@article {pmid41269513,
year = {2025},
author = {Jude, EB and Saluja, S and Mannan, F and Heagerty, A and Frier, B},
title = {UK Resuscitation Advanced Life Support Guidelines: Should the Paradigm be Extended?.},
journal = {Diabetes therapy : research, treatment and education of diabetes and related disorders},
volume = {},
number = {},
pages = {},
pmid = {41269513},
issn = {1869-6953},
abstract = {Cardiac arrest continues to be a predominant cause of mortality worldwide, necessitating its rapid identification, and intervention by reversible aetiologies to optimise successful outcomes. The established 4H 4T framework has served as a foundational guide for advanced life support (ALS) protocols since its formal introduction in the 2000 International Guidelines on Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care (ECC), effectively targeting critical conditions such as hypoxia, hypothermia, hypo-/hyperkalaemia, hypovolaemia, tension pneumothorax, cardiac tamponade, thrombosis, and exposure to toxins. However, this framework inadequately addresses other significant factors: specifically hypoglycaemia and tachy- and bradyarrhythmias. Hypoglycaemia, a reversible and treatable metabolic state, poses substantial threats to cardiovascular stability, particularly in people with diabetes and in association with sepsis. It disrupts myocardial repolarisation, prolongs the QT interval, and may instigate the R-on-T phenomenon, which can precipitate life-threatening arrhythmias. Likewise, tachyarrhythmias and bradyarrhythmias often precipitate cardiac arrest, thereby warrant dedicated attention within ALS protocols. This paper advocates expanding the current 4H 4T framework to include hypoglycaemia and tachy- and bradyarrhythmias as critical and reversible causes of cardiac arrest (5H 5T). The rationale for such a paradigm shift is supported by evidence from clinical studies, case reports, and experimental models that demonstrate the adverse effect of these conditions on cardiovascular integrity and alert clinicians to look for these reversible factors. The inclusion of these factors into ALS protocols will necessitate revising resuscitation guidelines, modifying training for healthcare practitioners, and including systematic monitoring of blood glucose alongside routine assessment of cardiac rhythm during resuscitation procedures. Future research should focus on elucidating the pathophysiological mechanisms underlying these conditions, to establish operational thresholds for intervention, and validate their integration into resuscitation frameworks. By expanding the conceptualisation of reversible causes, the proposed 5H/5T framework would offer a more rational and practical approach to the management of cardiac arrest, to improve the survival and recovery of these critically ill patients.},
}

@article {pmid41269421,
year = {2025},
author = {Asadinejad, H and Taherkhani, S and Golboos, SM and Azizi, Y and Mohammadkhanizadeh, A},
title = {Targeting Neurodegeneration with SGLT2is: From Molecular Mechanisms to Clinical Implications.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {119},
pmid = {41269421},
issn = {1559-1182},
mesh = {Humans ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; },
abstract = {Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a class of antidiabetic drugs that have demonstrated significant cardiovascular and renal benefits. Accumulating evidence suggests that SGLT2is also exert neuroprotective effects and may influence the progression of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). SGLT2is modulate glucose metabolism, reduce oxidative stress, suppress inflammation, and enhance mitochondrial function. Beyond glycemic control, they show potential therapeutic effects in ameliorating the metabolic dysregulation associated with neurodegenerative pathologies. Current preclinical and clinical evidence including metabolic regulation, anti-inflammatory actions, and neuroprotective effects mediated through SGLT2is associated molecular pathways have been critically evaluated to delineate their therapeutic potential in neurodegenerative disorders. Although preclinical studies have shown promising results, more clinical trials are needed. This review highlights key research gaps and proposes future translational applications.},
}

Humans
*Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology
Animals
*Neurodegenerative Diseases/drug therapy/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology

@article {pmid41269403,
year = {2025},
author = {Jin, J and Hand, R and Meltzer, M and Abate, C and Geva, M and Hayden, MR and Ross, CA},
title = {Sigma-2 Receptor Antagonism Enhances the Neuroprotective Effects of Pridopidine, a Sigma-1 Receptor Agonist, in Huntington's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {121},
pmid = {41269403},
issn = {1559-1182},
mesh = {*Receptors, sigma/antagonists & inhibitors/agonists/metabolism ; *Huntington Disease/drug therapy/pathology/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; Sigma-1 Receptor ; *Piperidines/pharmacology/therapeutic use ; Mice ; Humans ; Neurons/drug effects/metabolism/pathology ; Huntingtin Protein/metabolism ; },
abstract = {Pridopidine is a selective sigma-1 receptor (S1R) agonist in clinical development for Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). Activation of the S1R by pridopidine is neuroprotective in multiple preclinical models of neurodegenerative disease. The sigma-2 receptor (S2R) is evolutionarily and structurally unique from the S1R. Nevertheless, the S1R and S2R share an overlapping yet distinct ligand binding profile. Inhibition of the S2R is neuroprotective and S2R antagonists are in clinical development for Alzheimer's Disease (AD), ⍺-synucleinopathies, and dry age-related macular degeneration. In this study, we hypothesized that simultaneous activation of the S1R by pridopidine and inhibition of the S2R by the selective S2R antagonist FA10 might provide enhanced protection against mutant huntingtin (mHTT) expression in an in vitro model of neurodegeneration. Consistent with previous studies, pridopidine reduced neuronal cell death in a mouse primary neuron mHTT model. Similarly, we found that inhibition of the S2R by FA10 was also sufficient to protect against mHTT induced neurodegeneration in this model. The combination treatment of pridopidine and FA10 achieved greater efficacy than either compound alone, even at lower concentrations. The combination of these compounds may allow for lower efficacious doses leading to improved safety profiles and reduced off-target effects. This novel combinatorial approach, in which the S1R is activated while simultaneously inhibiting the S2R may prove to be a highly effective therapeutic strategy for HD and other neurodegenerative diseases.},
}

*Receptors, sigma/antagonists & inhibitors/agonists/metabolism
*Huntington Disease/drug therapy/pathology/metabolism
Animals
*Neuroprotective Agents/pharmacology/therapeutic use
Sigma-1 Receptor
*Piperidines/pharmacology/therapeutic use
Mice
Humans
Neurons/drug effects/metabolism/pathology
Huntingtin Protein/metabolism

@article {pmid41269363,
year = {2025},
author = {Schito, P and Domi, T and Russo, T and Pozzi, L and Falzone, YM and Pipitone, GB and Agosta, F and Carrera, P and Quattrini, A and Riva, N and Filippi, M},
title = {The genetic architecture of primary lateral sclerosis in a cohort of Italian patients.},
journal = {Journal of neurology},
volume = {272},
number = {12},
pages = {780},
pmid = {41269363},
issn = {1432-1459},
mesh = {Humans ; Italy ; Male ; Female ; Middle Aged ; Aged ; Cohort Studies ; Adult ; C9orf72 Protein/genetics ; *Motor Neuron Disease/genetics ; High-Throughput Nucleotide Sequencing ; Amyotrophic Lateral Sclerosis/genetics ; },
abstract = {BACKGROUND AND PURPOSE: Recent studies suggest that primary lateral sclerosis (PLS) may have a genetic component. In this work, we performed a next-generation sequencing (NGS) analysis in order to explore the genetic architecture of PLS in a cohort of Italian patients.

METHODS: NGS was conducted to analyze 228 genes associated with amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP), and parkinsonian syndromes (PS) in a cohort of PLS patients diagnosed between 2003 and 2021 at our center. All patients were also screened for C9orf72 hexanucleotide repeat expansion (C9orf72-HRE) by repeat-primed PCR. Genetic variants were classified according to the ACMG criteria.

RESULTS: In our study, including 47 PLS patients, we detected 22 rare variants in 17 patients, including 8 likely pathogenic or pathogenic variants and 14 variants of uncertain significance. Four patients carried more than one variant. Among the variants identified, 18 (81.8%) were found in ALS-associated genes. Variants in TBK1 were associated with extra-motor involvement.

CONCLUSIONS: Although the majority of the PLS patients in our cohort tested negative for an expanded panel of genes associated with ALS, HSP and PS, in 36.2% of the cases, a genetic variant was identified and it mostly belongs to genes associated with ALS, including a C9orf72 expansion and a rare SOD1 variant. Based on these results, we emphasize the need for genetic screening in PLS patients. Further studies on the genetic background are necessary to better understand the complex pathomechanism of each phenotype within the MND-FTD spectrum disorder.},
}

Humans
Italy
Male
Female
Middle Aged
Aged
Cohort Studies
Adult
C9orf72 Protein/genetics
*Motor Neuron Disease/genetics
High-Throughput Nucleotide Sequencing
Amyotrophic Lateral Sclerosis/genetics

@article {pmid41269218,
year = {2025},
author = {Elias, LLK and Elias, PCL and Antunes-Rodrigues, J and Moreira, AC},
title = {Plasma osmolality affects ACTH and cortisol regulation besides magnocellular vasopressin.},
journal = {European journal of endocrinology},
volume = {193},
number = {5},
pages = {L29-L30},
doi = {10.1093/ejendo/lvaf224},
pmid = {41269218},
issn = {1479-683X},
mesh = {Humans ; Osmolar Concentration ; *Hydrocortisone/blood ; *Adrenocorticotropic Hormone/blood ; *Arginine Vasopressin/deficiency ; Hypothalamo-Hypophyseal System/metabolism ; Pituitary-Adrenal System/metabolism ; *Vasopressins ; },
abstract = {The recently published article entitled "Disrupted ACTH and cortisol response to osmotic and non-osmotic stress in patients with arginine vasopressin deficiency," authored by Nikaj et al. evaluated the HPA axis response to osmotic and non-osmotic stimuli in patients with AVP deficiency (AVP-D) and with primary polydipsia (PP). Patients with AVP-D showed increased plasma ACTH and cortisol concentrations, in response to arginine stimulation, compared to patients with PP. The authors attributed altered ACTH and cortisol responses in AVP-D patients mainly to non-osmotic stress. However, PP patients may also show impaired osmolality and psychological comorbidities, which would be better assessed if there was a healthy control group in the study. We raised this aspect because data from our previous published study (Elias et al.), evaluating the interaction of plasma osmolality and plasma AVP, as well as plasma ACTH and cortisol responses to human CRH alone and combined with osmotic stimulus or isotonic volume loading in patients with AVP-D and healthy controls, showed a significant correlation between plasma osmolality and the ACTH response to hCRH across both healthy and AVP-D subjects during tests. Moreover, the enhanced ACTH and cortisol responses to hCRH with increasing pOsm were also observed in both healthy controls and patients with AVP-D. These findings suggest that the acute rise in plasma osmolality amplifies the ACTH and cortisol responses to hCRH, involving factors beyond magnocellular AVP. Importantly, Itagaki. et al. also demonstrated a positive correlation between plasma ACTH and plasma osmolality in AVP-D patients subjected to hypertonic saline infusion. In conclusion, while Nikaj. et al.'s study provides confirmation of the HPA axis activity in AVP-D patients, it seems unlikely that disruption of HPA axis regulation in these patients is due to impaired feedback regulation between AVP and CRH.},
}

Humans
Osmolar Concentration
*Hydrocortisone/blood
*Adrenocorticotropic Hormone/blood
*Arginine Vasopressin/deficiency
Hypothalamo-Hypophyseal System/metabolism
Pituitary-Adrenal System/metabolism
*Vasopressins

@article {pmid41268542,
year = {2025},
author = {Baird, LA and Teener, SJ and Webber-Davis, IF and Carter, AD and Huang, F and Jang, DG and Famie, JP and Piecuch, CE and Guo, K and Feldman, EL and Murdock, BJ},
title = {Tofacitinib extends survival in a mouse model of ALS through NK cell-independent mechanisms.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1662197},
pmid = {41268542},
issn = {1664-3224},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/immunology/mortality/pathology ; *Pyrimidines/pharmacology/therapeutic use ; *Piperidines/pharmacology/therapeutic use ; Disease Models, Animal ; Mice ; *Killer Cells, Natural/immunology/drug effects ; Mice, Transgenic ; *Protein Kinase Inhibitors/pharmacology ; Superoxide Dismutase-1/genetics ; Spinal Cord/drug effects/immunology ; Motor Neurons/drug effects/immunology ; Male ; Female ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease with few treatment options, rendering the development of new, effective therapeutics of critical importance. The immune system plays a substantial role in ALS pathology, with multiple cell populations implicated in disease progression. Natural killer (NK) cells are innate immune cells that accumulate in the brain and spinal cord during ALS, increasing neuroinflammation and killing motor neurons. Depleting NK cells extends survival in mouse models of ALS. Tofacitinib, an FDA-approved janus kinase (Jak) and signal transducer and activator (STAT) pathway inhibitor, reduces NK cytotoxicity and decreases overall levels in peripheral blood and may represent a potential ALS therapy. Therefore, we aimed to evaluate the effects of tofacitinib treatment on survival and phenotype in an ALS mouse model. Additionally, we sought to determine the impact of dose and regimen on efficacy.

METHODS: SOD1 [G93A] mice, the most used rodent model of ALS, were treated with low- (5 mg/kg) and high-dose (30 mg/kg) tofacitinib following a prevention regimen, an intervention regimen, or a drug-cycling regimen, with survival being the primary outcome. Symptom onset was assessed via body weight, agility, and grip strength measurements. At end-stage disease (i) motor neurons and neuromuscular junctions were counted, (ii) immune populations were quantified via flow cytometry in peripheral blood and spinal cord, (iii) microglial surface marker expression was quantified to assess neuroinflammation, and (iv) bulk RNA-seq was performed on spinal cord.

RESULTS: Low-dose, but not high-dose, tofacitinib significantly increased survival and delayed weight loss. Notably, beginning treatment before symptom onset (prevention) did not offer any survival advantage over the intervention nor cycling regimen; further analyses were pooled by dose. There were no differences in motor neuron or neuromuscular junction counts. Peripheral NK and CD8+ T cells were decreased dose-dependently. Interestingly, spinal cord infiltrating NK cells increased with low-dose tofacitinib, though no other changes in neuroinflammation were observed. RNA-seq revealed that low-dose tofacitinib treatment reversed the dysregulation of multiple immune and metabolic pathways.

CONCLUSIONS: These data support the repurposing of tofacitinib as a potential ALS treatment.},
}

Animals
*Amyotrophic Lateral Sclerosis/drug therapy/immunology/mortality/pathology
*Pyrimidines/pharmacology/therapeutic use
*Piperidines/pharmacology/therapeutic use
Disease Models, Animal
Mice
*Killer Cells, Natural/immunology/drug effects
Mice, Transgenic
*Protein Kinase Inhibitors/pharmacology
Superoxide Dismutase-1/genetics
Spinal Cord/drug effects/immunology
Motor Neurons/drug effects/immunology
Male
Female

@article {pmid41268324,
year = {2025},
author = {Thakur, DK and Padole, S and Sarkar, T and Arumugam, S and Chattopadhyay, S},
title = {Liquid-Liquid Phase Separation: Mechanisms, Roles, and Implications in Cellular Function and Disease.},
journal = {FASEB bioAdvances},
volume = {7},
number = {11},
pages = {e70054},
pmid = {41268324},
issn = {2573-9832},
abstract = {Liquid-liquid phase separation is a basic biophysical process that creates essential membraneless organelles that support different cellular activities, including chromatin organization and gene expression. The malfunction of liquid-liquid phase separation (LLPS) plays a critical role in numerous diseases, such as neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), which involve TDP-43 and Tau, various cancers that utilize SPOP and YAP/TAZ proteins, and viral infections where pathogens use LLPS to replicate and avoid immune detection. This review brings together the fast-growing knowledge about LLPS across multiple scientific fields. The paper examines the physiological functions of LLPS along with its disease pathogenesis mechanisms and presents various experimental techniques (e.g., advanced microscopy, FRAP, FCS) for its investigation. It introduces new therapeutic approaches such as PTM modulation, small molecules like 1,6-hexanediol and Lipoamide, and advanced genetic tools including CRISPR and PROTACs like PSETAC, which also explores diagnostic applications. The thorough integration of knowledge presented here is essential to connect separate scientific findings while propelling research forward and turning LLPS discoveries into new biomedical developments.},
}

@article {pmid41267644,
year = {2025},
author = {Tahedl, M and Siah, WF and Karavasilis, E and Hengeveld, JC and Doherty, MA and McLaughlin, RL and Hardiman, O and Tan, EL and Christidi, F and Kleinerova, J and Bede, P},
title = {Anatomical Associations Between Focal Mitochondrial Metabolism and Patterns of Neurodegeneration in Amyotrophic Lateral Sclerosis.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78099},
pmid = {41267644},
issn = {1531-8249},
abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) has a very specific neuroimaging signature, but the molecular underpinnings of the strikingly selective anatomic involvement have not elucidated to date. Accordingly, a large neuroimaging study was conducted with 258 participants to evaluate associations between patterns of neurodegeneration and focal metabolic metrics.

METHODS: Structural and diffusivity alterations were systematically evaluated in a genetically stratified cohort. Voxelwise associations between neurodegeneration and physiological mitochondrial indices were systematically evaluated over the entire brain and also examined in specific regions.

RESULTS: Significant topological associations were identified between physiological mitochondria tissue density, nicotinamide adenine dinucleotide (NADH)-ubiquinone oxidoreductase, succinate dehydrogenase, cytochrome c oxidase (COX), mitochondrial respiratory capacity (MRC), tissue respiratory capacity (TRC), and propensity to focal atrophy in ALS. Anatomic correlations between mitochondrial metrics and morphometric change were particularly strong in GGGGCC hexanucleotide repeat carriers in C9orf72. Diffusivity analyses also confirmed associations between brain metabolism and microstructural degeneration. Higher focal mitochondria tissue density was associated with higher likelihood of frontal, temporal, cerebellar, opercular, thalamic, cingulum, putamen, corpus callosum, and corona radiata degeneration. Uncinate fasciculus degeneration was associated with higher Complex I, II, COX, and TRC activity. Topological associations were readily replicated in an external validation cohort.

INTERPRETATION: Our data indicate that brain regions with high metabolic activity are particularly vulnerable to neurodegeneration in ALS. Anatomic associations between physiological cerebral metabolism and patterns of neurodegeneration implicate mitochondrial dysfunction in the pathophysiology of ALS. Although mitochondrial dysfunction may not be the primary etiological factor, it may represent a shared bottleneck of multiple converging molecular and genetic pathways, offering a potential opportunity for meaningful pharmacological intervention. ANN NEUROL 2025.},
}

@article {pmid41267271,
year = {2025},
author = {Xue, S and Wang, T and Zhou, J and Liu, S and Wang, C and Zhang, Y and Li, H and Chen, D and Lu, Y},
title = {Safety evaluation of aristolactams from the edible herb Houttuynia cordata: implications for dietary exposure and food safety.},
journal = {Food research international (Ottawa, Ont.)},
volume = {222},
number = {Pt 1},
pages = {117663},
doi = {10.1016/j.foodres.2025.117663},
pmid = {41267271},
issn = {1873-7145},
mesh = {Animals ; *Houttuynia/chemistry ; Mice, Inbred BALB C ; Mice ; *Aristolochic Acids/toxicity/pharmacokinetics ; *Food Safety ; Humans ; Male ; *Dietary Exposure/adverse effects ; Biological Availability ; Oxidative Stress/drug effects ; Kidney/drug effects ; Cell Line ; *Drugs, Chinese Herbal/toxicity ; Complement Activation/drug effects ; },
abstract = {Houttuynia cordata Thunb., a traditional edible and medicinal herb widely consumed in Asia, has raised concerns about food safety due to the presence of aristolactams (ALs), which are structural analogues of the nephrotoxic aristolochic acid I (AA I). This study investigated the subacute toxicity, metabolism and oral bioavailability of predominant ALs-aristolactam I (AL I), aristolactam BII (AL BII), and ALs fractions from H. cordata (HCA)-in BALB/c mice, with AA I as a positive control. The AL I, AL BII and HCA groups exhibited only modest elevations in body weight, serum renal indicators and urinary injury biomarkers. In contrast, AA I induced significant increases through oxidative stress and complement activation (C3a/C3aR and C5a/C5aR pathways). Although AL I demonstrated greater cytotoxicity to HK-2 cells (IC50 = 2.76 μM) than its metabolite AL Ia (IC50 = 35.41 μM) and even AA I (IC50 = 79.85 μM) in vitro, its in vivo toxicity was lower. This was attributed to the lower oral bioavailability of AL I (52.71 %) and AL BII (39.60 %) compared to AA I (99.83 %), combined with metabolism into less toxic derivatives. Furthermore, no parent ALs were detected in urine. These toxicokinetic properties limited renal exposure and reduced in vivo toxicity despite their notable cytotoxicity in vitro. These findings provided scientific support for the safe consumption of H. cordata at typical dietary levels, while emphasizing the importance of monitoring ALs content in edible herbs to ensure food safety and inform regulatory guidelines.},
}

Animals
*Houttuynia/chemistry
Mice, Inbred BALB C
Mice
*Aristolochic Acids/toxicity/pharmacokinetics
*Food Safety
Humans
Male
*Dietary Exposure/adverse effects
Biological Availability
Oxidative Stress/drug effects
Kidney/drug effects
Cell Line
*Drugs, Chinese Herbal/toxicity
Complement Activation/drug effects

@article {pmid41266705,
year = {2025},
author = {Di Rienzo, L and Genovese, I and Galluzzi, G and Ruocco, G and Fornetti, E},
title = {Uncovering the molecular details of the 14-3-3 recruitment by mutant Sod1 species.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {41091},
pmid = {41266705},
issn = {2045-2322},
mesh = {*Superoxide Dismutase-1/genetics/metabolism/chemistry ; *14-3-3 Proteins/metabolism/chemistry ; Humans ; Molecular Dynamics Simulation ; *Mutation ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Molecular Docking Simulation ; Protein Binding ; },
abstract = {Mutations in superoxide dismutase 1 (SOD1) are a major cause of familial Amyotrophic Lateral Sclerosis (ALS), promoting disease progression through metal depletion, aggregation, and abnormal protein interactions. Among proteins interacting with pathological SOD1 aggregates, 14-3-3 proteins are involved in key cellular pathways often disrupted in ALS, such as cell survival, axonal growth, and DNA repair. Their sequestration by mutant SOD1 may impair their neuroprotective functions, exacerbating disease pathology. Despite this, 14-3-3 proteins remain understudied in ALS research, presenting an opportunity for novel insights. This study employs molecular dynamics simulations to investigate structural changes in two ALS-linked SOD1 mutations, A4V and L144F, compared to wild-type SOD1. A4V is associated with a severe disease form, while L144F leads to a slower progression, allowing an analysis of different ALS severities. Using Zernike polynomials and hydropathy assessments, we identified key structural alterations that promote aggregation and aberrant interactions. Large-scale docking simulations further suggest a stable complex between mutant SOD1 and 14-3-3 proteins, confirmed through molecular dynamics analyses. By elucidating structural features driving SOD1 aggregation and pathological interactions, our findings support targeting protein-protein interactions as a potential therapeutic strategy in ALS, offering an alternative to direct aggregate inhibition.},
}

*Superoxide Dismutase-1/genetics/metabolism/chemistry
*14-3-3 Proteins/metabolism/chemistry
Humans
Molecular Dynamics Simulation
*Mutation
*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology
Molecular Docking Simulation
Protein Binding

@article {pmid41265061,
year = {2025},
author = {Aphale, P and Dokania, S and Shekhar, H},
title = {Constructive appraisal of Zhong et al.'s study on Mycobacterium tuberculosis dormant antigens and PB2-DIMQ vaccine: Opportunities for translational strengthening.},
journal = {Tuberculosis (Edinburgh, Scotland)},
volume = {155},
number = {},
pages = {102708},
doi = {10.1016/j.tube.2025.102708},
pmid = {41265061},
issn = {1873-281X},
}

@article {pmid41264881,
year = {2025},
author = {Genuis, SK and Luth, W and Adams, B and Johnston, WS},
title = {Patient-based evidence for amyotrophic lateral sclerosis prognostic health communication: "the clock is ticking…how long do I have?".},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/21678421.2025.2589782},
pmid = {41264881},
issn = {2167-9223},
abstract = {Objectives: Prognostic health communication is a critical challenge for amyotrophic lateral sclerosis (ALS) health-care professions, however patient-based evidence for best practice remains limited. We investigated how the experiences of ALS patients and caregivers can inform prognostic communication and whether patient-based evidence supports clinical use of predictive tools. Methods: Data were drawn from ALS Talk, an asynchronous, online focus group study. Patients and family caregivers were recruited from across Canada. Seven groups interacted in a threaded web-forum structure. Sixty-four participants shared experiences and perspectives on prognostic communication. Data were qualitatively analyzed using conventional content analysis and the constant-comparative approach. Results: Primary themes were prognostic communication as an ongoing, evolving conversation; prognostic heterogeneity; progression as an embodiment of prognosis; and functional prognosis. The theme, information needs/wants, contributed to the primary themes. Participants highlighted the importance of stepwise discussions of general and personalized prognosis; prognostic heterogeneity as a source of hope and a potential communication barrier; and how progression facilitates material understanding of prognosis, adaptation, and future planning. Further, participants wanted more information about functional prognosis and the impact of interventions/therapies on function and survival. Conclusions: We discuss participants' central questions: "how long" and "how well," and provide recommendations for patient-centred ALS prognostic communication. Participants' embodied understanding of prognosis and desire for information that anticipates functional change, informs disease management, and facilitates timely planning suggests that clinical application of ALS staging systems may meet patient and caregiver need. Testing in real-world clinical settings is needed to ensure the development of patient-centred predictive tools.},
}

@article {pmid41263806,
year = {2025},
author = {Kalkowski, K},
title = {[Genetic and Molecular Pathomechanisms of Amyotrophic Lateral Sclerosis and Therapeutic Perspectives – Current State of Knowledge].},
journal = {Postepy biochemii},
volume = {71},
number = {3},
pages = {252-259},
doi = {10.18388/pb.2021_599},
pmid = {41263806},
issn = {0032-5422},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; Humans ; Genetic Therapy ; Superoxide Dismutase-1/genetics ; C9orf72 Protein/genetics ; Mutation ; RNA-Binding Protein FUS/genetics ; DNA-Binding Proteins/genetics ; Protein Serine-Threonine Kinases/genetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease leading to progressive degeneration of motor neurons, muscle weakness and respiratory failure. Despite intensive research, the pathomechanisms of ALS have not been fully elucidated. This article presents the current state of knowledge on the genetic and molecular mechanisms of this disease, with a focus on mutations in the SOD1, C9ORF72, TARDBP, FUS, TBK1 genes, as well as recent discoveries in this area. Key pathogenetic processes are discussed, including disruption of RNA homeostasis, oxidative stress, mitochondrial dysfunction and protein aggregation. In addition, current therapeutic strategies are reviewed, including both registered drugs, such as riluzole and edaravone, and modern approaches, such as gene therapy, antisense oligonucleotides, immunotherapy and gene editing technologies, including CRISPR/Cas9. Special attention was given to clinical trials and their potential impact on future treatment options for ALS.},
}

*Amyotrophic Lateral Sclerosis/genetics/therapy
Humans
Genetic Therapy
Superoxide Dismutase-1/genetics
C9orf72 Protein/genetics
Mutation
RNA-Binding Protein FUS/genetics
DNA-Binding Proteins/genetics
Protein Serine-Threonine Kinases/genetics

@article {pmid41262412,
year = {2025},
author = {Rajagopalan, V and Pioro, EP},
title = {Detour ahead: possible causes of corticospinal tract truncation in upper motor neuron-predominant amyotrophic lateral sclerosis.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf419},
pmid = {41262412},
issn = {2632-1297},
abstract = {Clinical diagnosis of amyotrophic lateral sclerosis (ALS) depends on finding evidence of combined of upper motor neuron (UMN) and lower motor neuron degeneration. T2- and proton density (PD)-weighted images reveal intracranial corticospinal tract (CST) hyperintensity in some UMN-predominant ALS patients who also exhibit faster disease progression compared to those without CST hyperintensity. Our previous study identified CST fibre tract truncation in a subset of UMN-predominant ALS patients, both with and without CST hyperintensity. In this study, we investigated the underlying cause(s) of CST fibre tract truncation in such ALS patients. Routine clinical diffusion tensor imaging (DTI) scans were acquired in 14 neurologic controls and 45 ALS patients using a 1.5 T magnetic resonance imaging (MRI) scanner. UMN-predominant ALS patients were categorized into two subgroups based on their clinically-acquired conventional MRI findings. DTI reconstruction was performed using both single-exponential and bi-exponential fitting approaches (the latter for free water [FW] estimation). DTI along the perivascular space (ALPS) index was also measured. CST fibres were reconstructed using tractography in both control and ALS subgroups. In CST-truncated ALS patients, the fibres deviated from their normal trajectory and entered the superior longitudinal fasciculus (SLF) at the level of the centrum semiovale, resulting in apparent truncation and overlap with the SLF. Axial diffusivity, radial diffusivity, FW content, and mean diffusivity values were normal along the expected CST pathway in cases of truncation, suggesting that axonal or myelin degeneration, inflammation, or oedema were unlikely to be responsible for CST truncation. ALPS index was significantly increased in CST-truncated patients compared to those without CST truncation. Based on these results, we hypothesize that impaired axonal guidance mechanisms or dysfunction of the glymphatic system may contribute to CST fibre tract truncation in ALS.},
}

@article {pmid41262008,
year = {2025},
author = {Scott, MR and Sverdlov, O and Davis-Plourde, K and Tripodis, Y},
title = {Assessment of Wiener Process Degradation Models With Application to Amyotrophic Lateral Sclerosis Decline.},
journal = {Statistics in medicine},
volume = {44},
number = {25-27},
pages = {e70323},
doi = {10.1002/sim.70323},
pmid = {41262008},
issn = {1097-0258},
mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Monte Carlo Method ; *Models, Statistical ; Computer Simulation ; Likelihood Functions ; Disease Progression ; Longitudinal Studies ; Stochastic Processes ; },
abstract = {Degradation models are commonly used in engineering to analyze the deterioration of systems over time. These models offer an alternative to standard longitudinal methods as they explicitly account for within-subject temporal variability through a latent stochastic process, allowing random fluctuations within a patient to be captured. This work investigates Wiener process-based degradation models with linear drift (i.e., slope) while considering a diffusion term to represent within-subject temporal variability, a random-effects term to capture between-subject variability of the slope, and a time-invariant term to account for measurement error. First-difference estimators that stabilize covariance matrix inversion and remove the influence of time-invariant confounders are presented and validated in clinically relevant settings. Monte Carlo simulations assessing relative error and coverage probability demonstrate that these models yield consistent and stable estimates. Profile likelihood methods, which reduce the dimensionality of the parameter space, also performed reliably, but should be used with caution when follow-up times are highly clustered. As a proof of concept, we applied these models to amyotrophic lateral sclerosis (ALS) data from the Pooled Resource Open-Access ALS Clinical Trials Database (PRO-ACT). We observed steeper slopes of the revised ALS Functional Rating Scale (ALSFRS-R) in individuals who died compared to those who survived, indicating that degradation model estimates are consistent with expected patterns of ALS decline. Our results demonstrate that these stochastic models provide accurate and efficient estimates of longitudinal deterioration. Future work aims to incorporate Wiener process degradation models into a joint modeling framework.},
}

*Amyotrophic Lateral Sclerosis/physiopathology
Humans
Monte Carlo Method
*Models, Statistical
Computer Simulation
Likelihood Functions
Disease Progression
Longitudinal Studies
Stochastic Processes

@article {pmid41261682,
year = {2025},
author = {Huang, X and Wang, X and Yang, Y and Chen, H},
title = {Assessing the potential causal influence of myasthenia gravis on neurodegenerative diseases via multivariable Mendelian randomization.},
journal = {Medicine},
volume = {104},
number = {44},
pages = {e45340},
pmid = {41261682},
issn = {1536-5964},
mesh = {Humans ; Mendelian Randomization Analysis ; *Myasthenia Gravis/genetics/complications/epidemiology ; Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics/etiology/epidemiology ; Amyotrophic Lateral Sclerosis/genetics ; Alzheimer Disease/genetics/epidemiology/etiology ; Parkinson Disease/genetics ; Genetic Predisposition to Disease ; Risk Factors ; },
abstract = {Myasthenia gravis (MG), an autoimmune condition known for impairing neuromuscular signaling, has increasingly been implicated in broader neurological dysfunctions. Recent studies point toward a possible connection between autoimmune and neurodegenerative processes. However, whether MG contributes causally to the onset of major neurodegenerative disorders such as Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) remains unclear. This study utilizes Mendelian randomization (MR) to explore the potential causal influence of MG on these disorders from a genetic standpoint. A univariable Mendelian randomization (UVMR) framework was employed using summary-level data from genome-wide association studies (GWAS) to evaluate the effect of MG on the risk of AD, PD, and ALS. To confirm the robustness of the association between MG and AD, 2 independent AD GWAS datasets were incorporated for external replication, followed by a meta-analysis to combine the evidence. Additionally, multivariable Mendelian randomization (MVMR) was conducted to adjust for smoking behavior as a potential confounding factor. The UVMR analysis revealed a statistically significant causal relationship between MG and increased susceptibility to AD (odds ratio (OR): 1.037; 95% confidence interval (CI): 1.007-1.068; P = .016). No significant causal effects were observed for PD (OR: 1.019; 95% CI: 0.964-1.077; P = .509) or ALS (OR: 1.055; 95% CI: 0.977-1.140; P = .171). The association between MG and AD was consistently validated in 2 independent datasets (ieu-a-297: OR = 1.084; 95% CI: 1.017-1.156; P = .013; ieu-b-2: OR = 1.054; 95% CI: 1.006-1.104; P = .027). Meta-analysis reinforced the evidence supporting MG as a risk factor for AD (OR: 1.047; 95% CI: 1.023-1.072; P < .001). Furthermore, MVMR adjusting for smoking confirmed that MG independently contributes to AD risk (OR: 1.037; 95% CI: 1.006-1.069; P = .020). This study provides robust genetic evidence suggesting that MG is a causal and independent risk factor for AD. These findings highlight a novel link between autoimmunity and neurodegeneration, offering new directions for mechanistic and therapeutic research.},
}

Humans
Mendelian Randomization Analysis
*Myasthenia Gravis/genetics/complications/epidemiology
Genome-Wide Association Study
*Neurodegenerative Diseases/genetics/etiology/epidemiology
Amyotrophic Lateral Sclerosis/genetics
Alzheimer Disease/genetics/epidemiology/etiology
Parkinson Disease/genetics
Genetic Predisposition to Disease
Risk Factors

@article {pmid41261122,
year = {2025},
author = {Gobert, F and Merida, I and Maby, E and Seguin, P and Jung, J and Morlet, D and André-Obadia, N and Dailler, F and Berthomier, C and Otman, A and Le Bars, D and Scheiber, C and Hammers, A and Bernard, E and Costes, N and Bouet, R and Mattout, J},
title = {Disorder of consciousness rather than complete Locked-In Syndrome for end stage Amyotrophic Lateral Sclerosis: a case series.},
journal = {Communications medicine},
volume = {5},
number = {1},
pages = {482},
pmid = {41261122},
issn = {2730-664X},
abstract = {BACKGROUND: The end-stage of amyotrophic lateral sclerosis (ALS) is commonly regarded as a complete Locked-In Syndrome (cLIS). Shifting the perspective from cLIS (assumed consciousness) to Cognitive Motor Dissociation (potentially demonstrable consciousness), we aimed to assess the preservation of covert awareness (internally preserved but externally inaccessible) using a multimodal battery.

METHODS: We evaluate two end-stage ALS patients using neurophysiological testing, passive and active auditory oddball paradigms, an auditory Brain-Computer Interface (BCI), functional activation-task imaging, long-term EEG, brain morphology, and resting-state metabolism to characterize underlying brain function.

RESULTS: Patient 1 initially follows simple commands but fails twice at BCI control. At follow-up, command following is no longer observed and his oddball cognitive responses disappear. Patient 2, at a single evaluation, is unable to follow commands or control the BCI. Both patients exhibit altered wakefulness, brain atrophy, and a global cortico-subcortical hypometabolism pattern consistent with a disorder of consciousness, regarded as an extreme manifestation of ALS-associated fronto-temporal dementia.

CONCLUSIONS: Although it is not possible to firmly prove the absence of awareness, each independent measure concurred with suggesting that a "degenerative disorder of consciousness" rather than a cLIS may constitute the final stage of ALS. This condition appears pathophysiologically distinct from typical tetraplegia and anarthria, in which behavioural communication and BCI use persist to enhance quality of life. Identifying the neuroimaging signatures of this condition represents a substantial milestone in understanding end-stage ALS. Large-scale longitudinal investigations are warranted to determine the prevalence of this profile among patients whose communication appears impossible.},
}

@article {pmid41260310,
year = {2025},
author = {Alberti, C and Parente, V and Corti, S and Sansone, VA},
title = {From molecular convergence to clinical divergence: Comparative pathogenic mechanisms and therapeutic trajectories in C9orf72-ALS/FTD and myotonic dystrophy.},
journal = {Neurobiology of disease},
volume = {217},
number = {},
pages = {107192},
doi = {10.1016/j.nbd.2025.107192},
pmid = {41260310},
issn = {1095-953X},
abstract = {Short tandem repeat expansions in C9orf72, DMPK, and CNBP genes cause amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) and myotonic dystrophy types 1 and 2 (DM1/DM2), respectively. Despite distinct clinical phenotypes, these disorders share convergent molecular mechanisms with tissue-specific vulnerability, offering a framework to inform precision therapeutic strategies. Shared pathogenic features include nuclear RNA foci sequestering RNA-binding proteins that disrupt splicing, and repeat-associated non-AUG translation generating toxic dipeptide repeat proteins. In C9orf72, GGGGCC repeats form RNA-driven condensates, including protein-free condensates, via G-quadruplex formation. Evidence also implicates autophagy-lysosome and mitochondrial dysfunction, suggesting a potential "two-hit" loss/gain-of-function model. Clinically, C9orf72 expansions primarily affect motor neurons and frontotemporal circuits, with ALS progression typically occurring over 2-5 years. Conversely, myotonic dystrophy manifests as a muscle-predominant multisystem disorder progressing over decades. Genomic instability contributes to disease variability, with anticipation and parent-of-origin effects strongest in DM1, not confirmed in DM2 and controversial in C9orf72. Sequence interruptions modulate repeat stability and phenotype, influencing diagnostic interpretation. Therapeutic development has yielded contrasting outcomes. Antisense oligonucleotides targeting C9orf72 achieved target engagement and reduced dipeptide repeat proteins but failed clinically, potentially due to sense-strand selectivity and persistence of TDP-43 pathology. In contrast, RNA-targeting conjugates for DM1 (delpacibart etedesiran and DYNE-101) received FDA Breakthrough Therapy designation. Therapeutic success depends on tissue accessibility and addressing both shared and circuit-specific pathogenic cascades. While nuclear RNA targets appear druggable in myotonic dystrophy, the bidirectional transcription and compartmentalized pathology of C9orf72 ALS/FTD may require multi-targeted approaches for precision medicine.},
}

@article {pmid41259707,
year = {2025},
author = {He, T and Lu, Y and Chen, Y and Wang, J and Zhang, H},
title = {Intelligent Microsphere Soil Conditioner Based on Aminated Lignosulfonate and Thermoresponsive Polymer.},
journal = {Langmuir : the ACS journal of surfaces and colloids},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.langmuir.5c04647},
pmid = {41259707},
issn = {1520-5827},
abstract = {In this research, a composite hydrogel microsphere material, SA/P(NVCL-ALS)-N-ZnO/A-Dol-urea (hereafter referred to as SA-PANZ), with dual responsiveness to temperature and pH, was developed by integrating aminated lignosulfonate sodium (ALS), poly(N-vinylcaprolactam) (PNVCL), nano zinc oxide (N-ZnO), and alkali-treated dolomite (A-Dol). The material exhibited excellent controlled-release performance, with a cumulative urea release rate of 67.22% at 40 °C and pH = 4. The Ritger-Peppas model fitted well with the release data, providing strong theoretical support for optimizing the microspheres. Compared to control groups, both the loading efficiency and encapsulation efficiency were significantly improved, achieving 38.50 and 12.83%, respectively. Water retention tests demonstrated that the microspheres maintained 39.92% of their moisture after 5 h, indicating an excellent water-holding capacity. Degradation experiments indicated a degradation rate of 60.14% under acidic conditions, demonstrating excellent biodegradability. Antibacterial assays revealed a clear inhibitory effect against Aspergillus niger, and plant cultivation experiments confirmed that the microspheres promoted pea growth under acidic and high-temperature stress. This research introduced a novel biodegradable microsphere-based soil conditioner with strong potential to improve nutrient use efficiency and soil quality in agricultural environments.},
}

@article {pmid41259564,
year = {2025},
author = {Araújo, RCP and Godoy, CMA and Ferreira, LMBM and Godoy, JF and Magalhães, H},
title = {Fiberoptic endoscopic evaluation of swallowing in amyotrophic lateral sclerosis: comparison with older people with dysphagia and relationship with time since diagnosis.},
journal = {CoDAS},
volume = {37},
number = {6},
pages = {e20240296},
doi = {10.1590/2317-1782/e20240296pt},
pmid = {41259564},
issn = {2317-1782},
mesh = {Humans ; *Deglutition Disorders/physiopathology/etiology/diagnosis ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; Cross-Sectional Studies ; Male ; Retrospective Studies ; Aged ; Female ; Middle Aged ; *Deglutition/physiology ; Time Factors ; Fiber Optic Technology ; Aged, 80 and over ; Severity of Illness Index ; },
abstract = {PURPOSE: (1) to compare the findings of the instrumental swallowing assessment between individuals with amyotrophic lateral sclerosis (ALS) and older dysphagic adults without neurological diagnosis; (2) to compare the onset of pharyngeal response, pharyngeal residues, and the level of oral intake in relation to the time since diagnosis in the ALS group.

METHODS: This cross-sectional, retrospective study collected data from medical records. Altogether, 101 individuals with dysphagia were included and stratified into two groups: the first had 56 patients diagnosed with ALS, and the second had 45 older adults. Dysphagia signs were analyzed through fiberoptic endoscopic evaluation of swallowing, using four food consistencies, classified by the International Dysphagia Diet Standardisation Initiative (IDDSI). Pharyngeal residues were classified by the Yale Pharyngeal Residue Severity Rating Scale (YPRSRS), and oral intake by the Functional Oral Intake Scale (FOIS).

RESULTS: The ALS group had differences in multiple swallows with one IDDSI consistency; posterior oral leakage, pharyngeal residues, and laryngeal penetration with three consistencies; and aspiration with one consistency. Individuals with more than 3 years since diagnosis had differences in the onset of the pharyngeal response in the pyriform sinuses, moderate pharyngeal residues, and oral intake.

CONCLUSION: The ALS group had significant differences in the occurrence of multiple swallows, posterior oral leakage, pharyngeal residues, penetration, and aspiration with three IDDSI consistencies. Furthermore, the time since diagnosis was a determining factor for all three parameters.},
}

Humans
*Deglutition Disorders/physiopathology/etiology/diagnosis
*Amyotrophic Lateral Sclerosis/physiopathology/complications
Cross-Sectional Studies
Male
Retrospective Studies
Aged
Female
Middle Aged
*Deglutition/physiology
Time Factors
Fiber Optic Technology
Aged, 80 and over
Severity of Illness Index

@article {pmid41259153,
year = {2025},
author = {Acheampong, HO and Rozich, E and Haupt, Z and Tokarz, C and Khan, M and Ghosn, ZA and Insolera, R},
title = {Kenny mediates the recruitment of the phagophore for ubiquitin-dependent mitophagy in Drosophila neurons.},
journal = {Molecular biology of the cell},
volume = {},
number = {},
pages = {mbcE25050235},
doi = {10.1091/mbc.E25-05-0235},
pmid = {41259153},
issn = {1939-4586},
abstract = {The maintenance of healthy mitochondria is essential to neuronal homeostasis. Mitophagy is a critical mechanism that degrades damaged mitochondria, and disruption of this process is associated with neurodegenerative disease. Previous work has shown that mammalian optineurin (OPTN), a gene mutated in familial forms of amyotrophic lateral sclerosis (ALS) and glaucoma, is an adaptor to recruit autophagy machinery to mitochondria for ubiquitin-dependent mitophagy in cultured cells. However, OPTN's role in neuronal mitophagy in vivo remains largely unknown. Here, we demonstrate the Drosophila autophagy adaptor gene Kenny, a homolog of OPTN, mediates the recruitment of the phagophore to mitochondria undergoing ubiquitin-dependent mitophagy. We find that Kenny colocalizes with ubiquitinated mitochondria targeted for autophagic degradation in larval motoneurons, and is concentrated on the mitochondrial surface in areas opposed to the phagophore. Removal of Kenny in conditions of induced mitophagy eliminates the recruitment of the phagophore to ubiquitinated mitochondria and decreases mitophagic flux. In basal conditions, loss of Kenny causes accumulation of ubiquitinated mitochondria in neurons, indicative of stalled mitophagy. These phenotypes were reproduced in Kenny mutants ablating the LC3-interacting region domain. Overall, this work establishes Kenny as a functional homolog of OPTN in flies, and a mediator of neuronal mitophagy in vivo.},
}

@article {pmid41258507,
year = {2025},
author = {Hashizume, A and Hanazawa, R and Yamada, S and Ito, D and Kishimoto, Y and Komori, S and Kawase, T and Iida, M and Kondo, A and Mori, Y and Obara, K and Morita, M and Yamamoto, T and Sato, H and Hirakawa, A and Katsuno, M},
title = {Therapeutic impact of leuprorelin acetate on spinal and bulbar muscular atrophy: pre- and post-marketing observational study.},
journal = {Journal of neurology},
volume = {272},
number = {12},
pages = {772},
pmid = {41258507},
issn = {1432-1459},
support = {24ek0109588//Japan Agency for Medical Research and Development/ ; 24K10658//Japan Society for the Promotion of Science/ ; },
mesh = {Humans ; *Leuprolide/therapeutic use/pharmacology ; Male ; Middle Aged ; Female ; Aged ; Adult ; *Product Surveillance, Postmarketing ; Disease Progression ; *Bulbo-Spinal Atrophy, X-Linked/drug therapy ; Treatment Outcome ; *Muscular Atrophy, Spinal/drug therapy ; Japan ; },
abstract = {Although leuprorelin acetate, a luteinizing hormone-releasing hormone agonist, has been approved based on short-term clinical trials conducted in Japan, its long-term efficacy on physical function remains unclear. We aimed to evaluate the long-term therapeutic efficacy of leuprorelin acetate using real-world clinical data through a self-controlled trend-shift analysis. The analysis included 91 genetically confirmed patients with spinal and bulbar muscular atrophy, with follow-up data collected before and after treatment initiation. The functional outcomes assessed included the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) and modified Norris scales, grip power, and serum creatinine levels. Leuprorelin acetate significantly slowed disease progression. For instance, the annual ALSFRS-R decline rate improved from approximately 0.5 points pre-treatment to 0.2 points post-treatment. The subgroup analysis supported the potential benefit of early intervention. These findings highlight the value of leveraging patient registries and post-marketing real-world data to evaluate treatment efficacy in slowly progressive diseases, such as SBMA, where traditional randomized controlled trials are often limited by insufficient statistical power to detect therapeutic efficacy. They also underscore the need for innovative methodologies to assess post-approval drug performance, paving the way for improved clinical outcomes for neurodegenerative diseases.},
}

Humans
*Leuprolide/therapeutic use/pharmacology
Male
Middle Aged
Female
Aged
Adult
*Product Surveillance, Postmarketing
Disease Progression
*Bulbo-Spinal Atrophy, X-Linked/drug therapy
Treatment Outcome
*Muscular Atrophy, Spinal/drug therapy
Japan

@article {pmid41258317,
year = {2025},
author = {Wang, S and Zhang, X and Zhang, },
title = {Charting the landscape and evolution of research on cell death in acute lymphoblastic leukemia: a comprehensive bibliometric analysis (1990-2024).},
journal = {Discover oncology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s12672-025-04102-w},
pmid = {41258317},
issn = {2730-6011},
abstract = {BACKGROUND: The interplay between regulated cell death pathways and Acute Lymphoblastic Leukemia (ALL) pathobiology profoundly influences disease progression and therapeutic responses.

OBJECTIVE: This study performs a comprehensive bibliometric analysis to delineate the historical trajectory, current status, and emerging research frontiers concerning cell death in ALL from 1990 to 2024.

METHODS: This bibliometric analysis maps global research on cell death in ALL (1990-2024) using 4,111 publications from the Web of Science Core Collection using search terms related to cell death and ALL. VOSviewer and CiteSpace were utilized to analyze publication trends, geographical and institutional distributions, international collaborations, journal and author productivity and impact, co-citation networks (references, authors, journals), and keyword co-occurrence, clusters, and citation bursts.

RESULTS: Publications grew slowly (1990-1992), expanded rapidly (1993-2015, peak in 2015), then moderated. The United States dominated research output (33.69% publications, 68.41 citations/paper) and collaborated strongly with China, Italy, and the UK. The University of Texas System was the most productive institution (153 articles). Blood ranked first in publications (236) and co-citations (3403). Uckun authored the most papers (31), while Pui was the most co-cited author (736 co-citations). Keyword clusters revealed evolving foci: from apoptosis (1990s) to BH3-only proteins (2000s), with current frontiers in ​ferroptosis, CAR-T cells, and drug resistance. Terwilliger et al.'s review showed the strongest citation burst.

CONCLUSION: This study dilineates the intellectual landscape of cell death research in ALL, highlighting ferroptosis, immunotherapy integration, and resistance mechanisms as critical future directions to improve therapeutic outcomes.},
}

@article {pmid41258169,
year = {2025},
author = {Straczkiewicz, M and Burke, KM and Carney, KT and Calcagno, N and Mandepudi, S and Premasiri, A and Vieira, FG and Berry, JD},
title = {Analytical and clinical validation of step counting method in people living with amyotrophic lateral sclerosis.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {40769},
pmid = {41258169},
issn = {2045-2322},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Walking/physiology ; *Gait/physiology ; *Accelerometry/methods ; Algorithms ; Aged ; Adult ; Reproducibility of Results ; },
abstract = {Accelerometer-based digital measures offer a scalable and low-burden means of quantifying physical function, but existing processing algorithms may not quantify pathological gait correctly. In people living with amyotrophic lateral sclerosis (ALS), where gait patterns are slow, variable, and asymmetric, validated tools to quantify mobility are urgently needed. We proposed a step-counting algorithm designed for ankle-worn accelerometers that leverage wavelet-based decomposition to quantify heel strikes under heterogeneous gait patterns. We validated this method using five datasets comprising healthy individuals and those with ALS in controlled and semi-controlled activities, and we performed clinical validation in a free-living cohort of 305 people with ALS. We tested our method for accuracy in detecting steps and recognizing walking activity. Reference labels used for analytical validation were obtained from annotated studies or video-based ground truth. Step counting accuracy was assessed using Bland-Altman analysis while clinical validity was evaluated by comparing step counts to gross motor functioning on the ALS Functional Rating Scale-Revised (ALSFRS-R). Walking recognition was robust across walking conditions and body types; sensitivity ranged from 0.94 to 0.98, and specificity exceeded 0.95 across all evaluated datasets. The mean step counting bias was minimal (e.g., 0.44 steps), and the 95% limits of agreement were narrow (LoA = [-5.90, 5.40]) relative to reference standards, including video-annotated ground truth. Clinical validation indicated substantial differences between groups with various levels of gait impairment, e.g., participants who reported "walks with assist" on the ALSFRS-R accumulated a mean of 1283 (95% CI 1063, 1503) steps/day, while those reporting "normal" walking covered 3984 (95% CI 3537, 4432) steps/day. Our study covered analytical and clinical validation of a step-counting method developed for ankle-worn accelerometers and demonstrated its applicability to pathological gait. The method provides accurate quantification of walking activity in controlled and free-living environments, supporting its use as a digital endpoint in ALS research.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology
Male
Female
Middle Aged
*Walking/physiology
*Gait/physiology
*Accelerometry/methods
Algorithms
Aged
Adult
Reproducibility of Results

@article {pmid41256634,
year = {2025},
author = {Li, Y and Dou, X and Xiao, Y and Zhang, Z and Ye, Y and Wright, N and Chang, K and Liu, C and Troncoso, JC and He, C and Sun, S},
title = {LINE1 RNA dysregulation impairs chromatin accessibility in C9ORF72- and TDP-43-linked ALS/FTD.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.30.679260},
pmid = {41256634},
issn = {2692-8205},
abstract = {The long interspersed element-1 (LINE1) retrotransposon RNAs are abnormally elevated in various neurodegenerative disorders, but their pathogenic roles remain unclear. Here we investigated the mechanism of LINE1 RNA accumulation and its function in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with C9ORF72 repeat expansion and TDP-43 loss-of-function, the leading causes of familial and sporadic forms of these neurodegenerative diseases. We show that LINE1 RNA is dysregulated due to an impaired nuclear exosome targeting (NEXT) degradation pathway. Its elevation epigenetically increases chromatin accessibility, enhancing global transcription via a retrotransposon-independent mechanism. Reducing LINE1 RNA mitigates chromosomal abnormalities and improves the survival of disease-relevant neurons. These findings uncover an essential noncoding RNA function and regulatory mechanism of LINE1 in neurons, providing insights into disease pathogenesis and highlighting potential therapeutic targets for neurodegenerative diseases.},
}

@article {pmid41256508,
year = {2025},
author = {Kozareva, V and Liu, Z and Blake, K and Qi, YA and Rollinson, S and Seddighi, S and Alsaidi, M and Tsitkov, S and Prudencio, M and Petrucelli, L and Dickson, DW and Brown, AL and Fratta, P and Kim, HJ and Taylor, JP and Ward, ME and Fraenkel, E and Kargbo-Hill, SE},
title = {Integrative multiomic analysis links TDP-43-driven splicing defects to cascading proteomic disruption of ALS/FTD pathways.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.29.679403},
pmid = {41256508},
issn = {2692-8205},
abstract = {Loss of nuclear TDP-43 is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 is known to regulate RNA processing, including repression of cryptic exons, we currently lack a systems-level understanding of the consequences of TDP-43 loss. To address this, we generated multiomic datasets, including RNA-seq and proteomics, from human iPSC-derived neurons depleted of TDP-43. We found that differentially spliced genes, many expressing cryptic exons, had the greatest protein reductions. Surprisingly, nearly half of differentially expressed proteins were neither mis-spliced, nor differentially expressed genes; most of these also had no reported mis-splicing in seven additional post-mortem and iPSC-derived neuron datasets. Integrative network analysis identified a high-confidence disease-specific subnetwork of over 700 interacting proteins, enriched for mRNA processing, synaptic function, and autophagy. Comparison with post-mortem ALS and FTD samples revealed convergent protein and pathway disruptions. We experimentally validated network-predicted effects of cryptic splicing in ATG4B, STMN2, and DAPK1. Our analyses reveal new TDP-43-dependent molecular cascades and nominate central genes as potential ALS/FTD therapeutic targets.},
}

@article {pmid41256495,
year = {2025},
author = {Waldron, FM and Langerová, T and Rahmanova, A and Read, FL and Spence, H and Roberts, K and Macleod, AD and Pattle, SB and Hanna, K and Gregory, JM},
title = {Skin TDP-43 pathology as a candidate biomarker for predicting amyotrophic lateral sclerosis decades prior to motor symptom onset.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.04.10.648122},
pmid = {41256495},
issn = {2692-8205},
abstract = {UNLABELLED: The recognition that disease-associated proteinopathies can manifest in peripheral organs outside the central nervous system preceding the onset of neurological symptoms, has transformed our understanding of Parkinson's disease, in wide terms of pathogenesis, detection and diagnosis. For amyotrophic lateral sclerosis, non-motor symptoms, and non-central nervous system pathologies are gaining increased recognition but remain incompletely understood. Here, using a TDP-43 RNA aptamer and a Stathmin-2 cryptic exon transcript BaseScope [TM] ISH probe, we identify widespread peripheral organ TDP-43 pathology prior to motor symptom onset in a discovery cohort of ante-mortem tissues from people who went on to develop ALS. Peripheral organs exhibiting both TDP-43 toxic gain- and loss-of function include muscle, lymph node, gallbladder, colon and with notably high incidence, skin. Given the accessibility of skin as a readily biopsiable tissue, representing a promising substrate for the detection of disease-associated proteinopathies and the development of minimally invasive biomarkers, we established an extended cohort of ante-mortem skin samples for TDP-43 pathology validation and further investigation. In skin biopsies taken during life from 17 individuals who went on to develop ALS we identify TDP-43 pathology from all 17 individuals in a wide distribution of anatomical sites, up to 26.5 years before ALS diagnosis - a presymptomatic period comparable to that observed for skin α-synucleinopathy in Parkinson's disease. TDP-43 pathology was most abundant in skin biopsies from the back and shoulder, with sweat and sebaceous glands showing the highest involvement. TDP-43 pathology was also associated with structural changes. As skin α-synucleinopathy has been established as a biomarker for both the detection of Parkinson's disease and the differentiation of Parkinson's disease from multiple system atrophy, we propose that skin TDP-43 likewise holds diagnostic and discrimination potential for diseases characterised by TDP-43 proteinopathy.

SHORT ABSTRACT: Peripheral manifestations of neurodegenerative disease can precede neurological symptoms and serve as biomarkers, as shown by α-synuclein in the skin of individuals who later develop Parkinson's disease. In amyotrophic lateral sclerosis (ALS), however, the distribution and diagnostic potential of peripheral TDP-43 pathology remain unclear. Using a TDP-43 RNA aptamer and a cryptic STMN2 BaseScope™ probe, we examined ante-mortem tissues from individuals who later developed ALS. In a discovery cohort, we detected widespread pre-symptomatic TDP-43 pathology across multiple organs, with skin emerging as the most consistent site. We then validated these findings in a validation cohort comprising 17 individuals, all of whom exhibited TDP-43 pathology enriched in sweat glands and structural changes detectable up to 26.5 years before ALS diagnosis. These findings establish skin as a robust and accessible site of pre-symptomatic TDP-43 pathology, supporting its potential as a minimally invasive biomarker for early diagnosis and disease stratification in ALS.

SUMMARY: Much like skin α-synucleinopathy has transformed biomarker development in Parkinson's disease, this study identifies skin TDP-43 pathology as a promising early marker of ALS. The results open avenues for earlier diagnosis and stratification in a disease where intervention is most needed before symptoms appear.

HIGHLIGHTS: Presymptomatic TDP-43 pathology occurs across a range on non-CNS peripheral organ systems including skin, gastrointestinal tract and lymph nodes prior to motor symptom onset in people who went on to develop ALS.In skin, presymptomatic TDP-43 pathology is associated with structural changes and can be detected up to 26.5 years prior to motor symptoms in ALS.As for Parkinson's disease, shoulder and back represents optimal skin sampling sites for pre-symptomatic pathology in ALS.Sweat and sebaceous glands present with high levels of TDP-43 pathology, offering a promising biomarker target for early pathology detection.

ONE SENTENCE SUMMARY: Using distinct biomarker discovery and validation ante-mortem tissue cohorts, we provide evidence of pre-symptomatic TDP-43 pathology across diverse non-CNS peripheral tissues, including skin decades before ALS symptom onset, highlighting skin TDP-43 pathology as a potential early biomarker for ALS and related TDP-43 proteinopathies.},
}

@article {pmid41256466,
year = {2025},
author = {Waldron, FM and Spence, H and Taso, OS and Read, FL and Sinha, IR and Irwin, KE and Wong, PC and Ling, JP and Gregory, JM},
title = {Brain Iron as a Surrogate Biomarker of Pathological TDP-43 Identifies Brain Region-Specific Signatures in Ageing, Alzheimer's Disease and Amyotrophic Lateral Sclerosis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.02.680028},
pmid = {41256466},
issn = {2692-8205},
abstract = {BACKGROUND: TDP-43 pathology is a defining feature of several neurodegenerative diseases, but its prevalence and regional distribution in ageing and disease are not well characterised. We investigated the burden of brain TDP-43 pathology across ageing, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS), and examined ferritin as a region-specific correlate of TDP-43 pathology.

METHODS: Pathological TDP-43 was detected using an HDGFL2 cryptic exon in situ hybridisation probe and a TDP-43 RNA aptamer, providing greater sensitivity and specificity than antibody-based approaches. Amygdala, hippocampus, and frontal cortex tissue was analysed from non-neurological controls (ages 40-80), AD cases, and ALS cases. Ferritin (as a proxy for iron accumulation) was quantified in parallel to assess its association with TDP-43 pathology.

FINDINGS: TDP-43 pathology was detectable from the fourth decade of life, with a 4.5-fold increase in hippocampal involvement after age 60 years. In AD, pathology was present in 90% of cases and distinguished from ageing by selective amygdala involvement. In ALS, TDP-43 pathology was nearly ubiquitous across all regions studied. Regional ferritin strongly predicted TDP-43 burden: amygdala ferritin explained 87% of TDP-43 variance in ALS and 66% in AD, while hippocampal ferritin differentiated AD from controls. Across AD, ferritin explained between 43-81% of regional TDP-43 variance.

INTERPRETATION: TDP-43 brain pathology emerges in midlife with increased involvement after age 60 years, exhibits disease-specific regional signatures in AD and ALS, and is closely linked to ferritin accumulation. As TDP-43 confers a worse prognosis in AD, the capacity of ferritin, detectable with iron-sensitive MRI, to serve as a proxy for regional TDP-43 burden highlights its promise as a biomarker for disease stratification and prognosis.

SHORT ABSTRACT: Here we show that pathological TDP-43 emerges during normal ageing from the fourth decade of life, with a 4.5-fold increase in hippocampal involvement after 60 years. In Alzheimer's disease (AD), TDP-43 pathology was present in 90% of cases and distinguished from ageing by disproportionate amygdala involvement, while in amyotrophic lateral sclerosis (ALS) it was nearly ubiquitous across hippocampus, amygdala, and frontal cortex. Using sensitive detection tools, we demonstrate that region-specific ferritin strongly predicts TDP-43 burden: amygdala ferritin explained 87% of variance in ALS and 66% in AD, while hippocampal ferritin differentiated AD from controls. Across AD, ferritin levels in all three regions explained 43-81% of TDP-43 variance. As TDP-43 pathology confers a worse prognosis in AD, the ability of ferritin, quantifiable with iron-sensitive MRI, to serve as a proxy for regional TDP-43 burden highlights its potential as a biomarker for disease stratification and prognostic assessment.

HIGHLIGHTS: TDP-43 brain pathology occurs in normal ageing from early in the fourth decade, characterised by a 4.5-fold increase in hippocampus pathology from the sixth decade.TDP-43 brain pathology is detectable in 90% of AD cases, with a disease-signature of increased amygdala pathology relative to age-matched controls.In ALS, TDP-43 is nearly ubiquitous in amygdala, hippocampus and frontal cortex.Hippocampus high brain ferritin distinguishes AD from and age-matched controlsBrain ferritin is a brain region-specific marker of TDP-43 pathology in ageing and disease, with amygdala ferritin explaining 87% of the variance in amygdala TDP-43 pathology in ALS, and 66% of amygdala TDP-43 pathology in ADIn AD, ferritin levels for all three brain regions explain between 43-81% of variance in their TDP-43 pathology levels.},
}

@article {pmid41256347,
year = {2025},
author = {Kanda, T and Sasaki-Tanaka, R and Kamimura, H and Terai, S},
title = {Is higher body mass index correlated with worse clinical outcomes in acute liver failure?.},
journal = {World journal of clinical cases},
volume = {13},
number = {32},
pages = {113514},
pmid = {41256347},
issn = {2307-8960},
abstract = {Krishnan et al's article is a comprehensive and vigorous retrospective cohort study regarding the association between obesity and clinical outcomes in acute liver failure (ALF). Among patients with ALF in the United States, mean body mass index (BMI) was significantly greater in those who underwent liver transplantation or who died than among survivors, although acetaminophen induced ALF was the most common etiology. A high BMI was associated with renal failure and high grades of hepatic encephalopathy. The prevalence of obesity and its related fatty liver diseases, such as metabolic dysfunction-associated fatty liver disease/ metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, has increased worldwide. Obesity is related to increased serum cytokines and immune abnormalities. These findings may explain why ALF in patients with high BMI is associated with worse clinical outcomes. Further studies are needed to determine the associations among BMI, ALF and acute-on-chronic liver failure.},
}

@article {pmid41256173,
year = {2025},
author = {Candrea, DN and Angrick, M and Luo, S and Ganji, R and Coogan, C and Milsap, GW and Rosenblatt, KR and Uchil, A and Clawson, L and Maragakis, NJ and Vansteensel, MJ and Tenore, FV and Ramsey, NF and Fifer, MS and Crone, NE},
title = {Longitudinal study of gesture decoding in a clinical trial participant with ALS.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.26.25335804},
pmid = {41256173},
abstract = {Brain-computer interfaces (BCIs) have the potential to preserve or restore communication and device control in people with paralysis from a variety of causes. For people living with amyotrophic lateral sclerosis (ALS), however, the progressive loss of cortical motor neurons could theoretically pose a challenge to the stability of BCI performance. Here we tested the stability of gesture decoding with a chronic electrocorticographic (ECoG) BCI in a man living with ALS and participating in a clinical trial (ClinicalTrials.gov , NCT03567213). We evaluated offline decoding performance of attempted gestures over two periods: a 5-week period beginning roughly 2 years post-implant and a 6-week period ending roughly 5 months later. Decoder sensitivity was high in both periods (90 - 98%), while classification accuracy was 37 - 68% in the first period and worsened to 23 - 39% in the second. We investigated multiple frequency bands that were used as model features in both periods, and we observed reductions in high gamma band power (70 - 110 Hz) and between-class separation during the second period compared to the first. Over the 5-month period motor function did not appreciably decline. These results, albeit preliminary, suggest that declines in the neural population responses that drive ECoG BCI performance can occur without overt signs of disease progression in people living with ALS, and could serve as a biomarker for disease progression in the future.},
}

@article {pmid41255818,
year = {2025},
author = {Doelemeyer, A and Vaishampayan, S and Zurbruegg, S and Morvan, F and Locatelli, G and Shimshek, DR and Beckmann, N},
title = {Deep learning-driven MRI for accurate brain volumetry in murine models of neurodegenerative diseases.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1632169},
pmid = {41255818},
issn = {1662-4548},
abstract = {Brain atrophy as assessed by magnetic resonance imaging (MRI) is a key measure of neurodegeneration and a predictor of disability progression in Alzheimer's disease and multiple sclerosis (MS) patients. While MRI-based brain volumetry is valuable for analyzing neurodegeneration in murine models as well, achieving high spatial resolution at sufficient signal-to-noise ratio is challenging due to the small size of the mouse brain. In vivo MRI allows for longitudinal studies and repeated assessments, enhancing statistical power and enabling pharmacological evaluations. However, the need for anesthesia necessitates compromises in acquisition times and voxel sizes. In this work we present the application of a deep-learning-based segmentation approach to the reliable quantification of total brain and brain sub region volumes, such as the hippocampus, caudate putamen, and cerebellum, from T2-weighted images with a pixel volume of 78x78x250 μm[3] acquired in 4.3 min at 7 Tesla using a conventional radiofrequency coil. The reproducibility of the fully automatic segmentation pipeline was validated in healthy C57BL/6 J mice and subsequently applied to models of amyotrophic lateral sclerosis, cuprizone-induced demyelination, and MS. Our approach offers a robust and efficient method for in vivo brain volumetry in preclinical mouse studies, facilitating the evaluation of neurodegenerative processes and therapeutic interventions. The dramatic reduction in acquisition time achieved with our AI-based approach significantly enhances animal welfare (3R). This advancement allows brain volumetry to be seamlessly integrated into additional analyses, providing comprehensive insights without substantially increasing study duration.},
}

@article {pmid41255704,
year = {2025},
author = {von Kügelgen, N and Ludwik, K and Mendonsa, S and Römer, C and Becher, E and Breimann, L and Strauch, M and Mari, T and Mongellaz, S and Zuckerman, B and Efendic, F and Grexa, N and Oliveras-Martinez, A and Woehler, A and Selbach, M and La Bella, V and Ulitsky, I and Chekulaeva, M},
title = {Neuromuscular dysfunction in patient-derived FUS[R244RR]-ALS iPSC model via axonal downregulation of neuromuscular junction proteins.},
journal = {NAR molecular medicine},
volume = {2},
number = {2},
pages = {ugaf005},
pmid = {41255704},
issn = {2976-856X},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by the progressive degeneration of motor neurons (MNs), ultimately resulting in death due to respiratory failure. A common feature among ALS cases is the early loss of axons, pointing to defects in axonal transport and translation as initial disease indicators. ALS is associated with mutations in RNA-binding proteins, such as FUS (Fused in Sarcoma). Here, we established a FUS[R244RR]-ALS hiPSC-derived model that recapitulates the MN survival and muscle contractility defects characteristic of ALS patients. Analysis of the protein and mRNA expression profiles in axonal and somatodendritic compartments of ALS-afflicted and isogenic control MNs revealed a selective downregulation of proteins essential for the neuromuscular junction function in FUS-ALS axons. Furthermore, analysis of FUS CLIP and RIP data showed that FUS binds mRNAs encoding these proteins. This work shed light on the pathogenic mechanisms of ALS and emphasized the importance of axonal gene expression analysis in elucidating the mechanisms of neurodegenerative disorders.},
}

@article {pmid41255457,
year = {2025},
author = {Hu, Y and Lu, Y and Lan, D},
title = {Early Multidisciplinary Rehabilitation Improves Swallowing and Speech Function in a Patient With Amyotrophic Lateral Sclerosis.},
journal = {Clinical case reports},
volume = {13},
number = {11},
pages = {e71486},
pmid = {41255457},
issn = {2050-0904},
abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic, progressive neurodegenerative disease for which there is a lack of effective treatment. This case report describes a 49-year-old male with ALS who presented with dysphagia, dysarthria, dyskinesia, sleep disorders, anxiety, and depression. Following 45 days of early multidisciplinary rehabilitation, the patient demonstrated significant improvement in swallowing and speech function, alleviation of non-motor symptoms, and maintenance of motor function. Notably, he retained the ability to consume soft foods at a two-year follow-up. This case highlights the vital role of early multidisciplinary rehabilitation in the comprehensive management of ALS.},
}

@article {pmid41254165,
year = {2025},
author = {Zhang, J and Lin, S and Zou, H and Ma, Y},
title = {Reply to: Utilizing foundation models for developing clinical tools.},
journal = {NPJ digital medicine},
volume = {8},
number = {1},
pages = {681},
pmid = {41254165},
issn = {2398-6352},
abstract = {This reply addresses Chan et al.'s comments on our previous study, clarifying the use of foundation models (e.g., RETFound), commercial data sources/anonymity, and DeLong test results. We highlight that the SDEDS-fine-tuned RETFound outperforms commercial models and acknowledge the need for further testing, while referencing an early benchmark value.},
}

@article {pmid41253416,
year = {2025},
author = {MacDonald, C and Barnum, E and Pradeep, M and Rivera, V and Smith, P and Dombrowski, M and Sparkman, J and Manero, A},
title = {Serious Game-Based Training for Improved Control of a Temporalis Electromyography Interface for Controlling Powered Wheelchairs.},
journal = {Games for health journal},
volume = {},
number = {},
pages = {},
doi = {10.1177/2161783X251397932},
pmid = {41253416},
issn = {2161-7856},
abstract = {Background: Amyotrophic lateral sclerosis (ALS) is characterized by a significant decrease in mobility due to its neurodegenerative etiology. Throughout the progression of ALS, patients lose independence in their motor control. An electromyography (EMG) interface that enables control of a powered wheelchair can restore autonomous movement. The use of serious game-based training that mimics EMG-temporalis wheelchair controls can be used as training prior to wheelchair usage in the real world. Purpose: Limbitless Runner, a forearm EMG training game, found improved player performance with no significant difference noted between the free and structured play training. This study aims to investigate the generalizability of this finding when applied to a temporalis EMG system. Methods: Participants were given Limbitless Runner's quantifiable, structured training mode, the "ring challenge," for a scored pretest. Participants were then assigned to one of three cohorts for training: Limbitless Journey, Limbitless Runner "free play mode," or the Limbitless Runner "ring challenge." To assess improvement in user's performance, the ring challenge was repeated and scored. Quantitative surveys, including the Game User Experience Satisfaction Scale (GUESS) and the System Usability Scale (SUS), were given to gauge users' perceptions of the games. Results: All cohorts showed a user score improvement; however, the ring challenge (Cohort 2) showed the highest improvement, from an average of 22.9 rings in the pretest to 31.1 rings posttraining. The SUS and GUESS scores were not significantly different between the two different video games, demonstrating that both versions can be satisfying or acceptable platforms for users.},
}

@article {pmid41253081,
year = {2025},
author = {Okagaki, N and Tsuboi, T and Chihara, Y and Sumi, K and Takeuchi, H and Yamamoto, K and Hajiro, T and Sato, A},
title = {Impact of pneumothorax on clinical course of patients with amyotrophic lateral sclerosis on long-term ventilation.},
journal = {Respiratory investigation},
volume = {64},
number = {1},
pages = {101329},
doi = {10.1016/j.resinv.2025.11.008},
pmid = {41253081},
issn = {2212-5353},
abstract = {BACKGROUND: Numerous clinical studies have shown that long-term positive pressure ventilation (PPV) improves quality of life and prognosis in patients with amyotrophic lateral sclerosis (ALS). Pneumothorax is an important complication of PPV; however, few studies investigated pneumothorax in patients with ALS on long-term PPV.

METHODS: This retrospective longitudinal cohort study included 85 patients with ALS treated from 2013 to 2024. We collected information from medical records on ALS and pneumothorax treatment, blood laboratory data, radiology data, equipment data, and mortality. Subsequently, we compared clinical parameters and prognosis between the pneumothorax and non-pneumothorax groups.

RESULTS: Of the 85 patients, 61 underwent long-term PPV. Nine patients developed pneumothorax following the initiation of long-term PPV. In contrast, 24 patients without long-term PPV did not experience pneumothorax. Among patients who received tracheostomy PPV as a maximum respiratory management, the pneumothorax group tended to have a poorer prognosis from ALS onset than the non-pneumothorax group. Moreover, the pneumothorax group had higher inspiratory positive airway pressure and support pressure of ventilator settings than the non-pneumothorax group. Among the nine pneumothorax cases, there were no deaths directly related to the complication, two patients who developed pneumothorax during non-invasive PPV transitioned to tracheostomy PPV as a result of the complication.

CONCLUSIONS: Pneumothorax should be recognized as a serious complication that can occur in patients with ALS on PPV. Higher inspiratory positive airway pressure and support pressure settings on long-term PPV may be significant risk factors for pneumothorax.},
}

@article {pmid41252681,
year = {2025},
author = {Yoo, SH and Cho, B and Kim, KH and Hwang, IY and Cho, W and Choi, SJ and Sung, JJ and Lee, SY},
title = {Quality of life and care burden of people living with amyotrophic lateral sclerosis who need home-based medical care in Korea and their family caregivers.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/21678421.2025.2589780},
pmid = {41252681},
issn = {2167-9223},
abstract = {Objective: Advanced neurodegenerative diseases (NDDs) lead to severe mobility limitations, creating significant challenges for patients and caregivers at home. We aimed to investigate the quality of life (QOL) and care burden of people living with amyotrophic lateral sclerosis (ALS, pALS) and other NDDs and their family caregivers in Korea. Methods: This prospective survey study included people living with NDDs with mobility restrictions and their caregiver enrolled in a home-based medical care (HBMC) program at one tertiary hospital in South Korea from 2022 to 2024. Data collected included demographics, clinical characteristics, care burden (the Zarit Caregiver Burden Interview Short Form, ZBI-12), QOL (EQ-5D-5L), and depression (Patient Health Questionnaire-9). The results were compared between ALS and other NDDs (non-ALS). Results: Of 44 patients requiring HBMC, 70.5% (31) were pALS. pALS were younger than non-ALS (median age, 65 vs. 79 years); more often, the caregiver was a spouse (64.5% vs. 46.1%, p = 0.30). One-fourth (25.8%) of pALS were on polypharmacy (>10 medications a day). One-third (29%) of pALS and 22.6% of their caregivers experienced moderate or severe depression. Half of pALS caregivers experienced high caregiving burden (ZBI-12 score ≥17). The mean EQ-5D-5L index score was 0.48 for pALS and 0.84 for their caregivers, which was lower than the results for the Korean general population. Conclusions: Patients with severe NDD and caregivers experienced low QOL and high caregiving burden, with pALS caregivers particularly vulnerable to depression and heavy burden. Designing optimal HBMC programs to support pALS and home caregivers is warranted.},
}

@article {pmid41252626,
year = {2025},
author = {Zimmerman, RS and Olson, K},
title = {Aids-Related Risk Behavior and Behavior Change in a Sexually Active, Heterosexual Sample: A Test Of Three Models of Prevention.},
journal = {AIDS education and prevention : official publication of the International Society for AIDS Education},
volume = {6},
number = {3},
pages = {189-204},
doi = {10.1521/aeap.1994.6.3.189},
pmid = {41252626},
issn = {1943-2755},
mesh = {Humans ; Male ; Female ; Adult ; *Sexual Behavior/psychology ; *Risk-Taking ; *Heterosexuality/psychology ; *Health Knowledge, Attitudes, Practice ; *HIV Infections/prevention & control/psychology ; Self Efficacy ; *Health Belief Model ; Young Adult ; Adolescent ; Middle Aged ; Surveys and Questionnaires ; Models, Psychological ; *Acquired Immunodeficiency Syndrome/prevention & control/psychology ; *Health Behavior ; Risk Reduction Behavior ; },
abstract = {Because a cure and a vaccine for the human immunodeficiency virus (HIV) are not expected for at least several years, prevention of AIDS is the only means of reducing the spread of the disease. While education, information, and persuasion may be changing the HIV-related attitudes and even behaviors of some individuals, without a theoretical framework, the reasons why some individuals have changed and why other individuals have not changed are elusive. Three social-psycho logical models that have been applied to health-related behavior-the Health Belief Model (HBM), the Ajzen-Fishbein attitude-behavior model (AFM), and Leventhal et al.'s Self-Regulatory Model (SRM)-are tested in this study. The extent to which each model's variables are related to self-reported behavior change related to HIV and current HIV-related behavior are compared. Results indicate that the SRM and AFM contributed significantly to predicting risk behavior change, and that the HBM and AFM contributed significantly to predicting current risk behavior, after controlling for risk behavior change. Significant predictors of risk behavior change included timeline, identity, and self-efficacy from the SRM; sexual impulse (a barrier) from the HBM; and attitudes about the behaviors from the AFM. Significant predictors of current risk behavior included several barriers from the HBM and negative attitude about risk-reducing behaviors from the AFM.},
}

Humans
Male
Female
Adult
*Sexual Behavior/psychology
*Risk-Taking
*Heterosexuality/psychology
*Health Knowledge, Attitudes, Practice
*HIV Infections/prevention & control/psychology
Self Efficacy
*Health Belief Model
Young Adult
Adolescent
Middle Aged
Surveys and Questionnaires
Models, Psychological
*Acquired Immunodeficiency Syndrome/prevention & control/psychology
*Health Behavior
Risk Reduction Behavior

@article {pmid41252371,
year = {2025},
author = {Lillelund, CM and Kalra, S and Greiner, R and , },
title = {A meaningful prediction of functional decline in amyotrophic lateral sclerosis based on multi-event survival analysis.},
journal = {PloS one},
volume = {20},
number = {11},
pages = {e0336476},
doi = {10.1371/journal.pone.0336476},
pmid = {41252371},
issn = {1932-6203},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality/drug therapy ; Male ; Female ; Survival Analysis ; Middle Aged ; Aged ; Kaplan-Meier Estimate ; Quality of Life ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of the motor neurons that causes progressive paralysis in patients. Current treatment options aim to prolong survival and improve quality of life. However, due to the heterogeneity of the disease, it is often difficult to determine the optimal time for potential therapies or medical interventions. In this study, we propose a novel method to predict the time until a patient with ALS experiences significant functional impairment (ALSFRS-R ≤ 2) for each of five common functions: speaking, swallowing, handwriting, walking, and breathing. We formulate this task as a multi-event survival problem and validate our approach in the PRO-ACT dataset ([Formula: see text]) by training five covariate-based survival models to estimate the probability of each event over the 500 days following the baseline visit. We then predict five event-specific individual survival distributions (ISDs) for a patient, each providing an interpretable estimate of when that event is likely to occur. The results show that covariate-based models are superior to the Kaplan-Meier estimator at predicting time-to-event outcomes in the PRO-ACT dataset. Additionally, our method enables practitioners to make individual counterfactual predictions-where certain covariates can be changed-to estimate their effect on the predicted outcome. In this regard, we find that Riluzole has little or no impact on predicted functional decline. However, for patients with bulbar-onset ALS, our model predicts significantly shorter time-to-event estimates for loss of speech and swallowing function compared to patients with limb-onset ALS (log-rank p < 0.001, Bonferroni-adjusted [Formula: see text]). The proposed method can be applied to current clinical examination data to assess the risk of functional decline and thus allow more personalized treatment planning.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/mortality/drug therapy
Male
Female
Survival Analysis
Middle Aged
Aged
Kaplan-Meier Estimate
Quality of Life

@article {pmid41251254,
year = {2025},
author = {Staehr-Rye, AK and Küchen, SHL and Salvesen, L and Blicher, J and Strange, DG and Svenstrup, K},
title = {[Chronic respiratory insufficiency in amyotrophic lateral sclerosis].},
journal = {Ugeskrift for laeger},
volume = {187},
number = {44},
pages = {},
doi = {10.61409/V03250140},
pmid = {41251254},
issn = {1603-6824},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/physiopathology ; *Respiratory Insufficiency/therapy/etiology/physiopathology ; Respiration, Artificial/methods ; Chronic Disease ; Noninvasive Ventilation ; Quality of Life ; },
abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by progressive loss of motor neurons in the brain and spinal cord. As the disease progresses, respiratory function becomes increasingly compromised. Supporting respiratory function is the treatment with the greatest potential impact on life expectancy and should align with the patient's wishes to ensure quality of life. Optimal secretion management is essential for effective non-invasive mechanical ventilation therapy, as argued in this review. Home invasive mechanical ventilation is reserved for a small subset of patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/therapy/physiopathology
*Respiratory Insufficiency/therapy/etiology/physiopathology
Respiration, Artificial/methods
Chronic Disease
Noninvasive Ventilation
Quality of Life

@article {pmid41251124,
year = {2025},
author = {Ozkose, GS and Topcu, Y and Ay, B and Ozdemir, O and Akgun-Dogan, O and Ng, OH and Alanay, Y},
title = {Expanding the Phenotypic Spectrum of ERLIN1-Related SPG62: Report of Two Siblings With Behavioral Features and Hyperacusis.},
journal = {Clinical genetics},
volume = {},
number = {},
pages = {},
doi = {10.1111/cge.70006},
pmid = {41251124},
issn = {1399-0004},
support = {//Acibadem Mehmet Ali Aydinlar University BAP Coordination Unit/ ; },
abstract = {Hereditary spastic paraplegia type 62 (SPG62) is a neurodegenerative disorder, with more than 20 individuals reported to date. This ultra-rare entity is inherited in an autosomal recessive manner and has been associated with ERLIN1 variants. In addition, ERLIN1-related biallelic variants have been linked to early-onset amyotrophic lateral sclerosis (ALS). We present two siblings with slowly progressive spastic paraplegia, with mild intellectual decline, behavioral findings, and hyperacusis. This study expands the clinical spectrum of hereditary spastic paraplegia associated with ERLIN1.},
}

@article {pmid41250939,
year = {2025},
author = {Ayvazian-Hancock, A and Butler, E and Meehan, CF and Miles, GB and Broadhead, MJ},
title = {Synaptopathy in the TDP-43ΔNLS Mouse Model of Sporadic Amyotrophic Lateral Sclerosis.},
journal = {The European journal of neuroscience},
volume = {62},
number = {10},
pages = {e70320},
doi = {10.1111/ejn.70320},
pmid = {41250939},
issn = {1460-9568},
support = {R434-2023-347//The Lundbeck Foundation/ ; //Tenovus Scotland/ ; //RS Macdonald Charitable Trust/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *DNA-Binding Proteins/genetics/metabolism ; *Synapses/pathology/metabolism ; Disease Models, Animal ; Mice ; Spinal Cord/pathology/metabolism ; Mice, Transgenic ; Astrocytes/pathology/metabolism ; Motor Neurons/pathology/metabolism ; Male ; },
abstract = {Sporadic cases of amyotrophic lateral sclerosis (sALS) represent the most common form of motor neuron disease. sALS is characterised by pathological cytoplasmic inclusions of TDP-43, so-called reactive astrocyte pathology and motor neuron degeneration. Alterations in certain subpopulations of synapses between neurons are thought to be a key driver of the pathological mechanisms of ALS. However, we do not have a clear understanding of which types of synapses are impacted in ALS. Identifying vulnerable synapses affected in sALS models may provide insights into the key sites of disease pathogenesis. In this study we have performed quantitative high-resolution microscopy to survey different synapse subtypes, including excitatory (glutamatergic), inhibitory (glycinergic) and modulatory (cholinergic C-Boutons) synapses, in the spinal cord of a mouse model of sALS showing inducible TDP-43 pathology (TDP43ΔNLS) restricted to neurons. We have identified changes in cholinergic synapses and a subpopulation of excitatory synapses. Mice display robust neuronal TDP-43 pathology and evidence of TDP-43 changes at cholinergic C-boutons. We also observe no evidence of astrocytic pathology nor changes in the fraction of synapses that are contacted by astrocytes. Overall, our findings highlight the selective vulnerability of distinct synapse populations in ALS.},
}

Animals
*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics
*DNA-Binding Proteins/genetics/metabolism
*Synapses/pathology/metabolism
Disease Models, Animal
Mice
Spinal Cord/pathology/metabolism
Mice, Transgenic
Astrocytes/pathology/metabolism
Motor Neurons/pathology/metabolism
Male

@article {pmid41250892,
year = {2025},
author = {Aliakbari, F and Volkening, K and Nayeri, Z and Polat, AY and Donison, N and Palik, J and Strong, MJ},
title = {Co-localization of tau and TDP-43 after extracellular vesicle delivery to cells.},
journal = {The FEBS journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/febs.70336},
pmid = {41250892},
issn = {1742-4658},
support = {201806SOP-411481/CAPMC/CIHR/Canada ; },
abstract = {Perturbations in the metabolism of microtubule-associated protein tau (tau) underlie the pathology of a broad array of dementias, including chronic traumatic encephalopathy, amyotrophic lateral sclerosis (ALS) with cognitive impairment (ALSci) and approximately half of the dementias associated with frontotemporal lobar degeneration. We recently observed significantly increased hippocampal tau pathology in rats injected with pseudophosphorylated human tau (2N4R tau[T175D]) co-expressing an ALS-associated TAR DNA-binding protein 43 (TDP-43) mutant (TDP-43[M337V]) when compared to wild-type rats. To understand this mechanism, we examined whether the extracellular vesicles (EVs) derived from wild-type TDP-43 (wtTDP-43) or tau-expressing cells could transfer expression of these proteins to recipient cells, and whether co-localization of these proteins occurs. mCherry-wtTDP-43 or EGFP-tau constructs were expressed in HEK293 or SH-SY5Y cells. The secretome and EV fractions contained wtTDP-43 or 2N4R tau protein and RNA, and could transfer proteins into nontransfected cells. Co-localization was also detected in the cytosol of recipient cells. In silico modeling of tau and TDP-43 interactions suggests hydrogen bonding underlies this interaction. These studies further our understanding of the interaction between tau and TDP-43 by demonstrating their ability to co-aggregate and in providing a mechanism by which cell-cell transfer of either protein via extracellular vesicles can lead to these synergistic interactions.},
}

@article {pmid41250565,
year = {2025},
author = {Serizawa, S},
title = {Clinical Care Experience of Multidisciplinary Professionals in Amyotrophic Lateral Sclerosis: A Cross-Sectional Study.},
journal = {The Tokai journal of experimental and clinical medicine},
volume = {50},
number = {3},
pages = {112-118},
pmid = {41250565},
issn = {2185-2243},
mesh = {*Amyotrophic Lateral Sclerosis/therapy/psychology ; Humans ; Surveys and Questionnaires ; Cross-Sectional Studies ; *Patient Care Team ; Male ; Female ; *Health Personnel/psychology ; Japan ; Middle Aged ; Adult ; Attitude of Health Personnel ; },
abstract = {OBJECTIVE: To clarify the characteristics of medical care for amyotrophic lateral sclerosis (ALS) by examining the most memorable experiences of multidisciplinary medical professionals involved in patient care.

METHODS: In a questionnaire, "the most impressive thing about the experience" was efficiently categorized using inductive thematic coding. Responses were categorized using keywords, and similar content was categorized using codes. The instances of each quantified item were calculated by expressing them as numbers and frequencies. Furthermore, representative quotations and context-specific nuances were analyzed to investigate the emotional and ethical dimensions of each category.

RESULTS: Questionnaires were distributed to 269 medical professionals treating patients with ALS at three hospitals in the western region of Kanagawa Prefecture. Of these, 164 (60%) responded to the questionnaire, and 143 were included (valid response rate: 53%). Based on the questionnaire responses, the experiences of the medical professionals were classified into 27 categories. Medical professionals are continuously involved in fulfilling the wishes of patients as much as possible, realizing individuality and patient commitment, and intervening without giving up.

CONCLUSION: For multidisciplinary medical professionals involved in the care of patients with ALS in clinical practice, the most memorable experiences coincided with those associated with the challenges of ALS care.},
}

*Amyotrophic Lateral Sclerosis/therapy/psychology
Humans
Surveys and Questionnaires
Cross-Sectional Studies
*Patient Care Team
Male
Female
*Health Personnel/psychology
Japan
Middle Aged
Adult
Attitude of Health Personnel

@article {pmid41250117,
year = {2025},
author = {Kulcsárová, K and Piel, JHA and Schaeffer, E},
title = {Environmental toxins in neurodegeneration - a narrative review.},
journal = {Neurological research and practice},
volume = {7},
number = {1},
pages = {93},
pmid = {41250117},
issn = {2524-3489},
abstract = {As the global incidence of neurodegenerative disorders rises at a rate beyond what can be attributed solely to population aging, the role of modifiable risk factors has come into research spotlight to inform preventive strategies. While many lifestyle interventions can be implemented at an individual level, addressing environmental pollutants that drive neurodegeneration requires a collective effort involving both public and political engagement. This narrative review summarizes current evidence on the role of selected environmental toxins-pesticides, solvents, air pollution, and heavy metals-in the development of Parkinson's Disease, Alzheimer's Disease, and Amyotrophic Lateral Sclerosis. Drawing from epidemiological and experimental studies, we highlight associations between these exposures and neurodegeneration, as well as potential converging pathophysiological mechanisms such as neuroinflammation and proteinopathy. Understanding these links may help inform public health measures aimed at reducing the burden of these diseases.},
}

@article {pmid41250094,
year = {2025},
author = {Chen, J and Mao, L},
title = {Limitations of single spot urine sampling and mixture model assumptions: commentary on Feng et al.'s study of heavy metal exposure and vascular age.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {1291},
pmid = {41250094},
issn = {1479-5876},
}

@article {pmid41249720,
year = {2025},
author = {Cabras, S and Manera, U and Di Pede, F and Zocco, G and Vasta, R and Novara, A and Minerva, E and Matteoni, E and De Mattei, F and Pellegrino, G and Grassano, M and Iazzolino, B and Palumbo, F and Callegaro, S and Polverari, G and Morbelli, SD and Pardini, M and Chiaravalloti, A and Schillaci, O and Leenders, KL and Kogan, RV and Moglia, C and Calvo, A and Chiò, A and Pagani, M and Canosa, A},
title = {Role of 2-[[18]F]FDG-PET as a biomarker of upper motor neuron involvement in amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {272},
number = {12},
pages = {766},
pmid = {41249720},
issn = {1432-1459},
support = {PRIN 2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 20228N7573//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; JPND (Strength//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; ALS-Care//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; Brain-Mend)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; Department of Excellence grant//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 259867//Seventh Framework Programme/ ; 101017598//Horizon 2020/ ; INSPIRED//Fondation Thierry Latran/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Male ; Female ; Middle Aged ; *Fluorodeoxyglucose F18 ; Cross-Sectional Studies ; Aged ; *Positron-Emission Tomography/methods ; *Motor Cortex/diagnostic imaging/metabolism ; *Motor Neurons/metabolism/pathology ; Adult ; Biomarkers/metabolism ; Radiopharmaceuticals ; },
abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) affects upper (UMN) and lower (LMN) motor neurons. ALS diagnosis is challenging, especially in predominant LMN phenotypes. Electromyography can disclose LMN damage, while UMN involvement is detectable by clinical examination, with possible support of magnetic resonance imaging (MRI) and transcranial magnetic stimulation. Our aim was to investigate the role of 2-[[18]F]FDG-PET as an UMN biomarker in ALS.

METHODS: In our cross-sectional study, we created an UMN burden score. Performing a multiple regression analysis in SPM12, we evaluated the relationship between UMNBS and brain metabolism. We split ALS cohort based on the UMN burden score median value (group A-under median, group B-above median). We ran a full factorial analysis including group A and B and healthy controls, followed by group comparisons.

RESULTS: We included 118 ALS patients (group A and B, N = 59), with a median UMN burden score of 9.50 and a left lateralization of UMN signs. We found a negative correlation between motor cortex metabolism and UMN burden score. Comparing each ALS group with healthy controls, we found relative hypometabolism in the left frontal lobe and relative bilateral, right-prevalent hypermetabolism of cerebellum and corticospinal tracts. The relative hypermetabolism in corticospinal tracts was more evident in the group with low UMN signs.

CONCLUSIONS: Motor cortex metabolism reflects UMN burden. Corticospinal tracts' metabolic changes could provide information about UMN involvement even in patients with predominant LMN phenotype, suggesting a possible role of brain 2-[[18]F]FDG-PET as an UMN biomarker in ALS patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism
Male
Female
Middle Aged
*Fluorodeoxyglucose F18
Cross-Sectional Studies
Aged
*Positron-Emission Tomography/methods
*Motor Cortex/diagnostic imaging/metabolism
*Motor Neurons/metabolism/pathology
Adult
Biomarkers/metabolism
Radiopharmaceuticals

@article {pmid41249315,
year = {2025},
author = {Yang, X and Zhan, L and Wang, Y},
title = {Semantic projection as a method to measure individual differences in semantic scale length: insights from autism-related traits.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {40119},
pmid = {41249315},
issn = {2045-2322},
support = {2442024CXTD02//the Fundamental Research Funds for the Central Universities of Beijing Language and Culture University/ ; },
mesh = {Humans ; Male ; Female ; *Semantics ; *Individuality ; Adult ; *Autistic Disorder/psychology ; *Autism Spectrum Disorder/psychology ; Young Adult ; Cognition ; Adolescent ; },
abstract = {Human perceive and navigate the world using internal scales constructed for various semantic features (e.g., danger, weight), and these scales vary considerably in length and endpoints among individuals. Quantifying these scale lengths is critical for understanding cognitive diversity, yet existing methods face reliability challenges. Here, we extend Grand et al.'s semantic projection approach through a free-response paradigm to measure individual differences in scale length. Applying this framework to autistic traits, we uncover a dissociation: in male participants, those with high Autism-Spectrum Quotient (AQ) scores exhibited significantly shorter scale lengths for abstract features compared to low-AQ males, revealing compressed conceptual representations in neurodivergent cognition. In contrast, no such differences were observed among females or for physical features. Potential implications and accounts are discussed.},
}

Humans
Male
Female
*Semantics
*Individuality
Adult
*Autistic Disorder/psychology
*Autism Spectrum Disorder/psychology
Young Adult
Cognition
Adolescent

@article {pmid41248812,
year = {2025},
author = {Di Nunzio, M and Mignogna, ML and Bacigaluppi, M and Panina-Bordignon, P and Ragonese, P and Muzio, L and Summa, V and Martino, G},
title = {The role of dopaminergic signalling from physiology to neuroprotection in acute and chronic disorders.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107194},
doi = {10.1016/j.nbd.2025.107194},
pmid = {41248812},
issn = {1095-953X},
abstract = {The dopaminergic system plays a central role in neuromodulation, involving motor control, reward, and cognition, and exerting its effects through five G protein-coupled receptors (DRD1-DRD5) with distinct tissue distributions and signalling mechanisms. While dopaminergic alterations are known to be associated to neuropsychiatric and movement disorders such as schizophrenia, Parkinson's disease, and Huntington's disease, growing evidence highlights a broader role in neurological and neurodegenerative conditions. This review explores the dopaminergic system's pathophysiological involvement in acute and chronic diseases such as stroke, spinal cord (SCI), traumatic brain (TBI) injury, and amyotrophic lateral sclerosis (ALS). Beyond characterizing its dysfunction, we aim to examine how this disrupted signalling contributes to the neurodegeneration underlying the neurological and neurodegenerative disorders discussed here, along with the associated pathophysiological factors of inflammation and altered plasticity. We further discuss emerging data supporting the potential of dopamine-based interventions not only to modulate disease mechanisms, but also to confer neuroprotection and reduce tissue damage in both acute and progressive neurodegeneration, while also considering sex-related dopamine alterations. By integrating findings across diverse conditions, we underscore the importance of advancing dopaminergic research beyond classical disease models into novel therapeutic territory.},
}

@article {pmid41247844,
year = {2025},
author = {Kawaguchi, T and Yorimoto, K and Kawakami, M and Hara, T and Hanai, A and Miyazaki, Y and Nishida, D and Takahashi, Y and Tsuji, T},
title = {Lung Volume Recruitment Slows Pulmonary Functional Decline and Prolongs Survival in ALS.},
journal = {Journal of neurologic physical therapy : JNPT},
volume = {},
number = {},
pages = {},
pmid = {41247844},
issn = {1557-0584},
abstract = {BACKGROUND AND PURPOSE: Few studies have examined the long-term effects of lung volume recruitment (LVR) in amyotrophic lateral sclerosis (ALS). This study aimed to clarify the impact of LVR on respiratory function (Aim 1) and survival (Aim 2).

METHODS: This retrospective cohort included hospitalized patients with ALS who underwent LVR from 2015 to 2020. For Aim 1, longitudinal changes in forced vital capacity (%FVC) were assessed every 3 months before and after LVR. For Aim 2, the survival study, data on sex, onset age, delay in diagnosis, duration of LVR, and subtype were also collected.

RESULTS: A total of 79 patients underwent LVR (Aim 2), 48 patients had %FVC data before and after LVR (Aim 1). Regarding long-term effects on respiratory function (Aim 1), %FVC declined at approximately 2% per month before LVR, with significant decreases observed at 12, 9, and 6 months relative to baseline (P < .001). After LVR, the decline slowed to less than 1% per month, and no significant decreases were observed at 3, 6, 9, or 12 months. In Aim 2, patients continuing LVR ≥6 months had longer survival than those with shorter use. Multivariate Cox regression identified LVR ≥6 months as a prognostic factor (hazard ratio [95% CI] = 0.42 [0.19-0.96], P = .04).

DISCUSSION AND CONCLUSIONS: These findings suggest a potential association between continued LVR and both a slower decline in %FVC and longer survival in patients with ALS. Further prospective studies are warranted to confirm these findings.

VIDEO ABSTRACT AVAILABLE: For more insights from the author (see the Video, Supplemental Digital Content Video, available at http://links.lww.com/JNPT/A552.},
}

@article {pmid41246746,
year = {2025},
author = {Bethea, JP and Sharma, H and Doberstein, N and Shenker, T and Gregory, B and Hoffman, R and Aizenman, D and Guirguis, G and Hoffmann, J and Tazani, S and Harris, Z and Costin, J},
title = {Application of Osteopathic Manipulative Treatment (OMT) in Neurodegenerative Disorders: A Scoping Review.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e94748},
pmid = {41246746},
issn = {2168-8184},
abstract = {Neurodegenerative diseases are comprised of a host of chronic conditions that impair the central nervous system. Osteopathic manipulative treatment (OMT) consists of many non-invasive modalities that can be used to treat a wide variety of ailments and conditions. OMT is reported to increase the range of motion and lymphatic flow, as well as decrease pain in a wide array of disorders. However, the efficacy of using OMT in neurodegenerative disorders has not been well established. The objective of this scoping review is to map the evidence that pertains to the application of OMT in treating neurodegenerative disorders and identify the gaps in the literature on this subject. This study was designed according to the Joanna Briggs Institute (JBI) guidelines for scoping reviews to gather information on OMT's potential efficacy in managing Parkinson's disease (PD), Alzheimer's disease (AD) dementia, amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Peer-reviewed literature was collected through the Excerpta Medica database (EMBASE), Ovid Medical Literature Analysis and Retrieval System Online (MEDLINE), and Web of Science. The criteria were limited to papers in English published between 1999 and 2023. The following search string was utilized: "osteopathic manipulative treatment" OR "osteopathic manipulation" AND "neurodegenerative disorders" OR "Alzheimer's disease" OR "dementia" OR "amyotrophic lateral sclerosis" OR "Parkinson's disease" OR "Huntington's chorea". One hundred and forty-three articles were identified following final screening and critical appraisal, with eleven articles selected for analysis in this study. Data from the selected articles demonstrated that OMT can possibly attenuate symptoms in patients diagnosed with neurodegenerative diseases. Studies in rats showed that OMT techniques were found to alter cholinergic neuronal genes, improve spatial learning and memory, reduce amyloid β protein levels, modulate synaptic transmission, and increase levels of the cytokines IL-1, IL-10, IL-13, RANTES, IL-17A, and EOTAXIN effects in AD dementia. ALS patients demonstrated a high level of satisfaction with OMT and did not report any adverse effects, though there was no decrease in pain or increased quality of life reported. PD patients reported improved postural stability, balance, and gait after OMT. No results were returned regarding OMT's effects on HD. Preliminary results in human PD and ALS patients who received OMT as an adjunct to traditional treatment regimens showed promising results, though few studies were found that address the topic, and the sample sizes of the studies that were found were small. There were no studies of the effects of OMT on human patients with AD or HD found, though preclinical studies in rats supported their trial in subsequent human studies. While current research on the impact of OMT on these neurodegenerative diseases is promising, there remain large gaps in the literature. Further research is necessary to support the use of and long-term efficacy of OMT in neurodegenerative diseases.},
}

@article {pmid41246229,
year = {2025},
author = {Şahin, TÖ and Cemali, Ö and Özdemir, M and Ayten, Ş and Ağagündüz, D},
title = {Flavonoids and phenolic compounds: a promising avenue for neurodegenerative disease therapy.},
journal = {Turkish journal of biology = Turk biyoloji dergisi},
volume = {49},
number = {5},
pages = {635-659},
pmid = {41246229},
issn = {1303-6092},
abstract = {BACKGROUND/AIM: Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS are characterized by a progressive loss of nerve cells, for which no definitive cure currently exists. These conditions share common pathological mechanisms, including chronic neuroinflammation, oxidative stress, protein aggregation, and mitochondrial dysfunction. Flavonoids and other plant-derived phenolic compounds have recently attracted attention for the treatment of such conditions due to their antiinflammatory and antioxidant properties. This review explores the neuroprotective mechanisms of flavonoids and evaluates their potential for the prevention and treatment of neurodegenerative diseases.

MATERIALS AND METHODS: A literature search of the Web of Science, PubMed, and ScienceDirect databases was conducted to evaluate the therapeutic potential of flavonoids and phenolic compounds against neurodegenerative diseases. The search terms included "polyphenols", "flavonoids", and related compounds, along with "Alzheimer's", "Parkinson's", "Huntington's", and "Amyotrophic lateral sclerosis". Eligible studies included clinical trials, randomized controlled trials, and in vitro and in vivo research published in English. Priority was given to studies from the last decade, although older but significant publications were also included.

RESULTS: The findings of multiple studies report the ability of flavonoid compounds such as quercetin, myricetin, apigenin, and epigallocatechin gallate (EGCG) to modulate critical signaling pathways, reduce oxidative stress, prevent the accumulation of neurotoxic proteins, and support mitochondrial function. These bioactive molecules have exhibited significant potential in slowing disease progression and preserving neuronal integrity. Their therapeutic application, however, has been limited by their poor bioavailability, low stability, and rapid metabolism.

CONCLUSION: Flavonoids have shown promise as naturally derived agents with multi-targeted activity against neurodegenerative processes. Enhancing their absorption and stability through novel delivery systems and structural modifications could significantly improve their clinical efficacy. When administered early or as a complementary therapy, flavonoids can be considered a safe and effective approach to the management of neurodegenerative diseases.},
}

@article {pmid41245603,
year = {2025},
author = {Almalki, S and Salama, M and Taylor, MJ and Ahmed, Z and Tuxworth, RI},
title = {FUS-related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1671910},
pmid = {41245603},
issn = {1662-5099},
abstract = {Mutations in Fused in Sarcoma (FUS) are associated with neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This systematic review examined the connections between DNA damage in the central nervous system (CNS), dysfunction of DNA repair processes and the FUS proteinopathy. Twelve peer-reviewed publications were analyzed, investigating this question across a range of models, including immortalized cell lines, ALS-FTD patient-derived induced pluripotent stem cells, mouse tissues and post-mortem samples from ALS-FTD patients. The studies also explored the impact of inducing DNA damage using several agents, including calicheamicin and etoposide, on FUS pathology. Our findings indicated that accumulated DNA damage was documented in all twelve studies, with a key finding being the disruption of interactions between FUS and the DNA damage response (DDR). FUS interactions with various DDR and DNA repair proteins involved in sensing DNA damage and executing the major repair pathways were impaired, resulting in elevated levels of DNA damage in both the nucleus and mitochondria. Therefore, FUS is an essential protein for the preservation of genomic integrity and this loss of genome stability is likely to be a key contributor to the neurodegeneration in ALS-FTD.},
}

@article {pmid41244779,
year = {2025},
author = {Sun, Z and Liu, C and Liu, W and Zhang, M and Ren, S and Gao, L and Ji, Z},
title = {Surgical treatment of autosomal recessive bestrophinopathy with angle-closure glaucoma: vitreous liquefaction as the key to correcting postoperative malignant glaucoma-three case reports.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1560475},
pmid = {41244779},
issn = {2296-858X},
abstract = {PURPOSE: This study aimed to evaluate the surgical treatment of autosomal recessive bestrophinopathy (ARB) combined with angle-closure glaucoma (ACG) through a retrospective case series.

METHODS: The treatment of three patients with ACG secondary to ARB was reviewed. The patients were admitted to the Department of Ophthalmology of Jinan Second People's Hospital from April 2023 to January 2024. Their conditions, treatments, and outcomes were extracted from the medical records and analyzed.

RESULTS: The patients were 48, 48, and 35 years old at the time of surgery. All had bilateral ARB and underwent surgery in the eye more severely affected by ACG. Topical eye drops failed to control the intraocular pressure (IOP), which measured 27, 28, and 47 mmHg before the surgery. The affected eyes also exhibited a shorter axial length (AL) and shallower anterior chamber depth (ACD). The ALs of the surgical eyes measured 22.73 mm, 21.52 mm, and 20.96 mm, while the ACDs were 2.51 mm, 1.97 mm, and 2.19 mm, respectively. After receiving trabeculectomy, they all immediately developed malignant glaucoma, which could not be resolved by conservative treatment. Following a second surgery, which importantly included an anterior vitrectomy and posterior capsulotomy, the IOP was normal, the ACD was satisfactory, and visual function was preserved.

CONCLUSION: For ACG/ARB patients, the risk of developing malignant glaucoma after glaucoma surgery is very high. Surgical intervention, such as anterior vitrectomy, is needed to increase vitreous fluidity, eliminate vitreous block, assist the formation of the anterior chamber, and stabilize the IOP to save the patient's vision. Long-term, close follow-up is essential due to the risk of recurrence in the operated eye and occurrence in the non-operated eyes.},
}

@article {pmid41244707,
year = {2025},
author = {Baeken, MW and Bekbulat, F and Körschgen, H and Clement, AM and Behl, C},
title = {The sigma-1 receptor as a neurohomeostatic decision hub for GABARAP-mediated receptor trafficking and macroautophagy.},
journal = {Frontiers in molecular biosciences},
volume = {12},
number = {},
pages = {1673249},
pmid = {41244707},
issn = {2296-889X},
abstract = {Gamma-aminobutyric acid receptor-associated protein (GABARAP) is a multifunctional member of the autophagy-related (ATG8) protein family, playing key roles in two distinct cellular pathways: macroautophagy and plasma membrane protein trafficking. In the context of autophagy, GABARAP modulates cargo recognition and supports the maturation and fusion of autophagosomes with lysosomes, a critical step in intracellular clearance and proteostasis. Separately, GABARAP also regulates vesicular receptor protein transport from the Golgi apparatus to the plasma membrane, contributing to proper surface localization and receptor recycling. Both tasks are especially vital for neurons, where protein turnover and receptor localization are tightly linked to synaptic plasticity and neuroprotection. We recently identified a direct interaction between GABARAP and the sigma-1 receptor (σ1R), an ER-resident receptor involved in diverse cellular stress responses, mitochondrial function, and protein homeostasis. Our findings suggest that σ1R acts as an upstream regulatory hub, influencing GABARAP's functional commitment to either membrane trafficking or autophagy. Specifically, we hypothesize that ligand-dependent σ1R activation promotes GABARAP's involvement in macroautophagy at the expense of its role in membrane transport. This regulatory switch may underline part of the neuroprotective effects observed with σ1R agonists in neurodegenerative disease models, where enhanced autophagy is often beneficial. Overall, we discuss the emerging molecular crosstalk between σ1R and GABARAP, its potential impact on neuronal homeostasis, and how σ1R's pharmacological modulation might be leveraged to bias GABARAP function toward autophagy in diseases such as amyotrophic lateral sclerosis, Huntington's, Parkinson's, and Alzheimer's disease.},
}

@article {pmid41243850,
year = {2025},
author = {Bao, W and Hao, Y and Wang, J and Hai, B and Wei, H},
title = {A cobalt-doped Prussian blue analogue as an efficient catalytic confinement matrix for high-performance aluminum-sulfur batteries.},
journal = {Chemical communications (Cambridge, England)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5cc05539c},
pmid = {41243850},
issn = {1364-548X},
abstract = {The development of cathode materials that combine effective polysulfide anchoring, and structural robustness is critical for advancing aluminum-sulfur (Al-S) battery performance. Herein, we propose a cobalt-based Prussian blue analogue (CoPBA) with a metal-organic framework structure as a cathode material for Al-S batteries. The S@CoPBA cathode exhibits a discharge capacity exceeding 414.0 mA h g[-1] after 650 cycles at a current density of 100 mA g[-1].},
}

@article {pmid41243423,
year = {2025},
author = {Araujo-Vieira, K and Dias, PHDS and Pereyra, MO and Blotto, BL and Caramaschi, U and Haddad, CFB and Faivovich, J and Grant, T},
title = {On a recent phylogenetic reanalysis of Sphaenorhynchini (Anura: Hylidae: Hylinae): Does it all come down to the method?.},
journal = {Cladistics : the international journal of the Willi Hennig Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/cla.70018},
pmid = {41243423},
issn = {1096-0031},
support = {2018/15425-0//Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil/ ; 2019/24979-2//Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil/ ; 2021/10639-5//Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil/ ; 2519/2019//Agencia Nacional de Promoción Científica y Tecnológica, Argentina/ ; 059/2021//Agencia Nacional de Promoción Científica y Tecnológica, Argentina/ ; 824/2021//Agencia Nacional de Promoción Científica y Tecnológica, Argentina/ ; 2800//Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina/ ; 314480/2021-8//Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil/ ; },
abstract = {Sphaenorhynchini comprises 15 species of small, greenish treefrogs from cis-Andean South America. Araujo-Vieira et al. (2019, A total evidence analysis of the phylogeny of hatch-faced treefrogs [Anura: Hylidae: Sphaenorhynchus], Cladistics 35, 469-486) conducted a total evidence parsimony analysis of DNA sequences and phenotypic data, corroborating the monophyly of Sphaenorhynchus, identifying three species groups, and placing the unusual species S. pauloalvini as sister to all other species. On this basis and numerous phenotypic differences, Araujo-Vieira et al. (2020, A new genus of lime treefrogs [Anura: Hylidae: Sphaenorhynchini], Zool. Anz. 286, 81-89) erected the genus Gabohyla for S. pauloalvini. Subsequently, Pereira et al. (2022, The dispersal between Amazonia and Atlantic Forest during the Early Neogene revealed by the biogeography of the treefrog tribe Sphaenorhynchini [Anura, Hylidae], Ecol. Evol. 12, e8754) performed a Bayesian analysis of a subset of Araujo-Vieira et al.'s (2019) molecular data and found G. pauloalvini to be nested within Sphaenorhynchus, which they attributed exclusively to choice of analytical method. To test this claim, we performed parsimony and Bayesian analyses of the total evidence dataset and the complete and partial molecular datasets with either the entire outgroup sample or a single terminal. The topology from the Bayesian analysis of the complete dataset is almost identical to that of Araujo-Vieira et al. (2019), with G. pauloalvini sister to Sphaenorhynchus, thereby refuting Pereira et al.'s claim. Moreover, the monophyly of Sphaenorhynchus sensu stricto was remarkably robust, being recovered in all analyses except the Bayesian analysis of the partial molecular dataset with a single outgroup terminal (i.e., the analysis performed by Pereira et al.). In addition to supporting the continued recognition of Gabohyla, our results underscore the importance of considering not only the choice of analytical method, but also character and taxon sampling-including outgroup sampling-before rejecting prior findings.},
}

@article {pmid41242668,
year = {2025},
author = {Chethana, HP and Rathan Kumar, U and Chakraborty, G and Sidhu, A},
title = {L-Arginine Interferes with Functional Studies of Amyloid Proteins.},
journal = {Protein expression and purification},
volume = {},
number = {},
pages = {106854},
doi = {10.1016/j.pep.2025.106854},
pmid = {41242668},
issn = {1096-0279},
abstract = {Intrinsically disordered proteins/regions are abundant in cancer signalling pathways and neurodegenerative diseases like Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, etc. Purification of intrinsically disordered proteins can be challenging due to their sticky nature. For intrinsically disordered amyloid proteins, in-vitro aggregation studies are ideal experiments to study their liquid to solid transition. However, over-expression of these proteins in E. coli often results in insoluble protein fraction that ends up in cell-pellet as inclusion bodies, on lysis and centrifugation. Supplementing purification buffers with l-arginine is known to increase the solubility of proteins. For most of the structured proteins increasing solubility translates into a higher yield of functional proteins. However, for aggregation prone proteins associated with neurodegenerative diseases, like α-synuclein (Parkinson's disease), Aβ (Alzheimer's disease), fused in sarcoma (amyotrophic lateral sclerosis), etc. inclusion of l-arginine might interfere with aggregation studies. To test our hypothesis, we purified aggregation prone α-synuclein and fused in sarcoma protein in the presence and absence of l-arginine and studied their fibrillization. While recombinant FUS is difficult to prepare, purification of α-synuclein is well established but in all the protocols a significant amount of protein remains as insoluble fraction in the pellet. Inclusion of l-arginine increases the yield of protein purification by about 3 folds for both the proteins, but the resulting protein does not aggregate into fibrils thus showing that increased solubility of amyloid proteins (α-synuclein and fused in sarcoma) in the presence of l-arginine is not suitable for aggregation studies.},
}

@article {pmid41242173,
year = {2025},
author = {McFarlane, R and Ross, R and Domhnaill, ÉM and Chiò, A and Corcia, P and Ingre, C and McDermott, CJ and Panadés, MP and Shaw, PJ and van Damme, P and van den Berg, L and Al-Chalabi, A and Walsh, C and Hardiman, O},
title = {Dynamic modelling of the ALSFRS-R: leveraging population-based scores using neural networks.},
journal = {EBioMedicine},
volume = {122},
number = {},
pages = {106029},
doi = {10.1016/j.ebiom.2025.106029},
pmid = {41242173},
issn = {2352-3964},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder with highly heterogeneous trajectories. The Revised ALS Functional Rating Scale (ALSFRS-R) is challenging to model due to irregularly spaced data and patient-level variability. Here we sought to develop and validate a short-horizon prediction tool leveraging a fully connected neural network (FCNN) to forecast individual ALSFRS-R trajectories, providing a natural history benchmark for trials and clinical practice.

METHODS: We retrospectively analysed 29,992 ALSFRS-R measurements from 5319 people living with ALS (plwALS) in the population-based PRECISION-ALS dataset. plwALS were randomised (80:20) into a training and test cohort using group-based splitting. A three-layer FCNN was built in TensorFlow to predict a third ALSFRS-R score given two historical scores and their respective time intervals. Performance was evaluated on the PRECISION-ALS test set and externally on the PROACT database. Linear extrapolation served as a baseline comparator.

FINDINGS: On the PRECISION-ALS test set, the FCNN achieved a mean absolute error (MAE) of 0.0552 (95% CI 0.0547-0.0576) on a normalised 0-1 scale, corresponding to 2.65 (2.63, 2.76) points on the 48-point ALSFRS-R. This remained consistent across all post-diagnostic periods. The model generalised well to the PROACT dataset, with an improved MAE of 0.0485 (95% CI 0.0481, 0.0489). Linear extrapolation performed significantly worse across all metrics. Error remained consistent across all clinical groups investigated, such as sex, genotype, site of onset, age at diagnosis, age at onset and diagnostic delay.

INTERPRETATION: A short-horizon FCNN can provide clinically interpretable, individualised ALSFRS-R forecasts from sparse, irregularly spaced data. By supporting rapid identification of those who step outside of the model, this approach holds promise for optimising patient counselling, clinical trial monitoring, and early intervention strategies. This approach allows us to better utilise our growing bank of ALS patient data to support decision making.

FUNDING: R McFarlane is supported by a grant from Target ALS, Precision ALS is funded by Taighde Éireann (Research Ireland, formerly Science Foundation Ireland).},
}

@article {pmid41242038,
year = {2025},
author = {Singh, A and Barasa, L and DeOrsey, L and O'Reilly, MD and Choudhary, S and Cahill, SE and Rossetti, T and Green, RM and Humphries, F and Thompson, PR},
title = {Triazole-based STING inhibitors.},
journal = {Bioorganic & medicinal chemistry},
volume = {132},
number = {},
pages = {118484},
doi = {10.1016/j.bmc.2025.118484},
pmid = {41242038},
issn = {1464-3391},
abstract = {Aberrant activation of the DNA sensing cGAS-STING pathway has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus (SLE), and autoinflammatory disorders such as Aicardi-Goutières syndrome (AGS) and STING-associated vasculopathy with onset in infancy (SAVI). Consequently, considerable efforts have been directed toward the development of STING inhibitors. We previously reported that BB-Cl-amidine and LB244 inhibit STING-dependent signalling with nanomolar potency both in vitro and in vivo. The nitrofuran warhead on LB244 provided superior potency and proteome-wide selectivity. Moreover, LB244 mirrored the efficacy of BB-Cl-amidinein vivo. Herein, we describe the development of a series of triazole-based analogues designed to inhibit STING signalling. These efforts led to the development of ASF24, a highly potent inhibitor of STING signalling (IC50 = 0.49 μM). In summary, our findings identify a novel triazole-based STING inhibitor and establish a promising scaffold for the development of therapeutics targeting STING-mediated inflammatory diseases.},
}

@article {pmid41241727,
year = {2025},
author = {Sironi, F and Tortarolo, M and Mazzucchi, S and Camporeale, L and Freschi, M and Arcadipane, E and De Giovanetti, G and Kurosaki, M and Terao, M and Parlanti, P and Podini, P and Gentile, F and Bonetto, V and Cappello, V and Riva, N and Quattrini, A and Bendotti, C},
title = {Loss of C9orf72 impacts the peripheral neuromuscular system via immune dysregulation and accelerates the progression of amyotrophic lateral sclerosis in SOD-1 mutant mice.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {272},
pmid = {41241727},
issn = {1742-2094},
support = {Grant N. 1157625//Regione Lombardia, Italy, "POR FESR 2014-2020 resources Call HUB Ricerca Innovazione"/ ; Grant N. 1157625//Regione Lombardia, Italy, "POR FESR 2014-2020 resources Call HUB Ricerca Innovazione"/ ; Grant N. 1157625//Regione Lombardia, Italy, "POR FESR 2014-2020 resources Call HUB Ricerca Innovazione"/ ; Grant N. 1157625//Regione Lombardia, Italy, "POR FESR 2014-2020 resources Call HUB Ricerca Innovazione"/ ; Grant N. 1157625//Regione Lombardia, Italy, "POR FESR 2014-2020 resources Call HUB Ricerca Innovazione"/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/immunology/metabolism ; *C9orf72 Protein/genetics/deficiency/metabolism ; Mice ; *Superoxide Dismutase-1/genetics ; Disease Progression ; Mice, Transgenic ; *Neuromuscular Junction/pathology/metabolism/immunology ; Disease Models, Animal ; Mutation/genetics ; Motor Neurons/metabolism/pathology ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder where neuromuscular health is central to disease progression. The degeneration of motor neurons (MNs) leads to muscle weakness and paralysis, underscoring the critical importance of neuromuscular junctions (NMJs) and axonal integrity. Among the genetic contributors to ALS, mutations in the C9orf72 gene are the most common, accounting for both ALS and frontotemporal dementia (FTD). While the role of C9orf72 has been studied across various cells and compartments, its function in the peripheral nervous system (PNS), a compartment crucial for maintaining neuromuscular connectivity in ALS,remains largely unexplored.

MAIN BODY: Our study investigates the role of C9orf72 loss-of-function in ALS, focusing on its neuromuscular effects. C9orf72 expression is localized in MNs, microglia, oligodendrocytes, and Schwann cells (SCs) in the sciatic nerve (SN), but not in astrocytes. The absence of C9orf72 in mice is associated with hypomyelination and axonal sorting defect in the SN, but not with MNs loss in lumbar spinal cord. Additionally, we identified immune dysregulation, with elevated CD8+ T cells transcript and increased major histocompatibility complex I (MHCI) expression in SCs, in association with enhanced NMJ denervation in C9orf72-deficient ALS mice, suggesting a potential contribution of immune dysregulation to disease progression. These changes contributed to NMJ denervation characterized by increase in the expression of acetylcholine receptor gamma (AChRγ). The combination of C9orf72-deficiency with the ALS-linked SOD1G93A mutation resulted in a more severe phenotype and accelerated disease progression, despite no additional spinal MN loss.

CONCLUSION: Our findings underscore the critical role of C9orf72 in maintaining neuromuscular health through its influence on myelination, immune response regulation, and NMJ integrity. Loss of C9orf72 function exacerbates ALS progression by promoting SC dysfunction and immune dysregulation. This highlights the significance of preserving normal C9orf72 function in ALS therapies through antisense oligonucleotides strategies. Furthermore, targeting immune responses and myelination pathways may offer novel avenues for ALS treatment strategies.},
}

Animals
*Amyotrophic Lateral Sclerosis/genetics/pathology/immunology/metabolism
*C9orf72 Protein/genetics/deficiency/metabolism
Mice
*Superoxide Dismutase-1/genetics
Disease Progression
Mice, Transgenic
*Neuromuscular Junction/pathology/metabolism/immunology
Disease Models, Animal
Mutation/genetics
Motor Neurons/metabolism/pathology
Mice, Inbred C57BL

@article {pmid41240557,
year = {2025},
author = {Jia, H and Chang, Y},
title = {Real-time photoelectric sensing of edaravone for therapeutic efficacy in amyotrophic lateral sclerosis.},
journal = {Journal of colloid and interface science},
volume = {704},
number = {Pt 2},
pages = {139457},
doi = {10.1016/j.jcis.2025.139457},
pmid = {41240557},
issn = {1095-7103},
abstract = {Amyotrophic lateral sclerosis (ALS) requires precise therapeutic monitoring of Edaravone, but current methods lack real-time capability. Herein, we developed a photoelectrochemical (PEC) sensor using a Bi4Ti3O12/BiOBr heterojunction for ultrasensitive Edaravone detection. The heterojunction interface enables Type II band alignment, facilitating efficient charge separation through electron transfer from BiOBr conduction band to Bi4Ti3O12 and hole migration in reverse, synergistically suppressing recombination. XRD, XPS, and HRTEM confirm the composite's crystal structure and intimate interface. UV-Vis DRS shows redshifted absorption (470 nm) with enhanced visible-light utilization, while PL quenching verifies improved charge dynamics. Under optimized conditions (0.4 V, pH = 7), the sensor exhibits linear response (0.1-10 μM) with 0.031 μM detection limit, high stability (92 % retention over 1500 s), and reproducibility (RSD 2.8 %). DFT calculations reveal modified interfacial charge distribution and narrowed bandgap (2.197 eV), enhancing optical absorption and conductivity. While machine learning analysis of ALS clinical trial data identifies Edaravone's superior efficacy (ALSFRS-R decline -5.04 ± 1.27) and patient subgroup responsiveness, enabling personalized therapeutic prediction. This novel integrated platform bridges material engineering, real-time sensing, and data analytics for ALS precision medicine.},
}

@article {pmid41240362,
year = {2025},
author = {Cogan, G and Houot, M and Bogoin, J and Noël, S and Larcher, K and David, I and Moreau, P and Bensalah, M and Fauret-Amsellem, AL and Lamari, F and Khrouf, W and Etcharry-Bouyx, F and Didic, M and Lagarde, J and Jagot, CR and Sarazin, M and Boutoleau-Bretonniere, C and Pasquier, F and Bombois, S and Auriacombe, S and Pariente, J and Chaussenot, A and Levy, R and Wallon, D and Zarea, A and Le Ber, I and LeGuern, E and Clot, F},
title = {The genetic landscape of frontotemporal lobar degeneration: investigation of a diagnostic cohort of 2747 probands.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf423},
pmid = {41240362},
issn = {1460-2156},
abstract = {Genetic factors play an important role in frontotemporal lobar degeneration (FTLD) with about 20 genes reported to be involved. Although it is known that genetic diagnostic yield depends on age at onset, clinical subtype and family history, there are no precise indication criteria for a cost-effective and efficient strategy in clinical setting. We report the molecular diagnostic experience in a French clinical laboratory in a large cohort of 2747 probands with sporadic or familial FTLD. We used a three-step genetic screening strategy. First, measurement of plasma progranulin assay was performed in all cases (n=2747), followed by screening of GRN when plasma progranulin was below the threshold. If GRN screening was negative, the second step consisted of the investigation of the G4C2 repeat expansion in C9orf72 (n= 2675). In a third step, targeted sequencing of 14 FTLD genes was performed in 1279 individuals depending on age at onset and family history. Diagnostic yield of this strategy was 12.2% (n=334). GRN (n=73) and C9orf72 (n=200) represent 81.7% of genetic diagnoses. Diagnostic yield of the panel sequencing was 4.8% (62/1279). Family history was the strongest factor related to genetic diagnosis, with four to five times more genetic diagnoses in cases with a family history of FTLD (32.1%) compared with sporadic cases (7.2%). Although the clinical presentation is not significantly associated with identifying a genetic mutation, behavioural variant of frontotemporal dementia (bvFTD) associated with amyotrophic lateral sclerosis (FTD/ALS) or not produced a higher diagnostic yield (15.5% and 13.3%, respectively) than the primary progressive aphasia subgroup (9.9% for semantic variant and 8.8% for non-fluent variant) and others (8.3% and 4.2% for progressive supranuclear palsy and corticobasal syndrome, respectively). Interestingly, the genetic distribution varies greatly between clinical subtypes. FTD/ALS and bvFTD were mostly driven by C9orf72 (82.1% and 63.5%, respectively). In contrast, GRN is the dominant gene in nfvPPA (41.2%). C9orf72, MAPT, GRN and TBK1 equally contributes to svPPA (around 20% each). These results allow us to show the phenotype-genotype architecture of FTLD and to provide data to establish a cost-effective genetic diagnostic strategy in clinical settings for FTLD.},
}

@article {pmid41239797,
year = {2025},
author = {Garg, N and Dhankhar, S and Dhariya, A and Parkash, C and Chauhan, S and Singh, TG},
title = {Role of Liposomes in the Treatment of Neurodegenerative Disorders: A Comprehensive Review.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {25},
number = {4},
pages = {496-512},
pmid = {41239797},
issn = {1875-6166},
mesh = {Humans ; *Liposomes/metabolism/chemistry ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Drug Delivery Systems/methods ; *Neuroprotective Agents/administration & dosage/therapeutic use ; Blood-Brain Barrier/metabolism/drug effects ; },
abstract = {The complex etiology and limited therapy options of neurodegenerative illnesses pose daunting challenges to modern medicine. Nonetheless, novel treatment approaches have exciting new possibilities because of developments in nanotechnology. Liposomes have garnered a lot of interest as a potential treatment for neurological illnesses due to the fact that they are able to adapt to their role as nanocarriers. This review article discusses various uses of liposomes, including their ability to help treat neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease, as well as their diagnostic and neuroprotective uses. Liposomes allow for the targeted delivery of medicines to specific brain areas with minimal systemic side effects since they encapsulate and carry therapeutic molecules across the blood-brain barrier. Due to the fact that they are biocompatible, have surface features that can be adjusted, and have the ability to co-deliver many drugs, liposomes are excellent candidates for combination therapy and personalized medicine procedures. In spite of this, there is a growing body of research that suggests liposomes could serve as a versatile platform for the improvement of neurodegenerative disease treatment. This is a positive sign for the future results of patients and their quality of life.},
}

Humans
*Liposomes/metabolism/chemistry
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
*Drug Delivery Systems/methods
*Neuroprotective Agents/administration & dosage/therapeutic use
Blood-Brain Barrier/metabolism/drug effects

@article {pmid41239791,
year = {2025},
author = {Bassi, P and Rana, S and Sapra, V and Raina, A and Kumar, P and Devi, S},
title = {Exploring Novel Therapeutic Avenues: Drug Repurposing for Neurodegenerative Movement Disorders.},
journal = {Current drug research reviews},
volume = {17},
number = {3},
pages = {375-393},
pmid = {41239791},
issn = {2589-9783},
mesh = {Humans ; *Drug Repositioning/methods ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Movement Disorders/drug therapy ; },
abstract = {Neurodegenerative movement disorders, encompassing conditions such as Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, represent a significant burden on individuals, families, and healthcare systems globally. Traditional drug discovery approaches for these disorders have encountered challenges, including high costs and lengthy timelines. Drug repurposing has emerged in recent years as a promising approach to expedite the discovery of new treatments by leveraging existing drugs approved for other indications. This review explores the landscape of drug repurposed for neurodegenerative movement disorders, highlighting promising candidates, underlying mechanisms, and clinical implications. The rationale behind repurposing, including the advantages of utilizing existing pharmacological agents with established safety profiles and known pharmacokinetics, along with techniques utilized for repurposing (computational and experimental), have been elaborated. Several studies on the potential of pre-existing drugs such as isradipine, tetracycline, ambroxol, metformin, deferiprone, simvastatin, etc., which have been repurposed for neurodegenerative movement disorders, including Parkinson's disease, Huntington's disease, Alzheimer's disease, Multiple Sclerosis, etc. have been discussed. Further, the current scenario and future prospective of drug repurposing have also been touched upon.},
}

Humans
*Drug Repositioning/methods
*Neurodegenerative Diseases/drug therapy
Animals
*Movement Disorders/drug therapy

@article {pmid41239785,
year = {2025},
author = {Inoue, K and Fujimura, H and Ueda, K and Nishio, H and Naruse, H and Izumi, Y},
title = {An Autopsy Case of ALS Which Clinically Presented Sporadic Adult-Onset Lower Motor Neuron Disease and Genetically Had p. Leu127Ser (L126S) Variant in SOD1 and SMN2 Deletion.},
journal = {Neuropathology : official journal of the Japanese Society of Neuropathology},
volume = {45},
number = {6},
pages = {e70032},
doi = {10.1111/neup.70032},
pmid = {41239785},
issn = {1440-1789},
support = {25wm0625126s0301//Japan Agency for Medical Research and Development/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Male ; Adult ; *Superoxide Dismutase-1/genetics ; Autopsy ; *Survival of Motor Neuron 2 Protein/genetics ; Middle Aged ; Motor Neurons/pathology ; },
abstract = {Herein, we report an autopsy case of sporadic amyotrophic lateral sclerosis (ALS) with a p. L127S (L126S) SOD1 variant, SMN2 deletion and one hybrid SMN. A 43-year-old Japanese man noticed muscle weakness in his left lower extremity. At the age of 51, his muscle strength was moderately diminished in the upper extremities and severely in the lower extremities with hyporeflexia. At the age of 55, he started noninvasive intermittent ventilation (NIV) during nighttime. At the age of 57, he developed dysphagia and died of pneumonia. The total clinical course was 14 years and 8 months (13 years 9 months until NIV). Pathologically we found severe loss of lower motor neurons, moderate neuronal loss in Clarke's nuclei and mild grumose degeneration of the dentate nucleus. The primary motor cortex was well preserved and the pyramidal tracts showed vague myelin pallor in the lumbar cord. There were a few conglomerate hyaline inclusions (CHIs) that were negative for Bodian staining. Immunohistochemically, CHIs were positive for phosphorylated neurofilament (pNF) and were stained with Uq and SOD1 to varying degrees. Some CHIs contained granular-like components positive for p62. A post-mortem genetic test revealed that the patient had 2 copies of SMN1, 0 copies of SMN2, and one hybrid gene with exon 1 to 7 of SMN2 and SMN1 exon 8. Additional gene research elucidated a heterozygous SOD1 p. Leu127Ser (L126S) mutation. Compared to previous reports of ALS with the same mutation, the distribution of degenerative lesions was similar. It has been suggested that SMN2 deletion may not be directly implicated in lower motor neuron pathology, but further research is needed to confirm this. Further accumulation of cases is necessary to determine the effect of SMN2 on SOD1-ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/pathology
Male
Adult
*Superoxide Dismutase-1/genetics
Autopsy
*Survival of Motor Neuron 2 Protein/genetics
Middle Aged
Motor Neurons/pathology

@article {pmid41238911,
year = {2025},
author = {Gao, G and Sumrall, ER and Walter, NG},
title = {Nanoscale domains govern local diffusion and ageing within fused-in-sarcoma condensates.},
journal = {Nature nanotechnology},
volume = {},
number = {},
pages = {},
pmid = {41238911},
issn = {1748-3395},
support = {GM131922//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; NS097542//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; DGE2241144//National Science Foundation (NSF)/ ; },
abstract = {Biomolecular condensates regulate cellular physiology by sequestering and processing RNAs and proteins, yet how these processes are locally tuned within condensates remains unclear. Moreover, in neurodegenerative diseases such as amyotrophic lateral sclerosis, condensates undergo liquid-to-solid phase transitions, but capturing early intermediates in this process has been challenging. Here we present a surface multi-tethering approach to achieve intra-condensate single-molecule tracking of fluorescently labelled RNA and protein molecules within liquid-like condensates. Using RNA-binding protein fused-in-sarcoma as a model for condensates implicated in amyotrophic lateral sclerosis, we discover that RNA and protein diffusion is confined within distinct nanometre-scale domains, or nanodomains, which exhibit unique connectivity and chemical environments. The properties of these nanodomains are tunable by guest molecules. As condensates age, nanodomains reposition, facilitating fused-in-sarcoma fibrilization at the condensate surface, a process further enhanced by anti-amyotrophic lateral sclerosis drugs. Our findings demonstrate that nanodomain formation governs condensate function by modulating the residence time and spatial organization of constituent biomolecules, providing previously unattainable insights into condensate ageing and mechanisms underlying disease.},
}

@article {pmid41238908,
year = {2025},
author = {Le, Y and Liu, G and Wu, S and Nissenbaum, M and Kusnecov, AW and Furmanski, P and Birge, RB and Zhou, R},
title = {AAV-mediated BDNF and GAS6 muscle delivery delays disease onset in SOD1[G93A] ALS mice.},
journal = {Gene therapy},
volume = {},
number = {},
pages = {},
pmid = {41238908},
issn = {1476-5462},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease, with limited treatments. Gene therapy offers an alternative strategy for treating a large portion of ALS patients, however, the disparate genetic alterations in ALS complicate the development of gene therapies. Tyrosine receptor kinase B (TRKB) and Tyro3 receptors are highly expressed in mouse spinal cord motor neurons, suggesting that their ligands, brain-derived neurotrophic factor (BDNF) and growth arrest-specific 6 (GAS6), respectively, are crucial for neuronal survival. In this study, we tested whether genetically induced and muscle tissue-specific expression of such survival-enhancing ligands would ameliorate symptom development in the SOD1[G93A] ALS mouse model. The therapeutic vectors (AAV-Pmus7-HuBDNF-teLuc or AAV-Pmus7-HuGAS6), or a control vector (AAV-Pmus7-teLuc) were injected intravenously via the retro-orbital route and intramuscularly into the hindlimb skeletal muscle of six-week-old mice. Treatment with the therapeutic vectors delayed disease onset and slowed progression in both male and female mice. Interestingly, a sex-specific response was observed, with female mice benefiting more from the treatments than males. Lumbar motor neuron survival was more sustained in the therapeutic vector-treated group compared to control vector group. No statistically significant extension of lifespan was observed in the treated groups.},
}

@article {pmid41238595,
year = {2025},
author = {Lee, SK and El Ghazaoui, E and Kweon, JJ and Lee, S and Parq, JH},
title = {Hyperconnected amorphous oxide networks under compression.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {9930},
pmid = {41238595},
issn = {2041-1723},
support = {NRF-2020R1A3B2079815/0409-20240067//National Research Foundation of Korea (NRF)/ ; },
abstract = {Irreversibly densified oxide glass under extreme deformation exhibits unexpected softening with plasticity, while the glass network typically becomes rigid as it densifies. These distinct mechanical responses in amorphous networks remain puzzling at the atomic level. Understanding this behavior requires knowledge of how the network entangles and connects under high pressure. Here, our measurements on densified amorphous oxides under irreversible densification via magnetic resonance spectroscopy provide evidence of enhanced network entanglement and, consequently, hyperconnectivity, as highlighted by an increase in highly coordinated Al's and their spatial proximity. The results reveal that configurational diversity in prototypical amorphous Al2O3 under irreversible densification is more prominent than those of other complex oxide glasses, reaching hyperconnected under much lower pressures. In general, attainment of configurational diversity at lower pressures is promoted by increasing field strength of non-network cations in glasses under irreversible densification. The enhanced connectivity with increasing densification allows us to postulate the origin of mechanical responses in glass networks. Particularly, attainment of hyperconnectivity under lower pressures may promote network flexibility during deformation. This conceptual protocol enables control of dual mechanical responses in glasses under extreme stress, guiding the discovery of super-hard densified glasses for technological innovation and accounting for the weakening of hyperconnected glasses in planetary interiors.},
}

@article {pmid41238422,
year = {2025},
author = {Liguori, F and Amadio, S and Angioli, C and Ferriero, A and Passaro, I and Alberti, F and Vernì, F and Volonté, C},
title = {Validation in Drosophila of the in silico predicted clomipramine as repurposable for SOD1-ALS.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00793},
doi = {10.1016/j.neurot.2025.e00793},
pmid = {41238422},
issn = {1878-7479},
abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive motor neuron degeneration and muscle weakness, generally leading to death due to respiratory failure within 2-5 years of symptom onset. Current Food and Drug Administration-approved drugs -riluzole, edaravone, and tofersen - offer limited clinical benefit due to ALS multifactorial etiology and high heterogeneity. To bypass this therapeutic letdown, we previously exploited network medicine and drug repurposing strategies. Leveraging the SAveRUNNER algorithm, we identified several potentially repurposable candidates, including clomipramine (Anafranil®), mianserin (Lantanon®/Tolvon®), and modafinil (Provigil®). Here, we evaluated the in vivo efficacy of these compounds in Drosophila models of ALS, precisely those expressing pan-neuronal human SOD1[A4V] or SOD1[G85R] mutations. Our results demonstrate that clomipramine is the most promising candidate, ameliorating lifespan reduction, improving climbing abilities, and mitigating both genomic instability and inflammation, key pathological hallmarks of these SOD1-ALS models. Despite needing further validation in higher organisms, our Drosophila findings represent preliminary yet significant support for clomipramine's action as an add-on treatment for SOD1-ALS.},
}

@article {pmid41238318,
year = {2025},
author = {Soriani, MH and Blasco, H and Corcia, P and Danel-Brunaud, V and Desmaison, A and Pradat, PF and Querin, G and Vourch, P and Guy, N},
title = {Markers of presymptomatic amyotrophic lateral sclerosis: State of the art, practical implications and perspectives.},
journal = {Revue neurologique},
volume = {181},
number = {9},
pages = {893-908},
doi = {10.1016/j.neurol.2025.07.008},
pmid = {41238318},
issn = {0035-3787},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy/blood ; *Biomarkers/analysis/blood ; C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; Mutation ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an identified genetic origin in 10-15% of cases, mainly involving C9orf72 and SOD1 mutations. The increasing number of genetically confirmed ALS cases has led to a growing identification of asymptomatic mutation carriers. While riluzole remains the standard treatment, mutation-specific therapies such as tofersen, that was recently approved in SOD1-ALS, are emerging. In this context, the identification of presymptomatic biomarkers is crucial for monitoring genetically at-risk individuals. Plasma neurofilament light chain can increase up to 3.5years before symptom onset in C9orf72 carriers. Metabolic and neuroimaging alterations together with cognitive or behavioral changes, that are sometimes detectable decades prior to diagnosis, have also been observed. These biomarkers may support early surveillance and intervention strategies. The present review provides an overview of current evidence on presymptomatic biomarkers in ALS mutation carriers and their potential role in genetic counseling, monitoring, and early therapeutic decisions.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy/blood
*Biomarkers/analysis/blood
C9orf72 Protein/genetics
Superoxide Dismutase-1/genetics
Mutation

@article {pmid41238313,
year = {2025},
author = {Rival, M and Thouvenot, E},
title = {Tracing Neurological Diseases in the presymptomatic phase: moving forward a detection panel.},
journal = {Revue neurologique},
volume = {181},
number = {9},
pages = {821-828},
doi = {10.1016/j.neurol.2025.08.004},
pmid = {41238313},
issn = {0035-3787},
mesh = {Humans ; Biomarkers/analysis ; *Nervous System Diseases/diagnosis ; Neurodegenerative Diseases/diagnosis ; Early Diagnosis ; Disease Progression ; *Prodromal Symptoms ; Asymptomatic Diseases ; },
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) often exhibit a prolonged presymptomatic phase during which neuropathological changes silently progress. Recent advances in biomarker research have revealed molecular and imaging signatures that precede clinical onset by years, offering a critical window for early intervention. This review synthesizes current knowledge on the most promising presymptomatic biomarkers across these conditions, highlighting their biological origins, diagnostic performance, and clinical utility. Particular emphasis is placed on the development and validation of biomarker panels, which combine multiple markers to enhance diagnostic sensitivity and specificity, enabling more accurate detection of disease in its earliest stages. Minimally invasive approaches, such as blood-based assays, are also discussed for their potential to facilitate widespread screening and longitudinal monitoring. As these biomarkers begin to integrate into clinical workflows, particularly in AD and MS, international collaboration will be essential to standardize methodologies and ensure equitable implementation. Ultimately, presymptomatic biomarkers hold transformative potential for shifting neurology toward a proactive and precision-based paradigm.},
}

Humans
Biomarkers/analysis
*Nervous System Diseases/diagnosis
Neurodegenerative Diseases/diagnosis
Early Diagnosis
Disease Progression
*Prodromal Symptoms
Asymptomatic Diseases

@article {pmid41238191,
year = {2025},
author = {Yang, Y and Wang, Q and Wang, Z and Wang, Y and Liu, B and Zhang, Y and Mao, X and Sun, H},
title = {The Role of Fatty Acids in Neurodegenerative Diseases: Mechanistic Insights and Therapeutic Strategies.},
journal = {Journal of lipid research},
volume = {},
number = {},
pages = {100944},
doi = {10.1016/j.jlr.2025.100944},
pmid = {41238191},
issn = {1539-7262},
abstract = {Fatty acids (FAs) play multifaceted roles in neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review systematically summarizes current understanding of fatty acid metabolism and its diverse implications in NDD pathology. Short-chain fatty acids (SCFAs), primarily generated by gut microbiota, regulate neuroinflammation, gut-brain communication, and blood-brain barrier (BBB) integrity via epigenetic modifications and immune modulation. Medium-chain fatty acids (MCFAs) exhibit therapeutic potential by improving energy metabolism and neuromuscular function, particularly in ALS models. Long-chain polyunsaturated fatty acids (PUFAs), notably docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), contribute to neuronal membrane integrity, synaptic plasticity, and antioxidant defense, mitigating oxidative stress and neuroinflammation. Conversely, saturated and certain n-6 fatty acids may exacerbate neurodegeneration through pro-inflammatory and oxidative pathways. Emerging evidence highlights fatty acid involvement in key pathological processes such as lipid peroxidation, mitochondrial dysfunction, ferroptosis, and BBB disruption. Therapeutically, targeted supplementation, dietary modification, microbiome manipulation, and advanced nanotechnology-based delivery systems are promising strategies. Nevertheless, precise therapeutic efficacy depends critically on disease stage, dosage, genetic background, and individual metabolic context. Integrating personalized medicine with precision nutritional strategies and novel drug-delivery platforms offers promising avenues to translate fatty acid-based interventions into clinical practice, potentially improving patient outcomes in the aging global population.},
}

@article {pmid41238183,
year = {2025},
author = {Iwasaki, H},
title = {Comment on Koo et al.'s observational study.},
journal = {Anaesthesia, critical care & pain medicine},
volume = {},
number = {},
pages = {101686},
doi = {10.1016/j.accpm.2025.101686},
pmid = {41238183},
issn = {2352-5568},
}

@article {pmid41212041,
year = {2025},
author = {Gyombolai, Z and Simon, A and Kubik, AZ and Jónásné Sztruhár, I and Mayer, R and Kovács, É},
title = {[Mobility of older people in institutions providing long-term care].},
journal = {Orvosi hetilap},
volume = {166},
number = {45},
pages = {1777-1785},
doi = {10.1556/650.2025.33414},
pmid = {41212041},
issn = {1788-6120},
mesh = {Humans ; Aged ; Female ; Cross-Sectional Studies ; Male ; Aged, 80 and over ; *Long-Term Care ; *Mobility Limitation ; *Nursing Homes ; Quality of Life ; *Geriatric Assessment/methods ; Hungary ; *Homes for the Aged ; Activities of Daily Living ; Middle Aged ; },
abstract = {Introduction: Mobility is a central element of health-related quality of life and functional capacity, the loss of which has long-term consequences affecting multiple organ systems, particularly in elderly individuals requiring long-term care. For healthcare professionals working in elderly care, maintaining, or improving basic mobility capacity is of primary importance. Objective: Our research had dual objectives: to assess the mobility capacity levels of elderly individuals living in long-term care facilities; and to understand the physical, cognitive, and self-care indicators of elderly individuals at different mobility levels, which could make optimal planning of institutional care easier. Method: We conducted a cross-sectional study among residents aged 60 years and over in three nursing homes between June 2023 and June 2024 (n = 209). Mobility was assessed using the validated Hungarian version of the de Morton Mobility Index (DEMMI), physical functions with the 30 Second Sit to Stand Test and Timed Up and Go test, cognitive functions with the Mini Mental State Examination, fear of falling with the FES-I questionnaire, and self-care with the Barthel Index. DEMMI results were categorized into four groups according to Thorsted et al.’s cut-off values. Results: The average age of participants was 81.34 years, with 71.3% being women. Based on DEMMI scores, 53 individuals (25.4%) had very low mobility, 41 (19.6%) had low mobility, 64 (30.6%) had moderately reduced mobility, and 51 (24.4%) had independent mobility. Higher mobility levels were associated with significantly better lower limb muscle strength, dynamic postural control, cognitive function, lower fear of falling, and better self-care. Discussion: DEMMI more sensitively indicates remaining mobility capabilities compared to traditional tests, and successfully avoids floor effects, thus can effectively help institutions allocate human resources appropriately, and plan needs-based care. Conclusion: DEMMI is suitable for differentiated assessment of mobility capacity in elderly individuals living in long-term care, and results can provide guidance to institutions for ensuring quality elderly care, and optimal assignment of human resources. Orv Hetil. 2025; 166(45): 1777–1785.},
}

Humans
Aged
Female
Cross-Sectional Studies
Male
Aged, 80 and over
*Long-Term Care
*Mobility Limitation
*Nursing Homes
Quality of Life
*Geriatric Assessment/methods
Hungary
*Homes for the Aged
Activities of Daily Living
Middle Aged

@article {pmid41238102,
year = {2025},
author = {Long, J and Liu, S and Shi, Y and Zhang, C and Qin, L and Ai, Q},
title = {Targeting lipid metabolism in neurodegenerative diseases: From experimental to clinical.},
journal = {Metabolism: clinical and experimental},
volume = {},
number = {},
pages = {156436},
doi = {10.1016/j.metabol.2025.156436},
pmid = {41238102},
issn = {1532-8600},
abstract = {The human brain, despite accounting for only 2 % of total body weight, exhibits an exceptionally high lipid content (approximately 20 % of its mass), highlighting the critical role of lipid metabolism in maintaining neural homeostasis and function. Neurodegenerative diseases-including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)-are characterized by progressive neuronal dysfunction and myelin degeneration. These conditions predominantly affect aging populations and represent a growing global health challenge. While aging remains the primary risk factor, compelling evidence now underscores the involvement of dysregulated lipid metabolism in their pathogenesis. However, the precise mechanisms linking dynamic lipid metabolic alterations to disease progression remain incompletely elucidated. This review systematically examines the multifaceted contributions of lipid metabolism to neurodegenerative processes and critically assesses emerging therapeutic strategies that target lipid pathways for the treatment of neurodegenerative disorders.},
}

@article {pmid41237982,
year = {2025},
author = {Streltsov, VA and Ganio, KE and Nuttall, SD and Hernandez, JA and Dennys, CN and Crouch, PJ and Estevez, AG and Franco, MC and Beckman, JS and Roberts, BR},
title = {The structure, redox chemistry and motor neuron toxicity of heterodimeric zinc-deficient SOD1-implications for the toxic gain of function observed in ALS.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107189},
doi = {10.1016/j.nbd.2025.107189},
pmid = {41237982},
issn = {1095-953X},
abstract = {A subset of familial cases of amyotrophic lateral sclerosis (fALS) are caused by mutations to copper, zinc superoxide dismutase (Cu, Zn SOD1). Over 200 mutations to SOD1 that have been associated with fALS and the majority of these mutations are dominantly inherited. Thus, individuals are heterozygous and express both wild-type SOD1 and the mutant form of the protein. Paradoxically, the motor neuron disease accelerates in rodent models that mimic the co-expression of wild-type SOD1 with mutant fALS SOD1. Previously, we have shown that the loss of zinc from SOD1 triggers motor neuron death in culture due to a gained, redox activity catalyzed by the active-site copper. Furthermore, motor neuron toxicity of zinc-deficient SOD1 is enhanced by wild-type Cu, Zn SOD1. Because SOD1 exists as a non-covalent dimer, the enhanced toxicity might result from stabilization of the heterodimeric interface between zinc-deficient SOD1 and Cu, Zn-SOD1. However, experimentation with the heterodimer is difficult because SOD1 subunits exchange in minutes. To better characterize the role of dimer stabilization on the enhanced toxicity of fALS mutant SOD1 by wild type SOD1, we genetically tethered a zinc-deficient SOD1 subunit with a Cu, Zn SOD1 subunit with a 16-residue linker. The x-ray structure of the tethered heterodimer showed that the zinc-deficient subunit adopts a wild-type-like conformation and is not misfolded. The heterodimer intermediate also produced peroxynitrite from nitric oxide, and the tethered SOD1 was strikingly toxic to primary cultures of motor neurons. This work supports the concept that zinc-deficient SOD1 is a likely toxic intermediate in ALS. Furthermore, the wild-type allele in human familial-SOD1 ALS patients may physically contribute to the dominant inheritance of SOD1 mutations through heterodimer formation.},
}

@article {pmid41236695,
year = {2025},
author = {Ciocarlan, A and Shvetsova, M and Aricu, A and Lungu, L and Peshkova, A and Zinicovscaia, I and Deleanu, M and Duca, G},
title = {Comparative Study of Nicotine Content in Moldavian Tobacco by UV-Vis Spectrophotometry and UHPLC and their Mineral Composition by ICP-OES.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {41236695},
issn = {1559-0720},
abstract = {Tobacco is one of the oldest cultures known to mankind for more than 5000 years. Despite the proven harm by smoking, the number of smokers in Moldova is growing, making the quality control of tobacco products an important task. This study focused on the quantification of nicotine and the determination of the mineral composition in autochthonous Moldavian tobacco selections. Ultraviolet-visible (UV-Vis) spectroscopy and ultrahigh performance liquid chromatography (UHPLC) were applied for quantification of nicotine in ten tobacco varieties (Molovata, Trapezond 209, Doina 210, Moldavschi 237, Virginia 263, Moldavschi 272, Burley 320, Virginia 401, Moldavschi 456, Jubileu M) and Nicotiana rustica L. species of Moldavian origin. The nicotine content determined by UV-Vis analysis ranged from 1.24% to 2.74%, while UHPLC analysis yielded a range of 0.97% to 2.16% and the difference is due to the higher selectivity and accuracy of the UHPLC method. A total of 14 chemical elements, Al, S, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Sr, Cd, Ba and Hg, were identified in tobacco varieties by inductively coupled plasma-optical emission spectrometry. The mean elements content in tobacco leaves samples was the following: Al (1390 ± 795 mg/kg), S (3043 ± 749 mg/kg), V (1.9 ± 1.1 mg/kg), Cr (2.5 ± 1.3 mg/kg), Mn (126 ± 21 mg/kg), Fe (1077 ± 579 mg/kg), Co (0.39 ± 0.19 mg/kg), Ni (2.4 ± 0.9 mg/kg), Cu (3.9 ± 1.5 mg/kg), Zn (13.8 ± 3.3 mg/kg), Sr (164 ± 17 mg/kg), Cd (1.4 ± 0.3 mg/kg), Ba (62 ± 12 mg/kg) and Hg (0.04 ± 0.005 mg/kg). Principal components analysis, applied for element grouping, revealed two groups of elements, which can be associated with elements uptake by plants from soil, agricultural practices, fuel combustion, and vehicles and road dust.},
}

@article {pmid41234489,
year = {2025},
author = {Chan, JM and Romano, C and Lee, AY and Wang, S and Lombardo, D and Kamdar, F and Dora, M and Khan, S and Mammen, P and Kimonis, V},
title = {Cardiomyopathy in valosin-containing protein multisystem proteinopathy: Evaluation, diagnosis, and management.},
journal = {American heart journal plus : cardiology research and practice},
volume = {60},
number = {},
pages = {100644},
pmid = {41234489},
issn = {2666-6022},
abstract = {Valosin-containing protein (VCP)-associated multisystem proteinopathy is a rare, autosomal dominant disease that affects skeletal muscle, bone, central nervous system, and the heart. While VCP mutations are well established as causing inclusion body myopathy, Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis, their role in cardiomyopathy remains underrecognized. This review aims to evaluate the pathophysiology, diagnostic approach, and management of VCP-associated cardiomyopathy to provide a framework for clinical care and future research. Emerging evidence from animal models and human case studies suggests that VCP dysfunction disrupts cardiomyocyte homeostasis, impairs protein degradation, and alters mitochondrial function, leading to maladaptive cardiac remodeling and susceptibility to dilated or hypertrophic cardiomyopathy. Echocardiographic studies in patients with VCP variants reveal a significant prevalence of diastolic dysfunction, conduction abnormalities, and variable degrees of systolic impairment. Despite these findings, there are no standardized guidelines for the diagnosis and management of VCP-associated cardiomyopathy. Current treatment strategies are extrapolated from heart failure guidelines, incorporating neurohormonal blockades with angiotensin-converting enzyme inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. Our review highlights the need for systematic screening protocols, genotype-phenotype correlation studies, and the development of targeted therapies. Future research should focus on identifying biomarkers for early detection, elucidating the molecular mechanisms underlying cardiac dysfunction, and assessing the efficacy of novel treatment strategies. Recognizing VCP-associated cardiomyopathy as a distinct clinical entity will facilitate earlier diagnosis, improve patient outcomes, pave the way for disease-specific therapeutic interventions and insights into the mechanism for isolated cardiomyopathy.},
}

@article {pmid41234281,
year = {2025},
author = {Polito, V and Howarth, S and Roberts, A and Arbige, S},
title = {Does transliminality predict subperceptual information processing?.},
journal = {Neuroscience of consciousness},
volume = {2025},
number = {1},
pages = {niaf044},
pmid = {41234281},
issn = {2057-2107},
abstract = {Anomalous experiences, such as hallucinations and mystical experiences, are positively related to delusional ideation, religiosity, and paranormal beliefs. Some researchers argue that these relationships are explained by 'transliminality'-a trait describing sensitivity to stimuli crossing the threshold into consciousness. This claim suggests such beliefs may be attempts to interpret barely perceptible stimuli. The strongest evidence for this comes from Crawley et al. (2002), who found transliminality was associated with responses to subperceptual primes. In the current study, we attempted a high-powered replication of Crawley et al.'s findings that: (i) transliminality predicts identification of subperceptual visual primes, and (ii) this relationship is explained by stimulus sensitivity rather than response bias. Participants completed a transliminality measure and an online card guessing task in two parts. In part one, participants were shown 100 images of playing cards and asked to guess which of five shapes was on the other side of the card. A total of 50 trials contained a subperceptual prime in the form of a target shape, and 50 trials were unprimed. In part two, participants were shown 20 primed and 20 unprimed trials. They were told a prime was sometimes present and asked to report whether they noticed this on each trial. We found strong evidence against an association between transliminality and prime perception in both tasks. These results do not support conceptualizing transliminality as a measure of subperceptual processing capabilities. This study did demonstrate the feasibility of conducting research involving rapidly presented visual stimuli in an online setting.},
}

@article {pmid41234248,
year = {2025},
author = {Evans, M},
title = {Race, Crime, and Lending Risk in Chicago: The Relevance of Crime and Disorder for HOLC's Neighborhood Assessments.},
journal = {Race and social problems},
volume = {17},
number = {4},
pages = {307-321},
pmid = {41234248},
issn = {1867-1748},
abstract = {UNLABELLED: While scholars have documented the importance of race for decisions on lending risk and value in the U.S. housing market, less is known about how crime shaped lending risk assessments or how a neighborhood's racial composition influenced appraisers' perceptions of crime and disorder. Drawing on the Home Owners' Loan Corporation (HOLC) residential security maps, this study examines appraisers' narratives around neighborhood crime and disorder, how observed neighborhood conditions shaped these narratives, and how both observed crime and perceptions of disorder influenced decisions on lending risk. Using the case of Chicago, this study integrates multiple historical datasets, including the HOLC residential security maps and their corresponding neighborhood area descriptions, the 1940 Census, and data on criminal activity reflected through Clifford Shaw et al.'s residence of male offenders map and Frederic Thrasher's gangland activity map. Findings suggest that perceptions of crime and disorder are largely driven by a neighborhood's Black racial composition, independent of observed measures of crime. While both observed crime and a neighborhood's Black racial composition predicted lending risk assessments, appraisers' perceptions of disorder did not. The results indicate that although HOLC appraisers' perceptions of crime and disorder were racially motivated, their biased perceptions did not exert a unique, independent influence on their decisions to redline Black neighborhoods. Rather, racial discrimination was already explicitly embedded into their neighborhood valuation practices. This study provides new insights into the historical roots of neighborhood stigmatization and institutional disinvestment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12552-025-09442-4.},
}

@article {pmid41233462,
year = {2025},
author = {Cattaneo, M and Bonanomi, M and Chirizzi, C and Malacarne, C and Giagnorio, E and Farinazzo, G and Bonanno, S and Porro, D and Lauria, G and Metrangolo, P and Bombelli, FB and Gaglio, D and Marcuzzo, S},
title = {Metabolic reprogramming in amyotrophic lateral sclerosis ependymal stem cells by FM19G11 nanotherapy.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39847},
pmid = {41233462},
issn = {2045-2322},
support = {1157625//Fondazione Regionale per la Ricerca Biomedica POR FESR/ ; IR0000010//Italian Ministry of University and Research (MIUR)-ELIXIR-IT through the empowering project ELIXIRNextGenIT/ ; T4-AN-09//CALabria HUB per Ricerca Innovativa ed Avanzata/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy ; Animals ; Mice ; Male ; *Nanoparticles/chemistry ; *Ependyma/metabolism/cytology/pathology/drug effects ; *Stem Cells/metabolism/drug effects ; Metabolomics ; Metabolome/drug effects ; Mice, Transgenic ; Disease Models, Animal ; *Cellular Reprogramming/drug effects ; Motor Neurons/metabolism ; Humans ; Metabolic Reprogramming ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons in the motor cortex, brainstem, and the spinal cord. In response to neurodegeneration, spinal cord exhibits ineffective regenerative attempt, thus suggesting that therapeutic strategies aimed at enhancing regenerative capacity of ependymal stem/progenitor cells (epSPCs), residing in the spinal cord, could promote neurogenesis. Dysregulated levels of metabolites might disturb epSPC differentiation, and their restoration might favour neurogenesis. This study aimed to investigate the metabolomic profile of epSPCs from ALS mice to identify altered metabolites as novel therapeutic targets for precision treatment. We performed a metabolome analysis to investigate changes in epSPCs from ALS compared to control male mice (B6SJL-Tg (SOD1*G93A)1Gur/J) and treated the epSPCs with FM19G11-loaded nanoparticles (NPs) to reestablish metabolic balance. Metabolomics analysis revealed significant changes in ALS epSPCs compared to controls. In vitro treatment with FM19G11-loaded nanoparticles (NPs) restored key metabolic networks, particularly in pathways related to glucose, glutamate and glutathione metabolism. These findings highlight the potential of FM19G11-loaded NPs to revert metabolic dysregulation in ALS epSPCs, providing a basis for innovative metabolic therapies and precision medicine approaches to counteract motor neuron degeneration in ALS and other motor neuron diseases.},
}

*Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy
Animals
Mice
Male
*Nanoparticles/chemistry
*Ependyma/metabolism/cytology/pathology/drug effects
*Stem Cells/metabolism/drug effects
Metabolomics
Metabolome/drug effects
Mice, Transgenic
Disease Models, Animal
*Cellular Reprogramming/drug effects
Motor Neurons/metabolism
Humans
Metabolic Reprogramming

@article {pmid41233180,
year = {2025},
author = {Fukutake, T},
title = {[Charcot and Sherlock Holmes: The Contemporary Rise of Neurodiagnostics and Detective Science and Its Significance].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {11},
pages = {1221-1229},
doi = {10.11477/mf.188160960770111221},
pmid = {41233180},
issn = {1881-6096},
mesh = {History, 19th Century ; Humans ; *Neurology/history ; History, 20th Century ; *Nervous System Diseases/diagnosis/history ; },
abstract = {Jean-Martin Charcot (1825-1893) gradually shifted his medical interest from internal medicine to neurology. Furthermore, he established neurodiagnostic methods that emphasized observation, such as in tabes dorsalis, and summarized core neurological diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and multiple sclerosis in a clinical-anatomical/pathological manner. For his contributions, he is known as the father of neurology. He then worked to elucidate hysteria. Sir Arthur Conan Doyle (1859-1930), born more than 30 years later, opened an ophthalmology clinic after earning his doctorate in research on tabes dorsalis. However, he then changed direction to writing books, such as Sherlock Holmes stories, and created full-fledged detective studies. Later, he shifted his focus to spiritualism, with an interest in Charcot's hypnotism. Although their careers are similar, there is no direct connection between Charcot's neurological studies and Conan Doyle's detective stories. However, neurodiagnostic and detective studies emerged in the second half of the 19th century at the same time, although they shared a commonality in content, in that they both emphasized observation and deduction without preconceptions. This contemporaneity was inevitable, as the background to this was the emergence of a middle class and urbanization in the era of war and revolution under capitalism after the Industrial Revolution.},
}

History, 19th Century
Humans
*Neurology/history
History, 20th Century
*Nervous System Diseases/diagnosis/history

@article {pmid41233177,
year = {2025},
author = {Ando, T and Fukutake, T},
title = {[Charcot and Spinal Cord Disease].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {11},
pages = {1194-1200},
doi = {10.11477/mf.188160960770111194},
pmid = {41233177},
issn = {1881-6096},
mesh = {Humans ; *Spinal Cord Diseases/history/pathology/diagnosis ; History, 19th Century ; *Arthropathy, Neurogenic/history ; },
abstract = {This paper outlines the contributions of Jean-Martin Charcot (1825-1893) to the study of spinal cord diseases. Charcot pioneered the anatomoclinical method, which correlated clinical symptoms with pathological findings through detailed observations and autopsies. He elucidated the dual structure of the motor system-gray and white matter-and established the clinical and pathological framework of amyotrophic lateral sclerosis, distinguishing it from other disorders. He also contributed to the understanding of tabes dorsalis by linking sensory ataxia to lesions of the dorsal columns and roots, and identified neurogenic joint disease (Charcot joint). Furthermore, Charcot described compressive myelopathy based solely on clinical signs and postmortem findings, highlighting the importance of symptom distribution, such as hand muscle atrophy, in the differential diagnosis. His legacy continues to influence modern neurology, reinforcing the value of precise clinical observation in the diagnostic process.},
}

Humans
*Spinal Cord Diseases/history/pathology/diagnosis
History, 19th Century
*Arthropathy, Neurogenic/history

@article {pmid41172876,
year = {2025},
author = {Li, C and Fan, W and Wu, G},
title = {Comment on "LMO2 confers value as a potential immunotherapy marker in pan-cancer analysis and inhibits progression of clear cell renal cell carcinoma".},
journal = {Translational oncology},
volume = {63},
number = {},
pages = {102588},
pmid = {41172876},
issn = {1936-5233},
abstract = {• Commendation of LMO2′s role: Wang et al.'s study demonstrates LMO2 as a promising immunotherapy marker and tumor suppressor in clear cell renal cell carcinoma (ccRCC), supported by multi-omics integration and mechanistic insights into the ZC3H13-m6A-LMO2-GATA2-BEX1-NF-κB axis. • Methodological enhancements suggested: Implement rigorous statistical corrections (e.g., Bonferroni or FDR for TCGA data) and adopt immunocompetent models (e.g., syngeneic ccRCC grafts in C57BL/6 mice) to improve robustness and translational relevance. • Direct validation required: Verify protein interactions (e.g., LMO2-GATA2 binding via co-immunoprecipitation) and m6A modification sites in LMO2 mRNA to strengthen mechanistic claims. • Functional testing for immunotherapy: Conduct in vitro co-culture or in vivo immunotherapy response models to causally link LMO2 to immune regulation and validate its biomarker potential. • Future innovation pathways: Explore epigenetic layers (e.g., m1A or m5C modifications via nanopore sequencing), apply single-cell multi-omics, and advance preclinical studies combining LMO2-targeted therapies with immune checkpoint inhibitors.},
}

@article {pmid41233174,
year = {2025},
author = {Uchihara, T},
title = {[Success and Failure during Three Centuries of Charcot's Clinical Neuropathology: From Amyotrophic Lateral Sclerosis to Functional Neurological Disorders].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {11},
pages = {1165-1175},
doi = {10.11477/mf.188160960770111165},
pmid = {41233174},
issn = {1881-6096},
mesh = {*Amyotrophic Lateral Sclerosis/history/pathology ; Humans ; History, 19th Century ; History, 20th Century ; *Nervous System Diseases/history/pathology ; Hysteria/history ; *Neuropathology/history ; },
abstract = {Clinical neuropathology was advanced by Charcot at la Salpêtrière Hospital in the 19th century. The lower and upper motor signs of amyotrophic lateral sclerosis were corroborated at autopsy by degeneration of the anterior horns and lateral columns, respectively. The redefinition of paralysis agitans as Parkinson's disease was substantiated in the 20th century through a series of pathological, biochemical, and genetic studies that provided definitive, museum-like evidence of neurological diseases. In contrast to these scientific achievements, the phenomenology of hysteria was publicly evaluated and recognized in front of the audiences that included non-medical professionals. This theater-like format, which encouraged interaction between patients and spectators, might have influenced the clinical presentation of hysteria and complicated its interpretation. Contrary to Charcot's expectations, attempts to identify the causative lesions of hysteria were unsuccessful. Paradoxically, however, this failure paved the way for the development of dynamic psychiatry by Freud and Janet, and later, the conceptualization of functional neurological disorders in the 21st century.},
}

*Amyotrophic Lateral Sclerosis/history/pathology
Humans
History, 19th Century
History, 20th Century
*Nervous System Diseases/history/pathology
Hysteria/history
*Neuropathology/history

@article {pmid41233143,
year = {2025},
author = {Cook, BE and McLaren, DG and Sullivan, JM and El Fakhri, G and Yokell, DL and Freeman, MW and Currier, N and Oestergaard, ME and Dobson, H and Hesterman, J and Salem, N and Nestorov, I and Monine, M and Martarello, L and Evans, KC and Fradette, S and Ferguson, TA and Graham, D and Passamonti, L},
title = {Central Nervous System Biodistribution and Pharmacokinetics of Radiolabeled Tofersen in Rodents, Nonhuman Primates, and Humans.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.125.270731},
pmid = {41233143},
issn = {1535-5667},
abstract = {Antisense oligonucleotides (ASOs) are an important therapeutic modality across several therapeutic areas, offering currently available and potential future treatment options for patients. ASO pharmacokinetics, biodistribution, and regional brain uptake are not fully characterized, particularly in humans. Here, we report preclinical studies and the first-in-human imaging trial measuring the biodistribution of [[99m]Tc]Tc-MAG3-tofersen. The tracer was designed to be a proxy for tofersen (Qalsody; Biogen), an ASO approved for the treatment of amyotrophic lateral sclerosis in adults who have a variant in the SOD1 gene (SOD1-ALS). Methods: Tofersen was conjugated to a MAG3 moiety, which chelates [99m]Tc to yield [[99m]Tc]Tc-MAG3-tofersen. [[99m]Tc]Tc-MAG3-tofersen and unlabeled tofersen were intrathecally injected in rats, nonhuman primates (NHPs), and healthy human volunteers (n = 3) via lumbar puncture, followed by SPECT/CT imaging. Tofersen was coadministered at a therapeutic dose. The tracer [[99m]Tc]Tc-MAG3-tofersen was prepared with greater than 99% purity. Results: Findings in rats demonstrated that [[99m]Tc]Tc-MAG3-tofersen was a proxy measure of unlabeled tofersen, and dosimetry was calculated from NHP imaging data. In a clinical study, unlabeled tofersen coadministered with a microdose of [[99m]Tc]Tc-MAG3-tofersen (≤129.5 MBq [3.5 mCi]) was well-tolerated. Human dosimetry estimates were within safe radiation dose levels. Imaging showed consistent distribution of radiolabeled ASO throughout the spinal cord and brain across species, with clearance patterns diverging in humans. Although rats and NHPs demonstrated declining brain concentrations over the study duration, human brain uptake increased during the first 4 h after injection. Additionally, tracer clearance from the spine in rodents and NHPs plateaued after 6 h but continued to decrease in humans. Radiolabeled ASO clearance from the lumbar spine was observed across all species, with peripheral clearance mediated primarily through the liver and kidneys. Broad uptake of the ASO in the brain and spinal cord is consistent with the clinical effects of tofersen observed in individuals with the SOD1-ALS variation. Conclusion: In preclinical and human SPECT/CT studies, [[99m]Tc]Tc-MAG3-tofersen mirrored unlabeled drug distribution, showing broad spinal cord and brain uptake, with some differences in kinetics among species.},
}

@article {pmid41232736,
year = {2025},
author = {Papathomas, A},
title = {Abandoning The Big Mick: A commentary on Smith et al.'s 25 years of qualitative research in sport and exercise psychology.},
journal = {Psychology of sport and exercise},
volume = {},
number = {},
pages = {103025},
doi = {10.1016/j.psychsport.2025.103025},
pmid = {41232736},
issn = {1878-5476},
abstract = {This essay provides a reflective commentary on Smith et al.'s "25 years of qualitative research in sport and exercise psychology" piece. Alongside summarising the primary insights of their review, I seek to situate current qualitative sport and exercise work within psychology's long-standing quest for scientific legitimacy. Including a whistle-stop tour of the history of psychology, I argue that a form of disciplinary imposter syndrome has shaped psychological science and continues to influence contemporary qualitative research. The consequences of this scientism are a trend towards formulaic, risk-averse, qualitative inquiry-by-numbers. Extending Brinkmann's (2015) McDonaldization metaphor, I propose McDowellisation; which positions qualitative methodolatry as motivated by a quest to appear more objective, more scientific, and ultimately more like our "real science" quantitative cousins. The danger is that the field of qualitative research foregoes the very qualities that inspired its rise. My optimistic conclusion is to follow the lead of those scholars that have rejected rigid fast-food processes in favour or rigorous, reflexive, interpretive work across a broad range of methodologies.},
}

@article {pmid41231952,
year = {2025},
author = {Lu, YN and Li, X and Hayes, L and Zhao, XF and Wang, J},
title = {MARK2 regulates C9orf72 repeat-associated non-AUG translation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {46},
pages = {e2514182122},
doi = {10.1073/pnas.2514182122},
pmid = {41231952},
issn = {1091-6490},
mesh = {*C9orf72 Protein/genetics/metabolism ; Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Protein Biosynthesis ; Frontotemporal Dementia/genetics/metabolism/pathology ; *Protein Serine-Threonine Kinases/metabolism/genetics ; DNA Repeat Expansion ; Eukaryotic Initiation Factor-2/metabolism/genetics ; Neurons/metabolism ; Signal Transduction ; Disease Models, Animal ; },
abstract = {Protein homeostasis is exquisitely regulated through processes involving protein synthesis essential for cellular health and disease prevention. Repeat-associated non-AUG (RAN) translation at expanded GGGGCC repeats in the C9orf72 gene produces dipeptide repeat (DPR) proteins that are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms promoting this noncanonical translation remain incompletely understood. Here, we identify microtubule affinity-regulating kinase 2 (MARK2) as a key eIF2α kinase that enhances RAN translation under proteotoxic stress. We show that MARK2-eIF2α signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues. Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions. These findings position MARK2 as a critical stress-sensing cytosolic regulator that promotes repeat-associated noncanonical translation and associated toxicity.},
}

*C9orf72 Protein/genetics/metabolism
Animals
Humans
Mice
*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology
*Protein Biosynthesis
Frontotemporal Dementia/genetics/metabolism/pathology
*Protein Serine-Threonine Kinases/metabolism/genetics
DNA Repeat Expansion
Eukaryotic Initiation Factor-2/metabolism/genetics
Neurons/metabolism
Signal Transduction
Disease Models, Animal

@article {pmid41231679,
year = {2025},
author = {Wang, T and Yu, G and Wu, Y and Wang, S and Zhu, Y and Li, H and Li, H and Yu, G},
title = {A Chiral Electrocatalyst for High-Performance Aluminum-Sulfur Battery.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.5c14506},
pmid = {41231679},
issn = {1520-5126},
abstract = {Aluminum-sulfur (Al-S) batteries are regarded as promising electrochemical energy storage systems due to their high energy density, cost-effectiveness, and environmental compatibility. However, their practical application is hindered by sluggish sulfur conversion kinetics. Although certain achievements have been made, conventional strategies for modulating the spin state of electrocatalysts, such as heteroatom doping or lattice strain engineering, exhibit inherent limitations in optimizing electron orbital interactions. Herein, we report a novel MoS2 electrocatalyst with spin orientation manipulation achieved through the chiral-induced spin selectivity (CISS) effect. This approach couples chiral molecules with layered MoS2 to regulate the spin polarization of molybdenum atoms, thereby enhancing the sulfur redox kinetics without relying on chemical modification. Electrochemical analyses demonstrated that the cathode with chiral MoS2 delivers a reversible specific capacity of ∼700 mAh g[-1] at 2 A g[-1] over 3000 cycles, accompanied by improved sulfur utilization efficiency. This work not only provides a paradigm for designing high-performance electrocatalysts in sulfur-based batteries but also highlights the critical role of spin effects in electrocatalytic systems, offering new perspectives for the innovation of electrocatalyst materials in batteries.},
}

@article {pmid41229731,
year = {2025},
author = {Nasir, AR and Delpirou Nouh, C},
title = {TDP-43-proteinopathy at the crossroads of tauopathy: on copathology and current and prospective biomarkers.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1671419},
pmid = {41229731},
issn = {1662-5102},
abstract = {Though usually described as isolated models, neurodegenerative diseases exist in a significant proportion of cases as mixed pathologies, particularly in older adults. The presence of co-pathologies may influence phenotypes and progression, and the correct classification in vivo has proven to be challenging, particularly without proper biomarker panels. Recent breakthroughs in biomarkers, enabling earlier detection in Alzheimer's disease and, more recently, in synuclein-related diseases, are promising as a first step toward the wider detection of all other abnormal proteins involved in neurodegenerative diseases. Over the past decade, the growing body of research on TDP-43 pathology has led to considering TDP-43 as a potential major contributor to the neurodegenerative process. TDP-43's normal function is essential for neuronal survival and the regulation of RNA processing and cellular stress response; abnormal TDP-43 protein leads to altered cell function and survival. TDP-43 is notably the neuropathological hallmark of amyotrophic lateral sclerosis (ALS) as well as some form of frontotemporolobar degeneration (FTLD). Tauopathies, divided in primary or secondary tauopathies cover other forms of FTLD including Pick disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) but also non-FTLD diseases like Alzheimer's disease (AD) which can be classified as secondary tauopathy. As the importance of copathology is more and more recognized, TDP-43 is also frequently observed in conjunction with other proteinopathies, possibly with a synergistic or additive effect, although the exact mechanism is still unclear. In Alzheimer's disease, the limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) co-occurrence with Alzheimer's disease neuropathologic changes (ADNC) lead to a more rapid course. Although there are currently no approved and validated biomarkers for its early detection, several promising tools, including neuroimaging and biofluid biomarkers, are under development, offering hope for the earlier detection of TDP-43 pathology in vivo. Accurate identification of the underlying proteinopathies and pathological processes could lead to better diagnosis and classification, more precise selection of clinical trial candidates, and ultimately, disease-specific tailored treatments.},
}

@article {pmid41229403,
year = {2025},
author = {Ackrivo, J and Bracy, D and Elman, LB and Hansen-Flaschen, J and Simmons, Z and Pasinelli, P and Heiman-Patterson, T and Kawut, SM and Lane-Fall, MB},
title = {How Patients With Amyotrophic Lateral Sclerosis Perceive Respiratory Interventions: A Mixed-Methods Study to Inform Implementation Efforts.},
journal = {Neurology. Clinical practice},
volume = {15},
number = {6},
pages = {e200560},
pmid = {41229403},
issn = {2163-0402},
abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that commonly leads to respiratory failure. Early respiratory interventions that may improve symptoms and outcomes are underused when prescribed. We sought to characterize patient perspectives and preferences for respiratory care to enable identification of implementation strategies to improve the uptake of ALS respiratory interventions.

METHODS: A prospective multicenter mixed-methods observational study was conducted using semistructured interviews of participants recently diagnosed with ALS at 4 academic centers in the United States. Eligible patients were those with an ALS diagnosis in the previous 12 months, forced vital capacity <80% predicted normal, or presence of dyspnea or orthopnea.

RESULTS: Twenty-four patients with ALS were interviewed. Ten participants were using some form of respiratory therapy, including 8 using noninvasive ventilation (NIV). The most endorsed factors related to openness to initiate respiratory therapy were a doctor's recommendation and abnormal pulmonary function test results. The most commonly endorsed preferences for learning about a respiratory device included kinesthetic and reading. Descriptions of lung volume recruitment were received with more openness than of NIV. For those not prescribed NIV, reasons for hesitancy to start NIV included fear of mask discomfort, claustrophobia, and lack of perceived benefit. Perceptions about NIV differed in participants identifying as "proactive" rather than "reactive" with their health.

DISCUSSION: Patients in the first year after ALS diagnosis have variable receptiveness to respiratory care. These patients place different weights on the factors supporting NIV and may have different educational needs about respiratory interventions. Implementation strategies for respiratory care interventions in ALS should consider patients' motivations for adopting interventions such as NIV, provide multiple educational formats, and identify barriers to incorporating home respiratory care.},
}

@article {pmid41229135,
year = {2025},
author = {Vacchiano, V and Ragucci, C and Rizzo, G and Di Stasi, V and Pastorelli, F and Rinaldi, R and Provini, F and Postiglione, E and Fiorentino, A and Carelli, V and Liguori, R},
title = {Nerve Root Enhancement and Elevated Cerebrospinal Fluid Protein in Four Patients With SOD1-Linked Amyotrophic Lateral Sclerosis.},
journal = {European journal of neurology},
volume = {32},
number = {11},
pages = {e70434},
pmid = {41229135},
issn = {1468-1331},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid/pathology/physiopathology/diagnosis ; Male ; *Superoxide Dismutase-1/genetics ; Middle Aged ; Female ; Magnetic Resonance Imaging ; Aged ; *Spinal Nerve Roots/pathology/diagnostic imaging ; Adult ; *Cerebrospinal Fluid Proteins/cerebrospinal fluid ; },
abstract = {INTRODUCTION: The superoxide dismutase type 1 (SOD1) gene has been implicated in both sporadic and familial forms of amyotrophic lateral sclerosis (ALS). We report four ALS cases carrying pathogenic or likely pathogenic SOD1 variants, characterized by albuminocytologic dissociation and nerve root enhancement.

METHODS: We present the results of the diagnostic work-up, including lumbosacral magnetic resonance imaging (MRI) with gadolinium, electromyography (EMG), and cerebrospinal fluid (CSF) analysis. We also assessed the relationship between the albumin quotient (Q-Alb)-an index of blood-brain barrier (BBB) dysfunction-and the disease progression rate (DPR) in 12 SOD1-linked ALS patients (including the four described above) and in a cohort of 137 non-genetic ALS (NgALS) cases.

RESULTS: The four patients presented with spinal onset (progressive lower limb weakness). The EMG ultimately showed diffuse subacute neurogenic changes, while CSF analysis revealed albuminocytologic dissociation. Lumbosacral MRI demonstrated contrast enhancement of the cauda equina roots. Immunomodulatory treatment was administered due to suspected immune-mediated neuropathy, but all patients continued to deteriorate. Genetic testing revealed pathogenic or likely pathogenic variants in the SOD1 gene, confirming the diagnosis of ALS. CSF Q-Alb and protein levels were similarly distributed between SOD1-linked and NgALS patients. Q-Alb and CSF protein levels showed a positive correlation with DPR in SOD1-linked patients (Rho = 0.625, p = 0.03; Rho = 0.755, p = 0.005), but not in NgALS patients.

CONCLUSION: Albuminocytologic dissociation and nerve root enhancement may occur in SOD1-related ALS, expanding the spectrum of atypical ALS phenotypes.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid/pathology/physiopathology/diagnosis
Male
*Superoxide Dismutase-1/genetics
Middle Aged
Female
Magnetic Resonance Imaging
Aged
*Spinal Nerve Roots/pathology/diagnostic imaging
Adult
*Cerebrospinal Fluid Proteins/cerebrospinal fluid

@article {pmid41228417,
year = {2025},
author = {de la Rubia Ortí, JE and Bargues-Navarro, G and Privado, J and Menarques-Ramírez, R and Sanchis-Sanchis, CE and Sancho-Castillo, S and Rubio, CP and Pardo-Marin, L and Benlloch, M and Martín-Ruiz, J},
title = {Dietary Vitamin Intake and Blood Biomarkers in Relation to Muscle Activation in Amyotrophic Lateral Sclerosis: A Cross-Sectional Study.},
journal = {Nutrients},
volume = {17},
number = {21},
pages = {},
pmid = {41228417},
issn = {2072-6643},
support = {2021-203-003//Catholic University of Valencia San Vicente Mártir/ ; },
mesh = {Humans ; Cross-Sectional Studies ; Biomarkers/blood ; *Amyotrophic Lateral Sclerosis/blood/physiopathology ; Male ; Female ; Middle Aged ; Aged ; *Muscle, Skeletal/physiopathology ; *Diet ; Aryldialkylphosphatase/blood ; Muscle Strength ; *Vitamins/administration & dosage ; Butyrylcholinesterase/blood ; },
abstract = {Background/Objectives: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor function, which affects mobility and leads to secondary complications, including altered dietary intake due to dysphagia, fatigue, and hypermetabolism, particularly affecting vitamin consumption, which are essential micronutrients for neuromuscular performance. The specific relationship between vitamin intake and muscle activation is not well understood in patients with ALS; thus, it is relevant to identify blood biomarkers that reflect muscle status. Methods: A cross-sectional study was conducted with 61 patients with bulbar- or spinal-onset ALS. The dietary intake of B vitamins (B1, B2, B6, B12, folate, and niacin); vitamins C, A, D, and E; and the B6/protein ratio were assessed using a seven-day dietary record and a Food Frequency Questionnaire. Blood concentrations of butyrylcholinesterase (BuChE), albumin, haptoglobin, C-reactive protein (CRP), and paraoxonase 1 (PON1) were determined. Basal muscle activation was measured using surface electromyography of the biceps brachii, triceps brachii, rectus femoris, and tibialis anterior muscles. Two confirmatory predictive models were developed to evaluate the effects of muscle damage and vitamin intake on muscle strength. Results: Arm muscle activation was negatively predicted by the B6/protein ratio (β = -0.33). Leg activation was positively predicted by vitamin B9 (β = 0.39) and B6/protein (β = 0.17) and negatively predicted by vitamin A (β = -0.24). For biomarkers, albumin (β = 0.18) and PON1 (β = 0.28) positively predicted activation. For legs, albumin predicted activation (β = 0.31), whereas BuChE and haptoglobin predicted negative activation (β = -0.32 and β = -0.15, respectively). Conclusions: Weak associations were observed in patients with ALS: vitamin B9 intake showed a modest association with leg activation, the B6/protein ratio exhibited inconsistent associations across muscle groups, and vitamin A showed a negative association with leg activation. Albumin demonstrated the most consistent association as a potential biomarker of muscle function. These findings are exploratory and require validation in larger, longitudinal studies.},
}

Humans
Cross-Sectional Studies
Biomarkers/blood
*Amyotrophic Lateral Sclerosis/blood/physiopathology
Male
Female
Middle Aged
Aged
*Muscle, Skeletal/physiopathology
*Diet
Aryldialkylphosphatase/blood
Muscle Strength
*Vitamins/administration & dosage
Butyrylcholinesterase/blood

@article {pmid41228121,
year = {2025},
author = {Wityshyn, S and Sanghai, N and Tranmer, GK},
title = {My Amyotrophic Lateral Sclerosis (ALS) Journey from Weakness to Diagnosis: A Journey of Hope.},
journal = {Healthcare (Basel, Switzerland)},
volume = {13},
number = {21},
pages = {},
pmid = {41228121},
issn = {2227-9032},
support = {202210PJT-495295/CAPMC/CIHR/Canada ; },
abstract = {Amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease is a progressive neurodegenerative disease that attacks and kills motor neurons in the brain and spinal cord, leading to muscle weakness and atrophy, eventually causing respiratory failure and death within 2-5 years after diagnosis. By 2040, the global population of individuals living with ALS is projected to approach 400,000. Since ALS was discovered by Charcot 150 years ago, only two drugs (Edaravone and Riluzole) have been available, offering modest clinical benefits in slowing disease progression. The increasing number of cases, along with the high costs of treatment and care, creates a growing burden on communities and the healthcare system. However, despite this rising burden and the failure of most clinical trials, the ALS community remains hopeful because of the patients themselves. ALS patients are the beating heart of the ALS community. They engage in efforts to improve lives for others, raising awareness through their real-life experiences, participating in research activities, fundraising, providing samples for research, and advocating strongly in front of communities and governments to raise funds. Their engagement is highly valuable, and collaboration with the research community is essential to understanding the disease process and developing effective disease-modifying therapies. Here, we share the story of Mrs. Sherry Wityshyn, an ALS patient and a true ALS warrior from Winnipeg, Manitoba, Canada. We believe her story will inspire and motivate the entire community to learn more about ALS. Furthermore, her story gives hope to everyone impacted. In this manuscript, we also emphasize the different stages of Sherry's journey from weakness to diagnosis and our efforts to share her enduring words with policymakers in the government.},
}

@article {pmid41227857,
year = {2025},
author = {Ma, H and Zong, M and Cedrick, N and Sun, Y and Wang, W and Yan, X and Liu, H and Zhu, P and Hua, M},
title = {Influence Mechanism of Chemically Modified Alumina on the Hydration of Gypsum-Based Self-Leveling Mortar.},
journal = {Materials (Basel, Switzerland)},
volume = {18},
number = {21},
pages = {},
pmid = {41227857},
issn = {1996-1944},
support = {42202034//National Natural Science Foundation of China/ ; 52508248//National Natural Science Foundation of China/ ; BK20220626//Natural Science Foundation of Jiangsu Province/ ; },
abstract = {This study investigates the effect of γ-aminopropyltriethoxysilane (KH550)-functionalized nano-active Al2O3 (KH-Al) on the properties of gypsum-based self-leveling mortar (GSL) prepared from industrial by-product gypsum. First, the effects of incorporating KH-Al at dosages of 0.05%, 0.1%, 0.25%, 0.5%, and 1% on the fluidity, setting time, and mechanical properties of GSL were analyzed. Subsequently, using X-ray diffraction (XRD), hydration heat analysis, thermogravimetric analysis (TG), and scanning electron microscopy (SEM), the influences of the nanomaterial on the mortar's morphology, hydration characteristics, and crystal forms of hydration products were thoroughly examined. Finally, by comparing the modified GSL with ordinary GSL, the mechanism of KH-Al's action on GSL was elucidated. The results demonstrate that nano-active Al2O3 modified with KH550 exhibits excellent dispersibility in the GSL paste. As the dosage of KH-Al increases, both the fluidity and setting time of GSL decrease. Upon incorporating KH-Al, the mechanical properties of GSL initially improve and then decline, with optimal mechanical performance observed at a 0.5% KH-Al addition. However, when the KH-Al dosage exceeds 0.5%, excess nano-active Al2O3 causes nanoparticle agglomeration, which impedes the hydration process. The nucleation effect of KH-Al promotes the formation of CŜH2 and AFt, refines the crystals of hydration products, and enhances the phase transformation efficiency of the mortar. These findings indicate that KH-Al has significant potential to improve the mechanical strength and hydration kinetics of gypsum mortar and provide theoretical support for the application of nanomaterials in gypsum building materials.},
}

@article {pmid41227379,
year = {2025},
author = {Spedding, M},
title = {Does Amyotrophic Lateral Sclerosis (ALS) Have Metabolic Causes from Human Evolution?.},
journal = {Cells},
volume = {14},
number = {21},
pages = {},
pmid = {41227379},
issn = {2073-4409},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Animals ; *Biological Evolution ; Mixed Function Oxygenases/metabolism/genetics ; },
abstract = {As so many drugs have failed in ALS a new approach is needed. The author proposes that recent human genetic variants may play major roles in the disease, changing metabolism. Evolution of hominins was accelerated 3-2.5 Mya, by cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) becoming a unitary pseudogene after a pathogenic infection, changing the sialome, and hence metabolism, brain development and neuromuscular junctions (NMJs). This was when hominins evolved to run in Africa and develop bigger brains. Deletion of CMAH in mice allows them to run for longer (~50%). The enzyme CMAH is critical for the sialome, particularly the neurotrophin GM1, a critical hub for viral infection and for NMJ stability, but which is lost from NMJs at the beginning of denervation, probably due a 10-fold increase in spinal cord glucosylceramidases (non-lysosomal GBA2). A GBA2 inhibitor, ambroxol, is currently in phase II for ALS. Human-specific GM1 may be critical for human evolution, lactate metabolism and ALS. Lipid/lactate metabolism changed to support these evolutionary changes and lactate is a major body/brain fuel, but compromised in ALS patients and a marker of disease progression. Recent progress in sports science involving lactate metabolism and human performance may also be relevant to ALS therapies, and incidence.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/genetics
Animals
*Biological Evolution
Mixed Function Oxygenases/metabolism/genetics

@article {pmid41226491,
year = {2025},
author = {Cappelli, S and Peradinovic, J and Mohovic, N and Mandal, P and Stuani, C and Longo, A and Cannon, JR and Baloni, P and Leoni, B and Krsmanovic, T and Stojanov, K and Apic, G and Russell, RB and Romano, M and Buratti, E and Munitic, I},
title = {Optineurin Shapes Basal and LPS-Induced Transcriptomes in BV2 Microglia.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
pmid = {41226491},
issn = {1422-0067},
support = {IP-2024-05-5814//Croatian Science Foundation/ ; IP-2018-01-8563//Croatian Science Foundation/ ; DOK-2018-09-7739//Croatian Science Foundation/ ; DOK-2020-01-8703//Croatian Science Foundation/ ; 861 329//SCiLS/ ; },
mesh = {*Lipopolysaccharides/pharmacology ; Animals ; *Microglia/metabolism/drug effects ; Mice ; *Transcriptome/drug effects ; Membrane Transport Proteins/genetics ; *Cell Cycle Proteins/genetics/metabolism ; *Transcription Factor TFIIIA/genetics/metabolism ; Cell Line ; Gene Expression Profiling ; Gene Expression Regulation/drug effects ; },
abstract = {The OPTN gene, which encodes the adaptor protein optineurin, is genetically linked to amyotrophic lateral sclerosis and frontotemporal dementia, diseases characterized by chronic microglial activation. Optineurin regulates inflammatory signaling, autophagy, and trafficking, but its role in microglia remains incompletely understood. Here, we used bulk RNA sequencing to profile CRISPR-Cas9-mediated optineurin knockout (KO) and wild-type BV2 microglia under basal conditions and upon LPS stimulation. At baseline, optineurin KO altered ~7% of the transcriptome, with a predominant downregulation of type I interferon and antiviral pathways, suggesting its role in maintaining basal immune readiness. LPS stimulation reprogrammed ~35% of genes in wild-type microglia, inducing immune effectors and suppressing cell cycle regulators, whereas in optineurin-deficient cells, the response was blunted with only ~16% of genes changing relative to the KO baseline. Furthermore, LPS-treated optineurin KO microglia notably diverged from LPS-treated wild-type cells, with ~26% differentially expressed genes (DEGs). This included impaired induction of inflammatory programs and persistence of cell cycle-associated transcripts. Most DEGs in LPS-treated KO cells were unique to this condition, highlighting optineurin-dependent pathways specific to inflammatory challenge. Overall, our study provides a systems-level framework for investigating optineurin in microglia and neurodegeneration, establishing it as a key regulator of the microglial transcriptome, with its loss reshaping innate immune and cell cycle programs.},
}

*Lipopolysaccharides/pharmacology
Animals
*Microglia/metabolism/drug effects
Mice
*Transcriptome/drug effects
Membrane Transport Proteins/genetics
*Cell Cycle Proteins/genetics/metabolism
*Transcription Factor TFIIIA/genetics/metabolism
Cell Line
Gene Expression Profiling
Gene Expression Regulation/drug effects

@article {pmid41226363,
year = {2025},
author = {Thakur, B and Tarazi, S and Doležalová, L and Behbahani, H and Darreh-Shori, T},
title = {Comparative Analysis of Cholinergic Machinery in Carcinomas: Discovery of Membrane-Tethered ChAT as Evidence for Surface-Based ACh Synthesis in Neuroblastoma Cells.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
pmid = {41226363},
issn = {1422-0067},
support = {//Åhlén-Foundation/ ; //Frimurarna Foundation/ ; //Ulla-Carin Linquist Foundation for ALS research/ ; AARG-24-1310046//Alzheimer´s Association/ ; //Dementia Foundation (Demensfonden)/ ; //Foundation for Old Servants (Gamla Tjänarinnor)/ ; //Karolinska Institutet´s Research Foundations/ ; //Olle Engkvist Byggmästare Foundation/ ; //Magnus Bergvalls Foundation/ ; //Gun and Bertil Stohnes Foundation/ ; ALF Med N 20200330//grant from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement/ ; #CAN2021/1469, and # 24 3793//the Swedish Cancer Society/ ; #221212, #241282 and #221383//the Stockholm Cancer Society/ ; },
mesh = {Humans ; *Neuroblastoma/metabolism/pathology ; *Acetylcholine/biosynthesis/metabolism ; Cell Line, Tumor ; *Choline O-Acetyltransferase/metabolism ; Choline/metabolism ; Cell Membrane/metabolism ; Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Signal Transduction ; },
abstract = {The cholinergic system is one of the most ancient and widespread signaling systems in the body, implicated in a range of pathological conditions-from neurodegenerative disorders to cancer. Given its broad relevance, there is growing interest in characterizing this system across diverse cellular models to enable drug screening, mechanistic studies, and exploration of new therapeutic avenues. In this study, we investigated four cancer cell lines: one of neuroblastoma origin previously used in cholinergic signaling studies (SH-SY5Y), one non-small cell lung adenocarcinoma line (A549), and two small cell lung carcinoma lines (H69 and H82). We assessed the expression and localization of key components of the cholinergic system, along with the cellular capacity for acetylcholine (ACh) synthesis and release. Whole-cell flow cytometry following membrane permeabilization revealed that all cell lines expressed the ACh-synthesizing enzyme choline acetyltransferase (ChAT). HPLC-MS analysis confirmed that ChAT was functionally active, as all cell lines synthesized and released ACh into the conditioned media, suggesting the presence of autocrine and/or paracrine ACh signaling circuits, consistent with previous reports. The cell lines also demonstrated choline uptake, indicative of functional choline and/or organic cation transporters. Additionally, all lines expressed the ACh-degrading enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), as well as the alfa seven (α7) nicotinic and M1 muscarinic ACh receptor subtypes. Notably, flow cytometry of intact SH-SY5Y cells revealed two novel findings: (1) ChAT was localized to the extracellular membrane, a feature not observed in the lung cancer cell lines, and (2) BChE, rather than AChE, was the predominant membrane-bound ACh-degrading enzyme. These results were corroborated by both whole-cell and surface-confocal microscopy. In conclusion, our findings suggest that a functional cholinergic phenotype is a shared feature of several carcinoma cell lines, potentially serving as a survival checkpoint that could be therapeutically explored. The discovery of extracellular membrane-bound ChAT uniquely in neuroblastoma SH-SY5Y cells points to a novel form of in situ ACh signaling that warrants further investigation.},
}

Humans
*Neuroblastoma/metabolism/pathology
*Acetylcholine/biosynthesis/metabolism
Cell Line, Tumor
*Choline O-Acetyltransferase/metabolism
Choline/metabolism
Cell Membrane/metabolism
Acetylcholinesterase/metabolism
Butyrylcholinesterase/metabolism
Signal Transduction

@article {pmid41226260,
year = {2025},
author = {Cutter, LR and Ren, AR and Banerjee, IA},
title = {Advances in Naturally and Synthetically Derived Bioactive Sesquiterpenes and Their Derivatives: Applications in Targeting Cancer and Neurodegenerative Diseases.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {21},
pages = {},
pmid = {41226260},
issn = {1420-3049},
support = {N/A//Henry Luce Foundation/ ; N/A//Fordham University/ ; },
mesh = {Humans ; *Sesquiterpenes/chemistry/pharmacology/therapeutic use/chemical synthesis ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neoplasms/drug therapy/metabolism ; Animals ; *Biological Products/chemistry/pharmacology/therapeutic use ; *Antineoplastic Agents/pharmacology/chemistry ; Antioxidants/chemistry/pharmacology ; },
abstract = {Sesquiterpenes are a diverse class of natural products that have garnered considerable interest for their potent bioactivity and structural variability. This review highlights advances in the derivatization of various sesquiterpene lactones, quinones, and alcohols, particularly in targeting cancer and neurodegenerative diseases. The structural modifications discussed include the incorporation of triazole, arylidene, or thiol moieties with eudesmane, guaiane, and germacranolide-type sesquiterpenes, among others. In addition, the conjugation with chemotherapeutics, as well as the development of nanoscale therapeutics, is also discussed. Such modifications have expanded the pharmacological potential, enabling improved specificity, cytotoxicity profiles, and sensitization toward tumor cells. Additionally, sesquiterpenes such as parthenolide (20), pterosinsade A (176), and cedrol (186) have demonstrated potential in mitigating neurodegeneration via anti-inflammatory and antioxidant signaling pathway-modulation mechanisms, with potential applications in Alzheimer's, Parkinson's, and ALS diseases. Mechanistic insights into redox signaling modulation, NF-κB inhibition, ROS regulation, and disruption of aggregation underscore their multifaceted modes of action. This review highlights the translational promise of sesquiterpene derivatives as dual-action agents for potential drug development in a plethora of diseases that are caused by inflammation and free-radical damage. It provides a framework for future rational design of multifunctional drug candidates and therapeutics.},
}

Humans
*Sesquiterpenes/chemistry/pharmacology/therapeutic use/chemical synthesis
*Neurodegenerative Diseases/drug therapy/metabolism
*Neoplasms/drug therapy/metabolism
Animals
*Biological Products/chemistry/pharmacology/therapeutic use
*Antineoplastic Agents/pharmacology/chemistry
Antioxidants/chemistry/pharmacology