@article {pmid41870813,
year = {2026},
author = {Upadhayay, S},
title = {Role of Pentacyclic Triterpenes in the Management of Neurological Disorders: An Insight into Molecular Mechanisms and Therapeutic Approaches.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41870813},
issn = {1559-1182},
mesh = {Humans ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; *Pentacyclic Triterpenes/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Neurological disorders represent major public health concerns globally, as they profoundly affect motor function, memory, and cognitive abilities, thus compromising patients' independence and quality of life. Despite extensive research, current treatment approaches predominantly offer palliative care, failing to hinder disease progression. The rising incidence of these disorders underscores an urgent necessity for more efficacious and disease-modifying therapies. According to findings, pentacyclic triterpenoids exhibit neuroprotective properties by inhibiting neuronal oxidative stress, neuroinflammation, apoptosis, and degeneration, making them promising candidates for targeting the underlying causes of neurodegeneration. Therefore, in this review, we explore natural and synthetic pentacyclic triterpenoids that exhibit neuroprotective effects by modulating signaling pathways, such as HMGB1, TLR4, NLRP3, NF-κB, Nrf2, PI3K, Akt, and CREB, which play crucial roles in regulating cell proliferation, differentiation, and neuronal plasticity. The present literature survey is performed by searching various keywords with several combinations: "pentacyclic triterpenes", "neurological disorders", Parkinson's Disease", "Huntington's Disease", "Alzheimer's Disease", "Multiple sclerosis", "Amyotrophic Lateral Sclerosis" "Epilepsy", "mitochondria dysfunction", "oxidative stress", "preclinical studies", "molecular mechanisms", and "clinical studies". Studies indicates that pentacyclic triterpenoids have a wide range of therapeutic potentials, current findings summarizes existing knowledge and examines the neuroprotective properties and potential molecular mechanisms of pentacyclic triterpenoids related with health benefits and neurological diseases. Available evidence suggests that pentacyclic triterpenoids possess the capacity to impede disease progression and may be beneficial in the treatment of neurological disorders. This review strengthens the understanding of pentacyclic triterpenoids and their molecular mechanisms, while also facilitating pharmaceutical discovery and development for neurodegenerative disorders.},
}

Humans
Animals
*Nervous System Diseases/drug therapy/metabolism
*Pentacyclic Triterpenes/therapeutic use/pharmacology
*Neuroprotective Agents/therapeutic use/pharmacology
Signal Transduction/drug effects
Oxidative Stress/drug effects

@article {pmid41868729,
year = {2026},
author = {Sethi, N and Levy, OA and Richardson, A and Harari, OA and Sellati, R},
title = {A Qualitive Investigation of Geographic Disparities in Genetic Testing and Care Access for Amyotrophic Lateral Sclerosis: Insights From Patient Journey Mapping.},
journal = {Patient preference and adherence},
volume = {20},
number = {},
pages = {566747},
pmid = {41868729},
issn = {1177-889X},
abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease that is associated with a high patient burden, reduced lifespan, and reduced quality of life. People living with ALS (PLwALS) often experience delays in diagnosis of ~1 year, and while current treatment options can slow disease progression, improve quality of life, and offer modest benefits in functional decline, they do not reverse neuronal damage. Defining and understanding the experiences of PLwALS can help identify gaps and barriers to optimal care.

PATIENTS AND METHODS: This non-interventional study was intended to obtain insights on the patient experience from the perspective of PLwALS. We sought to develop an ALS patient journey map from initial presentation through to end-of-life care for 4 regions (North America, Asia-Pacific, Latin America, and Europe/Middle East/Africa). The map was based on results from a global audit of data sources (including publications, patient narratives, society guidelines, academic reports, industry white papers [n=104]), and one-to-one, 60-minute, semi-structured interviews with PLwALS (n=12) or those caring for PLwALS (n=2). The initial patient journey map was subsequently reviewed during 2 advisory sessions with patient advocates (7 PLwALS and 2 caregivers) in September and November 2023.

RESULTS: We identified several barriers and challenges that most impact PLwALS, caregivers, and clinicians, with many similarities but also some differences across the regions.

CONCLUSION: These insights will enable targeted improvements in education, personalized care, resource allocation, care coordination, policy development, and funding, ultimately improving patient outcomes.},
}

@article {pmid41868461,
year = {2026},
author = {Yu, J},
title = {Postoperative acute ultra-early fish mouthing of a Surpass Evolve flow diverter leading to ischemic complication.},
journal = {Radiology case reports},
volume = {21},
number = {6},
pages = {2346-2354},
pmid = {41868461},
issn = {1930-0433},
abstract = {Currently, the Surpass Evolve flow diverter (SE FD) is widely adopted for endovascular treatment of intracranial aneurysms. Although generally safe, acute ultra-early fish mouthing remains an exceptionally rare complication. Following Torche et al.'s 2023 report of the first case, the present case represents the second documented instance. A 66-year-old woman was diagnosed with a left posterior communicating artery aneurysm and a left ophthalmic artery aneurysm. Physical examination revealed no abnormalities. The endovascular treatment (EVT) procedure was performed. After advancing a microcatheter into the left middle cerebral artery, an SE FD with appropriate size was deployed to cover both aneurysms, achieving confirmed complete expansion and optimal wall apposition. Two hours postoperatively, the patient developed aphasia and hemiparesis. Subsequent angiography at 4 hours revealed thrombosis within the SE FD and fish mouthing at the proximal segment. Successful microguidewire traversal through the affected site restored complete FD expansion and wall apposition. Postoperatively, the patient's hemiparesis improved, and her motor aphasia resolved. Magnetic resonance imaging confirmed multiple acute infarctions, while computed tomography demonstrated proper FD expansion. At 3-month follow-up, near-normal functional recovery was observed. This case indicates that SE FD deployment may be complicated by acute ultra-early fish mouthing attributable to post-deployment tension release. Preventive strategies should emphasize appropriate device sizing, adequate landing zone selection, and post-implant tension assessment.},
}

@article {pmid41863659,
year = {2026},
author = {Mullick, S and Chakraborty, A and Porel, P and Nath, R and Chaudhary, P and Islam, A and Das, J and Pramanik, S and Panigrahy, UP and Sridhar, SB and Mondal, M and Debnath, B and Ashique, S},
title = {Decoding Neuroinflammatory Pathways: The Role of the CXCL12-CXCR4/CXCR7 Axis in ALS-Related Cognitive Impairment.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41863659},
issn = {1559-1182},
mesh = {Humans ; *Chemokine CXCL12/metabolism ; *Receptors, CXCR/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/complications/pathology ; Animals ; *Receptors, CXCR4/metabolism ; *Cognitive Dysfunction/metabolism ; *Signal Transduction/physiology ; *Neuroinflammatory Diseases/metabolism/pathology ; Inflammation/metabolism/pathology ; },
abstract = {Cognitive impairment (CI) and accelerating neuronal deterioration are hallmarks of amyotrophic lateral sclerosis (ALS). Under these circumstances a crucial molecular mechanism in the pathophysiology of CI has been identified: the CXC chemokine receptor type 7 (CXCR7)/CXC chemokine receptor type 4 (CXCR4)/Cysteine-X-cysteine chemokine ligand 12 (CXCL12) region. Research on ALS shows that the CXCR7/CXCR4/CXCL12 complex plays a role in the degeneration of motor neurons and the resulting cognitive decline. JAK/STAT, PI3K/AKT, MAPK, and other signaling pathways are among the ways the axis controls neuronal inflammation, synaptic remodeling, and neuronal maintenance in each of these scenarios. The CXC motif chemokine ligand 12 (CXCL12) and CXC chemokine receptor type 4 (CXCR4) axis is crucial for the start of the inflammatory mechanism because of their function in mediating the chemotaxis of inflammatory cells. By preventing the migration of inflammatory cells via CXCL12 in the inflammatory area, the response to inflammation can be prevented or reduced. Consequently, the development of CXCR4 antagonists has emerged as a cutting-edge strategy for inflammation treatment. Recent research suggests that managing this relationship could reduce cognitive deficits and offer neuroprotective benefits. According to the current review, the CXCL12/CXCR4/CXCR7 pathway may be a promising target for treating cognitive dysfunction in neurodegenerative disorder. It also emphasizes the need for additional research to completely comprehend its function and identify efficient treatments which may result in improved clinical treatment modalities for these debilitating illnesses.},
}

Humans
*Chemokine CXCL12/metabolism
*Receptors, CXCR/metabolism
*Amyotrophic Lateral Sclerosis/metabolism/complications/pathology
Animals
*Receptors, CXCR4/metabolism
*Cognitive Dysfunction/metabolism
*Signal Transduction/physiology
*Neuroinflammatory Diseases/metabolism/pathology
Inflammation/metabolism/pathology

@article {pmid41864292,
year = {2026},
author = {Liu, H and Zhu, J and Chen, Y and Lin, X and Hua, C and Chen, H},
title = {Response to Jia et al.'s "Comment on the "genetic classification helps with precise sirolimus treatment in slow-flow vascular malformations"".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2026.03.041},
pmid = {41864292},
issn = {1097-6787},
}

@article {pmid41866066,
year = {2026},
author = {Qian, J and Li, C and Wang, Y and Tong, J},
title = {Extracorporeal sliding knot technique for simplified hysteroscopic suture fixation of levonorgestrel-releasing intrauterine device.},
journal = {Journal of minimally invasive gynecology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jmig.2026.03.020},
pmid = {41866066},
issn = {1553-4669},
abstract = {OBJECTIVE: Approximately 20% of adenomyosis cases occur in women under 40 years of age [1]. While LNG-IUD is the first-line medical therapy, its treatment failure is closely associated with uterine volume [2], with expulsion rates reported as high as 37.5% in uteri exceeding 12 gestational weeks [3]. Tong et al's hysteroscopic suture fixation technique (HCSS) reduced expulsion to 2.6% [4][5]. Although clinical studies have confirmed the safety and efficacy of this technique [5], its technical complexity and the requirement for repeated instrument exchanges have limited widespread adoption. We therefore developed an optimized extracorporeal sliding knot method to overcome these barriers.

SETTING: University hospital.

PARTICIPANTS: A 45-year-old woman diagnosed with adenomyosis and prior LNG-IUD expulsion.

INTERVENTIONS: The key modification involves three critical steps: Step 1) Construction of a secure multi-loop sliding knot using 2-0 Ethibond suture attached to the "T junction" of the LNG-IUD; Step 2) Introduction of the pre-formed knot into the uterine cavity in a single maneuver using a knot-pusher; Step 3) Adjustment of the knot position under the hysteroscopic cold-knife surgery system (HCSS), achieving secure device fixation. The complete procedure obviates repeated instrument exchanges and intracavitary knot manipulation required by the original technique.

CONCLUSION: The extracorporeal sliding knot optimization preserves therapeutic efficacy while simplifying intrauterine manipulation, significantly enhancing surgical reproducibility and accessibility for widespread clinical adoption.},
}

@article {pmid41852184,
year = {2026},
author = {Gagliardi, D and Villella, C and Zanovello, M and Iacobelli, V and Corti, S and Comi, GP and Fratta, P and Houlden, H and Tucci, A and Ronchi, D},
title = {High Prevalence of SOD1 Pathogenic Variants in the UK Biobank: Implications for Early Intervention in Amyotrophic Lateral Sclerosis.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78195},
pmid = {41852184},
issn = {1531-8249},
support = {//Italian Ministry of Health/ ; MR/Z506503/1//UK Medical Research Council/ ; MR/S006753/1//UK Medical Research Council/ ; },
abstract = {OBJECTIVE: SOD1 is the second most frequently mutated gene in European patients with amyotrophic lateral sclerosis (ALS). Given the recent authorization of SOD1-targeted antisense oligonucleotides for SOD1-ALS, prompt screening for SOD1 mutations in patients with ALS patients is highly recommended. Large-scale genomic analysis could inform on the population-based prevalence of SOD1 mutation carriers, who would potentially benefit from treatment. We aim to determine the number of people with pathogenic SOD1 variants in the UK Biobank (UKB), to address a critical gap between clinical and genetic prevalence of SOD1-ALS.

METHODS: We analyzed SOD1 variants within exome sequencing data from 470,000 individuals aged over 40 years. Pathogenicity was evaluated using referenced databases and American College of Medical Genetics and Genomics (ACMG) guidelines. Leveraging the UKB carrier frequency and age at onset data, we estimated the genetic prevalence of SOD1-ALS. We examined factors that may influence penetrance.

RESULTS: We identified 122 individuals with monoallelic SOD1 coding variants, 93.4% of whom were asymptomatic. Additionally, the low-penetrance p.Asp91Ala variant was observed in heterozygosis in 535 subjects, whereas it was never found in homozygosis. Excluding this variant, the expected number of people developing SOD1-ALS is 1.04:100,000 in the UK population, 4 times higher than clinically reported figures. Symptomatic carriers had significantly increased levels of serum neurofilament at baseline. Age-related penetrance was higher in non-p.Asp91Ala carriers versus p.Asp91Ala carriers. Long-term survivor status was associated with p.Asp91Ala genotype, older age, and lower neurofilament levels.

INTERPRETATION: Incomplete and age-related penetrance, along with underascertainment due to disease heterogeneity and limitations in data collection, likely account for the reduced number of symptomatic patients identified. Our findings highlight the need to identify genetic and environmental factors, as well as biological indicators, able to influence disease penetrance and phenoconversion risk in presymptomatic carriers and to predict treatment response in patients. ANN NEUROL 2026.},
}

@article {pmid41853322,
year = {2026},
author = {Elshaer, A and Thomas, L},
title = {Investigating inequality in Advanced Life Support courses: a retrospective, single-centre, survey-based pilot study.},
journal = {Resuscitation plus},
volume = {28},
number = {},
pages = {101283},
pmid = {41853322},
issn = {2666-5204},
abstract = {BACKGROUND: With more International Medical Graduates (IMGs) joining the United Kingdom's medical workforce, the demand for Advanced Life Support (ALS) courses has increased. Whilst differential attainment among IMGs is well-documented, little is understood about this phenomenon in ALS courses. This study explores the relationship between ALS course participants' background and course outcomes.

METHODS: Doctors who attended ALS courses at a UK course centre were retrospectively recruited to participate in a 28-question online survey about their language, education and clinical backgrounds, as well as their ALS course experience and outcomes. Quantitative and qualitative analyses were carried out, and recommendations were thematically summarised.

RESULTS: Of 419 invited healthcare professionals, 38 doctors (9%) completed the survey. 27 (71.1%) of the respondents graduated outside the UK, 32 (84.2%) studied medicine in English, and 15 (39.5%) were native English speakers. Passing the Cardiac Arrest Simulation Tests (CAS-Test) was statistically associated with more previous scenario-based simulation experience. Thematic analysis of responses suggested that biased treatment, language barriers, communication anxiety, inadequate undergraduate training, vulnerability, rigid professionalism and psychological insecurity were obstacles to IMGs attaining course outcomes. Suggestions for improvement focused on enhancing course accessibility, learning materials, the educational environment, assessment, and faculty development.

CONCLUSIONS: This exploratory study investigates IMGs' self-reported challenges and proposes interventions to promote the inclusivity of ALS courses. Further prospective research is required to evaluate the nature and generalisability of these findings and the applicability of the offered recommendations.},
}

@article {pmid41854370,
year = {2026},
author = {Morojele, NK and London, L and Saban, A and Myers, B and Harker, N and Mokwena, K and Zingela, Z and Nkosi, S and Ayieko, P and Kapiga, S},
title = {Implications of COVID-19 Restrictions on the Ethics and Methods of a Multi-Site Study on Alcohol and Other Drug (AOD) Use Treatment among Men in South Africa.},
journal = {Journal of empirical research on human research ethics : JERHRE},
volume = {},
number = {},
pages = {15562646261427563},
doi = {10.1177/15562646261427563},
pmid = {41854370},
issn = {1556-2654},
abstract = {Public health measures for medical emergencies generate methodological and ethical challenges for human research. Using Emanuel et al.'s framework, we assessed the ethical integrity of the research methods used in a men's alcohol and other drug (AOD) use disorder study following their revision due to COVID-19 restrictions in South Africa. Following the amendments, the study's social value, favorable risk-benefit ratio, and respect for participants increased. Collaborative partnership, scientific validity, fair participant selection, independent review, and informed consent improved in terms of successful stakeholder engagements and interviewing procedures, but were compromised due to a cellphone access eligibility criterion and complicated consenting procedures. Methodological and ethical challenges of research during health emergencies can be navigated with flexibility and innovation.},
}

@article {pmid41863273,
year = {2026},
author = {Singh, DD},
title = {PROTAC-Based Therapeutics: From Design to Clinical Potential in Neurodegenerative Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X438970260115164001},
pmid = {41863273},
issn = {1875-6190},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and ALS, are characterized by a progressive loss of neuronal function and a direct correlation between their progression and proteins with misfolded and aggregated structures. Although significant efforts have been made, and various therapies are available for their treatment, they show only a modest beneficial response to their progression. The main reasons for this phenomenon can be correlated with a loss of target specificity, low permeability in crossing the BBB, and their ineffectiveness in clearing proteins from neurons. Within this therapeutic paradigm, proteolysis-targeting chimaeras, or PROTACS, have been identified as a novel therapeutic strategy. Unlike traditional smallmolecule inhibitors, PROTACS take advantage of the natural ubiquitin proteasome system to specifically degrade target proteins. At a molecular level, PROTACS consist of a ligand that specifically recognizes a target protein, a linker, and an E3 ligand-recruiting ligand that specifically recruits an E3 ligase. At a therapeutic level, this offers the advantage of catalytic protein degradation that should allow for reduced dosing. Preclinical studies carried out using neurodegenerative disease models have shown the potential for selective targeting of major pathologic proteins, such as tau, α- synuclein, TDP-43, and mHTT, which are crucial for pathogenesis. In addition, developments in the formulation of brain-permeable PROTACS, understanding of E3 ligase expression levels in the central nervous system, and application of iPSC-derived neuronal systems have contributed to rapid developments in this area. Although pharmacokinetic modification and degradation-specific approaches are still required, evidence suggests a major therapeutic potential for PROTAC-based approaches for the treatment of neurodegenerative disorders.},
}

@article {pmid41845971,
year = {2026},
author = {Dahlhaus, R and Braun, RJ},
title = {The role of TDP-43 fragments in regular cellular functions and homeostatic failure.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107349},
doi = {10.1016/j.nbd.2026.107349},
pmid = {41845971},
issn = {1095-953X},
abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons, leading to severe muscle weakness, loss of voluntary movement, and respiratory failure. A widely noted feature of the disease is the presence of TDP-43 proteinopathies. Under homeostatic conditions, the RNA/DNA-binding protein TDP-43 mainly resides in the nucleus, where it functions to regulate gene expression, controlling not only RNA transcription and splicing, but also stability and transport to the cytoplasm. Upon the arrival at ribosomes, TDP-43 may further moderate translation, acting as a global repressor of protein synthesis. However, in over 95% of ALS cases, TDP-43 mislocalies from the nucleus to the cytoplasm, where it enriches in cytoplasmic inclusions that are marked by the presence of misfolded, ubiquitinated, phosphorylated and fragmented protein species of TDP-43. Although recent studies have tried to untangle the relationship between TDP fragments on the one hand, and cytotoxicity as well as neurodegeneration on the other, the results are still a matter of debate. Here, we review our current understanding of the different TDP fragments derived from proteolytic cleavage as well as alternative splicing, addressing the different N-terminal and C-terminal species and evaluating differences in rodent and primate models. We focus our analysis on the potential homeostatic functions of TDP fragments in the context of viral infections and myelination control, which are potentially pivotally interconnected. The findings illustrate several facets of fragmented TDP-43 protein species in scenarios of enhanced cellular stress. Gaining a detailed understanding could help to reveal new treatment options for ALS and other TDP-43 proteinopathies.},
}

@article {pmid41846014,
year = {2026},
author = {Yang, L and Fan, W and Wang, Z and Wu, M and Chen, Y and Cheng, J and Zhou, F and Guo, Z},
title = {The role of IRF5 in Microglia-Mediated neuroinflammation in ALS.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {138580},
doi = {10.1016/j.neulet.2026.138580},
pmid = {41846014},
issn = {1872-7972},
abstract = {The occurrence and development of amyotrophic lateral sclerosis (ALS) involve neuroinflammatory responses, in which microglial activation plays a critical role. IRF5, a key regulator of inflammatory responses, is implicated in the disease mechanisms of various conditions. However, its mechanism in ALS remains unclear. This study found that IRF5 expression was significantly increased in hSOD1-G93A transgenic ALS mice and cell models, primarily localized in activated microglia. Silencing IRF5 altered microglial polarization, suppressed the release of inflammatory factors, enhanced phagocytic function, and reduced motor neuron apoptosis in a co-culture system. Mechanistic studies suggested that IRF5 may regulate microglial function through the NF-κB signaling pathway. This study reveals the key role of IRF5 in microglia-mediated neuroinflammation and neuronal damage in ALS, indicating that targeting IRF5 could represent a promising treatment strategy for this disease.},
}

@article {pmid41850233,
year = {2026},
author = {Guise, AJ and Ferber, KL and Young, D and Edwards, AL and Sabouri, S and Fraser, KB and Milliman, E and Plowey, ED and Zoghbi, J and Fradette, SM and Graham, DL},
title = {Identification of tofersen PD-response biomarkers in VALOR clinical trial CSF via multiplexed quantitative proteomics.},
journal = {Cell reports. Medicine},
volume = {7},
number = {3},
pages = {102648},
doi = {10.1016/j.xcrm.2026.102648},
pmid = {41850233},
issn = {2666-3791},
mesh = {Humans ; *Proteomics/methods ; *Biomarkers/cerebrospinal fluid ; *Amyotrophic Lateral Sclerosis/drug therapy/cerebrospinal fluid/genetics ; Superoxide Dismutase-1/genetics ; Male ; Female ; Middle Aged ; Adult ; Membrane Glycoproteins/cerebrospinal fluid ; Aged ; },
abstract = {Tofersen, the first approved genetically targeted therapy for amyotrophic lateral sclerosis (ALS), demonstrates significant lowering of plasma neurofilament in adults carrying mutations in the superoxide dismutase 1 (SOD1) gene; however, additional biomarkers of treatment response in ALS are lacking. Here, we analyze longitudinally collected cerebrospinal fluid (CSF) samples from the phase 3 VALOR clinical trial to identify candidate tofersen treatment-response biomarkers in SOD1-ALS via quantitative proteomics. We observe significant modulation from baseline abundance for 56 proteins in tofersen-treated participants relative to placebo, including CSF GPNMB, which is significantly and continuously elevated across all post-baseline timepoints. We orthogonally confirm this observation by GPNMB immunoassay in independent tofersen-treated cohorts. Taken together, these data identify pharmacodynamic-response biomarkers of tofersen treatment that can be measured as early as 4 weeks post-treatment in SOD1-ALS patients and demonstrate the utility of leveraging unbiased proteomic screening integrated with targeted validation methods to identify pharmacodynamic-response biomarkers in clinical trial patient samples.},
}

Humans
*Proteomics/methods
*Biomarkers/cerebrospinal fluid
*Amyotrophic Lateral Sclerosis/drug therapy/cerebrospinal fluid/genetics
Superoxide Dismutase-1/genetics
Male
Female
Middle Aged
Adult
Membrane Glycoproteins/cerebrospinal fluid
Aged

@article {pmid41830107,
year = {2026},
author = {Chen, Y and Feng, Y and Sonksen, M and Wang, T and Jin Song, J},
title = {Propensity Score-Based Stratified Win Ratio for Augmented Control Designs.},
journal = {Statistics in medicine},
volume = {45},
number = {6-7},
pages = {e70487},
doi = {10.1002/sim.70487},
pmid = {41830107},
issn = {1097-0258},
mesh = {Humans ; *Propensity Score ; Amyotrophic Lateral Sclerosis/drug therapy ; Computer Simulation ; Models, Statistical ; *Clinical Trials as Topic/methods/statistics & numerical data ; Research Design ; *Randomized Controlled Trials as Topic/methods/statistics & numerical data ; Bias ; },
abstract = {This paper proposes a propensity score (PS)-based stratified win ratio method to address challenges of small patient populations in clinical trials, especially for rare or pediatric diseases, by incorporating external control data. Our approach enhances traditional win ratio analysis by leveraging PS stratification to account for heterogeneity between the current and external studies. Additionally, down-weighting based on the overlapping coefficient of PS distributions of current treatment and external control groups further mitigates the patient bias due to heterogeneity. Simulations show significant improvements in statistical power for detecting treatment effects within the composite endpoint combining continuous and time-to-event components, over nonborrowing and pooling methods, with utilizing Mantel-Haenszel (MH)-type weights achieving the highest power. The proposed methods are also applied to an amyotrophic lateral sclerosis (ALS) study incorporating the external control arm from a prior ALS trial. The proposed PS-based stratified win ratio method thus provides a rigorous framework for borrowing external data and analyzing composite endpoints with limited patient availability.},
}

Humans
*Propensity Score
Amyotrophic Lateral Sclerosis/drug therapy
Computer Simulation
Models, Statistical
*Clinical Trials as Topic/methods/statistics & numerical data
Research Design
*Randomized Controlled Trials as Topic/methods/statistics & numerical data
Bias

@article {pmid41831326,
year = {2026},
author = {Furlan, R and Di Sapio, A and Ferraro, D and Rossi, E and Valentino, P and Terracciano, D},
title = {Translating neurofilament light chain testing into clinical practice: a multidisciplinary implementation roadmap.},
journal = {Clinical chemistry and laboratory medicine},
volume = {},
number = {},
pages = {},
pmid = {41831326},
issn = {1437-4331},
abstract = {Neurofilament light chain (NfL) has been identified as a sensitive and broadly validated biomarker of neuroaxonal injury across multiple neurological conditions, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and atypical parkinsonian syndromes. This position paper provides a multidisciplinary roadmap for translating circulating NfL testing into routine clinical practice, integrating analytical, interpretative, and organizational dimensions. It summarizes the biological basis and clinical evidence supporting NfL as a diagnostic, prognostic, and monitoring tool, emphasizing its high sensitivity to neuroaxonal injury across both acute inflammatory and chronic degenerative processes. Comparative analysis of immunoassay technologies identifies strengths and critical sources of variability, while operational guidelines highlight the need for pre-analytical standardization, inter-laboratory harmonization, and participation in quality control schemes. Confounders such as age, BMI, renal function, and comorbidities are shown to significantly influence interpretation, supporting the use of age-adjusted Z-scores, percentiles, and longitudinal normalization for accurate patient-level evaluation. From a clinical standpoint, the paper focuses on practical indications for NfL testing in MS, recommending its use for disease activity prediction and monitoring, treatment decisions and treatment response assessment. Integration of blood NfL with magnetic resonance imaging (MRI), glial fibrillary acidic protein (GFAP) and other biomarkers measurement is proposed as a core strategy for biomarker-driven precision neurology. The authors outline an implementation model encompassing laboratory validation, structured reporting and alignment with national neurological care pathways. They conclude that the transition of NfL into clinical use requires harmonized analytical procedures, interdisciplinary education, and sustainable governance frameworks. Priority actions include regulatory qualification, establishment of international reference materials, and development of pragmatic real-world trials to consolidate its clinical utility. When these measures are achieved, NfL will represent a cornerstone biomarker for precision neurology and neurodegeneration monitoring.},
}

@article {pmid41837970,
year = {2026},
author = {Cudkowicz, M and Drory, VE and Chio, A and Lunetta, C and Shoesmith, C and van Eijk, RPA and Salomon-Zimri, S and Shtossel, D and Kerem, N and Shapira, G and Shomron, N and Russek-Blum, N and Tracik, F and Rosenfeld, J and Shefner, J},
title = {Safety and Efficacy of PrimeC in Amyotrophic Lateral Sclerosis: The PARADIGM Randomized Clinical Trial.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
pmid = {41837970},
issn = {2168-6157},
abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. PrimeC is a fixed-dose oral combination of celecoxib and ciprofloxacin designed to target ALS-related mechanisms, including neuroinflammation, iron homeostasis, and dysregulated microRNAs.

OBJECTIVE: To evaluate the safety, tolerability, and potential efficacy of PrimeC in people living with ALS.

This was a randomized, double-blind, placebo-controlled, phase 2b trial conducted at 4 ALS referral centers from May 2022 to November 2023 and followed by 12-month open-label extension. Adults with definite or probable ALS and disease duration of 30 months or less were eligible. Of 73 screened, 69 were randomized and 68 were included in the intent-to-treat population.

INTERVENTIONS: Participants were randomized 2:1 to receive PrimeC or placebo for 6 months, followed by open-label extension PrimeC for all.

MAIN OUTCOMES AND MEASURES: The primary outcome was safety and tolerability. The prespecified primary biomarker outcome was plasma neuron-derived-exosomal TAR DNA-binding protein 43 (TDP-43) or prostaglandinJ2. Secondary outcomes included change in ALS Functional Rating Scale-Revised (ALSFRS-R) score at 6 and 18 months, survival, and time-to-composite events. Exploratory biomarkers included neurofilament light chains, iron-regulatory proteins, and circulating microRNAs.

RESULTS: The 68 participants were well balanced in age at entry and sex. In the PrimeC group, the mean (SD) age was 59.1 (9.1) years, and 27 of 45 participants were male. In the placebo group, the mean (SD) age was 55.0 (13.0) years, and 14 of 23 participants were male. PrimeC was well tolerated, with a safety profile comparable to placebo (adverse event rate, 66.7% PrimeC vs 65.2% placebo). Drug-related adverse events were more frequent with PrimeC (20.0% vs 4.3%), mostly mild to moderate, and transient. At month 6, the mean ALSFRS-R difference was 2.23 points between PrimeC and placebo (95% CI, -0.61 to 5.07; P = .12). At month 18, ALSFRS-R scores in participants continuously treated with PrimeC maintained a difference (7.92 points; 95% CI, 2.25 to 13.60; P = .007), with significant bulbar difference (3.18 points; 95% CI, 1.32 to 5.04; P = .001). Continuous treatment was associated with lower risk of ALS complications, including hospitalization, respiratory failure, or death (HR, 0.36; 95% CI, 0.15-0.85; P = .02). In the double-blind period, transferrin levels were preserved with PrimeC (1.90 μmol/L difference; P = .03), the negative ferritin-ALSFRS-R correlation observed in placebo (ρ = -0.50; P = .02) was abolished, and ALS-associated microRNAs were downregulated (log2 fold change: miR-199a-3p, -1.87; false discovery rate [FDR] P = .004; miR-199a-5p, -2.23; FDR P < .001; miR-181a-5p: -1.89; FDR P = .001; miR-181b-5p, -1.62; FDR P = .005). Prespecified neuron-derived exosome TDP-43/PgJ2 analyses will be reported separately following completion of development and analyses.

CONCLUSIONS AND RELEVANCE: PrimeC was safe and well tolerated over 18 months. Although not powered for efficacy, functional and biomarker findings support a confirmatory trial.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05357950.},
}

@article {pmid41822688,
year = {2026},
author = {Cortes-Flores, H and Torrandell-Haro, G and Brinton, RD},
title = {Immunotherapies for risk reduction in age-associated neurodegenerative diseases: impact of sex and treatment duration.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.06.26347446},
pmid = {41822688},
abstract = {INTRODUCTION: Neurodegenerative diseases (NDDs) including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and non-AD dementias share chronic neuroinflammatory mechanisms that contribute to neuronal injury and disease progression. While anti-inflammatory therapies (AITs) are associated with reduced neurodegenerative disease risk, knowledge regarding the impact of biological sex and treatment duration across multiple NDDs remains limited.

METHODS: We conducted a retrospective cohort analysis using a large propensity-score-matched population (n = 190,308; 95,154 treated vs 95,154 untreated) to evaluate associations between long-term AIT exposure and incidence of major NDDs. Disease-specific and combined outcomes were assessed across drug classes (NSAIDs, corticosteroids, immunomodulators), sex, age, and therapy duration.

RESULTS: AIT exposure was associated with a significantly lower risk of developing any NDD (RR = 0.47, 95% CI 0.43-0.48, p < .0001) and was equally effective in both sexes. Risk reduction was observed for each individual disease: AD (RR = 0.40), non-AD dementia (RR = 0.51), PD (RR = 0.43), MS (RR = 0.25), and ALS (RR = 0.48). Among drug classes, immunomodulators conferred the largest reduction (RR = 0.19), followed by corticosteroids (RR = 0.41) and NSAIDs (RR = 0.42). Duration analyses revealed a graded benefit, with RR declining from 0.94 (<1 year) to 0.25 (>6 years). Risk reduction was strongest in older participants (75-79 years).

DISCUSSION: Chronic use of anti-inflammatory or immunomodulatory therapies was associated with substantially reduced incidence of multiple neurodegenerative diseases in both sexes. The strongest effects were observed with immunomodulator use and prolonged therapy duration, suggesting that sustained modulation of systemic inflammation confers broad neuroprotective effects in both sexes. These findings highlight the potential of targeting immune-inflammatory pathways for neurodegenerative disease prevention and can inform prospective mechanistic and interventional studies.},
}

@article {pmid41821425,
year = {2026},
author = {Bilić, H and Begović, M and Sitaš, B and Hančević, M and Šepec, BI and Zemba Čilić, A and Peček, V and Gotovac Jerčić, K and Mateševac, J and Bahčić, T and Peček, L and Borovečki, F and Njirić, N and Nemir, J and Petrović, M and Jurjević, I and Klarica, M and Merćep, I and Bilić, E},
title = {Tofersen treatment in SOD1 p.Leu145Phe ALS: real-world outcomes in a genetically homogeneous Croatian cohort.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/21678421.2026.2638589},
pmid = {41821425},
issn = {2167-9223},
abstract = {Background: Antisense oligonucleotide tofersen targets SOD1 mRNA and reduces production of misfolded SOD1 protein, with demonstrated biomarker and functional signals in clinical trials and open-label extensions. Real-world reports from genetically heterogeneous SOD1 ALS cohorts describe variable functional trajectories. Data from genetically homogeneous founder populations remain limited. We investigated clinical trajectories in a cohort carrying the same pathogenic SOD1 variant to better characterize mutation-specific patterns in a real-world setting. Methods: We conducted a single-center observational study at the National Referral Center for Neuromuscular Diseases and Clinical Electromyoneurography (UHC Zagreb, Croatia). Eight adults with genetically confirmed SOD1 p.Leu145Phe ALS received intrathecal tofersen according to the approved regimen. ALS Functional Rating Scale-Revised (ALSFRS-R) scores were recorded at each dosing visit, and longitudinal slopes were calculated using linear regression. Safety and tolerability were evaluated descriptively. Biomarker and formal respiratory measurements were not routinely available. Results: All patients exhibited lower limb-onset, predominantly lower motor neuron phenotypes consistent with a slow-progressing founder variant. Median age at symptom onset was 60 years, and median therapeutic delay was 48 months. Median on-treatment ALSFRS-R slope was -0.28 points/month (range +0.04 to -0.57). Two patients demonstrated stable trajectories, while the remainder showed gradual decline. These patterns fall within the slower range reported in heterogeneous real-world SOD1 cohorts and are consistent with the known natural history of this mutation. Tofersen was well tolerated, with no serious treatment-related adverse events. Conclusions: In this genetically homogeneous SOD1 p.Leu145Phe cohort, functional trajectories during tofersen therapy reflected the mutation's slow-progressing phenotype. These findings provide real-world clinical context but do not permit conclusions regarding treatment efficacy. Further mutation-specific studies incorporating prospective baseline assessment and biomarker monitoring are needed to clarify therapeutic impact.},
}

@article {pmid41817655,
year = {2026},
author = {Bakshi, V and Pathak, B and Majie, A and Ghosh, A and Gupta, A and Jain, N and Pandey, M and Nair, AB and Jacob, S and Mazumder, PM and Sharma, N and Kumari, N and Gorain, B},
title = {Advancement in therapeutic application of quantum dots in amyotrophic lateral sclerosis: current opportunities and challenges.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {41817655},
issn = {2190-3948},
abstract = {Despite advancements in healthcare settings in developed countries, the early detection and higher mortality rate associated with amyotrophic lateral sclerosis (ALS), a fatal motor neuronal disorder, remain challenging. Recently, quantum dots (QDs) have emerged as a promising nanocarrier in the prognosis and treatment of ALS owing to their unique multifunctional properties. QDs, through their photoluminescence properties upon excitation, can facilitate the identification and real-time monitoring of disease biomarkers. They also act as a nanocarrier for the targeted delivery of therapeutics, avoiding accumulation at the non-targeted sites and minimising toxicity. QDs can be fabricated to conjugate with protein biomarkers linked to ALS, such as specific proteins, nucleic acids, or genetic variants, for the diagnosis of the disease. Such fabrication could lead to enhanced identification and diagnostic patterns of ALS, thereby contributing to improved therapeutic intervention strategies. Furthermore, these tiny structures could be applied in combined biosensor formats to identify ALS-associated biomarkers in body fluids, which would be a highly sensitive diagnostic system. Subsequently, comprehensive multiomics techniques have demonstrated improved identification of newer protein targets associated with neurological complications. Overall, QDs can be explored as a potential tool to identify biomarkers relevant to ALS, diagnose the disease at its early stages, and track the effectiveness of the treatment. The integration of QD with omic-based strategies and network analysis can potentially catalyse a breakthrough in the management of ALS. Therefore, this review aims to explore the application of QDs in ALS diagnosis and management, advancements in research, clinical trials, and patents.},
}

@article {pmid41813498,
year = {2026},
author = {Reimer, RJ and Soper, B and Wilson, JL and Goncalves, AR and Cadena, J and Suarez, P and Gryshuk, AL and Osborne, TF and Grimes, KV and Ray, P},
title = {Identification of drug repurposing candidates for amyotrophic lateral sclerosis using electronic health records: a retrospective cohort study.},
journal = {The Lancet. Digital health},
volume = {},
number = {},
pages = {100963},
doi = {10.1016/j.landig.2025.100963},
pmid = {41813498},
issn = {2589-7500},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a life expectancy of only 3-5 years and few approved treatments. To identify drug repurposing candidates for the treatment of ALS, we analysed the electronic health records (EHRs) of a large cohort of military veterans with ALS.

METHODS: We analysed the EHRs of individuals in the US Veterans Health Administration (VHA) database who were diagnosed with ALS between Jan 1, 2009 and Dec 31, 2019 to assess medication effects. Individuals without recorded prescriptions after the date of diagnosis were excluded. Two sets of criteria were applied to ascertain exposure. Exposure criteria A were met if the dispense date or the end date of the medication was within 12 months of ALS diagnosis and the end date was at least 6 months after the dispense date. Exposure criteria B were met if there were at least two dispenses within 6 months before diagnosis and 12 months after diagnosis. Propensity score-matched control groups were generated on the basis of confounders included in the EHR, with methodology of potential outcomes used to infer treatment effects. The primary outcome was death. A standard Cox proportional hazards analysis was done to assess association with survival. Survival was defined as the time from diagnosis date recorded in the EHR to death reported in the Department for Veterans Affairs Vital Status File. Follow-up survival time was censored on Dec 31, 2020, for those alive on this date. Downstream protein targets of drugs with clinically significant effects were analysed using the protein-protein interaction networks-based algorithm PathFX.

FINDINGS: The EHRs of 11 003 individuals with ALS in the VHA database were appropriate for analysis. 162 medications with treatment groups of 30 or more individuals were identified. Among these 162 medications, 27 were associated with statistically significant changes (≥0·1) in the hazard ratio (HR) for death. 18 of the medications were associated with a reduced HR for death (prolonged survival), and nine were associated with an increased HR for death (reduced survival). Drugs associated with reduced HR included HMG-CoA reductase inhibitors (simvastatin, pravastatin, lovastatin, and atorvastatin), PDE5 inhibitors (vardenafil and sildenafil), and α-adrenergic antagonists (tamsulosin and terazosin). The medications associated with an increased HR were drugs used either in the management of clinical features of ALS associated with poor outcomes or in end-of-life care. PathFx analysis identified a complex of proteins interacting with several of the identified drugs.

INTERPRETATION: To our knowledge, this analysis is the largest EHR-based study for identifying drug repurposing candidates for ALS. We identified several drugs that warrant further assessment as therapeutic options in ALS, as well as a protein network complex that might serve as a therapeutic target for ALS.

FUNDING: Congressionally Directed Medical Research Programs, US Department of Defense.},
}

@article {pmid41813136,
year = {2026},
author = {Perry, CM and Martin, DDO},
title = {ALS and Huntington Disease: Unraveling the Connections between TDP-43 and Huntingtin.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {46},
number = {10},
pages = {},
pmid = {41813136},
issn = {1529-2401},
mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Huntington Disease/metabolism/genetics/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Huntingtin Protein/metabolism/genetics ; Animals ; },
abstract = {Amyotrophic lateral sclerosis (ALS) and Huntington disease (HD) are lethal neurodegenerative diseases affecting motor function. Though their etiology and pathology are distinct, recent evidence suggests commonalities between TAR DNA-binding protein (TDP-43), which is associated with 97% of ALS cases, and huntingtin (HTT), the causative protein of HD. ALS is a heterogeneous, lethal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, as well as brainstem and spinal cord degeneration. The causes of ALS are complex, variable, and, in some cases, unknown, but most cases involve mislocalization of the protein TDP-43. In contrast, HD is a monogenic, autosomal dominant, lethal neurodegenerative disease caused by polyglutamine expansion in HTT protein and characterized by the progressive loss of neurons in the brain, particularly in the striatum, which results in motor, cognitive, and behavioral changes. Although HD is not typically associated with motor neuron loss, recent evidence suggests a link between HTT and TDP-43 within the context of both ALS and HD, as well as links to related neurodegenerative diseases, such as frontotemporal dementia (FTD) and spinocerebellar ataxia type 2 (SCA2). Herein, we discuss confirmed cases of concurrent ALS and HD and the overlap of underlying disease mechanisms that potentially contribute to the onset and progression of these two devastating neurodegenerative diseases, with a focus on commonalities between TDP-43 and HTT. We propose that elucidating these commonalities will aid in the identification of broad-spectrum disease risk factors and potential overlapping treatment targets.},
}

Humans
*DNA-Binding Proteins/metabolism/genetics
*Huntington Disease/metabolism/genetics/pathology
*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology
*Huntingtin Protein/metabolism/genetics
Animals

@article {pmid41811044,
year = {2025},
author = {Wang, Y and Lu, Z and Cheng, S and Wang, Y and Yuan, H and Yuan, H},
title = {[Clinical phenotype and genetic analysis of a child with Acid-labile subunit deficiency due to variant of IGFALS gene].},
journal = {Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics},
volume = {42},
number = {12},
pages = {1465-1470},
doi = {10.3760/cma.j.cn511374-20241122-00615},
pmid = {41811044},
issn = {1003-9406},
mesh = {Humans ; Male ; Phenotype ; Child, Preschool ; *Carrier Proteins/genetics ; *Glycoproteins/genetics/deficiency ; Exome Sequencing ; Female ; Mutation ; Insulin-Like Growth Factor I/genetics/metabolism ; Growth Disorders/genetics ; },
abstract = {OBJECTIVE: To explore the clinical phenotypes and genetic characteristics of a child with Acid-labile subunit deficiency (ALS).

METHODS: A male child diagnosed with ALS at Dongguan Maternal and Child Health Care Hospital in March 2021 was selected as the study subject. Clinical data of his family was collected. Peripheral blood samples were collected from the child and his parents. Following extraction of genomic DNA, whole-exome sequencing (WES) was carried out, and Sanger sequencing was used for family verification of candidate variants. Based on guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of the candidate variant was classified. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 2020-6).

RESULTS: The patient, a 5-year-and-7-month-old boy, presented with short stature and delayed bone age. Endocrine examinations showed decreased serum concentrations of insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP3). WES revealed that he has harbored compound heterozygous variants of the IGFALS gene, namely c.741_742del, p.Y248Pfs83 and c.272del, p.P91Rfs31. Sanger sequencing verified that the variants were inherited from his father and mother, respectively. According to the ACMG guidelines, c.741_742del, p.Y248Pfs83 and c.272del, p.P91Rfs31 variants were classified as likely pathogenic (PVS1+PM2_supporting). Based on the pre-set literature search strategy, 11 research literature on ALS were retrieved, which involved a total of 33 families and 62 patients. Combined with the patient in this study, 31 IGFALS gene variants were identified among the 63 patients, which mainly consisted of missense variants (20 types), with variant sites concentrated in exon 2. The main clinical features were short stature in conjunct with delayed puberty, with a significant genotype-phenotype correlation.

CONCLUSION: The IGFALS gene variants NM_004970.2: c.741_742del, p.Y248Pfs83 and c.272del, p.P91Rfs31 may be the genetic etiology in this family. This study has expanded the variant spectrum of the IGFALS gene and provided valuable information for the diagnosis, genetic counseling and clinical treatment of the disease.},
}

Humans
Male
Phenotype
Child, Preschool
*Carrier Proteins/genetics
*Glycoproteins/genetics/deficiency
Exome Sequencing
Female
Mutation
Insulin-Like Growth Factor I/genetics/metabolism
Growth Disorders/genetics

@article {pmid41809878,
year = {2026},
author = {Xu, S and Zhu, Z and Zhang, HM and Xu, YT and Shi, PH and Zheng, Y and Chen, YT and Lu, GR and Zheng, BJ},
title = {Targeting Dialister-driven succinate accumulation: A novel strategy for Crohn's disease activity control and recurrence prevention.},
journal = {World journal of gastroenterology},
volume = {32},
number = {8},
pages = {116173},
pmid = {41809878},
issn = {2219-2840},
mesh = {Humans ; *Crohn Disease/microbiology/metabolism/blood ; *Succinic Acid/metabolism/blood ; Recurrence ; Gastrointestinal Microbiome/drug effects ; Secondary Prevention/methods ; Feces/microbiology/chemistry ; Severity of Illness Index ; Quality of Life ; },
abstract = {Crohn's disease (CD) activity and postoperative recurrence significantly affect patients' quality of life, highlighting the need for new treatment and prevention strategies. We read with interest Boronat-Toscano et al's study on Dialister-driven succinate accumulation in CD. By analyzing the fecal microbiota, circulating succinate levels, and clinical indices using clinical samples, the researchers explored the roles of Dialister and succinate in CD, a previously unaddressed area. They revealed that active CD is characterized by high succinate levels, which are associated with disease severity and inflammatory indicators. The enrichment of Dialister, linked to impaired succinate clearance and postoperative recurrence, offers new insights. The study identified succinate and Dialister as potential therapeutic targets, advancing understanding of CD pathophysiology and paving the way for further investigations. Future studies should involve large, multicenter cohorts for validation, explore Dialister's strain-specific metabolic mechanisms, and develop treatments targeting the "succinate axis", thus connecting fundamental research with clinical applications.},
}

Humans
*Crohn Disease/microbiology/metabolism/blood
*Succinic Acid/metabolism/blood
Recurrence
Gastrointestinal Microbiome/drug effects
Secondary Prevention/methods
Feces/microbiology/chemistry
Severity of Illness Index
Quality of Life

@article {pmid41809632,
year = {2026},
author = {Mazurek, CY and Kaniuk, JK and Ahuja, CS},
title = {Mesenchymal stem cells and the central nervous system: historical perspectives and future directions.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1742864},
pmid = {41809632},
issn = {1662-5099},
abstract = {Mesenchymal stem cells (MSCs) have been studied as a potential therapy for a wide range of conditions for approximately 30 years. MSCs have shown promise in treating pathologies of or affecting the central nervous system (CNS), specifically Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), traumatic brain injury (TBI), degenerative disc disease (DDD), and sepsis/meningitis. The therapeutic benefits of MSCs derive primarily from their arsenal of secreted factors that promote anti-inflammatory and pro-survival pathways while attenuating harmful immune responses, thus making them powerful immunomodulatory entities which are also capable of affecting a diverse range of cellular functions to promote endogenous mechanisms of repair. This review summarizes the current state of clinical trials research regarding pathologies of the CNS with a focus on historical progression and upcoming trials. We take a mechanistic approach to explain the therapeutic basis of MSCs and how this has informed clinical trials. We also mention the role of the MSC secretome and MSC exosomes in the treatment of CNS pathologies as well as their increasing use in clinical trials. Finally, we address the challenges inherent to the clinical translation and implementation of MSC therapies along with future directions of the field.},
}

@article {pmid41809457,
year = {2026},
author = {Maurya, P and Gupta, A and Gupta, N},
title = {Influence of blood transfusion on outcomes in patients with gastric cancer.},
journal = {World journal of gastroenterology},
volume = {32},
number = {10},
pages = {115683},
pmid = {41809457},
issn = {2219-2840},
mesh = {Humans ; *Stomach Neoplasms/surgery/mortality/immunology/therapy ; Treatment Outcome ; *Gastrectomy/adverse effects ; *Blood Transfusion/statistics & numerical data ; *Blood Loss, Surgical/prevention & control ; *Transfusion Reaction ; },
abstract = {Chen et al's research provides valuable data supporting the cautious use of transfusions during gastric cancer surgery. However, to interpret causality, it must be acknowledged that recent tend-adjusted studies have consistently shown that the independent effect of transfusions may be smaller than that shown in unadjusted analyses. Future research should employ the following approaches: (1) Extended temporal characterization; (2) Functional immunological assessment; (3) Prospective designs incorporating detailed transfusion data; (4) Machine learning methods; and (5) Mechanistic studies. The relationship between transfusions and cancer treatment outcomes goes far beyond simple immunosuppression or inflammation. It reflects a complex interplay between patient vulnerability, surgical factors, and immune responses, requiring a comprehensive study across multiple biological levels and temporal dimensions.},
}

Humans
*Stomach Neoplasms/surgery/mortality/immunology/therapy
Treatment Outcome
*Gastrectomy/adverse effects
*Blood Transfusion/statistics & numerical data
*Blood Loss, Surgical/prevention & control
*Transfusion Reaction

@article {pmid41807991,
year = {2026},
author = {Solheim, MH and Riise, T and Cortese, M and Nakken, O and Tysnes, OB and Igland, J and Bjornevik, K},
title = {Distinct Prescription Patterns Emerge Years Before ALS Diagnosis: A Nationwide Registry-Based Study.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78191},
pmid = {41807991},
issn = {1531-8249},
support = {F-12830//Helse Vest/ ; },
abstract = {OBJECTIVE: The prodromal phase of amyotrophic lateral sclerosis (ALS) is poorly defined. We aimed to characterize prescription drug use patterns in the pre-diagnostic period by analyzing nationwide prescription data to identify the earliest divergence between individuals who developed ALS and matched healthy controls. We used this divergence as an indirect marker to estimate the onset and duration of the prodrome.

METHODS: We conducted a nested case-control study using nationwide Norwegian registries (2005-2019). ALS cases were individually matched to 100 controls by sex, age, and education level using incidence density sampling. Drug prescription data were gathered from the Norwegian Prescription Database (NorPD). We calculated prescription rates up to 10 years before diagnosis, performed lag-time analyses, and used machine learning to predict ALS based on drug prescription patterns.

RESULTS: We identified 2,084 incident patients with ALS and 208,400 matched healthy controls. Overall, changes in prescription patterns occurred 2 to 3 years before ALS diagnosis. Among specific drug groups, 25 of 42 therapeutic drug classes were prescribed more frequently to patients with ALS than matched controls. Muscle relaxants and bone disease treatments were prescribed significantly more frequently 6 and 5 years before diagnosis, respectively.

INTERPRETATION: Prescription pattern changes occurred as early as 6 years before ALS diagnosis. These findings are consistent with a prodromal phase preceding the clinical stage of ALS, which may last several years. In contrast, the broad increase in medication use during the final year before diagnosis likely reflects increased health care utilization as patients seek treatment for the various emerging symptoms of the clinically manifest disease. ANN NEUROL 2026.},
}

@article {pmid41807703,
year = {2026},
author = {Guo, S and Jin, H and Sun, H and Huang, S and Chen, Y and Chang, Y and Zhang, Y and Ding, L and Chen, S and Fu, C and Yin, Y and Cheng, W},
title = {TDP-43 pathology triggers neuroinflammation and cognitive impairment by inducing microglial necroptosis.},
journal = {EMBO molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {41807703},
issn = {1757-4684},
support = {82472014//MOST | National Natural Science Foundation of China (NSFC)/ ; 24ZR1450000//STCSM | Natural Science Foundation of Shanghai Municipality ()/ ; 23ZR1441200//STCSM | Natural Science Foundation of Shanghai Municipality ()/ ; },
abstract = {Pathological TAR DNA-binding protein-43 (TDP-43) is a defining feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). However, the mechanism by which TDP-43 pathology disrupts microglial function and drives neuroinflammation remains unclear. In this study, we demonstrated that cytoplasmically mis-localized TDP-43 exacerbated neuroinflammation, induced cell death, and impaired phagocytic function in microglial cells, primarily through receptor interacting serine/threonine kinase 3 (RIPK3)-dependent necroptosis. Pharmacological inhibition of RIPK3 with GSK872 markedly attenuated these pathological effects in vitro. These findings were further corroborated in a murine model with cytoplasmic TDP-43 mis-localization, where GSK872 treatment remarkably alleviated neuroinflammation and restored cognitive deficits. Mechanistically, our findings indicate that the nuclear depletion of TDP-43, resulted from its cytoplasmic mis-localization, impairs its ability to transcriptionally repress the Ripk3 gene, subsequently leading to RIPK3 upregulation and activation of RIPK3-dependent necroptosis. Collectively, our findings establish RIPK3-dependent necroptosis as a critical driver of TDP-43 pathology-mediated neuroinflammation and identified necroptosis as a promising therapeutic target in TDP-43-associated neurodegenerative disorders.},
}

@article {pmid41804798,
year = {2026},
author = {Jagaraj, CJ and Saravanabavan, S and Parakh, S and Jayakumar, M and Kashani, SA and Shadfar, S and Mehta, P and Gautam, S and Farzana, F and Suchowerska, AK and Yap, K and Vidal, M and Ragagnin, AMG and Jamali, MS and Yang, S and Fath, T and Craik, D and Atkin, JD},
title = {Cofilin hyperphosphorylation triggers TDP-43 pathology in sporadic amyotrophic lateral sclerosis.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag096},
pmid = {41804798},
issn = {1460-2156},
abstract = {Pathological forms of TAR-binding protein 43 (TDP-43), involving its aberrant mislocalization to the cytoplasm, inclusion formation, hyperphosphorylation and fragmentation, are present in ∼45-50% frontotemporal dementia (FTD) and Alzheimer's disease individuals, and most (97%) amyotrophic lateral sclerosis (ALS) cases. Hence, identifying mechanisms that induce TDP-43 pathology are central to neurodegeneration and developing new therapeutic targets in these conditions. Cofilin is a multi-functional protein with a crucial role in regulating the actin cytoskeleton. Actin has important neuronal-specific activities in dendritic spines, axonal growth cones and synapses and it is in constant equilibrium between two forms: monomeric globular actin (G-actin) and polymeric filamentous actin (F-actin). Cofilin controls actin dynamics by depolymerising and severing actin filaments. When cofilin is phosphorylated (at Serine-3) by LIM kinase1 (LIMK1), it becomes inactive, leading to production of more F-actin. Defects in cofilin are well described in other neurodegenerative disorders, unlike in ALS. We examined phosphorylation of cofilin and actin dynamics in post-mortem spinal cord tissue from sporadic ALS (SALS) patients, the TDP-43 rNLS8 transgenic mouse model, and NSC34 motor neuronal cells expressing cytoplasmic TDP-43. F-actin was pharmacologically stabilized to mimic cofilin hyperphosphorylation, and TDP-43 pathology was assessed. Neuronal cells were treated with a non-phosphorylatable cofilin S3A peptide (MAAGVAVSDGVIKVFN), and TDP-43 pathology and apoptosis were evaluated. Here, we show that cofilin is hyper-phosphorylated in human ALS and disease models compared to controls. This was detected in spinal motor neurons from sporadic ALS (SALS) patients and a TDP-43 mouse model (rNLS8) displaying key ALS phenotypes, and in motor neuronal NSC34-cells expressing cytoplasmic TDP-43. Supporting this observation, more F-actin relative to G-actin was present in cortical/spinal cord lysates from SALS patients and TDP-43 rNLS8 mice, and NSC34-cells expressing TDP-43. We also show that mimicking cofilin hyperphosphorylation by pharmacological stabilization of F-actin induced TDP-43 pathology: cytoplasmic mislocalization, inclusion formation, hyperphosphorylation, and fragmentation, and promoted its recruitment into stress granules (SGs). Furthermore, we detected increased levels of LIMK1 phosphorylation and tropomyosin isoforms 4.1 and 4.2 in SALS patients. These findings reveal aberrant cofilin hyperphosphorylation disrupts actin dynamics, triggering TDP-43 pathology and SG recruitment in SALS. They imply that preventing cofilin phosphorylation is a novel therapeutic strategy applicable to most ALS cases. Treatment of neuronal cells with the S3A peptide prevented features of TDP-43 pathology and apoptosis compared to control peptides. These findings thus describe a novel pathogenic mechanism producing TDP-43 pathology, applicable to most ALS cases and other neurodegenerative diseases.},
}

@article {pmid41804597,
year = {2026},
author = {Georgiadou, P and Erkaya, B and Niwa-Kawakita, M and Oltan, M and Keskin, YK and Sahin, E and Öztürk, H and Tiryaki, F and Yildiz, K and Özgenç, I and Odabasi, E and Pekbilir, E and Dogan, SA and Lallemand-Breitenbach, V and Vargas, S and Prochiantz, A and Firat-Karalar, EN and de Thé, H and Sahin, U},
title = {Pml loss worsens NEK1-linked ALS and Pml induction drives NEK1 degradation, precluding disease onset.},
journal = {The FEBS journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/febs.70487},
pmid = {41804597},
issn = {1742-4658},
support = {679140//H2020 European Research Council/ ; 119N095//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; Installation Grant IG3336//European Molecular Biology Organization/ ; },
abstract = {Germinal mono-allelic loss-of-function mutations of NEK1 drive amyotrophic lateral sclerosis (ALS) at variable penetrance, presumably through haploinsufficiency. Modeling the ALS-associated Arg812Ter mutation in mice revealed that the resulting truncated Nek1 (Nek1[t]) is aggregation-prone, particularly in alpha-motoneurons (αMNs), and drives canonical ALS symptoms when bi-allelically expressed (Nek1[t/t]). Promyelocytic leukemia (Pml) ablation allows for ALS symptoms to occur even in heterozygote Nek1[wt/t] animals, mimicking the human situation. Pml precludes disease occurrence by promoting SUMO-facilitated degradation of Nek1[t] proteins through PML nuclear bodies (NBs). Conversely, Pml induction, achieved by activating the interferon pathway via poly(I:C) treatment, clears Nek1[t] puncta in αMNs, dramatically reducing ALS-associated symptoms and extending survival by 5 months. Our studies highlight the role of mutant NEK1 expression in ALS pathogenesis and identifies activation of interferon pathways as a candidate therapeutic strategy that promotes Pml-triggered SUMOylation/degradation of toxic misfolded proteins in vivo, yielding dramatic clinical improvement. These observations provide strong proof-of-concept support to validate PML as a relevant therapeutic target in neurodegenerative conditions associated with protein misfolding and putative aggregation.},
}

@article {pmid41804301,
year = {2026},
author = {Koropouli, E and Bellos, S and Aristeidou, S and Daponte, A and Gklinos, P and Athanasopoulos, F and Tsionis, A and Andreadou, E and Zouvelou, V and Rentzos, M},
title = {Motor neuron disease can present as a paraneoplastic neurologic syndrome with various phenotypes.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag024},
pmid = {41804301},
issn = {2632-1297},
abstract = {Paraneoplastic motor neuron disease is an uncommon paraneoplastic neurologic syndrome whose existence has fallen into ambiguity. Epidemiologic studies that have addressed the association between cancer and motor neuron disease have provided conflicting results. Case studies that report motor neuron disease presentation at the time of active malignant disease, in the presence of another paraneoplastic neurologic syndrome or onconeural antibody or with neurologic response to antineoplastic treatment provide strong evidence for paraneoplastic motor neuron disease. However, conclusive evidence about the existence and the clinical and laboratory profiles of this neurologic syndrome is lacking. In this study, we report four new cases of paraneoplastic motor neuron disease, two of whom with expression of Sry-like high mobility group box 1 (SOX1) antibody. We also present a systematic review of all cases of paraneoplastic motor neuron disease reported to date that fulfill prespecified inclusion criteria with individual participant data meta-analysis of the demographic, clinical and laboratory features of the disease. Our data demonstrate that motor neuron disease can present as a paraneoplastic neurologic syndrome. Paraneoplastic motor neuron disease spans the whole motor neuron disease phenotypic spectrum, and it is associated with a wide variety of neoplastic diseases, onconeural antibodies and it may present concurrently with other well-recognized paraneoplastic neurologic syndromes. Paraneoplastic motor neuron disease may be clinically indistinguishable from idiopathic motor neuron disease. Its only distinctive clinical feature is the rapidly progressive course. A subset of cases display immune derangements in cerebrospinal fluid, including increased white cell count, elevated protein, albumin index, IgG index and/or oligoclonal band expression. Cancer-induced inflammatory pathways may trigger the disease in genetically predisposed individuals harboring amyotrophic lateral sclerosis-causing genetic deficits. A thorough evaluation for neoplastic diseases should be carried out upon strong suspicion of this rare paraneoplastic neurologic syndrome to increase the diagnostic yield for this entity. Paraneoplastic motor neuron disease apparently results from complex interactions between degenerative and immune pathways and its pathophysiology may elucidate previously unresolved aspects of idiopathic motor neuron disease pathogenesis.},
}

@article {pmid41798433,
year = {2026},
author = {Matsuzawa, K and Takahashi, T and Sakata, J and Uchida, T and Suzuki, T and Sakai, T},
title = {Effectiveness of a Progressive Rehabilitation Approach Without Sport Activity Restriction for Acute Lumbar Spondylolysis in High-Level Athletes: A Retrospective Case Series.},
journal = {Cureus},
volume = {18},
number = {2},
pages = {e103041},
pmid = {41798433},
issn = {2168-8184},
abstract = {OBJECTIVE: This study aimed to examine the characteristics and clinical outcomes of high-level athletes with acute lumbar spondylolysis (ALS) treated with a progressive rehabilitation (PR) approach without rigid bracing or activity restriction.

METHODS: This retrospective consecutive case series included seven high school or collegiate athletes competing at the national level who underwent a PR approach for ALS at our institution between January 2023 and December 2024. One athlete was excluded due to loss to follow-up, leaving six athletes for analysis. The intervention consisted of a PR program without rigid bracing or activity restriction, emphasizing stepwise mobility, stability, strengthening, and pain-based progression of functional movements. Main outcomes included MRI findings, pain status, return-to-sport (RTS) rate and period, and follow-up duration.

RESULTS: Traumatic episodes were the most common etiological factor (66.7%), involving high ground reaction force movements or excessive lateral bending. MRI improvement was observed in five patients (83.3%), and pain resolution occurred in all six patients (100%). The RTS rate was 100%, with a median RTS period of 65 days (range, 54-112), which was shorter than previously reported for conservative treatment. No recurrence occurred during follow-up (median, 109 days).

CONCLUSIONS: A PR approach without rigid bracing or activity restriction enabled early RTS in high-level athletes with ALS, with symptom improvement and no recurrence. This approach may allow modification of pain-provoking or injury-related movements and help minimize declines in physical fitness and body composition associated with activity restriction. It may be suitable for post-growth high-level athletes who understand the risks related to bone healing and require timely RTS, although further research is needed to clarify stage-specific indications and long-term outcomes.},
}

@article {pmid41795667,
year = {2026},
author = {Burgess, A and Allen, O and Barkhaus, P and Barnes, B and Benatar, M and Bertorini, T and Bowser, R and Mascias Cadavid, J and Carter, GT and Cudkowicz, M and Denson, K and Dyckman, K and Elsharif, B and Feldman, E and Foucher, J and Fullum, T and Glass, J and Helmold, B and Jackson, C and Jhooty, S and Leday, A and Mallon, E and Mcdermott, C and Olby, N and Ostrow, L and Pattee, G and Pioro, E and Ratner, D and Sang, H and Tito, E and Vieira, F and Wicks, P and Bedlack, R and Gelevski, D},
title = {ALS untangled #83: clenbuterol.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/21678421.2026.2638588},
pmid = {41795667},
issn = {2167-9223},
abstract = {ALS Untangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review clenbuterol, a β-2 adrenergic agonist, as a potential treatment for amyotrophic lateral sclerosis (ALS). Clenbuterol has biological effects that could be relevant to the pathophysiology of ALS such as inducing muscle hypertrophy, improving mitochondrial function, and reducing neuroinflammation. Two studies in mouse models of motor neuron disease and two open label trials suggest possible benefits. However these have methodological flaws which limit interpretation. Clenbuterol can have an array of side effects, some severe. Drop-outs due to side effects were very common in one of the ALS trials and in a separate expanded access program. Based on this information, we cannot currently endorse clenbuterol as an ALS treatment, but we do hope to see further studies of it, or another long acting β-2 adrenergic agonist in people with ALS.},
}

@article {pmid41408351,
year = {2025},
author = {Ibragimov, U and Giordano, NA and Amaresh, S and Getz, T and Matuszewski, T and Steck, AR and Li, Y and Blum, EH and Tuttle, J and Pipalia, H and Cooper, HLF and Carpenter, JE},
title = {Implementation outcomes and strategies of a peer recovery coach program: findings from a qualitative assessment in the U.S. South, 2024-2025.},
journal = {Addiction science & clinical practice},
volume = {20},
number = {1},
pages = {95},
pmid = {41408351},
issn = {1940-0640},
support = {R01 CE003509/CE/NCIPC CDC HHS/United States ; R01CE003509/ACL/ACL HHS/United States ; R01CE003509/CC/CDC HHS/United States ; },
mesh = {Humans ; *Peer Group ; *Substance-Related Disorders/rehabilitation/therapy ; Qualitative Research ; *Emergency Service, Hospital ; Male ; Female ; Georgia ; Adult ; Program Evaluation ; Middle Aged ; *Mentoring ; Interviews as Topic ; },
abstract = {INTRODUCTION: Successful implementation of peer recovery coach (PRC) programs may help improve linkage to services and clinical outcomes for emergency department (ED) patients with substance use disorder (SUD). However, literature on implementation outcomes and strategies of PRC programs is limited. We conducted a qualitative assessment of implementation outcomes and strategies for an ED-based PRC program in Atlanta, Georgia.

METHODS: We conducted qualitative interviews with 27 program participants (ED patients with SUD served by PRC program) and 29 service providers and partners (peer recovery coaches, ED physicians and staff, SUD treatment and other service providers) in October 2023 - March 2025. We transcribed audio-recordings and analyzed data using rapid qualitative analysis approach mapping emerging themes to Proctor's model of implementation outcomes and Leeman et al.'s implementation strategies framework.

RESULTS: We identified two major themes related to implementation outcomes: (1) PRC program acceptability (patients' positive interactions with PRCs) and (2) appropriateness (sub-themes include: successful linkage to community services; PRC program as an important resource for patients; added value of PRC team; no negative impact on ED workflow). Themes related to implementation strategies include (1) streamlined communication between PRC and ED teams (direct communication via electronic medical records system, single contact phone number, informing ED service providers of clinical and program outcomes), (2) addressing barriers to community-based services (preparing patient's medical documentation, insurance, transportation to community services); (3) supportive supervision of PRCs (addressing daily and long-term issues through regular meetings; limiting caseload; and providing orientation, on-job training and mental health support) and (4) addressing telehealth implementation challenges (ensuring access to electronic medical records system).

CONCLUSION: This study outlines key implementation outcomes and strategies for PRC programs, offering practical guidance for successful ED-based PRC program implementation.},
}

Humans
*Peer Group
*Substance-Related Disorders/rehabilitation/therapy
Qualitative Research
*Emergency Service, Hospital
Male
Female
Georgia
Adult
Program Evaluation
Middle Aged
*Mentoring
Interviews as Topic

@article {pmid40543562,
year = {2025},
author = {Pope, E and Ameral, V and Falcón, A and Smith, J and Shoemaker-Hunt, SJ and Bounthavong, M and McCullough, M and Kim, B},
title = {Knowledge and attitudes regarding substance use disorder treatment and harm reduction practices among US pharmacists: A scoping review.},
journal = {Journal of the American Pharmacists Association : JAPhA},
volume = {65},
number = {5},
pages = {102462},
doi = {10.1016/j.japh.2025.102462},
pmid = {40543562},
issn = {1544-3450},
mesh = {Humans ; Attitude of Health Personnel ; *Harm Reduction ; *Health Knowledge, Attitudes, Practice ; Opioid-Related Disorders/drug therapy ; *Pharmacists/psychology/statistics & numerical data ; Professional Role ; *Substance-Related Disorders/therapy/drug therapy ; United States ; },
abstract = {BACKGROUND: Pharmacists are uniquely positioned to address substance use disorders (SUDs) and expand harm reduction services due to their accessibility and expertise in medication management. However, attitudinal and structural barriers may limit their full potential in this role.

OBJECTIVE: This scoping review examines pharmacists' knowledge, attitudes, and engagement in SUD treatment and harm reduction.

METHODS: A scoping review was conducted using Levac et al.'s enhancement of Arksey and O'Malley's framework. A systematic search of MEDLINE (PubMed), PsycInfo, Embase, ProQuest Health & Medical, and ProQuest Psychology was performed on August 3, 2024, yielding 87 articles addressing pharmacists' knowledge, attitudes, and practices related to SUD and harm reduction.

RESULTS: Pharmacists generally acknowledge the efficacy of medications for opioid use disorder (MOUDs) in reducing opioid-related mortality but often hold stigmatizing beliefs about individuals with SUDs. While supportive of harm reduction strategies, such as naloxone distribution and needle and syringe programs, engagement varies widely. Significant gaps in education and training persist, leaving pharmacists with limited confidence and practical experience in SUD care, despite their reported familiarity with MOUDs and naloxone pharmacology.

CONCLUSION: This review highlights a complex interplay of support, barriers, and knowledge gaps shaping pharmacists' roles in SUD treatment and harm reduction. Targeted education, supportive policies, and interprofessional collaboration are crucial to enabling pharmacists to provide stigma-free, comprehensive care for individuals with SUDs.},
}

Humans
Attitude of Health Personnel
*Harm Reduction
*Health Knowledge, Attitudes, Practice
Opioid-Related Disorders/drug therapy
*Pharmacists/psychology/statistics & numerical data
Professional Role
*Substance-Related Disorders/therapy/drug therapy
United States

@article {pmid32238767,
year = {2020},
author = {Kalimuthu, K and Kim, JM and Subburaman, C and Kwon, WY and Hwang, SH and Jeong, S and Cho, MG and Kim, HJ and Park, KS},
title = {Characterization of Rajath Bhasma and Evaluation of Its Toxicity in Zebrafish Embryos and Its Antimicrobial Activity.},
journal = {Journal of microbiology and biotechnology},
volume = {30},
number = {6},
pages = {920-925},
pmid = {32238767},
issn = {1738-8872},
mesh = {Animals ; *Anti-Infective Agents/chemistry/pharmacology/toxicity ; Bacteria/drug effects ; Embryo, Nonmammalian/drug effects ; India ; *Medicine, Ayurvedic ; *Metal Nanoparticles/chemistry/toxicity ; Microbial Sensitivity Tests ; Particle Size ; *Silver/chemistry/pharmacology/toxicity ; Zebrafish ; },
abstract = {In India, nanotechnology has been used in therapeutic applications for several millennia. One example of a traditional nanomedicine is Rajath Bhasma (als°Called calcined silver ash), which is used as an antimicrobial and for the treatment of various ailments and conditions such as memory loss, eye diseases, and dehydration. In this study, we aimed t°Characterize the physical composition and morphology of Rajath Bhasma and its suitability for use as a non-toxic antimicrobial agent. First, Rajath Bhasma was physically characterized via i) Fourier-transform infrared spectroscopy to analyze the surface functional groups, ii) scanning electron microscopy coupled with energydispersive X-ray spectroscopy to observe the morphology and elemental composition, and iii) X-ray diffraction to determine the crystalline phases. Thereafter, functional characterization was performed through toxicity screening using zebrafish embryos and through antimicrobial activity assessment against gram-positive (Staphylococcus epidermidis) and gram-negative (Escherichia coli) bacteria. Rajath Bhasma was found to harbor alkene, hydroxyl, aldehyde, and amide functional groups originating from biological components on its surface. The main component of Rajath Bhasma is silver, with particle size of 170-210 nm, and existing in the form of spherical aggregates with pure crystalline silver structures. Furthermore, Rajath Bhasma did not exert toxic effects on zebrafish embryos at concentrations below 5 μg/ml and exhibited effective antimicrobial activity against both gram-positive and gram-negative bacteria. The present results indicate that Rajath Bhasma is a potentially effective antimicrobial agent without toxicity when used at concentrations below 5 μg/ml.},
}

Animals
*Anti-Infective Agents/chemistry/pharmacology/toxicity
Bacteria/drug effects
Embryo, Nonmammalian/drug effects
India
*Medicine, Ayurvedic
*Metal Nanoparticles/chemistry/toxicity
Microbial Sensitivity Tests
Particle Size
*Silver/chemistry/pharmacology/toxicity
Zebrafish

@article {pmid30950445,
year = {2019},
author = {Bahcaci, U and Demirbuken, I},
title = {Effects of chemotherapy process on postural balance control in patients with breast cancer.},
journal = {Indian journal of cancer},
volume = {56},
number = {1},
pages = {50-54},
doi = {10.4103/ijc.IJC_47_18},
pmid = {30950445},
issn = {1998-4774},
mesh = {Adult ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Breast Neoplasms/*drug therapy/pathology ; Female ; Follow-Up Studies ; Humans ; Middle Aged ; Postural Balance/drug effects/*physiology ; Prognosis ; Prospective Studies ; Survivors/*statistics & numerical data ; },
abstract = {BACKGROUND: Breast cancer (BC) is the most common type of cancer among women in the world. Patients can face musculoskeletal disorders due to treatment side effects that result in failure to walk, falling, or fractures associated with balance problems.

PURPOSE: The aim of this study was to determine whether postural balance would be affected during chemotherapy (CT) in people with BC.

MATERİALS AND METHODS: A total of 32 women who consulted the medical oncology department, between 31 and 63 years of age, were admitted to the study. For fear of falling, fall efficiacy scale; for static balance, double-leg, single-leg, and tandem stance tests with eyes opened and eyes closed; Romberg test; for dinamic balance, Sit To Stand (STS) test, and Time Up and Go (TUG) tests were performed in the patients.

RESULTS: Reduced fear of falling between CT cycles (P < 0.0125), no change in postural sway in double-leg stance test with eyes opened (P = 0.734) and eyes closed (P = 0.127), significantly increased postural instability in single-leg and tandem stance test with eyes opened and eyes closed (P = 0.000), no change in postural stability in Romberg test (P > 0.05), significantly increased postural instability in STS (P = 0.000) and TUG tests (P = 0.000), and significantly increased time of finishing the STS (P = 0.021) and TUG tests (P = 0.010) were noted.

CONCLUSİON: Patients demonstrated postural instability which can ruin the daily life activities in many parameters of measurements. Postural balance exercises should be performed by BC survivors undergoing CT.},
}

Adult
Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
Breast Neoplasms/*drug therapy/pathology
Female
Follow-Up Studies
Humans
Middle Aged
Postural Balance/drug effects/*physiology
Prognosis
Prospective Studies
Survivors/*statistics & numerical data

@article {pmid27800224,
year = {2015},
author = {Savku, E and Gündüz, K},
title = {Diagnosis, Follow-Up and Treatment Results in Thyroid Ophthalmopathy.},
journal = {Turkish journal of ophthalmology},
volume = {45},
number = {4},
pages = {156-163},
pmid = {27800224},
issn = {2149-8695},
abstract = {OBJECTIVES: To discuss our follow-up and treatment results in thyroid-associated ophthalmopathy (TAO).

The records of 168 TAO cases who were followed at our clinic between October 1998 and October 2013 were reviewed retrospectively. The severity and activity of the disease were evaluated according to the criteria of the European Group on Graves' Ophthalmopathy (EUGOGO) and Clinical Activity Score (CAS).

RE­SULTS: Sixty-three men and 105 women participated in the study. The mean age of the patients was 42.3±12.4 years. Smoking habit was noted in 54.2% of the cases. Graves' disease was the most common (80.4%) thyroid pathology accompanying TAO. TAO was mild in 64.4%, moderate-to-severe in 33.6% and severe in 2% of the eyes. Male gender was found as an independent risk factor for severity of the disease (p=0.040). TAO was in the active phase in 32.6% of the eyes. Older age and high thyroid receptor antibody titer were correlated with disease activity (P=0.031 and P<0.001, respectively). Thirty-four patients (20%) were treated for ocular findings. The most common treatment was systemic steroid therapy (12%); others included orbital decompression (5%), orbital radiotherapy (2%), and topical application of guanethidine (1%).

CONCLUSION: Non-infiltrative phase and mild ocular findings were generally seen in TAO. Therefore, treatment is not recommended for many cases. Systemic steroid therapy is the most commonly used treatment modality in the active phase. However, orbital decompression surgery is necessary in a small number of cases with sight-threatening ocular findings.},
}

@article {pmid27800223,
year = {2015},
author = {Altıntaş, AG and Arifoğlu, HB and Köklü, ŞG},
title = {Modified Y-splitting Procedure for the Treatment of Duane Retraction Syndrome.},
journal = {Turkish journal of ophthalmology},
volume = {45},
number = {4},
pages = {152-155},
pmid = {27800223},
issn = {2149-8695},
abstract = {OBJECTIVES: To present the outcomes of modified lateral rectus Y-splitting combined with either unilateral or bilateral horizontal rectus recession in Duane Retraction Syndrome (DRS) with significant upshoot or downshoot.

A total of 12 patients including 10 patients with Type I DRS and 2 with Type III DRS underwent modified Y-splitting surgery. Amount of additional recessions varied with the degree of preoperative deviation by intraoperative adjustable suture technique. Preoperatively 3 patients had esotropia (ET), 6 had exotropia (XT), and 3 patients had orthotropia. The mean preoperative deviation was 19.3 prism diopters (PD) (range, 18-20 PD) in ET patients and 19.2 PD (range, 16-20 PD) in XT patients.

RE­SULTS: Postoperatively, all patients had significant correction in horizontal deviation and aligned within 4 PD of orthotropia, and no patients exhibited abnormal head posture. Co-contraction and globe retraction were markedly reduced and abnormal ocular vertical movement disappeared or significantly decreased in all cases. No patients experienced recurrence of ocular motility disorders in the mean 26-month (range, 13-66 months) follow-up period.

CONCLUSION: Modified Y-splitting surgery combined with co-contracting horizontal muscle recession technique seems to be a safe and effective treatment in DRS.},
}

@article {pmid27800220,
year = {2015},
author = {Betül Türkoğlu, E and Tuna, S and Alan, S and İhsan Arman, M and Tuna, Y and Ünal, M},
title = {Effect of Systemic Infliximab Therapy in Patients with Sjögren's Syndrome.},
journal = {Turkish journal of ophthalmology},
volume = {45},
number = {4},
pages = {138-141},
pmid = {27800220},
issn = {2149-8695},
abstract = {OBJECTIVES: To investigate the effect of systemic infliximab therapy on tear function tests and the ocular surface in patients with Sjögren's syndrome secondary to various autoimmune diseases.

This prospective study included 22 eyes of 22 patients with Sjögren's syndrome who began treatment with systemic infliximab. Tear film break-up time (TBUT), anesthetized Schirmer's 1 test, fluorescein staining test, and Ocular Surface Disease Index (OSDI) scores were recorded before treatment and in the 3rd and 6th months of treatment.

RE­SULTS: In the 3rd month of infliximab therapy, no significant changes were observed in Schirmer's values, TBUT, fluorescein staining, or OSDI scores (p=0.260, p=0.357, p=0.190 and p=0.07, respectively). In the 6th month of infliximab therapy, no significant changes were observed in TBUT, fluorescein staining, Schirmer's value or OSDI scores (p=0.510, p=0.320, p=0.220 and p=0.344, respectively).

CONCLUSION: Infliximab therapy, which is commonly used in systemic autoimmune diseases such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, and ankylosing spondylitis, did not show a positive effect on ocular surface and tear function tests.},
}

@article {pmid41792996,
year = {2026},
author = {Magen, I and Kaneb, HM and Masnata, M and Pulimood, N and Emde, A and Genge, A and Hornstein, E},
title = {Cell free miRNAs are pharmacodynamic biomarkers for enhanced Dicer activity by Enoxacin in human patients with Amyotrophic lateral sclerosis.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymthe.2026.03.002},
pmid = {41792996},
issn = {1525-0024},
abstract = {The activity of the RNase III enzyme DICER is downregulated in both sporadic and genetic forms of Amyotrophic Lateral Sclerosis (ALS). Accordingly, hundreds of microRNAs (miRNAs) are broadly downregulated, leading to de-repression of their mRNA targets. Enoxacin is a fluoroquinolone that enhances DICER activity and miRNA biogenesis. Here, we tested for the first time the molecular effect of Enoxacin on miRNA biogenesis in ALS patients and demonstrated that Enoxacin's engagement with DICER can be pharmacodynamically monitored via miRNA levels in human subjects. In an investigator-initiated, first-in-human study (REALS1), we explored miRNAs as pharmacodynamic biomarkers of DICER activation. Patients with sporadic ALS received oral Enoxacin twice daily for 30 days in a double-blind, randomized clinical trial. The study demonstrated comparable Enoxacin levels in plasma and cerebrospinal fluid (CSF). Furthermore, an increase in cell-free miRNA levels in both plasma and CSF at all time points following Enoxacin treatment (400 mg or 800 mg/day), was measured relative to baseline. Additionally, no serious adverse events were reported. In conclusion, pharmacological enhancement of DICER activity by Enoxacin increases miRNA biogenesis in patients with ALS. These results support further investigation of Enoxacin efficacy in larger clinical trials.},
}

@article {pmid41789732,
year = {2026},
author = {Scarpa, E and D'Amora, U and De Cesare, N and Bonadies, I and Dubbioso, R and Nolano, M and Dardano, P and De Stefano, L and Fasolino, A and Zeppetelli, S and Silvestri, A and Zanardi, C and Milella, E and Fasolino, I},
title = {3D Artificial Skin Model As a Novel Strategy for the Detection of Pyroptosis-Cascade Activation in Amyotrophic Lateral Sclerosis.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.5c23366},
pmid = {41789732},
issn = {1944-8252},
abstract = {Amyotrophic lateral sclerosis (ALS) is a severe adult-onset neurodegenerative disease with limited treatment approaches. Evidence has shown that degeneration of cutaneous nerves may reflect neurodegenerative processes occurring within the central nervous system. Although skin biopsy is widely adopted in clinical practice, the procedure is invasive and requires multiple patients' tissue removals. Therefore, we developed a 3D innervated skin model by combining 3D printing of methacrylated hyaluronic acid as an innovative tool for better reproducing the dermis and epidermis and electrospinning of polylactic acid for mimicking skin innervation. Later, 3D artificial skin was colonized with a preneuronal cell line (SH-SY5Y) and fibroblasts isolated from skin biopsy of ALS patients at different disease stages. 3D skin possesses a porosity suitable for cell colonization and a high stability. Importantly, biological results reveal an increase of TAR DNA-binding protein 43 aggregates, NOD-like receptor pyrin domain containing protein 3, interleukin (IL)-18, IL-6, and nitrites in 3D skin of ALS patients, thus indicating pyroptosis activation linked to neurodegeneration. This physiologically relevant 3D skin model reduces the need for repeated biopsies, allows standardized experimental conditions, and supports biomarker research and preclinical drug testing in ALS.},
}

@article {pmid41783572,
year = {2026},
author = {Liu, W and Xue, Y and Cao, C and Yang, L and Zhang, L},
title = {Copper Homeostasis and Cuproptosis in Neurological Disorders.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {580005},
pmid = {41783572},
issn = {1177-8881},
mesh = {*Copper/metabolism ; Humans ; *Homeostasis ; *Nervous System Diseases/metabolism/drug therapy ; Animals ; },
abstract = {Neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose a serious global public health threat, with complex etiologies involving genetic, environmental, and metabolic factors. Current data indicate that the prevalence of these disorders is rapidly increasing with the aging population, resulting in a growing economic and healthcare burden worldwide. In recent years, the imbalance of copper homeostasis has been increasingly implicated in the pathogenesis of neurological diseases. Copper overload can aggravate neuronal injury by inducing oxidative stress (OS), mitochondrial dysfunction, and protein misfolding, while copper deficiency disrupts the function of copper-dependent enzymes and leads to metabolic abnormalities. The mechanism of cuproptosis, proposed in 2022, describes a novel form of programmed cell death characterized by lipoylated protein aggregation and the loss of Fe-S cluster proteins, offering new insights into copper-related diseases. Multiple studies have demonstrated the crucial role of copper homeostasis and cuproptosis in the onset, progression, and treatment of neurological diseases. This narrative review summarizes the molecular mechanisms involved in copper homeostasis regulation and, on that basis, discusses the role of copper metabolism abnormalities in AD, PD, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Wilson's disease (WD), Menkes disease (MD), and stroke. Additionally, we highlight the mechanisms of existing copper-regulating drugs and their therapeutic potential in neurological disorders, while pointing out the limitations of current drug development.},
}

*Copper/metabolism
Humans
*Homeostasis
*Nervous System Diseases/metabolism/drug therapy
Animals

@article {pmid41778725,
year = {2026},
author = {Rizvi, FAS and Jimoh, Y and Allouh, MZ and Rahmon, D and Chaudhry, GR},
title = {Mesenchymal stem cell therapies for neurodegenerative diseases: Advancements, challenges, and opportunities.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01147},
pmid = {41778725},
issn = {1673-5374},
abstract = {Neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, retinal degenerative diseases, Alzheimer's disease, and Parkinson's disease, continue to pose a significant clinical challenge due to the progressive loss of neural tissue structure and function. Stem cell-based therapies are gaining attention for the treatment of neurodegenerative diseases. Mesenchymal stem cells, particularly those derived from perinatal tissues, exhibit remarkable plasticity, along with immunomodulatory, neurotrophic, and regenerative capabilities. Mesenchymal stem cells primarily influence their environment through paracrine signaling and can also differentiate into neural lineages, aiding in neuronal repair. Tissue-specific progenitor cells, such as neural stem cells and retinal progenitor cells, offer greater therapeutic precision. This review examines advancements in mesenchymal stem cell-based therapies for neurodegenerative diseases, discusses relevant clinical trials, and highlights the challenges, while proposing that personalized regenerative treatments utilizing lineage-restricted progenitors may improve patient outcomes in these complex disorders.},
}

@article {pmid41777232,
year = {2026},
author = {Yerraguntla, S and Bakshi, B and Chandran, K and Foucher, J and Benatar, M and Wicks, P and Bedlack, R and Shirilla, D and Sun, Y and Maragakis, N and Greenstein, E and Mascias Cadavid, J and Rao, A and Allen, O and Dyckman, K and Wang, O and Beauchamp, M and Chang, V and Brown, A and Carbunar, O and Paganoni, S and Bertorini, T and Pioro, E and Elsharif, B and Jiang, N and Pattee, G and Carter, G and Breevoort, S and Tito, E and Nathaniel, G and Jackson, C and Olby, N and McDermott, C and Ratner, D and Li, X},
title = {ALSUntangled #82: N-acetylcysteine.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/21678421.2026.2638590},
pmid = {41777232},
issn = {2167-9223},
abstract = {N-acetylcysteine is a thiol-containing compound and a precursor of glutathione, with mechanistic plausibility for ALS, including reducing oxidative stress, regulating neuroinflammation, and mitigating mitochondrial dysfunction. Preclinical studies have yielded conflicting results on whether N-acetylcysteine can delay the onset of motor impairment and prolong survival in ALS mouse models. Several case studies of oral or subcutaneous administration of N-acetylcysteine in patients with ALS did not demonstrate convincing benefits. Clinical trials to date have also failed to demonstrate efficacy in slowing ALS progression. While N-acetylcysteine shows theoretical promise, further research is needed to clarify its therapeutic role in ALS. At present, ALSUntangled does not support the use of N-acetylcysteine as a treatment to slow ALS progression.},
}

@article {pmid41776544,
year = {2026},
author = {Hirota, R and Lankford, KL and Nakazaki, M and Toyoshima, M and Kocsis, JD},
title = {Intranasal administration of human mesenchymal stromal cell-derived small extracellular vesicles delays disease progression in the SOD1(G93A) mouse model.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01288-0},
pmid = {41776544},
issn = {1756-6606},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, with no established disease-modifying therapy. Mesenchymal stem/stromal cells (MSCs) have been reported to exert neuroprotective effects in models of injury and disease, acting primarily through release of small extracellular vesicles (sEVs). MSC-derived sEVs (MSC-sEVs) have therefore attracted attention as a potential cell-free therapeutic approach for treating neurological conditions such as ALS. Because MSC-sEVs can cross both the nasal epithelial barrier and blood-brain barrier to reach the central nervous system (CNS), intranasal administration represents an attractive approach for repeated delivery of MSC-sEVs for long-term administration. In this study, we administered bone marrow-derived MSC-sEVs or vehicle intranasally to a SOD1(G93A) transgenic mouse model of ALS; the large majority of the sEVs had surface markers for exosomes. Dosing was for three consecutive days per week beginning one day after onset of neurological symptoms and continuing until a moribund state. Neurological score and body weight were recorded daily. Although total survival time and post-onset survival duration were not significantly prolonged by MSC-sEV treatment, MSC-sEV treatment significantly delayed progression from a mild symptom phase (NeuroScore 1) to more severe symptoms (NeuroScore 2) compared with vehicle-treated controls and showed a trend toward slower weight loss. These findings indicate that intranasal administration of MSC-sEVs can delay functional deterioration and prolong the mild impairment stage in an ALS mouse model. If translatable to human patients, such preservation of neurological function could represent a clinically meaningful outcome.},
}

@article {pmid41772227,
year = {2026},
author = {Rizzo, GEM and Vanella, G and Fuccio, L and Facciorusso, A and Mazza, S and Catena, F and Fabbri, C and Anderloni, A and Tarantino, I},
title = {Endoscopic ultrasound-guided gastrointestinal anastomoses for the treatment of afferent limb syndrome: a systematic review and meta-analysis.},
journal = {Surgical endoscopy},
volume = {},
number = {},
pages = {},
pmid = {41772227},
issn = {1432-2218},
abstract = {BACKGROUND AND STUDY AIMS: Afferent limb syndrome (ALS) is a rare condition resulting in a mechanical obstruction in the afferent loop after surgical gastrointestinal (GI) reconstruction. Endoscopic ultrasound (EUS)-guided gastrojejunostomy (GJ) or jejunojejunostomy (JJ) is increasing in clinical practice. Therefore, the aim of this systematic review with meta-analysis is to evaluate the efficacy and safety of EUS-GJ or EUS-JJ for ALS.

PATIENTS AND METHODS: The most important medical databases were systematically searched through May 2025. The primary outcome was technical success of EUS-GJ/JJ for ALS. Secondary outcomes were clinical success, safety, and recurrence rate. A random-effects model was used to pool the results. Heterogeneity was expressed as inconsistency index (I[2]) and explored through subgroup analyses.

RESULTS: 9 studies (all retrospective) involving 188 patients were included in the analysis. The weighted mean age was 65.38(± 10.57) years and the etiology of the ALS was mostly malignant. Technical success was 96.3% (CI95% 93.2-99.4%, I[2] = 0%). Clinical success was 95% (CI95% 91.2-98.7%, I[2] = 0%) and adverse events (AEs) rate was 6.9% (CI95% 2.9-11.1%, I[2] = 0%). Recurrence rate was 16.6% (CI95% 7.7-25.4%, I[2] = 43.79%). Subgroup analyses showed differences in the recurrence rate between the use of a fully covered self-expandable metal stent (FCSEMS) (35.9% [CI95% 20.3-51.6%, I[2] = 0%]) and a lumen-apposing metal stent (LAMS)(10.4% [CI95% 4-16.8%, I[2] = 0%], p = 0.003). Follow-up ranged from a median of 96.5 to 185 days.

CONCLUSIONS: EUS-guided GI anastomosis is an effective treatment for ALS, showing high technical and clinical success rates and a low incidence of AEs. The use of LAMS over FCSEMS seems to reduce the recurrence rate, suggesting the routine use of LAMS in the case of EUS-guided GI anastomosis for treating ALS.},
}

@article {pmid41765421,
year = {2026},
author = {Niidome, T and Ishida, T},
title = {[Mechanism of action and clinical trial results of a new drug for amyotrophic lateral sclerosis (ALS), Mecobalamin (Rozebalamin[®]) for intramuscular injection, 25 mg].},
journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica},
volume = {161},
number = {2},
pages = {115-122},
doi = {10.1254/fpj.25066},
pmid = {41765421},
issn = {0015-5691},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Vitamin B 12/administration & dosage/analogs & derivatives/therapeutic use/pharmacology ; Injections, Intramuscular ; Animals ; Clinical Trials as Topic ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, intractable neurodegenerative disease characterized by generalized muscle atrophy and weakness, dysarthria, dysphagia, and respiratory muscle paralysis. Respiratory dysfunction due to muscle weakness is the primary cause of death; without mechanical ventilation, death typically occurs within 2 to 5 years after onset. Mecobalamin, an active form of vitamin B12, is thought to suppress homocysteine-induced neuronal cell death in ALS by acting as a coenzyme for methionine synthase, which catalyzes the conversion of homocysteine to methionine. Since the 1990s, research on neurodegenerative diseases supported by Japan's Ministry of Health, Labour and Welfare has suggested that high-dose mecobalamin may confer clinical benefits in ALS. This led to the initiation of clinical development. A Phase II/III double-blind, placebo-controlled comparative trial was conducted, but did not meet its primary endpoint. Based on these trial findings, an investigator-initiated Phase III placebo-controlled, double-blind comparative trial was conducted primarily at Tokushima University Hospital, targeting patients who developed ALS within one year before starting the trial. The trial demonstrated the efficacy of high-dose mecobalamin in slowing the decline in the Revised ALS Functional Rating Scale total score, which was the primary endpoint. Safety was also confirmed. Based on these results, mecobalamin received regulatory approval in September 2024 for the indication "slowing the progression of functional impairment in ALS." It is expected to offer a new treatment option for patients with ALS.},
}

*Amyotrophic Lateral Sclerosis/drug therapy
Humans
*Vitamin B 12/administration & dosage/analogs & derivatives/therapeutic use/pharmacology
Injections, Intramuscular
Animals
Clinical Trials as Topic

@article {pmid41764146,
year = {2026},
author = {Ciuro, M and Sangiorgio, M and Leanza, G and Gulino, R},
title = {Neuroinflammation and Oxidative Stress in SOD1 Animal Models of ALS: A Meta-analysis Study of Their Effects on Disease Onset and Progression.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41764146},
issn = {1559-1182},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Oxidative Stress/physiology ; Disease Models, Animal ; *Disease Progression ; *Superoxide Dismutase-1/metabolism ; *Neuroinflammatory Diseases/pathology ; Humans ; Mice ; *Inflammation/pathology ; Male ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder characterized by progressive motor neuron degeneration. Among the key mechanisms implicated in ALS pathogenesis, neuroinflammation and oxidative stress have emerged as prominent contributors to disease progression. This systematic review with meta-analysis involved 344 preclinical studies conducted on SOD1 animal models of ALS, to quantitatively evaluate the effects of treatments targeting neuroinflammation and oxidative stress on functional outcomes such as disease onset, survival, motor neuron degeneration, and locomotion. Data extraction and validation were performed using a combination of a large language model and human review. Results show that while most interventions led to reduced astrogliosis, M1 microgliosis, and oxidative stress, and increased M2 microgliosis, these effects were more strongly associated with improved survival and motor outcomes than with delayed disease onset. The analysis also revealed that treatment timing significantly influences outcomes, with interventions initiated during the late pre-onset window showing the highest efficacy. Furthermore, sex differences were noted, with male mice displaying better outcomes in progression metrics but worse in the age at onset. Overall, this meta-analysis indicates that inflammation and oxidative stress are important contributors to ALS progression in SOD1 animal models, identifies potentially critical therapeutic windows, and supports the consideration of sex-balanced and stage-specific treatment strategies at the preclinical level.},
}

Animals
*Amyotrophic Lateral Sclerosis/pathology/metabolism
*Oxidative Stress/physiology
Disease Models, Animal
*Disease Progression
*Superoxide Dismutase-1/metabolism
*Neuroinflammatory Diseases/pathology
Humans
Mice
*Inflammation/pathology
Male

@article {pmid41763443,
year = {2026},
author = {Zafarjonovna, AZ and Aysulu, E and Matlyuba, S and Rashid, H and Azamatovich, JB and Ahmadjon, A and Barno, A and Kurbanovna, AM and Ugli, MRM and Shaxodat, I and Rustam, T and Jumaniyazovna, MG and Ishankulov, A},
title = {Small extracellular vesicles as emerging biomarkers and therapeutic targets in neurodegenerative diseases.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {120932},
doi = {10.1016/j.cca.2026.120932},
pmid = {41763443},
issn = {1873-3492},
abstract = {Small extracellular vesicles (sEVs) have rapidly emerged as versatile mediators of intercellular communication with significant potential to transform the diagnosis and treatment of neurodegenerative diseases (NDDs). Increasing evidence shows that sEVs not only participate in the propagation of pathogenic proteins but also serve as accessible, CNS-informative carriers of molecular signatures that reflect neuronal, glial, and systemic disease processes. This dual role positions sEVs at the intersection of biomarker discovery and therapeutic innovation. In the diagnostic domain, advances in immunoaffinity capture, single-vesicle analysis, and multi-omics profiling have enabled increasingly precise characterization of neuron-, astrocyte-, and microglia-derived sEVs, revealing candidate markers for Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and related disorders. However, translation remains limited by methodological heterogeneity, a lack of large-scale validation, and the need for standardized pre-analytical and analytical pipelines aligned with the ISEV/MISEV guidelines. On the therapeutic front, native and engineered sEVs, particularly those derived from mesenchymal and neural stem cells, demonstrate promising neuroprotective effects, including the modulation of neuroinflammation; the enhancement of synaptic resilience; and the delivery of antioxidant, anti-amyloid, or gene-modifying cargo across the blood-brain barrier. Scalable GMP manufacturing, cargo-loading strategies, targeting specificity, and long-term safety remain key challenges for clinical translation. This narrative review synthesizes current advances in sEV-based biomarkers and therapeutics, outlines technological and regulatory barriers, and proposes a translational roadmap spanning mechanistic discovery, platform standardization, and integration into precision-medicine frameworks. Collectively, emerging data position sEVs as powerful tools capable of reshaping the diagnostic and therapeutic landscape of NDDs, provided that coordinated multidisciplinary efforts address the remaining gaps in validation, scalability, and regulatory readiness.},
}

@article {pmid41763422,
year = {2026},
author = {Li, Y and Liu, S and Cao, L and Zhu, M and Lin, S and Wang, X and Qiu, Z and Teng, Y},
title = {Ginsenoside compound K inhibited the gelation of GGGGCC repeats and regulated co-aggregation with arginine-rich poly-dipeptides in C9orf72-related ALS.},
journal = {International journal of biological macromolecules},
volume = {351},
number = {},
pages = {151138},
doi = {10.1016/j.ijbiomac.2026.151138},
pmid = {41763422},
issn = {1879-0003},
abstract = {GGGGCC repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It produces toxic RNA repeats and poly-dipeptides, leading to abnormal phase separation and deposition in nerve cells. In particular, repeat RNAs form gels that induce cellular toxicity. Thus, they are potential therapeutic targets. Ginsenoside compound K (CK) is the major metabolite of Panax ginseng, a traditional Chinese medicine commonly used for the treatment of neurodegenerative diseases. In this study, CK significantly inhibited the gelation of GGGGCC repeats both in vitro and in vivo. Moreover, it reduced the co-aggregation of RNA and arginine-rich poly-dipeptides via electrostatic interactions. Further investigation suggested that CK preferentially interacts with G-quadruplex monomers formed by GGGGCC repeats rather than with complex multimers, thereby inhibiting the formation of toxic RNA foci. These results elucidate the mechanism of action of CK in C9orf72-related ALS/FTD. Thus, this study provides new avenues for the potential application of ginsenoside in the treatment of neurodegeneration.},
}

@article {pmid41762049,
year = {2026},
author = {Zhang, Y and Chen, B and Lin, Y and Kang, D and Zhao, T},
title = {Advances and Challenges in the Use of Spinal Cord Organoids in ALS.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {2},
pages = {44709},
doi = {10.31083/JIN44709},
pmid = {41762049},
issn = {0219-6352},
support = {82301543//National Natural Science Foundation of China/ ; 2021QNA025//Youth Scientific Research Project of Fujian Provincial Health Commission/ ; 2021Y2001//Technology Platform Construction Project of Fujian Province/ ; 2020Y2003//Technology Platform Construction Project of Fujian Province/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/pathology/therapy ; *Organoids/pathology ; Humans ; *Spinal Cord/pathology ; Animals ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease. No effective treatments have yet been found for ALS, primarily because the molecular mechanisms that underlie its pathogenesis are unknown. Although animal models are suitable for ALS research, species differences between these models and human spinal cord organs make it difficult to accurately predict the progression of disease in humans. Therefore, the development of more suitable models is urgently needed. Human stem cells have unlimited development potential and can be used to make three-dimensional organoid structures that mimic the architecture and function of actual organs. Organoid models can be used to overcome some of the species differences and accelerate experimental research, leading to the development of practical applications for the treatment of ALS. This article discusses the pathological mechanisms and cell types involved in ALS, as well as the genes associated with this disease. We also discuss the possible applications of spinal cord organoids (SCOs) in ALS research, such as the modeling of disease characteristics, study of pathological mechanisms, and drug screening. Finally, the prospects for SCOs in ALS treatment are highlighted, while acknowledging the need for further development of relevant technologies.},
}

*Amyotrophic Lateral Sclerosis/pathology/therapy
*Organoids/pathology
Humans
*Spinal Cord/pathology
Animals

@article {pmid41760732,
year = {2026},
author = {Sinderewicz, E and Dąbkowska, M and Sarnowska, A and Staszkiewicz-Chodor, J and Mystkowska, D and Holak, P and Drozd, I and Chodkowska-Michalowska, M and Rytel, M and Paczkowska, E and Mycko, MP and Machalinski, B and Jezierska-Wozniak, K},
title = {Safety and biodistribution of intrathecal administration of mesenchymal stem cells (MSCs) and neurotrophin-releasing nanoparticles in a porcine CSF-guided delivery model for amyotrophic lateral sclerosis (ALS) drug discovery.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-40196-0},
pmid = {41760732},
issn = {2045-2322},
support = {No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder that complicates the identification of effective therapeutic targets. The potential of stem cells and neurotrophins as promising candidates has become increasingly evident, owing to their neuroprotective and anti-inflammatory properties. In this study, a preclinical evaluation of the safety and biodistribution of mesenchymal stromal/stem cells (MSCs) combined with neurotrophin-releasing polyelectrolyte nanoparticles (NTs) was conducted in a porcine intrathecal delivery model relevant to ALS therapy development. Four groups of male pigs were administered saline with NTs, adipose-derived stem cells (ASCs) with NTs, Wharton's jelly-derived MSCs (WJ-MSCs) with NTs, or spinal puncture only. The safety of the treatment was assessed using magnetic resonance imaging (MRI), haematological and biochemical analyses, cerebrospinal fluid profiling, and histology. No adverse effects or significant systemic alterations were observed. It is noteworthy that C-reactive protein levels diminished following NT and NT-MSC administration, suggesting a systemic anti-inflammatory effect. The migration of MSCs was facilitated by cerebrospinal fluid, leading to their accumulation around the spinal cord and brain parenchyma. The present findings demonstrate short-term safety and biodistribution patterns following intrathecal administration of MSCs combined with neurotrophin-releasing nanoparticles in a large-animal model. These preliminary observations provide a pilot framework for future efficacy studies in disease-specific ALS models. This work establishes a translational platform for the development of future ALS therapies, with subsequent studies focused on efficacy testing in disease-specific models that more accurately reflect the slow, heterogeneous, multisystem nature of human ALS.},
}

@article {pmid41759589,
year = {2026},
author = {Cooper, M and Singh, S and Ferrer, E and Turner, S and Timko, CA},
title = {Calculating developmental weight suppression in practice: A commentary demonstrating the use and misuse of Singh and colleagues' new approach.},
journal = {Appetite},
volume = {222},
number = {},
pages = {108513},
doi = {10.1016/j.appet.2026.108513},
pmid = {41759589},
issn = {1095-8304},
abstract = {Eating disorders (ED) typically onset during youth, a critical period of growth and development. Maintenance of appropriate body weight is a criterion in multiple ED diagnoses and informs weight restoration. Data suggest that weight suppression (WS), the difference between an individual's highest historical and current weights, may be linked to ED severity and prognosis. Singh et al. (2021) formulated a developmentally-adjusted measure of WS using BMI z-scores to account for developmental growth during adolescence. Studies since have established both the face and incremental validity of developmental WS with respect to eating concerns, binge eating behavior, and abnormal endocrine and metabolic markers of ED, suggesting its benefit over traditional estimates of WS. Unfortunately, however, many studies have misapplied Singh et al.'s method by using z-scores based on highest premorbid weight, rather than using highest premorbid BMI z-score. This error can lead to underestimation of developmental WS. In this commentary, we present several case examples to demonstrate the importance of using growth chart data to identify the highest BMI z-score for the purpose of developmental WS calculation, as opposed to self-report highest past weight and height. We discuss how this procedure influences target weight calculation, the need for weight restoration in treatment, and diagnostic and clinical care considerations.},
}

@article {pmid41756852,
year = {2026},
author = {Malik, T and Jones, S and Ma, O and Mohan, S and Burger, RM and Babcock, DT},
title = {Autophagy induction mitigates FUS aggregate formation and early synaptic dysfunction at the NMJ in the FUS-ALS model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.19.706635},
pmid = {41756852},
issn = {2692-8205},
abstract = {Mutations in Fused in Sarcoma (FUS), a RNA binding protein, cause Amyotrophic Lateral Sclerosis (ALS). ALS is an aggressive neurodegenerative disease resulting in motor neuron degeneration. Defects in synaptic integrity precede neuronal loss in ALS, but the mechanisms responsible for these early synaptic defects are unclear. To investigate early synaptic defects associated with ALS, we expressed an ALS-linked variant of human FUS in adult motor neurons and assessed synaptic pathology at the neuromuscular junction (NMJ). Here we highlight the accumulation of FUS-positive aggregates at synaptic terminals and subsequent reduction in microtubule stability. We show that inducing autophagy via expression of Rab1 or Fragile-X Mental Retardation Protein 1 (FMR1), or treatment with Rapamycin reduces aggregate formation and restores synaptic structure and function. These findings reveal the utility of inducing autophagy to address early synaptic dysfunction in an ALS model and demonstrate a potential therapeutic target to preventing later stages of disease progression.},
}

@article {pmid41756461,
year = {2026},
author = {Petriti, B and Subramanian, S and Williams, P and Chau, KY and Licznerski, P and Lascaratos, G and Aguilar-Munoa, S and Kamal, D and Bae, H and Alavian, K and Garway-Heath, D and Jonas, E},
title = {Reversing Mitochondrial Dysfunction in Optineurin E50K Glaucoma: A Metabolic Approach to Neuroprotection.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8380062/v1},
pmid = {41756461},
issn = {2693-5015},
abstract = {Mutations in optineurin (OPTN) are linked to neurodegenerative diseases such as normal tension glaucoma (NTG) and amyotrophic lateral sclerosis. The E50K-OPTN mutation is the most common genetic cause of NTG, where it disrupts mitophagy and leads to the accumulation of dysfunctional mitochondria. To understand how cellular metabolism is altered in these persistent mitochondria, and whether any pathological state can be reversed, we investigated NTG-patient-derived fibroblasts carrying the E50K-OPTN mutation. We identified a form of mitochondrial leak metabolism driven by elevated levels of the ATP synthase c-subunit leak channel (ACLC). These cells exhibit reversed F1FO ATP synthase activity, increased mitochondrial proton leak, and fragmented mitochondria, resulting in inefficient oxidative phosphorylation and a shift toward aerobic glycolysis and high protein synthesis rate. The ratio of ATP synthase c-subunit to β-subunit was markedly elevated, suggesting open ACLC pores. Treatment with dexpramipexole normalized ATP synthase function and cellular metabolism, promoted ATP synthesis rather than hydrolysis and reduced protein synthesis rates. Dexpramipexole reduced p62 levels in E50K fibroblasts, consistent with a reduced mitophagic burden from decreased accumulation of damaged mitochondrial cargo. These findings identify ACLC-mediated leak as a central driver of metabolic dysfunction in E50K-OPTN glaucoma and suggest ACLC closure as a viable therapeutic strategy.},
}

@article {pmid41752118,
year = {2026},
author = {Kurdi, MA and Alotaibi, H and Alkhuraymi, AT and Aldahery, LN and Alhawaj, AF and Aldali, HJ},
title = {Amyotrophic Lateral Sclerosis (ALS) Genetics and Microbiota: A Comprehensive Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {4},
pages = {},
pmid = {41752118},
issn = {1422-0067},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/microbiology/therapy ; Humans ; Genetic Therapy ; *Gastrointestinal Microbiome ; C9orf72 Protein/genetics ; Animals ; Superoxide Dismutase-1/genetics ; Mutation ; RNA-Binding Protein FUS/genetics ; DNA-Binding Proteins/genetics ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a severe, progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons, affecting 0.5 to 2.6 per 100,000 people, with a median survival of 2 to 5 years. It is increasingly seen as a multisystem disorder, sharing essential clinicopathological features with Frontotemporal Dementia (FTD). This convergence arises from overlapping molecular processes, including severe oxidative stress, glutamate-mediated excitotoxicity, mitochondrial dysfunction, and widespread aggregated TDP-43 proteinopathy in both sporadic and familial cases. Several key genetic factors have been identified, particularly mutations in C9orf72, SOD1, TARDBP, and FUS, which serve as important targets for novel treatments, such as Tofersen, a recently approved SOD1-specific antisense oligonucleotide (ASO) gene therapy. Additionally, there is increasing evidence of the gut-brain connection. Dysbiosis, involving species such as Akkermansia muciniphila, and lower levels of neuroprotective metabolites, such as nicotinamide, may affect the course of the disease. As a result, treatment strategies are shifting toward a personalized approach. This includes using gene therapy, ranging from ASOs and RNA interference (RNAi) to new CRISPR-based genome editing. It also involves exploring microbiome-modulating treatments, such as specific probiotics and Fecal Microbiota Transplantation (FMT). While microbiome and gene therapies remain largely experimental, their potential is promising, as highlighted by the recent approval of Tofersen. These novel approaches could be further enhanced and guided by more robust diagnostic criteria and by investigating early multimodal treatment strategies to slow the progression of this complex disease.},
}

*Amyotrophic Lateral Sclerosis/genetics/microbiology/therapy
Humans
Genetic Therapy
*Gastrointestinal Microbiome
C9orf72 Protein/genetics
Animals
Superoxide Dismutase-1/genetics
Mutation
RNA-Binding Protein FUS/genetics
DNA-Binding Proteins/genetics

@article {pmid41751955,
year = {2026},
author = {Luong, DT and Niu, C and Kim, E and Tanji, N and Duong, I and Galero, B and Zhang, YJ and Bennett, CL and La Spada, AR},
title = {PPAR-Delta Agonist Therapies Did Not Rescue Hallmark Disease Phenotypes in Two Sets of Preclinical Trials in ALS TDP-43 and C9orf72 Model Mice.},
journal = {International journal of molecular sciences},
volume = {27},
number = {4},
pages = {},
pmid = {41751955},
issn = {1422-0067},
support = {W81XWH-20-1-0154//United States Department of Defense/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; Mice ; *PPAR delta/agonists/metabolism ; Disease Models, Animal ; Mice, Transgenic ; *C9orf72 Protein/genetics/metabolism ; Phenotype ; *DNA-Binding Proteins/genetics/metabolism ; Male ; Neurofilament Proteins/blood ; Humans ; },
abstract = {Peroxisome-proliferator-activated receptor delta (PPARδ) regulates metabolic, mitochondrial, and inflammatory pathways implicated in neurodegeneration, making it an attractive therapeutic target for amyotrophic lateral sclerosis (ALS). In this study, we evaluated two PPARδ agonists, KD3010 and T3D-959, in two established ALS/FTD mouse models: an AAV-mediated C9orf72 G4C2-repeat expansion model (C9-149R) and the TDP-43[Q331K] transgenic model. Drug treatment was initiated prior to the emergence of key disease features and continued for 9-10 months. Comprehensive behavioral, neuropathological, and biomarker analyses revealed marked differences between the two models. C9-149R mice exhibited reduced body weight and subtle behavioral alterations without robust motor deficits, whereas TDP-43[Q331K] mice developed pronounced, progressive motor and cognitive impairments accompanied by a ~7-fold elevation in plasma neurofilament light chain (NfL). Despite effective target engagement-particularly for T3D-959-neither PPARδ agonist improved motor performance, cognitive behavior, neuroanatomical measures, plasma NfL levels, or disease-associated molecular phenotypes in either model. Prolonged KD3010 treatment resulted in loss of target engagement, consistent with drug tolerance, while T3D-959 sustained PPARδ activation without therapeutic benefit. Together, these findings demonstrate that PPARδ agonism is insufficient to modify disease progression in these ALS/FTD mouse models and underscore the importance of publishing well-powered negative preclinical studies to refine therapeutic strategies for ALS.},
}

Animals
*Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology
Mice
*PPAR delta/agonists/metabolism
Disease Models, Animal
Mice, Transgenic
*C9orf72 Protein/genetics/metabolism
Phenotype
*DNA-Binding Proteins/genetics/metabolism
Male
Neurofilament Proteins/blood
Humans

@article {pmid41751793,
year = {2026},
author = {Ptáček, O and Musil, Z and Guarnieri, G and Vrbacká, A and Moudrá, P and Zlámalová, A and Röszlerová, P and Tonhajzer, M and Musil, V and Morelli, A and Zach, P},
title = {Amyotrophic Lateral Sclerosis: The State of the Art on Treatments and the Therapeutic Role of the Intestinal Microbiome in Human Studies.},
journal = {International journal of molecular sciences},
volume = {27},
number = {4},
pages = {},
pmid = {41751793},
issn = {1422-0067},
support = {Cooperatio 39 - Oncology and Haematology//Charles University/ ; Cooperatio 33-Intensive Care Medicine//Charles University/ ; Cooperatio 36-Medical Diagnostics and Basic Medical Sciences//Charles University/ ; #NEXTGENERATIONEU//European Commission/ ; MNESYS (PE0000006) - A Multiscale integrated approach to the study of the nervous system in health and disease (DR. 1553 11.10.2022)//Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP)/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/microbiology ; *Gastrointestinal Microbiome ; *Fecal Microbiota Transplantation/methods ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disorder; to date, there is no long-term effective treatment. Recently, a relationship has been discovered between the human intestinal microbiome and the pathogenesis of ALS, on which basis faecal microbiota transplantation (FMT) has been proposed as a potential treatment for ALS. In this review, we compare three existing case studies examining the effect of FMT on the course of ALS, highlighting differences in methodology and results. In two of the studies, a halt in the progression of ALS symptoms was observed following FMT, accompanied by improvement in patient health. However, in the third and largest study, no significant effect of FMT was observed. The possible explanation for this discrepancy may be the intentional depletion of intestinal microorganisms using antibiotics prior to FMT in the third study. Future studies and/or completion of the ongoing clinical studies will help clarify the therapeutic effectiveness of FMT in ALS patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/microbiology
*Gastrointestinal Microbiome
*Fecal Microbiota Transplantation/methods

@article {pmid41745965,
year = {2026},
author = {Haroun, M and Tratrat, C and Mathew, RT and Munir, M and Sattar, MN and Shawky, M and Kochkar, H and Aldakhilallah, ON and Ghafoor, A and Turk, KGB and Geronikaki, A and Ghazzawy, HS},
title = {Avian Candidiasis: A Comprehensive Review of Pathogenesis, Diagnosis, and Control.},
journal = {Veterinary sciences},
volume = {13},
number = {2},
pages = {},
pmid = {41745965},
issn = {2306-7381},
support = {Grant number: KFU260519//Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University, Saudi Arabia/ ; },
abstract = {This review is a comprehensive investigation of avian candidiasis, mainly caused by Candida albicans, although the prevalence of non-albicans Candida species has increased in domestic and wild birds. Avian candidiasis causes significant economic losses in poultry production through increased mortality, cost of treatments, and reduced growth rates, particularly in young birds and intensive farming operations. The pathogenesis section provides a description of the molecular virulence factors such as adhesin-mediated attachment (ALS, Agglutinin-Like Sequence family; HWP1, Hyphal Wall Protein 1), yeast-to-hypha morphogenesis, tissue damage by Candidalysin, biofilm formation on mucosal and abiotic surfaces, and secreted hydrolytic enzymes including secreted aspartyl proteinases (SAPs) and phospholipases. The identified predisposing factors include immunosuppression, malnutrition, abuse of antibiotics, bad husbandry, and crop stasis. The diagnostic methods discussed encompass cytological analysis and fungal culture on selective media to more sophisticated methods of molecular analysis (PCR, MALDI-TOF MS, and NGS). Antifungal susceptibility investigations indicate that nystatin and amphotericin B are still very effective against most avian isolates and that resistance to the azoles is on the rise, especially with respect to the non-albicans Candida species. Nystatin is still the first-line treatment of localized infections; azoles are still used for resistant or systemic infections despite their hepatotoxicity. Sanitation, proper nutrition, and proper use of antimicrobials are essential to prevent diseases. The knowledge gaps comprise the absence of avian-specific pharmacokinetic information, poor knowledge of species-species virulence phenotypes, and the lack of point-of-care diagnostics. The need to have integrated One Health surveillance systems is emphasized by the zoonotic potential of the avian Candida reservoirs.},
}

@article {pmid41744765,
year = {2026},
author = {Dellazizzo Toth, T and Bond, S and Saxena, S},
title = {The Calcium Connection: Explaining Motor Neuron Vulnerability in ALS.},
journal = {Cells},
volume = {15},
number = {4},
pages = {},
pmid = {41744765},
issn = {2073-4409},
abstract = {ALS is a severe neuromuscular disease classically characterized by the progressive loss of motor neurons, leading to incremental muscle weakness and eventually death. Current treatment options for ALS have proven to have limited effect, merely delaying the progression of symptoms and prolonging patient survival. This motor neuron subtype-related differential vulnerability has been linked to neuron excitability, metabolism, and protein aggregation. Calcium dysregulation, which serves as an important second messenger in neural signaling pathways, has been implicated in each of these mechanisms and represents a potential target for therapeutic intervention. Armed with cutting-edge tools for visualizing and recording calcium transients in vivo, ALS researchers have delved deeper into the role of calcium dysregulation in disease in recent years. Vulnerable motor neuron populations display an excess of calcium-permeable ion channels together with reduced expression of calcium-binding proteins, generating a cellular environment primed for excitotoxic stress. Loss of inhibitory synaptic input further heightens susceptibility to calcium overload. Paradoxically, some evidence suggests that elevated neuronal activity can exert neuroprotective effects, highlighting the complexity of activity-dependent calcium signaling in ALS. Additionally, ALS-related toxic protein accumulation disrupts calcium homeostasis, contributing to endoplasmic reticulum stress and mitochondrial dysfunction. Emerging data indicate that calcium dysregulation impairs neuron-glia communication, amplifying neuroinflammation and accelerating disease progression. This review aims to synthesize current evidence on how calcium imbalance contributes to motor neuron vulnerability and degeneration in ALS. By exploring the cellular, synaptic, and network-level mechanisms of calcium dysregulation in ALS, the review examines its interplay with mitochondrial and ER stress and explores its impact on neuron-glia interactions with the aim of synthesizing key mechanistic insights into the disease pathogenesis and therapeutic targets.},
}

@article {pmid41744255,
year = {2026},
author = {Labeit, B and Bach, J and Harborth, E and Dziewas, R and Meuth, SG and Grefkes, C and Willems, L and Lapa, S},
title = {Impact of a Neurogenic Dysphagia Outpatient Clinic on Diagnosis, Treatment, and Nutrition.},
journal = {European journal of neurology},
volume = {33},
number = {3},
pages = {e70544},
pmid = {41744255},
issn = {1468-1331},
support = {529859742//Deutsche Forschungsgemeinschaft/ ; },
abstract = {BACKGROUND: The aim was to evaluate the diagnostic, therapeutic, nutritional, and complication-related impact of a university-led neurogenic dysphagia outpatient clinic.

METHODS: We retrospectively analyzed all patients seen at the University Hospital Frankfurt Neurogenic Dysphagia Outpatient Clinic (January 2021-July 2023). Data included demographics, neurological diagnoses, Functional Oral Intake Scale (FOIS), Penetration-Aspiration Scale (PAS) from Flexible Endoscopic Evaluation of Swallowing (FEES), nutritional status, therapy adjustments, and pneumonia requiring hospitalization. We quantified diagnostic revisions, therapeutic/nutritional interventions, and modeled pneumonia risk using logistic regression.

RESULTS: Among 255 patients (mean age 65.9 years; 60.0% men), Parkinsonian syndromes (18.0%) and stroke (12.9%) were most frequent. Complications included weight loss (32.8%), choking (20.0%), and pneumonia (12.6%). Primary diagnosis changed in 38.8% of patients. Of 110 patients with initially unexplained dysphagia, 70.9% received a neurological diagnosis, most often ALS and Parkinsonian syndromes (each 19.5%). Therapy recommendations changed in 42.0% of patients, including symptomatic and disease-modifying treatments; nutritional management was dynamic (new PEG in 16.1%; removal in 50.0% of existing PEGs); 42.9% of tracheostomized patients were decannulated. Frailty (OR 1.49, p = 0.005) and PAS 8 (OR 3.67, p = 0.007) independently predicted pneumonia.

CONCLUSION: A dedicated outpatient dysphagia clinic enhances diagnostic precision, optimizes therapy, and supports individualized nutritional and airway management. FEES-based phenotyping strengthens differential diagnostics and enables the identification of previously unrecognized neurological syndromes. Silent aspiration and frailty identify patients at the highest pneumonia risk. Dysphagia should be regarded as an independent therapeutic target within disease-specific neurological treatment, and dysphagia outpatient clinics should be integrated into standard neurological care pathways.},
}

@article {pmid41744126,
year = {2026},
author = {Yang, Q and Wu, H and Huang, X and Xie, M and Shan, Y and Dou, Z and Li, Y and Wen, H and Li, C},
title = {Prevalence and Risk Factors of Dysphagia in Amyotrophic Lateral Sclerosis: A Retrospective Study Using the Nationwide Inpatient Sample Database.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70188},
pmid = {41744126},
issn = {1097-4598},
support = {2024FYQ001//Affiliated Hospital of Shandong Second Medical University/ ; 2023B110003//Guangdong Provincial Clinical Research Center for Rehabilitation Medicine/ ; },
abstract = {INTRODUCTION/AIMS: Dysphagia is a common but under-characterized complication in Amyotrophic lateral sclerosis (ALS), contributing to morbidity and healthcare burden. This study aimed to investigate the prevalence, pinpoint risk factors, and assess the adverse clinical outcomes linked to dysphagia in hospitalized patients with ALS.

METHODS: This retrospective cohort study analyzed 23,997 ALS cases derived from the Nationwide Inpatient Sample (NIS) database, covering the years 2010 to 2019. Data collection included patient demographics (age, sex, race/ethnicity), hospital characteristics (size, teaching status, location), clinical parameters (comorbidity profiles, complications), and healthcare utilization metrics (length of stay and hospitalization costs).

RESULTS: Among 23,997 ALS patients, 7419 (31.7%) were diagnosed with dysphagia. The annual prevalence of dysphagia in ALS patients varied substantially over the decade. Patients with dysphagia experienced a longer hospital stay (5 vs. 4 days; p < 0.001), incurred $6656 in additional hospitalization costs (p < 0.001), and faced heightened risks of complications such as cognitive impairment, cerebrovascular accidents, respiratory muscle paralysis, and tracheostomy. Multivariate analysis identified several independent risk factors for the development of dysphagia, including age ≥ 65 years, female sex, Hispanic ethnicity, treatment at large or medium-sized hospitals, care at urban teaching hospitals, and comorbidities such as depression, malnutrition, and weight loss.

DISCUSSION: Dysphagia affected approximately one-third of hospitalized ALS patients in this study, contributing to extended hospital stays and increased healthcare costs. Timely screening and tailored interventions are crucial for minimizing complications and maximizing the efficient use of resources.},
}

@article {pmid41744019,
year = {2026},
author = {Shi, Y and Xiao, S and He, D},
title = {Visualization analysis of the use of traditional Chinese medicine in the diagnosis and treatment of rare diseases in mainland China based on CiteSpace.},
journal = {Intractable & rare diseases research},
volume = {15},
number = {1},
pages = {71-84},
pmid = {41744019},
issn = {2186-3644},
abstract = {This study used CiteSpace (version 6.4.R1) to perform a visualization analysis of 3,058 articles on traditional Chinese medicine (TCM) diagnosis and treatment of rare diseases retrieved from the China National Knowledge Infrastructure (CNKI) database, the VIP Chinese Science and Technology Periodical Database (VIP), the Wanfang database (Wanfang), and the Chaoxing database (Chaoxing). The goal was to ascertain the current status of research, hotspots in research, and trends in the development of TCM for rare disease diagnosis and treatment in mainland China, providing insights for future TCM research in this field. Visual maps of annual publication volume, authors, institutions, keywords, and other content have revealed that TCM demonstrates prominent advantages in 5 out of 207 defined rare diseases: idiopathic pulmonary fibrosis, hepatolenticular degeneration (Wilson's disease), osteosarcoma, retinitis pigmentosa, and multiple sclerosis. Potential advantages are identified in treating melanoma, amyotrophic lateral sclerosis, homocysteinemia, primary biliary cholangitis, and lymphangioleiomyomatosis. TCM research on rare diseases focuses on etiology, pathogenesis, and syndrome differentiation-based treatment. Case-control studies and mechanism investigations have been initiated for some conditions, while clinical research is gradually incorporating integrated TCM-Western medicine approaches. However, enhanced team and institutional collaboration, development of multicenter networks, exploration of multidisciplinary research, and clinical studies yielding high-level evidence are still needed to provide quality evidence-based support for clinical decision-making in the TCM treatment of rare diseases.},
}

@article {pmid41743427,
year = {2026},
author = {Luo, Y and Liu, X and Yang, M},
title = {Current status and future prospects of brain-computer interfaces in the field of neurological disease rehabilitation.},
journal = {Frontiers in rehabilitation sciences},
volume = {7},
number = {},
pages = {1666530},
pmid = {41743427},
issn = {2673-6861},
abstract = {Neurological disorders represent a significant category of diseases that profoundly affect human health, accounting for the second leading cause of global mortality. This group of conditions includes stroke, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, Parkinson's disease, and cerebral palsy, among others. These disorders are highly susceptible to sequelae and profoundly impact individuals' daily lives. In this context, Brain-Computer Interface (BCI) technology has demonstrated considerable potential in the domain of neurorehabilitation, although numerous challenges remain. The manuscript provides a comprehensive review of recent advancements in research and clinical applications, highlighting current limitations and outlining future directions. It elucidates the applicability and constraints of Brain-Computer Interface (BCI) technology across various diseases and patient populations. To facilitate insights across different conditions, comparative tables are presented, aligning BCI strategies with therapeutic targets, outcomes, advantages, limitations, and existing evidence gaps. The scope extends beyond motor restoration to include under-explored domains, such as neuropathic pain, with a focus on real-world translation, including home and community feasibility and the distinction between assistive and rehabilitative applications. The review distills overarching limitations within the field, such as small sample sizes, protocol heterogeneity, and limited longitudinal evidence, while synthesizing the most recent studies. An actionable research and development roadmap is proposed to guide next-generation BCI rehabilitation, incorporating individualized cortical-network simulators, self-architecting decoders, adaptive therapy approaches akin to game seasons, and proprioceptive "write-back" mechanisms via peripheral interfaces. Moreover, the review reveals significant research focal points and critical issues that warrant further investigation in the context of neurological rehabilitation utilizing BCI technology.},
}

@article {pmid41740899,
year = {2026},
author = {Al Tawil, A and Lauseker, M and Mansmann, U},
title = {Estimating Causal Effects on Quality of Life Under Treatment Discontinuation: The ALTA-1L Trial.},
journal = {Journal of clinical epidemiology},
volume = {},
number = {},
pages = {112189},
doi = {10.1016/j.jclinepi.2026.112189},
pmid = {41740899},
issn = {1878-5921},
abstract = {BACKGROUND: Time to worsening in health-related quality of life (HRQoL) is increasingly used in oncology trials. Treatment discontinuation poses a challenge: once discontinued, patients cease HRQoL assessments, precluding outcome observation. Standard survival analyses censor at discontinuation, assuming non-informative censoring-an assumption often violated when discontinuation relates to disease progression or toxicity. Bridging the ICH E9(R1) estimand framework with causal inference methods clarifies how to define and estimate treatment effects in such settings. We reanalyse time to worsening in global health status (GHS) from the ALTA-1L trial (brigatinib versus crizotinib in ALK+ non-small-cell lung cancer), integrating both frameworks.

METHODS: Following Young et al.'s (2020) causal framework for competing events, we defined two estimands structured according to ICH E9(R1): (1) a controlled direct effect under a hypothetical strategy, envisioning a scenario where treatment discontinuation would not occur, estimated using inverse probability of censoring weighted Kaplan-Meier to adjust for informative censoring; and (2) a total effect under a while-on-treatment strategy, with discontinuation as a competing event, estimated using the Aalen-Johansen estimator. Risk ratios (RRs) were estimated at 36 months with bootstrap confidence intervals.

RESULTS: The original ALTA-1L analysis reported HR = 0.69 (95% CI: 0.49, 0.98), censoring at discontinuation and assuming non-informative censoring. Deriving the RR at 36 months from Kaplan-Meier curves yields 0.75 (95% CI: 0.59, 0.97). After adjusting for informative censoring, the controlled direct effect was RR = 0.89 (95% CI: 0.65, 1.26). The total effect was RR = 1.03 (95% CI: 0.76, 1.40), reflecting the competing risk structure: earlier discontinuation in the crizotinib arm (discontinuation RR = 0.54; 95% CI: 0.38, 0.72) reduced observed worsening events. These different estimates illustrate how different estimands address distinct clinical questions.

CONCLUSION: This study bridges the ICH E9(R1) estimand framework with causal inference methods for time-to-event HRQoL analysis when discontinuation precludes observation. By quantifying bias from standard approaches, we provide methodological clarity for applied researchers. To facilitate practical implementation, we translate these insights into a decision flowchart for estimand specification and method selection when intercurrent events (ICEs) act as competing events. Future trials should pre-specify ICE-handling strategies and consider data collection beyond ICEs to support treatment policy estimation.},
}

@article {pmid41723979,
year = {2026},
author = {Gao, Y and Lu, Y and Zhao, S and Chen, R and Liu, J and Zhang, S and Bai, X and Zhang, J},
title = {Allicin improves motor neuron survival in amyotrophic lateral sclerosis by reducing neuroinflammation and modulating gut microbiota.},
journal = {Biochemical and biophysical research communications},
volume = {809},
number = {},
pages = {153503},
doi = {10.1016/j.bbrc.2026.153503},
pmid = {41723979},
issn = {1090-2104},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons (MNs). Allicin, a defensive molecule in garlic with anti-inflammatory and gut microbiota-modulating properties, has shown therapeutic potential in animal models of various diseases including Alzheimer's disease (AD). However, its possible therapeutic role in ALS remains unclear. The purpose of this study is to investigate the therapeutic effect of allicin in ALS transgenic SOD1[G93A] mice. Starting at 60 days of age, SOD1[G93A] mice received oral gavage of allicin (10 mg/kg) on alternate days, while the control group received an equal volume of normal saline (NS) on the same schedule. Twelve mice per group were used for monitoring disease onset and survival. Nissl staining and choline acetyltransferase (ChAT) immunofluorescence were used to quantify MNs in the anterior horn. Microglial activation was analyzed by immunofluorescence staining for Iba1, ARG1, and CD86. The mRNA expression levels of IL-10, TGF-β, IL-1β, and TNF-α were examined using qPCR. Additionally, fecal samples were collected for 16S rDNA sequencing to evaluate changes in gut microbiota composition. We observed that allicin treatment failed to prolong the onset time and survival period of SOD1[G93A] mice, but it extended the disease duration. Nissl staining analysis revealed that allicin treatment delayed the loss of spinal MNs, a finding corroborated by ChAT immunofluorescence. Furthermore, allicin treatment significantly reduced neuroinflammation and improved gut microbiota. Taken together, although allicin may prolong disease duration in ALS, it did not improve overall survival or delay disease onset. Therefore, its potential disease-modifying effects require further validation.},
}

@article {pmid41718290,
year = {2026},
author = {Messina, C},
title = {Silent Damage, Delayed Symptoms: A Case of Breast Cancer Radiation-Induced Lumbosacral Plexopathy.},
journal = {Reports (MDPI)},
volume = {9},
number = {1},
pages = {},
pmid = {41718290},
issn = {2571-841X},
abstract = {Background and Clinical Significance: Radiation-induced lumbosacral plexopathy (RILP) is a rare but potentially debilitating complication of radiotherapy, typically affecting patients treated for pelvic malignancies. We report the first documented case of asymmetric RILP following radiotherapy for breast cancer. Case Presentation: A 64-year-old woman developed progressive left lower limb weakness, foot drop, and sensory disturbances four years after receiving locoregional radiotherapy extending to the left thoracoabdominal and lumbar areas. Electrophysiological studies revealed an asymmetric sensorimotor axonal neuropathy predominantly involving the left lower limb, without conduction block and sparing the upper limbs, whereas needle electromyography of the lower limbs showed fibrillation potentials, positive sharp waves, and fasciculations in the vastus lateralis, tibialis anterior, and medial gastrocnemius muscles on the left. Magnetic resonance imaging demonstrated edema and contrast enhancement of bilateral L2-L4 nerve roots with paraspinal muscle atrophy. Cerebrospinal fluid analysis showed albuminocytologic dissociation and elevated neurofilament levels. After exclusion of alternative diagnoses, including amyotrophic lateral sclerosis and inflammatory neuropathies, a diagnosis of radiation-induced peripheral neuropathy and RILP was made. The patient's condition stabilized with physiotherapy and symptomatic treatment. Conclusions: This case highlights the need for heightened awareness of RILP as a late complication of breast cancer radiotherapy, underscoring the importance of accurate diagnosis to avoid misclassification and unnecessary treatments. Clinicians should carefully integrate all clinical elements-including a thorough remote medical history-since radiation-related neurological damage may manifest many years after the initial insult.},
}

@article {pmid41714394,
year = {2026},
author = {Warmann, S},
title = {[Motor neuron diseases from a radiological perspective : Focus on amyotrophic lateral sclerosis].},
journal = {Radiologie (Heidelberg, Germany)},
volume = {},
number = {},
pages = {},
pmid = {41714394},
issn = {2731-7056},
abstract = {BACKGROUND: Motor neuron diseases (MND) affect the upper and/or lower motor neurons. Radiological diagnostics primarily serve to systematically exclude treatable mimics and support the clinical and electrophysiological diagnosis. The focus is on amyotrophic lateral sclerosis (ALS); supplementary progressive muscular atrophy (PMA, purely lower motor neuron, LMN disease) and spinal muscular atrophy (SMA).

OBJECTIVE: Which imaging signs support the diagnosis of ALS, how do electromyography/magnetic resonance imaging (EMG/MRI) fit into the Gold Coast criteria and which other motor neuron diseases are relevant?

MATERIAL AND METHODS: Overview of clinical criteria (Gold Coast), genetics and typical MRI findings of the brain, spinal cord and musculature.

RESULTS: Gold Coast core: progressive motor deterioration, upper motor neuron (UMN) and LMN signs in ≥ 1 region or LMN in ≥ 2 regions and exclusion of alternative causes.

IMAGING: susceptibility-weighted imaging (SWI) motor band sign as UMN marker; T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities along the corticospinal tract with low sensitivity, moderate specificity; T1 bright tongue as an indication of chronic denervation in bulbar involvement. EMG: detection of subclinical LMN involvement, sometimes limited in UMN-dominant/bulbar courses. PMA: Pure purely LMN symptoms, often continuum to ALS. SMA: Autosomal autosomal recessive (SMN1 deletion).

DISCUSSION: The diagnosis remains primarily clinical; EMG and MRI are supportive. The radiological priority is the exclusion of mimics. The UMN markers increase diagnostic certainty in the context of clinical/EMG findings but do not replace them. Clear findings facilitate classification according to Gold Coast. The PMA and SMA require careful differential diagnostics; characteristic MRI patterns support progression and treatment planning.},
}

@article {pmid41710977,
year = {2026},
author = {Liu, Q and Zhang, X and Wang, L and Chen, H and Wang, G and Sun, Y and He, B and Gao, J and Qiu, W and Ma, C and Sun, M and Cui, L and Zhang, X},
title = {BTK inhibition suppresses neuroinflammation and neurodegeneration in amyotrophic lateral sclerosis.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag070},
pmid = {41710977},
issn = {1460-2156},
abstract = {Amyotrophic lateral sclerosis(ALS) is a devastating neurodegenerative disorder with limited therapeutic interventions. Neuroinflammation represents a central pathogenic mechanism in ALS, yet the upstream molecular regulators that integrate multiple inflammatory cascades remain poorly understood. Here, we investigated whether Bruton's tyrosine kinase (BTK), which integrates DNA-sensing and Toll-like receptor signals upstream of the cGAS-STING-NF-κB cascade, serves as a key regulatory node in ALS pathogenesis. Public RNA-seq datasets of motor neurons and post-mortem tissues from ALS patients were utilized to identify BTK expression patterns. SOD1-mutant human induced pluripotent stem cells (hiPSC) were differentiated into motor neurons (hiPSC-MNs) and microglia (hiPSC-MGs). NF-κB dysregulation was profiled by scRNA-seq (hiPSC-MGs) and bulk RNA-seq (hiPSC-MNs). DNA damage (γH2AX), inflammatory signalling (western blot/ELISA) and phagocytosis (pH-rodo uptake) were quantified, and MG-conditioned medium was tested for MN toxicity. Monocultures and MN-MG co-cultures received zanubrutinib (3 µM, 12 h). SOD1-G93A mice were administered zanubrutinib (30 mg/kg, daily) from 2.5 months; motor performance, survival, spinal histology and PI3K-AKT-mTOR activity were assessed after 2 months of treatment. ALS spinal cord and cortex tissues of patients, as well as SOD1-mutant hiPSC-MGs and hiPSC-MNs, demonstrated elevated BTK phosphorylation with increased p-STING, p-TBK1, and nuclear NF-κB accumulation. ALS hiPSC-MGs exhibited inflammatory activation, NLRP3 induction, and impaired phagocytosis, while ALS hiPSC-MNs showed DNA damage and caspase-3-mediated apoptosis. Conditioned medium from inflammatory microglia amplified neuronal STING-NF-κB activity and apoptosis, demonstrating non-cell-autonomous toxicity. The STING inhibitor H-151 reduced neuronal p-STING/p-TBK1/NF-κB and apoptosis, confirming pathway causality. Pharmacological BTK inhibition reduced DNA damage in ALS hiPSC-MNs by 61.4% (p<0.05), restored phagocytosis in ALS hiPSC-MGs to 87.2% of control levels (p<0.01), and prevented neuronal apoptosis induced by microglial conditioned medium. In SOD1-G93A mice, BTK blockade extended median survival from 158 to 173 days (p<0.01, log-rank test), improved motor function, and attenuated neuroinflammation while moderately rebalancing PI3K-AKT-mTOR signaling without impairing autophagy-lysosome dynamics. We identify BTK as a critical upstream regulator of the dysregulated cGAS-STING-NF-κB signalling axis characteristic of ALS pathogenesis. BTK orchestrates both cell-autonomous dysfunction in motor neurons and non-cell-autonomous toxicity through microglial activation, representing a convergent regulatory node that integrates multiple pathogenic pathways. These mechanistic insights provide a molecular framework for understanding ALS neuroinflammation and establish a rational basis for BTK-targeted therapeutic intervention in neurodegeneration.},
}

@article {pmid41708347,
year = {2026},
author = {Gontier, G and Kim, G and Wang, C and Zhu, K and Gau, R and Zhang, N and Naphade, S and Stewart, A and Schmidt, MJ and Galemmo, R and Shook, B and Tarachandani, A and Choi, I and Raines, S and Scannevin, RH and Grievink, HW and Smits, LMG and Kremer, PHC and Cadavid, D},
title = {Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB): A Translational Pharmacodynamic Biomarker for PIKfyve Inhibition With VRG50635.},
journal = {Clinical and translational science},
volume = {19},
number = {2},
pages = {e70489},
pmid = {41708347},
issn = {1752-8062},
support = {//Verge Genomics/ ; },
mesh = {Humans ; Animals ; Mice ; *Membrane Glycoproteins/metabolism/blood/cerebrospinal fluid ; Male ; *Amyotrophic Lateral Sclerosis/drug therapy/cerebrospinal fluid/blood ; Biomarkers/blood/cerebrospinal fluid ; Female ; Adult ; Middle Aged ; *Phosphoinositide-3 Kinase Inhibitors ; Phosphatidylinositol 3-Kinases/metabolism ; Leukocytes, Mononuclear/drug effects/metabolism ; Induced Pluripotent Stem Cells/drug effects ; Healthy Volunteers ; Administration, Oral ; },
abstract = {Glycoprotein non-metastatic melanoma protein B (GPNMB) was investigated as a pharmacodynamic (PD) biomarker for PIKfyve inhibition across translational studies ex vivo, in vitro, in animals, and in the clinic, demonstrating significant response to VRG50468 in cells, in vivo in the central nervous system (CNS) and in peripheral fluids and tissues. VRG50468 is the active metabolite of VRG50635, a small molecule PIKfyve inhibitor pro-drug in development for treating amyotrophic lateral sclerosis (ALS). Peripheral pharmacology was evaluated in peripheral blood mononuclear cells (PBMCs) from healthy volunteers ex vivo and in vitro and in PBMCs from mice given oral VRG50635. Central pharmacology was evaluated in vitro using C9orf72 ALS patient-derived induced pluripotent stem cell motor neurons and mouse primary neurons, and in vivo in brains of mice given oral VRG50635. Two clinical studies in healthy adults examined plasma, PBMCs, and cerebrospinal fluid following oral VRG50635 for peripheral and central pharmacologic activity via GPNMB induction. PD GPNMB upregulation with VRG50468 was demonstrated across preclinical translational and clinical studies. A PD response to VRG50468 was observed ex vivo in rodent and human PBMCs and in primary rodent neurons and motor neurons induced from stem cells of people with ALS. Repeated administration of VRG50635 to rodents and healthy human volunteers robustly induced GPNMB peripherally and in the CNS, which was concentration and time dependent in vitro and dose and treatment duration dependent in vivo, peripherally, and in CNS. GPNMB is a robust translatable PD biomarker for clinical trials with the PIKfyve inhibitor VRG50635. TRIAL REGISTRATION: Clinical trial number: VGCS-50635-001 and VGCS-50635-003; identifier: NL81735.056.22 and NCT06286475.},
}

Humans
Animals
Mice
*Membrane Glycoproteins/metabolism/blood/cerebrospinal fluid
Male
*Amyotrophic Lateral Sclerosis/drug therapy/cerebrospinal fluid/blood
Biomarkers/blood/cerebrospinal fluid
Female
Adult
Middle Aged
*Phosphoinositide-3 Kinase Inhibitors
Phosphatidylinositol 3-Kinases/metabolism
Leukocytes, Mononuclear/drug effects/metabolism
Induced Pluripotent Stem Cells/drug effects
Healthy Volunteers
Administration, Oral

@article {pmid41707709,
year = {2026},
author = {He, K and Wang, H and Cao, Y},
title = {Response to Bingyang Xu et al.'s "Optimized combination: Isotretinoin in conjunction with oral tranexamic acid for the treatment of moderate to severe acne vulgaris-A randomized, double-blind, placebo-controlled trial".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2025.12.117},
pmid = {41707709},
issn = {1097-6787},
}

@article {pmid41707703,
year = {2026},
author = {Xu, B and Wu, J},
title = {Response to He et al.'s comments of "Optimized combination: Isotretinoin in conjunction with oral tranexamic acid for the treatment of moderate to severe acne vulgaris-A randomized, double-blind, placebo-controlled trial".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2026.01.092},
pmid = {41707703},
issn = {1097-6787},
}

@article {pmid41705073,
year = {2026},
author = {Sotgia, S and Zinellu, A and Zoroddu, S and Pateri, MI and Loi, E and Pisano, A and Sabalic, A and Tutedde, D and Benedetti, AFV and Floris, F and Puligheddu, M and Valera, P and Zavattari, P and Borghero, G and Madeddu, R},
title = {Elevated serum trimethylamine N-oxide (TMAO) and trimethyllysine in patients with amyotrophic lateral sclerosis (ALS): An exploratory case-control study.},
journal = {IBRO neuroscience reports},
volume = {20},
number = {},
pages = {227-231},
pmid = {41705073},
issn = {2667-2421},
abstract = {Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite implicated in protein homeostasis, inflammation, and chronic disease, but its relevance in amyotrophic lateral sclerosis (ALS) remains poorly characterized. In this exploratory pilot study, we quantified circulating TMAO and related trimethylammonium-containing compounds in a Sardinian ALS cohort using targeted LC-MS/MS. Serum samples were collected under fasting conditions from 12 ALS patients and 8 age- and sex-matched healthy controls. Median serum TMAO levels were markedly higher in ALS patients than in controls (27.9 vs. 4.0 µmol/L, P < 0.05), with substantial inter-individual variability in the ALS group (range 2.4-125.0 µmol/L). Trimethyllysine (TML) concentrations were also significantly elevated in ALS (0.43 vs. 0.34 µmol/L, P < 0.05), whereas choline, carnitine, betaine, ergothioneine, and γ-butyrobetaine levels did not differ between groups. Most ALS patients were receiving acetyl-L-carnitine (ALCAR) supplementation, suggesting that ALCAR intake may contribute to the observed metabolite profiles. Overall, these findings indicate alterations in trimethylammonium-containing compound metabolism in ALS and underscore the need for larger, well-controlled studies to determine whether such changes reflect disease-related mechanisms, treatment effects, or their interaction.},
}

@article {pmid41677019,
year = {2026},
author = {Bjørnstadjordet, M and Kvernmo, HB and Bråthen, G and Simpson, MR and Sando, SB and Hagen, K and Devik, K and Wergeland, T},
title = {Four decades of ALS care: a retrospective study of epidemiology, clinical course and changes in management.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2026.2627903},
pmid = {41677019},
issn = {2167-9223},
abstract = {BACKGROUND: Several interventions have been introduced for amyotrophic lateral sclerosis (ALS) in recent decades, and population-level studies investigating their use and impact are needed. This study describes the epidemiology, disease trajectory, and changes in clinical management of ALS in a county of Norway over a 38-year period.

METHODS: We conducted a retrospective chart review of all ALS cases diagnosed between 1986 and 2024 in Trøndelag county, Norway. Data were extracted from medical records using a standardized electronic case report form. Patients were stratified by time of diagnosis into four groups.

RESULTS: A total of 429 patients were included (56% male). Median age at symptom onset was 68 years. The age-standardized incidence of ALS was 3.32 per 100,000 person-years (95%CI 2.90-3.74) and increased over time (p = 0.002). Bulbar onset occurred in 38% of cases. Median diagnostic delay was 13 months (95%CI 12-14), without significant improvement over time. Median survival was 28 months (95%CI 26-31) from symptom onset, shorter among bulbar-onset patients. Use of riluzole, percutaneous endoscopic gastrostomy, and noninvasive ventilation (NIV) increased over the study period, whereas median survival remained stable. Emergency initiation of ventilation occurred in 25% (NIV n = 41/167) and 89% (invasive ventilation n = 16/18) of cases in which these treatment modalities were used.

CONCLUSION: This comprehensive regional study reveals a rising incidence of ALS in Trøndelag, with increased adoption of supportive interventions over time.},
}

@article {pmid41675725,
year = {2026},
author = {Patel, T and Henna, F and Sharif, I and Javed, I and Mustafa, F and Sharif, H and Nasir, F and Javaid, M and Usman, SF and Hanani, C and Anand, N},
title = {A narrative review on the therapeutic potential of stem cells in neurodegenerative diseases: advances, insights, and challenges.},
journal = {Annals of medicine and surgery (2012)},
volume = {88},
number = {2},
pages = {1441-1453},
pmid = {41675725},
issn = {2049-0801},
abstract = {BACKGROUND: Neurodegenerative diseases (NDs) such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) are set apart by progressive neuronal loss and concomitant functional decline. Traditional therapies are equipped with only symptomatic relief, devoid of neurorestorative properties. Stem-cell-based therapies have the potential to revolutionize neurological care by replenishing lost cells, mitigating inflammation, and fostering a neuroprotective environment.

OBJECTIVES: This narrative review aims to appraise the treatment potential of various stem cell types in managing NDs, highlighting their functional pathways, delivery methods, and current experimental validation.

METHODS: A comprehensive literature search was carried out based on data retrieved from PubMed, The Cochrane Library, and ClinicalTrials.gov. Thirty-one studies that fulfill PICO criteria and only English-language publications are incorporated in this review. No part of the study design, data collection, analysis, or interpretation was conducted using artificial intelligence.

RESULTS: Stem cells, including embryonic stem cells, mesenchymal stem cells (MSCs), induced pluripotent stem cells, and neural stem cells, possess distinctive regenerative properties. MSC-derived exosomes can traverse the blood-brain barrier and improve nerve cell longevity. Administration routes such as intravenous, intranasal, and direct brain transplantation are being studied. Neurodegenerative conditions such as PD, AD, HD, and ALS have been widely studied for therapeutic benefits.

CONCLUSION: Regardless of their potential, stem cell therapies raise health risks, including neoplastic growth and immunological incompatibility, alongside bioethical issues. Developments in genetic modification, nanotechnology, and preconditioning strategies are being analyzed to optimize outcomes. Long-term research, harmonization of protocols, and extended patient follow-up are essential for the safe and effective development of medical applications.},
}

@article {pmid41673790,
year = {2026},
author = {Zheng, W and Xu, L and Cai, J and Hou, J and Chen, L and Zhang, N and Zhan, S and Fan, D and He, J},
title = {Comprehensive clinical and genetic architecture of familial amyotrophic lateral sclerosis in China: A 15-year cohort study with 302 families.},
journal = {Neural regeneration research},
volume = {21},
number = {6},
pages = {2573-2579},
doi = {10.4103/NRR.NRR-D-24-00701},
pmid = {41673790},
issn = {1673-5374},
abstract = {JOURNAL/nrgr/04.03/01300535-202606000-00072/figure1/v/2026-02-11T151048Z/r/image-tiff The growing recognition of the role of genetics in the development of amyotrophic lateral sclerosis is evident. However, there has yet to be a comprehensive analysis of the clinical characteristics and genetics of familial amyotrophic lateral sclerosis in an Asian population. This study aimed to provide an in-depth analysis of the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinic-based cohort of patients from the Chinese mainland. Enrollment of 302 amyotrophic lateral sclerosis families from 28 provinces was undertaken from January 2008 to September 2023. A group-based trajectory model for disease progression based on amyotrophic lateral sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores was validated using bootstrap internal validation in patients with familial amyotrophic lateral sclerosis, as well as patients with sporadic amyotrophic lateral sclerosis (matched at a 1:4 ratio, with replacement). DNA samples from 244 index patients were screened for variants in the pathogenic genes SOD1, FUS, TDP43, and C9ORF72, of which 146 were also subjected to genome-wide next-generation sequencing. Gene-level burden analysis was used to evaluate the distribution of rare variants in the cohort. We found that rapid dynamic disease progression was associated with an older age at onset, shorter diagnostic delay, lower body mass index, bulbar onset, and ≥ 1 affected first-degree relative. Certain attributes, such as age at onset and time from onset to diagnosis, had comparable impacts on the clinical progression trajectories of both familial amyotrophic lateral sclerosis and sporadic amyotrophic lateral sclerosis. Harboring pathogenic/likely pathogenic variants in amyotrophic lateral sclerosis-causative genes reduced the age of onset of familial amyotrophic lateral sclerosis. Among the patients with familial amyotrophic lateral sclerosis, 17.8% possessed ≥ 2 pathogenic/likely pathogenic variants. Sequencing kernel association test analysis showed that the SOD1 rare variant burden (P = 1.3e-15) was associated with a significant risk of familial amyotrophic lateral sclerosis. Our findings conclusively confirmed the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinical cohort from China, contributing to a deeper understanding of genotype-phenotype relationships in familial amyotrophic lateral sclerosis. This comprehensive evaluation of specific clinical characteristics, clinical prognosis, and genetic variants of amyotrophic lateral sclerosis based on detailed clinical and genetic information may lead to the development of genotype-specific treatment approaches.},
}

@article {pmid41672134,
year = {2026},
author = {Maneu, V and García, AG},
title = {P2X7 receptors as targets for neuroprotection.},
journal = {Neuropharmacology},
volume = {289},
number = {},
pages = {110877},
doi = {10.1016/j.neuropharm.2026.110877},
pmid = {41672134},
issn = {1873-7064},
abstract = {In this review we explore the potential of P2X7 receptor blockers to elicit neuroprotection. This conjecture is based on a reasonably well-established role of this receptor in activating glial cells to maintain a chronic low-level neuroinflammatory state in the brain of patients suffering some neurodegenerative diseases (NDDs). In this context we briefly discuss evidence supporting the role of P2X7 receptors (P2X7) in the pathogenesis of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. From a pathogenic point of view these diseases have specific features but all share a low level neuroinflammatory state with microglia activation and enhanced P2X7 expression. Next, we comment on available P2X7 blockers with central nervous system (CNS) target engagement. Then, we deal with the proof-of-concept concerning the potential of some blockers to mitigate the neuroinflammatory state in preclinical models of the target diseases above mentioned. We follow with a discussion of the scarce number of clinical trials done with some P2X7 blockers in inflammatory diseases. Finally, we discuss the current discrepancy between promising preclinical data and the limited number of clinical trials exploring P2X7 antagonists in NDDs. We provide some clues that may boost clinical trials with single P2X7 blockers but particularly, with their association with other medicines currently being used or that are intended to be prescribed in the treatment of NDDs.},
}

@article {pmid41672113,
year = {2026},
author = {Prova, NS and Elsayyid, MW and Tanis, JE},
title = {Superoxide dismutase impacts extracellular vesicle shedding and uptake.},
journal = {Free radical biology & medicine},
volume = {247},
number = {},
pages = {540-550},
doi = {10.1016/j.freeradbiomed.2026.02.008},
pmid = {41672113},
issn = {1873-4596},
abstract = {Extracellular vesicles (EVs), which transfer bioactive macromolecules between cells, play a critical role in the pathogenesis of multiple neurodegenerative diseases. Focus has centered on how altered EV contents propagate disease and on the potential for EVs as diagnostic biomarkers, while the effects of pathogenic factors on EV release are poorly understood. Using a functional endogenous reporter, we showed that the key antioxidant enzyme superoxide dismutase 1 (SOD-1) is expressed in C. elegans EV-releasing neurons, localizes to the cytoplasm, and reduces levels of reactive oxygen species (ROS). We then defined how sod-1 mutations affect EV shedding from sensory neuron primary cilia into the environment, ciliary enrichment of proteins packaged into EVs, and glial uptake of EVs in vivo, by imaging C. elegans expressing fluorescent protein-tagged EV cargoes. Deletion of SOD-1, as well as the SOD-1(G85R) amyotrophic lateral sclerosis (ALS) pathogenic variant, increased EV shedding from the cilium distal tip, and this was associated with greater abundance of EV cargo in this ciliary compartment. In contrast, loss of SOD-1 reduced the glial uptake of a different EV subpopulation that is shed from the ciliary base, without affecting release into the environment. These results demonstrate that SOD-1 has a subtype-specific effect on the release of EVs with distinct signaling potentials. Intriguingly, we discovered that exposure to paraquat, which increases mitochondrial ROS, reduced the shedding of both distal tip and ciliary base-derived EVs. These opposing effects of the sod-1 mutations and paraquat treatment on EV release suggest that ROS in distinct subcellular compartments may differentially impact ciliary EV shedding.},
}

@article {pmid41670738,
year = {2026},
author = {Thorarinsson, BL and Sveinsson, OA and Hilmarsson, A and Sigurthorsdottir, TB and Andersen, PM},
title = {Treating SOD1-ALS with tofersen results in nonprogressive chronic ALS-a case series from Iceland.},
journal = {Journal of neurology},
volume = {273},
number = {2},
pages = {140},
pmid = {41670738},
issn = {1432-1459},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/cerebrospinal fluid ; Male ; Iceland ; *Superoxide Dismutase-1/genetics ; Middle Aged ; Female ; Aged ; Adult ; *Oligonucleotides/therapeutic use/administration & dosage ; Mutation/genetics ; Neurofilament Proteins/cerebrospinal fluid ; *Oligonucleotides, Antisense/therapeutic use ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. We describe four patients with hereditary ALS caused by the p.Gly94Ser SOD1 mutation who were treated monthly with the intrathecal antisense oligonucleotide tofersen in a clinical setting at Landspitali University Hospital of Iceland. After initiating treatment 15-26 months ago, no significant clinical deterioration was observed, and three patients showed signs of clinical improvement, with some recovery of motor function. All four patients currently present with chronic nonprogressive ALS, a phenotype not previously observed or documented. Concomitantly, the concentration of neurofilament light chain (Nf-L) in the cerebrospinal fluid decreased to the normal range. This clinical benefit and decrease in Nf-L levels were detected regardless of the patient's initial ALSFRS-R score. No serious adverse events were observed. Notably, we observed a clinically meaningful effect in two patients who had been ill for several years before treatment was instituted, raising questions about who should receive treatment and the biology of paresis and motor neuron cell loss in patients with ALS. Although only a minority of ALS patients carry a SOD1 mutation, the advent of this new precision medicine has profound implications for ALS management.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/drug therapy/cerebrospinal fluid
Male
Iceland
*Superoxide Dismutase-1/genetics
Middle Aged
Female
Aged
Adult
*Oligonucleotides/therapeutic use/administration & dosage
Mutation/genetics
Neurofilament Proteins/cerebrospinal fluid
*Oligonucleotides, Antisense/therapeutic use

@article {pmid41665706,
year = {2026},
author = {Giacomini, PS and Voss, P and Devonshire, V and Schneider, R and Macaron, G and Hussein, S and Blanchette, F and de Villers-Sidani, É},
title = {Eye tracking as a digital biomarker in neurodegenerative diseases.},
journal = {Journal of neurology},
volume = {273},
number = {2},
pages = {133},
pmid = {41665706},
issn = {1432-1459},
mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/physiopathology/complications ; Biomarkers ; *Eye-Tracking Technology ; *Eye Movements/physiology ; },
abstract = {Oculomotor abnormalities are a common finding in neurodegenerative diseases due to degeneration of neural pathways and brain regions involved in controlling eye movements. Pathological changes to the dorsolateral prefrontal cortex, basal ganglia, superior colliculus and cerebellum produce subtle changes in eye-movement metrics that may not be detected by clinical examination. The present review addresses the potential use of eye-movement biomarkers in neurodegenerative conditions such as multiple sclerosis, Parkinson's disease, Alzheimer's disease and other dementias, and amyotrophic lateral sclerosis. Eye-movement metrics such as saccades, anti-saccades, fixation and smooth pursuit are prognostic of disease progression, can differentiate pathologic subtypes as an aid to diagnosis, and enable clinicians to evaluate early worsening of motor and cognitive function. The cost of medical technologies limits their optimal use and accessibility in clinical practice. The shortage of subspecialist neurologists further limits access to care. New eye-tracking technologies incorporated into widely-accessible digital devices such as smart phones and tablets now permit detailed assessments with minimal equipment requirements, providing an important non-invasive and potentially cost-effective method for patient evaluation in routine clinical practice and as an aid to treatment decision-making. Digital biomarkers can be readily employed by healthcare professionals such as family physicians, nurses and pharmacists to bridge the care gaps, potentially providing them with powerful tools that can be broadly adopted to improve the delivery of care to patients with neurodegenerative conditions.},
}

Humans
*Neurodegenerative Diseases/diagnosis/physiopathology/complications
Biomarkers
*Eye-Tracking Technology
*Eye Movements/physiology

@article {pmid41663779,
year = {2026},
author = {Roy, KK and Kumari, R and Upadhyay, AK and Mohanty, S},
title = {Tailoring treatments: pharmacogenomics in the management of neurodegenerative diseases.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {41663779},
issn = {2240-2993},
abstract = {Neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis are growing more common worldwide, yet treatment is still poor. Conventional therapies can have unforeseen side effects, produce poor medication reactions, and take longer to work. This persistent treatment gap highlights the need for novel approaches to these disorders' complex distinctions. Pharmacogenomics, which examines how genetic differences affect drug response, is a promising new subject and an urgent solution. Pharmacogenomics tailors medicine selection and administration to each patient's genetic profile, addressing the main causes of poor treatment response and preventable side effects. This research has enabled precision medicine that can improve neurodegenerative disease therapy and reduce harm. In this in-depth research, we examine neurodegenerative disease management issues, pharmacogenomics breakthroughs, and how incorporating genetics to clinical practice can improve outcomes. We examine the latest evidence that genetics affect drug breakdown, efficacy, and toxicity. We also discuss the challenges and opportunities of applying this knowledge. Pharmacogenomic approaches must be widely applied to make medicines for these awful disorders safer, more effective, and really suited to patient needs, according to our compilation.},
}

@article {pmid41661214,
year = {2026},
author = {Miller, TM and Cudkowicz, ME and Shaw, PJ and Genge, A and Sobue, G and Bucelli, RC and Chiò, A and Van Damme, P and Ludolph, AC and Glass, JD and Andrews, JA and Babu, S and Benatar, M and McDermott, CJ and Salachas, F and Bruneteau, G and Al-Chalabi, A and Amorin, M and Nestorov, I and Graham, D and Lin, L and Sun, P and McNeill, M and Malek, S and Inra, J and Garafalo, S and Fradette, S and , },
title = {Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis.},
journal = {JAMA neurology},
volume = {83},
number = {2},
pages = {115-125},
pmid = {41661214},
issn = {2168-6157},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Male ; Middle Aged ; Female ; Double-Blind Method ; *Superoxide Dismutase-1/genetics ; Aged ; Adult ; *Oligonucleotides/therapeutic use/administration & dosage ; *Oligonucleotides, Antisense/therapeutic use ; Treatment Outcome ; },
abstract = {IMPORTANCE: Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are attributable to a pathogenic variant in the superoxide dismutase 1 (SOD1) gene. Tofersen, an intrathecal antisense oligonucleotide designed to reduce SOD1 protein synthesis, is the first and only approved therapy for the treatment of ALS in adults who have a variant in the SOD1 gene.

OBJECTIVE: To evaluate the long-term effects of tofersen in adults with SOD1-ALS.

The phase 3, randomized, double-blind, placebo-controlled VALOR trial (A Study to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tofersen in SOD1-ALS; conducted from March 2019 to July 2021) evaluated tofersen use over 28 weeks in adults (18 years and older) with weaknesses attributable to ALS and a confirmed SOD1 pathogenic variant at 32 sites in 10 countries; participants could then enroll in an open-label extension (OLE; completed August 2024).

INTERVENTION AND EXPOSURE: Adults with SOD1-ALS were randomly assigned 2:1 to receive tofersen (100 mg) or placebo over a 24-week period in the VALOR study. All participants in the OLE were treated with tofersen.

MAIN OUTCOMES AND MEASURES: Integrated analysis of VALOR and the OLE study aimed to compare early start vs placebo/delayed start (approximately 6 months later) treatment with tofersen. Key efficacy end points included measures of axonal injury and neurodegeneration (neurofilament), function and strength, quality of life, and survival.

RESULTS: VALOR enrolled 108 participants with 42 unique SOD1 pathogenic variants (mean [SD] age: placebo/delayed-start group 51.2 [11.6] [n = 36]; early-start group: 48.1 [12.6] [n = 72]) with 19 (53%) and 43 (60%) of participants being male in the placebo/delayed- and early-start groups, respectively. Overall, 95/108 participants (88%) enrolled in the OLE, and 46 participants completed the OLE (early-start group, 34 [47%]; placebo/delayed-start group, 12 [33%]). At OLE completion, participants could have accumulated 3.5 years or more (range, 192-276 weeks) of follow-up from the start of VALOR. Over 148 weeks, earlier initiation of tofersen (compared to later initiation) was associated with numerically less decline in measures of clinical function (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, -9.9 vs -13.5 points), respiratory function (slow vital capacity, -13.8% vs -18.1%), muscle strength (handheld dynamometry megascore, -0.38 vs -0.43 points), and quality of life (Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 score, 17.0 vs 22.5 points; EuroQol 5 Dimension, 5 Level Questionnaire score, -0.1 vs -0.2 points). Tofersen prolonged survival relative to the expected natural history of SOD1-ALS. Most adverse events were consistent with ALS progression or known procedural adverse effects. All serious neurological adverse events were reversible; few led to tofersen discontinuation.

CONCLUSIONS AND RELEVANCE: Final data from VALOR and the OLE demonstrated the benefit of tofersen in SOD1-ALS and provide clear rationale for its use in this population.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: VALOR NCT02623699; OLE NCT03070119.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy/genetics
Male
Middle Aged
Female
Double-Blind Method
*Superoxide Dismutase-1/genetics
Aged
Adult
*Oligonucleotides/therapeutic use/administration & dosage
*Oligonucleotides, Antisense/therapeutic use
Treatment Outcome

@article {pmid41657419,
year = {2026},
author = {Wang, Z and Huang, J and Yun, D},
title = {Current and emerging therapeutic strategies for amyotrophic lateral sclerosis: from pharmacological approaches to gene and stem cell therapies.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1729302},
pmid = {41657419},
issn = {1664-2295},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that involves upper and lower motor neurons, severely impairing patients' quality of life. The complex interaction of genetic and environmental factors in ALS pathophysiology complicates therapeutic development. Currently available disease-modifying pharmacological therapies for ALS offer limited efficacy, only slowing disease progression to a modest degree. The recent market withdrawal of a previously approved therapy (AMX0035) further underscores the challenges in this field. Biological targets for ALS and related neurodegenerative diseases offer a unique avenue for therapeutic intervention. With the advancement of genetic engineering technology, innovative therapies such as Stem cell therapy and gene therapy are also discussed, offering a promising horizon for ALS treatment. In addition, the management of ALS symptoms plays a key role in improving the daily lives of people with the disease. In this review, we summarize various strategies for treating ALS, providing an overview of the disease.},
}

@article {pmid41656808,
year = {2025},
author = {Yu, C and Zeng, W and Meekrathok, P and Bu, Y and Wang, J and Qiu, J},
title = {[Heterogeneity in the regulation of cellular stress responses by FUS gene mutations associated with amyotrophic lateral sclerosis].},
journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences},
volume = {50},
number = {10},
pages = {1755-1770},
pmid = {41656808},
issn = {1672-7347},
support = {2019RS1010//the Project of Department of Science and Technology of Hunan Province/ ; },
mesh = {*RNA-Binding Protein FUS/genetics/chemistry ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Mutation ; Nuclear Localization Signals/genetics ; Reactive Oxygen Species/metabolism ; *Stress, Physiological/genetics ; },
abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective death of motor neurons, exhibiting marked clinical heterogeneity and lacking effective treatment. The etiology and pathogenic mechanisms remain incompletely understood. The FUS (fused in sarcoma) gene is one of the key causative genes in ALS. Pathogenic mutations in the encoded protein are predominantly clustered in the C-terminal nuclear localization signal (NLS) region, and distinct NLS mutation sites show considerable differences in pathogenic potency, clinical phenotypes, and molecular mechanisms. This study focuses on 2 representative pathogenic NLS mutations of FUS (FUS[R514S] and FUS[P525L]) to investigate their differential regulation of cellular stress responses and explore the underlying mechanisms.

METHODS: Multiple sequence alignment of FUS protein homologs from 12 species was performed using an online tool from the National Center for Biotechnology Information (NCBI) to determine the evolutionary conservation of residues R514 and P525. The three-dimensional (3D) structure of the nuclear transport receptor-FUS complex [Protein Data Bank (PDB) ID: 5YVG] was analyzed and visualized using PyMOL. Structure of FUS mutants were generated using the mutation wizard tool in PyMOL by selecting the target conformational isomer and executing the mutation workflow. Tet-on inducible expression cell models for FUS wild-type (WT) and mutant FUS (FUS[R514SS] and FUS[P525L]) were established in human embryonic kidney 293T (HEK293T) cells. Protein expression levels and subcellular localization of FUS were assessed by Western blotting and immunofluorescence assay, respectively. FUS aggregation states were compared between WT and mutant FUS using a digitonin-based permeabilization and extraction assay, followed by sodium dodecylsulfate-polyacrylamide gel electrophoresis-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting analysis. Blue native PAGE (BN-PAGE) was used to evaluate the stability of FUS-containing complexes. Mitochondrial membrane potential and reactive oxygen species (ROS) levels were measured by flow cytometry. Stress granule (SG) formation was induced using sodium arsenite, and the effects of WT and mutant FUS on SG dynamics were analyzed by immunofluorescence assay. Protein expression changes of mitochondrial function-related proteins [translocase of outer membrane 20 kD subunit (Tom20) and voltage-dependent anion channel 1 (VDAC1)] and key molecules of the integrated stress response (ISR) pathway [phosphorylated-eukaryotic initiation factor 2 alpha (p-eIF2α) and activating transcription factor 4 (ATF4)] were examined by Western blotting.

RESULTS: Sequence alignment revealed that R514 and P525 are highly conserved across FUS homologs from 12 species. Structural analysis indicated that the FUS[R514S] and FUS[P525L] mutations disrupt hydrogen bonding or hydrophobic interactions between FUS and importin-β2, weakening the stability of these interactions. Western blotting confirmed the successful establishment of inducible WT and mutant FUS expression cell models, and exogenous FUS expression slightly suppressed endogenous FUS protein levels. Immunofluorescence assay demonstrated that WT FUS is predominantly localized in the nucleus, whereas both FUS[R514S] and FUS[P525L] mutants mislocalize to the cytoplasm with a punctate, granular distribution. Compared with WT FUS, neither mutant significantly affected mitochondrial membrane potential, ROS levels, or the homeostasis of mitochondrial function-related proteins (all P>0.05). Upon sodium arsenite exposure, mutant FUS formed SGs more rapidly, generated SGs with larger diameters, and displayed distinct intracellular distribution and aggregation patterns relative to WT (P>0.05). After drug withdrawal, WT and mutant FUS showed no significant difference in their effects on SG disassembly (P<0.05). Under basal conditions, FUS[R514S] exhibited significantly higher eIF2α phosphorylation levels than WT, and ATF4 protein levels also showed an increasing trend (P<0.05). No statistically significant difference was observed between FUS[P525L] and WT FUS in these measures (P>0.05). Sodium arsenite treatment increased eIF2α phosphorylation across all groups, eliminating inter-mutant differences.

CONCLUSIONS: Distinct pathogenic NLS mutations of FUS differentially regulate cellular stress responses through different mechanisms, contributing to ALS initiation and progression. Among these, FUS[P525L] promotes the formation of larger stress granules, whereas FUS[R514S] more readily activates the cellular ISR.},
}

*RNA-Binding Protein FUS/genetics/chemistry
Humans
*Amyotrophic Lateral Sclerosis/genetics
*Mutation
Nuclear Localization Signals/genetics
Reactive Oxygen Species/metabolism
*Stress, Physiological/genetics

@article {pmid41653014,
year = {2026},
author = {Abrahao, A and Ciepielewska, M and Zinman, L},
title = {Value of Clinical Evidence and Health Economics and Outcomes Research (HEOR) Studies.},
journal = {Muscle & nerve},
volume = {73 Suppl 1},
number = {Suppl 1},
pages = {S7-S12},
pmid = {41653014},
issn = {1097-4598},
support = {//Mitsubishi Tanabe Pharma America, Inc./ ; },
mesh = {Humans ; *Outcome Assessment, Health Care/economics ; *Economics, Medical ; Randomized Controlled Trials as Topic ; Amyotrophic Lateral Sclerosis/therapy/economics ; *Evidence-Based Medicine/economics ; Cost-Benefit Analysis ; },
abstract = {Randomized controlled trials (RCTs) remain the gold standard for establishing the efficacy and safety of new treatments. However, clinical evidence derived from the systematic analysis of real-world data generated through routine clinical practice can complement RCT data by offering insights into treatment performance in broader, more heterogeneous patient populations and clinical care settings. The integration of high-quality clinical evidence into health economics and outcomes research (HEOR) is increasingly important, as it supports healthcare decision-making across multiple stakeholders, including regulatory agencies, payers, clinicians, and patients. Multiple study designs, such as pragmatic trials, hybrid RCTs, external control arms, and observational studies, can provide valuable clinical evidence beyond the controlled trial setting. These data can enhance understanding of comparative effectiveness, patient-reported outcomes, treatment safety, and healthcare utilization and costs. The field of amyotrophic lateral sclerosis offers a compelling example of how clinical evidence derived from global registries and clinical studies has advanced understanding of disease epidemiology, treatment patterns, and the effectiveness of therapies, including riluzole and edaravone. Consequently, this review and the associated supplementary articles are meant to serve as a primer to inform clinicians of the potential contribution of clinical evidence to HEOR studies.},
}

Humans
*Outcome Assessment, Health Care/economics
*Economics, Medical
Randomized Controlled Trials as Topic
Amyotrophic Lateral Sclerosis/therapy/economics
*Evidence-Based Medicine/economics
Cost-Benefit Analysis

@article {pmid41653010,
year = {2026},
author = {Abrahao, A and Zinman, L and Apple, S},
title = {Current and Ongoing Clinical Studies.},
journal = {Muscle & nerve},
volume = {73 Suppl 1},
number = {Suppl 1},
pages = {S26-S28},
pmid = {41653010},
issn = {1097-4598},
support = {//Mitsubishi Tanabe Pharma America, Inc./ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Edaravone/therapeutic use ; *Clinical Trials as Topic ; *Free Radical Scavengers/therapeutic use/administration & dosage ; },
abstract = {This article provides a comprehensive overview of current and ongoing studies evaluating intravenous (IV) edaravone and edaravone oral suspension in the treatment of amyotrophic lateral sclerosis (ALS). In addition to data from clinical practice and post hoc analyses, multiple observational and interventional studies are underway to better understand the efficacy, safety, and biological impact of edaravone in clinical settings. Key studies include SUNRISE Japan, a long-term postmarketing surveillance study of IV edaravone in Japanese patients with ALS; the ALS/Motor Neuron Disease Natural History Study, a longitudinal registry designed to inform clinical trial design and track ALS progression; and the REFINE-ALS study, which is actively collecting biomarker data to elucidate the pathophysiologic mechanisms influenced by edaravone. For edaravone oral suspension, United States Food and Drug Administration approval was supported by Study MT-1186-A01, a phase 3 trial assessing safety and tolerability over 48 weeks, with extension Study MT-1186-A03. Study MT-1186-A02, conducted as an FDA postmarketing commitment, and its extension, Study MT-1186-A04, evaluated whether investigational once daily dosing showed superior efficacy vs. the approved on/off dosing regimen. Collectively, these studies contribute to a growing body of evidence supporting the use of edaravone as a therapeutic option for ALS. They also underscore the importance of continued data collection from both clinical trials and clinical settings to inform optimal treatment strategies and combination therapy approaches as more agents become available in an evolving ALS treatment landscape.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy
*Edaravone/therapeutic use
*Clinical Trials as Topic
*Free Radical Scavengers/therapeutic use/administration & dosage

@article {pmid41653008,
year = {2026},
author = {Brooks, BR and Ennist, DL and Beaulieu, D and Apple, S},
title = {Generalizability of Edaravone Efficacy.},
journal = {Muscle & nerve},
volume = {73 Suppl 1},
number = {Suppl 1},
pages = {S16-S18},
pmid = {41653008},
issn = {1097-4598},
support = {//Mitsubishi Tanabe Pharma America, Inc./ ; },
mesh = {Humans ; *Edaravone/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Male ; Female ; Middle Aged ; *Free Radical Scavengers/therapeutic use ; Treatment Outcome ; Aged ; Disease Progression ; Retrospective Studies ; Vital Capacity/drug effects ; Machine Learning ; },
abstract = {The pivotal phase 3 trial MCI186-19 (Study 19) demonstrated the efficacy of intravenous edaravone in slowing functional decline in patients with amyotrophic lateral sclerosis (ALS), leading to United States Food and Drug Administration approval. Study 19 utilized a targeted enrollment enrichment strategy based on post hoc analyses from earlier trials, selecting patients with higher baseline function, more rapid disease progression, and better respiratory status. To evaluate the generalizability of Study 19 results, subsequent post hoc analyses assessed the efficacy of edaravone in broader ALS populations. One machine learning-based analysis retrospectively applied a validated model to Study 16 data, stratifying patients by predicted risk of respiratory decline. This detectable effect cluster analysis suggested that up to 70% of Study 16 participants may have benefited from edaravone. A second analysis investigated edaravone efficacy in patients from Study 19 with forced vital capacity (FVC) < 80% predicted (%p) at the start of treatment, since FVC ≥ 80%p was one of the Study 19 inclusion criteria. Both high- and low-FVC subgroups demonstrated reduced ALS functional rating scale-revised decline at 48 weeks when treated continuously with edaravone. These findings support the potential benefit of edaravone in a wider range of patients with ALS than those enrolled in Study 19, providing important insights into how clinical trial enrichment strategies may influence perceived efficacy, and underscoring the need for future prospective studies in more diverse ALS populations.},
}

Humans
*Edaravone/therapeutic use
*Amyotrophic Lateral Sclerosis/drug therapy/physiopathology
Male
Female
Middle Aged
*Free Radical Scavengers/therapeutic use
Treatment Outcome
Aged
Disease Progression
Retrospective Studies
Vital Capacity/drug effects
Machine Learning

@article {pmid41653006,
year = {2026},
author = {Gwathmey, KG and Apple, S},
title = {Introduction to the Supplement.},
journal = {Muscle & nerve},
volume = {73 Suppl 1},
number = {Suppl 1},
pages = {S3-S6},
pmid = {41653006},
issn = {1097-4598},
support = {//Mitsubishi Tanabe Pharma America, Inc./ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Edaravone/therapeutic use ; *Neuroprotective Agents/therapeutic use ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease with marked phenotypic and clinical heterogeneity. Three active pharmaceutical agents are currently approved by the United States Food and Drug Administration (FDA) for ALS: riluzole, edaravone (including intravenous [IV] and oral suspension formulations), and tofersen. Study MCI186-19 (Study 19) was a pivotal, phase 3 randomized controlled trial that demonstrated a significant reduction in physical functional decline vs. placebo in Japanese patients with ALS and contributed to FDA approval of IV edaravone in 2017. Edaravone oral suspension was FDA-approved in May 2022 following the results of Study MT-1186-A01, which showed it was well tolerated with a safety profile consistent with IV edaravone. Following Study 19, the clinical benefit of edaravone has remained an active area of investigation. This supplement presents data from clinical trials, post hoc analyses, and clinical studies that expand understanding of the use of edaravone in broader ALS populations. Topics include safety in clinical practice, generalizability of efficacy, clinical treatment outcomes, and health economics and outcomes research studies. Together, these findings aim to inform clinicians, researchers, and stakeholders regarding the evolving evidence base for edaravone in the management of ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy
*Edaravone/therapeutic use
*Neuroprotective Agents/therapeutic use

@article {pmid41653005,
year = {2026},
author = {Genge, A and Apple, S},
title = {Safety of Intravenous Edaravone in Clinical Practice.},
journal = {Muscle & nerve},
volume = {73 Suppl 1},
number = {Suppl 1},
pages = {S13-S15},
pmid = {41653005},
issn = {1097-4598},
support = {//Mitsubishi Tanabe Pharma America, Inc./ ; },
mesh = {Humans ; Edaravone/adverse effects/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; *Free Radical Scavengers/adverse effects/administration & dosage ; Middle Aged ; Administration, Intravenous ; Pharmacovigilance ; Aged ; *Antipyrine/analogs & derivatives/adverse effects/administration & dosage ; Adult ; Product Surveillance, Postmarketing ; },
abstract = {This article summarizes the post-marketing pharmacovigilance safety data of intravenous (IV) edaravone during the 1- and 3-year periods following its launch for amyotrophic lateral sclerosis (ALS) in the United States. The most frequently reported adverse events (AEs) and serious AEs (SAEs) included those consistent with ALS disease progression, such as fatigue and muscular weakness, and were not qualitatively different from those reported in previous ALS trials. There were AEs and SAEs associated with IV administration, such as administration site reactions, and five non-fatal anaphylaxis SAEs were reported. No new safety signals were identified, and IV edaravone continues to demonstrate a favorable safety profile. These insights are especially useful as treatment transitions to edaravone oral suspension, which avoids IV-related complications. These findings underscore the importance of ongoing clinical safety assessments in informing ALS treatment decisions.},
}

Humans
Edaravone/adverse effects/administration & dosage
*Amyotrophic Lateral Sclerosis/drug therapy
Male
Female
*Free Radical Scavengers/adverse effects/administration & dosage
Middle Aged
Administration, Intravenous
Pharmacovigilance
Aged
*Antipyrine/analogs & derivatives/adverse effects/administration & dosage
Adult
Product Surveillance, Postmarketing

@article {pmid41653004,
year = {2026},
author = {Brooks, BR and Berry, JD and Ciepielewska, M},
title = {Survival of Intravenous Edaravone-Treated Patients With ALS: Evidence From Administrative Claims Analyses.},
journal = {Muscle & nerve},
volume = {73 Suppl 1},
number = {Suppl 1},
pages = {S23-S25},
pmid = {41653004},
issn = {1097-4598},
support = {//Mitsubishi Tanabe Pharma America, Inc./ ; },
mesh = {Humans ; *Edaravone/administration & dosage/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/mortality ; Female ; Male ; Middle Aged ; Retrospective Studies ; Aged ; *Free Radical Scavengers/administration & dosage/therapeutic use ; Administration, Intravenous ; Adult ; Neuroprotective Agents ; Databases, Factual ; United States ; Treatment Outcome ; },
abstract = {Randomized controlled trials remain the cornerstone of evidence generation in amyotrophic lateral sclerosis (ALS), yet their inherent challenges, including disease rarity, heterogeneity, and limited validated biomarkers, highlight the need for complementary clinical evidence. This exploratory, retrospective study assessed overall survival in patients with ALS treated with intravenous (IV) edaravone using data from a large United States administrative claims database of patients enrolled from August 2017 to March 2020. Patients receiving IV edaravone (n = 318) were propensity score matched 1:1 with controls not treated with IV edaravone (n = 318), adjusting for 11 covariates. Median overall survival was 29.5 versus 23.5 months for the edaravone-treated group compared to controls, with a 27% reduced risk of death observed in the treated cohort (p = 0.005). These findings, together with existing data from the pivotal phase 3 Study MCI186-19 of IV edaravone, contribute to the growing body of literature suggesting a dual benefit of edaravone on both function and survival in ALS, offering critical insights for clinicians, patients, and payers navigating ALS treatment decisions.},
}

Humans
*Edaravone/administration & dosage/therapeutic use
*Amyotrophic Lateral Sclerosis/drug therapy/mortality
Female
Male
Middle Aged
Retrospective Studies
Aged
*Free Radical Scavengers/administration & dosage/therapeutic use
Administration, Intravenous
Adult
Neuroprotective Agents
Databases, Factual
United States
Treatment Outcome

@article {pmid41653003,
year = {2026},
author = {Brooks, BR and Shefner, J and Apple, S},
title = {Study 19 (MCI186-19) Post Hoc Analyses.},
journal = {Muscle & nerve},
volume = {73 Suppl 1},
number = {Suppl 1},
pages = {S19-S22},
pmid = {41653003},
issn = {1097-4598},
support = {//Mitsubishi Tanabe Pharma America, Inc./ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Edaravone/therapeutic use ; Treatment Outcome ; Disease Progression ; Male ; Female ; *Free Radical Scavengers/therapeutic use ; Randomized Controlled Trials as Topic ; Middle Aged ; *Neuroprotective Agents/therapeutic use ; },
abstract = {While randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy of therapies in amyotrophic lateral sclerosis (ALS), post hoc analyses can provide critical insights into clinical effectiveness, treatment durability, and subpopulation responses. Several post hoc analyses of Study MCI186-19 (Study 19), the pivotal phase 3 RCT that supported the United States Food and Drug Administration approval of intravenous edaravone, have been performed to explore the broader clinical impact of this therapy. These analyses assessed the long-term treatment efficacy, changes in individual ALS Functional Rating Scale-Revised item scores, survival and additional milestone events, and the impact of edaravone in patient subgroups defined by disease progression trajectories using latent class analysis. Collectively, these findings reinforce the long-term clinical benefit of edaravone and demonstrate that edaravone may offer benefits across a spectrum of ALS disease trajectories, beyond those defined in the original study criteria. These studies help address questions not captured in the original RCT and may inform future trial design and treatment decisions.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy
*Edaravone/therapeutic use
Treatment Outcome
Disease Progression
Male
Female
*Free Radical Scavengers/therapeutic use
Randomized Controlled Trials as Topic
Middle Aged
*Neuroprotective Agents/therapeutic use

@article {pmid41652348,
year = {2026},
author = {Johansen, H and Nakken, O and Holmøy, T and Fredheim, OMS},
title = {Disease trajectories and end of life care in a Norwegian ALS cohort.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-04698-8},
pmid = {41652348},
issn = {1471-2377},
abstract = {OBJECTIVE: This retrospective cohort study aims to provide comprehensive data on the disease trajectory and end-of-life care in patients dying from ALS.

METHODS: The study presents detailed information on a cohort dying from ALS in the area served by Akershus University Hospital from 2011 to 2022. Data was obtained from the patient medical records.

RESULTS: 118 patients were included. 65 patients (55%) were referred to the Department of Palliative medicine for specialist palliative care, with a median duration from referral to death of two months and one third of patients not being able to communicate verbally at the time of referral. The most common life-sustaining treatment was non-invasive ventilation and percutaneous endoscopic gastrostomy, whereas most prevalent limitation of life-sustaining treatment was withholding of tracheostomy with invasive ventilation. Hospital was the most common place of death with 54 (46%) of all deaths. For in-hospital-deaths, the most common place of death was the palliative care ward, with 21 patients (39%), but a substantial proportion (17%) died at intensive or intermediate care units. Overall, 37% of in-hospital deaths had been admitted to either intensive or intermediate care units during their last week of life, which may suggest these patients deteriorated rapidly without having documented advanced care planning and therefore received resource demanding and futile treatment during the last week of life.

CONCLUSION: Many patients lived in their own homes until admitted to their last hospital stay in life. However, these last hospital stays were frequently characterized by insufficient advanced care planning, leading to futile overtreatment.

TRIAL REGISTRATION: Retrospectively registered.},
}

@article {pmid41651385,
year = {2026},
author = {Raina, GS and Mehan, S and Das Gupta, G},
title = {Neuroprotection via IGF-1 Neuronal Signaling Activation by Melatonin and Edaravone Synergy in Methylmercury-Induced ALS-like Neurotoxicity: Comprehensive Analysis of Brain Regions, Spinal Cord, CSF, and Blood Plasma.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {103398},
doi = {10.1016/j.neuro.2026.103398},
pmid = {41651385},
issn = {1872-9711},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration, oxidative stress, neuroinflammation, and neurotransmitter imbalances. This study explored the neuroprotective potential of melatonin (MLT), alone and in combination with edaravone (EDR), in a methylmercury (MEME)-induced ALS rat model. MEME exposure effectively replicated ALS pathology, causing behavioral deficits, oxidative stress, neuroinflammation, apoptosis, and widespread structural damage in critical brain regions and the spinal cord. MLT administration at 5mg/kg (MLT5) and 10mg/kg (MLT10) significantly mitigated MEME-induced neurotoxicity in a dose-dependent manner. MLT improved motor function, reduced depressive-like behavior, and restored body weight. Biochemically, MLT enhanced antioxidant defenses, including superoxide dismutase (SOD) and catalase (CAT), reduced pro-inflammatory cytokines, interleukin-1 beta (IL-1β), increased anti-inflammatory cytokines, interleukin-10 (IL-10), and restored neurotransmitter balance like dopamine and Gamma-Aminobutyric Acid (GABA). Mechanistically, MLT activated the IGF-1 signaling pathway, promoting neuronal survival and reducing apoptosis (Caspase-3 expression). Histopathological analyses confirmed that MLT preserved neuronal and glial integrity, reduced demyelination, and restored myelin basic protein (MBP) levels in brain and cerebrospinal fluid. The combination of MLT and EDR exhibited synergistic neuroprotective effects, surpassing the efficacy of individual treatments in reducing oxidative stress, inflammation, and neuronal damage. Behavioral and biochemical improvements were paralleled by systemic recovery, as evidenced by normalized hematological parameters and reduced methylmercury accumulation in brain tissues. These findings underscore MLT, particularly in combination with EDR, as a potent therapeutic agent for ALS, offering multi-targeted neuroprotection. Future studies should explore its translational potential in clinical settings for the treatment of neurodegenerative diseases.},
}

@article {pmid41649614,
year = {2026},
author = {Mukherjee, R and Mehan, S and Choudhary, D and Rana, R and Das Gupta, G and Samant, R and Tongra, M},
title = {Sulforaphane-Mediated Multitarget Therapeutic Effects in Methylmercury-Induced ALS-Like Pathology: Comparative Analysis and Multifaceted Approach to Neuroprotection and Systemic Recovery.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {422},
pmid = {41649614},
issn = {1559-1182},
mesh = {Animals ; *Isothiocyanates/pharmacology/therapeutic use ; Sulfoxides ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Methylmercury Compounds/toxicity ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/chemically induced/physiopathology ; Female ; Rats ; Rats, Sprague-Dawley ; *Recovery of Function/drug effects ; *Neuroprotection/drug effects ; Male ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; Antioxidants/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by motor neuron loss driven by oxidative stress, neuroinflammation, and dysregulated survival signaling. The objective of this study was to evaluate the neuroprotective efficacy and safety of sulforaphane (SUFP) in a methylmercury (MMHg[+])-induced preclinical rat model of ALS, with comparison to omaveloxolone (OVX) and dimethyl fumarate (DIMT). SUFP treatment, particularly at 4 mg/kg, significantly restored antioxidant defense mechanisms through upregulation of Nrf2, HO-1, and SIRT1 while suppressing pro-inflammatory cytokines (IL-1β, TNF-α), apoptotic markers (Bax, caspase-3), and stress-related signaling pathways including p75NTR, PI3K/Akt, and MAPKs. These molecular effects translated into meaningful functional recovery, as evidenced by improvements in grip strength, locomotor performance, spatial memory, and depressive-like behavior. Histopathological evaluation demonstrated attenuation of demyelination and preservation of neuronal architecture in cortical, hippocampal, and cerebellar regions. Beyond central neuroprotection, SUFP exerted systemic benefits by normalizing hepatic enzymes, improving skeletal muscle integrity, restoring redox balance, stabilizing neurofilament and myelin-associated proteins, and correcting hematological alterations. Comparative analysis revealed that SUFP conferred superior neuroprotection with a favorable safety profile relative to OVX and, although slightly less efficacious than DIMT, exhibited reduced systemic toxicity. Molecular docking further supported SUFP's interaction with Nrf2-Keap1 targets, reinforcing its antioxidant and anti-inflammatory mechanisms. Collectively, these findings identify SUFP as a multifaceted and well-tolerated therapeutic candidate for ALS, supporting its further translational and clinical evaluation.},
}

Animals
*Isothiocyanates/pharmacology/therapeutic use
Sulfoxides
*Neuroprotective Agents/pharmacology/therapeutic use
*Methylmercury Compounds/toxicity
*Amyotrophic Lateral Sclerosis/drug therapy/pathology/chemically induced/physiopathology
Female
Rats
Rats, Sprague-Dawley
*Recovery of Function/drug effects
*Neuroprotection/drug effects
Male
Oxidative Stress/drug effects
Apoptosis/drug effects
Antioxidants/metabolism

@article {pmid41642483,
year = {2026},
author = {Alhajeri, MM and Abukhaled, Y and Alkhanjari, RR and Bassiouni, W and Al-Ali, H and Baig, A and Sembaij, SH and Al Muhairi, FA and Dimassi, Z and Hamdan, H and Abd-Elrahman, KS},
title = {Neuroglial Function and Hormonal Modulation in Neurodegenerative Diseases: The Influence of Sex Hormones.},
journal = {Cellular and molecular neurobiology},
volume = {46},
number = {1},
pages = {43},
pmid = {41642483},
issn = {1573-6830},
mesh = {Humans ; *Neuroglia/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; *Gonadal Steroid Hormones/metabolism ; Animals ; },
abstract = {Astrocytes, microglia, and oligodendrocytes, key neuroglial cell types, are essential for central nervous system (CNS) homeostasis, immune regulation, and neuronal support. In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), glial dysfunction contributes to pathogenesis via chronic inflammation, synaptic disruption, oxidative stress, and impaired myelination. Growing evidence highlights the regulatory influence of sex hormones on glial function. These hormones modulate inflammatory tone, synaptic remodeling, and remyelination, potentially contributing to sex-based differences in disease incidence, progression, and treatment response. This review synthesizes current understanding of glial involvement in neurodegeneration and examines how gonadal hormones interact with astrocytes, microglia, and oligodendrocytes. By integrating glial biology with neuroendocrinology, we propose that hormone-glia interactions represent promising, personalized targets for sex-informed therapies in CNS disorders.},
}

Humans
*Neuroglia/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology
*Gonadal Steroid Hormones/metabolism
Animals

@article {pmid41641779,
year = {2026},
author = {Varderidou-Minasian, S and Jakobs, CE and Pasteuning-Vuhman, S and Gal, L and Timmers, A and Altelaar, M and Lorenowicz, MJ and Pasterkamp, RJ},
title = {Mesenchymal stem cell-derived extracellular vesicle treatment of induced pluripotent stem cell-derived motor neurons with different amyotrophic lateral sclerosis genetic backgrounds.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01790},
pmid = {41641779},
issn = {1673-5374},
abstract = {Motor neurons derived from induced human pluripotent stem cells offer a powerful model to study motor neuron diseases, such as amyotrophic lateral sclerosis. While widely used, our knowledge of the proteomic changes in these models is rather rudimentary. In this study, we conducted a comparative proteomic analysis of induced pluripotent stem cell-derived motor neurons carrying amyotrophic lateral sclerosis-associated mutations in C9ORF72, TARDBP, or FUS. This revealed both mutation-specific and shared proteomic signatures, unveiling common and divergent disease mechanisms. Using these new insights, we then evaluated the therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. These experiments showed a functional effect of mesenchymal stem cell-derived extracellular vesicles in amyotrophic lateral sclerosis-FUS motor neurons in vitro and their ability to reverse proteomic changes more generally in motor neurons with different amyotrophic lateral sclerosis genetic backgrounds. These findings highlight key molecular pathways involved in amyotrophic lateral sclerosis at the protein level and support the potential of mesenchymal stem cell-derived extracellular vesicles as a versatile therapeutic approach.},
}

@article {pmid41640104,
year = {2026},
author = {Karros, M and DiFulco, M and Nogid, A},
title = {Tofersen: A Novel Option for the Treatment of Amyotrophic Lateral Sclerosis.},
journal = {The Annals of pharmacotherapy},
volume = {},
number = {},
pages = {10600280251408862},
doi = {10.1177/10600280251408862},
pmid = {41640104},
issn = {1542-6270},
abstract = {OBJECTIVE: This review summarizes current evidence on the efficacy and safety of tofersen (Qalsody) in treating amyotrophic lateral sclerosis (ALS).

DATA SOURCES: PubMed, MEDLINE, Google Scholar, and ClinicalTrials.gov were searched using the keywords: Qalsody, BIIB067, antisense oligonucleotides, SOD1, and amyotrophic lateral sclerosis. Articles published from inception to November 2025 were included.

English-language studies assessing the pharmacokinetics, pharmacology, efficacy, and safety of tofersen were included. Prescribing information and real-world evidence were also reviewed.

DATA SYNTHESIS: Tofersen is an intrathecally administered antisense oligonucleotide targeting superoxide dismutase 1 (SOD1) mRNA. Early trials demonstrate dose-dependent reductions in cerebrospinal fluid (CSF) SOD1 protein levels of -33% and slower ALS Functional Rating Scale (ALSFRS-R) decline compared to placebo (-1.19 vs -5.63 points). In Phase 3 trials, tofersen reduced CSF SOD1 by 29% and plasma neurofilament light chain (NfL) by 60%, while biomarkers increased in the placebo group. There was no significant difference in ALSFRS-R decline between tofersen and placebo (-6.98 vs -8.14; P = 0.97). Real-world data show favorable patient-related outcomes and improvement in ALSFRS-R. Adverse effects are primarily lumbar puncture related with serious neurologic events documented in 7% of tofersen recipients.Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs:As the first Food and Drug Administration (FDA)-approved gene-directed therapy for SOD1 ALS, tofersen directly targets the underlying genetic cause. Barriers include the need for genetic confirmation and intrathecal administration.

CONCLUSION: Tofersen provides a promising targeted treatment option for pathogenic SOD1 ALS. Ongoing studies will clarify its long-term clinical impact.},
}

@article {pmid41639167,
year = {2026},
author = {Jansén-Storbacka, LR and Honasoge, KS and Molnárová, E and Soboleva, A and Agema, BC and Paats, MS and Moes, DJAR and Veerman, GDM and Barbaro, ABT and Dobbe, R and Grossmann, I and Azimi, S and Mathijssen, RHJ and Dingemans, AC and Staňková, K},
title = {Can evolutionary therapy be applied in non-small cell lung cancer?.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41639167},
issn = {2045-2322},
support = {VI.Vidi.213.139//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 955708//European Commission/ ; },
mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/pathology/drug therapy/therapy ; *Lung Neoplasms/pathology/drug therapy/therapy ; Erlotinib Hydrochloride/therapeutic use ; Male ; Models, Biological ; },
abstract = {Evolutionary therapy (ET) applies principles of evolutionary biology to steer tumour dynamics and forestall or delay treatment resistance, typically guided by data-driven mathematical models. Our aim is to assess whether ET protocols, and specifically Zhang et al.'s protocol proposed for metastatic castrate-resistant prostate cancer, can be theoretically effective for fast-growing metastatic cancers such as stage IV non-small-cell lung cancer (NSCLC). Using longitudinal tumour-burden data from NSCLC patients treated with erlotinib, we systematically evaluate 26 two-population differential-equation models based on classical tumour-growth dynamics, with varying assumptions about density- and frequency-dependent interactions, pharmacokinetics, and treatment-induced death. Previous work by Yin et al. on the same dataset employed an exponential model that omitted density- and frequency-dependent interactions; although it provided a good fit to tumour-burden data, its structure would theoretically lead to poorer outcomes under ET protocols. In contrast, our analysis identifies the minimal model structure required to reproduce the resistance-driven regrowth observed in NSCLC, with the Gompertzian model featuring log-kill dynamics and both density- and frequency-dependent interactions providing the best fit. In this model, Zhang et al.'s protocol prolonged median time-to-progression to 42.3 months compared with 24.8 months under maximum tolerated dose. These results indicate that ET is theoretically a viable treatment strategy for NSCLC. This study offers a practical framework for assessing ET feasibility using clinical data and supports future clinical translation of ET in NSCLC.},
}

Humans
*Carcinoma, Non-Small-Cell Lung/pathology/drug therapy/therapy
*Lung Neoplasms/pathology/drug therapy/therapy
Erlotinib Hydrochloride/therapeutic use
Male
Models, Biological

@article {pmid41628987,
year = {2026},
author = {Xue, X and Cui, H and Hu, S and Ma, H and Wei, S and Huang, H and Li, X and Huang, Z},
title = {Both target-site and non-target-site resistance mechanisms confer mesosulfuron-methyl resistance in Silene conoidea L.},
journal = {Pesticide biochemistry and physiology},
volume = {218},
number = {},
pages = {106905},
doi = {10.1016/j.pestbp.2025.106905},
pmid = {41628987},
issn = {1095-9939},
mesh = {*Sulfonylurea Compounds/pharmacology ; Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Silene/drug effects/genetics ; Plant Proteins/genetics/metabolism ; Molecular Docking Simulation ; Mutation ; },
abstract = {Silene conoidea L., a common weed in wheat fields, is mainly controlled by acetolactate synthase (ALS)-inhibiting herbicides such as mesosulfuron-methyl. In this study, we investigated a mesosulfuron-methyl resistant population to elucidate the resistance mechanisms. The resistant (R) population displayed a high level of resistance to mesosulfuron-methyl, with the resistance index (RI) of 18.87. It also exhibited cross-resistance to halosulfuron-methyl, florasulam, flumetsulam, and flucarbazone‑sodium. In vitro ALS enzyme activity in the R population was 22.85-fold higher than in the susceptible (S) population. A W574L mutation (leucine replaced tryptophan) was identified in the ALS gene of the R population. Through molecular docking, this substitution of amino acid weakened the π-π stacking interaction between mesosulfuron-methyl molecule and the non-mutated ALS enzyme. The R population also showed significantly higher ALS expression than the S population, while the ALS gene copy number did not differ between the two populations. Pretreatment with malathion (cytochrome P450 inhibitor) and NBD-Cl (glutathione S-transferases inhibitor) reduced mesosulfuron-methyl resistance by 43.92 % and 29.20 %, respectively. Indicating that CYP450s and GSTs are involved in resistance. Transcriptome and qPCR analyses identified significant upregulation of three ABC transporter genes, three CYP450 genes, and one GST gene in the R population. Meanwhile, KEGG pathway analysis indicated that the photosynthetic pathways were significantly affected after mesosulfuron-methyl treatment. This is the first report of mesosulfuron-methyl resistance in S. conoidea, involves both target site resistance and non-target site resistance mechanisms.},
}

*Sulfonylurea Compounds/pharmacology
Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors
*Herbicide Resistance/genetics
*Herbicides/pharmacology
*Silene/drug effects/genetics
Plant Proteins/genetics/metabolism
Molecular Docking Simulation
Mutation

@article {pmid41626491,
year = {2026},
author = {Akimoto, Y and Miyamae, Y and Shigemori, H},
title = {Effects of Cyanidin Derivatives for the Aggregation of Cu/Zn Superoxide Dismutase 1.},
journal = {ACS omega},
volume = {11},
number = {3},
pages = {3849-3865},
pmid = {41626491},
issn = {2470-1343},
abstract = {Cu/Zn superoxide dismutase 1 (SOD1), whose aggregation is considered cytotoxic, is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Therefore, inhibiting SOD1 aggregation may represent a promising strategy for the treatment and prevention of this disease. We first screened seven polyphenols using an optimized thioflavin T (Th-T) assay and found that cyanidin exhibited the strongest inhibitory activity among the seven polyphenols. We then compared cyanidin with its derivatives(?)delphinidin, petunidin, malvidin, and cyanidin-3-glucoside (C3G). In this study, we concluded that delphinidin had the strongest antifibrillation activity among the five cyanidin derivatives. Turbidity, transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS), circular dichroism (CD) spectroscopy, and Fourier transform infrared (FT-IR) spectroscopy indicated that the inhibitory activity was influenced by the number of phenolic hydroxyl groups on the B-ring of the cyanidin derivatives. Based on the LDH assay, delphinidin was the most effective compound in preventing the formation of cytotoxic SOD1 aggregates in the cells. Furthermore, we found that the compounds also interfered with the SOD1 cross-linking. Finally, we transfected GFP-SOD1A4 V into Neuro2a cells and observed that the compounds' inhibitory activity on intracellular aggregation was limited.},
}