@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.},
}

@article {pmid41616079,
year = {2026},
author = {Steenkjaer, CH and Storgaard, JH and Levison, L and Blicher, JU},
title = {A national survey of pseudobulbar affect and symptomatic treatment in Amyotrophic Lateral Sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/21678421.2026.2620448},
pmid = {41616079},
issn = {2167-9223},
abstract = {OBJECTIVE: We aimed to determine diagnostic prevalence and symptom burden of pseudobulbar affect (PBA) in patients with Amyotrophic Lateral Sclerosis (ALS) in Denmark and differences in ongoing symptomatic treatment.

METHODS: In this national cross-sectional survey study, participants with ALS completed an online survey regarding PBA and PBA symptoms, which were quantified through the Center for Neurologic Study Lability Scale (CNS-LS). A CNS-LS score ≥ 13 served as a threshold indicative of PBA.

RESULTS: 157 participants with ALS were recruited. 12.1% were diagnosed with PBA and were more likely to receive antidepressant medication compared to those not diagnosed with PBA (47.4% compared to 15.2%, p = 0.002). 30.6% scored ≥13 in the CNS-LS; however, the proportion of participants treated with antidepressants was similar compared to those scoring below the ≥13 threshold (25% compared to 16.5%, p = 0.27). Of those not diagnosed with PBA, 23.2% scored ≥13 in the CNS-LS. This PBA symptomatic, but undiagnosed group was less likely to receive symptomatic treatment compared to patients with diagnosed PBA (12.5% compared to 47.4%, p = 0.009). No differences were seen in CNS-LS score between these groups.

CONCLUSIONS: The proportion of diagnosed PBA among the study population was low compared to previous studies; however, the proportion of patients with symptoms of possible PBA was markedly higher. Patients with known PBA were more likely to receive recommended symptomatic treatment compared to patients not diagnosed with PBA, despite symptoms indicative of PBA. These findings highlight the potential underrecognition of PBA in ALS and concurrent absence of symptomatic treatment.},
}

@article {pmid41609605,
year = {2026},
author = {Bridges, AJ and Fradley, MF and Karlsson, ME and Zielinski, MJ},
title = {Centering the client in PTSD treatments: Commentary on Rubenstein et al. (2024).},
journal = {The American psychologist},
volume = {81},
number = {1},
pages = {109-111},
doi = {10.1037/amp0001480},
pmid = {41609605},
issn = {1935-990X},
mesh = {Humans ; *Stress Disorders, Post-Traumatic/therapy ; *Implosive Therapy/methods ; },
abstract = {We offer commentary examining conclusions that may be drawn from Rubenstein et al.'s (2024) perspective on the need for exposure-based posttraumatic stress disorder (PTSD) treatments. Here, we employ our shared expertise in implementing and evaluating exposure-based group therapy to reconsider the following impressions garnered from the referenced article: (a) exposure is not necessary for successful PTSD treatment; (b) clients do not want to talk about traumatic memories and will drop out of treatment; (c) exposure may be destabilizing to clients; and (d) clients will spontaneously expose, rendering exposure in therapy unnecessary. In this commentary, we focus on data that center clients' perspectives and acknowledge client choice in the use of exposure. As did Rubenstein et al. (2024), we conclude that exposure is useful for a diverse range of clients, frequently preferred over other forms of treatment, and highly effective for treatment of PTSD. We support efforts to increase access to efficacious PTSD treatments, urging that exposure-based treatments be offered to clients alongside other evidence-based therapies. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

Humans
*Stress Disorders, Post-Traumatic/therapy
*Implosive Therapy/methods

@article {pmid41609131,
year = {2026},
author = {García Estévez, DA},
title = {Effectiveness of Risdiplam Treatment in Adult Patients With Spinal Muscular Atrophy Type IIb-III.},
journal = {Revista de neurologia},
volume = {81},
number = {1},
pages = {44408},
pmid = {41609131},
issn = {1576-6578},
support = {SP240424010//Roche/ ; },
mesh = {Humans ; Male ; Female ; Adult ; *Spinal Muscular Atrophies of Childhood/drug therapy/physiopathology ; Middle Aged ; Aged ; Treatment Outcome ; Drug Combinations ; Azo Compounds ; Pyrimidines ; },
abstract = {INTRODUCTION: Risdiplam is a pharmacological agent developed for the treatment of spinal muscular atrophy (SMA) associated with 5q deletion, with the therapeutic objective of increasing the concentration of the survival motor neuron 2 protein. Most clinical trials and real-world studies have focused on pediatric and young adult populations. Our aim was to assess the effectiveness of risdiplam treatment in adult patients with SMA type IIb and III.

METHODS: We studied 8 adult patients with SMA (3 females/5 males). Patient functionality was assessed using the Egen Klassifikation version 2 (EK2) scale, upper limb function with the 9-hole peg test (9HPT, seconds), and respiratory function with peak flow (L/min) and sniff nasal inspiratory pressure (SNIP, cmH2O). Plasma levels of neurofilament light chain (NFL, pg/mL) and glial fibrillary acidic protein (GFAP, pg/mL) were also measured. Patients were evaluated at baseline, and after 6 and 12 months of treatment.

RESULTS: The median age was 55 years (range: 41-66). At 12 months, EK2 scores showed a trend toward improvement in swallowing [item 16] (p = 0.06), peak flow increased significantly (244 ± 112 vs. 259 ± 124 L/min, p = 0.036), and there was a trend toward decreased NFL levels (11.4 ± 4.9 vs. 9.4 ± 2.7 pg/mL, p = 0.093). Both NFL and GFAP concentrations were negatively correlated with peak flow and SNIP values.

CONCLUSIONS: In our series, treatment with risdiplam may stabilize adult patients with type IIb-III SMA.},
}

Humans
Male
Female
Adult
*Spinal Muscular Atrophies of Childhood/drug therapy/physiopathology
Middle Aged
Aged
Treatment Outcome
Drug Combinations
Azo Compounds
Pyrimidines

@article {pmid41607656,
year = {2025},
author = {Ha, LL and Mitra, S and Ho, DT and Fillingham, B and Berry, JD and Swoboda, KJ and Alves, CRR},
title = {Circulating Tau Profiles in Pediatric and Adult Patients with Spinal Muscular Atrophy.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {41607656},
support = {K01 NS134784/NS/NINDS NIH HHS/United States ; R01 HD054599/HD/NICHD NIH HHS/United States ; R21 NS108015/NS/NINDS NIH HHS/United States ; },
abstract = {OBJECTIVE: To determine alterations in circulating Tau and phosphorylated Tau (pTau) profiles in pediatric and adult patients with spinal muscular atrophy (SMA).

METHODS: Circulating total Tau, pTau-181, pTau-217, pTau-262, and pTau-396 concentrations were measured across three cohorts: 1) adults including healthy controls, SMA patients, and ALS patients; 2) pediatric SMA patients and age-matched controls; and 3) pediatric SMA patients treated with onasemnogene abeparvovec.

RESULTS: Distinct alterations in circulating Tau species were detected in adult SMA and ALS. Among all measurements, pTau-262 emerged as the only species specifically elevated in adult SMA, while total Tau levels were comparable between adult SMA and controls but significantly increased in ALS. Tau alterations were not consistently observed in pediatric SMA, although a small subset showed elevated levels, underscoring the value of individualized biomarker monitoring upon diagnosis. In gene-therapy-treated infants, Tau levels increased transiently several weeks after onasemnogene abeparvovec injection, paralleling previously described neurofilament kinetics and suggesting acute, treatment-associated neuronal stress.

CONCLUSIONS: Circulating Tau, particularly pTau-262, may serve as a disease-relevant biomarker in adult SMA, while pediatric profiles appear more heterogeneous. Transient Tau elevations after gene therapy may reflect acute neuronal vulnerability and warrant further investigation.},
}

@article {pmid41605460,
year = {2026},
author = {Martínez-Alesón, P and Benito-Casado, C and Fernández-Martos, CM and Polanco Mora, MJ},
title = {Pleiotrophin/Midkine Pathway Is Dysregulated in a TDP-43[A315T] Mouse Model of Amyotrophic Lateral Sclerosis (ALS).},
journal = {Neuropathology : official journal of the Japanese Society of Neuropathology},
volume = {46},
number = {1},
pages = {e70044},
pmid = {41605460},
issn = {1440-1789},
support = {FUSPBS-PPC03/2018//University San Pablo CEU-Santander precompetitive grants/ ; SBPLY/17/180501/000303//Junta de Comunidades de Castilla-la Mancha/ ; PIPF-2023/SAL-GL-29613//Consejería de Educación, Ciencia y Universidades Comunidad de Madrid/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Midkine/metabolism ; *Cytokines/metabolism ; Disease Models, Animal ; Mice ; Signal Transduction/physiology ; *Carrier Proteins/metabolism ; DNA-Binding Proteins/genetics ; Spinal Cord/metabolism/pathology ; Mice, Transgenic ; Receptor-Like Protein Tyrosine Phosphatases, Class 5/metabolism ; Motor Neurons/metabolism/pathology ; Male ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) characterized by progressive degeneration of both upper and lower motor neurons, along with skeletal muscles innervated by them. The identification of key molecules involved in disease pathology remains crucial for ALS, as no curative treatment is currently available. Pleiotrophin (PTN) and midkine (MK) are closely related, heparin-binding cytokines with overlapping effects. These molecules have been shown to be neuroprotective by modulating neuroinflammation, supporting neuronal survival, growth, and differentiation, and enhancing synaptic strength and plasticity. Despite their reported neuroprotective properties, the involvement of PTN and MK signaling in ALS has not been previously investigated. In this study, we characterized the expression of the PTN/MK pathway in the lumbar spinal cords (SCs) of TDP-43[A315T] mice across different disease stages. We report a significant upregulation of Ptn, Mdk, and its receptor protein tyrosine phosphatase zeta (Ptprz1) mRNA levels at end-stage of disease in the lumbar SC of TDP-43[A315T] mice compared with age-matched wild-type littermates. Protein levels of PTN and MK were also upregulated at end-stage of disease. By immunofluorescence analysis, we also observed an upregulation of the immunostaining of both cytokines in neurons, astrocytes, microglia, and pericytes-like structures at end-stage of disease in the SC of TDP-43[A315T] mice. These findings open a new avenue to further study the potential role of the PTN/MK signaling axis in the pathogenesis of ALS. Trial Registration: Animal Ethics Committee of the Hospital Nacional de Parapléjicos in Toledo (Spain): Approval No. 26/OH 2018.},
}

Animals
*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics
*Midkine/metabolism
*Cytokines/metabolism
Disease Models, Animal
Mice
Signal Transduction/physiology
*Carrier Proteins/metabolism
DNA-Binding Proteins/genetics
Spinal Cord/metabolism/pathology
Mice, Transgenic
Receptor-Like Protein Tyrosine Phosphatases, Class 5/metabolism
Motor Neurons/metabolism/pathology
Male

@article {pmid41603250,
year = {2026},
author = {Naumann, M and Wierschin, TM and Kretschmer, S and Dash, BP and Held, A and Salzinger, A and Peikert, K and Karlek, A and Glaß, H and Großmann, D and Günther, R and Petri, S and Rödiger, A and Brenner, D and Pan-Montojo, F and Aronica, E and Kipp, M and Zimyanin, V and Sterneckert, J and Grehl, T and Seebacher, ND and Böckers, TM and Catanese, A and Wainger, BJ and Oeckl, P and Lee-Kirsch, MA and Hermann, A},
title = {RIG-I Mediated Neuron-Specific IFN Type 1 Signaling in FUS-ALS Induces Neurodegeneration and Offers New Biomarker-Driven Individualized Treatment Options for (FUS-)ALS.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e17135},
doi = {10.1002/advs.202417135},
pmid = {41603250},
issn = {2198-3844},
support = {CRC237 369799452/B21//German Research Foundation (DFG)/ ; CRC237 369799452/A11//German Research Foundation (DFG)/ ; CRC369 501752319/C06//German Research Foundation (DFG)/ ; 01GM2206C (GAIN)//German Federal Ministry of Education and Research (BMBF)/ ; 01GL2405H (DZKJ)//German Federal Ministry of Education and Research (BMBF)/ ; na//Stichting ALS Nederland/ ; na//Hermann und Lilly Schilling-Stiftung für Medizinische Forschung/ ; //Clinician Scientist program of the Medical Faculty of the University of Rostock (RAS)/ ; },
abstract = {Recent research demonstrated activation of the innate immune system in ALS models. This pathway can be activated by cGAS-STING sensing of cytosolic DNA that accumulates as a result of chronic DNA damage and defective mitochondria, both of which was identified as pathology in FUS-ALS. Therefore, we analyzed innate immune pathways in FUS-ALS, which revealed upregulation of interferon-stimulated genes (ISGs) and activation of the TBK1-IRF3 pathway in FUS[mut] iPSC-derived spinal motor neurons (sMNs). Accumulation of cytosolic dsRNA and its sensor RIG-I, but not MDA5, was found to be significantly upregulated in FUS[mut] sMNs, which was abolished upon siRNA-mediated knockdown of RIG-I. RIG-I was highly expressed in FUS-ALS post-mortem α-MNs. IFN treatment of FUS[wt] sMNs phenocopied the axonal degeneration of FUS[mut] sMNs. Mitochondrial transcription, a known source of dsRNA, was found to be upregulated in compartmental axonal RNAseq analysis and its inhibition reduced ISGs in FUS-ALS sMNs. The JAK-STAT inhibitor ruxolitinib alleviated the upregulated ISG expression and reversed the axonal degeneration of sMNs. Finally, we analyzed ISG expression in peripheral blood from 18 FUS-ALS patients, eight of whom had a significantly elevated interferon signature. RIG-I-mediated innate immune activation in sMNs may be an interesting novel individualized biomarker-driven therapeutic target in (FUS-) ALS. A one-sentence summary of your paper: RIG-I-mediated innate immune activation is found in FUS-ALS spinal motor neurons caused by cytosolic dsRNA accumulation due to mitochondrial transcriptional activation and is amenable to JAK-STAT inhibition and might thus be an interesting novel individualized biomarker-driven therapeutic approach in (FUS-) ALS.},
}

@article {pmid41599225,
year = {2026},
author = {Bernatoniene, J and Kopustinskiene, DM and Casale, R and Medoro, A and Davinelli, S and Saso, L and Petrikonis, K},
title = {Nrf2 Modulation by Natural Compounds in Aging, Neurodegeneration, and Neuropathic Pain.},
journal = {Pharmaceutics},
volume = {18},
number = {1},
pages = {},
pmid = {41599225},
issn = {1999-4923},
support = {S-A-UEI-23-7//Research Council of Lithuania (LMTLT)/ ; },
abstract = {This review summarizes the role of nuclear factor erythroid 2-related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders-including Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis-evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management.},
}

@article {pmid41599185,
year = {2026},
author = {Benech, H and Flament, V and Lhotellier, C and Roucairol, C and Joudinaud, T},
title = {New Insights into Drug Development via the Nose-to-Brain Pathway: Exemplification Through Dodecyl Creatine Ester for Neuronal Disorders.},
journal = {Pharmaceutics},
volume = {18},
number = {1},
pages = {},
pmid = {41599185},
issn = {1999-4923},
abstract = {Brain disorders remain a major global health challenge, highlighting the urgent need for innovative therapeutic strategies and efficient drug-delivery approaches. Among alternative routes, intranasal administration has garnered significant interest over recent decades, not only for its systemic delivery but also for its unique ability to bypass the bloodstream and the blood-brain barrier via the Nose-to-Brain (NtB) pathway. While numerous reviews have explored the opportunities and challenges of this route, industrial considerations-critical for successful clinical implementation and commercial development-remain insufficiently addressed. This review provides a comprehensive and critical assessment of the NtB pathway from a drug development and chemistry, manufacturing, and controls perspective, addressing key constraints in pre-clinical-clinical extrapolation, formulation design, device selection, dose feasibility, chronic safety, and regulatory requirements. We also discuss recent advances in neuronal targeting mechanisms, also with a focus on the role of trigeminal nerves. Dodecyl creatine ester (DCE), a highly unstable in plasma creatine prodrug developed by Ceres Brain Therapeutics, is presented as an illustrative case study. Delivered as a nasal spray, DCE enables direct neuronal delivery, exemplifying the potential of the NtB pathway for disorders characterized by neuronal energy deficiency, including creatine transporter deficiency and mitochondrial dysfunction. Overall, the NtB pathway-or, more precisely, the "Nose-to-Neurons" pathway-offers distinct advantages for unstable molecules and metabolic supplementation, particularly in neuron-centric diseases. Its successful implementation will depend on rational molecule design, optimized nasal formulations, appropriate devices, and early integration of industrial constraints to ensure feasibility, scalability, and safety for long-term treatment.},
}

@article {pmid41596266,
year = {2026},
author = {Ryu, IS and Ha, DI and Jung, YJ and Lee, HJ and Kim, I and Lim, YN and Min, HS and Kim, SH and Yoon, I and Cho, HJ and Ryu, JH},
title = {Modulation of the miR-485-3p/PGC-1α Pathway by ASO-Loaded Nanoparticles Attenuates ALS Pathogenesis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {2},
pages = {},
pmid = {41596266},
issn = {1422-0067},
support = {RS-2023-00283779//Ministry of SMEs and Startups/ ; },
mesh = {*MicroRNAs/genetics/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/drug therapy ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics ; *Nanoparticles/chemistry/administration & dosage ; Mice ; Mice, Transgenic ; Humans ; *Oligonucleotides, Antisense/pharmacology/administration & dosage/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Spinal Cord/metabolism/pathology/drug effects ; Disease Models, Animal ; Signal Transduction/drug effects ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration with limited treatment options. In this study, we investigated the pathological role of microRNA-485-3p (miR-485-3p) in ALS, particularly its regulation of PGC-1α, a transcriptional coactivator essential for mitochondrial function and neuroprotection. We also evaluated the therapeutic potential of BMD-001S, a nanoparticle-based formulation encapsulating an antisense oligonucleotide targeting miR-485-3p. Our results demonstrated that miR-485-3p expression was significantly elevated in both SOD1[G93A]-expressing HMC3 microglial cells and in the spinal cords of SOD1[G93A] transgenic mice at late disease stages, implicating its contribution to ALS pathogenesis. Intravenous administration of BMD-001S effectively reduced miR-485-3p levels and restored PGC-1α mRNA and PGC-1α protein expression in the spinal cord. These molecular changes were associated with notable therapeutic outcomes, including reduced SOD1 protein aggregation, decreased neuroinflammation, and lower neurofilament light chain concentrations in cerebrospinal fluid. Moreover, BMD-001S treatment was associated with improvements in electrophysiological parameters and preservation of neuromuscular junction integrity during the observation period in SOD1[G93A] transgenic mice. Taken together, these findings suggest that miR-485-3p/PGC-1α pathway is a promising therapeutic target in ALS and support the potential of BMD-001S as a novel treatment strategy for the disease.},
}

*MicroRNAs/genetics/metabolism
Animals
*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/drug therapy
*Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics
*Nanoparticles/chemistry/administration & dosage
Mice
Mice, Transgenic
Humans
*Oligonucleotides, Antisense/pharmacology/administration & dosage/genetics
Superoxide Dismutase-1/genetics/metabolism
Spinal Cord/metabolism/pathology/drug effects
Disease Models, Animal
Signal Transduction/drug effects

@article {pmid41594924,
year = {2026},
author = {Bao, Y and Miao, G and He, N and Bao, X and Shi, Z and Hu, C and Liu, X and Wang, B and Sun, C},
title = {Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases.},
journal = {Biology},
volume = {15},
number = {2},
pages = {},
pmid = {41594924},
issn = {2079-7737},
abstract = {Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer's disease, Parkinson's disease, and Huntington's disease-the major protagonists of NDs-while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials.},
}

@article {pmid41593242,
year = {2026},
author = {Hobson, R and Levy, SHS and Singal, CMS and Flaherty, D and Xiao, H and Ciener, B and Reddy, H and Zabinyakov, N and Kim, CY and Teich, AF and Shneider, NA and Bradshaw, EM and Elyaman, W},
title = {Clonal CD8[+] T cells populate the leptomeninges and coordinate with immune cells in human degenerative brain diseases.},
journal = {Nature immunology},
volume = {27},
number = {2},
pages = {323-335},
pmid = {41593242},
issn = {1529-2916},
support = {PF-IMP-870699//Parkinson's Foundation (Parkinson's Foundation, Inc.)/ ; UL1 TR001873/TR/NCATS NIH HHS/United States ; RF1 NS142171/NS/NINDS NIH HHS/United States ; R01 AG067581/AG/NIA NIH HHS/United States ; P30 CA013696/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; *CD8-Positive T-Lymphocytes/immunology ; *Meninges/immunology ; *Alzheimer Disease/immunology ; Female ; Male ; Aged ; Brain/immunology/pathology ; Receptors, Antigen, T-Cell/genetics/immunology ; Microglia/immunology ; Aged, 80 and over ; Middle Aged ; Amyotrophic Lateral Sclerosis/immunology ; *Neurodegenerative Diseases/immunology ; Parkinson Disease/immunology ; Immunologic Memory ; Single-Cell Analysis ; },
abstract = {Meningeal immune cells monitor the central nervous system (CNS) and influence neuroinflammation in mice, but the human leptomeningeal immune landscape and the changes that occur in this immunological niche in neurodegeneration remain underexplored. Here we performed single-cell RNA and T cell receptor (TCR) sequencing of 99,625 high-quality immune cells from 57 leptomeninges and brain samples from donors with Alzheimer's disease (AD), amyotrophic lateral sclerosis and Parkinson's disease and found that although the leptomeninges are home to highly clonally expanded CD8 tissue-resident memory (TRM) T cells, the maximal level of clonal expansion was decreased in AD in comparison to non-neurodegenerative controls. Intra-patient paired tissue analysis further revealed that brain and leptomeningeal TCR repertoires share significant similarities, but tissue-specific clones emerge in AD. Finally, in AD, the degree of CD8 TRM clonal expansion was positively correlated with microglial TGFB2, suggesting that brain and leptomeningeal immune cells coordinate their activities in AD. In addition to identifying key inflammatory dynamics in the human degenerating CNS, this study establishes a foundational resource for future studies that could inform treatment for AD and other neuroinflammatory diseases.},
}

Humans
*CD8-Positive T-Lymphocytes/immunology
*Meninges/immunology
*Alzheimer Disease/immunology
Female
Male
Aged
Brain/immunology/pathology
Receptors, Antigen, T-Cell/genetics/immunology
Microglia/immunology
Aged, 80 and over
Middle Aged
Amyotrophic Lateral Sclerosis/immunology
*Neurodegenerative Diseases/immunology
Parkinson Disease/immunology
Immunologic Memory
Single-Cell Analysis

@article {pmid41592787,
year = {2026},
author = {Mammone, RM and Willis, E and Ruivo, P and Finesso, GE and Cox, A and Assenmacher, CA and Radaelli, E and Piersigilli, A and Miranda, IC},
title = {Pathology associated with human CAR T cell administration in NOD.Cg-Prkdc[scid]Il2rg[tm1Wjl]/SzJ (NSG) mice: A retrospective analysis.},
journal = {Veterinary pathology},
volume = {},
number = {},
pages = {3009858251409216},
doi = {10.1177/03009858251409216},
pmid = {41592787},
issn = {1544-2217},
abstract = {Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment for neoplasia and autoimmune diseases. Immunocompromised mice are a common model to test the efficacy and safety of CAR T cells of human origin. Preclinical toxicity associated with human CAR T-cell products encompasses a spectrum of morphologic changes, with currently limited documentation in the scientific literature. The purpose of this retrospective study was to characterize the histopathologic features associated with human CAR T-cell administration in immunodeficient NOD.Cg-Prkdc[scid] Il2rg[tm1Wjl]/SzJ (NSG) mice (n = 392) submitted to 3 different academic institutions in the United States between 2017 and 2024. Lesions were categorized into xenogeneic graft-versus-host disease (xGvHD) (n = 287), aberrant proliferation of human T cells (n = 188), vascular pathologies (n = 66), on-target/off-tumor (OTOT) toxicity (n = 44), immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) in mice previously humanized with human CD34+ hematopoietic stem cells (HSCs) (n = 21), and acute lysis syndrome (ALS) (n = 5). This study provides veterinary pathologists with descriptive guidance on the pathology associated with human CAR T-cell therapy in immunodeficient mice. Additional molecular data and detailed information related to each construct are necessary to further investigate the translatability of such liabilities to the clinical setting.},
}

@article {pmid41588889,
year = {2026},
author = {Thakur, A and Chowdhury, KR and Kumar, A and Sharma, VV and Bhatia, R},
title = {Targeting Non-coding RNAs in Neurodegeneration: Advances in Therapeutic RNA Modalities and Next-Gen Delivery Technologies.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050421604251108045622},
pmid = {41588889},
issn = {1875-5828},
abstract = {Non-coding RNA (ncRNA)-based therapies represent an emerging and transformative approach in the treatment of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)/Motor Neuron Disease (MND). This review explored the potential for targeting microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, reinforced by promising results from clinical trials demonstrating their capacity to modulate disease pathways. The incorporation of cutting-edge computational methodologies, including RNA structure prediction and gene regulatory network analysis, has been at the forefront in enhancing the efficacy of ncRNA-based treatments. Moreover, chemical methods have improved RNA molecules' stability, accuracy, and directed delivery, enhancing their therapeutic effects. Moreover, cutting-edge RNA editing technologies like Clustered Regularly Interspaced Short Palindromic Repeats/CRISPRassociated protein 13 (CRISPR/Cas13) are advancing our ability to directly manipulate ncRNA expression, offering a powerful avenue for addressing the molecular origins of neurodegeneration. Despite these advances, challenges persist, particularly in ensuring the specificity, delivery efficiency, and long-term efficacy of these treatments. Nanotechnology provides innovative solutions to these obstacles, facilitating more efficient and precise RNA delivery, especially to neuronal tissue. In conclusion, ncRNA-based therapies, while still in nascent stages, represent a hopeful frontier in the fight against NDs. With ongoing research and technological advancements, these therapies could not only halt disease progression but also redefine the future of ND treatment, offering new avenues for patients' care and clinical success.},
}

@article {pmid41586107,
year = {2025},
author = {Berthiaume, AA and Kleist, KN and Reda, SM and Setti, SE and Wu, W and Johnston, JL and Taylor, RW and Stein, LR and Church, KJ},
title = {ATH-1105 mitigates multiple pathologies in ALS models both alone and in combination with riluzole.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1582765},
pmid = {41586107},
issn = {1664-2295},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration, muscle atrophy, and paralysis. The complexity of ALS pathology, driven by factors such as TDP-43 pathology, excitotoxicity, and neuroinflammation, has hindered therapeutic development. While riluzole (an anti-excitotoxic agent) is the current standard treatment, additional therapeutics are needed to address the broad spectrum of ALS-related pathology. ATH-1105, a small-molecule positive modulator of hepatocyte growth factor (HGF) signaling, has shown promise in preclinical models of ALS. Given the multifactorial nature of ALS and the growing recognition that combination approaches may represent the best treatment options, we investigated the therapeutic potential of ATH-1105 in a TDP-43-driven mouse model of ALS, by comparing and combining it with the known efficacious treatment of riluzole. Additionally, we characterize the mechanism by which ATH-1105 induces neuroprotective effects, emphasizing its effects on TDP-43 pathology.

METHODS: In vivo, the impact of daily oral treatment with ATH-1105, alone and in combination with riluzole, was evaluated in Prp-TDP43[A315T] hemizygous transgenic ALS mice. In vitro, the impact of ATH-1105 on TDP-43-related pathology was assessed in rat primary spinal motor neurons subjected to glutamate toxicity. To demonstrate target engagement, the neuroprotective effects of ATH-1105 were assessed via siRNA-mediated knockdown of MET (HGF receptor).

RESULTS: In vivo, ATH-1105 significantly improved neuromuscular function and reduced body weight loss, neurodegeneration, inflammation, and TDP-43 phosphorylation. The combination of ATH-1105 with riluzole led to greater therapeutic effects than either treatment alone. In vitro, the neuroprotective effects of ATH-1105 were shown to be associated with MET activation in motor neurons, which was confirmed via siRNA-mediated knockdown of MET. In motor neurons subjected to glutamate toxicity, ATH-1105 reduced extranuclear and phosphorylated TDP-43, and increased GSK3β phosphorylation (inactivation), a kinase involved in TDP-43 pathology. Additionally, ATH-1105 reduced the abnormal increase in autophagic proteins following glutamate toxicity.

DISCUSSION: Our study underscores the therapeutic potential of ATH-1105 in treating ALS, both as a standalone treatment and in combination with riluzole. ATH-1105 demonstrates neuroprotective effects that slow neuromuscular deterioration in a relevant mouse model, aligning with the need to counteract the neurodegeneration central to ALS.},
}

@article {pmid41585268,
year = {2025},
author = {Srivastav, J and Sharma, S},
title = {Viral and non-viral cellular therapies for neurodegeneration.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1718669},
pmid = {41585268},
issn = {2296-858X},
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive loss of neurons and still lack curative treatment options. In this review, we describe current and developing therapeutic strategies that include viral vector-based gene delivery, antisense oligonucleotide (ASO) and RNA interference methods, stem cell transplantation, and genome editing technologies. Adeno-associated viruses (AAVs) and lentiviruses have been used for gene delivery in preclinical and clinical studies, while ASOs are under development to reduce expression of pathogenic proteins such as tau, α-synuclein, and mutant huntingtin. Cellular therapies, including mesenchymal stem cell (MSC)-based paracrine support and transplantation of neurons derived from induced pluripotent stem cells (iPSCs), are being evaluated, particularly in PD and AD. We also discuss important gene targets such as APOE4, GBA1, SCNA, and MAPT, and how treatment strategies may differ between monogenic and polygenic forms of these disorders. Lastly, we highlight recent efforts focused on genes like TREM2, PINK1, and progranulin, and examine their role in the future development of gene- and cell-based interventions.},
}

@article {pmid41582437,
year = {2026},
author = {Chen, X and Cao, Z and Liang, X and Zhao, T and Wang, Y},
title = {TRIM9 and TRIM26 Interact with UBQLN2[P497H] to Modulate Its Proteasomal Degradation.},
journal = {ACS chemical biology},
volume = {21},
number = {2},
pages = {230-234},
pmid = {41582437},
issn = {1554-8937},
support = {R35 ES031707/ES/NIEHS NIH HHS/United States ; },
mesh = {Humans ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; *Proteasome Endopeptidase Complex/metabolism ; *Autophagy-Related Proteins/metabolism/genetics ; Proteolysis ; *Ubiquitin-Protein Ligases/metabolism ; *Tripartite Motif Proteins/metabolism/genetics ; HEK293 Cells ; *Cell Cycle Proteins/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Protein Binding ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss. ALS-linked mutations in UBQLN2 promote protein aggregation and disrupt proteostasis, yet the mutation-specific protein interactomes and their functional relevance remain poorly defined. We employed APEX2 proximity labeling, together with affinity enrichment of biotinylated peptides and LC-MS/MS analysis, to profile the interactomes of wild-type UBQLN2 and two ALS-linked variants, UBQLN2[P497H] and UBQLN2[P497S]. We identified 785 unique biotinylated proteins, many of which exhibit augmented enrichment in the proximity proteomes of the two mutants over wild-type UBQLN2. Notably, the E3 ubiquitin ligases TRIM9 and TRIM26 were selectively enriched in the proximity proteome of UBQLN2[P497H], which we validated by coimmunoprecipitation followed by Western blot analysis. Fractionation analysis revealed coaccumulation of TRIM9 and TRIM26 with UBQLN2[P497H] in the insoluble fraction, consistent with its heightened aggregation propensity. Treatment of UBQLN2[P497H]-expressing cells with a proteasomal inhibitor led to elevated accumulation of a C-terminal UBQLN2 fragment that is absent in cells expressing wild-type UBQLN2 or its P497S mutant. Individual knockdown of TRIM9 and TRIM26 significantly increased the abundance of the fragment, establishing UBQLN2[P497H] as a substrate for TRIM9- and TRIM26-mediated ubiquitinylation and subsequent proteasomal degradation. These findings nominate TRIM9 and TRIM26 as specific interactors of UBQLN2[P497H] and as regulators of a previously underexplored C-terminal UBQLN2 fragment, suggesting that impaired clearance of this species may contribute to ALS pathogenesis.},
}

Humans
*Adaptor Proteins, Signal Transducing/metabolism/genetics
*Proteasome Endopeptidase Complex/metabolism
*Autophagy-Related Proteins/metabolism/genetics
Proteolysis
*Ubiquitin-Protein Ligases/metabolism
*Tripartite Motif Proteins/metabolism/genetics
HEK293 Cells
*Cell Cycle Proteins/metabolism/genetics
Amyotrophic Lateral Sclerosis/metabolism/genetics
Protein Binding

@article {pmid41579929,
year = {2026},
author = {Murakami, K and Sudou, N and Kurata, A and Kawaguchi-Niida, M},
title = {An ALS-associated mutant SOD1 protein can be eliminated in microglia culture by selective autophagy.},
journal = {Neuroscience},
volume = {598},
number = {},
pages = {47-58},
doi = {10.1016/j.neuroscience.2026.01.017},
pmid = {41579929},
issn = {1873-7544},
abstract = {The acquired toxicity of the familial amyotrophic lateral sclerosis (ALS)-associated mutant Zn-superoxide dismutase 1 (SOD1) protein has been implicated in motoneuron death, and cytosolic aggregates or inclusions have been observed in the cytoplasm of motoneurons, astrocytes, and neuronal axons but not in that of microglia. This study elucidates the mechanisms by which mutant SOD1 does not aggregate in and is cleared by microglia. We generated pcDNA3-Venus-tagged SOD1 constructs: wild-type SOD1 and mutant SOD1 were used as controls, and the A4V, D90A, and G93A SOD1 mutants were used as disease-related constructs; these plasmids were introduced into the Ra2 microglia line for subsequent evaluation. In spinal cords collected from postsymptomatic G93A mice, very little aggregation of the mutant SOD1 protein was detected in microglia, consistent with previous reports. Our new findings, which were based on immunohistochemical, Western blot, and enzyme immunoassay analyses, revealed that the protein expression of mutant SOD1 in microglia is significantly lower than that of wild-type SOD1. Furthermore, we observed the recovery of mutant SOD1 protein levels in autophagy suppression experiments and its colocalization with WDFY3, a selective autophagy-related protein. These in vitro results demonstrate that only the mutant SOD1 protein (i.e., not wild-type SOD1) is degraded by selective autophagy. Furthermore, we found that both wild-type and mutant SOD1 are secreted directly from microglia. These findings provide an opportunity to elucidate the precise mechanism through which microglia manage mutant SOD1 proteins during the pathological process of ALS and are likely to lead to improvements in ALS treatment strategies.},
}

@article {pmid41577127,
year = {2026},
author = {Padilla-Lichtenberger, F and Hem, S and Haumont, E and Jungberg, E and Pajanoti, G and Astur, N and Guiroy, A and Landriel, F},
title = {Spanish Translation, Cross-Cultural Adaptation and Validation of the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ) for Patients With Spinal Metastases.},
journal = {World neurosurgery},
volume = {207},
number = {},
pages = {124822},
doi = {10.1016/j.wneu.2026.124822},
pmid = {41577127},
issn = {1878-8769},
abstract = {BACKGROUND: Spinal metastases significantly impair health-related quality of life (HRQoL), particularly neurological function, pain, and physical independence. The Spinal Oncology Study Group Outcome Questionnaire (SOSGOQ 2.0) is a disease-specific PROM, but no validated Spanish version exists. This study aimed to translate, culturally adapt, and validate the SOSGOQ 2.0 for Spanish-speaking patients with spinal metastases.

METHODS: Following Beaton et al.'s cross-cultural adaptation guidelines, the SOSGOQ 2.0 was forward- and back-translated, reviewed by experts, and pretested with 10 patients. Psychometric validation was performed prospectively in 81 patients. Internal consistency was assessed using Cronbach's α, test-retest reliability using intraclass correlation coefficients (ICC, n = 21), and construct validity through correlations with SF-36 and EQ-5D domains. Known-groups validity was analyzed according to neurological status (ASIA scale) and pain severity (VAS).

RESULTS: The Spanish SOSGOQ 2.0 showed excellent internal consistency (overall α = 0.89; domain range 0.70-0.93) and high test-retest reliability (ICC = 0.88; 95% CI, 0.81-0.93). Convergent validity was supported by moderate-to-strong correlations with SF-36 domains (r = 0.67-0.71). Known-groups analysis demonstrated expected differences between ambulatory (ASIA D-E) and non-ambulatory (ASIA A-C) patients, and between low (VAS ≤4) and high pain (VAS ≥5) groups. Neurological improvement post-treatment was observed in 32% of the patients. The questionnaire was well understood and culturally appropriate.

CONCLUSIONS: The Spanish SOSGOQ 2.0 is a reliable and valid tool for assessing HRQoL in Spanish-speaking patients with spinal metastases, enabling standardized, disease-specific outcome measurement and supporting patient-centered care and international research collaboration.},
}

@article {pmid41575675,
year = {2026},
author = {Kopalli, SR and Wankhede, N and Rahangdale, SR and Sammeta, S and Aglawe, M and Koppula, S and Taksande, B and Upaganlawar, A and Umekar, M and Kale, M},
title = {Age-driven dysbiosis: gut microbiota in the pathogenesis and treatment of aging disorders.},
journal = {Biogerontology},
volume = {27},
number = {1},
pages = {42},
pmid = {41575675},
issn = {1573-6768},
mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Dysbiosis/therapy/microbiology ; *Aging/physiology ; Animals ; Probiotics/therapeutic use ; },
abstract = {Aging, a complex physiological and molecular process, has undergone significant changes, of which gut microbiome composition has surfaced as an important key in the maintenance of neurological health. Recent studies have revealed the significant impact of age-related gut dysbiosis in the induction of neuroinflammation, metabolic syndrome, disruptions in gut-brain axis, and age-related neurological decline. Although significant studies have revealed the impact of the microbiome-gut-brain axis in individual neurological diseases, an aging-focused holistic synthesis has not yet been adequately developed. This review provides a critical assessment of the involvement of age-related dysbiosis of gut microbiota in the development and progression of neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and cognitive aging of the elderly, and to focus on age-related microbial patterns and mechanisms of dysbiosis related to neurological aging, including inflammation and immune system dysregulation, metabolic changes, oxidative stress, barrier dysfunction, and gut-brain communication through enteroendocrine, enteric neural, and vagal mechanisms, and to emphasize disease-specific and common microbial patterns of dysbiosis and beneficial and harmful microbial roles in aging diseases. This review assesses some of the latest promising therapies aimed at the microbiota, such as probiotics, prebiotics, dietary therapies, fecal microbiota transplantation, as well as pharmacological therapies, and critically discusses their limitations in terms of interindividual variability and their generalisation and applicability. Focusing on mechanistic, comparative, and translation aspects, this review offers a comprehensive approach to neurological aging due to gut microbiota and identifies gaps for future precision microbiome-based interventions.},
}

Humans
*Gastrointestinal Microbiome/physiology
*Dysbiosis/therapy/microbiology
*Aging/physiology
Animals
Probiotics/therapeutic use

@article {pmid41569095,
year = {2026},
author = {Charbonnel, T and Richard, E and Dupuis, A and Palla, M and Vourc'h, P and Corcia, P and Al Ojaimi, Y and Blasco, H},
title = {The preclinical discovery and development of edaravone for the treatment of amyotrophic lateral sclerosis: what lessons have we learnt?.},
journal = {Expert opinion on drug discovery},
volume = {21},
number = {2},
pages = {147-160},
doi = {10.1080/17460441.2026.2619067},
pmid = {41569095},
issn = {1746-045X},
mesh = {*Edaravone/pharmacology/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Humans ; Animals ; *Neuroprotective Agents/pharmacology/administration & dosage ; Disease Models, Animal ; Free Radical Scavengers/pharmacology/administration & dosage/pharmacokinetics ; Drug Development/methods ; Drug Discovery/methods ; Oxidative Stress/drug effects ; Mice, Transgenic ; Mice ; Drug Evaluation, Preclinical ; Blood-Brain Barrier/metabolism ; },
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, with limited therapeutic options. Among the few approved drugs, edaravone, a free radical scavenger developed originally for ischemic stroke, has attracted particular attention for its ability to counteract oxidative stress, a key driver of neurodegeneration. Its amphipathic structure and ability to cross the blood-brain barrier support its potential neuroprotective action.

AREAS COVERED: The authors discuss preclinical studies demonstrating edaravone's ability to reduce oxidative damage, preserve mitochondrial function, and modulate neuroinflammatory responses in ALS cellular and animal models. They discuss variations in dosage, timing, and disease models that produced heterogeneous results. In transgenic mice, edaravone may delay symptom onset and modestly extend survival, but these effects are inconsistent and often limited to early disease stages.

EXPERT OPINION: Clinically, edaravone provides modest benefits in a subset of patients, reflecting the translational gap between preclinical efficacy and clinical relevance. This case highlights broader challenges in ALS drug discovery, including limited model predictivity, methodological variability, and lack of patient stratification. The edaravone experience highlights key lessons for future neuroprotective approaches: the importance of standardized preclinical design, integration of human-based models, early pharmacokinetic validation, and biomarker-driven trials to advance precision neuroprotection in ALS.},
}

*Edaravone/pharmacology/administration & dosage
*Amyotrophic Lateral Sclerosis/drug therapy/physiopathology
Humans
Animals
*Neuroprotective Agents/pharmacology/administration & dosage
Disease Models, Animal
Free Radical Scavengers/pharmacology/administration & dosage/pharmacokinetics
Drug Development/methods
Drug Discovery/methods
Oxidative Stress/drug effects
Mice, Transgenic
Mice
Drug Evaluation, Preclinical
Blood-Brain Barrier/metabolism

@article {pmid41562880,
year = {2026},
author = {Fiorella, ML and Ballini, L and Lavermicocca, V and Ragno, MS and Restivo, DA and Marchese-Ragona, R},
title = {Dysphagia and Dysarthria in Neurodegenerative Diseases: A Multisystem Network Approach to Assessment and Management.},
journal = {Audiology research},
volume = {16},
number = {1},
pages = {},
pmid = {41562880},
issn = {2039-4330},
abstract = {Dysphagia and dysarthria are common, co-occurring manifestations in neurodegenerative diseases, resulting from damage to distributed neural networks involving cortical, subcortical, cerebellar, and brainstem regions. These disorders profoundly affect patient health and quality of life through complex sensorimotor impairments. Objective: The aims was to provide a comprehensive, evidence-based review of the neuroanatomical substrates, pathophysiology, diagnostic approaches, and management strategies for dysphagia and dysarthria in neurodegenerative diseases with emphasis on their multisystem nature and integrated treatment approaches. Methods: A narrative literature review was conducted using PubMed, Scopus, and Web of Science databases (2000-2024), focusing on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). Search terms included "dysphagia", "dysarthria", "neurodegenerative diseases", "neural networks", "swallowing control" and "speech production." Studies on neuroanatomy, pathophysiology, diagnostic tools, and therapeutic interventions were included. Results: Contemporary neuroscience demonstrates that swallowing and speech control involve extensive neural networks beyond the brainstem, including bilateral sensorimotor cortex, insula, cingulate gyrus, basal ganglia, and cerebellum. Disease-specific patterns reflect multisystem involvement: PD affects basal ganglia and multiple brainstem nuclei; ALS involves cortical and brainstem motor neurons; MSA causes widespread autonomic and motor degeneration; PSP produces tau-related damage across multiple brain regions. Diagnostic approaches combining fiberoptic endoscopic evaluation, videofluoroscopy, acoustic analysis, and neuroimaging enable precise characterization. Management requires multidisciplinary Integrated teams implementing coordinated speech-swallowing therapy, pharmacological interventions, and assistive technologies. Conclusions: Dysphagia and dysarthria in neurodegenerative diseases result from multifocal brain damage affecting distributed neural networks. Understanding this multisystem pathophysiology enables more effective integrated assessment and treatment approaches, enhancing patient outcomes and quality of life.},
}

@article {pmid41560764,
year = {2026},
author = {Ge, Y and Zhu, J and Ren, Y and Wu, X and Zhou, B and Wu, Y and Ge, Y},
title = {Trans-Generational Morphological Trait Plasticity in Parthenogenetic Offspring of Two Brachionus dorcas Morphotypes Induced by Asplanchna Kairomones.},
journal = {Ecology and evolution},
volume = {16},
number = {1},
pages = {e72956},
pmid = {41560764},
issn = {2045-7758},
abstract = {We compared trans-generational (F0-F12) morphological trait plasticity induced by Asplanchna kairomones between two Brachionus dorcas morphotypes (long-posterior spines, LS; short-posterior spines, SS) along with life-table parameters of the non-induced morphotypes. Under control conditions, SS rotifers tended to show higher fertility and smaller body size than LS rotifers. Low kairomone concentrations (50 and 200 ind./L) tended to increase body size in SS offspring, while exposure to 50, 200, and 800 ind./L kairomones induced spine elongation in both morphotypes, with posterolateral spine (PS) length increasing with kairomone concentration. Compared to the F0 generation, offspring of both morphotypes in unexposed controls showed generational fluctuations in body size; LS offspring exhibited shortening or no change in anteromedian spine (AMS) and anterolateral spine (ALS) lengths, while SS offspring showed elongation or no change in these spine lengths and PS length. Across all kairomone treatments, significant elongation of AMS and ALS in LS offspring was typically observed only in later generations, whereas SS offspring exhibited significant elongation from F1 through F12; LS offspring showed significant PS elongation from F2 through F12, with maximum lengths in the later generations (F5-F12), while SS offspring showed significant PS elongation from F1 through F12, peaking in early generations (F2-F4). Notably, the multi-generational mean PS length in SS offspring remained significantly shorter than that in LS offspring under each kairomone treatment. Overall, SS offspring appeared to employ a synergistic defense combining increased body size and spine elongation favoring a "rapid and moderate response," whereas LS offspring exhibited a "slow and extreme defense" strategy. These divergent strategies may result from evolutionary trade-offs involving resource allocation, environmental predictability, and genetic constraints.},
}

@article {pmid41557593,
year = {2026},
author = {Meyer, T and Maier, A and Grehl, T and Weyen, U and Rödiger, A and Smesny, U and Steinbach, R and Grosskreutz, J and Göricke, B and Bernsen, S and Weydt, P and Fabian, R and Petri, S and Lumi, R and Bjelica, B and Boentert, M and Lingor, P and Kettemann, D and Norden, J and Walter, B and Riitano, A and Schumann, P and Münch, C and Spittel, S},
title = {Minimum important slowing of disease progression as determined by the ALS functional rating scale - a survey of patient expectations toward disease-modifying drugs in ALS.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/21678421.2026.2615117},
pmid = {41557593},
issn = {2167-9223},
abstract = {Objective: To define the minimum important slowing (MIS) of ALS progression that patients would expect from disease-modifying drug treatment in ALS. Methods: In a survey of ALS patients, the MIS in ALS progression (change in the ALS Functional Rating Scale-Revised, ALSFRS-R) was assessed by asking: "At what point of slowing of ALS, as determined by the ALSFRS-R, do you consider a drug to be important?" Data were collected during clinic visits or remotely via the ALS App. Participants were differentiated in the prognostic groups of slower (<0.5), intermediate (≥0.5 and ≤1.0), or faster (>1.0) ALS progression (ALSPR; ALSFRS-R/month). Results: Of 522 participants (ALS App, n = 397; clinic, n = 125), 395 (75.7%) completed the survey, while 127 (24.3%) selected the option "cannot estimate". The distribution of MIS was as follows: modest slowing of ALS progression (5% and 10% slowing, n = 146 patients, 36.9%), moderate slowing (20%, 30%, and 40% slowing, n = 135, 34.2%), and major slowing (≥50% slowing, n = 114, 28.9%). Median MIS was 20% (IQR 10-50%). Patients with faster ALSPR more frequently assessed a major slowing as the MIS (n = 18, 36.0%) compared to those with slower ALSPR (n = 54, 25.2%). Conclusion: A considerable number of participants viewed a modest slowing in ALS progression as the MIS, followed closely by preferences for moderate and major slowing. Expectations varied according to patients' individual ALS progression. These insights may inform the design of future clinical trials in ALS. Study limitations include potential selection and response biases, as well as the predominantly remote digital assessment.},
}

@article {pmid41556400,
year = {2026},
author = {Howard, I and Lyerly, M and Reimer, R and Patwa, H and Darling, L},
title = {Symptom Burden and Care Satisfaction in US Military Veterans With ALS: Results of a National Survey.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70147},
pmid = {41556400},
issn = {1097-4598},
abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) affects military veterans at a higher rate than the general civilian population. The aim of the present study is to assess symptom burden and satisfaction with care among persons with ALS care enrolled in the US Veterans Health Administration (VA).

METHODS: A custom online survey was created with questions about symptom prevalence and management as well as care satisfaction. A survey link was sent by email to all veterans with an ICD-10 diagnosis of ALS in the VA for whom an email address was available in the electronic health record.

RESULTS: Responses were received from 413 individuals (16% response rate). Respondents reported high care satisfaction and higher prevalence of treatment of symptoms compared to prior surveys of persons with ALS in the United States. Self-reported outcomes, including treatment, education, and satisfaction, were better for Veterans receiving care exclusively within the VA compared to those receiving care at both VA and non-VA facilities or receiving care exclusively at non-VA facilities. Areas for further improvement identified in the survey include education on genetic testing and research and management of non-motor symptoms.

DISCUSSION: This survey indicates that, overall, veterans with ALS receive comprehensive symptom-based care within the nationalized VA care system and report high levels of satisfaction. Furthermore, this study provides baseline data and findings that may be used for quality improvement efforts across a large healthcare system and may serve as a model for similar efforts in other health systems.},
}

@article {pmid41553108,
year = {2026},
author = {Rudnicki, SA and Giacomelli, E and Herder, K and Ingre, C and Kupfer, S and Malik, FI and Meng, L and Paganoni, S and Schellenberg, K and Scirocco, E and Simkins, T and Wei, J and Shefner, JM and , },
title = {The Use of Durable Medical Equipment in COURAGE-ALS, a Phase 3, Multicentre, Randomized Clinical Trial for ALS.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70150},
pmid = {41553108},
issn = {1097-4598},
support = {//Cytokinetics, Incorporated/ ; },
abstract = {INTRODUCTION/AIMS: Durable medical equipment (DME)-wheelchairs, non-invasive ventilation, gastrostomy tubes, and communication devices-provides vital support for individuals with amyotrophic lateral sclerosis (ALS). Here, we describe DME use in COURAGE-ALS evaluating reldesemtiv's efficacy and safety in ALS, to evaluate if DME use can be considered an endpoint of interest in ALS trials.

METHODS: COURAGE-ALS, a multicentre, double-blind, randomized, placebo-controlled clinical trial was conducted at 83 sites in the United States, Canada, Europe, and Australia. Participants were randomized 2:1 to receive reldesemtiv or placebo for 24 weeks, followed by 24 weeks of active drug treatment. Exploratory outcomes included reasons for prescribing, extent of use, DME types, and regional differences.

RESULTS: Among 482 participants, 166 (34.4%) were using at least one DME item at baseline. Among 276 participants completing study visits through Week 24, 130 (47.1%) initiated use of a total of 188 new DME items post-baseline through 24 weeks. Manual wheelchairs were most used at baseline (89 items) and initiated (47 items) during the trial. Both baseline DME use and initiating a new item were associated with lower ALS Functional Rating Scale-Revised scores and worse quality of life. The trial was terminated early due to futility. Treatment assignment did not impact DME use. Regional disparities were noted.

DISCUSSION: This study shows that DME is commonly prescribed to ALS trial participants. Further understanding of geographic differences in DME access and their impact on clinical outcomes is warranted prior to including DME use as an endpoint in ALS trials.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: (NCT04944784).},
}

@article {pmid41549027,
year = {2026},
author = {Shenouda, M and Shenouda, S and Kartono, B and Eid, S and Cheng, C and Robertson, J},
title = {Small molecule JRMS modulating importin-β1 chaperone activity as a therapeutic strategy reducing TDP-43 pathology.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00834},
doi = {10.1016/j.neurot.2026.e00834},
pmid = {41549027},
issn = {1878-7479},
abstract = {Neuronal cytoplasmic aggregation and nuclear depletion of the TAR DNA-binding protein 43 (TDP-43) is the most characteristic pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), causing toxicity through cytoplasmic gain and nuclear loss of function mechanisms. In addition to its canonical role in nuclear cytoplasmic transport (NCT), the nuclear import receptor, importin-β1 (KPNB1) also acts as a molecular chaperone capable of preventing and reversing aberrant protein aggregation. Previous studies have demonstrated that increased expression of KPNB1 solubilizes TDP-43 aggregates and restores its nuclear localization. Here, we identify JRMS, a small molecule that enhances the chaperone activity of KPNB1 by increasing its cytoplasmic availability. JRMS treatment reduced cytoplasmic aggregation and promoted nuclear localization of full-length and pathological truncated TDP-43 variants across multiple experimental systems, including cell lines, primary neurons, iPSC-derived cortical neurons, organotypic brain slices and in vivo model. The effects of JRMS were KPNB1 dependent and occurred without inducing cytotoxicity or perturbing basal NCT. These findings identify JRMS as a promising therapeutic strategy for targeting TDP-43 pathology in ALS/FTD and other related TDP-43 proteinopathies.},
}

@article {pmid41546910,
year = {2026},
author = {Elyasi, L and Wężyk, M},
title = {Exosome-derived microRNAs from stem cells from human exfoliated deciduous teeth (SHED): Emerging therapeutics for neurodegenerative disorders.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {119001},
doi = {10.1016/j.biopha.2026.119001},
pmid = {41546910},
issn = {1950-6007},
mesh = {Humans ; *Neurodegenerative Diseases/therapy/genetics/metabolism ; *Tooth, Deciduous/cytology/metabolism ; *Exosomes/metabolism/genetics ; *MicroRNAs/metabolism/genetics ; Animals ; *Stem Cells/metabolism ; *Stem Cell Transplantation/methods ; },
abstract = {Neurodegenerative diseases (NDDs) cause progressive damage of brain structures, resulting in a loss of function and, eventually, the patient's death. Current therapeutic strategies are limited to late stages of the disease, culminating in palliative care, while tackling the underlying causes of neurodegeneration could halt or at least slow down the disease at an early stage. In this vein, stem cell transplantation therapies are emerging as a promising alternative, as such as cells can penetrate the central nervous system, engraft, differentiate, and secrete neurotrophic, neuro-regenerative, and neuroprotective factors. Stem cells derived from human exfoliated deciduous teeth (SHED) have demonstrated significant regenerative potential in various biological systems and pathological conditions, showing high proliferative capacity and multipotency to differentiate into neuronal cells both in vivo and in vitro, apparently functioning through exosome-derived microRNAs (exos-miRs). Here, we summarize recent reports on specific miRs from SHED's exosomes, which exert diverse regulatory functions counteracting oxidative stress, and provide immunomodulatory and neurotrophic benefits contributing to the treatment of neurodegeneration in NDDs. We discuss clinical and preclinical evidence supporting the potential of SHED cells in the treatment of NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, focal cerebral ischemia, and peripheral nerve damage. We also highlight that the use of SHED in NDDs treatment remains largely underexplored, opening a wide field for further research. We suggest deeper studies on the role of SHED-exos-miRs in NDDs, including their proneurotrophic activity, reduction of genotoxic neuronal stress, and disruption of proinflammatory signaling pathways.},
}

Humans
*Neurodegenerative Diseases/therapy/genetics/metabolism
*Tooth, Deciduous/cytology/metabolism
*Exosomes/metabolism/genetics
*MicroRNAs/metabolism/genetics
Animals
*Stem Cells/metabolism
*Stem Cell Transplantation/methods

@article {pmid41545051,
year = {2026},
author = {Trad, G and Lenglet, T and Ledoux, I and Querin, G and Blancho, S and Marchand-Pauvert, V and Hogrel, JY and Pradat, PF},
title = {Safety and efficacy of the Atalante exoskeleton in the rehabilitation of French patients with amyotrophic lateral sclerosis: a prospective, monocentric, open, uncontrolled, interventional protocol, EXALS.},
journal = {BMJ open},
volume = {16},
number = {1},
pages = {e109620},
pmid = {41545051},
issn = {2044-6055},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology ; Prospective Studies ; *Exoskeleton Device ; France ; Quality of Life ; Female ; Male ; Middle Aged ; Walking ; Gait ; *Exercise Therapy/methods/instrumentation ; Aged ; Muscle Strength ; Adult ; Postural Balance ; *Gait Disorders, Neurologic/rehabilitation/etiology ; Treatment Outcome ; },
abstract = {INTRODUCTION: Robotic rehabilitation on locomotion is a new approach in amyotrophic lateral sclerosis (ALS) and previous studies showed its feasibility. In this study, we aim to evaluate safety, patient's experience and efficacy of a gait training programme with the Atalante exoskeleton, compared with usual care, on walking ability, functional capacity and other symptoms associated with ALS.

METHODS AND ANALYSIS: EXALS is a monocentric, prospective, interventional, open trial. 20 slowly progressing patients with gait deficits will be recruited. The study is conducted in three phases, each lasting 6 weeks, following the ABA procedure. Phase B represents the intervention phase, during which patients practise their gait training at a rhythm of three sessions/week, as an add-on to usual care. In the two phases A, patients receive usual care with no additional treatment. An evaluation is planned before, in the middle and at the end of each phase. The primary outcome of the study is safety and tolerability of the Atalante exoskeleton. Secondary outcomes include: participants' subjective impact and experience, attitude and motivation, efficacy and interactivity of the exoskeleton, walking ability, functional capacity, spasticity, balance, postural stability, lower limb muscle strength, quality of life, pain, fatigue, anxiety and depression. Statistical analyses will include descriptive methods for all variables and adverse events. Quantitative outcomes are analysed using repeated-measures ANOVA (analysis of variance) across the seven visits, with post hoc tests applied when appropriate. Nominal outcomes are evaluated using Cochran's Q test with McNemar pairwise comparisons when significant. Associations between variables are examined using Spearman correlation coefficients. Missing data will be replaced using linear interpolation, and sensitivity analyses will be planned. Qualitative interview data are analysed using thematic analysis.

ETHICS AND DISSEMINATION: This study was approved by the French ethics committee CPP Nord-Ouest I (no. 23.02378.000201). Participant data are anonymised and securely stored in the laboratory's database, accessible only to the research team. Results will be disseminated through peer-reviewed journals and conferences.NCT06199284.},
}

Humans
*Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology
Prospective Studies
*Exoskeleton Device
France
Quality of Life
Female
Male
Middle Aged
Walking
Gait
*Exercise Therapy/methods/instrumentation
Aged
Muscle Strength
Adult
Postural Balance
*Gait Disorders, Neurologic/rehabilitation/etiology
Treatment Outcome

@article {pmid41536515,
year = {2026},
author = {Voldřich, R and Svoboda, N and Kachlířová, Z and Bartáková, L and Charvát, F and Netuka, D},
title = {Urodynamic outcomes and prognostic determinants following endovascular treatment of spinal dural arteriovenous fistulas.},
journal = {Brain & spine},
volume = {6},
number = {},
pages = {105913},
pmid = {41536515},
issn = {2772-5294},
abstract = {INTRODUCTION: The prognosis of untreated spinal dural arteriovenous fistulas (SDAVFs) is unfavorable. Current outcome scales used to assess the effect of surgery or endovascular treatment (EVT) rely largely on patient-reported symptoms and may underestimate actual impairment. Moreover, prognostic factors remain debated and conclusions in the literature are inconsistent.

RESEARCH QUESTION: The aim was to quantify urological outcomes after SDAVF embolization using specialized urodynamic testing, compare these objective findings with subjective outcomes derived from traditional scales, and identify prognostic factors associated with unfavorable clinical results.

METHODS: In this single-center retrospective study, all patients underwent EVT as first-line therapy. Clinical status was assessed using Aminoff-Logue scale (ALS), compared with preoperative data, and correlated with angiographic findings. Urodynamic testing was performed to objectively evaluate bladder function.

RESULTS: Twent-four patients met the inclusion criteria. Urodynamic testing was performed in 14 (58 %) patients. The most frequent abnormal finding was bladder hyposensitivity (79 %), followed by pathological post-void residual volume (64 %) and elevated bladder capacity (50 %). Six (43 %) patients reported no subjective urological symptoms (ALS = 0); urodynamic testing revealed two or more pathological parameters in all of them. EVT failure and subsequent surgery predicted gait deterioration (p = 0.011) as well as detrusor overactivity (p = 0.001). Symptom duration over one year (p = 0.038) and fistula location above the T9 level (p = 0.021) were negative prognostic factors for bladder function.

CONCLUSION: The results suggest a potential underestimation of urological impairment when relying on subjective scales and highlight the need for standardized urodynamic testing. They also emphasize the importance of early treatment of SDAVF.},
}

@article {pmid41530082,
year = {2026},
author = {Cooper, P and Lu, M and Chan, M and Wilman, A and Kalra, S and Ghavanini, AA},
title = {Exploring the Value of Brain T2* Weighted and FLAIR Imaging for Diagnosing Amyotrophic Lateral Sclerosis.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-6},
doi = {10.1017/cjn.2026.10527},
pmid = {41530082},
issn = {0317-1671},
abstract = {OBJECTIVES: Early diagnosis of amyotrophic lateral sclerosis (ALS) is essential for treatment initiation and symptom management, yet it remains challenging due to nonspecific symptoms and the lack of reliable diagnostic biomarkers. Although conventional MRI sequences such as T2* weighted and fluid-attenuated inversion recovery (FLAIR) have shown potential in identifying upper motor neuron abnormalities, their diagnostic utility in ALS is not well established. This study aimed to evaluate the sensitivity and specificity of brain T2* weighted and FLAIR MRI sequences in diagnosing ALS using prospectively collected data and to assess associations with disease severity.

METHODS: Data were analyzed from 20 patients with ALS and 20 healthy controls enrolled at the Edmonton site of the Canadian ALS Neuroimaging Consortium 1 (CALSNIC-1) study. Single-slice 2D axial susceptibility-weighted echo planar imaging (SWEPI) and FLAIR images were independently rated by a blinded neurologist and radiologist for signs of corticospinal tract and motor cortex abnormalities. Sensitivity and specificity were calculated, and linear regression was used to examine associations with ALS Functional Rating Scale-Revised (ALSFRS-R) scores.

RESULTS: T2* weighted and FLAIR MRI sequences showed high specificity (0.95 and 0.85, respectively) but low sensitivity (both 0.25) for ALS diagnosis. No significant correlation was found between imaging abnormalities and ALSFRS-R scores. Inter-rater reliability was poor (κ = 0.25 for SWEPI; κ = 0.14 for FLAIR).

CONCLUSION: While T2* weighted and FLAIR MRI sequences may have some specificity for ALS, our study suggests they are not sufficiently sensitive to be used as reliable diagnostic tools for ALS.},
}

@article {pmid41527739,
year = {2026},
author = {Le, J and Hu, X and Jiang, Y and Wang, Q and Ma, Q and Cui, W},
title = {Insights into phosphoproteomic studies and prospects of phosphoproteins as biomarkers for brain disorders.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411546},
doi = {10.1177/13872877251411546},
pmid = {41527739},
issn = {1875-8908},
abstract = {The dysregulation of phosphorylation networks plays a critical role in the pathogenesis of a wide spectrum of brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, ischemic stroke, drug abuse, major depressive disorder, and schizophrenia. Notably, phosphorylated isoforms of microtubule-associated protein tau and neurofilament heavy polypeptide are already utilized in clinical diagnostics, highlighting the promise of protein phosphorylation signatures as biomarkers for prediction, diagnosis, prognosis, and treatment monitoring. Recent advances in deep phosphoproteomic technologies now facilitate the comprehensive mapping of phosphorylation alterations across diverse biological samples and disease stages. This review summarizes current phosphoproteomic studies aimed at identifying biomarkers for brain disorders and elaborates on the promising application of phosphorylated proteins in this context.},
}

@article {pmid41518572,
year = {2026},
author = {Zhang, Z and Zhang, M and Cao, Z and Zhao, H and Li, X and Luo, P},
title = {Fibrillarin: bridging ribosome biogenesis and apoptosis in cellular stress and disease.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {31},
number = {1},
pages = {11},
pmid = {41518572},
issn = {1573-675X},
support = {82171363//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Apoptosis/genetics ; *Ribosomes/metabolism/genetics ; *Neoplasms/genetics/metabolism/pathology ; *Stress, Physiological ; Animals ; Tumor Suppressor Protein p53/metabolism/genetics ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; Cell Nucleolus/metabolism ; Signal Transduction ; Chromosomal Proteins, Non-Histone ; },
abstract = {Nucleolar stress has emerged as a critical regulatory mechanism linking ribosome biogenesis defects to apoptotic cell death in various pathological conditions. Fibrillarin (FBL), the catalytic component of box C/D small nucleolar ribonucleoproteins, participates in multiple forms of programmed cell death through both p53-dependent and p53-independent pathways across diverse disease contexts including cancer and neurodegeneration. In malignancies including breast cancer, colorectal cancer, and hepatocellular carcinoma, FBL overexpression promotes apoptosis resistance, whereas in Alzheimer's disease and ALS/FTD, FBL dysfunction contributes to pathological neuronal death. Dysregulation of FBL can lead to excessive apoptosis or apoptosis resistance depending on cellular context and disease state. Various cellular stressors trigger aberrant FBL function, disrupting rRNA processing and ribosome assembly, which then activates nucleolar stress responses that culminate in cell death through ribosomal protein-MDM2-p53 axis activation or selective translational control of survival factors in a context-dependent manner. Therefore, targeting FBL-mediated apoptotic pathways is considered an important avenue for the treatment of various cancers and neurodegenerative diseases. In this review, we summarize the major and recent findings focusing on the mechanisms of FBL-regulated apoptosis in disease pathogenesis and provide a systematic overview of current therapeutic strategies targeting nucleolar stress pathways, including RNA polymerase I inhibitors and precision medicine approaches based on p53 status, which may provide important therapeutic targets that merit further investigation.},
}

Humans
*Apoptosis/genetics
*Ribosomes/metabolism/genetics
*Neoplasms/genetics/metabolism/pathology
*Stress, Physiological
Animals
Tumor Suppressor Protein p53/metabolism/genetics
*Neurodegenerative Diseases/genetics/metabolism/pathology
Cell Nucleolus/metabolism
Signal Transduction
Chromosomal Proteins, Non-Histone

@article {pmid41510728,
year = {2026},
author = {González-Jiménez, KA and Herrera-Mayorga, EV and Paredes Sánchez, FA and Niño-García, N and Torres-Castillo, JA and Martínez-Padrón, HY and Sánchez-Sánchez, M},
title = {New Drug Therapies Against Targeting Neurodegenerative Diseases: A Comprehensive Review.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249397580251117044621},
pmid = {41510728},
issn = {1875-6166},
abstract = {Neurodegenerative diseases encompass well-characterized behavioral, cognitive, and movement disorders that affect older people, impacting all facets of daily life. In Alzheimer's disease, specific antibodies targeting the β-amyloid protein (aducanumab, lecanemab, and others) are gaining special interest due to the approval of the first particular drugs against this disease. In Parkinson's disease, most drugs were approved several decades ago; however, new Phase II clinical trials point to monoclonal antibodies as a promising approach, and the report of alkaloids also suggests various therapeutic targets against this disease. Pick's disease has a low prevalence; currently, no drugs are approved by government agencies. However, thanks to molecular tools, it has been possible to elucidate therapeutic targets implicated in the appearance of the disease. α-synuclein is the main therapeutic target in Lewy body disease; most of the reported molecules are in clinical Phases I and II. Additionally, drug repositioning may emerge as a viable option in the search for effective treatments against this disease. In amyotrophic lateral sclerosis, the appearance of newly approved drugs such as tofersen and edaravone, and some others in clinical Phase II (bosutinib), opens a new era in the understanding and treatment of this condition. Altered emotions and progressive damage in some brain regions characterize schizophrenia and vascular dementia. Combinations of tricyclic drugs are a trend that aims to increase the cognitive performance of patients with schizophrenia. In vascular dementia, numerous in vivo trials with molecules of different natures (flavonoids and lactones) have yielded positive results, delaying the progression of the disease. This review examines recent reports on molecules evaluated in vivo and in vitro models of the primary neurodegenerative diseases.},
}

@article {pmid41510716,
year = {2026},
author = {Bano, A and Khan, AA and Kushwaha, SP and -, A and Zaidi, SMH and Misbahul Hasan, S and Fatima, A},
title = {Indole Scaffolds in Neurological Therapeutics: Synthesis, Structure-Activity Relationships and Drug-Receptor Interactions.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575415521251021091530},
pmid = {41510716},
issn = {1875-5607},
abstract = {INTRODUCTION: Indole is a privileged heterocyclic scaffold that plays a crucial role in medicinal chemistry due to its strong ability to bind to various biological receptors and interact with diverse molecular targets. Indole exhibits both biological and chemical significance. Its structural versatility allows for precise chemical modifications, making it an essential framework in drug discovery. This review discusses the structure-activity relationships, synthesis, and interactions of indole derivatives, particularly in relation to targets within the central nervous system.

METHODS: A detailed literature survey was conducted using databases such as Google Scholar, Elsevier, PubMed, ACS, PubChem, ScienceDirect, and RSC to understand the structural modifications of indole derivatives and their therapeutic potential. Both research and review articles related to indole- based compounds were thoroughly studied to prepare this review article.

RESULTS: There are over 40 FDA-approved drugs containing an indole nucleus used to treat various diseases, underscoring its potential in neurotherapeutics. This review highlights innovative synthetic strategies, including green chemistry approaches, that improve the drug-likeness and bioavailability of indole derivatives. Indole continues to be an indispensable scaffold in the development of novel therapeutics aimed at addressing the growing burden of neurological disorders.

DISCUSSION: This review aims to provide a comprehensive analysis of the therapeutic potential of indole-based compounds for the treatment of neurological disorders. However, challenges like blood-brain barrier permeability and long-term safety must be addressed for clinical success. Nonetheless, this review will help in designing and developing newer indole-based molecules in the discovery of neurological drug development.

CONCLUSION: Due to its broad spectrum of biological activities and favorable pharmacokinetic properties, indole is an impressive scaffold for the treatment of various neurological disorders. Indole demonstrates remarkable therapeutic potential against a range of central nervous system-related conditions, including Alzheimer's disease, epilepsy, migraine, stroke, Parkinson's disease, prion disease, amyotrophic lateral sclerosis, and Huntington's disease.},
}

@article {pmid41510529,
year = {2026},
author = {Reedy, MB and Abdul Azeem, M and Subramaniam, T and Salamat, S and Rowley, H and Beinlich, B},
title = {Neuroinvasive West Nile Virus Presenting as Subacute Progressive Quadriparesis and Intractable Pain: A Case Report.},
journal = {Case reports in neurological medicine},
volume = {2026},
number = {},
pages = {5565739},
pmid = {41510529},
issn = {2090-6668},
abstract = {West Nile virus (WNV) is the most common mosquito-borne infection in North America; while most cases are asymptomatic, fewer than 1% develop neuroinvasive disease with significant morbidity and mortality. We report a 57-year-old man from rural Wisconsin who presented with a 10-week history of progressive asymmetric quadriparesis and severe intractable pain, preceded by fatigue, shoulder pain, and paresthesias. Neurologic examination demonstrated mild encephalopathy, bulbar involvement, and mixed upper and lower motor neuron signs. MRI showed patchy thoracic cord T2 hyperintensities and diffuse lumbar ventral root enhancement. Electrodiagnostic studies revealed diffuse active denervation and reduced compound muscle action potentials, initially raising concern for amyotrophic lateral sclerosis. Elevated WNV IgM and IgG titers in serum and cerebrospinal fluid confirmed neuroinvasive WNV infection. Despite treatment with corticosteroids and intravenous immunoglobulin, the patient deteriorated and was transitioned to hospice care. Autopsy demonstrated T-cell-mediated meningoencephalitis with widespread lymphocytic inflammation involving motor neurons, spinal cord, ventral rootlets, and peripheral nerves, consistent with diffuse axonopathy. This case underscores that neuroinvasive WNV may closely mimic motor neuron disease and emphasizes the importance of serologic testing for accurate diagnosis. Management remains supportive, and outcomes can be severe due to extensive central and peripheral nervous system involvement.},
}

@article {pmid41504056,
year = {2025},
author = {Lymperopoulos, A and M'Sadoques, AJ and Stoicovy, RA and Altsman, VL},
title = {Why Is Epinephrine Preferred for Cardiac Arrest? The Answer May Lie in β2-Adrenergic Receptor Activation.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {30},
number = {12},
pages = {47927},
doi = {10.31083/FBL47927},
pmid = {41504056},
issn = {2768-6698},
support = {R01 #HL155718-01//National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) grant/ ; #333609-2025//American Foundation for Pharmaceutical Education (AFPE) Gateway to Research Scholarship/ ; },
mesh = {*Epinephrine/therapeutic use/pharmacology ; Humans ; *Heart Arrest/drug therapy ; *Receptors, Adrenergic, beta-2/metabolism ; *Vasoconstrictor Agents/therapeutic use/pharmacology ; Cardiopulmonary Resuscitation/methods ; Animals ; },
abstract = {Epinephrine (Epi, adrenaline) is routinely used during cardiopulmonary resuscitation (CPR) for cardiac arrest and is a first line treatment according to the international advanced life support (ALS) guidelines, which recommend 1 mg Epi be administered every 3-5 minutes during CPR. However, specific pharmacological factors that may distinguish Epi from other vasopressor agents used during CPR are unclear. This opinion article argues that one such factor, perhaps even the most important, is the activation of the β2-adrenergic receptor (AR) subtype, which only Epi, among all vasopressor hormones, can induce. β2AR activation equips Epi with more robust capabilities for pulse generation in the pacemaker cells (sinoatrial node) for the heart and of restoring contractile function in ischemic/hypoxic cardiomyocytes via sodium/potassium pump activation, compared to all other vasopressor hormones, including the closely related catecholamine norepinephrine (NE, noradrenaline). These additional actions of Epi via the β2AR, which are probably not shared by NE or other vasopressor agents, may make it particularly useful in situations where simple blood pressure elevation is insufficient, such as cardiac arrest.},
}

*Epinephrine/therapeutic use/pharmacology
Humans
*Heart Arrest/drug therapy
*Receptors, Adrenergic, beta-2/metabolism
*Vasoconstrictor Agents/therapeutic use/pharmacology
Cardiopulmonary Resuscitation/methods
Animals

@article {pmid41499157,
year = {2026},
author = {Sousa-Leite, M and Gameiro, S},
title = {A multi-country study to co-design and evaluate digital educational resources to support conversations about ending fertility treatment.},
journal = {Human reproduction (Oxford, England)},
volume = {41},
number = {3},
pages = {381-393},
doi = {10.1093/humrep/deaf248},
pmid = {41499157},
issn = {1460-2350},
support = {//Research Wales Innovation Fund/ ; JA1710IF63//Higher Education Funding Council for Wales/ ; SFRH/BD/144429/2019//Portuguese Foundation for Science and Technology/ ; ES/Z503125/1//UK Economic and Social Research Council/ ; UIDB/04750/2020//FTC/ ; LA/P/0064/2020//FTC/ ; },
abstract = {STUDY QUESTION: How can educational resources be feasibly co-designed and used to support conversations between staff and patients about ending fertility treatment?

SUMMARY ANSWER: Co-design workshops allow for the development of educational resources that account for all stakeholders' perspectives and are considered sensitive, informative, and helpful to support end-of-treatment conversations, but staff and patients have different views about how these can be used within the treatment pathway.

WHAT IS KNOWN ALREADY: Ending treatment without children is a common outcome but seldom discussed with patients. Preventive end-of-treatment care aims to promote healthy transitions at the end of treatment by preparing and helping patients cope with this possible outcome. Nine in ten patients want to receive such care, but only 3 in 10 report receiving it. Knowledge of perceived barriers to implementing preventive end-of-treatment care at clinics and whether digital educational resources can be developed to support its provision is lacking.

STUDY DESIGN, SIZE, DURATION: Co-design workshops with fertility staff (March 2022), patients, and patient advocates (March-December 2022) from Europe (Belgium, Finland, Germany, Italy, Portugal, Spain, and UK) and South America (Argentina, Brazil, and Chile). Staff were invited to participate through fertility professional and scientific associations, and patients and advocates via charities and social media. Eligibility criteria were being aged 18 or older and working in fertility care (for staff) or charity (for advocates) or being waiting to initiate, undergoing, or having undergone treatment within 6 months (for patients).

A preliminary specification and initial prototypes of digital educational resources to support staff and patients, respectively, in having conversations about ending treatment were developed with relevant stakeholders. Co-design workshops with study participants were conducted. A semi-structured script, following Bowen et al.'s (2009)feasibility framework, was used to guide the workshops. Questions covered: (i) experiences, views, and preferences on the provision of preventive end-of-treatment care at clinics and iterative prototypes of the resources to support this provision (acceptability); (ii) perceived need and benefits (demand); and (iii) perceived barriers and facilitators to its implementation at clinics (practicalities). Workshops were recorded and transcribed verbatim, and data were analysed using Framework Analysis.

Fifteen fertility staff, 34 patients, and 7 advocates participated. Staff were mainly psychologists/counsellors (40.0%) or clinicians (26.7%) working in the field for around 23 years. Patients were mostly women (91.2%), on average aged 38 years. Most were childless (73.5%) and trying to conceive for around 3 years. Framework analysis of data collected during the co-design workshops generated four themes and one meta-theme, reflecting a need for a normative shift across countries towards the routine implementation of preventive end-of-treatment care. Themes reflected: (i) demand for routine provision of holistic psychosocial care, including preventive end-of-treatment care; (ii) different views between staff and patients about the risks and extent of benefits of routinely implementing preventive end-of-treatment care; (iii) patient high clarity about the functions of preventive end-of-treatment care (ensuring patients feel prepared and supported in moving through the grief and cope with short-term challenges; explore other pathways to parenthood and re-orient one's life goals; and ensure informed consent for fertility treatment) versus staff lower clarity, with care being equated to signposting patients for timely psychological support; and (iv) co-designed digital educational resources are helpful to support the routine provision of preventive end-of-treatment care at clinics.

Non-probability sample. Although the patient sample was heterogeneous (heterosexual and same-sex couples; private and public sectors), patients were primarily White, well-educated, employed, and childless women, limiting the generalization and comparisons across gender and other personal characteristics (ethnicity, socioeconomically disadvantaged, and disabled), where access to and acceptance of psychosocial support are expected to be lower.

Routine discussions about the end of treatment are needed and beneficial, but staff will require reassurance and training on with whom, when, and how to engage in these. The final version of the digital educational resources is seen as valuable to support a cultural shift in implementing end-of-treatment preventive care at clinics. The co-designed webpages are freely available online in four languages (for staff: www.myjourney.pt/clinics, for patients: www.myjourney.pt/patients). Future research is needed to raise awareness and further investigate how best to support staff in such care provision and measure its impact.

This work was supported by a Research Wales Innovation Fund from the Higher Education Funding Council for Wales (HEFCW, grant No.: JA1710IF63). M.S.-L. was supported by the Portuguese Foundation for Science and Technology (FCT; fellowship No.: SFRH/BD/144429/2019) and the UK Economic and Social Research Council (ESRC; fellowship No.: ES/Z503125/1). The EPIUnit and ITR were funded by the FTC through the Portuguese State Budget (projects No.: UIDB/04750/2020 and LA/P/0064/2020 and DOI identifiers https://doi.org/10.54499/UIDB/04750/2020 and https://doi.org/10.54499/LA/P/0064/2020). S.G. reports grants from the European Society for Human Reproduction and Embryology (ESHRE), the Wellcome Fund (UK), and the Health and Care Research Wales (UK). Cardiff University holds the Intellectual Property rights for the tool www.myjourney.pt, licensed under a Creative Commons AttributionNonCommercial-ShareAlike 4.0 International Licence (CC BY-NCSA 4.0).

TRIAL REGISTRATION NUMBER: n/a.},
}

@article {pmid41498587,
year = {2026},
author = {Maskell, KG and Cook, AL and King, AE and Dickson, TC and Blizzard, CA},
title = {Modeling amyotrophic lateral sclerosis (ALS) in vitro: from mechanistic studies to translatable drug discovery.},
journal = {Lab on a chip},
volume = {26},
number = {5},
pages = {1108-1122},
doi = {10.1039/d5lc00577a},
pmid = {41498587},
issn = {1473-0189},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; Humans ; *Drug Discovery ; Animals ; *Models, Biological ; },
abstract = {Amyotrophic lateral sclerosis is a rapidly progressing, fatal neurodegenerative disease that causes selective degeneration of the corticomotor system. Currently, ALS remains incurable, and the available treatment options offer little in the way of extending life or improving quality of life. This is due, at least in part, to a lack of representative disease models. In vitro modeling offers rapid, experimentally accessible platforms for mechanistic discovery research and drug screening, but modeling the complexity of ALS - a multicellular, multisystem disease - in a dish, is not without its challenges. Here, we review the current landscape of in vitro pre-clinical ALS research, with emphasis on the development of compartmentalised culture and the promise this holds for translatable modeling of ALS.},
}

*Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism
Humans
*Drug Discovery
Animals
*Models, Biological

@article {pmid41498281,
year = {2026},
author = {Santamaria, MP and Mathias-Santamaria, IF and Tavelli, L and Barootchi, S and Prato, GPP},
title = {An updated evidence-based recommendation for the treatment of gingival recession associated with non-carious cervical lesions.},
journal = {Journal of periodontology},
volume = {},
number = {},
pages = {},
doi = {10.1002/jper.70049},
pmid = {41498281},
issn = {1943-3670},
abstract = {BACKGROUND: Approximately 50% of the gingival recessions (GRs) are associated with non-carious cervical lesions (NCCLs), forming what are known as combined defects (CDs), which often require specific treatment protocols that differ from those used for GRs on teeth with an intact and sound surface. This narrative review aims to evaluate the current and relevant literature on the treatment of CDs and update the latest decision-making process with the new literature.

METHODS: Medline/PubMed, Embase, BIREME, and Google Scholar databases were searched. The NCCL portion of the CDs was classified according to Pini-Prato et al.'s classification (2010). The GR portion of the CDs was classified according to Cairo et al.'s classification (2011) and gingival phenotype. Based on these, a decision tree, supported by the current literature, was proposed.

RESULTS: Several approaches associating different surgical techniques/graft materials with different NCCL restoration protocols and materials are available. When A-, A+, and B- NCCL are present, only a surgical procedure for root coverage is needed based on GR characteristics. When either B+ or V-shaped NCCL is present, a composite restorative protocol and a root coverage procedure should be considered.

CONCLUSIONS: CDs are characterized by the coexistence of gingival recession and a non-carious cervical lesion. This updated decision-making process incorporated current literature, including new evidence on soft tissue grafts, which can guide clinicians in the treatment of CDs.

PLAIN LANGUAGE SUMMARY: Gum recession often occurs alongside defects in the tooth that are not caused by cavities. These two conditions can appear on the same tooth in about half of the cases. When that happens, treatment becomes more complex and requires careful planning. Choosing the best approach depends on the shape and severity of the tooth defect. This recommendation helps dentists and patients understand how to manage these combined problems. Most cases fall into mild categories (A-, A+, and B-; i.e., shallow tooth defects) and can be treated with standard procedures for gum recession alone. However, about 25% of cases have a more advanced defect (B+; i.e., deep tooth defects), which requires both a tooth restoration and gum surgery. The way gum recession is treated also depends on how thick the gum tissue is. If the tissue is thin, using the patient's own tissue for a graft usually gives the best results. If the tissue is already thick, a graft may not be necessary. In moderate cases, a graft using either patient tissue or commercial materials can improve long-term success. This recommendation summarizes the latest research and provides practical guidance to improve treatment outcomes for both patients and clinicians.},
}