2 cm; 95% BI, 0.1-0.3; P = 0.003; pariëtaal: mediaan verschil, 0.1 cm; 95% BI, 0.0-0.2; P = 0.01). Er werden geen verschillen gedetecteerd in de concentraties van serotonine, cTnI en NT-proBNP. Conclusies en klinisch belang: De mate van MVB is tot op een bepaalde hoogte waarschijnlijk fysiologisch. De rol van serotonine en iMg in MVB en MR vergt verder onderzoek. Zowel cTnI als NT-proBNP vertoonden een beperkte meerwaarde als biomarkers bij het bepalen van de ernst van MR.},
}

Animals
Horses
*Magnesium/blood
*Troponin I/blood
*Natriuretic Peptide, Brain/blood
*Mitral Valve Insufficiency/veterinary/blood/diagnostic imaging
*Serotonin/blood
*Horse Diseases/blood/diagnostic imaging/pathology
Female
*Peptide Fragments/blood
Male
Cross-Sectional Studies
Biomarkers/blood
Prospective Studies
Echocardiography/veterinary
Mitral Valve Prolapse/veterinary/blood

@article {pmid42995649,
year = {2026},
author = {Howard, JM and Tuite, M and Mueth, T and Varela, MC and Lazzaro, M and Lieber, L and Liu, S and Rai, KM and Chopra, R},
title = {Discovery and Deployment of Herbicide Tolerance in Domesticated Pennycress (Thlaspi arvense L.) to Enable Modern Agronomic Integration.},
journal = {Plant biotechnology journal},
volume = {},
number = {},
pages = {},
pmid = {42995649},
issn = {1467-7652},
abstract = {Modern agronomic systems for large-scale oilseed production rely heavily on chemical weed control, presenting a barrier to the adoption of newly domesticated crops that lack herbicide tolerance. Pennycress (Thlaspi arvense L.), a domesticated winter oilseed developed to increase land productivity and support sustainable biofuel production, is highly sensitive to commonly used herbicides targeting acetolactate synthase (ALS) and 4-hydroxyphenylpyruvate dioxygenase (HPPD). Here, we report complementary strategies for identifying and deploying herbicide-tolerant alleles in pennycress. ALS inhibitor tolerance was identified through Ethyl methanesulfonate (EMS)-derived chemical mutagenesis, whereas HPPD inhibitor tolerance was explored using a microbial-based rational enzyme design platform as proof of concept. Selected alleles were introduced into advanced germplasm via homology-directed repair (HDR) and evaluated across developmental stages. Plants carrying the P187S mutation in the ALS gene exhibited robust tolerance at both seedling and rosette stages without detectable penalties to growth or seed yield. In contrast, the G419A allele in the HPPD gene conferred tolerance to residual herbicide activity when overexpressed but showed limited efficacy when expressed from its native locus, indicating context-dependent functionality. Collectively, this study demonstrates the feasibility of integrating herbicide tolerance into a newly domesticated oilseed crop and highlights the utility of combining mutagenesis-based discovery, rational enzyme engineering, and precision genome editing to support agronomic compatibility and crop deployment.},
}

@article {pmid42995797,
year = {2026},
author = {Haizel, SA and Ceballos, AV and Ko, AN and Lyu, L and Manning, L and Ge, X and Park, V and Zou, H and Cheng, C and Afful, R and Kher, S and Widjaja, A and Jean-Baptiste, J and Khazhinsky, S and Spealman, P and Jones, AN and Valasek, LS and Vogel, C},
title = {Multi-level repression ensures tight translation control of C9ORF72.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.09.669471},
pmid = {42995797},
issn = {2692-8205},
abstract = {C9ORF72 is involved in multiple neuronal functions and a major factor in Amyotrophic Lateral Sclerosis, a fatal neurodegenerative disease. Pathogenicity is implemented through an intronic repeat expansion in the gene's mRNA leader that produces long, repetitive RNA and dipeptides when translated through repeat associated non-canonical translation. The expanded repeat also suppresses transcription of the major transcript variant (Variant 2) which comprises 90% of the C9ORF72 levels in healthy cells, leading to an additional loss-of-function effect. Examining the sequence, structure, and ribosome occupancy of Variant 2's mRNA leader in detail, we found that translation of C9ORF72 is tightly regulated through a multi-layered system. To deconvolute this system, we conducted a mutant screen and developed a method to evaluate the results quantitatively. We found that near-cognate start codons in all three frames, a start-stop element in frame 2, a uTranslon in frame 1, and secondary structures cooperate to keep baseline C9ORF72 translation low. Further, initiation at upstream near-cognate start codons reduces the impact of both the start-stop and the uTranslon, effectively buffering their repressive function and creating a feedforward loop. A strong secondary structure in the Variant 2-specific sequence further modulates initiation at all the elements. We hypothesize that this buffered repressor system has evolved to ensure reliable, noise-insensitive expression of this critical regulator of neuronal function. Finally, we used ADAR-based RNA editing of specific sites in Variant 2's mRNA leader, increasing translation of the gene and providing a novel avenue to rescue the loss-of-function phenotype in disease.},
}

@article {pmid42995867,
year = {2026},
author = {Amoros, MA and Ekambaram, S and Iskandar, RM and Simmons, Z and Dokholyan, NV},
title = {ALSmiR: a curated evidence resource for ALS-associated microRNAs for biomarker discovery.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.16.759728},
pmid = {42995867},
issn = {2692-8205},
abstract = {Amyotrophic lateral sclerosis is a multifactorial, late-onset neurodegenerative disease with incompletely understood pathogenesis. Limited survival after symptom onset creates an urgent need for biomarkers to support diagnosis, prognosis, and patient stratification. MicroRNAs are among the candidate biomarkers investigated in this disease. Although reviews have synthesized microRNA expression findings, differences in patient populations, biospecimens, and methods complicate comparisons. In the age of data-driven research, we need an updated, searchable resource that links each finding to its context and incorporates growing evidence. Here, we present ALSmiR, a public, manually curated database of polymerase chain reaction-based microRNA expression findings from human biological fluids and their components. ALSmiR currently contains 1,620 expression records from 49 publications comparing patients with amyotrophic lateral sclerosis with healthy controls, covering 816 microRNA names across 13 biospecimen categories. We link publication, cohort, and microRNA-result tables to preserve each finding's clinical and experimental context. We retain significant and non-significant results and provide searchable records and comma-separated values exports for independent analysis. We update ALSmiR annually and verify author submissions against source publications before inclusion. Researchers can use ALSmiR to assess candidate biomarkers, formulate hypotheses, and design independent validation studies. ALSmiR is freely accessible worldwide without registration at https://alsmir.dokhlab.org/ .},
}

@article {pmid42998121,
year = {2026},
author = {Propes, C and Montgomery, T and Cheung, K and Kass, N and Morain, S and Alexander, GC},
title = {Public Participation in U.S. Food and Drug Administration (FDA) Advisory Committees: A Qualitative Analysis.},
journal = {Therapeutic innovation & regulatory science},
volume = {},
number = {},
pages = {},
pmid = {42998121},
issn = {2168-4804},
abstract = {IMPORTANCE: The FDA frequently solicits public input to inform advisory committee meetings reviewing new drug applications. Although intended to enhance transparency and incorporate patient perspectives, the content of these submissions has not been well described.

OBJECTIVE: To characterize public comments to FDA advisory committee meetings and examine the values and considerations expressed.

DESIGN: Qualitative study using inductive content analysis with an iterative coding framework. Comments were coded by one reviewer and independently double-coded for a random subset; disagreements were resolved through discussion (Light's kappa = 0.81).

SETTING: Public comments associated with FDA advisory committee meetings for five new drug applications reviewed between January 2020 and December 2024.

PARTICIPANTS: A random sample of 600 public comments from the five products with the highest public engagement: (1) sodium phenylbutyrate-taurursodiol for ALS; (2) teplizumab for type 1 diabetes; (3) midomafetamine (MDMA-assisted therapy) for PTSD; (4) delandistrogene moxeparvovec for Duchenne muscular dystrophy; and (5) eflornithine tablets for pediatric neuroblastoma.

MAIN OUTCOME MEASURES: Stakeholder role, stance regarding drug approval, and thematic content.

RESULTS: Submissions were most commonly from caregivers or immediate family members (31.5%), individuals without disclosed roles (20.0%), friends or extended family (18.5%), and patients (17.2%). Most comments supported approval (90.2%), with few neutral (7.8%) or opposing (1.3%) views. Four themes emerged: (1) experiential considerations; (2) evidentiary considerations, including clinical trial data and personal observations; (3) regulatory and policy considerations, such as urgency of access; and (4) values-based considerations, such as therapeutic hope and autonomy.

CONCLUSIONS AND RELEVANCE: Public comments were overwhelmingly supportive of approval, reflecting experiential, evidentiary, policy, and values-based considerations. Strengthening mechanisms for synthesizing public input may enhance transparency and confidence in the FDA regulatory process.},
}

@article {pmid42999187,
year = {2026},
author = {Aliya, B and Liu, S and Mansfield, A and Yao, SX and Mouhi, S and Wariyar, SS and Tenkorang, JS and Smith, NE and Chung, M and Rachel Yu, AJ and Pio, T and Smith, NEJ and Zhu, SH and Trautwig, AN and Parameswaran, J and Yin, L and Watson, CM and Hub, BO and Jiang, J and Seyfried, NT and McEachin, ZT and Yao, B and Andersen, J},
title = {Temporal RNA splicing dysregulation in a human multicellular model of C9orf72 ALS.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.13.755334},
pmid = {42999187},
issn = {2692-8205},
abstract = {Amyotrophic lateral sclerosis (ALS) is a complex and heterogenous disease, comprising of familial and sporadic forms, numerous genetic mutations, and a wide range of affected cell types and proposed dysregulated processes. While the usage of in vitro cell cultures, mouse models, and postmortem patient tissue have advanced our understanding of ALS disease mechanisms, the temporal progression of the disease and how early molecular changes evolve remain poorly understood. Here, we establish human spinal cord organoids (hSpO) derived from C9orf72 patient induced pluripotent stem cells (C9-ALS hiPSCs) as a platform to model longitudinal changes across the disease trajectory. We show that C9-ALS hSpO recapitulate hallmark C9orf72 -related pathologies, increased cell death, and progressive neuronal dysfunction. We further identify RNA splicing dysregulation as an early and persistent feature of C9-ALS, with splicing signatures in hSpO closely mirroring those observed in postmortem patient tissue. Finally, prediction of RNA binding proteins (RBPs) that induce early splicing changes in C9-ALS reveals signatures consistent with a broad RBP network dysfunction. Together, this work establishes hSpO as an in vitro system for investigating early disease mechanisms of ALS in a human multicellular context and highlights dysregulated events that precede cell death.},
}

@article {pmid42990966,
year = {2026},
author = {Herrmann, C and Jagodzinski, L and Elmas, Z and Herschmann, T and Fröhlich, E and Bachhuber, F and Ruschitzka, T and Willkomm, F and Parlak, Ö and Weiland, U and Becker, F and Richter, L and Wiesenfarth, M and Uzelac, Z and Michels, S and Witzel, S and Tumani, H and Weishaupt, JH and Maier, L and Mayer, B and Dreyhaupt, J and Schuster, J and Dorst, J},
title = {Efficacy and tolerability of D-β-hydroxybutyrate ester in patients with amyotrophic lateral sclerosis (KETO-ALS)-a randomised, placebo-controlled, double-blind study.},
journal = {EClinicalMedicine},
volume = {101},
number = {},
pages = {104272},
pmid = {42990966},
issn = {2589-5370},
abstract = {BACKGROUND: Hypermetabolism and weight loss are prominent features of amyotrophic lateral sclerosis (ALS). Here, we sought to target the energy deficit in ALS by applying oral ketone bodies as high-energetic substrates.

METHODS: Patients with probable or definite ALS were enrolled to this randomised, placebo-controlled, parallel-group, double-blind, monocentre phase 2 trial. Eligible patients had a decline of ALS functional rating scale revised (ALSFRS-R) of at least 0.33 points/month. They were randomly assigned (1:1) to receive D-β-hydroxybutyrate ester (βHB, 30 g/day) or placebo. Primary endpoint was change of neurofilament light chain (NfL) per month, measured as slope over 6 months. Multiple linear regressions models were applied to adjust for NfL, age, BMI, and slow vital capacity (SVC) at baseline. The trial is registered with clinicaltrials.gov, number NCT04820478.

FINDINGS: Between April 5, 2022, and February 12, 2025, 81 patients were randomly assigned to receive βHB (n = 40) or placebo (n = 41) and included in the intention-to-treat analysis. In the unadjusted analysis, the primary endpoint NfL slope was negative, showing a decline of -0.5 pg/mL/month (IQR -3.2 to 2.0, minimum -11.2, maximum 10.4) in the βHB group and a stable course of 0.0 pg/mL/month (IQR -1.7 to 3.3, minimum -6.2, maximum 49.0) in the placebo group (p = 0.094). In the adjusted analysis, the NfL slope showed a benefit for the βHB group (-1.5 pg/ml/month in βHB vs. +2.8 pg/ml/month in placebo, mean difference -4.2 pg/ml/month, 95% CI - ∞ to -1.1, p = 0.014). When using a mixed effect model, this effect was not statistically different (-0.4 pg/ml/month in βHB vs. +0.3 pg/ml/month in placebo, mean difference -0.7 pg/ml, month, p = 0.30). In the unadjusted analysis, ALSFRS-R showed a faster decline in the verum group (-1.4 points/month (IQR -2.1 to -0.6) vs. -0.8 points/month (IQR -1.2 to -0.2), p = 0.020). No significant difference between βHB and placebo was found regarding clinical endpoints such as ALSFRS-R or BMI in the adjusted analysis. βHB was well tolerated, with similar frequency of adverse events across both groups.

INTERPRETATION: Whether the effects on NfL can be confirmed and translated into meaningful clinical effects, remains to be clarified by a larger phase 3 trial with extended treatment duration. βHB was well tolerated.

FUNDING: This was an investigator-initiated study, funded by a private donation.},
}

@article {pmid42991605,
year = {2026},
author = {Hauser, W and Keller, JE and Pasnoor, M and Wright, DE},
title = {Small-fiber degeneration, sensory dysfunction, and nociception comorbidity in central neurodegenerative disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1854989},
pmid = {42991605},
issn = {1663-4365},
support = {P20 GM103418/GM/NIGMS NIH HHS/United States ; R01 NS043314/NS/NINDS NIH HHS/United States ; },
abstract = {Progressive neurodegenerative disease typically calls for clinical effort to improve cognitive and motor deficits. It is also focused on improving patients' quality of life. However, across these dementias and other diseases, the underlying causes and potential mechanisms remain unclear. Most experimental and clinical research focuses on the central nervous system, examining pathogenic proteins such as tau and amyloid beta, as well as the potential cascade following mitochondrial damage and neuroinflammation. Although peripheral involvement, including gut microbiome influences and other visceral organs, is well-documented, the peripheral nervous system remains an understudied component of these progressive diseases. As peripheral terminals of primary afferent neurons are exposed to inflammatory or toxic mediators, these neurons respond to these threats via neuron-specific phenotypic changes, including the generation of pain. Although normal peripheral sensitization is protective, exposure to damage in a chronic disease state can have long-term detrimental effects. Diseases that lead to central neurodegeneration often also feature peripheral neuropathy and chronic pain. We provide an overview of the incidence of peripheral neuropathy within these diseases, the contribution of changes in sensation to disease, and secondary neuropathic phenotypes resulting from disease. Woven in are discussions of the intersection of degeneration and toxic protein aggregation, briefly touching on resulting inflammatory signaling. Altogether, this review aims to synthesize current understanding of sensory peripheral nerve involvement across these neurodegenerative diseases.},
}

@article {pmid42992452,
year = {2026},
author = {Wang, B and Wang, I and Park, C and Barkhaus, PE and Shirilla, D},
title = {Leuprorelin Acetate for Spinal and Bulbar Muscular Atrophy: A Systematic Review of Clinical Efficacy, Long-Term Outcomes, and Safety Considerations.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70454},
pmid = {42992452},
issn = {1097-4598},
abstract = {Spinal and bulbar muscular atrophy (SBMA; Kennedy disease) is a rare X-linked neuromuscular disorder caused by a CAG repeat expansion in the androgen receptor gene. Leuprorelin acetate, a luteinizing hormone-releasing hormone agonist, suppresses androgen signaling and is approved for SBMA-associated dysphagia in Japan; however, evidence regarding efficacy remains heterogeneous. PubMed and Embase were searched from inception through June 18, 2026, for studies evaluating leuprorelin in genetically confirmed SBMA. Randomized trials, observational cohorts, natural history-controlled studies, extension studies, and safety case reports were included, and findings were synthesized narratively because of substantial heterogeneity. Eleven studies met inclusion criteria, including eight efficacy studies (460 patients) and three safety-focused case reports. Leuprorelin reduced pathogenic androgen receptor accumulation and improved biochemical markers, including serum creatine kinase and creatinine decline. Although neither pivotal randomized trial demonstrated significant short-term functional improvement at 48 weeks, longer-term studies showed slower decline in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), Limb Norris, and Norris Bulbar scores and improved event-free survival from pneumonia and death. Benefits were greatest with earlier treatment, particularly disease duration < 10 years. Leuprorelin was generally well tolerated; common adverse effects included hot flushes, sexual dysfunction, and decreased bone mineral density. Leuprorelin may slow long-term functional deterioration in SBMA, with greater benefit following early initiation and prolonged treatment.},
}

@article {pmid42990340,
year = {2026},
author = {Kaufhold, R and Dong, W and Purwar, I and Saladin, B and Wieland, CM and Krans, A and Laimon, E and Malik, I and Leskaj, S and Havilio, T and Sokabe, M and Fraser, CS and Todd, PK and Querido, JB},
title = {Structural basis for repeat-associated non-AUG translation initiation on C9orf72 mRNA.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.25.761709},
pmid = {42990340},
issn = {2692-8205},
abstract = {A GGGGCC (G 4 C 2) hexanucleotide repeat expansion in the first intron of C9orf72 is the most common monogenic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). This element serves as a template for repeat-associated non-AUG (RAN) translation, which generates neurotoxic dipeptide repeat (DPR) proteins that aggregate in patient brains and contribute to neurodegeneration in model systems. To understand the mechanisms underlying RAN translation initiation, we used cryo-electron microscopy to determine the structure of an in vitro assembled human late-stage C9orf72 translation initiation complex at 3.2 Å resolution and a near-native complex purified from human cell lysate at 3.5 Å resolution. RAN translation on C9orf72 mRNA initiates predominantly at a near-cognate CUG codon that is located 24 nucleotides upstream of the G 4 C 2 repeat and is flanked by a strong endogenous Kozak sequence. The structures further reveal a direct interaction between the G 4 C 2 repeat and 18S ribosomal RNA expansion segment 9 (ES9S) on the 40S small ribosomal subunit through a kissing-loop interaction. Preventing this RNA-RNA interaction using complementary antisense oligonucleotides significantly reduces RAN translation in vitro and in patient-derived iNeurons, indicating that this structural interaction is functionally important. These findings provide mechanistic insights into RAN translation initiation and highlight a novel potential therapeutic approach to mitigate toxic DPR production in C9orf72-associated neurodegenerative disease.},
}

@article {pmid42990486,
year = {2026},
author = {Obara, K and Mastrangelo, A and Ranieri, A and Janelidze, S and Ito, D and Yamamoto, M and Vacchiano, V and Liguori, R and Caldera, S and Riku, Y and Iwasaki, Y and Tran, S and Kawase, T and Mori, Y and Hiraga, K and Yamada, S and Tsujikawa, K and Nishio, Y and Ogi, T and Nakamura, R and Atsuta, N and Sobue, G and Stomrud, E and Palmqvist, S and Hansson, O and Parchi, P and Katsuno, M and Mattsson-Carlgren, N},
title = {Cerebrospinal fluid α-synuclein seed amplification assay positivity identifies a prognostically distinct subgroup in amyotrophic lateral sclerosis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.23.26366349},
pmid = {42990486},
abstract = {BACKGROUND: α-synuclein (Lewy body-type) co-pathology has been identified at autopsy in a subset of patients with amyotrophic lateral sclerosis (ALS). However, its prevalence and prognostic relevance in vivo remain poorly characterized.

METHODS: We analyzed baseline cerebrospinal fluid (CSF) α-synuclein seed amplification assay (αSyn SAA) status in 443 patients with ALS from two cohorts (Nagoya, Japan, n = 248; Bologna, Italy, n = 195). Samples were classified as strong-positive, weak-positive, or negative based on RT-QuIC reactivity across replicate wells, using the assay's established a priori criteria at initial and repeat testing; classifications were corroborated by quantitative kinetic parameters. We compared age- and sex-adjusted odds of positivity in ALS with those in cognitively unimpaired (CU; n = 999; stratified by amyloid-β [Aβ] status), Aβ-positive mild cognitive impairment (n = 224), and Alzheimer's disease dementia (n = 319) groups from the Swedish BioFINDER cohort. In ALS, we examined tracheostomy-free survival and longitudinal functional decline using cohort-stratified Cox and linear mixed-effects models, respectively. We also assessed interactions between αSyn SAA status and baseline CSF neurofilament light chain (NfL). Prognostic analyses were performed in sporadic ALS and repeated after including familial or genetic cases.

RESULTS: Strong αSyn SAA positivity was detected in 24/443 patients with ALS (5.4%); overall positivity, including weak-positive samples, was 37/443 (8.4%). Patients with ALS did not have significantly higher odds of SAA positivity than Aβ-negative CU participants (age- and sex-adjusted odds ratio [OR] 1.33, 95% CI [0.82, 2.14]) and had significantly lower odds than patients with Alzheimer's disease dementia (OR 0.44, [0.27, 0.70]). Among patients with sporadic ALS, strong αSyn SAA positivity was associated with shorter tracheostomy-free survival after adjustment for established predictors including NfL (adjusted HR 2.08 [1.25, 3.45]), whereas weak positivity showed no clear survival association. In linear mixed-effects models, strong αSyn SAA positivity modified the association between NfL and ALSFRS-R decline (NfL × αSyn SAA × time interaction β-0.70 points/month [-1.26, -0.14] per SD NfL). These findings persisted in analyses including familial or genetic ALS cases and in those restricted to Aβ-negative patients. Neuropathological findings (n = 5) were concordant with the CSF αSyn SAA classification.

CONCLUSIONS: A strong α-synuclein seeding profile was uncommon in ALS but identified a subgroup with shorter survival and a stronger association between NfL and functional decline. These findings provide ante-mortem evidence that α-synuclein co-pathology may contribute to prognostic heterogeneity in ALS.},
}

@article {pmid42990777,
year = {2026},
author = {Huang, J and Li, H and Zhou, H and Li, T and Li, J and Liu, D and Yan, K},
title = {Pathological separation utility of plasma neurofilament light chain (NfL) detected by a single-molecule immunoassay platform in neurodegenerative diseases.},
journal = {BMJ neurology open},
volume = {8},
number = {2},
pages = {e001715},
pmid = {42990777},
issn = {2632-6140},
abstract = {BACKGROUND: To establish age-stratified plasma neurofilament light chain (NfL) reference intervals using a domestic Digital Single-Molecule Sensing (DiSMS) platform and to explore neuropathological profiles across amyotrophic lateral sclerosis (ALS), inflammatory demyelinating diseases (IDD) and healthy individuals.

METHODS: We enrolled 719 participants (510 healthy controls, 121 ALS, 88 IDD). Age-specific reference intervals defining the healthy boundary were established using the 2.5th-97.5th percentile method. Pathological separation utility was evaluated via age-stratified subgroup comparisons and receiver operating characteristic (ROC) analysis.

RESULTS: Plasma NfL levels in healthy individuals increased significantly with age (p<0.0001), with reference intervals of 2.68-17.09 pg/mL (20-49 years), 7.14-61.95 pg/mL (50-69 years) and 14.20-104.71 pg/mL (≥70 years). Out-of-boundary NfL elevation rates demonstrated prominent age-dependent fluctuations. In ALS, out-of-boundary elevation rates were 98.3% (57/58) for the 20-49 age group, 68.4% (39/57) for the 50-69 group and 50.0% (3/6) for the ≥70 group, capturing the aggressive tempo of primary motor neuron degeneration. In IDD-which primarily comprised patients in early, clinically stable phases-out-of-boundary rates were 17.0% (8/47) in the 20-49 group and 2.6% (1/38) in the 50-69 group. Age-stratified ROC analysis demonstrated exceptional separation capacity for ALS against healthy controls (area under the curve (AUC): 20-49 years=0.999; 50-69 years=0.964; ≥70 years=0.981) and against IDD (AUC: 20-49 years=0.910; 50-69 years=0.976). Intriguingly, in the 20-49 group where physiological ageing noise was minimal, the platform retained a modest capability to distinguish stable IDD from healthy controls (AUC=0.607).

CONCLUSION: Age-stratified plasma NfL mapping provides a rigorous normative framework for defining population-specific healthy boundaries in China. Rather than functioning as a standalone differential classifier, the dramatic cross-sectional variance in peripheral NfL magnitude successfully maps the distinct pathological spaces separating primary, continuous neurodegeneration (ALS) from quiescent neuroinflammation (IDD) across the adult lifespan, validating the analytical utility of domestic DiSMS platforms.},
}

@article {pmid42990859,
year = {2026},
author = {Benech, H and Krebs-Drouot, L and Viardot, G and Bertaina-Anglade, V and Lhotellier, C and Flament, V and Roucairol, C and Mabondzo, A and Pinquier, JL and Joudinaud, T},
title = {Intranasal CBT101 demonstrates favorable safety and neurophysiological evidence of central activity in healthy male volunteers.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1940627},
pmid = {42990859},
issn = {1664-2295},
mesh = {Humans ; Male ; Administration, Intranasal ; Adult ; Double-Blind Method ; Electroencephalography ; Young Adult ; *Evoked Potentials/drug effects ; Healthy Volunteers ; *Prodrugs/administration & dosage/adverse effects/pharmacology ; Dose-Response Relationship, Drug ; Middle Aged ; },
abstract = {OBJECTIVES: CBT101 is a creatine prodrug under development for disorders driven by impaired neuronal energy homeostasis, with initial development focused on creatine transporter deficiency and amyotrophic lateral sclerosis. This first-in-human study aimed to assess the safety and tolerability of single and repeated ascending intranasal doses of CBT101 in healthy male volunteers and explored neurophysiological evidence of central pharmacodynamic activity using quantitative EEG (qEEG) and event-related potentials (ERPs).

METHODS: This was a randomized, double-blind, single-center, placebo-controlled phase 1 trial including single ascending dose (SAD) and multiple ascending dose (MAD) parts. Forty-eight healthy male volunteers were randomized 3:1 to CBT101 or placebo. CBT101 was administered intranasally at 4.2, 8.4, or 12.6 mg in the SAD part and at 4.2, 8.4, or 12.6 mg/day for 14 days in the MAD part. The primary objective was safety and tolerability. Secondary analyses assessed quantitative EEG (qEEG) and event-related potentials (ERPs) as pharmacodynamic evaluations.

RESULTS: No serious or severe treatment-emergent adverse events occurred, no dose-limiting toxicity was observed, and no clinically relevant safety findings were reported. As expected, plasma CBT101 concentrations were below the limit of quantification in all analyzed samples. qEEG analyses identified an acute post-dose increase in relative beta activity after single dosing. After repeated dosing, the qEEG profile evolved toward a more sustained pattern characterized by beta-1 modulation and early gamma-band changes. ERP/P300 analyses showed a transient decrease in P300 latency, with no statistically significant change in P300 amplitude.

CONCLUSION: Intranasal CBT101 was safe and well tolerated across the evaluated SAD and MAD dose ranges in healthy male volunteers. Convergent qEEG and ERP findings provided early neurophysiological evidence of central pharmacodynamic engagement. These findings support continued clinical development of CBT101 for disorders associated with impaired neuronal energy homeostasis.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT07050316.},
}

Humans
Male
Administration, Intranasal
Adult
Double-Blind Method
Electroencephalography
Young Adult
*Evoked Potentials/drug effects
Healthy Volunteers
*Prodrugs/administration & dosage/adverse effects/pharmacology
Dose-Response Relationship, Drug
Middle Aged

@article {pmid42982035,
year = {2026},
author = {Lee, K and Kwak, T and Park, W},
title = {Retraction to "Integrative ALS therapy: gene targeted therapy by base editing and potential exercise rehabilitation as synergistic strategies for functional recovery".},
journal = {Physical activity and nutrition},
volume = {},
number = {},
pages = {},
doi = {10.20463/pan.2026.0045.r1},
pmid = {42982035},
issn = {2733-7545},
}

@article {pmid42983429,
year = {2026},
author = {Bubphachat, P and Majumder, P and Wang, IF and Huang, JK and Kao, TJ and Lee, YC and Shen, CJ and Chen, GC and Chen, PC and Huang, CS},
title = {The TNKS/PI31-proteasome axis as a central node in TDP-43 neuropathies.},
journal = {Journal of biomedical science},
volume = {33},
number = {1},
pages = {},
pmid = {42983429},
issn = {1423-0127},
support = {NSTC110-2320-B-038-067-MY3//National Science and Technology Council/ ; },
mesh = {Animals ; *Proteasome Endopeptidase Complex/metabolism/genetics ; Mice ; *DNA-Binding Proteins/genetics/metabolism ; *Tankyrases/metabolism/genetics ; Humans ; Mice, Transgenic ; *TDP-43 Proteinopathies/genetics ; },
abstract = {BACKGROUND: Pathological aggregation of Tar DNA-binding protein 43 (TDP-43) and disruption of neuronal protein homeostasis are defining features of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and related TDP-43 proteinopathies. Efficient axonal transport of proteasomes is essential for maintaining local protein quality control in neurons. Proteasome inhibitor 31 (PI31) regulates both 26S proteasome assembly and dynein-mediated transport of 20S proteasomes. Although Tankyrase 1/2 (TNKS)-mediated ADP-ribosylation of PI31 promotes 26S proteasome assembly, its role in proteasome transport and its contribution to TDP-43 pathology remain unclear.

METHODS: Live-cell imaging was performed to examine 20S proteasome transport in primary cortical and motor neurons from wild-type and Prp-TDP-43[A315T] transgenic mice. Protein interactions among TDP-43, TNKS, and PI31 were analyzed by immunoprecipitation and Förster resonance energy transfer (FRET). Insoluble protein accumulation and colocalization were assessed by RIPA/urea fractionation, Western blotting, and immunofluorescence. Proteasome assembly and activity were evaluated using native gel electrophoresis and a 20S proteasome-specific fluorogenic substrate. TDP-43 aggregation was examined by semi-denaturing detergent agarose gel electrophoresis (SDD-AGE).

RESULTS: In cell models expressing TDP-43-FL, TDP-43-A315T, or TDP-25 and in Prp-TDP-43[A315T] transgenic mice, pathological TDP-43 species formed distinct aggregates, ranging from oligomers to prominent cytoplasmic aggregates, yet all reduced proteasome activity, impaired axonal proteasome transport, and caused the accumulation of polyubiquitinated proteins, PI31, 20S proteasomes, and TDP-43 in the proximal axon and cell body. Pathological TDP-43 sequestered TNKS and proteasome components into insoluble fractions, thereby limiting the availability of free and soluble TNKS for interaction with PI31 and subsequent PI31 ADP-ribosylation, ultimately impairing 19S/20S proteasome assembly. Notably, disruption of the TNKS-PI31 interaction or inhibition of TNKS activity recapitulated the proteasome dysfunction induced by pathological TDP-43, supporting a role for the aberrant TNKS-TDP-43 interaction and consequent impairment of TNKS-mediated PI31 ADP-ribosylation in TNKS/PI31/proteasome axis dysfunction.

CONCLUSIONS: Pathological TDP-43 disrupts proteasome function by impairing the TNKS/PI31/proteasome axis, suggesting that this axis may represent a potential therapeutic target for TDP-43 proteinopathies. Selectively restoring this pathway may enhance pathological TDP-43 clearance while minimizing nonspecific proteasome activation, thereby providing a more precise and safer therapeutic strategy for ALS and FTLD.},
}

Animals
*Proteasome Endopeptidase Complex/metabolism/genetics
Mice
*DNA-Binding Proteins/genetics/metabolism
*Tankyrases/metabolism/genetics
Humans
Mice, Transgenic
*TDP-43 Proteinopathies/genetics

@article {pmid42983584,
year = {2026},
author = {Xiong, M and Huang, Y and Jiang, H and Zhang, Z},
title = {Brain clearance of protein aggregates in degenerative diseases: the role of microglia and astrocytes.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42983584},
issn = {2047-9158},
support = {82501688//National Natural Science Foundation of China/ ; 82525025//National Natural Science Foundation of China/ ; 2025AFB243//Natural Science Foundation of Hubei Province/ ; },
mesh = {Humans ; *Astrocytes/metabolism/pathology ; *Microglia/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; *Protein Aggregates/physiology ; *Protein Aggregation, Pathological/metabolism/pathology ; Phagocytosis/physiology ; Proteotoxic Stress ; },
abstract = {Protein aggregation and impaired clearance constitute central pathological hallmarks of numerous neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Misfolded proteins, both extracellular and intracellular, disrupt proteostasis and contribute to synaptic dysfunction, neuroinflammation, and neuronal loss. Within the central nervous system, glial cells serve as the primary mediators of pathological protein clearance. Microglia detect, phagocytose, and degrade aggregated proteins. However, under chronic pathological stress, microglial function turns from clearing pathological proteins to paradoxically facilitating their spread. Astrocytes, which provide metabolic and homeostatic support for neurons, also participate in the clearance of aggregates through phagocytosis and glymphatic drainage. Critically, crosstalk between astrocytes and microglia enhances the clearance: microglia can recruit and process aggregates internalized by astrocytes, while astrocyte-derived signals modulate the microglial phagocytic activity. Aging, genetic risk factors, or sustained neuroinflammation may reduce the efficiency of glial removal of aggregates and accelerate disease progression. Understanding the cellular and molecular underpinnings of microglial and astrocytic clearance pathways is essential for developing therapies aimed at restoring proteostasis and mitigating neurodegeneration.},
}

Humans
*Astrocytes/metabolism/pathology
*Microglia/metabolism/pathology
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Brain/metabolism/pathology
*Protein Aggregates/physiology
*Protein Aggregation, Pathological/metabolism/pathology
Phagocytosis/physiology
Proteotoxic Stress

@article {pmid42983872,
year = {2026},
author = {Kiryu-Seo, S},
title = {[Damage response mechanisms for evading neurodegeneration: mitochondrial supply driven by logistics gate disassembly].},
journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica},
volume = {161},
number = {6},
pages = {422-426},
doi = {10.1254/fpj.26064},
pmid = {42983872},
issn = {0015-5691},
mesh = {Animals ; *Mitochondria/metabolism/pathology ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Axons/pathology/metabolism ; Motor Neurons/pathology/metabolism ; },
abstract = {Mature neurons are highly vulnerable to trauma and neurodegenerative diseases. Conversely, certain peripheral neurons exhibit remarkable survival and regenerative capacities by synchronously activating damage responses to undergo a transient "rejuvenation." Identifying and elucidating these unresolved mechanisms is essential for understanding disease pathogenesis and developing fundamental therapies. Because these responses are driven by complex intercellular interactions, in vivo investigations are indispensable. To address this, we developed the Atf3:BAC Tg mice, a powerful tool that enables damaged neuron-specific genetic manipulation coupled with mitochondrial visualization. Tracking mitochondrial dynamics-which sensitively reflect neuronal states-revealed a novel damage response: injured motor neurons actively disassemble the axon initial segment (AIS), a structural hallmark of mature neurons, via the proteasome to evade axonal degeneration. The AIS functions as a logistical gate restricting axonal transport between the soma and the axon. Strikingly, dismantling this gate allows healthy mitochondria to surge from the soma into the distal axon, successfully preventing energy depletion. In contrast, in amyotrophic lateral sclerosis (ALS) motor neurons, this disassembly switch malfunctions from the early stages of the disease; the gate remains closed under pathological insults, leading to energetic starvation and subsequent degeneration. Intriguingly, ALS-resistant sensory neurons inherently lack this logistical gate, allowing unrestricted mitochondrial supply to axons even under proteasomal dysfunction. This review outlines these cutting-edge findings and introduces the forefront of fundamental research aiming to uncover the pathogenesis of neurodegenerative diseases through the lens of neuronal damage responses.},
}

Animals
*Mitochondria/metabolism/pathology
Humans
*Neurodegenerative Diseases/metabolism/pathology
Axons/pathology/metabolism
Motor Neurons/pathology/metabolism

@article {pmid42983891,
year = {2026},
author = {Ikegami, I and Hongo, S and Koyama, A and Hayakawa-Yano, Y and Yano, M and Sugai, A and Ishihara, T and Tada, M and Kakita, A and Onodera, O and Koike, YM},
title = {TDP-43-related cryptic splicing reflects pathological heterogeneity in amyotrophic lateral sclerosis.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {42983891},
issn = {2051-5960},
support = {24K10506//the Japan Society for the Promotion of Science (JSPS)/ ; Program for Forming Japan's Peak Research Universities (J-PEAKS) JPJS00420240016//the Japan Society for the Promotion of Science (JSPS)/ ; 24K10635//the Japan Society for the Promotion of Science (JSPS)/ ; MoonShot 7 Program JP24zf0127012//the Japan Agency for Medical Research and Development (AMED)/ ; 23ek0109641h0001//the Japan Agency for Medical Research and Development (AMED)/ ; PRESTO, Sakigake, JPMJPR248A//the Japan Science and Technology Agency (JST)/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Female ; Male ; Aged ; Middle Aged ; Retrospective Studies ; *Nerve Tissue Proteins/genetics/metabolism ; *Motor Cortex/pathology/metabolism ; Aged, 80 and over ; },
abstract = {Amyotrophic lateral sclerosis (ALS) involves TAR DNA-binding protein 43 (TDP-43) dysfunction, leading to cryptic splicing, including UNC13A cryptic exon inclusion and truncated STMN2 production. Pathologically, ALS is classified into three phosphorylated TDP-43 subtypes (Types 1, 2a, and 2b) based on the distribution of neuronal and glial cytoplasmic inclusions and the density of dystrophic neurites. However, the relationship between these pathological subtypes and TDP-43-associated cryptic splicing remains unclear. This retrospective postmortem study aimed to analyze motor cortex tissue from sporadic ALS cases (Type 1, n = 12; Type 2a, n = 12; Type 2b, n = 11) with previously described subtype-specific morphological features. UNC13A cryptic RNA and truncated STMN2 RNA levels were quantified using quantitative real-time PCR (qRT-PCR). Compared with Types 1 and 2a, Type 2b, characterized by abundant thread-, dot-, and grain-like dystrophic neurites, exhibited significantly higher levels of UNC13A cryptic RNA and truncated STMN2 RNA. Droplet digital PCR revealed a similar subtype-dependent trend and showed strong correlations with qRT-PCR measurements, providing partial support for the primary findings. UNC13A cryptic RNA and truncated STMN2 RNA levels were positively correlated (Spearman's ρ = 0.58), indicating coordinated dysregulation of multiple TDP-43-dependent splicing targets. Our results demonstrate that the burden of TDP-43-associated cryptic splicing differs across ALS pathological subtypes. Additional analyses indicated that these subtype-dependent differences were not readily accounted for by disease duration, RNA quality, normalization strategy, or semiquantitative neuronal loss scores. These findings suggest that molecular heterogeneity parallels pathological heterogeneity in ALS and provide additional insight into the biological diversity of TDP-43 proteinopathy.},
}

Humans
*Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism
*DNA-Binding Proteins/genetics/metabolism
Female
Male
Aged
Middle Aged
Retrospective Studies
*Nerve Tissue Proteins/genetics/metabolism
*Motor Cortex/pathology/metabolism
Aged, 80 and over

@article {pmid42986019,
year = {2026},
author = {Deng, X and Mitchison, T},
title = {STMN2: Membrane-Binding Microtubule Regulator or Tubulin Effector?.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {48},
number = {11},
pages = {},
doi = {10.1002/bies.70200},
pmid = {42986019},
issn = {1521-1878},
support = {R35GM131753/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; *Tubulin/metabolism ; Animals ; *Microtubules/metabolism ; *Stathmin/metabolism/genetics ; Signal Transduction ; },
abstract = {STMN2, a protein implicated in motor neuron degeneration, is widely viewed as a membrane-associated microtubule inhibitor, but emerging evidence challenges whether this activity defined its cellular function. Three alternative models integrates available evidence to offer perspectives beyond microtubule regulation. The vesicle cargo adaptor model proposes that STMN2 recruits diverse cargos to transport vesicles for axonal delivery. The membrane-bound signaling messenger model links STMN2 turnover to local signaling, effector, degradation, or effector release. The traffic director model proposes that STMN2 regulates cargo routing between delivery and degradative pathways. These models are not mutually exclusive and position tubulin binding as a regulator of STMN2 function rather than its defining activity.},
}

Humans
*Tubulin/metabolism
Animals
*Microtubules/metabolism
*Stathmin/metabolism/genetics
Signal Transduction

@article {pmid42987653,
year = {2026},
author = {Bilgorai, J and Rafferty, GF and Carobin, A and Scott, J and Chen, M and Zhou, P and Shaw, CE and Vanhoestenberghe, A and Bashford, J},
title = {A revised motor unit number estimate detects presymptomatic motor neuron loss in amyotrophic lateral sclerosis.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {194},
number = {},
pages = {2112448},
doi = {10.1016/j.clinph.2026.2112448},
pmid = {42987653},
issn = {1872-8952},
abstract = {OBJECTIVE: To assess the feasibility and sensitivity of a revised stimulation-free motor unit number estimate (REMUNE) for detecting motor unit (MU) loss in amyotrophic lateral sclerosis (ALS).

METHODS: Eighteen ALS patients and twelve healthy controls underwent up to six assessments over one year. High-density surface EMG was recorded bilaterally from clinically relevant hand and lower-leg muscles during stable contractions across ten force levels. MU decomposition used blind source separation, following a novel REMUNE algorithm. In ALS patients, ALS functional rating scale-revised scores and motor unit number index were recorded in parallel.

RESULTS: REMUNE was lower in ALS than controls after adjusting for age and gender (24.9 vs. 52.1, p=0.006; -52%). This difference persisted when only strong ALS muscles were analysed (26.0 vs. 56.1, p=0.027; -54%; strength data available only at first visits). Within ALS, weak muscles produced lower REMUNE values than strong ones (15.5 vs 26.0, p=0.003; -40%). An age-related decline in REMUNE was observed across all participants (-0.85 units/year, p=0.014). REMUNE remained stable over time in ALS muscles (p=0.997).

CONCLUSIONS: REMUNE distinguished ALS from healthy muscles and captured strength-dependent MU loss.

SIGNIFICANCE: REMUNE's sensitivity to presymptomatic MU loss highlights its potential as an early diagnostic aid and trial stratification tool.},
}

@article {pmid42988481,
year = {2026},
author = {Vila-Trias Jover, E and Alcántara Souza, R and Moncusí Armengol, A and Vernet Tomás, MM and Comerma Blesa, L and Maiques Llácer, JM and Azcona Sáenz, J},
title = {Diagnostic value of contrast-enhanced mammography versus magnetic resonance imaging in invasive lobular carcinomas: Correlation with pathological assessment and detection of additional lesions.},
journal = {Radiologia},
volume = {68},
number = {6},
pages = {501753},
doi = {10.1016/j.rxeng.2025.501753},
pmid = {42988481},
issn = {2173-5107},
mesh = {Humans ; Female ; *Carcinoma, Lobular/diagnostic imaging/pathology ; *Breast Neoplasms/diagnostic imaging/pathology ; *Magnetic Resonance Imaging/methods ; Retrospective Studies ; *Mammography/methods ; *Contrast Media ; Middle Aged ; Aged ; Sensitivity and Specificity ; Neoplasm Invasiveness ; Adult ; Aged, 80 and over ; },
abstract = {OBJECTIVE: To compare the diagnostic performance of contrast-enhanced mammography (CEM) with magnetic resonance imaging (MRI) in the preoperative assessment of invasive lobular carcinoma (ILC).

MATERIALS AND METHODS: This was a single-centre, retrospective observational study including women with histologically confirmed ILC who underwent both preoperative CEM and MRI between January 2018 and June 2022. The detection sensitivity of ILC was evaluated using low-energy images (LEI), recombined images (RCI), CEM (LEI + RCI), and MRI. We analysed the correlation of tumour size estimated by each imaging modality and pathology, and the correlation between lesion conspicuity and tumour grade. We also assessed the detection of additional lesions (AL).

RESULTS: Fifty-eight patients with 60 ILCs were included. LEIs showed a sensitivity of 83.3% compared to 100% for RCI, CEM and MRI. MRI demonstrated the strongest correlation with tumour size on HP (r = 0.792). High conspicuity was observed in 68% of ILCs and strongly correlated with MRI enhancement level (ρ = 0.81; P < .001). No significant association was found between conspicuity and tumour grade (P = .074). Of the 53 ALs detected, 39 were malignant. MRI identified all malignant lesions, whereas CEM failed to detect five.

CONCLUSION: CEM may be a comparable alternative to MRI in the detection and size estimation of ILC; however, MRI appears to be superior in identifying malignant additional lesions.},
}

Humans
Female
*Carcinoma, Lobular/diagnostic imaging/pathology
*Breast Neoplasms/diagnostic imaging/pathology
*Magnetic Resonance Imaging/methods
Retrospective Studies
*Mammography/methods
*Contrast Media
Middle Aged
Aged
Sensitivity and Specificity
Neoplasm Invasiveness
Adult
Aged, 80 and over

@article {pmid42988796,
year = {2026},
author = {Long, A and Currey, HN and Goldberg, M and Eck, RJ and Han, M and Kow, RL and Kraemer, BC and Liachko, NF},
title = {Shared and distinct gain-of-function consequences from pathologic cytoplasmic versus nuclear TDP-43.},
journal = {Cell death & disease},
volume = {17},
number = {1},
pages = {},
pmid = {42988796},
issn = {2041-4889},
support = {R01AG066729//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; F31AG082391//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01NS064131//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; I01BX005762//U.S. Department of Veterans Affairs (Department of Veterans Affairs)/ ; IK6BX006467//U.S. Department of Veterans Affairs (Department of Veterans Affairs)/ ; },
mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; *Cytoplasm/metabolism ; *Cell Nucleus/metabolism ; Caenorhabditis elegans/metabolism/genetics ; Humans ; Nuclear Localization Signals/metabolism ; Caenorhabditis elegans Proteins/metabolism/genetics ; Unfolded Protein Response ; Neurons/metabolism/pathology ; Phosphorylation ; },
abstract = {While predominantly nuclear localized in healthy cells, TDP-43 can transit between the nucleus and cytoplasm. In frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), TDP-43 accumulates in hyperphosphorylated cytoplasmic aggregates. However, a subset of patients develops nuclear aggregates. Expression of wild-type TDP-43 in C. elegans neurons results in nuclear protein accumulation and toxic gain of function. To enable comparative study of nuclear and cytoplasmic TDP-43 phenotypes, we generated new models with inactivating mutations in the nuclear localization sequence (NLS) of TDP-43. When compared to nuclear TDP-43 strains, similar protein levels of cytoplasmic TDP-43 cause less neuronal dysfunction in C. elegans. Using RNA sequencing, we determine that transcriptomes are largely unchanged in these models. However, we identify innate immune pathway increases in response to cytoplasmic but not nuclear TDP-43. We find phosphorylation-mediated neurotoxicity of both cytoplasmic and nuclear localized TDP-43 is controlled by the phosphatase calcineurin. We also find that overexpression of the unfolded protein response (UPR) transcription factor XBP-1s worsens outcomes for wild-type TDP-43 animals but improves TDP-43 ΔNLS, suggesting different pathways controlling toxicity and clearance of nuclear versus cytoplasmic TDP-43. Taken together, these data support shared and distinct cellular responses to nuclear versus cytoplasmic TDP-43 localization in an intact animal nervous system. This comparative approach supports a better understanding of human disease and informs therapeutic development for pathological subtypes of TDP-43 proteinopathies.},
}

Animals
*DNA-Binding Proteins/metabolism/genetics
*Cytoplasm/metabolism
*Cell Nucleus/metabolism
Caenorhabditis elegans/metabolism/genetics
Humans
Nuclear Localization Signals/metabolism
Caenorhabditis elegans Proteins/metabolism/genetics
Unfolded Protein Response
Neurons/metabolism/pathology
Phosphorylation

@article {pmid42989888,
year = {2026},
author = {Ruisinger, MM},
title = {Ansichtssache. Ein menschliches Herz als Fragengenerator und Exponat.},
journal = {Berichte zur Wissenschaftsgeschichte},
volume = {},
number = {},
pages = {},
doi = {10.1002/bewi.70053},
pmid = {42989888},
issn = {1522-2365},
abstract = {Ideally, provenance research concerning a human specimen leads from its extracorporeal fate back to its intracorporeal location within a living individual and its biography. This article traces the history of a paraffinated heart from the collection of the German Museum of the History of Medicine in Ingolstadt all the way back to its former owner. Furthermore, it discusses whether and how the research findings obtained in this manner can be incorporated into a public exhibition as part of the museum's science communication efforts.},
}

@article {pmid42989982,
year = {2026},
author = {Cimmino, FA and Comandini, G and Bigliazzi, C and D'Alessandro, M and Salvadori, E and Pianigiani, T and De Stefano, N and Ginanneschi, F and Casali, S and Bargagli, E},
title = {The decline of respiratory function in amyotrophic lateral sclerosis patients and the role of non-invasive ventilation.},
journal = {Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace},
volume = {},
number = {},
pages = {},
doi = {10.4081/monaldi.2026.3644},
pmid = {42989982},
issn = {2532-5264},
abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by a poor prognosis, with an average survival of 3 to 5 years from symptom onset. Respiratory failure is the main cause of death, and non-invasive ventilation (NIV) is a cornerstone in the management of ALS patients. This single-center retrospective study was conducted at Siena University Hospital between 2010 and 2024 to analyze respiratory function parameters in ALS patients undergoing NIV, stratified by disease severity and followed over one year, to assess the relationship between lung function decline and the timing of NIV initiation. A total of 49 patients (29 males, 20 females; mean age 67±12 years) were enrolled, and 31 (63%) received NIV. Clinical and functional parameters, including forced vital capacity (FVC), pCO2, respiratory symptoms at baseline, and longitudinal measurements of sitting FVC (FVCsit%), supine FVC (FVCsup%), and pCO2, were collected and analyzed over time. Differences in FVC decline were observed according to the timing of NIV initiation. Among non-severe patients, those starting NIV at T0 showed a 22.5% reduction in FVC over a mean follow-up of 12.8±4.8 months. Patients initiating NIV at T2 exhibited a reported FVCsit decline of 26% (p=0.0488) and a survival of 51.3±50 months from NIV initiation, whereas those starting later (T3-T6) showed a greater decline (FVCsit decline 34%, p=0.0002) and shorter survival duration (15.7±28.6 months). These findings describe differences in respiratory function trajectories and observed survival among patients initiating NIV at different follow-up time points. However, the retrospective design, small sample size, baseline differences between groups, and potential confounding and survival-related selection bias limit causal interpretation. Further studies are needed to clarify the relationship between NIV initiation timing and clinical outcomes in ALS.},
}

@article {pmid42977507,
year = {2026},
author = {Li, M and Xu, D and Li, Y and Zhao, Q},
title = {Mitochondria-Associated Membranes as a Convergent Hub of Brain Aging: From Neurodegeneration to Cerebral Ischemia.},
journal = {The European journal of neuroscience},
volume = {64},
number = {9},
pages = {},
doi = {10.1111/ejn.70746},
pmid = {42977507},
issn = {1460-9568},
support = {CY2024-MS-A05//Lanzhou University Second Hospital/ ; CY2023-MS-A01//Lanzhou University Second Hospital/ ; 82660095//National Natural Science Foundation of China/ ; GSWSQNPY2024-13//Major Scientific and Technological Innovation Project of the Gansu Provincial Health Sector/ ; 2022RCCX0023//Science and Technology Planning Project of Chengguan District/ ; 2025B-017//Gansu Provincial Department of Education/ ; },
mesh = {Humans ; *Aging/metabolism/pathology ; *Mitochondria Associated Membranes/metabolism ; *Brain Ischemia/metabolism/pathology ; Animals ; *Brain/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; *Mitochondria/metabolism/pathology ; },
abstract = {Brain aging is the principal risk factor for both neurodegenerative diseases (NDDs) and cerebral ischemic disorders, yet the subcellular mechanisms linking these conditions remain incompletely defined. Mitochondria-associated membranes (MAMs)-specialized contact sites between the endoplasmic reticulum (ER) and mitochondria-sit at the intersection of two well-established hallmarks of aging, mitochondrial dysfunction, and loss of proteostasis, making them an attractive mechanistic node for understanding age-related brain decline. In this review, we propose a MAM-centered framework that unifies neurodegenerative and ischemic brain pathology under the broader paradigm of brain aging. We first summarize the molecular architecture of MAMs and their core functions in neuronal Ca[2+] transfer, mitochondrial dynamics, lipid metabolism, inflammasome assembly, and autophagic quality control, together with emerging evidence from non-neuronal brain cells. We then examine how MAM dysfunction intersects with five hallmarks of aging-mitochondrial dysfunction, loss of proteostasis, disabled macroautophagy, chronic inflammation (inflammaging), and altered intercellular communication-drawing on evidence from physiological aging and cellular senescence models. Next, we discuss disease-specific roles of MAMs in cerebral ischemia and in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. A central theme emerges: Rather than a unidirectional decline of MAMs, brain aging is associated with a loss of MAM homeostasis, in which both insufficient and excessive ER-mitochondria coupling can be pathological and the shared deficit is the failure to maintain contact-site function within an optimal range. Finally, we consider age-relevant therapeutic and biomarker strategies targeting MAMs and their potential translation into geriatric neurology. To our knowledge, this is the first review to integrate MAM biology across physiological brain aging, cerebral ischemia, and the four major NDDs within a single homeostatic framework, offering a unified perspective on the mechanisms of age-related brain decline.},
}

Humans
*Aging/metabolism/pathology
*Mitochondria Associated Membranes/metabolism
*Brain Ischemia/metabolism/pathology
Animals
*Brain/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology
*Mitochondria/metabolism/pathology

@article {pmid42978072,
year = {2026},
author = {Zhao, J and Jin, W and Hu, L and Yang, L and Wang, Y and Li, Z and Bai, L},
title = {Multi-omics dissection of interactive cross-stress tolerance to Penoxsulam and salinity in Echinochloa crus-galli.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.71436},
pmid = {42978072},
issn = {1526-4998},
support = {32472586//Natural Science Foundation of China/ ; 2024RC2015//Yuelushan Laboratory Talent Program/ ; 2024JJ2036//Natural Science Foundation of Hunan Province/ ; 2024JJ1005//Natural Science Foundation of Hunan Province/ ; YLS-2025-ZY01003//Yuelushan Laboratory Breeding Program/ ; //Hunan Agriculture Research System (HARS-02)/ ; 2026CX20//Agricultural Science and Technology Innovation Fund Project of Hunan Province/ ; },
abstract = {BACKGROUND: Herbicide resistance and soil salinization increasingly co-occur in rice paddies, yet how evolved penoxsulam resistance shapes the fitness of barnyardgrass (Echinochloa crus-galli) under combined salt and herbicide stress remains poorly understood. This study aimed to resolve the physiological and molecular basis of such cross-stress tolerance.

RESULTS: Using a fully factorial design contrasting a penoxsulam-resistant (AH-225, RI = 4.21) and a susceptible (HN-232) biotype under 100 mm NaCl, 25 g a.i. ha[-1] penoxsulam, and their combination, integrated phenotyping, untargeted metabolomics and RNA-seq revealed that the two biotypes were equally suppressed by salinity alone but diverged under penoxsulam exposure; under combined dual stress, resistant plants maintained 3.78-fold greater aboveground biomass, corresponding to an antagonistic buffering interaction quantified by Bliss independence modelling. Sequencing of eight ALS codons associated with target-site resistance detected no mutation in either biotype, indicating a nontarget-site (metabolic) basis of resistance. Metabolome-wide profiling showed that susceptible plants mounted a costly defensive burst of flavonoids and anthocyanins (Group 9), whereas resistant plants preferentially sustained lignin precursors and accumulated rosin-type diterpenoids (Group 15). Weighted gene co-expression network analysis resolved two antagonistic transcriptional programs: a damage-responsive module marked by the DNA-repair gene MSH4, and a growth-homeostasis module enriched in lipid transfer proteins.

CONCLUSION: Penoxsulam resistance in E. crus-galli operates through constitutive homeostasis maintenance and targeted carbon partitioning rather than amplified defence, providing a mechanistic framework for integrated resistance management in saline paddy fields. © 2026 Society of Chemical Industry.},
}

@article {pmid42979863,
year = {2026},
author = {Choudhury, AK and Rani, P and Gupta, R and Gulati, M and Kapoor, B},
title = {Liposomal Delivery of a Riluzole-Butyric Acid Mutual Prodrug Enhances Neuroprotection and Cognitive Recovery in Experimental Alzheimer's Disease.},
journal = {Journal of drug targeting},
volume = {},
number = {},
pages = {1-21},
doi = {10.1080/1061186X.2026.2759730},
pmid = {42979863},
issn = {1029-2330},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, impaired synaptic signaling, and persistent neuroinflammation. Current therapies primarily provide symptomatic relief and have limited effects on disease progression. Riluzole, approved for amyotrophic lateral sclerosis, exhibits neuroprotective effects through modulation of glutamatergic signaling, but its poor oral bioavailability limits its therapeutic potential. Butyric acid, a short-chain fatty acid postbiotic produced by gut microbial fermentation, possesses well-established anti-inflammatory and neuroprotective properties. In this study, a mutual prodrug of riluzole and butyric acid was synthesized and encapsulated into liposomes to investigate its effects on drug distribution and preclinical efficacy. The prodrug-loaded liposomes exhibited an average particle size of 322 nm, zeta potential of -7.95 mV, and entrapment efficiency of 43.49%. Oral administration significantly improved cognitive performance and attenuated neuroinflammation and oxidative stress in an AlCl3-induced AD-like rat model. Administration of prodrug-loaded liposomes led to the highest concentrations of riluzole in brain homogenates among the relevant treatment groups. Overall, the prodrug-loaded liposomes demonstrated better therapeutic efficacy than the prodrug suspension, individual drug-loaded liposomes, and their respective conventional formulations. The enhanced therapeutic performance is attributed to the complementary pharmacological actions of riluzole and butyric acid, combined with the ability of the liposomal system to improve drug bioavailability and facilitate cerebral delivery.},
}

@article {pmid42980086,
year = {2026},
author = {Yardimci, BI and Zurel, AG and Biterge, B},
title = {Protein Isoaspartate Repair in Amyotrophic Lateral Sclerosis: An Integrative Bioinformatic Analysis of the PCMT Gene Family.},
journal = {ACS chemical neuroscience},
volume = {17},
number = {21},
pages = {3526-3537},
doi = {10.1021/acschemneuro.6c00479},
pmid = {42980086},
issn = {1948-7193},
support = {THD-2025-47488//Bilimsel Arastirma Projeleri Birimi, Istanbul Teknik ?niversitesi/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Computational Biology/methods ; *Protein D-Aspartate-L-Isoaspartate Methyltransferase/genetics/metabolism ; *Isoaspartic Acid/metabolism ; Animals ; },
abstract = {Protein homeostasis is a fundamental determinant of neuronal survival, and its disruption contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS). Protein L-isoaspartate O-methyltransferases (PCMTs) are evolutionarily conserved proteins involved in the recognition and processing of damaged proteins through the repair of isoaspartyl residues and protein quality-control pathways; however, their potential involvement in ALS remains largely unexplored. Here, we performed a comprehensive in silico characterization of the PCMT family (PCMT1, PCMTD1, and PCMTD2) by integrating structural, transcriptomic, single-cell, genetic, and protein modeling analyses. Domain analysis demonstrated that all three proteins share a conserved PCMT domain, while predicted S-adenosylmethionine-binding motifs were identified in PCMT1 and PCMTD2 but not PCMTD1, indicating evolutionary conservation with functional divergence. Expression profiling revealed that PCMT family genes are expressed in ALS-relevant tissues and broadly distributed across neuronal, glial, vascular, and immune cell populations in both healthy and ALS-associated brain single-cell data sets. Analysis of multiple independent ALS transcriptomic cohorts identified consistent upregulation of PCMT family members, with PCMTD1 exhibiting the most reproducible disease-associated expression changes across nervous system tissues and peripheral blood. Gene set correlation analyses further revealed distinct relationships between PCMT expression and neuronal pathways, with PCMT1 showing positive associations with axonal transport and synaptic signaling, whereas PCMTD1 and PCMTD2 displayed largely inverse correlation patterns. Rare missense variants identified in ALS patients were predicted to impair protein function and decrease protein stability, while structural modeling suggested that several substitutions may disrupt conserved residues and the local protein architecture. Collectively, these findings identify the PCMT family as previously underexplored candidates associated with ALS and provide a comprehensive framework for future mechanistic studies investigating their roles in neuronal protein homeostasis and neurodegeneration.},
}

*Amyotrophic Lateral Sclerosis/genetics/metabolism
Humans
Computational Biology/methods
*Protein D-Aspartate-L-Isoaspartate Methyltransferase/genetics/metabolism
*Isoaspartic Acid/metabolism
Animals

@article {pmid42980369,
year = {2026},
author = {Kumar, N and Paruchuri, N and Punshon, T and Jackson, B and Cornell, K and Stommel, E and Deosthali, H and Ravikumar, V and Mostafa, E and Palisoul, S and Vaickus, L and Ho, S and Levy, J},
title = {Integrative spatial metallomics: a tutorial review of multimodal elemental imaging workflows, challenges and opportunities.},
journal = {Analytical methods : advancing methods and applications},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6ay01718e},
pmid = {42980369},
issn = {1759-9679},
abstract = {Spatially resolved molecular assays are increasingly used to study human health and disease, revealing complex tissue organization beyond what is accessible through bulk analyses. While spatial transcriptomic, metabolomic, and proteomic approaches have rapidly matured, quantitative mapping of metals and trace elements in biological tissues and biominerals through elemental imaging remains comparatively nascent. Elemental distributions alone often provide limited biological interpretation without contextualization within the tissue microenvironment. Here, we summarize themes and computational strategies for integrating spatial elemental data with histopathology and complementary spatial molecular assays. We highlight multimodal approaches for tissue alignment, pixel-wise clustering, and correlative analysis, illustrated through limited use cases involving amyotrophic lateral sclerosis (ALS) and kidney stone formation. In the ALS cohort, pixel-level elemental profiles were clustered and compared with annotated tissue structures. In the kidney stone cohort, spatial gradients and correlations in elemental and biomolecular features from the renal papilla through the medulla to cortex were examined. Finally, we discuss key challenges for cross-sample, cohort-level analyses, including differences in spatial resolution, normalization, tissue architecture, and mechanistic inference. Addressing these challenges will require interdisciplinary collaboration, enhanced biobanking practices, and development of computational and statistical frameworks.},
}

@article {pmid42980747,
year = {2026},
author = {He, BH and Yang, W and Yang, M and Lv, X and Zhao, JJ},
title = {Advances in plant polysaccharide research for neurodegenerative diseases therapy.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42980747},
issn = {1573-4978},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Polysaccharides/therapeutic use/pharmacology/chemistry ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Oxidative Stress/drug effects ; *Plants/chemistry ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), represent a growing global public health burden with limited therapeutic options. Plant polysaccharides are natural, biocompatible, and multi-target bioactive macromolecules that have emerged as promising candidates for ND intervention. This review systematically summarizes recent progress in elucidating the structural characteristics, structure-activity relationships, and neuroprotective mechanisms of plant polysaccharides. Key structural features such as molecular weight, monosaccharide composition, glycosidic bond configuration, and spatial conformation critically modulate the biological activity of these molecules. Furthermore, we summarize the numerous protective effects of plant polysaccharides against NDs, including inhibiting abnormal protein aggregation, alleviating oxidative stress via the Nrf2/HO-1 pathway, suppressing neuroinflammation through the NF-κB and MAPK signaling pathways, regulating neuronal apoptosis, and modulating the gut-brain axis. Clinical translation challenges, primarily blood-brain barrier penetration, structural heterogeneity, and insufficient clinical validation, are discussed. Future directions include developing advanced delivery systems, conducting large-scale randomized controlled trials, and exploring synergistic combination therapies. Collectively, plant polysaccharides show considerable promise as potential multi-target candidates for the intervention of NDs, although further studies are needed to clarify their therapeutic potential and facilitate clinical translation.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism
*Polysaccharides/therapeutic use/pharmacology/chemistry
Animals
*Neuroprotective Agents/pharmacology/therapeutic use/chemistry
Oxidative Stress/drug effects
*Plants/chemistry

@article {pmid42981879,
year = {2026},
author = {Sanchez-Santos, C and Madruga, E and Recio, J and Diaz-Palacios, K and Aledavood, E and Lietha, D and Gil, C and Martinez, A},
title = {Targeting the DFG-out conformation of TTBK1 enables the discovery of selective type II neuroprotective inhibitors.},
journal = {European journal of medicinal chemistry},
volume = {321},
number = {Pt 3},
pages = {119468},
doi = {10.1016/j.ejmech.2026.119468},
pmid = {42981879},
issn = {1768-3254},
abstract = {Tau Tubulin Kinase 1 (TTBK1) is an emerging therapeutic target for neurodegenerative diseases because it promotes the pathological phosphorylation of tau and TDP-43, key drivers of Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). However, the development of selective TTBK1 inhibitors is hindered by the high structural similarity between TTBK1 and the essential paralog TTBK2, making ATP-competitive strategies challenging. Here, we report the discovery of computationally supported type II TTBK1 inhibitors by targeting the inactive DFG-out kinase conformation. A druggable DFG-out model was generated using metadynamics and molecular dynamic simulations and employed for virtual screening of the MBC chemical library. This approach identified novel chemotypes that were validated as selective TTBK1 inhibitors with improved discrimination over TTBK2. The most promising compounds also displayed neuroprotective activity in SH-SY5Y neuroblastoma cells. These findings demonstrate that targeting the inactive TTBK1 conformation is a viable strategy to achieve isoform selectivity and establish a new framework for developing disease-modifying therapies for ALS, AD, and other TTBK1-driven neurodegenerative disorders.},
}

@article {pmid42933032,
year = {2026},
author = {Arabinour, M and Sultani, N and Zhou, X and Tayebi, L},
title = {From prediction to design rules: explainable machine learning analysis of cryoprotectant effects in GelMA-based cryobioprinting bioinks.},
journal = {Biomedical physics & engineering express},
volume = {12},
number = {6},
pages = {},
doi = {10.1088/2057-1976/aeb94c},
pmid = {42933032},
issn = {2057-1976},
mesh = {*Cryoprotective Agents/pharmacology/chemistry ; *Machine Learning ; *Cryopreservation/methods ; Random Forest ; },
abstract = {Machine learning has been used to predict cryoprotective-agent (CPA) effects in cryobioprinting, but prediction accuracy alone does not yield experimentally usable formulation rules. Here, we performed a secondary explainable analysis of Qiaoet al's GelMA-HUVEC dataset using formulation-grouped validation, SHAP interpretation, stability metrics, and multi-objective ranking. A compact Random Forest model using permeable CPA identity, sugar CPA identity, permeable CPA concentration, sugar concentration, and storage day achieved MAE = 4.842%, RMSE = 6.106%, andR[2]= 0.649, with bootstrap 95% confidence intervals of 4.418-5.274% for MAE and 0.585-0.710 forR[2]. SHAP analysis identified permeable CPA concentration and storage day as the strongest viability drivers, with directional patterns favoring balanced 15% permeable CPA and 15% sugar CPA rather than simple concentration maximization. Multi-objective ranking identified GL_15_RA_15 as the strongest individual formulation, whereas EG + trehalose showed the highest average CPA-family performance. Cross-domain tests showed limited transfer between EG and GL formulations, indicating that the extracted rules should be treated as local, data-supported design hypotheses rather than universal cryoprotectant principles. Together, these results show that explainable secondary analysis can convert small cryobioprinting datasets into experimentally testable CPA hypotheses while explicitly defining their transferability limits.},
}

*Cryoprotective Agents/pharmacology/chemistry
*Machine Learning
*Cryopreservation/methods
Random Forest

@article {pmid42974963,
year = {2026},
author = {Libonati, L and Cambieri, C and Ceccanti, M and Moret, F and Petrucci, A and Carbone, A and Suppa, A and Inghilleri, M},
title = {Urinary Dysfunction in ALS Patients: Assessment With the Overactive Bladder Awareness Tool.},
journal = {Neurourology and urodynamics},
volume = {},
number = {},
pages = {},
doi = {10.1002/nau.70527},
pmid = {42974963},
issn = {1520-6777},
abstract = {AIMS: To compare urinary symptom bother and overactive bladder screening positivity between patients with amyotrophic lateral sclerosis (ALS) and controls using the Overactive Bladder Awareness Tool (OAB-V8).

METHODS: This retrospective study included 101 patients with definite ALS and 324 controls. OAB-V8 scores were compared using Welch's t-test and multiple linear regression adjusted for age and sex with HC3 robust standard errors. Screening positivity (OAB-V8 ≥ 8) was evaluated using Firth's logistic regression adjusted for age and sex.

RESULTS: Mean OAB-V8 scores were 14.0 ± 6.8 in ALS patients and 12.40 ± 5.10 in controls (unadjusted p = 0.026). The adjusted mean difference was 1.65 points (95% confidence interval [CI] 0.20-3.10; p = 0.026). Screening positivity was observed in 101/101 ALS patients (100%) and 272/324 controls (84.0%). The adjusted odds ratio was 41.03 (95% penalized profile-likelihood CI 5.75-5205.66; p < 0.001), indicating substantial uncertainty in its magnitude.

CONCLUSIONS: ALS patients reported modestly greater urinary symptom burden than controls after adjustment for age and sex. These findings support clinical attention to urinary symptoms in ALS but do not establish their underlying urodynamic mechanism.},
}

@article {pmid42975030,
year = {2026},
author = {Ayoubi, R and MacDougall, EJ and McDowell, I and Biddle, MS and Ferreira, BT and Zha, C and Dorion, MF and Ross, JP and Bolivar, SG and Ruiz Moleon, V and Alende, C and Francis, V and Fotouhi, M and Chaineau, M and Chen, CX and Piscopo, VEC and Soubannier, V and Shlaifer, I and You, Z and Nicouleau, M and Keates, T and Lee, WH and Marsden, BD and Koukouflis, L and Wigren, E and Marks, CA and Healy, LM and Dion, PA and Rouleau, GA and Fon, EA and Virk, HS and Gräslund, S and Gileadi, O and Edwards, AM and Durcan, TM and McPherson, PS and Laflamme, C},
title = {A validated antibody toolbox for ALS research.},
journal = {eLife},
volume = {15},
number = {},
pages = {},
pmid = {42975030},
issn = {2050-084X},
support = {ALS-RAP//Motor Neurone Disease Association, Amyotrophic Lateral Sclerosis Association and ALS Society of Canada/ ; OGI-210//Genome Canada, Genome Quebec and Genome Ontario/ ; YCharOS: A platform enabling neuroscience target validation//Québec Consortium for Drug Discovery/ ; NC/NAM0019/1//National Centre for the Replacement Refinement and Reduction of Animals in Research/ ; MRC UKRI076/MRC_/Medical Research Council/United Kingdom ; OGI-196//Genome Canada and Ontario Genomics/ ; grant no. 875510//EUbOPEN/ ; PJT-195804/CAPMC/CIHR/Canada ; Tier 1//Canada Research Chairs/ ; ALS Scholars//Sean M. Healey & AMG Center for ALS/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/immunology/genetics/metabolism ; Humans ; *Antibodies/immunology ; *C9orf72 Protein/immunology/genetics ; Induced Pluripotent Stem Cells/metabolism ; },
abstract = {A substantial fraction of amyotrophic lateral sclerosis (ALS)-associated proteins remains poorly characterized, in part because of the limited availability of validated research antibodies. We established knockout (KO)-based antibody characterization workflows and demonstrated that widely used antibodies against the major ALS-associated protein C9orf72 lacked specificity (Laflamme et al., 2019). We subsequently scaled this framework to systematically benchmark research antibodies, revealing that up to 61% fail to perform as recommended by manufacturers (Ayoubi et al., 2023b). Here, we extend this approach by establishing the ALS-Reproducible Antibody Platform (ALS-RAP), a comprehensive effort to generate a publicly available dataset of KO-validated antibodies targeting proteins encoded by ALS risk genes. In total, we characterized 303 antibodies against 33 ALS-associated proteins to identify high-quality reagents for use in western blot, immunoprecipitation, and immunofluorescence. Using these antibodies, we profiled protein levels across human induced pluripotent stem cell-derived and primary neurological cell types. These analyses revealed diverse cellular distributions and higher levels of several ALS-associated proteins in glial populations, consistent with emerging evidence for immune contributions to ALS. Together, ALS-RAP provides a validated antibody toolbox and protein expression resource to support the study of ALS-associated proteins.},
}

*Amyotrophic Lateral Sclerosis/immunology/genetics/metabolism
Humans
*Antibodies/immunology
*C9orf72 Protein/immunology/genetics
Induced Pluripotent Stem Cells/metabolism

@article {pmid42975041,
year = {2026},
author = {Kuiper, MM and Kruithof, WJ and Broekman-Peters, N and Visser-Meily, JMA and Beelen, A},
title = {Personalizing nutritional care in amyotrophic lateral sclerosis (ALS): a multi-perspective qualitative focus group study of experiences and challenges.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2026.2750614},
pmid = {42975041},
issn = {2167-9223},
abstract = {Background: Proactive, timely nutritional care is important for people living with amyotrophic lateral sclerosis (plwALS), as weight loss and malnutrition are associated with faster disease progression and shorter survival. However, previous studies have shown that there is considerable practice variation in nutritional care, and that care is not always delivered proactively. Objectives: To gain insight into how healthcare professionals (HCPs), plwALS and their primary caregiver experience nutritional care. Methods: A generic qualitative study was conducted using semi-structured focus group discussions. Five focus group discussions were organized: two with HCPs and three with plwALS and their primary caregivers. Data were transcribed verbatim and analyzed inductively using thematic analysis. Results: In total, 14 HCPs, 19 plwALS, and three primary caregivers participated. Analyses resulted in four major themes: (1) A gap between knowing and acting, (2) balancing providing and withholding care, (3) sufficiently informed to participate in shared decision-making? and (4) opportunities for improvement. Conclusion: Findings suggest that improving nutritional care in ALS requires clear and transparent communication to ensure that plwALS and caregivers are well-informed about the importance of nutrition and monitoring of nutritional status, and more involved in clinical decision-making. Clear explanations about the dietitian's role and nutritional care process may improve patient engagement and facilitate shared decision-making.},
}

@article {pmid42975618,
year = {2026},
author = {Xu, Z and Fan, T and Xu, R},
title = {Current findings, application, and diagnosis of magnetic resonance imaging in amyotrophic lateral sclerosis.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {42975618},
issn = {2191-0200},
abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disorder within the motor neuron disease (MND) spectrum, characterized by progressive degeneration of upper and lower motor neurons. The clinical phenotype ranges from pure motor syndromes to forms with cognitive and behavioral impairment, and the pathological burden extends beyond the motor system. Diagnosis remains primarily clinical, supported by electrophysiology and exclusion of mimics. Therefore, objective imaging biomarkers are urgently needed. Magnetic resonance imaging (MRI) is widely used as an auxiliary and differential diagnostic tool in ALS. T1- and T2-weighted imaging can assess cortical thickness, gray matter atrophy, and signal changes. Diffusion tensor imaging probes white matter microstructure. Magnetic resonance spectroscopy detects neurochemical alterations. Resting-state functional MRI assesses functional connectivity and network organization. Susceptibility-weighted imaging is sensitive to iron and calcium deposition. Ultra-high-field MRI provides higher resolution and improved metabolite quantification. This critical review summarizes current findings on MRI in ALS, but importantly organizes the evidence by the specific question being addressed: pathological/histological correlates, diagnostic or discriminatory performance, and clinical associations with phenotype, severity, progression, and prognosis. We also discuss major limitations, including methodological heterogeneity, limited standardization, small and clinically heterogeneous cohorts, frequent use of healthy rather than disease controls, and scarce multicenter validation. Although advanced MRI has revealed robust group-level alterations, none of these techniques has yet become established in routine clinical diagnosis of ALS. We, therefore, distinguish promising research findings from validated clinical biomarkers and outline priorities for future translation.},
}

@article {pmid42975660,
year = {2026},
author = {Yin, Y and Tu, Y and Wang, B and Chen, Y and Zhao, Y and Tang, J and Zhang, M and Zhang, J},
title = {Subtype and stage inference of tract-level diffusion abnormalities in amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {42975660},
issn = {1432-1459},
support = {No.82471967//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/classification/pathology ; Female ; *Diffusion Tensor Imaging ; Male ; Middle Aged ; Retrospective Studies ; Anisotropy ; Aged ; *White Matter/diagnostic imaging/pathology ; Adult ; Severity of Illness Index ; },
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) shows substantial heterogeneity in clinical presentation and white matter involvement, but conventional diffusion tensor imaging analyses provide limited information on whether tract-level abnormalities follow distinct patient level patterns.

METHODS: This retrospective secondary analysis included 73 patients with ALS and 30 healthy controls. Fractional anisotropy (FA) and mean diffusivity (MD) from 11 predefined tracts were used as SuStaIn biomarkers, with healthy controls providing the normative reference for Z-score standardization. SuStaIn subtypes and stages were examined against Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), King's stage, and peak width of skeletonized mean diffusivity (PSMD).

RESULTS: The three-subtype model classified patients into cingulate callosal motor mixed subtype (n = 34), hippocampal cingulum posterior projection subtype (n = 32), and posterior callosal projection, MD predominant subtype (n = 7). Exploratory comparisons showed lower PSMD in subtype 0 than subtypes 1 and 2 (both p = 0.026), lower ALSFRS-R in subtype 2 than subtype 1 (p = 0.026), and higher SuStaIn stage in subtype 2 than subtype 0 (p = 0.025). Higher SuStaIn stage correlated with higher King's stage (rho = 0.318, p = 0.006) and lower ALSFRS-R (rho = - 0.289, p = 0.013). After adjustment, higher SuStaIn stage remained associated with lower ALSFRS-R (β = - 0.333, p = 0.013) and more advanced King's stage (odds ratio = 1.181, p < 0.001).

CONCLUSION: Tract-level diffusion SuStaIn identified anatomically interpretable patterns of white matter involvement in ALS and provided patient-level stage estimates associated with clinical disease burden.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging/classification/pathology
Female
*Diffusion Tensor Imaging
Male
Middle Aged
Retrospective Studies
Anisotropy
Aged
*White Matter/diagnostic imaging/pathology
Adult
Severity of Illness Index

@article {pmid42976580,
year = {2026},
author = {Jiménez-Villegas, J and Carnicero-Senabre, D and Sicart, A and Van Den Bosch, L and Cuadrado, A and Rojo, AI},
title = {Lack of NRF2 expression alters the dynamics of stress granules promoting the aggregation of ALS disease-associated proteins.},
journal = {Redox biology},
volume = {98},
number = {},
pages = {104462},
doi = {10.1016/j.redox.2026.104462},
pmid = {42976580},
issn = {2213-2317},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron death. Although ALS pathogenesis is multifactorial, increasing evidence highlights a close interplay between dysfunction of RNA metabolism and redox imbalance in disease progression. Redox perturbation converges with RNA dysregulation at the level of the dynamics of stress granules, transient ribonucleoprotein assemblies implicated in protein aggregation, in ALS. The redox-sensitive transcription factor NRF2 (Nuclear factor erythroid 2-related factor 2) plays a pivotal role in cellular homeostasis, yet its function and regulation remain poorly defined in ALS. In this study, we explore how NRF2 modulates stress granule dynamics under oxidative and non-oxidative stress conditions. Using live-cell imaging, we reveal that NRF2 deficiency enhances the formation of stress granules in response to oxidative and non-oxidative stressors, facilitates their persistence, and promotes increased stress granule recruitment of ALS-linked proteins such as TDP-43 and FUS. Likewise, we uncover a protective role of pharmacological NRF2 activation in limiting exacerbated stress granule responses in iPSC-derived motor neurons from C9orf72-ALS patients and show how NRF2 activation can impact TDP-43 aggregation and loss of function in SH-SY5Y cells. Together, these findings position NRF2 as a crucial integrator of redox signalling and RNA metabolism in ALS pathogenesis. Targeting NRF2 may offer novel therapeutic avenues to counteract the vicious cycle of oxidative stress, dysfunctional stress granule dynamics, and protein aggregation in motor neuron disease.},
}

@article {pmid42977228,
year = {2026},
author = {Mercadante, S and Travia, M and Scimone, P and Dabbene, M and Cascio, AL},
title = {Cancer versus Non-Cancer Patients Admitted to Hospice: a comparison study.},
journal = {Journal of pain and symptom management},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jpainsymman.2026.10.030},
pmid = {42977228},
issn = {1873-6513},
abstract = {CONTEXT: Malignant disease remains the leading reason for hospice admission, and direct, patient-level comparisons of cancer and non-cancer patients within the same residential hospice are scarce.

OBJECTIVES: To compare sociodemographic and clinical characteristics, symptom burden, nutritional support, length of stay and outcome between oncological and non-oncological patients admitted to a single hospice.

METHODS: Prospective observational cohort study of 175 consecutive admissions over one year, after removal of duplicate records. Patients were classified as oncological (n=151, 86.3%) or non-oncological (n=24, 13.7%) based on structured case report form fields. Sociodemographic, functional (Karnofsky Performance Status, KPS), nutritional, symptom (Edmonton Symptom Assessment System, ESAS) and cognitive (Memorial Delirium Assessment Scale, MDAS) data were collected at admission (T0); ESAS completion was also examined at 1 week (T7). Categorical variables were compared with the chi-square or Fisher's exact test, continuous variables (reported as median and interquartile range, including ESAS and MDAS scores) with the Mann-Whitney U test; p-values were adjusted for multiple comparisons with the Benjamini-Hochberg procedure (q).

RESULTS: Most non-oncological patients had a neurological disease (21/24), mainly neurodegenerative diseases, amyotrophic lateral sclerosis and dementia. Non-oncological patients were older (median 78.5 vs 72 years, P=0.002, q=0.012) and had worse performance status at admission (median KPS 20 vs 30, P<0.001, q=0.006). Artificial nutrition was more frequent among non-oncological patients (37.5% vs 14.9%, P=0.018), although not after correction for multiple comparisons (q=0.060). MDAS scores were higher in non-oncological patients (median 13 vs 4, P=0.021). ESAS data were missing in about half of oncological and three quarters of non-oncological patients; no ESAS item differed between groups after correction for multiple comparisons, and the non-oncological group's valid ESAS sample fell to a single patient by T7. Length of stay (11 vs 8 days, P=0.518) and in-hospice mortality (80.0% vs 70.8%, P=0.455) did not differ significantly.

CONCLUSION: In this single-centre series, non-oncological patients, mostly affected by neurological diseases, were admitted older, more functionally compromised and with higher MDAS scores than oncological patients, despite comparable length of stay and mortality. Apparent differences in symptom burden are confounded by substantial, likely informative, missing data and should be interpreted with caution. Whether these differences reflect later referral or the age profile of the underlying diseases cannot be determined from these data.},
}

@article {pmid42967168,
year = {2026},
author = {Cao, S and Liu, T and Cheng, X and Tian, X and Wei, J},
title = {The "Invisible Killer" of Neurodegeneration: Mitochondrial Dysfunction in Neurodegenerative Disorders, Mechanisms, Emerging Pathways and Therapeutic Strategies.},
journal = {Journal of inflammation research},
volume = {19},
number = {},
pages = {653025},
pmid = {42967168},
issn = {1178-7031},
abstract = {Neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) place substantial burden on global public health. Mounting evidence identifies mitochondrial dysfunction as a central contributor to neuronal damage and progressive brain functional decline. As a narrative review, this work aims to dissect mitochondrial‑associated pathological features across these major neurodegenerative disorders, summarize under‑recognized emerging mechanisms, and highlight translational bottlenecks for mitochondrial‑targeted therapies. Mitochondria sustain neuronal survival by mediating oxidative‑phosphorylation‑driven energy production, biomolecule biosynthesis, calcium homeostasis, reactive oxygen species (ROS) metabolism, and apoptotic regulation. In PD, aggregated α‑synuclein (α‑syn) damages respiratory‑chain complex I, perturbs mitochondrial dynamics and blocks PINK1/Parkin‑dependent mitophagy. In AD, amyloid‑β together with hyper‑phosphorylated tau (p-Tau) impairs respiratory complex activity, axonal mitochondrial trafficking and mitophagic clearance. Mutant huntingtin induces multiple mitochondrial lesions in HD, while inflammation‑triggered oxidative stress secondarily compromises mitochondrial function in MS. Pathogenic mutations in ALS disrupt respiratory‑chain assembly, mitochondrial dynamics and mitophagy. Beyond classic mitochondrial defects including respiratory‑chain impairment, dynamic imbalance and defective mitophagy, emerging mechanisms such as mitocytosis, mitochondrial aminoacyl‑tRNA synthetase (mt‑aaRS) dysfunction and mitochondria‑associated membrane (MAM) disruption are discussed. Mitochondrial dysfunction drives neurodegeneration via energy exhaustion, aggravated oxidative stress, pathological protein aggregation and excessive neuronal apoptosis. We further recapitulate mitochondrial‑oriented therapeutic approaches including small‑molecule regulators, mitophagy activators, mitochondrial biogenesis promoters, gene‑editing strategies and mitochondrial transplantation. Notable translational obstacles remain, including limited blood‑brain‑barrier penetration of candidate drugs, narrow therapeutic time‑window post‑symptom onset, and prominent disease heterogeneity. By synthesizing basic experimental findings and pre‑clinical and clinical trial progress, this review provides updated insights into the pathogenesis of neurodegenerative diseases and facilitates the development of precise mitochondrial‑targeted therapeutic regimens.},
}

@article {pmid42969635,
year = {2026},
author = {Bannwarth, S and Paquis-Flucklinger, V},
title = {[Mitochondria in sporadic amyotrophic lateral sclerosis: actor or initiator?].},
journal = {Medecine sciences : M/S},
volume = {42},
number = {10},
pages = {797-799},
doi = {10.1051/medsci/2026146},
pmid = {42969635},
issn = {1958-5381},
}

@article {pmid42970317,
year = {2026},
author = {Pourhadi, M and LeWitt, PA and Todi, SV},
title = {Ceruloplasmin in Disorders of the Nervous System.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0988},
pmid = {42970317},
issn = {2152-5250},
abstract = {Ceruloplasmin (Cp) is a multicopper ferroxidase that links copper handling, iron export, and redox homeostasis. Within the nervous system, these functions are critical because disruption of iron and copper balance can amplify oxidative stress, neuroinflammation, and neuronal vulnerability. Although Cp has long been studied as a circulating biomarker, most reports characterize it only by protein concentration, leaving its enzymatic and structural status comparatively unexplored. Here, we synthesize human literature on Cp across major neurological disorders, with attention to studies that assess Cp's ferroxidase activity, oxidation, fragmentation, and copper-binding state alongside its circulating levels. The evidence is by far most extensive in Alzheimer's and Parkinson's diseases, which together account for the majority of the reviewed literature: reduced ferroxidase activity, increased Cp oxidation, and altered non-Cp-bound copper are repeatedly linked to disease severity, regional iron accumulation, and biomarker-defined patient subgroups; in several studies, these alterations were independent of total Cp concentration. A smaller but growing body of evidence in amyotrophic lateral sclerosis, multiple sclerosis, essential tremor, and the cerebellar ataxias points to a related pattern of Cp-linked iron mishandling contributing to neuronal vulnerability. Preliminary findings from a few small studies in schizophrenia and a single study in obsessive-compulsive disorder further suggest that circulating Cp levels track systemic inflammatory and oxidative states in these conditions. From these investigations, a picture emerges where Cp's functional and structural integrity, rather than its abundance alone, is the more informative correlate of disease-relevant metal dyshomeostasis, most clearly demonstrated in Alzheimer's and Parkinson's diseases. Based on this body of work, we propose that future studies adopt combined assessments of Cp quantity and function to clarify disease-specific Cp signatures and to evaluate whether correcting Cp activity or copper/iron imbalance can improve outcomes.},
}

@article {pmid42970788,
year = {2026},
author = {Poppe, A and Gruen, E and Butz, C and Meenen, B and Lampe, D and Schmidt, J and Greiner, W and Köberlein-Neu, J and Meyer, I and , },
title = {Using a Living Lab to Refine an Electronic Prescribing Workflow: Insights From the eRIKA Project.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e100362},
doi = {10.2196/100362},
pmid = {42970788},
issn = {2561-326X},
mesh = {*Workflow ; *Electronic Prescribing/standards ; Humans ; Germany ; Digital Health ; },
abstract = {BACKGROUND: The integration of eHealth solutions into routine health care remains challenging despite their potential to improve care quality and efficiency. Living labs (LLs) have emerged as an approach to addressing these challenges by enabling co-design and iterative testing of eHealth tools. LLs promote collaboration among patients, health care professionals, developers, and policy makers. However, systematic insights into their practical implementation remain limited.

OBJECTIVE: This study explores the use of an LL approach to dynamically create and adapt project workflows, as well as its potential as a methodological framework for developing an implementation plan for a digital prescribing workflow (eRIKA [eRezept als Element Interprofessioneller Versorgungspfade für Kontinuierliche Arzneimitteltherapiesicherheit]). The analysis focuses on intervention-level insights identified throughout the LL process. The study also reflects on the limitations of the approach.

METHODS: The co-design process was structured into 4 thematic sprints conducted across 3 regions in Germany (Saarland, Berlin, and Westphalia-Lippe) between November 2022 and September 2024. Workshops were held with general practitioners (GPs), pharmacists (PHs), medical assistants, and pharmacy technicians recruited from 6 GP practices, 6 pharmacies, and 1 hospital (n=17). Audio-recorded workshop data were analyzed using reflexive thematic analysis.

RESULTS: Three themes were identified: (1) Workflow Efficiency, encompassing demands for filtering and prioritization mechanisms to manage information volume, direct digital communication channels, and concerns about workload; (2) Technical Implementation, addressing the need for seamless system integration, data integrity of the medication history, and interoperability with existing practice management systems; and (3) A New Way of Working, reflecting interprofessional negotiations around roles and responsibilities and regulatory requirements, including data privacy. Notably, strongly divergent views emerged between GPs and PHs regarding what data PHs require to conduct effective medication safety reviews.

CONCLUSIONS: Consistent with previous research, the results highlight concerns about workload, system interoperability, roles and responsibilities, and regulatory barriers to implementation. Beyond these established challenges, the results also reveal interprofessional tensions between GPs and PHs regarding the extent of data sharing required for effective pharmaceutical counseling. These findings inform the subsequent phase 1 and phase 2 evaluation studies and contribute to the growing evidence base on LL methodology in digital health implementation.

RR2-10.2196/87277.},
}

*Workflow
*Electronic Prescribing/standards
Humans
Germany
Digital Health

@article {pmid42970872,
year = {2026},
author = {Wang, XC and Wen, YJ and Huang, YJ and Wu, HX and Zhang, XJ and Cui, JY and Yu, YJ and Fu, HY and She, Y},
title = {Roasting-time dependent aroma development in sesame oil: time-resolved VOCs evolution revealed by deconvolution-assisted HS-SPME-GC-MS.},
journal = {Food chemistry},
volume = {532},
number = {Pt 4},
pages = {151826},
doi = {10.1016/j.foodchem.2026.151826},
pmid = {42970872},
issn = {1873-7072},
abstract = {Roasting is essential for developing sesame oil's color, aroma, and texture. This study investigated the effects of roasting time on key volatile organic compounds (VOCs) and sensory profiles. An optimized HS-SPME-GC-MS coupled with DEMCR-ALS-based deconvolution (AntDAS-GCMS) was established to profile VOC dynamics during roasting at 150 °C for 0-40 min. Among 731 resolved differential features, 94 VOCs changed significantly across 30 samples. Volatile composition changed markedly during the first 20 min, when the characteristic roasted aroma emerged. However, odor activity values (OAVs) of key aroma-active compounds continued to change with prolonged roasting, particularly those associated with caramel-sweet and smoky notes. Hydrocarbon-associated signals progressively decreased, whereas nitrogen-containing heterocyclic compounds increased. Sensory and OAV-based analyses showed a shift from fresh, seed-like profile toward a thermally derived flavor system. Roasting for 20-30 min enhanced desirable aromas, whereas longer roasting increased smoky notes and reduced aroma balance.},
}

@article {pmid42972546,
year = {2026},
author = {Zhuang, SP and Cai, ZW and Huang, ZY and Lin, LY and Chen, S and Zou, ZY and Ding, H and Qin, W and Chen, HJ},
title = {Voxel-based texture similarity networks reveal abnormal brain network topology linked to molecular signatures in amyotrophic lateral sclerosis.},
journal = {BMC medicine},
volume = {24},
number = {1},
pages = {},
pmid = {42972546},
issn = {1741-7015},
support = {No. 82572160//National Natural Science Foundation of China/ ; Nos. 2023CXA009//Fujian Provincial Health Technology Project/ ; No.2024J01625//Fujian Provincial Natural Science Foundation of China/ ; Nos. 2024Y9253//Fujian Province Joint Funds for the Innovation of Science and Technology/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/genetics ; Female ; Male ; *Brain/diagnostic imaging/physiopathology/pathology ; Magnetic Resonance Imaging/methods ; Middle Aged ; *Nerve Net/diagnostic imaging/physiopathology ; Aged ; Adult ; Case-Control Studies ; },
abstract = {BACKGROUND: While amyotrophic lateral sclerosis (ALS) is characterized by disrupted brain network function, the abnormal patterns of structural similarity networks and their biological underpinnings remain poorly understood. This study employed voxel-based texture similarity network (vTSN) analysis to identify complex brain network disruptions in ALS, aiming to advance the pathophysiological understanding of the disease.

METHODS: Individual vTSNs were constructed based on structural T1-weighted magnetic resonance imaging data from 113 patients with ALS and 144 healthy controls. We first explored the vTSN disruption patterns in ALS patients and compared their sensitivity with two other popular structural similarity networks: morphometric similarity networks (MSN) and morphometric inverse divergence (MIND). We then linked vTSN abnormalities with molecular signatures. Finally, we explored the potential of vTSN in predicting the clinical traits and states of ALS patients.

RESULTS: ALS patients demonstrated bidirectional patterns of both increased and decreased connectivity in vTSN (P < 0.05, Bonferroni correction), particularly involving sensorimotor network (SMN), default mode network (DMN), frontoparietal network (FPN) and subcortical network (SN). vTSN showed the highest sensitivity in detecting abnormal connectivity (N = 137) compared to the two well-known approaches, MSN (N = 0) and MIND (N = 30) (P < 0.05, Bonferroni correction), and revealed unique disruption patterns (r < 0.02, P > 0.05). Notably, vTSN alterations were linked to ALS risk genes; representative genes CHMP2B and SOD1 showed distinct developmental profiles and significant regional correlations. Furthermore, vTSN changes mirrored neuroreceptor distributions (notably M1, 5-HT6, and MOR), with M1 showing coupling in the SN and FPN, linking network decay to neurochemical imbalances. Finally, the network-based vTSN model achieved robust diagnostic power (AUC = 0.757), which was statistically equivalent to edge-level or whole-brain models (DeLong's test, P > 0.05).

CONCLUSIONS: vTSN exhibits excellent performance for detecting network abnormality in ALS and reveals potential molecular signatures of the pathophysiology of disease. These findings underscore the potential of vTSN-derived network measure as a biologically meaningful biomarker for ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/genetics
Female
Male
*Brain/diagnostic imaging/physiopathology/pathology
Magnetic Resonance Imaging/methods
Middle Aged
*Nerve Net/diagnostic imaging/physiopathology
Aged
Adult
Case-Control Studies

@article {pmid42972606,
year = {2026},
author = {Bedarf, L and Neuhaus, D and Bauer, M and Berger, C and Wendebourg, MJ and Schlaeger, R and Birkl, C and Scheurer, E and Lenz, C},
title = {Evidence of White Matter R2* Homogenization After Formalin Fixation.},
journal = {Magnetic resonance in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/mrm.70646},
pmid = {42972606},
issn = {1522-2594},
support = {//Stiftung zur Foerderung der gastroenterologischen und allgemeinen klinischen Forschung sowie der medizinischen Bildauswertung/ ; 219548//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung/ ; //Neuromuscular Research Association Basel/ ; },
abstract = {PURPOSE: Disentangling intrinsic susceptibility-driven R2* characteristics in white matter (WM) from fixation-related effects using in vivo, postmortem (PM) in situ, and formalin-fixed PM ex situ MRI.

METHODS: DTI and multi-echo gradient-echo MRI were acquired in vivo, PM in situ and PM ex situ. PM cases included neurologically healthy individuals and patients with amyotrophic lateral sclerosis (ALS). Voxel-wise R2* values were obtained using a mono-exponential fit and evaluated both as whole WM averages and according to WM fiber-to-field orientation. For the PM ex situ orientation-dependency analysis, PM ex situ R2* data were registered to the corresponding in situ DTI acquisition. Averaged as well as orientation-dependent R2* profiles were pooled across WM and compared across conditions.

RESULTS: Whole WM averaged and orientation-dependent R2* values differed across in vivo, PM in situ, and PM ex situ conditions. No differences were observed between PM in situ healthy and PM in situ ALS cases. Compared with in vivo measurements, both PM conditions showed elevated whole WM averaged R2* values and reduced orientation dependency, with the strongest R2* anisotropy in vivo and nearly absent orientation dependency in the PM ex situ condition.

CONCLUSION: While orientation-dependent R2* is reduced but preserved in unfixed PM in situ tissue, it is largely eliminated after prolonged formalin fixation without rehydration, likely due to microstructural reorganization and protein cross-linking. Collectively, these findings indicate that orientation-dependent R2* measured in fixed tissue has limited translational validity, while underscoring its sensitivity to intact microstructural organization in vivo and in unfixed PM tissue.},
}

@article {pmid42974031,
year = {2026},
author = {Wang, M and Yang, J and Gao, C and Qu, S and Mi, H and Guo, Y and Gui, T and Gai, Z},
title = {Utility of extracellular vesicles in the diagnosis of central nervous system diseases.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1959745},
pmid = {42974031},
issn = {1664-2295},
mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Central Nervous System Diseases/diagnosis/metabolism ; Biomarkers/metabolism/cerebrospinal fluid ; Animals ; Parkinson Disease/diagnosis ; Alzheimer Disease/diagnosis/metabolism ; },
abstract = {Central nervous system (CNS) disorders encompass a diverse spectrum of conditions characterized by intricate pathological mechanisms, and the presence of the blood-brain barrier (BBB) has long impeded early diagnosis. Extracellular vesicles (EVs) are lipid bilayer nanoparticles released by living cells that can encapsulate and transport bioactive molecules such as proteins and nucleic acids across the BBB. EVs can be detected in biofluids such as blood and cerebrospinal fluid (CSF) through non-invasive or minimally invasive assays, and have emerged as highly promising vehicles for CNS liquid biopsies. Recent studies demonstrate that specific EV-associated protein cargoes (e.g., phosphorylated tau, α-syn) and non-coding RNAs (e.g., miR-422a, miR-409-3p) exhibit distinct differential expression profiles across various pathologies. These molecular signatures hold promise for early detection, differential diagnosis, and disease staging, with some biomarker panels showing high diagnostic accuracy. However, whether they outperform conventional CSF biomarkers still requires direct comparison and validation within the same cohorts. This review highlights recent research advances in the use of EVs for the diagnosis of Alzheimer's disease and Parkinson's disease, briefly touches upon other CNS disorders including stroke, glioma, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis, and discusses the clinical translational potential and remaining challenges of EV-based diagnostics.},
}

Humans
*Extracellular Vesicles/metabolism
*Central Nervous System Diseases/diagnosis/metabolism
Biomarkers/metabolism/cerebrospinal fluid
Animals
Parkinson Disease/diagnosis
Alzheimer Disease/diagnosis/metabolism

@article {pmid42974758,
year = {2026},
author = {Xue, L and Ma, J and Wan, G and Long, B and Mao, Y and Wang, F and Bai, S},
title = {A Wavelet-ALS-Assisted CNN-BiGRU Method for Peak Recognition in CCD-Based Capillary Electrophoresis Fluorescence Detection.},
journal = {Electrophoresis},
volume = {},
number = {},
pages = {},
doi = {10.1002/elps.70177},
pmid = {42974758},
issn = {1522-2683},
support = {62163006//National Natural Science Foundation of China/ ; 61605153//National Natural Science Foundation of China/ ; },
abstract = {Capillary electrophoresis (CE) is an efficient, rapid, and sensitive separation and analysis technique that has been widely applied in biochemistry, pharmaceutical research, and environmental monitoring. However, charge-coupled device (CCD)-based CE fluorescence signals are susceptible to baseline drift, random noise, and channel crosstalk, which reduce the accuracy of peak recognition. To meet the demand for high-precision signal analysis, this study proposes a convolutional neural network (CNN)-bidirectional gated recurrent unit (BiGRU) peak recognition algorithm on the basis of wavelet transform and one-dimensional asymmetric least squares (ALS). In the proposed system, an FPGA-based platform is used for real-time signal acquisition and data transmission, whereas the host computer performs subsequent processing of the received spectral data. Experimental results show that the proposed method achieves high-accuracy peak recognition on the spectral dataset, with Precision, Recall, and F1-score reaching 98.44%, 99.93%, and 99.18%, respectively. These results demonstrate its good robustness and practical applicability, providing technical support for the miniaturization and intelligent development of portable gene sequencers.},
}

@article {pmid42974926,
year = {2026},
author = {Gangfuß, A and Gowda, VK and Natera-de Benito, D and Munot, P and Vanegas, M and Darling, A and Reutlinger, C and Carrera-Garcia, L and Wunderlich, G and Kölbel, H and Stüve, B and Muhmann, D and Monfort Belenguer, L and Barca, DG and Reddy C, VS and Srinivasan, VM and Anguita, CM and Jungbluth, H and Dafsari, HS and Rossor, T and Böhm, J and Schara-Schmidt, U and Roos, A},
title = {Clinical Variability and Genotype Driven Outcomes in an International Cohort of 14 Pediatric FIG4 Patients.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
pmid = {42974926},
issn = {2328-9503},
support = {//Mediment/ ; //Josepha und Charlotte von Siebold Habilitandinnen-Förderprogramm/ ; //German Society of Muscular Diseases (DGM)/ ; CP22/00141//Miguel Servet program from Instituto de Salud Carlos III, Spain/ ; B2B-RARE//European Regional Development Fund (ERDF)/ ; },
abstract = {BACKGROUND: Biallelic FIG4 variants classically cause distinct conditions characterized by peripheral neuropathy (Charcot-Marie-Tooth disease type 4J) or skeletal dysplasia (Yunis-Varón syndrome). However, central nervous system involvement is increasingly recognized. The prevalence and specific characteristics of movement disorders within FIG4-related disease remain poorly characterized, prompting a need to redefine its clinical continuum.

OBJECTIVE: To delineate the phenotypic spectrum of FIG4-related disorders beyond established entities (Yunis-Varón syndrome, Charcot-Marie-Tooth disease type 4J, bilateral temporooccipital polymicrogyria, and amyotrophic lateral sclerosis type 11) using an international multicentre cohort.

METHODS: We retrospectively analyzed clinical, genetic, and neurophysiological data from patients with biallelic FIG4 variants to redefine genotype-phenotype correlations, focusing on motor development, cognitive status, and movement disorders.

RESULTS: Evaluating 14 pediatric FIG4 patients revealed a continuous phenotypic spectrum rather than the clinical entities previously described in the literature. Instead of the typical peripheral neuropathy classically associated with pathogenic FIG4 variants, the predominant clinical picture in this age group was a severe neurodevelopmental disorder. Patients showed profound motor and cognitive delay, with a subset additionally displaying distinct movement abnormalities such as dystonia and bradykinesia.

CONCLUSION: Loss of functional FIG4 causes a broader and more severe disease spectrum with central nervous system involvement, including intellectual disability and movement abnormalities such as dystonia and bradykinesia. Recognizing these features should prompt clinicians to consider FIG4-associated disorders, allowing for optimized patient care and tailored therapeutic strategies.},
}

@article {pmid42963097,
year = {2026},
author = {Hald, K and Fagerström, M and Thomsen, JL and Johnsen, SP and Nilsen, P},
title = {Implementation of artificial intelligence in healthcare: a protocol for a phased mixed-methods multiple case study in the North Denmark Region.},
journal = {BMJ open},
volume = {16},
number = {10},
pages = {e124097},
pmid = {42963097},
issn = {2044-6055},
abstract = {BACKGROUND: Artificial intelligence (AI) is increasingly being implemented across healthcare systems with the potential to improve diagnostic accuracy, support clinical decision-making and enhance healthcare delivery. Despite growing investments in AI, evidence on how AI innovations are successfully implemented, adopted and sustained in routine clinical practice remains limited. Existing research has predominantly focused on technical performance and clinical effectiveness, while implementation-related factors have received less attention. This study aims to evaluate the implementation of AI innovations across multiple healthcare settings over time.

METHODS AND ANALYSIS: This study applies a phased mixed-methods multiple case study design to evaluate the implementation of 11 AI innovations introduced across hospital-based and cross-sectoral healthcare settings in the North Denmark Region. Each AI innovation is conceptualised as an individual case. The study consists of three sequential phases: (1) exploratory cross-case mapping of implementation processes and contextual determinants. (2) In-depth longitudinal case studies of selected cases. (3) Cross-case synthesis and programme-level evaluation. Data collection includes interviews, observations, document analysis, questionnaires and regional register data. The study is informed by the Consolidated Framework for Implementation Research, Proctor et al’s Implementation Outcomes Taxonomy, the Quality Implementation Framework and the WHO’s Health System Performance Assessment framework. Qualitative and quantitative data will be analysed separately and integrated through triangulation at case and cross-case levels.

ETHICS AND DISSEMINATION: According to Danish legislation, this study does not require approval from a regional research ethics committee. The study has been assessed by the Aalborg University Research Ethics Committee and registered as a research project involving the processing of personal data at Aalborg University. All participants will provide informed consent prior to participation. Findings will be disseminated through peer-reviewed publications, conference presentations and reports targeting relevant stakeholders.},
}

@article {pmid42963841,
year = {2026},
author = {Xu, J and Guo, B and Li, B and Qi, Z and Liu, X and Wang, G and Chen, S and Xu, X},
title = {Ala-205-met mutation in acetolactate synthase (ALS) of Bromus japonicus confers resistance to ALS-inhibiting herbicides.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.71450},
pmid = {42963841},
issn = {1526-4998},
support = {2024060203//Basic Research Funds of Hebei Academy of Agriculture and Forestry Sciences/ ; 2023LYS03//HAAFS Youth Innovation Fund Project/ ; },
abstract = {BACKGROUND: Acetolactate synthase (ALS)-inhibitor-resistant Bromus japonicus populations are widespread in wheat fields in China. A novel population BD-R has evolved resistance to flucarbazone-sodium, whereas its underlying resistance mechanism remains unclear. The objectives of this study were to (i) determine the resistance and cross-resistance levels to ALS inhibitors; (ii) investigate the resistance mechanisms; (iii) evaluate response to herbicides with other modes of action; and (iv) develop a CAPS molecular marker for rapid resistance detection.

RESULTS: The resistant index (RI) value of BD-R to flucarbazone-sodium was 62.4, and the cross RI values to mesosulfuron-methyl and pyroxsulam were 62.5 and 142.4. A novel Ala-205-Met substitution was found in BD-R. ALS activity bioassays showed the I50 values of BD-R and HS-S to flucarbazone-sodium were 7753.82 and 144.12 nm. 3D modelling and molecular docking results revealed the Ala-205-Met mutation reduced the binding affinity between ALS and the three ALS inhibitors. Homozygous transgenic Arabidopsis thaliana lines harboring ALS from BD-R exhibited resistance to flucarbazone-sodium, with FW inhibition merely 4.93%. Haloxyfop-P-methyl and quizalofop-P-ethyl showed excellent control of BD-R, whereas topramezone and mesotrione exhibited no efficacy. A CAPS-ALS marker with the primers CAPS-ALS-F (5'-TCATCACCAACCATCTCTTCC-3') and CAPS-ALS-R (5'-ATCAGAGTAGTTGTAACTGGAATC-3') was developed and could reliably identify the resistant BD-R plants.

CONCLUSION: BD-R conferred high-level resistance and cross-resistance levels to ALS-inhibitors. Haloxyfop-P-methyl and quizalofop-P-ethyl can be used for effective control BD-R. This study is the first report of the Ala-205-Met mutation conferring resistance to ALS inhibitors in weeds, indicating the complexity of the evolution of herbicide resistance in weeds. © 2026 Society of Chemical Industry.},
}

@article {pmid42964735,
year = {2026},
author = {Ghiasvand, K and Meftahi, GH},
title = {Black Myrobalan (Terminalia chebula) as a potential multitarget neuroprotective agent: Translational insights and future directions in neurodegenerative diseases.},
journal = {Biochemistry and biophysics reports},
volume = {48},
number = {},
pages = {102850},
pmid = {42964735},
issn = {2405-5808},
abstract = {Myrobalan or Haritaki (Terminalia chebula Retz.) has been integrated into Ayurvedic, Unani, and even Tibetan medicine systems for over 2000 years. The "King of Medicines" has traditionally been used for diverse ailments such as digestive issues, wound healing, and general body strengthening. Now, modern medicine is focusing on the myrobalan's potential neuroprotective properties and its use in Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis (ALS) neurodegenerative disorders. These ailments are characterized by some combination of enduring oxidative damage, mitochondrial dysfunction, neuroinflammation, irregular protein aggregation, and progressive neuron cell death. Most of the current treatment options revolve around addressing the symptoms of the diseases, which is insufficient as the underlying disease continues to progress. There is an urgent need to devise therapies that work simultaneously on multiple disease pathways. Some of the noted secondary metabolites in T. chebula include hydrolyzable tannins like chebulinic and chebulagic acid as well as corilagin. Others occur as phenolic acids such as gallic and ellagic acid and flavonoids quercetin and kaempferol. Moreover, glycosides, sterols, and a wide range of alkaloids are also present. A number of these compounds are known to possess multifunctional biological properties like scavenging ROS, activating Nrf2/ARE signaling, downregulating pro-inflammatory mediators through blockade of NF-κB, and exerting protective effects on the mitochondria, as well as modulating apoptosis via Bcl-2 and caspases. T. chebula extracts and some isolated compounds have also been shown to improve cognitive function, reduce neuroinflammation, and protect dopaminergic neurons, and ameliorate neurotoxic effects of amyloid-β or α-synuclein through in vitro and in vivo animal studies. A review of the contributions from the phytochemistry, mechanism of action, preclinical, translational, and adjunctive applications of Terminalia chebula in neurodegenerative disease therapy is presented here.},
}

@article {pmid42966163,
year = {2026},
author = {Gao, C and Shi, R and Jiang, X and Chai, H and He, X},
title = {Immunometabolic dysregulation of reactive microglia and astrocytes in neurodegenerative diseases: Mechanistic insights and therapeutic implications.},
journal = {Journal of the neurological sciences},
volume = {491},
number = {},
pages = {126237},
doi = {10.1016/j.jns.2026.126237},
pmid = {42966163},
issn = {1878-5883},
abstract = {Neurodegenerative diseases (NDDs) are increasingly understood as multifactorial disorders characterized by intertwined pathological processes, in which metabolic dysfunction may act as a critical and potentially disease-amplifying contributor to the proteinopathy-driven pathological cascade. Despite growing recognition that microglial and astrocytic metabolism governs central nervous system tissue damage-repair homeostasis, intercellular metabolic crosstalk between glia and neurons remains insufficiently synthesized across major NDDs. This review delineates how core metabolic pathways, including glycolysis, mitochondrial respiration, lipid processing, and amino acid transport, shape glial reactivity in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We highlight glial metabolic reprogramming, a proposed theoretical framework arising from severe glial metabolic dysregulation. Within this framework, persistent pathological stress may drive reactive glia to sequester local energy substrates in excess, which is hypothesized to trigger bioenergetic failure in neighboring neurons. Broad-spectrum anti-inflammatory agents show poor clinical performance because they only block cytokine outputs rather than reverse glial metabolic exhaustion. Therapeutic efforts should therefore shift toward restoring glial metabolic flexibility. Cell-type-specific metabolic reprogramming, instead of pan-metabolic suppression, may circumvent systemic adverse effects. Precision strategies targeting such intercellular metabolic imbalance could provide promising cell-resolved metabolic avenues to retard NDD progression.},
}

@article {pmid42966271,
year = {2026},
author = {D'Antoni, L and Viccaro, F and D'Andria, M and Sanna, A and Cardini, ME and Tomsa, C and Flore, R and Di Meo, F and Fabozzi, A and Baccolini, V and Siena, L and Palange, P and Ceccanti, M},
title = {The impact of diagnostic criteria on the detection of nocturnal hypoventilation in adult amyotrophic lateral sclerosis patients.},
journal = {Sleep medicine},
volume = {149},
number = {},
pages = {109344},
doi = {10.1016/j.sleep.2026.109344},
pmid = {42966271},
issn = {1878-5506},
abstract = {BACKGROUND: Nocturnal hypoventilation (NH) is an early manifestation of respiratory muscle weakness in amyotrophic lateral sclerosis (ALS) and plays a key role in determining the optimal timing for non-invasive ventilation (NIV). However, several diagnostic definitions of NH have been proposed, and their impact on NH prevalence remains unclear.

METHODS: In this cross-sectional study, 56 non-ventilated ALS patients underwent home-based overnight monitoring with transcutaneous carbon dioxide (TcCO2) and pulse oximetry. NH prevalence was assessed using seven definitions derived from daytime arterial blood gases, nocturnal oximetry, and TcCO2 parameters. Agreement between definitions was evaluated using Cohen's and Light's kappa coefficients.

RESULTS: NH prevalence varied widely depending on the definition used, ranging from approximately 5% with daytime arterial criteria to 36.7% using peak TcCO2 ≥49 mmHg. Overall concordance among definitions was low (Light's κ = 0.27), indicating that current NH definitions are not interchangeable.

CONCLUSIONS: Currently used definitions of NH in ALS show substantial heterogeneity and identify different patient subsets. These findings highlight the need for ALS-specific consensus definitions of NH.},
}

@article {pmid42963796,
year = {2026},
author = {Hirayama, T and Shibukawa, M and Morioka, H and Ogawa, M and Yorimoto, K and Ebihara, S and Sakano, T and Iguchi, Y and Katsuno, M and Aoki, M and Fujita, K and Izumi, Y and Morita, M and Nakamura, R and Atsuta, N and Yamanaka, K and Kobayakawa, Y and Bokuda, K and Iwata, I and Sakushima, K and Imamura, K and Tsuda, H and Nakayama, Y and Urushitani, M and Shimizu, T and Nagano, S and Kano, O},
title = {Patient and public involvement in amyotrophic lateral sclerosis research in Japan: a survey through nationally advertised ALS Café events and a pilot advocacy training program.},
journal = {Research involvement and engagement},
volume = {12},
number = {1},
pages = {},
pmid = {42963796},
issn = {2056-7529},
support = {JP23K10515//Japan Society for the Promotion of Science/ ; JP25K22608//Japan Society for the Promotion of Science/ ; JP24wm0625301//Japan Agency for Medical Research and Development/ ; JP24mk0121294//Japan Agency for Medical Research and Development/ ; JPMH23FC1008//Ministry of Health, Labour and Welfare/ ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) remains an incurable, progressive neurodegenerative disease. Patient and public involvement (PPI) has been increasingly recognized as a means to enhance the relevance, quality, and efficiency of research; however, its implementation in intractable neurological disease research remains limited in Japan. This webinar-based study, conducted through nationally advertised ALS Café events, aimed to clarify current PPI awareness among the Japanese ALS community and to explore strategies for promoting patient advocacy. Data were collected during the "ALS Café" held in September 2024 and a subsequent patient advocacy training program organized in October 2025. Among 79 respondents (42 patients with ALS and 37 caregivers), approximately 80% reported being unfamiliar with the concept of PPI, yet 72.2% expressed willingness to participate once the concept was explained. Among the 57 respondents willing to participate, interest was highest for involvement in translating research findings into practice (56.1%) and in identifying research themes (47.4%), and most (93%) stated that they expected no remuneration beyond reimbursement of expenses. The subsequent training program was well received, with mean evaluation scores exceeding 8.0 on a 0-10 scale, indicating high comprehensibility among participants (changes in knowledge or willingness to participate were not assessed). Respondents were a self-selected group of ALS Café participants with limited demographic characterization who may not represent patients and caregivers who do not participate in such events, and the training program evaluation lacked a pre-training baseline; these limitations should be considered when interpreting our findings.

CONCLUSIONS: These findings reveal substantial stated willingness among Japanese patients with ALS and their caregivers to contribute to research despite low baseline awareness of PPI. This gap between limited awareness and high stated willingness suggests that targeted educational efforts could meaningfully expand patient engagement in ALS research. Systematic awareness-building initiatives, structured and accessible engagement opportunities, and sustained collaborative relationships between researchers and the patient community are essential for strengthening patient advocacy and accelerating drug development for ALS in Japan.},
}

@article {pmid42957098,
year = {2026},
author = {Kuo, YC and Ting, CH and Lai, HJ and Huang, PY and Shih, YA and Yang, CC and Cheng, LF and Tai, ST and Chao, CC and Chang, HY and Wang, IF and Tsai, LK},
title = {Characterization of plasma misfolded superoxide dismutase 1 in amyotrophic lateral sclerosis.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107669},
doi = {10.1016/j.nbd.2026.107669},
pmid = {42957098},
issn = {1095-953X},
abstract = {OBJECTIVE: To characterize the dynamics of plasma misfolded superoxide dismutase 1 (mSOD1) and evaluate its utility as a state-dependent biomarker for patient stratification and therapeutic monitoring in amyotrophic lateral sclerosis (ALS).

METHODS: We utilized an SOD1/G93A mouse model and a cohort of 160 ALS patients, including four with SOD1 mutations, 12 with non-SOD1 mutations (C9orf72, TARDBP, FUS, OPTN), and 144 with nongenetic ALS. Chemical precipitation and enzyme-linked immunosorbent assay were used to quantify mSOD1 levels in plasma, spinal cord extracts, and cerebrospinal fluid (CSF). Clinical outcomes were assessed by the annual reduction in the revised ALS Functional Rating Scale (ALSFRS-R) score and ventilator-free survival.

RESULTS: In mice, plasma mSOD1 increased at the late symptomatic stage with subsequent numerical decline at the humane endpoint, accompanied by progressive motor neuron loss and increasing mSOD1-associated pathology. In humans, mSOD1 was elevated in 100% of SOD1-mutant, 25% of non-SOD1-mutant, and 22.2% of nongenetic ALS patients. Elevation was state-dependent, enriched in patients with moderate disability (ALSFRS-R 17-45). Plasma and CSF mSOD1 levels were correlated across the overall ALS cohort, but this association was no longer significant after exclusion of SOD1-mutant ALS cases. In one tofersen-treated patient, plasma mSOD1 showed rapid, parallel, and sustained reduction with CSF levels. No significant differences in clinical outcomes were observed in nongenetic ALS based on mSOD1 status.

INTERPRETATION: Approximately 22% of nongenetic ALS patients exhibit elevated plasma mSOD1, primarily during the moderate disease stage. Plasma mSOD1 is a candidate state-dependent biomarker for biological stratification and may have potential for treatment monitoring.},
}