@article {pmid42869255,
year = {2026},
author = {Zhang, ZY and Qin, BQ and Wu, SZ and Zhang, H},
title = {Conformational allocation of mitofusin 2 in neuronal mitochondrial dynamics: Mechanisms and therapeutic targeting.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118545},
doi = {10.1016/j.bcp.2026.118545},
pmid = {42869255},
issn = {1873-2968},
abstract = {Neurons must sustain functional mitochondria far from the cell body. Mitofusin 2 (MFN2), a dynamin-like large guanosine triphosphatase (GTPase), coordinates outer mitochondrial membrane remodeling with axonal transport, bioenergetic support, inter-organelle communication, and stress-responsive quality control. Studying these activities separately obscures how disruption of one protein produces diverse neuronal phenotypes. We propose a testable conformational-allocation framework in which molecular state distributions and transition kinetics bias MFN2 participation across cellular outputs. Integrating structural and functional evidence, we distinguish experimentally resolved mechanisms from working models. Variants associated with Charcot-Marie-Tooth disease type 2A (CMT2A) are compared by the molecular step or functional output affected. Fusion loss alone does not capture this mechanistic diversity. Structure-guided docking supports local compatibility at a shallow, conformationally conditional C-terminal surface, without establishing native accessibility, affinity, or therapeutic response. CMT2A provides the strongest context for intervention, combining causal genetics, direct mitofusin engagement studies, and multiscale rescue. Amyotrophic lateral sclerosis (ALS) provides secondary preclinical evidence, whereas Alzheimer's and Parkinson's diseases remain exploratory. The mitofusin pathway is chemically tractable, but paralog selectivity and state-dependent target engagement remain unresolved. A state- and variant-informed strategy may better match intervention to the affected output than indiscriminate enhancement of fusion.},
}

@article {pmid42869714,
year = {2026},
author = {Zhang, X and Xu, B and Peng, C and Li, H and Yang, K and Shen, A and Wang, J and Yang, X and Xia, Y and Hu, J and Aris, IM},
title = {Life-course associations of early-life risk factors, modifiable adult lifestyles, and transitions of cardiometabolic disease and multimorbidity: A prospective cohort study.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {101486},
doi = {10.1016/j.ajcnut.2026.101486},
pmid = {42869714},
issn = {1938-3207},
abstract = {BACKGROUND: Whether associations of early-life risk factors with cardiometabolic disease (CMD) transitions vary by adult lifestyles remains unclear.

OBJECTIVES: We aimed to examine the associations between early-life risk factors and CMD transitions, and to assess whether adult lifestyles can modify these associations.

METHODS: We analyzed data from 174,718 adults participating in the United Kingdom Biobank prospective cohort study. We defined 5 CMD transitions using a multistate model: from CMD-free to first CMD (FCMD; including stroke, ischemic heart disease, and type 2 diabetes), from FCMD to cardiometabolic multimorbidity (CMM), and from CMD-free, FCMD, and CMM to death. An early-life risk score (ERS; 0-3) summed low birth weight, maternal smoking around birth, and absence of human milk feeding in infancy. Adult lifestyle was quantified using an adult lifestyle score (ALS) adapted from 4 behavioral metrics of the Life's Essential 8 framework, and data were collected at study enrollment when participants had a median age of 55 y.

RESULTS: During a median follow-up of 14.6 y, individuals with both high early-life risk (ERS ≥2) and an unhealthy adult lifestyle (ALS: 0-49) had the highest risks for most adverse transitions, including CMD-free to FCMD [hazard ratio (HR): 2.04; 95% confidence interval (CI): 1.89, 2.21], FCMD to CMM (HR: 1.46; 95% CI: 1.27, 1.69), CMD-free to death (HR: 2.31; 95% CI: 1.95, 2.72), and FCMD to death (HR: 1.64; 95% CI: 1.34, 2.01). The associations of ERS with the risk of most CMD transitions were less pronounced among participants with a healthy adult lifestyle than among those with an unhealthy adult lifestyle.

CONCLUSIONS: Joint exposure to adverse early-life experiences and an unhealthy adult lifestyle was associated with elevated risks of CMD progression and mortality. Notably, the detrimental associations of early-life risk factors with specific CMD transitions were less pronounced among individuals with healthier adult lifestyles.},
}

@article {pmid42869990,
year = {2026},
author = {Castro, J and de Carvalho, M and Swash, M},
title = {Revisiting the muscle spindle in ALS: Implications for spinal motor network dysfunction.},
journal = {Pflugers Archiv : European journal of physiology},
volume = {478},
number = {11},
pages = {},
pmid = {42869990},
issn = {1432-2013},
mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Humans ; Animals ; *Muscle Spindles/physiopathology/physiology ; *Motor Neurons/physiology ; Motor Neurons, Gamma/physiology ; *Spinal Cord/physiopathology ; Interneurons/physiology ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is typically characterized by progressive degeneration of upper and lower motor neurons. However, the contribution of afferent sensory pathways to spinal motor network disorganization has received little attention. Converging human histological evidence from multiple independent laboratories demonstrates that fusimotor (gamma) motor neuron innervation of muscle spindles degenerates in ALS while sensory endings remain morphologically intact at the end organ, although the afferent neurons and ascending sensory pathways are also affected. This dissociation creates unmodulated proprioceptive input. Spindle-derived sensory signals reach spinal interneuron circuits without fusimotor gain-control adjustment, degrading spindles from forward sensory models encoding predicted kinematic states into crude stretch receptors. We propose that this gain-control failure, compounded by the loss of associated alpha-gamma coactivation and beta skeletofusimotor denervation, constitutes an upstream driver of the spinal inhibitory interneuron circuit dysfunction documented by recent electrophysiological studies in ALS. The resulting early disinhibition, followed by maladaptive excitation, mirrors cortical ALS pathophysiology. However, transgenic mouse ALS models show selective sparing of gamma motor neurons, unlike the human disease, constituting a critical translational limitation. We present a temporal model of human ALS, linking fusimotor denervation to progressive disruption of spinal inhibitory and excitatory circuits.},
}

*Amyotrophic Lateral Sclerosis/physiopathology/pathology
Humans
Animals
*Muscle Spindles/physiopathology/physiology
*Motor Neurons/physiology
Motor Neurons, Gamma/physiology
*Spinal Cord/physiopathology
Interneurons/physiology

@article {pmid42870990,
year = {2026},
author = {Nazir, A and Hanan, NP and Roberts, T},
title = {GEDI canopy cover assessment using airborne LiDAR across eco-climate regions of the United States.},
journal = {Frontiers in plant science},
volume = {17},
number = {},
pages = {1951245},
pmid = {42870990},
issn = {1664-462X},
abstract = {Information about woody plant density and canopy cover is central to our definition of terrestrial ecosystem types and crucial for understanding ecosystem state, dynamics, biogeochemical processes, and biodiversity. The Global Ecosystem Dynamics Investigation (GEDI) LiDAR on the International Space Station (ISS) samples 3-D structural information on woody vegetation structure, including an estimate of canopy cover in each 25 m diameter footprint. This study presents an evaluation of the GEDI fractional canopy cover estimates by comparing GEDI retrievals to high-resolution airborne laser scanning (ALS) data at 20 study sites with ~460,000 GEDI footprints across the United States. Based on the statistical assessment, we observed high correlations (R[2] = 0.84 without geolocation correction; R[2] = 0.96 with geolocation correction) with a Root Mean Square Error (RMSE) of 14.1% (without geolocation correction) and 7.2% (with geolocation correction). However, error in GEDI L2B canopy cover in some eco-climate regions is still significant, particularly in drylands (mean relative error (MRE) = 69.8%) and shrublands (MRE = 84.1%). The analysis also determined that the GEDI fractional cover retrievals are most effective when actual canopy cover is low (<20%) or high (>70%), with errors typically inflated in areas where canopy cover is in the 20-70% range. This study provides a baseline evaluation of GEDI canopy cover accuracy across eco-climate regions of CONUS, supporting improved interpretation and future refinement of the GEDI canopy cover product.},
}

@article {pmid42871488,
year = {2026},
author = {Monfared Jahromi, N and Maleki, A},
title = {Short-term Classification of Neurodegenerative Diseases using Time-series Features Based on Analysis of Gait Dynamics.},
journal = {Journal of biomedical physics & engineering},
volume = {16},
number = {5},
pages = {395-406},
pmid = {42871488},
issn = {2251-7200},
abstract = {BACKGROUND: Neurodegenerative Diseases (NDDs) refer to disorders, leading to the gradual degeneration of neurons in the human nervous system and profoundly affecting individuals' motor and cognitive functions. Early diagnosis and monitoring of the progression of NDDs are of critical importance.

OBJECTIVE: The primary aim of this study is to present an automatic diagnostic method using time-domain analysis of short-term gait signals of two consecutive steps, for the classification of Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), and a Healthy Control Group (HC).

MATERIAL AND METHODS: This analytical study used datasets from PhysioNet, including 64 five-minute recordings from 13 individuals with ALS, 15 with Parkinson's, 20 with Huntington's, and 16 healthy individuals. To reduce noise and enhance signal quality, a median filter was applied. The preprocessed gait signals were then systematically segmented into consecutive two-step windows, which were used to construct the feature vectors. Finally, the constructed feature vectors were used as inputs for both linear and nonlinear classifiers. The proposed method was evaluated by calculating the accuracy index.

RESULTS: The quaternary classification of ALS vs. PD vs. HD vs. HC using the bag-tree classifier achieved an accuracy of 82.8%. Furthermore, for the binary classifications of HC vs. HD, HC vs. ALS, HC vs. PD and NDD vs. HC, the accuracies were 88.4%, 97.6%, 90% and 89.1%, respectively.

CONCLUSION: Gait dynamics analysis has a high potential for the rapid diagnosis of neurodegenerative diseases. Short term analysis in two consecutive stages enables the use of the Kinect sensor for gait analysis.},
}

@article {pmid42871744,
year = {2026},
author = {Castells-Ballester, J and Shcherbik, N},
title = {Scp160 deletion suppresses TDP-43 aggregation and toxicity in Saccharomyces cerevisiae.},
journal = {Microbial cell (Graz, Austria)},
volume = {13},
number = {},
pages = {358-377},
pmid = {42871744},
issn = {2311-2638},
abstract = {Protein misfolding and aberrant protein aggregation are central features of neurodegenerative disorders, including amyotrophic lateral sclerosis, where the RNA-binding protein TDP-43 accumulates in abnormal intracellular assemblies. Although yeast models have identified multiple modifiers of TDP-43 toxicity, the cellular factors that determine how aggregation-prone proteins are organized remain incompletely understood. Here, we investigated whether the ribosome- and mRNP-associated proteins Scp160 and Bfr1 influence TDP-43 proteotoxicity and aggregate formation. We report that deletion of SCP160 or BFR1 improves growth during TDP43-GFP induction without reducing steady-state reporter abundance and decreases formation of prominent TDP43-GFP foci. Deletion of BFR1 produced an intermediate TDP-43 phenotype, with a weaker effect than SCP160 deletion on severe foci formation and toxicity. Importantly, the effect of SCP160 or BFR1 deletion on visible protein aggregation was not specific to TDP-43: severe Htt103Q-GFP aggregation was strongly reduced, and formation of VHL-GFP foci was suppressed, including under conditions of proteasome inhibition. Despite these shared effects, the two mutants were not phenotypically identical. Deletion of SCP160 produced a distinct spatial phenotype in which residual TDP43-GFP foci showed markedly increased association with Sec63-positive ER structures and reduced distance to these regions, whereas bfr1 Δ cells did not show the same Sec63-associated shift. Together, these findings uncouple TDP43-GFP abundance from toxicity and prominent foci formation and identify Scp160 and Bfr1 as factors that influence the intracellular partitioning of aggregation-prone and misfolded proteins, with an additional role for Scp160 in the spatial organization of TDP43 relative to the ER.},
}

@article {pmid42872064,
year = {2026},
author = {Cai, W and Yi, Y and Zeng, R and Yin, Y and Zhao, J and Zhang, J and Fu, G and Xu, H},
title = {HMGB1 functional plasticity in neurodegenerative diseases and its translational implications.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1928641},
pmid = {42872064},
issn = {1664-3224},
mesh = {Humans ; *HMGB1 Protein/metabolism/genetics ; *Neurodegenerative Diseases/metabolism ; Animals ; Translational Research, Biomedical ; Signal Transduction ; Alarmins/metabolism ; Biomarkers ; },
abstract = {High mobility group box 1 (HMGB1) is a chromatin-associated protein that can be redistributed and released during cellular stress, when it acts as an extracellular alarmin within the broader family of damage-associated molecular patterns (DAMPs). Its functions depend on subcellular localization, redox and post-translational modification state, cellular source, mode of release, and molecular partners. This critical narrative review examines how these variables shape HMGB1 biology in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxias (SCAs), frontotemporal dementia (FTD), and related disorders, and considers their implications for biomarker and therapeutic development. Intracellular HMGB1 contributes to chromatin organization, DNA repair, mitochondrial genome maintenance, and proteostasis. After redistribution and release, extracellular HMGB1 signals through receptors including the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), interacts with disease-associated proteins, and links proteostatic stress with glial activation, neuronal dysfunction, and blood-brain barrier impairment. Across disease models, two recurrent patterns emerge: loss or sequestration of intracellular HMGB1 in models of polyglutamine disorders, including HD and SCAs, and extracellular HMGB1 signaling as a progression-associated inflammatory amplifier in AD, PD, and ALS models. Central-peripheral inflammatory communication and cell-specific HMGB1 release further shape these responses. Clinical studies have associated total HMGB1 or anti-HMGB1 autoantibodies with clinical features, but current assays do not resolve redox form, cellular source, or biological activity. Most therapeutic studies remain preclinical, while available human intervention studies involve drugs with multiple molecular actions. Clinical translation requires redox-resolved and standardized assays, longitudinal human sampling, compartment- and cell-specific causal studies, and interventions with documented target engagement, central nervous system exposure, and long-term safety. HMGB1 is best understood as a context-dependent mediator rather than a uniformly pathogenic factor or a single treatment target.},
}

Humans
*HMGB1 Protein/metabolism/genetics
*Neurodegenerative Diseases/metabolism
Animals
Translational Research, Biomedical
Signal Transduction
Alarmins/metabolism
Biomarkers

@article {pmid42872742,
year = {2026},
author = {Onoichenco, A and Morris, SL and Aloe, S and McCay, K and Song, Y and Brady, ST},
title = {Isolated Axoplasm from Squid and Pathogenic Mechanisms in Amyotrophic Lateral Sclerosis.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {236},
pages = {},
doi = {10.3791/72560},
pmid = {42872742},
issn = {1940-087X},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Decapodiformes ; *Axons/pathology/metabolism ; Kinesins/metabolism ; },
abstract = {The squid giant axon is an experimental model that has been instrumental in providing answers to many fundamental questions in cell biology, including the discovery of the motor protein kinesin and probing molecular mechanisms of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). The giant axon offers scale and ease of access that is not possible in mammalian models. The power of this model stems from the fact that one can introduce reagents and proteins that would not cross a plasma membrane at defined concentrations in a buffer environment that is closely modeled on normal components of the axoplasm. By leveraging the unique biology of the squid axon, early studies were able to define the channels and ion specificities of the action potential. Subsequent studies using video-enhanced contrast- differential Interference contrast microscopy (VEC-DIC) and the isolated axoplasm led to the identification of kinesins, a class of motor proteins responsible for intracellular vesicle trafficking toward the plus end of microtubules. This combination of isolated axoplasm and advanced imaging continues to provide insights into pathogenic mechanisms for adult-onset neurodegeneration, including ALS, and regulation of fast axonal transport, a process disrupted in motor neuron disease. Here, procedures for dissecting the giant axon, isolating axoplasm, and perfusing defined amounts of proteins and/or reagents into the axoplasm are detailed, as well as methods for visualizing and interactively analyzing vesicle traffic in real time. This model represents a singular avenue to understand the critical function of neurons, shedding light on the mechanisms driving ALS pathology and other neurodegenerative diseases. This system also offers a tractable platform for drug testing, where candidate therapeutic compounds can be introduced directly into the axoplasm, and their effects on vesicle trafficking can be assessed in real time, providing a rapid and physiologically relevant means of identifying potential ALS therapeutic targets.},
}

Animals
*Amyotrophic Lateral Sclerosis/pathology/metabolism
*Decapodiformes
*Axons/pathology/metabolism
Kinesins/metabolism

@article {pmid42873357,
year = {2026},
author = {Gündoğdu, AA and Özkan, NG and Adapınar, DÖ},
title = {The small giant actor in the pathogenesis of neurodegenerative diseases: Microtubules.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42873357},
issn = {1573-7365},
mesh = {Humans ; *Microtubules/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; tau Proteins/metabolism ; Axonal Transport/physiology ; },
abstract = {Neurodegenerative diseases are a clinically and pathologically diverse group of disorders characterized by progressive neuronal dysfunction, synaptic impairment, and neuronal loss. Although research has traditionally focused on disease-associated protein misfolding and aggregation, increasing evidence implicates abnormalities of cytoskeletal organization and intracellular transport in several neurodegenerative conditions. Microtubules contribute to neuronal polarity, axonal and dendritic transport, organelle distribution, and synaptic maintenance. These functions are regulated in part by tubulin isotypes, post-translational modifications collectively described as the tubulin code, microtubule-associated proteins, and molecular motors. This narrative review examines evidence linking alterations in these processes with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. We summarize proposed interactions among microtubule instability, impaired axonal transport, mitochondrial dysfunction, and disease-associated proteins, including tau, α-synuclein, mutant huntingtin, TDP-43, and prion protein. Evidence connecting tau pathology with microtubule dysfunction is comparatively well established in Alzheimer's disease and MAPT-related tauopathies, whereas findings in other disorders are more heterogeneous and are frequently derived from cellular or animal models. We also discuss emerging experimental approaches, candidate biomarkers, and investigational microtubule-directed treatments. However, no tubulin-specific biomarker or microtubule-targeted disease-modifying treatment discussed in this review has yet been clinically validated. Overall, microtubule dysfunction may represent one component of broader, disease-specific pathological networks rather than a universal primary cause of neurodegeneration. Further longitudinal and clinical studies are needed to determine whether microtubule-related alterations act as causes, consequences, or modifiers of disease progression.},
}

Humans
*Microtubules/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology
Animals
tau Proteins/metabolism
Axonal Transport/physiology

@article {pmid42873683,
year = {2026},
author = {Wei, Z and Yanlin, G and Jing, L and Shazhen, A and Zhihan, Z and Zhuo, Z and Jiajia, Y and Xia, G and Xue, L and Shiyi, Y and Fei, X},
title = {Body composition characteristics in patients with inflammatory myopathy based on bioelectrical impedance analysis.},
journal = {Clinical and experimental rheumatology},
volume = {},
number = {},
pages = {},
doi = {10.55563/clinexprheumatol/fhq0ug},
pmid = {42873683},
issn = {0392-856X},
abstract = {OBJECTIVES: To investigate body composition features in idiopathic inflammatory myopathy (IIM) using bioelectrical impedance analysis (BIA) and evaluate their clinical, diagnostic and follow-up value.

METHODS: This study included 103 patients with inflammatory myopathy over a 6-year period, excluding 15 cases, resulting in a final cohort of 88 IIM patients. Clinical assessments and BIA were performed. Healthy controls and patients with amyotrophic lateral sclerosis (ALS) were independently recruited as separate comparison groups.

RESULTS: IIM patients showed reduced muscle mass (SMM: 20.9±4.4 vs. 23.4±4.8, p=0.001), elevated ECW/TBW ratio (ECW/TBW total (ETT): 0.398±0.015 vs. 0.381±0.007, p<0.001), and decreased phase angle (PhARA: 3.50 [2.92, 4.50]° vs. 5.15 [4.50, 5.62]°, p<0.001; PhALA: 3.55 [2.84, 4.43]° vs. 5.03 [4.48, 5.42]°, p<0.001). These features correlated with disease severity, inflammation, and nutritional status. Compared to ALS, IIM patients had more marked ECW retention (ETT: 0.397±0.0145 vs. 0.389±0.0110, p=0.001) and impaired membrane integrity (PhARA: 3.450±0.99° vs. 4.295±1.44°, p=0.014; PhALA: 3.500 [2.850, 4.400]° vs. 4.400 [3.875, 4.925]°, p=0.003). Body composition demonstrated substantial potential for diagnostic application (XGBoost model: specificity 85.00%, sensitivity 88.46%), and more importantly, may serve as a valuable tool for disease management.

CONCLUSIONS: BIA technology provides important novel disease characteristics for IIM patients, which are closely related to traditional clinical features and demonstrate significant diagnostic and management potential.},
}

@article {pmid42586272,
year = {2026},
author = {Chen, RF and Chen, SC},
title = {Response to Tognaccini et al, "Comment on Chen et al's 'Disparities of itch severity in outpatient clinics as measured by the ItchyQuant'".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2026.08.022},
pmid = {42586272},
issn = {1097-6787},
}

@article {pmid42762993,
year = {2026},
author = {Lei, L and Tan, R and Xu, F and Chen, J and Ma, F and Wang, W and Liu, Y},
title = {Response to Rodríguez-Conde et al's "Prognostic determinants of early and late relapse in cutaneous squamous cell carcinoma: A multicenter retrospective cohort study".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2026.08.124},
pmid = {42762993},
issn = {1097-6787},
}

@article {pmid42863380,
year = {2026},
author = {Mustafayev, B and Mustafayeva, A and Bakhtiyarov, A and Nikatov, K and Satylkhan, B and Mustafayev, A},
title = {Expanded Longitudinal Validation of Adaptive Learning Stability in AI-Assisted Neurosurgical Residency Training.},
journal = {Journal of surgical education},
volume = {83},
number = {11},
pages = {104210},
doi = {10.1016/j.jsurg.2026.104210},
pmid = {42863380},
issn = {1878-7452},
abstract = {OBJECTIVE: To evaluate the longitudinal stability, reproducibility, and robustness of Adaptive Learning Stability (ALS) within an expanded AI-assisted neurosurgical residency cohort during a 12-month observation cycle.

DESIGN: This was a prospective controlled educational study. Residents completed 4 consecutive quarterly checkpoints integrating cognitive, technical, and decision-making assessments over 12 months. The RCKaS-AI framework incorporated predictive analytics, individualized adaptive remediation, and mentor-validated feedback pathways. Primary analysis evaluated longitudinal entrustment trajectory stability across checkpoints. Secondary analyses included inter-resident variance dynamics, remediation frequency, faculty workload, and predictive agreement between forecasted and observed competency progression.

SETTING: Two accredited neurosurgical residency programs in Kazakhstan, from January 2025 to January 2026.

PARTICIPANTS: Sixty-four neurosurgical residents randomized into standard RCKaS (n = 32) and AI-enhanced RCKaS-AI (n = 32) cohorts.

RESULTS: Both cohorts demonstrated progressive improvement in entrustment scores across sequential checkpoints. In the RCKaS-AI cohort, mean entrustment scores increased from 59.1 ± 12.8 at CP1 to 94.3 ± 6.9 at CP4, compared with 58.4 ± 13.1 to 85.7 ± 10.4 under standard RCKaS conditions (p = 0.001). Inter-resident variance decreased by 41% in the AI-assisted cohort versus 18% in the standard cohort. Residents within the RCKaS-AI framework achieved entrustment level 4 significantly earlier than controls (38 ± 7 weeks vs 50 ± 9 weeks, p = 0.003). Mean remediation frequency decreased from 3.4 ± 1.1 to 1.9 ± 0.7 sessions per resident, while faculty workload declined by 34%. Predictive analytics demonstrated strong agreement between forecasted and observed competency trajectories (r = 0.84; 95% CI, 0.77-0.89).

CONCLUSIONS: Expanded longitudinal implementation of the RCKaS-AI framework demonstrated reproducible stabilization of competency trajectories during neurosurgical residency training. These findings support the robustness of adaptive AI-assisted feedback systems as a practical mechanism for longitudinal competency regulation within structured surgical education programs. Further multicenter validation is required to evaluate external reproducibility across broader residency environments.},
}

@article {pmid42864293,
year = {2026},
author = {Wang, S and Wang, M and Sun, Y and Liu, G and Li, Y and Zhang, W and Yao, J},
title = {[Effect of electroacupuncture at Jiaji (EX-B2) on disease progression in mice with amyotrophic lateral sclerosis based on NLRP3/Caspase-1/ASC signaling pathway].},
journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion},
volume = {46},
number = {10},
pages = {1677-1684},
doi = {10.13703/j.0255-2930.20250518-k0001},
pmid = {42864293},
issn = {0255-2930},
mesh = {Animals ; *Electroacupuncture ; *Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; Mice ; Signal Transduction ; Humans ; Male ; *Caspase 1/metabolism/genetics ; Disease Progression ; *Acupuncture Points ; CARD Signaling Adaptor Proteins/metabolism/genetics ; Female ; Mice, Inbred C57BL ; Disease Models, Animal ; Spinal Cord/metabolism ; *Carrier Proteins/metabolism/genetics ; },
abstract = {OBJECTIVE: To explore the underlying mechanism of electroacupuncture (EA) at "Jiaji" (EX-B2) on the disease progression through modulating NOD-like receptor family pyrin domain containing 3 (NLRP3)/cysteine-aspartic acid protease 1 (Caspase-1)/apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) signaling pathway in mice with amyotrophic lateral sclerosis.

METHODS: Forty-five mice carrying the human superoxide dismutase 1 G93A (hSOD1[G93A]) gene were randomly divided into a model group, a Jiaji EA group, and an inhibitor group, 15 mice per group. The other 15 mice without hSOD1[G93A] gene carried were collected as a wild group. When the mice were aged 60 days, in the Jiaji EA group, EA was operated at "Jiaji" (EX-B2) of L1/L2, L5/L6, with continuous wave, a frequency of 2 Hz and an intensity of 1 mA, retained for 20 min, twice a week; in the inhibitor group, the intraperitoneal injection with NLRP3 inhibitor (10 mg/kg) was administered, twice a week. The interventions lasted for 4 weeks in each group. When the mice were aged 120 days, 9 mice in each group were randomly selected for tissue collection from lumbar spinal cord, and the disease progression and limb function were observed for the remaining 6 mice. The neurological function score was employed to assess the disease progression of mice in each group, and the gait experiment was conducted to observe the gait and stride length; HE staining was used to observe the motor neuron morphology in the anterior horn of the lumbar spinal cord, immunohistochemistry was used to detect the expression of ionic calcium-binding adapter molecule 1 (Iba-1) in the anterior horn of the lumbar spinal cord, and Western blot was used to detect the protein expression of NLRP3, Caspase-1, ASC, interleukin (IL)-18 and IL-1β in lumbar spinal cord.

RESULTS: Compared with the wild group, in the model group, the disease was worsened progressively, on days 90 and 120 after birth, the stride length of mice was reduced (P<0.05, P<0.01), and the gait was unstable and dragging on 120 days after birth; the motor neurons in the anterior horn of the spinal cord exhibited obvious cellular edema and rupture, marked vacuolization and nuclear pyknosis, along with severe neuron loss; the expression of Iba-1 increased in the anterior horn of the lumbar spinal cord (P<0.01), colored dark brown and densely aggregated; and the protein expression of NLRP3, Caspase-1, ASC, IL-18, IL-1β in lumbar spinal cord was up-regulated (P<0.01). When compared with the model group, in the inhibitor group and the Jiaji EA group, the onset of paresis and the progression of paralysis were delayed and the survival rates increased (P<0.01); stride length was larger in the mice at the age of 120 d (P<0.01); more clear gait was presented, and the ages in days was significantly delayed for gait dragging; the improvements were exhibited in the degree of edema, vacuolization, and nuclear pyknosis observed in the motor neurons of the anterior horn of the lumbar spinal cord; the expression of Iba-1 was reduced in the anterior horn of the lumbar spinal cord (P<0.01), appearing gray-brown, and scattered clusters in small number; and the protein expression of NLRP3, Caspase-1, ASC, IL-18, and IL-1β in lumbar spinal cord was decreased (P<0.05, P<0.01). The protein expression of NLRP3, Caspase-1 and IL-18 in lumbar spinal cord in the Jiaji EA group was up-regulated in comparison with that in the inhibitor group (P<0.05).

CONCLUSION: Electroacupuncture at "Jiaji" (EX-B2) can delay the disease progression in mice with amyotrophic lateral sclerosis, which may be related to modulating NLRP3/Caspase-1/ASC signaling pathway and inhibiting the inflammatory response, thereby attenuating the inflammatory injury of lumbar spinal cord.},
}

Animals
*Electroacupuncture
*Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics
Mice
Signal Transduction
Humans
Male
*Caspase 1/metabolism/genetics
Disease Progression
*Acupuncture Points
CARD Signaling Adaptor Proteins/metabolism/genetics
Female
Mice, Inbred C57BL
Disease Models, Animal
Spinal Cord/metabolism
*Carrier Proteins/metabolism/genetics

@article {pmid42864345,
year = {2026},
author = {Agarwal, T and Sneideris, T and Svara, F and Jermakovs, K and Coyle, H and Qamar, S and Kava, E and Scrutton, R and Pleschka, N and Peres, P and Cereghetti, G and Andrzejewska, E and Diaz-Barreiro, A and Palmer, G and Costa-Filho, AJ and Krainer, G and Knowles, TP and Nixon-Abell, J},
title = {Mapping high resolution, multidimensional phase diagrams of near-physiological protein condensates.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42864345},
issn = {2041-1723},
support = {227745/Z/23/Z//Wellcome Trust (Wellcome)/ ; },
mesh = {Humans ; *RNA-Binding Protein FUS/genetics/metabolism/chemistry ; *Biomolecular Condensates/chemistry/metabolism ; Cell Nucleolus/metabolism/chemistry ; *Stress Granules/metabolism/chemistry ; Animals ; Mutation ; Microfluidics/methods ; Phase Separation ; Machine Learning ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Aptamers, Nucleotide ; },
abstract = {Biomolecular condensates are membraneless compartments, crucial for organising and regulating diverse cellular processes. Current approaches to study condensate biology either use simplified recombinant protein systems with limited physiological relevance, or complex live-cell models with restricted experimental control and scalability. Here, we present ExVivo PhaseScan, a droplet microfluidics platform that couples mammalian lysate-based reconstitution with scalable analysis to generate high-resolution phase diagrams of compositionally complex protein condensates. We apply this approach to study two multicomponent condensate systems, stress granules and nucleoli, and dissect the physicochemical interactions that influence their stability. We further developed a machine learning pipeline to analyse condensate morphology which we use to reveal how mutations in the amyotrophic lateral sclerosis (ALS)-linked protein Fused in Sarcoma (FUS) remodels condensate properties. We identify liquid-to-solid transitions of mutant FUS within stress granules and nucleoli, and show that these transitions can be reversed by RNA aptamer-based interventions. Together, these findings establish ExVivo PhaseScan as a versatile tool for dissecting the physicochemical and pathological regulation of condensates, with potential to inform therapeutic strategies for diseases driven by aberrant phase transitions.},
}

Humans
*RNA-Binding Protein FUS/genetics/metabolism/chemistry
*Biomolecular Condensates/chemistry/metabolism
Cell Nucleolus/metabolism/chemistry
*Stress Granules/metabolism/chemistry
Animals
Mutation
Microfluidics/methods
Phase Separation
Machine Learning
Amyotrophic Lateral Sclerosis/genetics/metabolism
Aptamers, Nucleotide

@article {pmid42864501,
year = {2026},
author = {Saha, T and Mehan, S},
title = {Combined rituximab and magnesium acetyl taurate therapy attenuates neurodegeneration via ERK/c-JNK/P38MAPK signaling modulation in methylmercury-induced amyotrophic lateral sclerosis-like neurotoxicity.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42864501},
issn = {1432-1912},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration, oxidative stress, neuroinflammation, mitochondrial dysfunction, and dysregulation of intracellular signaling pathways. The present study investigated the neuroprotective potential of rituximab (RTXMB), alone and in combination with magnesium acetyl taurate (MACT600), against methylmercury (MLMC5)-induced ALS-like pathology in adult Wistar rats through modulation of the ERK/c-JNK/P38MAPK signaling pathway. ALS was induced by oral administration of MLMC5 (5 mg/kg) for 21 days. RTXMB (50 and 100 mg/kg) and MACT600 (600 mg/kg) treatments were administered from day 22 to day 42. Behavioral assessments, neurochemical estimations, ELISA, Western blotting, hematological analysis, gross morphology, and histopathological evaluations were performed. MLMC5 exposure produced significant impairments in locomotion, muscular strength, cognition, and emotional behavior, accompanied by increased oxidative stress, inflammatory cytokines, glutamate excitotoxicity, apoptotic markers, methylmercury accumulation, and dysregulation of ERK/c-JNK/P38MAPK signaling. Moreover, MLMC5 caused marked demyelination, neuronal degeneration, neurotransmitter imbalance, skeletal muscle damage, and hematological dysfunction. RTXMB treatment significantly attenuated these pathological alterations in a dose-dependent manner, with RTXMB100 showing greater neuroprotective efficacy. Combined administration of RTXMB100 and MACT600 demonstrated the most pronounced therapeutic effects by restoring antioxidant defenses, suppressing neuroinflammation and apoptosis, normalizing neurotransmitter levels, preserving myelin integrity, and improving neuronal morphology. The findings suggest that RTXMB, particularly in combination with MACT600, exerts potent neuroprotective effects against ALS-like pathology via modulation of MAPK signaling pathways and may represent a promising therapeutic strategy for ALS management.},
}

@article {pmid42864601,
year = {2026},
author = {Li, M and Jiao, YG and Tao, R and Hu, Y and Fei, JY and Wang, CT and Yao, SH},
title = {Optimized gGBE enables robust G-to-Y conversion in mammalian cells and zebrafish embryos.},
journal = {Zoological research},
volume = {47},
number = {6},
pages = {1839-1850},
doi = {10.24272/j.issn.2095-8137.2025.361},
pmid = {42864601},
issn = {2095-8137},
mesh = {Animals ; *Zebrafish/genetics/embryology ; Humans ; *Gene Editing/methods ; Embryo, Nonmammalian ; CRISPR-Cas Systems ; Amyotrophic Lateral Sclerosis/genetics ; *Glycoside Hydrolases/genetics/metabolism ; },
abstract = {Base editing is a powerful and precise genome-editing tool capable of introducing single-base substitutions with high resolution. Depending on the base-modification domains employed, base editors can mediate both transition and transversion base editing in mammalian cells. While deaminase-derived base editors have enabled efficient transition editing in the zebrafish genome, glycosidase-derived transversion editing remains a significant challenge. In this study, guided by structural insights into the Cas9 complex, we engineered a series of glycosidase guanine base editor (gGBE) constructs by inlaying the N-methylpurine DNA glycosylase (MPG) domain into Cas9 protein. Among these variants, we identified a high-performance gGBE in which MPG was inserted between residues G1246 and S1247 of the PI domain in Streptococcus pyogenes Cas9, which we named gGBE-PIGS. This variant improved editing efficiency by up to 3.5-fold in mammalian cells and 13-fold in zebrafish embryos, without compromising editing precision. Furthermore, we developed a gGBE-editing-responsive GFP reporter to monitor editing efficiency and enrich for gGBE-edited cells and embryos. Using a combination of the optimized gGBE-PIGS and the GFP reporter, we successfully generated zebrafish models carrying mutations homologous to human amyotrophic lateral sclerosis (ALS)-associated variants. Together, these findings highlight the robustness and versatility of the gGBE platform for precise base editing and underscore its promising potential for in vivo disease modeling and therapeutic genome engineering.},
}

Animals
*Zebrafish/genetics/embryology
Humans
*Gene Editing/methods
Embryo, Nonmammalian
CRISPR-Cas Systems
Amyotrophic Lateral Sclerosis/genetics
*Glycoside Hydrolases/genetics/metabolism

@article {pmid42864685,
year = {2026},
author = {Liao, K and Lin, J and Zhou, Y and Lewandowski, SA},
title = {Vascular profiling of the spinal cord and cortex reveals region-specific endothelial dysfunction and fibroblast remodeling in human ALS.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {42864685},
issn = {2051-5960},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics/physiopathology ; *Fibroblasts/pathology/metabolism ; *Spinal Cord/blood supply/pathology/metabolism ; *Endothelial Cells/pathology/metabolism ; *Cerebral Cortex/blood supply/pathology/metabolism ; Blood-Brain Barrier/metabolism/pathology ; Transcriptome ; Female ; Male ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Increasing evidence suggests that neurovascular dysfunction contributes to ALS pathogenesis, but a comprehensive understanding of vascular cell alterations in the human central nervous system remains lacking. Here, to systematically characterize neurovascular changes in ALS, we curated single-nucleus transcriptomic datasets from human spinal cord and cortical tissues with a specific focus on vascular cell populations. Comparative analyses revealed substantial vascular perturbations in the spinal cord compared to the cortex. Among vascular-associated cell populations, endothelial cells and fibroblasts exhibited the most pronounced transcriptional alterations. Endothelial cells from ALS spinal cords displayed reduced blood-brain barrier integrity signatures and increased expression of inflammatory and stress-response programs, with the greatest changes manifested in capillary endothelial cells. In parallel, we generated a refined cellular atlas of spinal cord fibroblasts and identified three major fibroblast populations, including a distinct LAMA1[low] perivascular fibroblast subtype. Fibroblast signatures were found to be consistently elevated in ALS across single-nucleus transcriptomic, bulk transcriptomic, and experimental validation datasets. Together, our findings establish a region-resolved view of neurovascular alternations in human ALS, which is characterized by endothelial barrier dysfunction and disease-associated remodeling of specialized perivascular fibroblasts. These findings broaden the cellular framework of ALS pathogenesis beyond neuronal and glial alterations and highlight the neurovascular niche as an integral component of human ALS disease biology.},
}

Humans
*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics/physiopathology
*Fibroblasts/pathology/metabolism
*Spinal Cord/blood supply/pathology/metabolism
*Endothelial Cells/pathology/metabolism
*Cerebral Cortex/blood supply/pathology/metabolism
Blood-Brain Barrier/metabolism/pathology
Transcriptome
Female
Male

@article {pmid42864786,
year = {2026},
author = {Hokkoku, K},
title = {[Lumbar Spinal Disease or Peripheral Nerve Disorder? The Role of Neurological Examination in Differential Diagnosis].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {78},
number = {10},
pages = {1089-1096},
doi = {10.11477/mf.188160960780101089},
pmid = {42864786},
issn = {1881-6096},
mesh = {Humans ; Diagnosis, Differential ; *Peripheral Nervous System Diseases/diagnosis ; *Neurologic Examination ; Nerve Conduction Studies ; *Spinal Diseases/diagnosis ; },
abstract = {Lower-limb numbness, pain, and weakness are common clinical complaints that require differentiation between cauda equina or radicular lesions associated with lumbar spinal disease and peripheral nerve disorders. Because degenerative findings on lumbar imaging are common, particularly among older adults, the responsible lesion should not be determined based on imaging findings alone. In this context, neurological examination contributes to anatomical localization and is central to the differential diagnosis. Particular emphasis is placed on interpreting muscle weakness and sensory disturbance according to myotomal, dermatomal, and peripheral nerve distributions. Other neurological findings, including gait disturbance, neurogenic claudication, bladder or bowel dysfunction, nerve stretch signs, and reflex changes, also provide important clues for localization. This review further addresses common diagnostic challenges encountered in daily practice, including differentiation of L5 radiculopathy from fibular neuropathy in patients with foot drop, distinction between cauda equina lesions and polyneuropathy, recognition of immune-mediated polyradiculoneuropathies, and identification of amyotrophic lateral sclerosis when it mimics lumbar spinal disease. Ancillary tests such as nerve conduction studies, needle electromyography, somatosensory evoked potentials, nerve ultrasound, and imaging should be interpreted in relation to the lesion localization suggested by neurological examination.},
}

Humans
Diagnosis, Differential
*Peripheral Nervous System Diseases/diagnosis
*Neurologic Examination
Nerve Conduction Studies
*Spinal Diseases/diagnosis

@article {pmid42865191,
year = {2026},
author = {Mohanty, SK and Vijayalakshmi, MK and Gopinath, S and Jaisudha, J and Venkatraman, D and Sandela, TM and Mohan, VK},
title = {Neurovascular Modulation of the Blood-brain Barrier Using Focused Ultrasound for Antisense Therapy Delivery in Amyotrophic Lateral Sclerosis.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026509618261001075016},
pmid = {42865191},
issn = {1875-5739},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, and the blood-brain barrier (BBB) restricts CNS delivery of macromolecular therapeutics such as antisense oligonucleotides (ASOs). Focused ultrasound (FUS) with microbubbles enables transient, noninvasive opening of the BBB for deliver SOD1-targeted ASOs.

METHODS: A narrative review of the literature in PubMed, Scopus, Web of Science, and Google Scholar (2020-2025) was conducted to evaluate FUS-assisted delivery of SOD1-targeted ASOs, with an emphasis on lipid- and calcium phosphate (CaP)- based nanoparticles.

RESULTS: Preclinical studies showed that FUS-mediated BBB opening (250 kHz; mechanical index 0.33; 30-s exposure; 0.15 mL/kg microbubbles) increased brain accumulation of nanoparticle- encapsulated ASOs by >3.5-fold compared with FUS without microbubbles. CaP lipid nanoparticles (~73 nm; -21 mV; 23-30% encapsulation efficiency) encapsulating tofersen demonstrated pH-responsive intracellular release. In wild-type and G93A SOD1 transgenic mice, FUS combined with CaP-ASO nanoparticles reduced SOD1 expression in sonicated cortical regions and increased lumbar spinal motor-neuron counts without detectable neuroinflammation or tissue damage.

DISCUSSION: Combining FUS-mediated BBB modulation with CaP nanoparticles provides a minimally invasive strategy for CNS ASO delivery. Observed spinal cord effects suggest wider CNS distribution, potentially involving CSF transport and retrograde axonal pathways. Clinical translation requires optimising FUS parameters, conducting long-term safety assessments, and managing skull acoustic variability.

CONCLUSION: MRI-guided FUS combined with CaP lipid nanoparticles represents a promising non-invasive platform for SOD1-targeted ASO delivery and precision gene therapy in ALS.},
}

@article {pmid42865281,
year = {2026},
author = {Pini, A and Cobel, C and Moretti, F and Governatori, G and Bonamici, M and Gobbato, T and Buonaccorso, L and Sireci, F and Ghirotto, L},
title = {Mapping the evidence on dignity therapy in amyotrophic lateral sclerosis: a scoping review.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2026.2742818},
pmid = {42865281},
issn = {2167-9223},
abstract = {Objective: To systematically map and synthesize the existing literature on the use of Dignity Therapy (DT) in amyotrophic lateral sclerosis (ALS), with particular attention to feasibility, acceptability, therapeutic outcomes, and clinical adaptations required for patients and caregivers. Methods: A systematic scoping review was conducted searching PubMed/MEDLINE, CINAHL, PsycINFO, and Scopus for studies published in the last ten years examining DT in individuals with ALS. Eligible studies were charted and compared qualitatively due to heterogeneity in design, outcomes, and measurement tools. Results: A total of 237 records were identified, of which five met the eligibility criteria. DT was generally feasible in ALS, including in advanced disease stages, when adapted with augmentative communication devices, email correspondence, or videoconferencing. Acceptability was high across studies, with participants frequently reporting meaningful engagement with the narrative process and positive perceptions of the generativity document. Qualitative evidence indicated potential benefits in existential well-being, emotional adjustment, maintenance of identity, and family communication. Quantitative outcomes were inconsistent, showing variable effects on dignity-related distress, mood symptoms, and spiritual well-being. Caregiver responses were mixed, with some reporting perceived support and others noting limited immediate impact. Conclusions: DT appears to be a promising intervention for addressing existential and relational needs in ALS, though current evidence is limited by small sample sizes and methodological variability. Larger, methodologically rigorous studies are needed to clarify therapeutic effects, optimize delivery adaptations, and evaluate outcomes for both patients and caregivers.},
}

@article {pmid42865955,
year = {2026},
author = {Long, Z and Guo, H and Sun, L},
title = {Mesenchymal stromal cells in age-related neurodegenerative disorders: mechanisms, translational barriers, and precision strategies.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1965598},
pmid = {42865955},
issn = {1664-3224},
mesh = {Humans ; *Neurodegenerative Diseases/therapy/metabolism/etiology ; *Mesenchymal Stem Cells/metabolism/immunology ; Animals ; *Aging/immunology ; Extracellular Vesicles/metabolism/transplantation ; *Mesenchymal Stem Cell Transplantation/methods ; Precision Medicine ; Translational Research, Biomedical ; },
abstract = {Ageing remodels the neuroimmune, metabolic, and vascular environment in ways that accelerate neuronal vulnerability and constrain tissue repair. Mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) are therefore attractive candidates for neurodegenerative disorders because their effects extend beyond cell replacement to coordinated paracrine, immunomodulatory, trophic, and vascular regulation. This critical review evaluates the biological rationale, disease-specific evidence, translational limitations, and precision-development strategies for MSC-based interventions in Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple system atrophy, and vascular dementia, whilst using selected rare hereditary neurodegenerative disorders as exploratory boundary cases. Current evidence supports three interconnected modes of action: reprogramming maladaptive neuroimmune responses; preserving neuronal homeostasis through trophic support, mitochondrial rescue, and proteostasis regulation; and restoring the neurovascular unit and blood-brain barrier. However, reproducible clinical efficacy remains limited by variation in tissue source, donor age, manufacturing, potency, dose, route, and outcome selection, as well as poor central nervous system exposure and inadequate patient stratification. Ageing-related changes in both the recipient microenvironment and the cellular product further complicate translation. Future development should replace empirical cell administration with mechanism-defined products, validated potency assays, quantitative biodistribution, biomarker-guided enrolment, engineered cells or vesicles, rational combinations, and trials using disease-modifying endpoints. MSC-based therapies are best positioned not as universal regenerative agents, but as mechanism-defined, biomarker-matched products-potentially engineered at the cell or EV level-that regulate biologically active and potentially reversible disease states.},
}

Humans
*Neurodegenerative Diseases/therapy/metabolism/etiology
*Mesenchymal Stem Cells/metabolism/immunology
Animals
*Aging/immunology
Extracellular Vesicles/metabolism/transplantation
*Mesenchymal Stem Cell Transplantation/methods
Precision Medicine
Translational Research, Biomedical

@article {pmid42866729,
year = {2026},
author = {Hassan, ST and Faheem, MSB and Yaqubi, AJ and Brhaish, MS},
title = {Brain-computer interfaces and neuroprostheses for severe speech impairment in amyotrophic lateral sclerosis.},
journal = {Annals of medicine and surgery (2012)},
volume = {88},
number = {10},
pages = {6221-6224},
pmid = {42866729},
issn = {2049-0801},
abstract = {Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder that frequently culminates in severe dysarthria and anarthria, profoundly isolating patients and diminishing their quality of life. Traditional speech therapy and conventional augmentative and alternative communication devices rely on residual motor control and become ineffective in late-stage ALS. In response, brain-computer interfaces and speech neuroprostheses have emerged as transformative solutions. By decoding neural signals directly from the motor cortex and translating them into synthesized speech, these devices bypass compromised neuromuscular pathways. Recent high-impact clinical trials have demonstrated unprecedented success, achieving high-speed decoding and integrating artificial intelligence-driven voice banking to preserve a patient's unique vocal identity. However, significant translational challenges remain, including signal degradation, surgical risks, high socioeconomic costs, and ethical dilemmas regarding patient autonomy and data privacy. This perspective reviews the current state-of-the-art in speech neuroprosthetics, analyzes the barriers to widespread clinical implementation, and advocates for increased interdisciplinary collaboration and funding to establish these technologies as a standard of care for patients with severe speech impairments.},
}

@article {pmid42867206,
year = {2026},
author = {Files, MC and Aranha, BC and Fipke, MV and Elias, DB and Camargo, ER and Carlos, FS and Miola, ECC and Souza, MF and Avila, LA},
title = {Elevated CO2 increases cover crop sensitivity to imidazolinones but does not substantially alter post-cultivation soil dissipation.},
journal = {International journal of phytoremediation},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/15226514.2026.2741670},
pmid = {42867206},
issn = {1549-7879},
abstract = {This study evaluated the effects of elevated (700 ± 50 µmol mol[-1]) and ambient (400 ± 50 µmol mol[-1]) atmospheric CO2 concentrations on soils treated with imazapyr, imazapic and imazethapyr using Italian ryegrass and Persian clover. Two open-top-chamber experiments assessed herbicide dissipation, soil microbial respiration (C-CO2) and plant biochemical responses, including acetolactate synthase (ALS) activity, free amino acids, proteins and soluble sugars. Soils amended with Persian clover residues showed greater herbicide dissipation (≈15-30%) than fallow soil after 40 days, regardless of CO2 level (except for imazethapyr under elevated CO2), whereas Italian ryegrass showed limited improvement, mainly for imazapic. Microbial respiration was highest in soils amended with Persian clover, while ryegrass resulted in the lowest respiration and reduced C-CO2 emission after imazapyr + imazapic application under elevated CO2. Elevated CO2 increased shoot biomass in both species but also reduced herbicide tolerance, decreasing GR50 values by 12-31% (from 64.5 to 44.6 g a.i. ha[-1] in Italian ryegrass and from 29.8 to 26.1 g a.i. ha[-1] in Persian clover), indicating greater plant susceptibility under future CO2 scenarios. At 28 days after emergence, herbicide application reduced ALS activity under both CO2 conditions, although ALS activity remained higher under elevated CO2. Persian clover showed greater biochemical resilience, maintaining higher amino acid contents under herbicide stress. Overall, cover-crop identity, rather than atmospheric CO2, was the primary determinant of herbicide dissipation in soil: Persian clover consistently enhanced microbial activity and imidazolinone degradation, whereas elevated CO2 increased plant sensitivity without improving post-cultivation soil remediation.},
}

@article {pmid42858780,
year = {2026},
author = {Ji, C},
title = {Partial convergence of alternative polyadenylation changes across ALS-Associated RNA-Binding proteins.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.10.012},
pmid = {42858780},
issn = {1873-7544},
abstract = {Alternative polyadenylation (APA) regulates transcript 3'-end architecture, stability, localization, and translation. Although RNA-binding protein dysfunction is central to amyotrophic lateral sclerosis (ALS), whether different ALS-associated proteins cause shared APA abnormalities remains unclear. We analyzed poly(A)-site usage after TDP-43 knockdown, TDP-43 K263E expression, FUS knockout, FUS P525L expression, and MATR3 knockout. Using false-discovery rate (FDR) < 0.05 as the primary criterion, evidence varied markedly among datasets. FUS knockout produced the strongest response, with 373 significant events affecting 239 genes. Three events involving two genes remained significant after TDP-43 knockdown, and two events involving one gene remained significant in the TDP-43 K263E dataset. No events survived FDR correction after FUS P525L expression or MATR3 knockout, and no FDR-significant events or genes were shared between datasets. We therefore examined nominal events (unadjusted P < 0.05) as an explicitly exploratory layer. Nominal event overlap was enriched in 7 of 10 pairwise comparisons, and nominal gene overlap in 9 of 10. TDP-43 knockdown and TDP-43 K263E showed the strongest directional agreement: 65 nominal events were shared; 25 were directionally classified in both datasets, of which 23 were concordant. FUS knockout and FUS P525L also showed enriched nominal overlap, but without significant directional concordance or correlated ΔPAU responses. Thus, FUS loss induces a robust FDR-supported APA phenotype, whereas evidence is substantially weaker in other contexts. Cross-dataset similarities occur mainly among exploratory nominal targets and do not consistently extend to direction or magnitude. APA responses therefore show partial, context-dependent convergence rather than a universal defect.},
}

@article {pmid42859482,
year = {2026},
author = {Sharma, T and Krishna, H and Dixit, A and Dixit, SG and Shukla, KK and Banerjee, M and Nayak, P},
title = {Aluminium as a Metalloestrogen: Toxicological Pathways, Endocrine Disruption and Systemic Health Implications.},
journal = {Maedica},
volume = {21},
number = {3},
pages = {759-766},
pmid = {42859482},
issn = {1841-9038},
abstract = {Aluminium (Al) is the most abundant metal in the Earth's crust and a common environmental contaminant due to industrial processes, recycling and consumer goods. Aluminium can enter the human body via the gastrointestinal, respiratory, and skin routes, as well as through injection, although this is not essential for biological function. It can then accumulate in different organs. Its physicochemical properties enable it to displace vital metals, bind to biomolecules and interfere with cellular processes, leading to genotoxicity, oxidative stress and protein misfolding. Aluminium toxicity impacts various body systems, such as neurodegeneration, bone disorders, heart conditions, endocrine disruption and reproductive issues. Notably, Al acts as a metalloestrogen, mimicking or disrupting estrogen receptor signaling. This interference affects the hypothalamic-pituitary-gonadal axis and changes estrogen-dependent processes in both males and females. This review explores Al's systemic toxicology and its emerging function as an endocrine disruptor, highlighting its dual nature as both a sustainable industrial resource and a common biological toxin. The findings highlight important public health issues and suggest the need for further research into how Al interacts with estrogen receptors to improve prevention and treatment.},
}

@article {pmid42860504,
year = {2026},
author = {Tsai, CY and Wu, HC and Su, TP and Weng, EF and Wang, SM},
title = {Sigma-1 Receptor Mitigates Poly-GR-Associated Redox Dysregulation by Restoring NRF2/HO1 Signaling in C9orf72-Associated ALS.},
journal = {Neuromolecular medicine},
volume = {28},
number = {1},
pages = {},
pmid = {42860504},
issn = {1559-1174},
mesh = {*Receptors, sigma/physiology/genetics/antagonists & inhibitors/agonists ; Animals ; *NF-E2-Related Factor 2/physiology/genetics/biosynthesis ; Sigma-1 Receptor ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Heme Oxygenase-1/physiology/biosynthesis/genetics ; Signal Transduction ; Mice ; Humans ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Oxidation-Reduction ; Motor Neurons/metabolism ; *C9orf72 Protein/genetics ; *Membrane Proteins/physiology/biosynthesis/genetics ; Mice, Transgenic ; Fluvoxamine/pharmacology ; Cell Line ; Mice, Inbred C57BL ; Male ; Morpholines ; },
abstract = {Hexanucleotide GGGGCC repeat expansions in C9orf72 produce arginine-rich dipeptide repeat proteins, including poly-GR and poly-PR, that contribute to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Although poly-GR has been linked to oxidative stress and mitochondrial dysfunction, the mechanisms that determine whether antioxidant defenses are preserved or suppressed in poly-GR-expressing motor neurons remain incompletely understood. Here, we investigated whether Sigma-1 receptor (Sigma-1R) modulates poly-GR-associated redox dysregulation in cellular and mouse models. In NSC34 cells, both EGFP-PR42 and EGFP-GR50 expression reduced NRF2 protein levels. EGFP-GR50 expression was also associated with reduced NRF1 and HO1 levels and increased reactive oxygen species (ROS) accumulation. Sigma-1R overexpression or pharmacological activation with fluvoxamine or PRE084 restored NRF2 and HO1 expression and attenuated both cellular and mitochondrial oxidative stress in EGFP-GR50-expressing cells. Co-treatment with the Sigma-1R antagonist NE100 attenuated the agonist-induced restoration of NRF2 and HO1. Furthermore, the NRF2 inhibitor ML385 attenuated agonist-mediated HO1 restoration, supporting the involvement of NRF2 activity in this downstream response. In an AAV-mediated EGFP-GR50 mouse model, Sigma-1R deficiency was associated with shortened survival, reduced NeuN-positive neuronal counts, and decreased NRF2 immunoreactivity in the brain. Together, these findings identify Sigma-1R as a modulator of poly-GR-associated redox dysregulation and neuronal vulnerability and support further investigation of Sigma-1R modulation as a potential therapeutic strategy for C9orf72-associated ALS.},
}

*Receptors, sigma/physiology/genetics/antagonists & inhibitors/agonists
Animals
*NF-E2-Related Factor 2/physiology/genetics/biosynthesis
Sigma-1 Receptor
*Amyotrophic Lateral Sclerosis/genetics/metabolism
*Heme Oxygenase-1/physiology/biosynthesis/genetics
Signal Transduction
Mice
Humans
Oxidative Stress
Reactive Oxygen Species/metabolism
Oxidation-Reduction
Motor Neurons/metabolism
*C9orf72 Protein/genetics
*Membrane Proteins/physiology/biosynthesis/genetics
Mice, Transgenic
Fluvoxamine/pharmacology
Cell Line
Mice, Inbred C57BL
Male
Morpholines

@article {pmid42860740,
year = {2026},
author = {Lee, K and Kwak, T and Park, W},
title = {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 = {30},
number = {3},
pages = {97-113},
doi = {10.20463/pan.2026.0045},
pmid = {42860740},
issn = {2733-7545},
abstract = {PURPOSE: A key pathological hallmark of amyotrophic lateral sclerosis (ALS) is transactive response DNA-binding protein 43 (TDP-43, encoded by TARDBP) proteinopathy. Mutations in TARDBP and cellular stress can drive nuclear clearance and cytoplasmic aggregation of TDP-43. TDP-43 is an essential nuclear RNA-binding protein that regulates RNA metabolism, and cytoplasmic TDP-43 aggregation leads to aberrant splicing of essential neuronal transcripts including stathmin-2 (STMN2) and unc-13 homolog A (UNC13A). Dysregulated RNA splicing causes cryptic exon (CE) inclusion in STMN2 and UNC13A mRNA, resulting in non-functional proteins and disruption of axonal regeneration and synaptic integrity. Splice-switching antisense oligonucleotides and gene-editing platforms can correct STMN2 and UNC13A mis-splicing defects. However, restoring STMN2 and UNC13A expression alone is not sufficient to regenerate neuromuscular junctions or reverse skeletal muscle atrophy, both of which are crucial for functional recovery in patients with ALS.

METHODS: We reviewed gene-targeted treatment strategies and rehabilitative mechanisms that inhibit ALS progression and reverse neuromuscular degeneration by analyzing databases, including Google Scholar, PubMed, and ScienceDirect. We proposed a dual-modality therapeutic approach integrating base-editing-mediated gene therapy with exercise-based rehabilitation.

RESULTS: Antisense oligonucleotides and genome editing can restore transcript fidelity by preventing cryptic exons inclusion in STMN2 and UNC13A, thereby stabilizing neuronal function. Gene-targeted therapies halt ALS progression; however, these treatments alone are insufficient to reverse neuromuscular degeneration or achieve functional recovery needed for patients with ALS to return to daily life.

CONCLUSION: Integrated rehabilitation is a crucial step in gene-targeted therapy for ALS. This strategy halts disease progression and restores neuromuscular function, thereby improving the lifespan and quality of life of patients with ALS.},
}

@article {pmid42861689,
year = {2026},
author = {Raheja, A and Ang, K and Lee, B and Saffari, SE and Tan, EK and Yeo, CJJ},
title = {Statin Exposure and Survival Outcomes in Amyotrophic Lateral Sclerosis in an Asian Cohort.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70427},
pmid = {42861689},
issn = {1097-4598},
support = {C210112024//Agency for Science, Technology and Research (A*STAR)/ ; IRNMR21CPGJJ//National Neuroscience Institute Singapore/ ; },
abstract = {INTRODUCTION: Data from Asian cohorts on whether statin therapy affects amyotrophic lateral sclerosis (ALS) progression are limited. We examined whether statin exposure was associated with ALS disease duration or tracheostomy-free survival in a multiethnic Asian ALS cohort.

METHODS: Data from patients diagnosed with ALS between 2012 and 2025 were retrospectively reviewed. Patients were categorized as "ever" or "never" statin users for primary analyses, and as "never," "former," or "current" users at diagnosis for additional analyses. Disease duration was defined as time from symptom onset to death, and tracheostomy-free survival as time from symptom onset to tracheostomy or death without tracheostomy. Kaplan-Meier and Cox regression analyses evaluated associations between statin exposure and both outcomes. Additional analyses examined statin discontinuation after diagnosis using time-varying exposures. Sensitivity analyses excluded post-diagnosis imitators and applied 30-, 90-, and 180-day lags.

RESULTS: Among 103 ALS patients, 27 (26.2%) had ever received statins. Statin exposure was not significantly associated with disease duration (hazard ratio [HR]: 1.42, 95% CI: 0.64-3.14, p = 0.387) or tracheostomy-free survival (HR: 1.04, 95% CI: 0.50-2.18, p = 0.913). Post-diagnosis statin discontinuation was associated with shorter survival in a time-varying analysis (HR: 6.52, 95% CI: 1.48-28.74, p = 0.013), although this finding was hypothesis-generating. Sensitivity analyses did not show statistically significant associations.

DISCUSSION: In this multiethnic Asian ALS cohort, statin exposure was not significantly associated with disease duration or tracheostomy-free survival. These findings add to the evidence that statins do not need to be discontinued due to ALS diagnosis. Larger studies are needed to define this association.},
}

@article {pmid42861801,
year = {2026},
author = {Alpana, and Dewangan, HK},
title = {Crossing the Blood-brain Barrier: Emerging Nanotechnological Approaches for Neurodegenerative Disease Therapy.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026454704261001071449},
pmid = {42861801},
issn = {1875-5739},
abstract = {Neurodegenerative disorders such as Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD) are characterized by progressive neuronal degeneration and severe therapeutic limitations due to the Blood-Brain Barrier (BBB). Recent advances in nanotechnology have enabled the development of nanoscale drug delivery systems capable of improving BBB penetration and enhancing therapeutic efficacy. This review discusses recent progress in Lipid Nanoparticles (LNPs), polymeric nanoparticles, exosomes, magnetic nanoparticles, gold nanoparticles, graphene quantum dots, and RNAloaded nanocarriers for brain-targeted delivery. Special emphasis is placed on receptor-mediated transcytosis, intranasal delivery, magnetic targeting, and ionizable lipid nanoparticle systems for nucleic acid delivery. Recent nanoformulations including curcumin-loaded nanoparticles, siRNA- loaded lipid nanoparticles, dopamine-loaded liposomes, and lactoferrin-functionalized polymeric nanoparticles are critically compared based on BBB penetration, therapeutic efficacy, toxicity, and translational potential. Furthermore, current clinical challenges including nanotoxicity, pharmacokinetics, large-scale manufacturing, and regulatory barriers are discussed. Nanotechnology- based therapeutics represent a promising strategy for improving diagnosis and treatment of neurodegenerative disorders and may facilitate the future development of precision nanomedicine.},
}

@article {pmid42862029,
year = {2026},
author = {Santos Silva, C and de Carvalho, M},
title = {Transcutaneous Carbon Dioxide Monitoring in Amyotrophic Lateral Sclerosis: A Scoping Review.},
journal = {European journal of neurology},
volume = {33},
number = {10},
pages = {e70782},
doi = {10.1111/ene.70782},
pmid = {42862029},
issn = {1468-1331},
mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis ; Humans ; *Carbon Dioxide ; *Blood Gas Monitoring, Transcutaneous/methods ; *Hypoventilation/diagnosis/etiology ; *Respiratory Insufficiency/diagnosis/etiology ; },
abstract = {BACKGROUND: Respiratory failure is the leading cause of death in amyotrophic lateral sclerosis (ALS). Conventional pulmonary function tests are effort-dependent and may fail to detect early nocturnal hypoventilation. Transcutaneous carbon dioxide (PtcCO2) measurement is a non-invasive method for assessing ventilation, but its role in ALS remains unclear. We performed a scoping review to map the current evidence.

METHODS: PubMed, Web of Science, Scopus, and Google Scholar were searched from inception to April 2026. Original studies evaluating PtcCO2 monitoring in ALS were included. Due to heterogeneity in study designs, populations, and outcomes, a narrative synthesis was performed, categorized by study characteristics, measurement protocols, and clinical endpoints.

RESULTS: Twenty-one studies were included. Most were observational and conducted in tertiary centres. Twelve studies evaluated PtcCO2 as a surrogate marker for nocturnal hypoventilation, mainly to guide initiation or titration of non-invasive ventilation. Definitions of hypoventilation and reported PtcCO2 metrics varied widely. Only three studies evaluated PtcCO2 in relation to respiratory impairment or hypercapnia, but none reported formal measures of diagnostic accuracy. Evidence regarding the prognostic value was limited and inconsistent. Three studies showed that nocturnal hypercapnia preceded abnormalities in spirometry or daytime hypercapnia.

CONCLUSIONS: PtcCO2 monitoring shows promise as a non-invasive method for assessing nocturnal ventilatory abnormalities in ALS, including nocturnal hypoventilation. However, due to methodological heterogeneity, its diagnostic and prognostic roles remain uncertain. Current evidence is insufficient to support PtcCO2 as a standalone criterion for NIV initiation. Large-scale prospective studies with standardized protocols are essential to delineate its clinical utility.},
}

*Amyotrophic Lateral Sclerosis/complications/diagnosis
Humans
*Carbon Dioxide
*Blood Gas Monitoring, Transcutaneous/methods
*Hypoventilation/diagnosis/etiology
*Respiratory Insufficiency/diagnosis/etiology

@article {pmid42862034,
year = {2026},
author = {Janse van Mantgem, MR and Kuiper, MM and Steyn, FJ and Holdom, CJ and Meyjes, M and Kok, A and Ngo, ST and van den Berg, LH and van Eijk, RPA},
title = {Assessing the metabolic rate in patients with Amyotrophic Lateral Sclerosis, Progressive Muscular Atrophy, and Primary Lateral Sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2026.2745871},
pmid = {42862034},
issn = {2167-9223},
abstract = {OBJECTIVE: To determine whether resting energy expenditure (REE) differs between patients with amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS).

METHODS: Patients with ALS, PMA, and PLS were enrolled between 2017 and 2021 in a prospective cross-sectional study. REE was measured by indirect calorimetry. Body composition was assessed using air displacement plethysmography and used to calculate predicted resting energy expenditure (pREE). Metabolic index (MI) was defined as mREE relative to pREE and expressed as a percentage. Differences between disease categories were assessed using multivariable regression adjusted for sex, age, fat-free mass, fat mass, height, and smoking status.

RESULTS: In total, 79 patients with ALS, 33 with PMA, and 30 with PLS were included. MI of ≥110% was observed in 55.7% of patients with ALS, 27.3% with PMA, and 26.7% with PLS. After adjustment, MI differed significantly between disease subtypes (p = 0.019), with the highest mean observed in ALS (108.5%, 95% CI 105.8-111.1), followed by PMA (105.9%, 95% CI 102.6-109.3) and PLS (103.2%, CI 99.8 -106.6). Metabolic measures were not statistically correlated with disease-specific clinical characteristics.

CONCLUSIONS: Our findings suggest that metabolic phenotype varies across MND subtypes. In the absence of non-neurological controls, findings are best interpreted as indicating that MI-defined hypermetabolism is most prevalent in ALS; however, whether metabolic rate is increased in PMA or PLS relative to the general population remains unknown.},
}

@article {pmid42862052,
year = {2026},
author = {Unnikrishnan, B and Anand, A and Fang, CN and Wu, SM and Wang, CC and Huang, CC and Chu, HW and Chang, HT},
title = {Carbon dot-based nanomaterials in neurodegeneration: addressing neurobiological barriers and targeting challenges.},
journal = {Chemical communications (Cambridge, England)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cc03262a},
pmid = {42862052},
issn = {1364-548X},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, represent a major global health challenge due to their progressive nature and limited therapeutic options. One of the primary obstacles to treating these disorders is the blood-brain barrier (BBB), which restricts the delivery of most therapeutic agents into the central nervous system. In recent years, carbon-based nanomaterials, particularly carbon dot (CD) nanostructures, have emerged as promising platforms for neurological applications owing to their ultrasmall size, BBB-crossing ability, and anti-inflammatory and neuroprotective properties, in addition to tunable surface chemistry, strong photoluminescence, and favorable biocompatibility. This review provides a comprehensive overview of recent research developments in the application of CD-based nanomaterials, including carbon nanodots, carbon quantum dots, graphene quantum dots, and carbon polymer dots, for the potential treatment of neurodegenerative diseases. The synthesis strategies and carbonization approaches used to produce these carbon nanomaterials are discussed, along with their physicochemical properties relevant to neurobiological applications, such as particle size, surface functionalization, heteroatom doping, optical properties, and stability in biological environments. Furthermore, the mechanisms by which CD-based nanomaterials can traverse the BBB are examined, including receptor-mediated and adsorptive-mediated transcytosis pathways. In addition, their applications are discussed, with particular focus on their roles in bioimaging, biosensing, inhibition of pathological protein aggregation, antioxidative activity, and targeted drug delivery. Finally, key challenges related to toxicity, biodistribution, large-scale synthesis, and clinical translation are discussed, along with future perspectives for the development of multifunctional theranostic platforms. Overall, use of CD-based nanomaterials represents a promising emerging strategy for overcoming neurobiological barriers and enabling the development of next-generation nanotherapeutics for the management of neurodegenerative diseases.},
}

@article {pmid42862306,
year = {2026},
author = {Sahu, S and Jain, P and Dharme, KK and Yadav, K},
title = {CRISPR/Cas9-based nanodelivery systems for precision gene editing in neuroinflammation.},
journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]},
volume = {75},
number = {1},
pages = {},
pmid = {42862306},
issn = {1420-908X},
support = {Probecell/Res/2026/124//Probecell Scientific Pvt. Ltd./ ; },
mesh = {Humans ; Animals ; *Neuroinflammatory Diseases/genetics/therapy ; *Gene Editing/methods ; *CRISPR-Cas Systems ; Nanoparticles/administration & dosage ; },
abstract = {BACKGROUND: Neuroinflammation is a characteristic feature of many neurological diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Uncontrolled activation of microglia and astrocytes results in the production of proinflammatory mediators that contribute to neuronal dysfunction and degeneration.

PURPOSE: CRISPR/Cas9 genome-editing technology provides highly precise targeting of genes involved in these pathways, enabling the deletion, correction, or modulation of disease-associated genetic alterations. Nonetheless, effective delivery of CRISPR components to the central nervous system (CNS) remains a major challenge because of protective barriers such as the blood-brain barrier (BBB), as well as concerns regarding genomic instability and immunogenicity.

METHODS: Nanotechnology-guided delivery platforms, such as lipid nanoparticles, liposomes, dendrimers and polymeric carriers, have been developed as promising strategies to address these challenges. These nanosystems can improve biodistribution, pharmacokinetic behavior, and cellular uptake, while potentially reducing off-target effects and systemic toxicity.

RESULTS: The preclinical studies demonstrate successful modulation of key neuroinflammatory targets, including the NLRP3 inflammasome, triggering receptor expressed on myeloid cells 2 (TREM2), Janus kinase (JAK) signaling, and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, with potential therapeutic relevance to neurodegenerative diseases. In addition, novel techniques, such as mitochondrial base editing, prime editing, and epigenetic modulation, expand the scope of CRISPR-mediated therapeutic strategies. Although outcomes from animal models are promising, translation to the clinical setting requires careful consideration of safety, ethical concerns, and long-term efficacy.

CONCLUSIONS: This review highlights the potential of integrating CRISPR/Cas9 with nanodelivery systems to advance precision medicine for neuroinflammatory disorders, while emphasizing their potential for therapeutic applications in complex CNS conditions. Ongoing studies aimed at optimizing delivery and reducing off-target effects will be essential for advancing these approaches toward clinical practice.},
}

Humans
Animals
*Neuroinflammatory Diseases/genetics/therapy
*Gene Editing/methods
*CRISPR-Cas Systems
Nanoparticles/administration & dosage

@article {pmid42862794,
year = {2026},
author = {Hawas, Y and Abdelmageed, A and Messak, M and Ziada, A and Gamal, M and Ghanem, TIE and Abdelwahab, MM and Meshref, M and Kashbour, MO},
title = {History of Head Injury and Risk of Amyotrophic Lateral Sclerosis: An Updated Comprehensive Systematic Review with Meta-Analysis of 5,033,215 Participants.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ned/adwag050},
pmid = {42862794},
issn = {1423-0208},
abstract = {BACKGROUND: Head injury has been proposed as a potential modifiable risk factor for amyotrophic lateral sclerosis (ALS); however, prior studies have yielded inconsistent findings. We aimed to re-evaluate this association through an updated systematic review and meta-analysis, incorporating the latest evidence and exploring the influence of injury severity, frequency, timing, and definition.

METHODS: A systematic search of PubMed, Scopus, Web of Science, Embase, EBSCO, and ProQuest from inception to January 2026 was conducted. Observational studies (cohort and case-control) reporting the association between head injury and ALS risk were included. Pooled effect estimates were generated using random-effects models. Subgroup, sensitivity, cumulative, and publication bias analyses were performed.

RESULTS: Twenty-nine studies encompassing 5,033,215 participants were included. These comprised 22 case-control studies and seven cohort studies. Case-control meta-analysis showed that head injury was associated with 36% higher odds of ALS (AOR = 1.36; 95% CI: 1.24-1.48; I² = 20.4%). Cohort studies showed a positive but non-significant association (RR = 1.59; 95% CI: 0.93-2.71). Subgroup analyses showed significant associations within mild, moderate, and severe injury categories and among studies with clearly defined traumatic brain injury exposure. Single head injury was associated with higher odds of ALS (AOR = 1.22; 95% CI: 1.11-1.34).

CONCLUSION: Head injury was associated with an increased risk of ALS across multiple analyses, including different injury severity levels and exposure definitions. However, the observational nature of available evidence and the possibility of reverse causation and residual confounding limit causal interpretation. Further prospective studies and mechanistic investigations are required to clarify the potential relationship between head injury and ALS development.},
}

@article {pmid42863218,
year = {2026},
author = {Saito, A and Sekioka, R and Nagashima, A and Washio, T and Honjo, E and Koganemaru, Y and Ohnuki, K and Miyoshi, S},
title = {Novel compounds induce AChR clustering and improve motor function in myasthenia gravis animal models.},
journal = {Biochemical and biophysical research communications},
volume = {839},
number = {},
pages = {154728},
doi = {10.1016/j.bbrc.2026.154728},
pmid = {42863218},
issn = {1090-2104},
abstract = {The neuromuscular junction (NMJ), the synapse between motor nerves and skeletal muscles, is implicated in the pathogenesis of various neuromuscular disorders, including myasthenia gravis (MG), congenital myasthenia, and amyotrophic lateral sclerosis. Postsynaptic clustering of acetylcholine receptors (AChRs) is crucial for NMJ formation. This process is initiated by agrin, a glycoprotein secreted from motor nerve terminals, which activates muscle-specific tyrosine kinase (MuSK) via its coreceptor, low-density lipoprotein receptor-related protein 4 (Lrp4), and thereby activates downstream signaling pathways that induce AChR clustering. MG is an autoimmune disease characterized by the production of autoantibodies against NMJ components such as AChR, MuSK, and Lrp4, which leads to impaired neuromuscular transmission and motor dysfunction. In this study, we identified orally active small-molecule compounds that promote AChR clustering through the Lrp4-MuSK signaling axis. Knockdown experiments demonstrated that Lrp4 was responsible for the compounds to induce AChR clustering. The compounds induced MuSK phosphorylation following the compound treatment in C2C12 cells and improved motor function and increased muscle volume in both MuSK-MG mice and AChR-MG rat models. Together, these findings identify orally active small molecules that potentiate Lrp4-MuSK signaling and highlight a pharmacological strategy to modulate NMJ function for MG and related neuromuscular disorders.},
}

@article {pmid42855802,
year = {2026},
author = {Zheng, X and Yu, X},
title = {A Comprehensive Review and Future Prospects of Aluminum-Sulfur Batteries: From Material Design to Practical Challenges.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e06181},
doi = {10.1002/adma.202506181},
pmid = {42855802},
issn = {1521-4095},
support = {2019-01 07-00-07-E00028//Innovation Program of the Shanghai Municipal Education Commission/ ; 51971065//National Science Foundation of China/ ; },
abstract = {Aluminum-sulfur (Al-S) batteries are promising next-generation energy storage systems owing to the high abundance, low cost, and multi-electron redox capability of Al, combined with the high theoretical capacity and environmental friendliness of S. This review systematically compares the dual electrochemical mechanisms based on S reduction (S[0]/S[2-]) and S oxidation (S[0]/S[4+]), highlighting their distinct advantages in energy density and safety. Key strategies for cathode design-including carbon-based, anchoring-functional, and catalytic-functional hosts-are discussed, alongside electrolyte engineering using ionic liquids, deep eutectic solvents, inorganic molten salts, and aqueous systems. Recent advances in dendrite suppression, anode protective layers, and functional separators are also summarized. A central challenge identified is the sluggish Al[3+] solvation/desolvation kinetics, which limits rate capability and low-temperature performance. The application of in situ/operando characterization techniques (XANES, Raman, UV-vis) to unravel complex reaction pathways is emphasized. By integrating multidisciplinary innovations, this review provides a comprehensive perspective and a phased commercialization roadmap, aiming to accelerate the transition of Al-S batteries from laboratory research to practical green energy storage.},
}

@article {pmid42855901,
year = {2026},
author = {Mayberry, EJ and Creer, S and Griffiths, AW and Hobson, EV and Davies, S and Bedford, J and Gould, RL and McDermott, CJ},
title = {Specialist psychology provision for ALS/MND: results from a survey of UK ALS/MND services.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/21678421.2026.2742816},
pmid = {42855901},
issn = {2167-9223},
abstract = {OBJECTIVE: This study aimed to map and evaluate specialist psychological and neuropsychological care provision within ALS/MND multidisciplinary teams across the UK.

METHODS: A cross-sectional, mixed-methods online survey was circulated to ALS/MND specialist services across England, Wales, Northern Ireland, and Scotland. The survey evaluated service demographics, specialist psychological staffing models, referral pathways, perceived adequacy of care, and access to other wellbeing support.

RESULTS: Responses were received from 25/36 services (69% response rate), representing an estimated 3,500 patients. Access to specialist care was highly variable, with 24% of services lacking an established referral pathway and 20% having a referral pathway for patients living in some parts of their service area but not others. Importantly, even for those services with access to specialist psychology, nearly all reported that the specialist psychology provision was insufficient to meet the needs of their service users and the service; 80% of these services reported insufficient capacity to deliver direct assessments and interventions. Qualitative data highlighted inequitable and insufficient provision, the fragmented nature of current psychological care, and the need for sufficient and stable funding for specialist psychology provision in ALS/MND.

CONCLUSIONS: Despite international guidelines recognizing the necessity of specialist psychological and neuropsychological care in ALS/MND, access across the UK remains highly inequitable and under-resourced. To meet UK national standards (NICE) and prevent the negative impacts of untreated psychological distress and inequitable access, more resource allocation is required to integrate specialist psychology as a core component of ALS/MND care.},
}

@article {pmid42856205,
year = {2026},
author = {Murimi-Worstell, DA and Freeman, M and Minkina, A and Vollger, MR and Stergachis, AB and Coffin, JM},
title = {Structural polymorphism and population-variable coding capacity of HERV-K(HML-2) in human pangenomes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.22.753638},
pmid = {42856205},
issn = {2692-8205},
abstract = {Approximately 8% of the human genome is derived from ancient retroviral infections. The most recently integrated of these endogenous retroviruses is the HERV-K(HML-2) clade, whose expression has been associated with cancer, amyotrophic lateral sclerosis, and embryogenesis. Studies of HERV expression, particularly HML-2, have relied predominantly on short-read sequencing. However, the high similarity among HML-2 proviruses prevents many short reads from being assigned uniquely to individual loci. We therefore compared haplotype-resolved long-read genome assemblies from 292 donors to resolve variation in proviral structure and coding capacity. Several loci previously thought to be fixed were structurally polymorphic. Tandem arrays occurred at 13 loci and contained up to six proviral copies in a single array. At 8q11.23, we identified a previously undescribed full-length provirus in one haplotype. All 583 other haplotypes carried a solo-LTR. We found that standard reference genomes failed to represent the coding capacity retained in many individuals, whose proviruses contained intact open reading frames despite disruptive mutations in the reference sequences. Short-read genotypes left 32.5% of the tested donor-variant pairs unresolved at sites associated with viral reading frames. These findings show why HML-2 expression must be interpreted in the context of the structural and coding alleles each individual carries.},
}

@article {pmid42856249,
year = {2026},
author = {MurthyGowda, S and Huyghue, K and Castillo, B and Gugala, F and Li, W and Dubnau, J},
title = {Early life social isolation primes flies for more rapid TDP-43 dependent neurodegeneration later in life.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.23.753732},
pmid = {42856249},
issn = {2692-8205},
abstract = {A key pathophysiological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is loss of nuclear localization and abnormal cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43). Upstream factors that trigger the onset and progression of such neurodegenerative diseases are largely unknown. Aging and environmental factors contribute as potential risk factors. But epidemiological evidence suggests psychological stressors such as social isolation and loneliness are also associated with increased risks of neurodegenerative disease [1-8]. We examined the impacts of social isolation on TDP-43 related neurodegeneration. To investigate the potential for causative impact on neurodegeneration, we compared the effects of social isolation versus social enrichment in Drosophila . We utilized an established social isolation paradigm in which flies were either housed alone or in groups as young adults. We found that early-life social isolation acts as a primer to exacerbate the rate of neurodegeneration in response to subsequent induction of pathological levels of TDP-43. Social isolation stress drives more rapid activation of mdg4, an endogenous retrovirus that functionally mediates TDP-43 effects and more aggressive propagation of TDP-43 protein pathology from surface glial cells to nearby neurons. Shortened life span also ensues. We demonstrate that providing isolated flies with visual, olfactory and tactile social cues from conspecifics living behind a divider was insufficient to alleviate these effects of social isolation on neurodegeneration. Our findings have implications for the association between psychological stressors such as loneliness and risk of neurodegenerative diseases in humans and provide a platform to investigate mechanistic underpinnings in animal models.},
}

@article {pmid42856371,
year = {2026},
author = {Soedirdjo, SDH and Holobar, A and Dhaher, YY},
title = {Beyond snapshots: A dynamic framework for continuous motor unit tracking to enhance neurophysiological assessments.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.25.754489},
pmid = {42856371},
issn = {2692-8205},
abstract = {Tracking individual motor units (MUs) across multiple testing visits is critical for understanding neuromuscular adaptations and disease progression. However, existing methods fail to account reliably for spatiotemporal variations in motor unit action potentials (MUAPs) and lack validation for longitudinal tracking. Here, we present a robust computational framework for continuous MU tracking that integrates automatic estimation of electrode grid displacements and compensation for MUAP shape variations. Our algorithm demonstrated superior tracking accuracy, capturing 63% and 75% of MUs in the tibialis anterior and medial gastrocnemius, respectively, substantially outperforming state-of-the-art methods. By applying this approach to investigate estradiol-driven neuromuscular plasticity as a model system, we reveal previously undetectable modulations in recruitment thresholds and firing rates, linking hormonal fluctuations to motor unit behavior. Beyond advancing fundamental neuromuscular research, our approach holds promise for enhancing biomarker sensitivity in clinical trials, particularly in conditions such as amyotrophic lateral sclerosis, where reliable MU tracking is paramount. These findings establish a new standard for non-invasive motor unit tracking, unlocking opportunities for longitudinal neurophysiological assessment and evaluation of therapeutics.},
}

@article {pmid42856515,
year = {2026},
author = {Jackvony Infurna, S and Ijaz, L and Hardin, EJ and Aikedan, A and Zhou, C and Yadavalli, T and Jang, MW and Mahoney, M and Gan, L and Shukla, D and Orr, AL and Orr, AG},
title = {ALS/FTD-linked TDP-43 alterations prevent HSV-1 infection by disrupting cell-adhesion pathways.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.28.755069},
pmid = {42856515},
issn = {2692-8205},
abstract = {TAR DNA-binding protein-43 (TDP-43) alterations are a key hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative disorders. Increasing evidence links these conditions to viral infections, but it is not known if and how viral pathogens may be affected by disease-associated TDP-43. We found that ALS/FTD-linked forms of human TDP-43 prevent infection by herpes simplex virus type-1 (HSV-1), a common neurotropic virus. This cell-autonomous protective effect was conserved across different TDP-43 mutations, sporadic ALS, and C9ORF72 -ALS, in neural and non-neural cell types, and in patient-derived cells and animal models. In addition to restricting infection, TDP-43 mutation prevented inflammatory and cell stress-related responses to HSV-1 exposure. TDP-43 knockdown but not overexpression was sufficient to protect cells from HSV-1 infection, implicating a loss-of-function mechanism. Neurons with TDP-43 mutation had disruptions in adhesion-related pathways and, accordingly, had reduced early-stage viral binding and entry. Further analyses revealed alternative RNA splicing and impairment of focal adhesion kinase (FAK/PTK2), a key mediator of cell-adhesion pathways. Inhibition of FAK was sufficient to decrease HSV-1 infection, and genetic enhancement of functional but not inactive FAK promoted infectivity in cells with TDP-43 mutation. Together, these data indicate that TDP-43 affects virus-host interactions by influencing adhesion pathways required for viral infection.},
}

@article {pmid42856741,
year = {2026},
author = {Settgast, T and Shriki, O and Northoff, G and Zilio, F and Borgheai, SB and Shahriari, Y and Kübler, A},
title = {All Roads Lead to Rome: Resting-State Criticality as a Neurophysiological Marker of Brain-Computer Interface (BCI) Performance in People with Amyotrophic Lateral Sclerosis (ALS) and Healthy Participants.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10422321/v1},
pmid = {42856741},
issn = {2693-5015},
abstract = {This exploratory study investigates the relationship between resting-state brain dynamics (EEG) and subsequent brain-computer interface (BCI) performance in people with amyotrophic lateral sclerosis (ALS) and healthy participants. Grounded in the critical brain hypothesis, we examined whether neurophysiological markers of criticality in resting-state EEG correlate with subsequent BCI performance. We analyzed neuronal avalanche dynamics, multiscale criticality measures, the spectral slope, and Lempel-Ziv complexity across two datasets: a longitudinal single-case study of a person in the locked-in state after a disease history with ALS (Dataset 1) and longitudinal data from 5 people with ALS and single sessions from 6 healthy participants (Dataset 2). Neuronal avalanche dynamics, the spectral slope, and Lempel-Ziv complexity consistently correlated with subsequent BCI performance in people with ALS. Conversely, healthy participants showed inverted correlation patterns for the neuronal avalanche dynamics. While group comparisons were not statistically significant, effect size analyses indicated supercritical brain dynamics in people with ALS. We integrate these findings into the B-ARC (BCI-Aptitude through Resting-State Criticality) framework proposing an inverted U-shaped relationship between the proximity of resting-state brain activity to criticality and BCI control. In this framework, healthy participants approach the critical optimum from a subcritical regime, while people with ALS appear to approach it from a putatively supercritical regime characterized by cortical hyperexcitability. These findings and the proposed framework provide potential resting-state predictors of BCI aptitude in people with ALS and may inform the detection of so-called Windows of Consciousness .},
}

@article {pmid42857254,
year = {2026},
author = {Ali, SI and Lian, L and Robinson, H and Daniels, N and Prieto, GA and Poplawski, GHD and Lopez-Gonzalez, R},
title = {Corrigendum to "Aberrant CDK4/6-driven cell-cycle reentry drives neuronal loss and defines a therapeutic target in C9orf72 ALS/FTD" [iScience 29 (2026) 114596].},
journal = {iScience},
volume = {29},
number = {10},
pages = {117845},
doi = {10.1016/j.isci.2026.117845},
pmid = {42857254},
issn = {2589-0042},
abstract = {[This corrects the article DOI: 10.1016/j.isci.2025.114596.].},
}

@article {pmid42858164,
year = {2026},
author = {Vocelle, A and Ensrud, E and Howard, IM},
title = {Prognostication in Amyotrophic Lateral Sclerosis: A Narrative Review of Pre-Diagnosis and Functional Outcomes.},
journal = {NeuroRehabilitation},
volume = {},
number = {},
pages = {10538135261490936},
doi = {10.1177/10538135261490936},
pmid = {42858164},
issn = {1878-6448},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a very heterogeneous disease, yet some of the most common questions received by physicians in the ALS clinic are "how much time do I have?" and "what can I expect to happen next?" This line of inquiry is not strictly limited to patients; clinicians also need an idea of prognosis to appropriately plan for treatment decisions and prepare the patient and caregiver for future care needs. This narrative review synthesizes current evidence on prognostic indicators in ALS, organized across three temporal phases: factors preceding diagnosis, factors present at diagnosis, and factors emerging after diagnosis. Pre-diagnosis predictors include age at onset, sex, socioeconomic status, genetic background, premorbid Body Mass Index (BMI) and nutritional status, and comorbid disease. At diagnosis, clinical phenotype and site of onset, diagnostic delay, baseline Amyotrophic Lateral Sclerosis Functional Rating Score-Revised (ALSFRS-R) and forced vital capacity, cognitive involvement, fluid biomarkers, and electrophysiologic measures carry prognostic weight. Post-diagnosis, the trajectory is refined by the rate of ALSFRS-R decline, serial respiratory measures, and weight loss, and is actively modified by clinical interventions including noninvasive ventilation, enteral nutrition, disease-modifying therapy, and multidisciplinary care. Notably, quality of life does not track with physical decline, consistent with the disability paradox described in other severe neurological conditions. For neurorehabilitation, these indicators support a shift from reactive to anticipatory practice: timing equipment provision, communication support, respiratory intervention, and goals-of-care discussions to the predicted trajectory rather than to established deficit. Refinement of prognostic models may also improve stratification in ALS clinical trials.},
}

@article {pmid42858511,
year = {2026},
author = {Maia, MEP and Lemes, LFR and Soares, FLF},
title = {Cocaine profiling: Implementation of MCR-ALS for adulterant identification using ATR-FTIR in forensic analysis.},
journal = {Forensic science international},
volume = {390},
number = {},
pages = {113155},
doi = {10.1016/j.forsciint.2026.113155},
pmid = {42858511},
issn = {1872-6283},
abstract = {Cocaine stands out due to its significant social problems stemming from trafficking, leading to increased violence and detrimental effects on the physical and mental health of its users. Brazil serves as a transit route for cocaine produced in Colombia, Peru, and Bolivia to Europe, with Paraná being a strategic region due to its border with Paraguay and the second-largest port in Brazil. Cocaine is gradually adulterated with cutting agents along the distribution chain, altering its chemical profile. Paradoxically, these components can create a unique chemical signature, enabling the tracing of the drug's origin and distribution routes. This study analysed 298 mid-infrared spectra of cocaine samples seized in Paraná and applied Multivariate Curve Resolution with Alternating Least Squares (MCR-ALS) to identify and characterise the main adulterants and diluents present. MCR-ALS was chosen due to its ability to decompose overlapping spectra into individual component contributions, making it ideal for analysing complex mixtures. Five distinct chemical profiles were identified, and based on their spectral interpretation and the most reported adulterants and diluents in cocaine samples, the five components were defined as: cornstarch, cocaine, caffeine, sodium bicarbonate, and creatine. The concentration profiles of the components were clustered using Hierarchical Cluster Analysis, and seven profiles of cocaine samples were identified based on the amount of cocaine and the presence of adulterants and diluents. The MCR-ALS method proved effective in identifying cocaine cutting agents via ATR-FTIR, offering a fast and reliable approach for forensic analysis that can help to identify commercial routes.},
}

@article {pmid42854356,
year = {2026},
author = {Cordts, I and Galhoz, A and Tzeplaeff, L and Gründel, A and Kohlmayer, F and Schwersenz, A and Marschalkowski, I and Bjelica, B and Panitz, V and Schulze, C and Svačina, M and Rau, P and Dorigan, AC and Deschauer, M and Witzel, S and Brenner, D and Weishaupt, JH and Bublitz, SK and Lorenzl, S and Hermann, A and Hagenacker, T and Wolf, J and Regensburger, M and Lehmann, HC and Dohrn, MF and Dorst, J and Guenther, R and Maier, A and Meyer, T and Zeller, D and Neuwirth, C and Weber, M and Koch, JC and Boentert, M and Weiler, M and Petri, S and Weyen, U and Grehl, T and Menden, MP and Lingor, P},
title = {EARLY-ALS: a multicentre study on prodromal amyotrophic lateral sclerosis.},
journal = {EBioMedicine},
volume = {133},
number = {},
pages = {106505},
doi = {10.1016/j.ebiom.2026.106505},
pmid = {42854356},
issn = {2352-3964},
abstract = {BACKGROUND: Neurodegenerative diseases often feature a prolonged phase of subtle changes preceding diagnosis. In amyotrophic lateral sclerosis (ALS), defining this prodromal period is critical for identifying early disease features and intervention windows.

METHODS: In this case-control study, 475 patients with ALS and 285 controls from 20 centres in Germany and Switzerland completed a digital questionnaire on prodromal symptoms and health-related factors. Logistic regression included subgroup analyses by sex and clinical strata.

FINDINGS: Patients with ALS reported a higher burden of prodromal complaints (OR 7.50, 95% CI 4.27-13.17; P < 0.001), particularly neuro-motor, sensory, and pain-related symptoms. Before symptom onset, patients consulted neurologists more often (OR 1.26, 1.10-1.44; P < 0.001) and females more often received speech therapy (OR 2.35, 1.05-5.28; P = 0.038). Prodromal herniated discs were more common in males (OR 2.21, 1.04-4.68; P = 0.038) and spinal-onset patients (OR 2.14, 1.25-3.67; P = 0.006). Patients more often had lower secondary education (OR 1.93, 1.24-3.01; P = 0.004), physically demanding occupations (OR 2.21, 1.42-3.43; P < 0.001), and higher consumption habits (P < 0.005). Weight trajectories differed by sex (P = 0.009), with pre-onset weight loss in male patients (P < 0.001).

INTERPRETATION: Patients with ALS retrospectively reported subtle motor impairment before recognised symptom onset, alongside altered healthcare use and sex- and subgroup-specific patterns. These findings suggest that sporadic ALS may be preceded by a prodromal period and identify mild motor impairment as a potential marker, pending prospective validation.

FUNDING: DGM e. V.},
}

@article {pmid42854693,
year = {2026},
author = {Citrano, KJ and Maheswari Jawahar, VB and Reeves, MM and Petrucelli, L and Carlomagno, Y and Yue, M and Alaiz Noya, J and Daughrity, LM and Baena Tomé, R and Jansen-West, K and Rawlinson, B and DeTure, M and Engelberg-Cook, E and Singh, A and Graff-Radford, NR and Day, GS and Boeve, BF and Boxer, AL and Knopman, DS and Josephs, KA and Petersen, RC and Oskarsson, B and Ashton, NJ and Dickson, DW and Gendron, TF and Prudencio, M and Zhang, YJ and Petrucelli, L},
title = {Anti-HDGFL2 cryptic protein antibodies provide a sensitive readout of TDP-43 pathology and clinical disease features.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {103105},
doi = {10.1016/j.xcrm.2026.103105},
pmid = {42854693},
issn = {2666-3791},
abstract = {TAR DNA-binding protein (TDP-43) cytoplasmic aggregates and nuclear depletion contribute to TDP-43 dysfunction in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) and forms of motor neuron disease (MND), particularly amyotrophic lateral sclerosis (ALS). TDP-43 regulates alternative splicing, but its dysfunction can engender the inclusion of cryptic exons (CEs) during splicing. Transcripts harboring an in-frame CE can generate de novo proteins. One example is the CE variant of hepatoma-derived growth factor-like protein 2 (HDGFL2-CE). To understand HDGFL2-CE as a readout of TDP-43 dysfunction, and its spatial relationship with TDP-43 pathology, we generate anti-HDGFL2-CE polyclonal and monoclonal antibodies and develop sensitive HDGFL2-CE immunoassays. With these tools, we observe that HDGFL2-CE accumulates in neurons with TDP-43 pathology, and that higher frontal cortex HDGFL2-CE in FTLD-TDP and FTLD-TDP/MND associates with greater pathological TDP-43, earlier age of onset, and shorter survival, supporting HDGFL2-CE as a marker tightly linked to TDP-43 dysfunction and clinical disease features.},
}

@article {pmid42855485,
year = {2026},
author = {Kiani, L},
title = {Progressive sleep abnormalities precede ALS clinical onset.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42855485},
issn = {1759-4766},
}

@article {pmid42855762,
year = {2026},
author = {Wang, HF and Sun, B and Pan, J and Pang, XY and Bai, JM and Feng, JL},
title = {[The role of the GSTP1/JNK signaling pathway in regulating oxidative stress and programmed cell death in amyotrophic lateral sclerosis].},
journal = {Zhonghua nei ke za zhi},
volume = {65},
number = {10},
pages = {1122-1129},
doi = {10.3760/cma.j.cn112138-20260501-00268},
pmid = {42855762},
issn = {0578-1426},
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Oxidative Stress ; *Glutathione S-Transferase pi/metabolism ; Humans ; *Apoptosis ; Animals ; *MAP Kinase Signaling System ; Signal Transduction ; JNK Mitogen-Activated Protein Kinases/metabolism ; },
}

*Amyotrophic Lateral Sclerosis/metabolism/pathology
*Oxidative Stress
*Glutathione S-Transferase pi/metabolism
Humans
*Apoptosis
Animals
*MAP Kinase Signaling System
Signal Transduction
JNK Mitogen-Activated Protein Kinases/metabolism

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

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

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

CLINICALTRIALS: gov identifier: NCT03766321.

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

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

FUNDING: Italian Ministry of Health.},
}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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