@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 = {},
number = {},
pages = {},
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 = {},
number = {},
pages = {},
doi = {10.1039/d5lc00577a},
pmid = {41498587},
issn = {1473-0189},
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.},
}

@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.},
}

@article {pmid41495620,
year = {2026},
author = {Li, Y and Feng, Y and Liu, X and Yuan, R and Chen, S and Wang, J and Pan, C and Li, G and Tang, Z},
title = {Functional near-infrared spectroscopy: Systematic mapping of abnormal brain function features in neurological disorders.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00595},
pmid = {41495620},
issn = {1673-5374},
abstract = {Functional near-infrared spectroscopy quantifies cerebral hemodynamic signals by capturing oxygenation-dependent changes in hemoglobin in a noninvasive, portable, and ecologically valid manner, providing a unique insight into neurovascular coupling. However, functional imaging biomarkers with high ecological validity for neurological disorders such as stroke, Parkinson's disease, dementia, amyotrophic lateral sclerosis, epilepsy, spinal cord injury, and traumatic brain injury are lacking, limiting the mechanistic understanding, treatment evaluations, and individualized interventions. The aim of this review is to systematically summarize evidence from the past decade on the use of functional near-infrared spectroscopy under the aforementioned conditions, synthesize its value for revealing neural mechanisms and assessing therapeutic responses, and identify current technical bottlenecks and future directions for advancement. Collectively, the findings demonstrate that functional near-infrared spectroscopy possesses substantial and far-reaching potential for uncovering the neural mechanisms underlying disease and for evaluating treatment-induced changes in brain function. Equipped with wearable probes, functional near-infrared spectroscopy can continuously and noninvasively monitor brain activity in naturalistic environments for extended periods, thereby overcoming the limitations of conventional imaging modalities that can only acquire data under restricted settings. This capability can furnish unprecedented objective neuroimaging evidence for neuroregenerative therapy research. Moreover, the portability of functional near-infrared spectroscopy allows it to be integrated into neurofeedback training systems: hemoglobin signals can be fed back to participants within milliseconds, enabling targeted, individualized, closed-loop modulation of brain function and considerably expanding the scope of hemodynamics-based neurofeedback. When combined with other brain function assays (such as electroencephalography) and intervention techniques (such as transcranial magnetic stimulation and transcranial direct current stimulation), functional near-infrared spectroscopy also supplies high-temporal-resolution hemodynamic information, laying a critical foundation for the construction of high-precision noninvasive brain-computer interfaces, real-time cognitive-state decoding, and adaptive neuromodulation. Admittedly, almost all existing functional near-infrared spectroscopy studies are still observational and have small sample sizes, short follow-ups, and insufficient controls-shortcomings that together produce low-grade evidence. Therefore, there is still a significant gap before clinical translation can be achieved. Technically, the limited penetration depth of functional near-infrared spectroscopy restricts sampling to the superficial cortex, leaving deep nuclei largely unreachable. In addition, no consensus exists across devices regarding optode layout, light-source choice, motion-artifact correction, or analytical pipelines, creating pronounced heterogeneity that undermines reproducibility. With artificial intelligence and big data analytics advancing rapidly, functional near-infrared spectroscopy embedded within multimodal fusion frameworks is now poised to systematically map aberrant brain function signatures of neurological disorders, identify pathological regions suitable for targeted intervention, and provide real-time assessments of functional changes produced by neuroregenerative therapies.},
}

@article {pmid41493797,
year = {2026},
author = {Esteve, D and Bresque, M and Okhuevbie, D and Ramachandran, S and Pehar, M and Vargas, MR},
title = {Lactate Dehydrogenase Inhibition Reverts the Fatty Acid-Induced Neurotoxic Phenotype of Astrocytes.},
journal = {Glia},
volume = {74},
number = {3},
pages = {e70136},
doi = {10.1002/glia.70136},
pmid = {41493797},
issn = {1098-1136},
support = {R01NS122973/NS/NINDS NIH HHS/United States ; R01NS089640/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; *Astrocytes/drug effects/metabolism/pathology/enzymology ; Humans ; *Fatty Acids/toxicity ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; *L-Lactate Dehydrogenase/antagonists & inhibitors/metabolism/genetics ; Mice, Transgenic ; Mice ; Cells, Cultured ; Motor Neurons/drug effects/metabolism/pathology ; Coculture Techniques ; Phenotype ; Spinal Cord/pathology ; Mice, Inbred C57BL ; Disease Models, Animal ; Lipid Metabolism/drug effects ; Lipid Droplets/metabolism/drug effects ; Male ; },
abstract = {Astrocytes are central to lipid metabolism in the central nervous system. Due to their morphological and functional characteristics, astrocytes can uptake fatty acids (FAs) from the bloodstream and extracellular space and store them in lipid droplets (LD). LD are dynamic organelles, whose accumulation in astrocytes has been shown to occur upon exposure to various stress stimuli. Different hypotheses proposed to explain motor neuron degeneration in amyotrophic lateral sclerosis (ALS) implicate mitochondrial dysfunction and oxidative stress. Mitochondrial dysfunction in astrocytes is associated with elevation of cytoplasmic lipids and lipid-binding proteins. We observed increased LD in the spinal cord of symptomatic ALS mice, as well as in human transdifferentiated astrocytes obtained from ALS patients. Using a co-culture model, we examined the effect of FA overload and its impact on astrocyte-motor neuron interaction. LD accumulation was tightly coupled with an NF-κB-driven proinflammatory response in nontransgenic astrocytes, correlating with motor neuron toxicity. These results provide additional evidence to the notion that altered energy balance may contribute to neuronal death in ALS. Furthermore, pharmacological inhibition of lactate dehydrogenase (LDH) reversed LD accumulation in mouse and human astrocytes expressing ALS-linked mutations. Genetic ablation of LDHA similarly reduced LD accumulation in response to FA treatment. Collectively, our data underscore the role of lipid metabolism in astrocyte-neuron interactions in ALS models and suggest that LD accumulation, rather than serving solely as a protective mechanism, reflects a metabolic stress state linked to a detrimental phenotypic transformation in astrocytes.},
}

Animals
*Astrocytes/drug effects/metabolism/pathology/enzymology
Humans
*Fatty Acids/toxicity
Amyotrophic Lateral Sclerosis/pathology/metabolism
*L-Lactate Dehydrogenase/antagonists & inhibitors/metabolism/genetics
Mice, Transgenic
Mice
Cells, Cultured
Motor Neurons/drug effects/metabolism/pathology
Coculture Techniques
Phenotype
Spinal Cord/pathology
Mice, Inbred C57BL
Disease Models, Animal
Lipid Metabolism/drug effects
Lipid Droplets/metabolism/drug effects
Male

@article {pmid41490238,
year = {2025},
author = {Ni, S and Chen, K and Wang, H and Chen, S and Qiu, Y and Wang, T and Mo, F and Wang, S and Li, B and Bai, Y and Zhao, J and Zhai, X and Li, Z},
title = {A new paradigm of bidirectional regulation of the gut-spinal cord axis.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01016},
pmid = {41490238},
issn = {1673-5374},
abstract = {The bidirectional interactions of spinal cord injury, multiple sclerosis, and amyotrophic lateral sclerosis with the gut operate through a distinct gut-spinal cord axis, rather than being fully explained by the conventional gut-brain axis. The spinal cord, with its unique anatomical and physiological features, serves as a central hub of communication. The gut and spinal cord communicate through various pathways, including the immune system and the autonomic and enteric nervous systems. This review summarizes existing clinical and basic research on the relationship between gut homeostasis and spinal cord diseases. First, we present findings from epidemiological studies showing that patients with spinal cord disorders often exhibit altered gut function, which may be influenced by antibiotic exposure and environmental factors. Second, we review the key physiological and anatomical structures of the gut-spinal cord axis, including the intestinal barrier, gut microbiota, and enteric nervous system, all of which are involved in maintaining gut health, as well as sensory neurons, motor neurons, and interneurons in spinal nerve regulation. Third, we describe the roles of the three axes (microbial, immune, and neural) in bidirectional regulation and their pathological mechanisms. Moreover, vicious cycles involving these axes can exacerbate spinal cord disorders. Fourth, we outline potential biomarkers in the gut-spinal cord axis, such as uridine, hypoxanthine, and 5-methoxytryptophan. Fifth, we propose several treatment strategies with potential clinical applications, including fecal microbiota transplantation and the use of probiotics and prebiotics. Finally, this review emphasizes the gut-spinal cord axis as a promising therapeutic target, highlighting the need for multi-omics integration, longitudinal cohort studies, and individualized interventions to resolve existing debates. Overall, the recognition of the gut-spinal cord axis provides a conceptual shift that extends beyond the gut-brain framework.},
}

@article {pmid41488323,
year = {2025},
author = {Lotlikar, MS and Zellmer, JC and Bhattacharyya, R},
title = {Sigma receptors and mitochondria-associated ER membranes are converging therapeutic targets for Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1733659},
pmid = {41488323},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) begins decades before clinical symptoms emerge. The "amyloid hypothesis" suggests that amyloid-β (Aβ) deposition initiates a cascade of tau hyperphosphorylation, neuroinflammation, and neuronal loss leading to cognitive decline. The recent success of anti-Aβ therapies such as Leqembi in prodromal or mild cognitive impaired patients underscores the importance of early intervention and Aβ clearance. However, safety and cost limitations highlight the need for alternative therapeutic strategies. Small-molecule modulators of Sigma-1 and Sigma-2 receptors (σ1R and σ2R) have emerged as promising candidates for AD treatment. σ1R agonists exhibit neuroprotective and anti-amnestic effects under pathological conditions without affecting normal cognition. Beyond AD, σ1R is implicated in several neurodegenerative diseases including ALS (amyotrophic lateral sclerosis), Parkinson's, and Huntington's diseases, stroke, and epilepsy. σ1R plays a key role at mitochondria-associated ER membranes (MAMs)-specialized lipid raft-like domains that form functional membrane contact sites between the endoplasmic reticulum (ER) and mitochondria. β-secretase (BACE1), γ-secretase, and their substrates APP and palmitoylated APP (palAPP) localize in the MAMs, promoting amyloidogenic Aβ production. MAMs serve as dynamic hubs for inter-organelle communication, calcium signaling, and lipid metabolism. The "MAM hypothesis" proposes that MAM dysregulation drives early AD pathology and persists throughout disease progression, contributing to neurofibrillary tangle formation, calcium imbalance, and neuroinflammation. This review aims to summarize the current understanding of σ1R-mediated regulation of MAMs and its neuroprotective mechanisms, highlighting potential therapeutic opportunities for targeting σ1R in AD and other neurodegenerative disorders.},
}

@article {pmid41484230,
year = {2026},
author = {Schneider, K and Spekking, L and Azimi, S and Peltanová, B and Rösel, D and Brown, JS and Gatenby, RA and Brábek, J and Staňková, K},
title = {Migrastatic therapy as a potential game-changer in adaptive cancer treatment.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-33902-x},
pmid = {41484230},
issn = {2045-2322},
support = {24-11903S//Grantová Agentura České Republiky/ ; 24-11903S//Grantová Agentura České Republiky/ ; 24-10672S//Grantová Agentura České Republiky/ ; LX22NPO5102//National Institute for Cancer Research/ ; LX22NPO5102//National Institute for Cancer Research/ ; LX22NPO5102//National Institute for Cancer Research/ ; 955708//European Union's Horizon 2020 research and innovation program/ ; 955708//European Union's Horizon 2020 research and innovation program/ ; VI.Vidi.213.139/NWO_/Dutch Research Council/Netherlands ; },
abstract = {Adaptive therapy, which anticipates and counters the evolution of resistance in cancer cells, has gained significant traction, especially following the success of the Zhang et al.'s protocol in treating metastatic castrate-resistant prostate cancer. While several adaptive therapies have now advanced to clinical trials, none currently incorporates migrastatics, i.e. treatments designed to inhibit cancer cell metastasis. In this study, we propose integrating migrastatics into adaptive therapy protocols and evaluate its potential benefits through a spatial game-theoretic model. Our results demonstrate that combining adaptive therapy with migrastatics effectively delays the onset of metastases and reduces both the number and size of metastases in most cancer scenarios analyzed. Including migrastatics to adaptive therapy not only extends the time to the first metastasis, but also enhances the overall efficacy of adaptive therapies. Our findings suggest a promising new direction for cancer treatment, where adaptive therapy, in combination with migrastatic agents, can target both the evolution of resistance and the metastatic spread of cancer cells.},
}

@article {pmid41480618,
year = {2025},
author = {Hu, G and Gogzheyan, C and Panja, S and Sil, S and Gendelman, HE},
title = {Extracellular vesicle-based therapies for neurodegenerative diseases.},
journal = {NeuroImmune pharmacology and therapeutics},
volume = {4},
number = {4},
pages = {377-390},
pmid = {41480618},
issn = {2750-6665},
abstract = {Extracellular vesicles (EVs) are mediators of neurodegeneration and emerging therapeutic tools for central nervous system disorders. On the one hand, they help spread beta amyloid, tau, α-synuclein, TDP-43, and mutant SOD1, contributing to the signs and symptoms of Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, and Huntington's Diseases. By activating glial cells, they promote chronic neuroinflammation through carrying cytokines, inflammasomes, and chemokines. On the other hand, EVs' ability to transport neuroregulatory products and cross the blood-brain barrier makes them ideal vehicles for drug delivery. Their function can be surface-modified to deliver targeted therapies, including anti-inflammatory and neuroprotective regulatory RNAs, proteins, and lipids, as well as factors that help maintain neural homeostasis. Notably, we suggest that colostrum-derived EVs, enriched with growth factors and immune-regulatory microRNAs, offer a natural, scalable, and biocompatible source for neuroprotective treatment. Although EVs can act as "Janus-faced" entities - serving both as disease initiators and versatile therapeutic vehicles - controlling their activity can enable immune-based therapeutics for neurodegenerative diseases.},
}

@article {pmid41479929,
year = {2025},
author = {Bagrodia, A and Vaithiyam, V and Laguduva Mohan, S},
title = {Large colorectal lesions: Expanding the boundaries of endoscopic management.},
journal = {World journal of gastrointestinal endoscopy},
volume = {17},
number = {12},
pages = {115008},
pmid = {41479929},
issn = {1948-5190},
abstract = {Large colorectal lesions (≥ 3 cm) present a significant therapeutic challenge due to their potential for malignancy and the technical difficulties they encounter. Endoscopic resection techniques, including endoscopic mucosal resection, endoscopic submucosal dissection, and endoscopic full-thickness resection, have revolutionized the management of these lesions by offering organ-preserving alternatives to surgery with favorable outcomes. We read with great interest and commended Zhu et al for their valuable study on the endoscopic treatment of large colorectal lesions. Zhu et al's study provides crucial real-world evidence regarding the safety and effectiveness of advanced endoscopic resection techniques in this challenging patient group. These findings support the possibility of achieving high rates of complete resection with acceptable adverse event profiles, reinforcing the role of endoscopic mucosal resection and submucosal dissection in routine practice. This editorial also offers a comprehensive review of the current literature, discusses its clinical implications, explores future directions, and compares endoscopic resection methods with surgical options. Zhu et al's study findings not only validate the efficacy of advanced endoscopic resection but also signify a paradigm shift from surgical to organ-preserving strategies in colorectal oncology, a transformation that requires deliberate system-wide training and capacity building.},
}

@article {pmid41478512,
year = {2025},
author = {Strohmer, B and Grosh, K and Montañana-Rosell, R and Mora, S and Ausborn, J and Allodi, I},
title = {Spinal circuit mechanisms constrain therapeutic windows for ALS intervention: A computational modeling study.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107253},
doi = {10.1016/j.nbd.2025.107253},
pmid = {41478512},
issn = {1095-953X},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive breakdown of neural circuits which leads to motoneuron death. Earlier work from our lab showed that dysregulation of inhibitory V1 interneurons precedes the degeneration of excitatory V2a interneurons and motoneurons and that stabilizing V1-motoneuron connections improved motor function and saved motoneurons in the SOD1[G93A] ALS mouse model. However, the optimal timing for this intervention remains unclear. To address this, we developed a spiking neural network model of spinal locomotor circuits to simulate healthy and ALS-like conditions. By modeling changes in network connectivity and synaptic dynamics, we predict that V1 dysregulation induces an imbalance in motoneuron output which results in flexor-biased activity, leading to the disruption of flexor-extensor coordination, and potentially contributing to selective vulnerability of flexor motoneurons. Stabilizing V1 synapses preserved motor output even after motoneuron loss, suggesting that therapeutic benefit is possible into symptomatic stages. However, model predictions also highlighted that after sustained synaptic loss and the development of slower synaptic dynamics within the network, synaptic stabilization leads to maladaptive extensor-biased activity, suggesting that excitatory/inhibitory balance impacts treatment effectiveness. Finally, the model indicated that V1 stabilization could lead to rescue of the V2a excitatory interneurons, a finding that we were able to confirm experimentally in the SOD1[G93A] ALS mouse model. By exploring different scenarios of synaptic loss and cell dysregulation during synaptic stabilization, our models provide a framework for predicting candidate time windows for spinal circuit interventions, which may guide future preclinical investigations.},
}

@article {pmid41477139,
year = {2025},
author = {Syamal, M},
title = {Treatment of Neurogenic Voice Disorders.},
journal = {World journal of otorhinolaryngology - head and neck surgery},
volume = {11},
number = {4},
pages = {541-547},
pmid = {41477139},
issn = {2589-1081},
abstract = {This overview serves as a foundational resource for clinicians caring for neurologically complex patients presenting with voice complaints. Neurogenic voice disorders are diverse in their clinical presentations and therapeutic approaches. A thorough medical history, including family history, detailed laryngeal examination, voice assessments, and neuroimaging, are imperative, as well as a multidisciplinary, collaborative approach with neurologists, speech language pathologists, and patient caregivers. Disorders such as amyotrophic lateral sclerosis (ALS), cerebrovascular accidents (strokes), Huntington's disease, myasthenia gravis (MG), Parkinson's disease (PD), and voice tremor should be understood by otolaryngologists. Each condition presents unique challenges and requires tailored treatment strategies ranging from supportive therapies and pharmacological interventions to surgery. Voice management techniques, including the use of botulinum toxin for hyperkinetic disorders and deep brain stimulation for refractory cases, are highlighted as promising interventions.},
}

@article {pmid41471389,
year = {2025},
author = {Gershoni Emek, N and Tan, AM and Geva, M and Fekete, A and Abate, C and Hayden, MR},
title = {Pridopidine, a Potent and Selective Therapeutic Sigma-1 Receptor (S1R) Agonist for Treating Neurodegenerative Diseases.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {12},
pages = {},
doi = {10.3390/ph18121900},
pmid = {41471389},
issn = {1424-8247},
abstract = {Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in clinical development for Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). The S1R is a ubiquitous chaperone protein enriched in the central nervous system and regulates multiple pathways critical for neuronal cell function and survival, including cellular stress responses, mitochondrial function, calcium signaling, protein folding, and autophagy. S1R has a crucial role in the ER mitochondria-associated membrane (MAM), whose dysfunction is implicated in several neurodegenerative diseases. By activating the S1R, pridopidine corrects multiple cellular pathways necessary to the cell's ability to respond to stress, which are disrupted in neurodegenerative diseases. Pridopidine restores MAM integrity; rescues Ca[2+] homeostasis and autophagy; mitigates ER stress, mitochondrial dysfunction, and oxidative damage; and enhances brain-derived neurotrophic factor (BDNF) axonal transport and secretion, synaptic plasticity, and dendritic spine density. Pridopidine demonstrates neuroprotective effects in in vivo models of neurodegenerative diseases (NDDs). Importantly, pridopidine demonstrates the biphasic dose response characteristic of S1R agonists. In clinical trials in HD and ALS, pridopidine has shown benefits across multiple endpoints. Pridopidine's mechanism of action, modulating core cellular survival pathways, positions it as a promising candidate for disease modification for different nervous system disorders. Its broad therapeutic potential includes neurodevelopmental disorders, and rare diseases including Wolfram syndrome, Rett syndrome, and Vanishing White Matter Disease. Here, we review the experimental data demonstrating pridopidine's S1R-mediated neuroprotective effects. These findings underscore the therapeutic relevance of S1R activation and support further investigation of pridopidine for the treatment of different neurodegenerative diseases including ALS and HD.},
}

@article {pmid41468784,
year = {2025},
author = {Palanivel, V and Salkar, A and Shenoy, A and Eva, TA and Perera, R and Chitranshi, N and Gupta, V and You, Y and Mirzaei, M and Graham, SL and Gupta, V and Basavarajappa, D},
title = {Neuropeptide Y at the crossroads of neurodegeneration: Mechanistic insights and emerging therapeutic strategies.},
journal = {Neuropeptides},
volume = {115},
number = {},
pages = {102583},
doi = {10.1016/j.npep.2025.102583},
pmid = {41468784},
issn = {1532-2785},
abstract = {Neuropeptide Y (NPY), a widely distributed and highly conserved neuropeptide, plays a central role in the regulation of diverse physiological processes, including stress responses, energy homeostasis, vascular tone, and immune modulation, via activation of its receptor subtypes. Beyond its physiological roles, the dysregulation of NPY expression has been documented in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Machado-Joseph disease, and retinal disorders such as diabetic retinopathy and glaucoma. These alterations in NPY levels and receptor activity highlight its potential not only as a biomarker for disease progression but also as a promising therapeutic target. Previous evidence revealed that NPY exerts neuroprotection by alleviating excitotoxicity, oxidative stress, mitochondrial dysfunction, and neuroinflammation while concurrently facilitating neurogenesis, synaptic plasticity, and cellular resilience. NPY activates receptor-mediated intracellular signaling cascades like PI3K/Akt, MAPK/ERK, and p38K, that control cellular survival, proteostasis, and inflammation and thereby influence disease trajectories. Understanding NPY operation with these mechanisms can unveil new avenues for targeted therapy. Current insights into the complex roles of NPY in neurodegeneration are discussed in this review, and their implications in diagnostic and treatment strategies are addressed.},
}

@article {pmid41467438,
year = {2025},
author = {Zhao, J and Wang, J and Guo, X},
title = {Organoids: Key advances, optimization, and technological iterations in their application to neurodegenerative diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00924},
pmid = {41467438},
issn = {1673-5374},
abstract = {Organoid technology, as an innovative approach, has shown great potential in disease modeling, target screening, and the development of treatment strategies. However, traditional organoids still have three major limitations in research: the absence of specific cell types, the lack of blood-brain barrier structure, and insufficient reproducibility of experimental results. In recent years, researchers have gradually overcome these limitations by introducing innovative techniques such as advanced culture methods, microfluidic systems, bioprinting, organoid transplantation, and assembloid construction. This progress has facilitated the widespread application of organoids in the study of neurodegenerative diseases. This paper aims to systematically review the technological innovations of organoids in the study of neurodegenerative diseases. By summarizing classical organoid construction strategies and their limitations, it emphasizes the value of organoids in comprehensive applications within neurodegenerative disease research. In this review, we focus on five specific neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Research in these diseases demonstrates that organoids improve experimental accessibility and reduce development cycles in disease modeling, target discovery, and therapeutic strategy formation. Using customized equipment and gene editing techniques, these organoids can be tailored to specific needs, providing pathophysiologically relevant disease models and enhancing our understanding of neurodegenerative diseases. Although organoid technology has demonstrated significant advantages in disease research, its potential for treating neurodegenerative diseases has not yet been fully explored, which may become an important direction for future research.},
}

@article {pmid41464612,
year = {2025},
author = {Klumb, S and Haley, L and Hathaway, C and Irby, J and Cheng, J and Rumley, J},
title = {Degenerative Cervical Myelopathy Diagnosis and Its Differentiation from Neurological Mimics, MS and ALS: A Literature Review.},
journal = {Journal of clinical medicine},
volume = {14},
number = {24},
pages = {},
doi = {10.3390/jcm14248711},
pmid = {41464612},
issn = {2077-0383},
abstract = {Multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and degenerative cervical myelopathy (DCM) share features that may confound diagnosis. DCM is caused by degenerative changes in the cervical spine leading to spinal cord compression and injury, resulting in significant disability. Misdiagnosis of DCM for a similar neurological condition can lead to further spinal cord damage from delayed surgical treatment. Here we review the diagnostic criteria, clinical signs and symptoms, and imaging typical for DCM, and two of its clinical mimics, MS and ALS. Shared motor symptoms of all three conditions can make diagnosis difficult, especially early in disease course. Noteworthy differences include neck and shoulder pain in DCM, visual disturbances in MS, and bulbar symptoms and the absence of sensory deficits in ALS. In DCM and MS, MRI is used to support the diagnosis, with specific findings on MRI that differentiate DCM versus MS. In ALS, MRI is used to rule out differential diagnoses. Applying the diagnostic criteria for MS and ALS, as well as understanding the typical presentation and MRI findings of DCM, is crucial. Through discussion of these conditions, this review aims to help limit misdiagnosis rates, allowing for early management, which can improve long-term patient outcomes.},
}

@article {pmid41463070,
year = {2025},
author = {Goyal, NA and Andrews, JA and Oskarsson, BE and Wiedau, MH and Kasarskis, EJ and Forrest, BD and Zhang, R and Bracci, PM and Davis, MW and Azhir, A and McGrath, MS},
title = {Quantitative Measures of Time to Loss of 15% Vital Capacity and Survival Extension in Slowly Progressive Amyotrophic Lateral Sclerosis (ALS) Patients Treated with the Immune Regulator NP001 Suggests an Immunopathogenic Subset of ALS.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13123060},
pmid = {41463070},
issn = {2227-9059},
support = {Neuvivo - NP001//Ari Azhir/ ; },
abstract = {Background/Objectives: Overall survival in patients with amyotrophic lateral sclerosis (ALS) is linked to the rate of predicted respiratory vital capacity (PVC) loss. The objective of this study was to test whether changes in quantitative PVC measures over time linked to survival would define an immunopathogenic subset of ALS responsive to NP001, a regulator of innate immunity. Methods: In a retrospective study, data from intent-to-treat (ITT) population of two phase 2 trials of NP001 were evaluated for over time changes in PVC, time-to-event (TTE) loss of 15% PVC and PVC change from baseline, as linked to survival outcomes in patients treated with NP001 vs placebo. Results: Treatment with NP001 was associated with a significantly lower risk compared to placebo in the loss of 15% PVC over six months (p = 0.01; HR = 0.60, 95% CI: 0.39, 0.90). Data from the two trials were subsequently divided by a disease progression rate (DPR) value of 0.50 units of ALSFRS-R score lost per month for analysis of slow vs. rapid disease. In ALS patients with slowly progressive disease (DPR < 0.50), TTE PVC changes from baseline were slowed (p < 0.0005) and overall survival extended significantly (18.5 months) in NP001-treated vs. placebo groups. The rapidly progressive ALS patients (DPR ≥ 0.50) treated with NP001 showed no significant difference in PVC change or survival from the placebo group. Conclusions: These hypothesis-generating observations suggest that inflammation might play a significant role in the loss of respiratory function in a major subset of ALS patients.},
}

@article {pmid41462890,
year = {2025},
author = {Fajkić, A and Belančić, A and Lam, YW and Rački, V and Pilipović, K and Janković, T and Mežnarić, S and Mršić-Pelčić, J and Vitezić, D},
title = {Novel Translational Concept: Axon-to-Muscle Exosomal Signaling as an Emerging Therapeutic Target in Spinal Muscular Atrophy.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13122876},
pmid = {41462890},
issn = {2227-9059},
abstract = {Spinal muscular atrophy (SMA) has transitioned from a uniformly fatal disease to a treatable condition, yet incomplete neuromuscular recovery underscores the limits of current SMN-restorative therapies. Emerging data implicate disrupted axon-to-muscle exosomal signaling as an important, overlooked driver of residual dysfunction. Exosomes, nanovesicles mediating bidirectional neuronal-muscular communication, carry synaptic organizers, trophic factors, and microRNAs essential for neuromuscular junction integrity. SMN deficiency alters exosomal biogenesis and cargo, leading to loss of agrin-MuSK signaling, impaired β-actin transport, and muscle atrophy. Comparative insights from amyotrophic lateral sclerosis and muscular dystrophy reveal that stem-cell-derived or engineered exosomes restore synaptic stability, enhance regeneration, and cross biological barriers safely. Thus, we speculate herein on a translational model integrating exosome-based therapies with existing genetic interventions to achieve durable, systems-level recovery in SMA. Exosomal profiling may further yield minimally invasive biomarkers for disease monitoring and treatment optimization, establishing vesicle-mediated communication as a novel therapeutic axis in neuromuscular medicine.},
}

@article {pmid41458376,
year = {2025},
author = {Qian, G and Ding, L and Tan, C and Wang, L and Long, C},
title = {Mucosal immune response modulated by secreted and membrane-bound hydrolases of Candida albicans in vulvovaginal candidiasis.},
journal = {Frontiers in fungal biology},
volume = {6},
number = {},
pages = {1692795},
pmid = {41458376},
issn = {2673-6128},
abstract = {Vulvovaginal candidiasis (VVC) affects the physical and mental health of millions of women worldwide. The leading cause of VVC, Candida albicans, can induce a strong mucosal inflammatory reaction during the VVC infection, where secreted and membrane-bound adhesion and hydrolases seem to be the key virulent factors to promote the mucosal antifungal immunity and immunopathology. Several hydrolases, such as Saps, Als, candidalysin, lipases, and phospholipases, have been identified in vaginal secretions isolated from VVC patients; however, the immune impacts of some hydrolases have not been well documented. In this review, we focus on the literature that addresses the immunopathogenic roles of the Als adhesin family or proteinase, such as Sap and candidalysin, in VVC. Our goal is to expand our knowledge of VVC pathogenesis in order to provide new strategies for VVC treatment.},
}

@article {pmid41455134,
year = {2025},
author = {Du, O and Wu, YJ and Li, MY and Du, JR},
title = {The role of HMGB1 in central nervous system (CNS) diseases: mechanisms and therapeutic perspectives.},
journal = {Cytokine},
volume = {198},
number = {},
pages = {157099},
doi = {10.1016/j.cyto.2025.157099},
pmid = {41455134},
issn = {1096-0023},
abstract = {Central nervous system (CNS) diseases represent a major global health burden and are among the leading causes of disability and mortality worldwide. The pathological mechanisms underlying CNS disorders are complex and multifactorial, involving processes such as neuroinflammation, oxidative stress, neuronal damage, and synaptic dysfunction. High-mobility group box 1 (HMGB1), a member of the high-mobility group box (HMGB) protein family, is predominantly localized in the nucleus under physiological conditions, where it contributes to DNA repair, transcriptional regulation, and other cellular functions. However, in various CNS pathologies-including stroke, traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), glioblastoma (GBM), epilepsy, depression, multiple sclerosis (MS), and schizophrenia-HMGB1 is released or secreted into the extracellular space. There, it plays a key role in regulating neuroinflammation, cell death, cell migration, and tissue damage and repair, thereby contributing to disease pathogenesis and progression. HMGB1 not only functions as a critical regulator in the progression of CNS diseases but also serves as a biomarker for predicting poor clinical outcomes. Moreover, a growing body of evidence indicates that therapeutic strategies targeting HMGB1 can significantly alleviate pathological damage in various CNS disorders, highlighting its potential as a promising therapeutic target. This review comprehensively summarizes the structure, post-translational modifications, release mechanisms, and receptor systems of HMGB1, along with its roles and mechanisms in CNS diseases. It also discusses the potential of HMGB1 as a biomarker and examines emerging HMGB1-targeted therapeutic strategies, aiming to provide a theoretical foundation for the treatment and drug development of CNS disorders.},
}

@article {pmid41454086,
year = {2025},
author = {Mi, X and Shan, K and Ye, X and Cheng, R},
title = {AAD-2004 through clearing H2O2 reduces astrocyte proliferation and promotes neural regeneration after spinal cord injury.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-33322-x},
pmid = {41454086},
issn = {2045-2322},
support = {ZKKY2023003//Zhejiang Medical Association/ ; 2024KY658//Scientific Research Program of Zhejiang Medical Technology/ ; },
abstract = {To assess the effect of AAD-2004 on spinal cord injury (SCI) and to explore its mechanism, we employed an in vitro model using OGD/R-challenged astrocytes to investigate the effects of AAD-2004 against cell death (terminal deoxynucleotidyl transferase dUTP nick-end labeling, tunel), oxidative stress (H2O2 level), and the expression of the key neuroprotective factor MAP2.AAD-2004[2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] is a hydrogen peroxide(H2O2) scavenger primarily used for the treatment of amyotrophic lateral sclerosis and Alzheimer disease that has demonstrated certain neuroprotective properties. In parallel, modified allen's method was adopted, further exploring the potential molecular mechanism in vivo. Based on these conditions, histological and behavioral analysis were performed by Nissl staining, basso mouse scale and footprint analysis. The level of molecules associated with glial scar formation, nerve regeneration, axonal regeneration and H2O2 level were analyzed using western blot, immunofluorescence staining and H2O2 kit. AAD-2004 significantly improved the movement function after SCI and inhibited the proliferation of astrocytes, thus preventing the formation of glial scar by inhibiting of H2O2. At the same time, AAD-2004 promoted nerve regeneration, and the effect was due to neuronal regeneration and axonal regeneration pathways. The expression levels of GFAP and vimentin were significantly downregulated in AAD-2004-treated, and the expression level of Ki67 and PH3 were downregulated. The mean fluorescence intensity of neuronal regeneration (Neun[+]and MAP2[+]) and axonal regeneration-related (NF[+] and GAP43[+]) were significantly upregulated after AAD-2004 treatment. Scavenging H2O2 level is a viable therapeutic strategy, and that AAD-2004 is prospective, and that scavenging H2O2 facilitated nerve regeneration and inhibited glial scar formation for SCI.},
}

@article {pmid41440030,
year = {2025},
author = {Su, J and Alaiz Noya, J and Lingappa, AF and Solas, D and Tong, J and Daughrity, L and Castanedes-Casey, M and Kurti, A and Dickson, DW and Lingappa, VR and Petrucelli, L and Zhang, Y},
title = {Preclinical Evaluation of the Assembly Modulator PAV-615 in a Mouse Model of C9orf72-Associated ALS/FTD.},
journal = {Cells},
volume = {14},
number = {24},
pages = {},
pmid = {41440030},
issn = {2073-4409},
support = {ADSF-24-1284327-C//Alzheimer's Disease Strategic Fund grant/ ; NA//Robert Packard Center for ALS Research at Johns Hopkins/ ; NA//Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Program/ ; NA//BrightFocus Foundation/ ; NA//Target ALS Foundation/ ; U19 AG063911/AG/NIA NIH HHS/United States ; NA//Cure Alzheimer's Fund/ ; NA//Kissick Family Foundation/ ; U54NS123743, R35 NS137447, P01NS084974, R01NS132330 and R01NS117461//National Institutes of Health/National Institute of Neurological Disorders and Stroke/ ; P01 NS084974/NS/NINDS NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; NA//Association for Frontotemporal Degeneration Biomarkers Initiative/ ; R01 NS117461/NS/NINDS NIH HHS/United States ; R01 AG089380/AG/NIA NIH HHS/United States ; R01 NS132330/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; 5P30AG0062677, ALLFTD U19AG063911, R01AG089380 and R01AG085307//National Institutes of Health/National Institute on Aging/ ; R01 AG085307/AG/NIA NIH HHS/United States ; R35 NS137447/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology/metabolism ; Disease Models, Animal ; *Frontotemporal Dementia/drug therapy/genetics/pathology/metabolism ; Mice ; Humans ; Male ; Mice, Transgenic ; Drug Evaluation, Preclinical ; },
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that share clinical and pathological features, as well as genetic causes. A G4C2 repeat expansion in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of ALS and FTD, collectively referred to as c9ALS/FTD. Assembly modulation is a new therapeutic approach which appears to target allosteric sites on aberrant forms of multi-protein complexes and restore them to the healthy state. Recent findings demonstrate that tetrahydroisoquinolone (THIQ)-based protein assembly modulators can ameliorate ALS/FTD-associated phenotypes in cellular and animal models. In the present study, we investigated the effects of PAV-615, a novel and advanced THIQ-based modulator, in a c9ALS/FTD mouse model expressing 149 G4C2 repeat expansions (referred to as 149R mouse model). Specifically, PAV-615 was administered to 5-month-old 149R mice via intraperitoneal injection for one month. Motor function was evaluated using the hang wire test, while anxiety-like behavior and hyperactivity were assessed using the open-field test. Pathological markers, including dipeptide repeat (DPR) proteins, phosphorylated TAR DNA-binding protein 43 (pTDP-43) and ataxin 2-positive stress granules, were quantified by Meso Scale Discovery and immunohistochemistry assays. Compared with vehicle-treated controls, PAV-615 significantly improved motor performance and modestly reduced anxiety-like behavior and hyperactivity in 149R mice. Moreover, PAV-615 treatment significantly decreased cortical DPR, pTDP-43 and ataxin 2-positive stress granule burdens. These results support assembly modulation as a promising therapeutic approach treatment of ALS/FTD.},
}

Animals
*C9orf72 Protein/genetics/metabolism
*Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology/metabolism
Disease Models, Animal
*Frontotemporal Dementia/drug therapy/genetics/pathology/metabolism
Mice
Humans
Male
Mice, Transgenic
Drug Evaluation, Preclinical

@article {pmid41438688,
year = {2026},
author = {Su, T and Li, Z and Yang, Y and Dai, Y and Li, Y and Zhao, H},
title = {In vitro 3D models of neuron-astrocyte interactions.},
journal = {Biochemistry and biophysics reports},
volume = {45},
number = {},
pages = {102400},
pmid = {41438688},
issn = {2405-5808},
abstract = {The pathological processes of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis) also include relationships between neuron and glia cells. Conventional two-dimensional (2D) cell cultures have limitations to mimic the microenvironment of cells inside living organisms because of flaws in intercellular relationships investigated using 2D cell cultures. Recent advances have introduced three-dimensional (3D) cell cultures that have the capability to create 3D cellular architecture to mimic advanced platforms for scientific inquiries into neurodegenerative diseases, simulating microenvironments inside living organisms.This review provides a brief overview of the development of in vitro 3D cell culture models of astrocytes and attempts to highlight the role of astrocytes in crucial pathophysiologic events occurring in 3D cultures. Studies have shown the use of in vitro 3D cultures to better represent the dual functions of astrocytes in neurodegenerative disorders. Looking ahead to the future, novel advances in microfluidics and multi-omics analysis promise to further improve 3D cultures and push forward new insights into neurological dysfunction to spark innovative advances for treatment strategies.},
}

@article {pmid41432316,
year = {2025},
author = {Genge, A and Rothstein, J and De Silva, S and Zinman, L and Chum, M and Chiò, A and Sobue, G and Aoki, M and Yoshino, H and Doyu, M and Selness, D and Todorovic, V and Hirai, M and Sasson, N and Takahashi, F and Cecić, M and Wamil, A and Apple, S},
title = {Phase 3b Extension Study MT-1186-A04 to Evaluate the Continued Efficacy and Safety of Edaravone Oral Suspension for Up to an Additional 48 Weeks in Patients With Amyotrophic Lateral Sclerosis.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70120},
pmid = {41432316},
issn = {1097-4598},
support = {//Tanabe Pharma America, Inc./ ; },
abstract = {INTRODUCTION/AIMS: An On/Off dosing regimen of intravenous (IV) edaravone and edaravone oral suspension is currently approved in the US for treatment of amyotrophic lateral sclerosis (ALS). Placebo-controlled clinical trials showed that IV edaravone slows physical functional decline. Study MT-1186-A04 continued to examine the efficacy and safety of investigational once daily and approved on/off dosing of edaravone oral suspension in patients with ALS.

METHODS: Study MT-1186-A04 (NCT05151471) was a phase 3b, multicenter, randomized, double-blind, parallel group extension study for up to an additional 48 weeks following 48-week Study MT-1186-A02 that randomized patients to investigational once daily or approved 105-mg on/off dosing of edaravone oral suspension. Patients who met Study MT-1186-A04 eligibility criteria, including Study MT-1186-A02 completion, continued in the same treatment regimen as Study MT-1186-A02. The primary efficacy endpoint for MT-1186-A04 was time from randomization in Study MT-1186-A02 to a ≥ 12-point decrease in ALS Functional Rating Scale-Revised (ALSFRS-R) or death, whichever happened first.

RESULTS: Over 96 weeks, including Study MT-1186-A02, daily dosing did not show a statistically significant difference vs. approved on/off dosing for the primary endpoint (p = 0.78). Edaravone oral suspension was well tolerated, and no new safety concerns were identified in either group.

DISCUSSION: Similar to Study MT-1186-A02, once daily edaravone oral suspension in extension Study MT-1186-A04 did not show superiority in terms of the primary efficacy endpoint, but had equivalent efficacy, safety, and tolerability, compared with the approved On/Off regimen. The results reinforce the appropriateness of the approved dosing regimen.},
}

@article {pmid41430470,
year = {2025},
author = {Piol, D and Khalil, B and Robberechts, T and Killian, T and Georgopoulou, M and Partel, G and Wouters, D and Hecker, N and Tziortzouda, P and Verresen, Y and Corthout, N and Kint, S and Vandereyken, K and Van Damme, P and Voet, T and Davie, K and Poovathingal, S and Van Den Bosch, L and Aerts, S and Sifrim, A and Da Cruz, S},
title = {Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41430470},
issn = {1546-1726},
support = {962700//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; 1060285//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; },
abstract = {Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined. Here we applied spatial transcriptomics to adult mouse motor nerve axons and cell bodies to enable subcellular mapping. Among transcripts found in mature axons, the most enriched biological process is protein translation, and localization of translation machinery was confirmed using multiplexed single-molecule spatial transcriptomics combined with immunofluorescence. Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery. In particular, eukaryotic initiation factor 5a (Eif5a), a translation factor involved in elongation and termination, is found to be locally impaired in mutant FUS axons with reduced levels of its active hypusinated form. Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis. Finally, in vivo spermidine treatment reduces ALS-related toxicity in mutant FUS and TDP-43 Drosophila models, which may have implications for therapy development.},
}

@article {pmid41428942,
year = {2025},
author = {Sannes, A and Rognli, EW and Hanssen-Bauer, K and Torp, NC and Storfossen, SK and Høstaker, MN and Aalberg, M},
title = {Barriers to and Facilitators of Implementation of Internet-Delivered Therapist-Guided Therapy in Child and Adolescent Mental Health Services: Systematic Review and Bayesian Meta-Analysis.},
journal = {Journal of medical Internet research},
volume = {27},
number = {},
pages = {e83543},
pmid = {41428942},
issn = {1438-8871},
mesh = {Adolescent ; Child ; Humans ; *Adolescent Health Services ; Bayes Theorem ; *Child Health Services ; *Internet ; *Mental Health Services ; *Psychotherapy/methods ; },
abstract = {BACKGROUND: Internet-delivered therapist-guided therapy (e-therapy) represents a promising approach for enhancing accessibility, treatment fidelity, and scalability within child and adolescent mental health services (CAMHS).

OBJECTIVE: This systematic review aimed to (1) identify and synthesize determinants of implementation, specifically barriers to and facilitators of e-therapy in CAMHS structured according to the Consolidated Framework of Implementation Research (CFIR); and (2) provide pooled benchmark estimates of key implementation outcomes for fidelity, cost-effectiveness, and acceptability.

METHODS: A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-compliant systematic review was performed across PsycINFO, MEDLINE, Web of Science, CINAHL, Embase, Cochrane, and ProQuest Dissertations & Thesis on June 6, 2025-to identify peer-reviewed studies assessing implementation outcomes or determinants of e-therapy in the context of outpatient CAMHS (ages 8-18 years). Barriers and facilitators were synthesized qualitatively with thematic analysis applying CFIR. A parallel quantitative synthesis of Proctor et al's taxonomy of implementation outcomes was performed using Bayesian multilevel random-effects meta-analyses to estimate pooled effect sizes and 95% credible intervals (CIs). By combining quantitative benchmarks of implementation success with qualitative insights into contextual determinants, the review provides an integrated understanding of what drives effective e-therapy implementation in CAMHS. Study quality was assessed using the CASP (Critical Appraisal Skills Programme) checklist, Cochrane Risk of Bias tool, and Risk Of Bias In Non-randomized Studies-of Interventions tool. Small study effects were evaluated using funnel plots, sensitivity analyses, and the Egger test.

RESULTS: From 50,026 screened reports, 50 studies published between 2007 and 2025 were included: 18 randomized controlled trials, 17 cohort, and 15 qualitative or mixed methods studies. Most studies originated from Western Europe (n=34), Northern America (n=11), and Oceania (n=5), targeting anxiety (n=24) and depression (n=9), through cognitive behavioral therapy-based programs (n=47), with parallel parent content (n=31). Therapist guidance was primarily asynchronous (n=43). Among the 39 studies reporting determinants, common barriers and facilitators were identified across intervention, organization, therapist, and patient domains, structured via CFIR. Pooled implementation outcomes showed modest dropout rates (~20%, CI 14%-27%), high module completion (~68%, CI 60%-75%), low therapist time (24 min per wk per patient, 95% CI 19-28), and high patient satisfaction (24/32 on Client Satisfaction Questionnaire-8, 95% CI 22-27; and 76% satisfaction rate, 95% CI 62%-87%), suggesting e-therapy is resource efficient and acceptable if implemented successfully.

CONCLUSIONS: This review provided the first integrated synthesis of pooled benchmarks for implementation outcomes of e-therapy in CAMHS and modifiable determinants to inform future service planning and scale-up. These findings highlighted service-level enablers, such as leadership anchoring, targeted use, technical stability, structured patient flow, and therapist training, that organizations could prioritize to strengthen sustainable e-therapy implementation in CAMHS.},
}

Adolescent
Child
Humans
*Adolescent Health Services
Bayes Theorem
*Child Health Services
*Internet
*Mental Health Services
*Psychotherapy/methods

@article {pmid41428860,
year = {2025},
author = {Curtis, SE and Tatlock, S and O'Hara, L and Seçinti, E and Mehdiyoun, NF and Ayala-Nunes, L and Flynn, J and Fernelius, K and Hodson, N and Delbecque, L},
title = {Patient experience and clinical outcome assessment validity in amyotrophic lateral sclerosis: a targeted literature review.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/21678421.2025.2604233},
pmid = {41428860},
issn = {2167-9223},
abstract = {OBJECTIVE: To identify relevant concepts of measurement for people with amyotrophic lateral sclerosis (ALS) and to evaluate the face and content validity of clinical outcome assessments (COAs) that can be used to measure treatment benefits in ALS clinical trials.

METHODS: A targeted literature review was conducted to explore patient experience (stage 1) and COAs used in ALS research (stage 2). Abstracts were screened against predefined eligibility criteria; full-text articles were reviewed for eligible abstracts and relevant data were extracted. Face and content validity of the identified COAs were assessed.

RESULTS: Stage 1 searches identified 3,527 abstracts, of which 12 full-text articles, two summary reports, and one conference poster were included in this review. Twenty-five symptoms and 35 health-related quality of life (HRQoL) impacts were identified. Frequently reported symptoms included breathing and speech difficulties and muscle/limb weakness, each associated with a diverse range of impacts, including those related to emotional wellbeing, physical function, social and leisure activities, and activities of daily living. Stage 2 searches identified 119 COAs, of which 28 were reviewed. Many had acceptable face (13/28) and content validity (15/28), but 13 had not involved patients during development; only 10 were clearly worded and seven were lengthy, increasing patient burden risk.

CONCLUSIONS: This review identified wide-ranging symptoms and HRQoL impacts experienced by people with ALS, but detailed qualitative evidence is sparse. Multiple COAs were identified as potential measures in ALS clinical trials.},
}

@article {pmid41417753,
year = {2025},
author = {Lam, P and Zygmunt, DA and Bennett, M and Ashbrook, A and Hefty, J and Martin, PT},
title = {Gne deletion in adult mice can cause thrombocytopenia, anemia, myopathy, bleeding, and death.},
journal = {Journal of neuromuscular diseases},
volume = {},
number = {},
pages = {22143602251405918},
doi = {10.1177/22143602251405918},
pmid = {41417753},
issn = {2214-3602},
abstract = {The GNE gene encodes the UDP-GlcNAc-2-epimerase/ManNAc kinase, a bifunctional enzyme required for the synthesis of sialic acid. The mouse Gne gene is essential for embryonic development, but humans with recessive partial loss of function GNE mutations can develop infantile thrombocytopenia, juvenile amyotrophic lateral sclerosis, or adult-onset myopathy (GNE myopathy). We have created inducible Gne[lox/lox] gene deletion mice to study how loss of Gne in adult mice relates to these disease states. Systemic Gne gene deletion in tamoxifen-treated Rosa-CreER[T2]/Rosa-CreER[T2]Gne[lox/lox] mice caused uniform fatality within 30 days of gene deletion with spontaneous bleeding, thrombocytopenia, and anemia. Skeletal myofiber-specific Gne deletion in tamoxifen-treated HSA-CreER[T2/+]Gne[lox/lox] mice had no bleeding and no muscle pathology at 60 or 270 days post-treatment. Intramuscular injection of AAV.MCK.GFP-Cre in Gne[lox/lox] mice also showed little to no evidence of muscle pathology, while AAV.CMV.GFP-Cre caused extensive muscle damage, reduced muscle force, and changed expression of markers for muscle regeneration, muscle cell senescence, muscle denervation, and muscle atrophy. These data demonstrate that Gne is an essential gene in adult mice that can mimic aspects of human hematologic and muscle diseases caused by GNE mutations, but suggests induction of muscle disease requires loss of gene GNE expression in cell types beyond skeletal myofibers.},
}

@article {pmid41417044,
year = {2025},
author = {Rott, N and Reinsch, L and Dirks, B and Böttiger, BW},
title = {[The new European Resuscitation Council (ERC) guidelines 2025-Overview of the most important changes; the first 3-5 min are decisive].},
journal = {Die Anaesthesiologie},
volume = {},
number = {},
pages = {},
pmid = {41417044},
issn = {2731-6866},
abstract = {In October 2025 the new resuscitation guidelines of the European Resuscitation Council (ERC) were published. In the chapter on advanced life support (ALS) for adults the update emphasizes topics such as efficient ventilation with adequate chest compressions, early defibrillation, identification and treatment of reversible causes as rapidly as possible and the administration of epinephrine in cases of non-defibrillatable cardiac arrest. The aim of the guidelines is to sustainably improve survival rates after cardiac arrest through structured and evidence-based care systems.},
}

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

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

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

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

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

@article {pmid41408263,
year = {2025},
author = {Doughty, J and Booth, J and Smith, M and Saini, K and Paisi, M and Rodriguez, A and Levine, A and Bedos, C and Muirhead, V and Martins de Barros, C and Freeborn, C},
title = {Unmasking oral health stigma: a qualitative scoping review.},
journal = {BMC oral health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12903-025-07329-9},
pmid = {41408263},
issn = {1472-6831},
abstract = {INTRODUCTION: Health-related stigma can limit access to care, impair adherence to treatment, and negatively impact mental health and quality-of-life. Oral health stigma, defined as stigma arising from oral conditions that diverge from sociocultural norms, operates through labelling, stereotyping, othering, and exclusion. Oral health stigma can lead to shame, diminished self-confidence, and avoidance of dental care, creating a self-perpetuating cycle of poor oral health and reinforcing internalised and anticipated stigma. While previous research has explored the social implications of oral appearance, little is known about the broader concept of oral health stigma or strategies to mitigate it.

METHODS: This scoping review adopted Levac et al.'s six-stage framework. The review utilised data from qualitative studies to explore lived experiences of oral health stigma and consider ways to mitigate it. Patient and public involvement (PPI) informed the development of the research question, search strategy, and interpretation of findings.

RESULTS: Seventy-two qualitative studies were included, comprising 2,455 participants. Themes included stigma associated with physical appearance and attractiveness, judgement, labelling, and stereotyping. Consequences included low self-esteem, social exclusion, impacts to care seeking behaviours, and efforts to conceal oral appearance. Participants highlighted the transformative value of dental care and described coping strategies to build resilience. Other proposed solutions included fostering social connection and implementing trauma-informed, non-judgemental dental care.

CONCLUSION: Oral health stigma has significant social and psychological consequences and impacts on care-seeking behaviours. Addressing it requires targeted interventions at multiple levels, including individual, community, professionals and wider system / policy.},
}

@article {pmid41406304,
year = {2025},
author = {Geva, M and Goldberg, YP and Leitner, ML and Cruz-Herranz, A and Hand, R and Chen, K and Gershoni Emek, N and Tan, AM and Paganoni, S and Berry, JD and Macklin, EA and Shefner, JM and Cudkowicz, ME and Hayden, MR},
title = {Pridopidine treatment in ALS: subgroup analyses from the HEALEY ALS Platform trial.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/21678421.2025.2597935},
pmid = {41406304},
issn = {2167-9223},
abstract = {Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Pridopidine, a selective sigma-1 receptor agonist, was evaluated in Regimen D of the HEALEY ALS Platform Trial. Although the primary endpoint (ALS Functional Rating Scale-Revised (ALSFRS-R) total score accounting for survival at 24 weeks) was not met, a predefined subgroup analysis suggested slowed disease progression in ALS patients with definite and early disease (<18 months from onset). This report presents an exploratory analysis that further investigates pridopidine in rapidly progressing participants with definite/probable ALS and early-disease, where treatment effects may be more pronounced. Methods: The randomized, double-blind, placebo-controlled phase 2 trial assigned participants to pridopidine 45 mg bid or placebo, and placebo patients were shared across four trial regimens. The primary outcome was ALSFRS-R total score, with secondary outcomes assessing respiratory, bulbar, and speech functions. Results: Of 163 participants randomized to Regimen D, 72 met subgroup criteria (pridopidine: n = 37; shared placebo: n = 35). At week 24, pridopidine slowed ALSFRS-R total score decline (32%; Δ2.90, p = 0.03) and slowed decline of ALSFRS-R respiratory function (62%; Δ1.20, p = 0.03) and dyspnea (88%; Δ0.85, p = 0.005). ALSFRS-R-Bulbar function stabilized, with articulation and speaking rate declines reduced by 93% (Δ0.43, p = 0.0007) and 70% (Δ0.43, p = 0.002), respectively. Pridopidine was well-tolerated, with a safety profile comparable to placebo. All p values are nominal. Conclusion: Post hoc subgroup analysis suggests therapeutic benefits of pridopidine in patients that had definite/probable ALS and with early-disease progression, supporting further evaluation in a Phase 3 trial.},
}

@article {pmid41404692,
year = {2025},
author = {Żur-Wyrozumska, K},
title = {A case of an ALS patient with an SQSTM1 mutation - implications for the p62/NF-κB/Nrf2/autophagy pathways in the selection of individualised therapeutic strategies: a preliminary report.},
journal = {Folia medica Cracoviensia},
volume = {65},
number = {3},
pages = {173-183},
doi = {10.24425/fmc.2025.156692},
pmid = {41404692},
issn = {0015-5616},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Sequestosome-1 Protein/genetics ; Middle Aged ; Female ; NF-E2-Related Factor 2/genetics/metabolism ; Autophagy/genetics ; NF-kappa B/genetics ; Mutation ; Signal Transduction ; },
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) represents a heterogeneous group of neurodegenerative disorders sharing a common ALS phenotype but arising from diverse genetic and molecular mechanisms. Among the genes implicated in ALS, SQSTM1, encoding the multifunctional protein p62, plays a pivotal role in maintaining neuronal homeostasis through the regulation of autophagy and the crosstalk between NF-κB and Nrf2 pathways. Disruption of these mechanisms contributes to oxidative stress, neuroinflammation, and protein aggregation in motor neurons.

MATERIAL AND METHODS: A comprehensive genetic analysis, including next-generation sequencing (NGS), whole-exome sequencing (WES), and multiplex ligation-dependent probe amplification (MLPA), was performed in a patient clinically diagnosed with ALS. Literature data regarding the role of SQSTM1, NF-κB/Nrf2 signaling, and autophagy modulation in ALS pathogenesis were reviewed to contextualize the findings.

CASE PRESENTATION: We describe a 49-year-old woman with a 12-month history of progressive - bulbar-onset ALS. Genetic testing revealed a heterozygous SQSTM1 c.1175C>T (p.Pro392Leu) variant inherited from her father, classified as likely pathogenic. The patient received dimethyl fumarate (Nrf2 activator), celecoxib (NF-κB inhibitor), and rapamycin (mTOR pathway modulator) as part of an individualized treatment strategy.

DISCUSSION: Mutations in SQSTM1 contribute to ALS pathogenesis through dysregulation of autophagy, impaired protein clearance, and excessive neuroinflammation mediated by NF-κB activation. The interplay between NF-κB and Nrf2 signaling pathways suggests that targeted therapeutic modulation may attenuate neurodegeneration. The patient's case illustrates the clinical and molecular heterogeneity of ALS and supports the concept of pathway-specific, precision medicine approaches.

CONCLUSIONS: This case highlights the relevance of SQSTM1-related pathogenic mechanisms within the heterogeneous ALS spectrum and underscores the importance of advanced genetic testing for identifying candidates for personalized therapy.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/drug therapy
*Sequestosome-1 Protein/genetics
Middle Aged
Female
NF-E2-Related Factor 2/genetics/metabolism
Autophagy/genetics
NF-kappa B/genetics
Mutation
Signal Transduction

@article {pmid41401652,
year = {2025},
author = {Braverman, A and Frenkel, A and Schwarzfuchs, D and Jaffe, E and Bitan, Y},
title = {Verbal and visual information exchange in EMS-to-ED patient handovers: An observational and attitudinal study.},
journal = {International emergency nursing},
volume = {84},
number = {},
pages = {101735},
doi = {10.1016/j.ienj.2025.101735},
pmid = {41401652},
issn = {1878-013X},
abstract = {BACKGROUND: Although effective information exchange during emergency medical services (EMS)-to-emergency department (ED) patient handovers is critical for care continuity and patient safety, handover communication patterns and information gaps remain poorly characterized.

OBJECTIVE: To characterize verbal and visual information exchange patterns in EMS-to-ED handovers while comparing EMS and ED staff perceptions of handover quality.

METHODS: This was a dual-methods study conducted at a tertiary medical center in Israel (June-November 2024) in which 83 EMS-to-ED handovers [35 advanced life support (ALS), 48 basic life support (BLS)] were directly observed. We documented information elements, duration, and communication patterns via a structured checklist. In addition, an electronic survey (Qualtrics) of 103 participants (62 EMS, 41 ED staff) was used to assess perceptions with 6-point Likert scales. Statistical analyses utilized Mann-Whitney U tests, effect sizes (Cohen's d), and 95 % confidence intervals (CIs).

RESULTS: The handovers were dominated by verbal communication (97.6 %, 95 % CI: 91.6-99.3 %) of brief duration [ALS: Median = 40 s, interquartile range (IQR) 35-45; BLS: Median = 25 s, IQR 25-35]. Significant information gaps included: pre-hospital treatment details, which were absent in 36.1 % of the handovers (95 % CI: 26.6-46.9 %), allergy details in 55.4 %, and demographic details in 61.4 %. The ALS teams provided more complete information than did BLS teams (treatment: 94 % vs. 46 %, p < 0.001; allergies: 60 % vs. 33 %, p = 0.02). EMS documentation was available in only 7.2 % of handovers (95 % CI: 3.4-14.9 %). Patient background documents were valued more by ED staff than by EMS personnel (Median = 4.84 vs. 3.44, p < 0.001, d = 0.98), and they reported higher confidence in using received information (Median = 4.12 vs. 3.15, p < 0.001, d = 0.78).

CONCLUSIONS: Because EMS-to-ED handovers rely almost exclusively on brief verbal communication, they are vulnerable to information loss. Critical safety-relevant information (allergies, medications) is frequently omitted, with BLS teams showing greater gaps than ALS teams. Structured handover protocols may improve information completeness and continuity of care by incorporating digital tools to complement verbal communication.},
}

@article {pmid41400574,
year = {2025},
author = {Huang, S and Li, A and Ling, Y and Yang, X and Wang, J and Yuan, J and Qin, D and Yao, X},
title = {Pharmacological Activation of Mitophagy Confers Neuroprotective Benefits for Amyotrophic Lateral Sclerosis.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1224},
pmid = {41400574},
issn = {2152-5250},
abstract = {Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disease characterized by the progressive degeneration of motor neurons in the brain and spinal cord, for which no cure currently exists. Previous studies have shown that abnormal mitochondrial homeostasis and defective mitophagy occur in neurodegenerative diseases, including ALS. Here, we provide evidence that PINK1-Parkin-dependent mitophagy is impaired in multiple ALS mouse models, including the SOD1[G93A], TDP43[A315T], and rNLS8 strains, leading to the accumulation of damaged mitochondria in affected motor neurons. These findings suggest that mitophagy may be a druggable target for ALS treatment. A classical mitophagy agonist, urolithin A (UA) was used in this study. UA-induced mitophagy antagonizes ALS pathologies in the ALS SOD1[G93A] transgenic C. elegans model in a pink-1 (PTEN-induced kinase 1)- and pdr-1 (Parkinson's disease-related 1)-dependent manner. Furthermore, pharmacological activation of mitophagy by UA improves locomotor behavior, delays motor neuron degeneration and reduces neuroinflammation in ALS SOD1[G93A] transgenic mice. In conclusion, our results establish impaired mitophagy as a hallmark of ALS motor neuron degeneration and demonstrate that its pharmacological activation offers a neuroprotective strategy with therapeutic potential.},
}

@article {pmid41400569,
year = {2025},
author = {Vacchiano, V and Cherici, A and Criante, MS and Mengoli, E and Fonti, C and Bonan, L and de Pasqua, S and Donadio, V and Giannoccaro, MP and Rizzo, G and Quarta, CC and Marzocchi, E and Taggi, F and Liguori, R and , },
title = {Cognitive and behavioral impairment may influence shared care planning and treatment decisions in amyotrophic lateral sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2025.2597937},
pmid = {41400569},
issn = {2167-9223},
abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons, often accompanied by cognitive and/or behavioral impairments. Shared Care Planning (SCP) involves a collaborative decision-making process, playing a key role in aligning medical treatments with patient values. This study aimed to investigate potential associations between neuropsychological impairment and treatment decisions in ALS patients. Methods: We included 118 ALS patients who had completed at least the cognitive section of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). As part of routine clinical practice, patients were invited to participate in Shared Care Planning (SCP) discussions regarding key medical interventions, namely noninvasive ventilation (NIV), artificial nutrition via PEG/RIG, and tracheostomy. Results: SCP discussions were initiated with 78% of patients. NIV was accepted by 96% of patients, PEG/RIG by 63.9% and tracheostomy by 17.8%. Patients who accepted PEG/RIG were more frequently female (p = 0.047) and had significantly lower adjusted scores on the total ECAS (p = 0.027), ALS-specific domains (p = 0.020), verbal fluency (p = 0.012), and semantic fluency (p = 0.042), compared to those who refused PEG/RIG. Acceptance of tracheostomy was more common among younger patients (p < 0.001) and those with cognitive or behavioral impairments (p = 0.014). Binary logistic regression analysis, using tracheostomy acceptance as the dependent variable and age, sex, and Strong's diagnostic categories as independent variables, revealed a significant association with age (p = 0.002) and with certain Strong's categories, particularly ALS with combined cognitive and behavioral impairment (ALS-CBI) (p = 0.031). Conclusions: Cognitive and behavioral impairment appeared to increase the likelihood of consenting to invasive treatments in ALS patients.},
}

@article {pmid41399798,
year = {2025},
author = {Ghosh, S and Debnath, I and Bhunia, S and Nandi, S and Ashique, S and Nayak, A and Mallick, S and Basak, S},
title = {Decoding natural products for neuroprotection: Pathway networks and structural insights for drug development.},
journal = {Chinese herbal medicines},
volume = {17},
number = {4},
pages = {643-672},
pmid = {41399798},
issn = {2589-3610},
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis, are progressive disorders marked by neuronal dysfunction and death, driven by pathological mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, apoptosis, and protein misfolding. Despite scientific advances, current treatments remain largely palliative, underscoring the need for multitargeted therapeutic strategies. This narrative review synthesizes preclinical and clinical evidence to explore the neuroprotective potential of natural products, with a focus on their ability to modulate key molecular pathways implicated in NDs. A comprehensive literature search across Scopus, ScienceDirect, PubMed, MDPI, and Web of Science identified relevant studies. Bioactive compounds such as curcumin, resveratrol, ginsenosides, quercetin, and marine-derived molecules like fucoxanthin and phlorotannin demonstrated antioxidant, anti-inflammatory, anti-amyloidogenic, and mitochondrial-protective effects by modulating pathways including PI3K/Akt, NF-κB, and Nrf2/ARE, thereby mitigating neuronal damage and promoting cell survival. Natural products from diverse sources, including honey, ginseng, marine macroalgae, and cyanobacteria, exhibited broad-spectrum neuroprotective properties, with advances in nano-formulations improving bioavailability and brain penetration. Furthermore, emerging approaches such as gene-drug interaction studies and scaffold-based drug design offer promising avenues for enhancing clinical translation. While natural products provide a holistic, multitargeted approach to combat NDs, challenges related to bioavailability and therapeutic translation persist, necessitating future research that integrates advanced drug delivery systems, precision medicine, and synthetic modifications to develop innovative and effective treatment paradigms.},
}

@article {pmid41399419,
year = {2025},
author = {Chen, HW},
title = {Axial Spinal Traction as a Potential Modulator of Cerebrospinal and Glymphatic Circulation in Neurodegenerative Diseases: A Technical Report and Biomechanical Hypothesis.},
journal = {Cureus},
volume = {17},
number = {12},
pages = {e99153},
pmid = {41399419},
issn = {2168-8184},
abstract = {Impairment of glymphatic function contributes to the accumulation of metabolic and proteinaceous waste products implicated in neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and certain spinocerebellar ataxias. Pelvis-stabilized axial spinal traction (PSAST) is a biomechanical technique designed to produce brief, controlled cranio-caudal elongation of the vertebral column and spinal dural sac, potentially generating transient pressure gradients capable of influencing cerebrospinal fluid (CSF) dynamics and glymphatic circulation. The technique has been applied in the author's musculoskeletal practice for more than eight years without observed persistent or treatment-related adverse effects, although such practice-based experience does not constitute a formal safety evaluation. Improved sleep quality has been the most consistently reported patient-perceived response to PSAST, a clinically notable observation given the dependence of glymphatic function on consolidated slow-wave sleep. These practice-based observations provide preliminary, hypothesis-generating support for exploring whether controlled axial elongation may modulate cerebrospinal and glymphatic physiology. To the best of the author's knowledge, this report presents the first peer-reviewed technical description of a reproducible, whole-axis axial spinal traction procedure with defined force parameters intended to examine potential modulation of CSF and glymphatic circulation. The report outlines the PSAST protocol and its biomechanical rationale and safety considerations and proposes its potential relevance as a noninvasive, investigational approach for conditions associated with impaired glymphatic function.},
}

@article {pmid41398684,
year = {2025},
author = {Fuad, NA and Pitros, P and Brown, G and Besi, E},
title = {Will L-PRF Be the Future of Endodontic Microsurgery? A Series of Case Reports.},
journal = {Clinical and experimental dental research},
volume = {11},
number = {6},
pages = {e70198},
pmid = {41398684},
issn = {2057-4347},
support = {//The authors received no specific funding for this work./ ; },
mesh = {Humans ; *Microsurgery/methods ; Periapical Tissue/surgery ; Root Canal Therapy/methods ; Treatment Outcome ; Wound Healing ; },
abstract = {OBJECTIVES: This case series aimed to evaluate the healing potential of apical tissues with large periapical radiolucencies (> 10 mm) after apical microsurgery with L-PRF. The secondary objectives were to evaluate L-PRF's benefits and adverse effects as well as to aid in the development of a clinical protocol.

MATERIALS AND METHODS: This case series was conducted in accordance with the Preferred Reporting Items for Case Reports in Endodontics (PRICE) 2020 guidelines. Thirteen patients with persistent endodontic infections, unresponsive to nonsurgical root canal treatment/retreatment, were treated at the Restorative and Oral Surgery Departments with endodontic microsurgery. L-PRF preparation followed Choukroun et al. (2001) and the L-PRF 2018 guidelines under the supervision of an experienced consultant. Postoperative follow-up included a phone call at 24 h to assess pain, swelling, and daily functions. Sutures were removed at 7 days, and a 6-month clinical and radiographic review was conducted. The clinical assessment included patient-reported symptoms and extraoral and intraoral examinations. Periapical radiographs were assessed for periapical healing based on Rud et al.'s (1972) radiographic criteria. Radiographs were reviewed by one clinician under standardized conditions.

RESULTS: Histopathological analyses identified 76.9% (n = 10) radicular cysts and 23.0% (n = 3) periapical granulomas from the 13 cases. At the 6-month review, 76.9% (n = 10) showed incomplete healing, 15.4% (n = 2) demonstrated complete healing, and 7.7% (n = 1) had incomplete healing at 4 months. All patients remained asymptomatic with no reported complaints. Radiographic assessments showed a significant reduction in the size of periapical radiolucency in all cases. At 24 h, 69.2% (n = 9) reported no pain, while mild pain was noted in 15.4% (n = 2). Swelling was observed in 69.2% (n = 9) and absent in 15.4% (n = 2), with missing records for 15.4% (n = 2).

CONCLUSION: L-PRF appears beneficial in endodontic microsurgery. However, larger, low-bias studies with extended follow-up periods are needed for definitive conclusions on its application.},
}

Humans
*Microsurgery/methods
Periapical Tissue/surgery
Root Canal Therapy/methods
Treatment Outcome
Wound Healing

@article {pmid41396180,
year = {2025},
author = {Xu, X and Zhou, Q and Zhang, X and Li, T and Niu, L and Xu, G and Chen, S and Shao, Y and Le, W},
title = {Untargeted metabolomics based on LC-MS and GC-MS reveal metabolic reprogramming and putative biomarkers in amyotrophic lateral sclerosis.},
journal = {Chinese medical journal},
volume = {},
number = {},
pages = {},
pmid = {41396180},
issn = {2542-5641},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unknown etiology. The absence of reliable biochemical and imaging markers often delays diagnosis and limits treatment effectiveness. As metabolic reprogramming is increasingly recognized as a hallmark of ALS, a comprehensive untargeted metabolomics analysis was employed to identify critical metabolic perturbations in ALS and explore novel candidate biomarkers with potential utility in clinical diagnosis.

METHODS: Plasma from two independent cohorts comprising 399 participants (170 ALS patients, 200 healthy controls, and 29 ALS-unrelated neurological disease controls) was included. Cohort 1 was recruited from Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital (April 2020-September 2022), and cohort 2 from Sichuan Academy of Sciences-Sichuan Provincial Hospital, Ruijin Hospital, Shanghai Jiaotong University Affiliated Sixth People's Hospital, and The First Affiliated Hospital of Dalian Medical University (October 2022-February 2023). Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approaches were used to identify metabolic alterations and potential diagnostic biomarkers for ALS. Complementary multivariable and univariable statistical approaches were applied to characterize disease-specific metabolic reprogramming in ALS. In addition, the receiver operating characteristic (ROC) curve was used to assess the discriminatory power of differential metabolites, and binary logistic regression analysis was used to construct a multivariate biomarker model.

RESULTS: Metabolic changes of ALS were mainly observed in amino acids, fatty acyls , and purines. Inosine and hypoxanthine were found to be the most significantly and critically dysregulated metabolites in ALS. Aminoacyl-transfer ribonucleic acid (tRNA) biosynthesis and amino acid metabolism were regarded as the most significantly perturbed pathways. Across both cohorts, 26 metabolites were consistently changed. Notably, a biomarker panel comprising hypoxanthine, inosine, and trigonelline was constructed using binary logistic regression, achieving excellent diagnostic performance in distinguishing ALS from controls, with an area under the ROC curve of 0.982 in cohort 1 (sensitivity 0.970, specificity 0.940) and 0.934 in cohort 2 (sensitivity 0.942, specificity 0.791).

CONCLUSION: The disturbed pathways and biomarker candidates identified in this study may provide novel insights into ALS pathogenesis and improve diagnostic strategies.},
}

@article {pmid41394670,
year = {2025},
author = {O'Connor, JT and Loo, HQ and Guo, C and Pickles, S and Sundali, S and Jawahar, VM and Dickson, DW and Bloom, AJ and Petrucelli, L and Gitler, AD and Milbrandt, J and DiAntonio, A},
title = {TDP-43 suppression of ATP8A2 cryptic splicing implicates phosphatidylserine-driven neuroinflammation in ALS/FTD.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {41394670},
issn = {2692-8205},
support = {R01 NS133348/NS/NINDS NIH HHS/United States ; R01 NS087632/NS/NINDS NIH HHS/United States ; R01 NS065053/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R35 NS137447/NS/NINDS NIH HHS/United States ; F32 AG086044/AG/NIA NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; R01 NS132330/NS/NINDS NIH HHS/United States ; R35 NS137159/NS/NINDS NIH HHS/United States ; },
abstract = {Inappropriate externalization of phosphatidylserine (PS) is a candidate mechanism of pathogenic neuroinflammation, a critical driver of neurodegenerative disease. ATP8A2, a flippase that maintains PS on the plasma membrane inner leaflet, is mutated in both Wabbler-lethal mice and patients with the ataxia syndrome CAMRQ4. Here, we identify ATP8A2 as a target of TDP-43 cryptic exon suppression, and demonstrate that ATP8A2 loss leads to immune-mediated neurodegeneration. ATP8A2 splicing is significantly dysregulated following TDP-43 depletion in human neurons and in brains of patients with Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD). In mice, Atp8a2 loss increases PS exposure and promotes neuroinflammation. Depletion of peripheral macrophages rescues motor axon degeneration and doubles Atp8a2 knockout mouse lifespan, while depletion of both peripheral macrophages and central microglia quadruples lifespan and improves coordination. Hence, ATP8A2 is a pathologically relevant TDP-43 target and inhibition of phagocytic immune cell attack against neurons is a potential treatment for patients with CAMRQ4 and ALS-FTD.},
}

@article {pmid41392158,
year = {2025},
author = {Le Friec, J and Mourier, H and Couly, S and Cubedo, N and Dubois, K and Meunier, J and Delprat, B and De Zordo-Banliat, A and Ayad, T and Virieux, D and Su, TP and Lasbleiz, C and Maurice, T and Liévens, JC},
title = {Positive modulation of sigma-1 receptor: a new weapon to mitigate disease progression in amyotrophic lateral sclerosis.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {68},
pmid = {41392158},
issn = {2047-9158},
support = {grant 23667//AFM-Téléthon/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/genetics/pathology ; *Receptors, sigma/metabolism/agonists ; Sigma-1 Receptor ; Zebrafish ; Disease Progression ; Mice ; Humans ; Mice, Transgenic ; Motor Neurons/drug effects/metabolism ; Disease Models, Animal ; C9orf72 Protein/genetics ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterised by degeneration of motor neurons, leading to muscle weakness and progressive paralysis. Currently, no treatment is available to halt or reverse the progression of the disease. Oxidative stress, mitochondrial dysfunction, accumulation of unfolded proteins and inflammation are interconnected key actors involved in ALS. A potent therapeutic strategy would be to find molecules that break this vicious circle leading to neuronal dysfunction and death. Targeting sigma-1 receptor (S1R) could meet this objective, as this chaperone protein modulates many cell survival mechanisms. So far, the impact of S1R activation in ALS has been studied using specific agonists and mostly on the SOD1 mutation that represents only 2% of patients. In the present study, the impact of two different S1R activators, the reference agonist PRE-084 and the positive modulator OZP002, was compared on two key ALS genes: TDP43 and C9orf72.

METHODS: The dissociation of S1R from Binding immunoglobulin Protein (BiP) was determined using ELISA. OZP002 toxicity was compared to PRE-084 on zebrafish larvae with increasing concentrations. The efficacy of OZP002 and PRE-084 was evaluated on the locomotor escape response of zebrafish expressing mutant TDP43 or one C9orf72 toxic dipeptide. Their effects on NRF2 target gene expression were studied by qPCR. The beneficial effect was further examined on the locomotor performances of TDP43[A315T] mice using rotarod and beam walking tests. We also performed analysis on motor neuron loss and glial reactivity.

RESULTS: OZP002 is a positive modulator of S1R, that increases the dissociation of the S1R-BiP complex induced by orthosteric agonists. S1R activation by both OZP002 and PRE-084 restored the locomotor response of ALS zebrafish expressing either TDP43 or one C9orf72 toxic dipeptide. The neuroprotection was due at least in part to the NRF2 cascade stimulation but not with a direct interaction. More importantly, OZP002 and PRE-084 prevented locomotor defects and degeneration of spinal motor neurons in TDP43[A315T] transgenic mice. Astroglial and microglial reactivities were also reduced by both activators.

CONCLUSIONS: We here emphasize the therapeutic value of S1R activation in mitigating ALS pathology. Additionally, we show that the positive modulators pave the way for the development of new S1R-activating compounds for ALS treatment.},
}

Animals
*Amyotrophic Lateral Sclerosis/metabolism/drug therapy/genetics/pathology
*Receptors, sigma/metabolism/agonists
Sigma-1 Receptor
Zebrafish
Disease Progression
Mice
Humans
Mice, Transgenic
Motor Neurons/drug effects/metabolism
Disease Models, Animal
C9orf72 Protein/genetics

@article {pmid41389988,
year = {2025},
author = {Gomez-Almeria, M and Martinez-Gonzalez, L and Matos, AT and Rodriguez-Cueto, C and Vaz, AR and Martín-Baquero, R and Pérez de la Lastra, C and Infantes, R and Fernández-Ruiz, J and Palomo, V and Gil, C and Brites, D and Martinez, A and de Lago, E},
title = {Assessment of the therapeutic effect of IGS2.7, a CK1δ protein kinase inhibitor, in combination with riluzole for the treatment of ALS-associated TDP-43 proteinopathy.},
journal = {Neuropharmacology},
volume = {285},
number = {},
pages = {110804},
doi = {10.1016/j.neuropharm.2025.110804},
pmid = {41389988},
issn = {1873-7064},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease for which no effective treatments currently exist. The FDA and EMA have approved only riluzole, a drug that modestly extends patient survival by 3-18 months. In our research, we have identified a novel CK1δ inhibitor, IGS2.7, which modulates TDP-43 proteinopathy, the main ALS pathological hallmark, in both patient-derived cellular models and TgTDP-43 mice. To assess the potential of IGS2.7 as a therapeutic candidate and considering riluzole remains the standard care for ALS patients, we evaluated its effects in combination with riluzole. Our results demonstrate that co-administration of IGS2.7 and riluzole at effective doses does not cause adverse effects. However, no additional therapeutic benefit was observed beyond that of IGS2.7 monotherapy, suggesting that IGS2.7 may be viable as either a stand-alone treatment or as an adjunct to riluzole. Notably, when suboptimal doses of both drugs were administered, a combined effect was observed. This suggests that, once IGS2.7 reaches clinical testing, its use together with lower doses of riluzole may enhance therapeutic efficacy while potentially minimizing side effects. Additional in vivo pre-clinical studies will be required to further evaluate this possibility, although only clinical trials will ultimately determine its clinical relevance.},
}

@article {pmid41389101,
year = {2025},
author = {Li, Y and Zhou, Y and Yu, L and Bi, Y and Yi, L and Li, C and Liu, Y},
title = {Myeloid Irf5 Deficiency Enhances the Therapeutic Efficacy of IMD-0354 in a TDP-25-Induced Neurodegeneration Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {290},
pmid = {41389101},
issn = {1559-1182},
support = {H2024206009//the Hebei Natural Science Foundation/ ; 81901290//the National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Interferon Regulatory Factors/deficiency/metabolism ; *DNA-Binding Proteins/toxicity/metabolism ; Macrophages/metabolism/drug effects ; Mice, Knockout ; Mice ; Disease Models, Animal ; Mice, Inbred C57BL ; Apoptosis/drug effects ; Motor Neurons/metabolism/drug effects/pathology ; Mitochondria/metabolism/drug effects ; Cell Line ; Amyotrophic Lateral Sclerosis/drug therapy ; Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Nerve Degeneration/drug therapy/pathology/metabolism ; *Myeloid Cells/metabolism/drug effects ; },
abstract = {Neuroinflammation is recognized as a key contributor to the pathogenesis and progression of amyotrophic lateral sclerosis (ALS), with dysregulated innate immune activation implicated in exacerbating neuronal injury. However, the molecular mechanisms by which macrophages contribute to neurodegeneration in motor neurons harboring TAR DNA-binding protein 43 (TDP-43) mutations are not fully understood. M1 macrophages were generated from the bone marrow of Irf5 knockout or wild-type mice and co-cultured with the NSC34 motor neuron-like cell line overexpressing the C-terminal fragment of TDP-43 (TDP-25) using a Transwell system. Mitochondrial alterations, and apoptosis were evaluated through Western blotting, flow cytometry, and transmission electron microscopy. IMD-0354 mitigated mitochondrial dysfunction and apoptosis induced by TDP-25 exposure. This neuroprotective effect was attenuated in the presence of pro-inflammatory macrophages. Notably, the absence of Irf5 expression in macrophages amplified the protective efficacy of IMD-0354. Irf5 expression in macrophages may modulate the therapeutic efficacy of IMD-0354 in the context of TDP-43-associated proteinopathy, indicating a potential target for enhancing treatment strategies in ALS-related neurodegeneration through inhibiting inflammation.},
}

Animals
*Interferon Regulatory Factors/deficiency/metabolism
*DNA-Binding Proteins/toxicity/metabolism
Macrophages/metabolism/drug effects
Mice, Knockout
Mice
Disease Models, Animal
Mice, Inbred C57BL
Apoptosis/drug effects
Motor Neurons/metabolism/drug effects/pathology
Mitochondria/metabolism/drug effects
Cell Line
Amyotrophic Lateral Sclerosis/drug therapy
Neuroprotective Agents/pharmacology/therapeutic use
*Neurodegenerative Diseases/drug therapy/metabolism/pathology
*Nerve Degeneration/drug therapy/pathology/metabolism
*Myeloid Cells/metabolism/drug effects

@article {pmid41388206,
year = {2025},
author = {Schmitt, P and Schumann, P and Koerbs, A and Lin, HJ and Grehl, T and Weyen, U and Petri, S and Rödiger, A and Steinbach, R and Großkreutz, J and Bernsen, S and Weydt, P and Wolf, J and Günther, R and Baum, P and Metelmann, M and Weishaupt, JH and Streubel, B and Kasper, DC and Koc, Y and Kettemann, D and Norden, J and Walter, B and Münch, C and Spittel, S and Maier, A and Körtvélyessy, P and Meyer, T},
title = {Motor phenotypes and neurofilament light chain in genetic amyotrophic lateral sclerosis-results from a multicenter screening program.},
journal = {Journal of neurology},
volume = {273},
number = {1},
pages = {22},
pmid = {41388206},
issn = {1432-1459},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/physiopathology/diagnosis ; *Neurofilament Proteins/blood ; Male ; Female ; Middle Aged ; C9orf72 Protein/genetics ; Phenotype ; Aged ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; Adult ; Disease Progression ; Cohort Studies ; DNA-Binding Proteins/genetics ; },
abstract = {OBJECTIVE: In genetic amyotrophic lateral sclerosis (ALS), the clinical phenotypes, disease progression and neurofilament light chain (NfL) levels are incompletely characterized.

METHODS: In a total cohort of 1988 ALS patients, a subcohort of genetic ALS linked to C9orf72 (n = 137), SOD1 (n = 54), TARDBP (n = 27), and FUS (n = 19) was investigated. The phenotypes of onset region, propagation and motor neuron involvement were analyzed according to the OPM classification. Serum NfL (sNfL) was measured and related to ALS progression (ALSPR, monthly change of ALS Functional Rating Scale-Revised). To quantify NfL elevation relative to ALSPR, the logNfL(index), the log-transformed ratio of sNfL to ALSPR was calculated.

RESULTS: C9orf72-associated ALS showed frequent bulbar onset (n = 42.6%), higher ALSPR (0.95, SD 0.84), highest NfL (116.3, SD 72.7 pg/mL) and logNfL(index) (5.02, SD 0.88). SOD1-ALS had mostly limb onset (n = 96.1%), slower ALSPR (0.57, SD 0.60), high NfL (76.1, SD 61.4 pg/mL) and a comparably high logNfL(index) (4.94, SD 1.03). FUS-ALS exhibited mostly limb onset (82.4%), lower motor neuron dysfunction (70.6%), a wide range of faster (22.2%) to slower ALSPR (55.6%), lower NfL (66.2, SD 32.9) and logNfL(4.65, SD 0.9). TARDBP-ALS displayed the lowest ALSPR (0.53, SD 0.52), the lowest NfL (43.3, SD 31.8 pg/mL) and the lowest logNfL(index) (4.40, SD 0.7).

CONCLUSION: In C9orf72-ALS, the phenotype and NfL profile are close to typical ALS. The finding of distinct phenotypes and NfL patterns in SOD1-, FUS- and TARDBP-associated ALS underscores the relevance of genetic ALS for prognostic counseling, clinical trial design, treatment expectations and unraveling of pathogenic mechanisms in ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/blood/physiopathology/diagnosis
*Neurofilament Proteins/blood
Male
Female
Middle Aged
C9orf72 Protein/genetics
Phenotype
Aged
RNA-Binding Protein FUS/genetics
Superoxide Dismutase-1/genetics
Adult
Disease Progression
Cohort Studies
DNA-Binding Proteins/genetics

@article {pmid41381656,
year = {2025},
author = {Riley, S and Nguyen, V and Bhattacharjee, R and Ng, PQ and Ritchie, T and Kamath, KS and Fisk, I and Gecz, J and Kumar, R and Searle, IR},
title = {TMT-based quantitative proteomic assessment of Vicia sativa induced neurotoxicity by β-cyano-L-alanine and γ-glutamyl-β-cyano-L-alanine in SH-SY5Y cells.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-30121-2},
pmid = {41381656},
issn = {2045-2322},
support = {BB/V018108/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; LP200200957//Australian Research Council/ ; LP200200957//Australian Research Council/ ; LP200200957//Australian Research Council/ ; UA720//South Australian Grains and Industry Trust/ ; },
abstract = {β-cyano-L-alanine (BCA) and γ-glutamyl-β-cyano-L-alanine (GBCA) are the primary antinutritional compounds in Vicia sativa, a high-protein, drought-tolerant legume. While their neurotoxicity in monogastric animals has been reported, the molecular basis remains largely unknown. In this study, we optimised a rapid in vitro assay using retinoic acid-differentiated SH-SY5Y human neuroblastoma cells to assess BCA and GBCA toxicity, and then applied Tandem mass tags (TMT)-mass spectrometry (MS)-based quantitative proteomics to identify dysregulated proteins. BCA treatment dysregulated the proteins involved in DNA damage, translation, and oxidative stress, many of which are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease, as well as various cancers. In contrast, GBCA impacted the proteins linked to mitosis, cell cycle regulation, and apoptosis pathways. Interestingly, the absence of overlapping dysregulated proteins between BCA- and GBCA-treated cells suggested that the two toxins likely induce neurotoxicity via distinct mechanisms. These findings offer new insights into the molecular and cellular alterations caused by V. sativa toxins and their implications for animal feed safety.},
}

@article {pmid41381004,
year = {2025},
author = {Maas, D and Spindler, A and Zappi, I and Shapiro, J and Lo Sicco, KI},
title = {Response to Olsen et al's ''Summation and recommendations for the safe and effective use of topical and oral minoxidil".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2025.09.118},
pmid = {41381004},
issn = {1097-6787},
}

@article {pmid41375893,
year = {2025},
author = {Gratzer, A and Gdynia, N and Sasse, N and Beese, R and Winterholler, C and Bauer, Y and Schröter, C and Gdynia, HJ},
title = {Rehabilitation in Amyotrophic Lateral Sclerosis: Recommendations for Clinical Practice and Further Research.},
journal = {Journal of clinical medicine},
volume = {14},
number = {23},
pages = {},
pmid = {41375893},
issn = {2077-0383},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition characterized by the degeneration of upper and lower motor neurons. This degeneration leads to a gradual muscle weakness, dysarthria, dysphagia, respiratory insufficiency, and, in some patients, alterations in cognitive and behavioral performance. Regardless of advancements made in pharmacological and gene-targeted interventions, a definitive curative treatment remains elusive. Consequently, rehabilitation plays a pivotal role in preserving autonomy, participation, and overall quality of life. This review outlines the current evidence and clinical approaches related to multidisciplinary rehabilitation in ALS. It covers physical and occupational therapy, respiratory, speech and language, psychological, and palliative care domains. Evidence supports moderate tailored exercise programs, early respiratory therapy, and structured management of mobility deficits, spasticity, pain, dysphagia, and communication impairments as key elements of symptomatic treatment. Psychological and social support, which includes the involvement of caregivers and relatives, enhances emotional well-being and coping resilience. Even with progressive development of gene-targeted and disease-modifying therapies, rehabilitation will stay relevant for maintaining long-term motor function. This review highlights the need for standardized, evidence-based rehabilitation protocols and intensified neurorehabilitation research to strengthen clinical outcomes and quality of life as key therapeutic goals in ALS management.},
}

@article {pmid41375620,
year = {2025},
author = {Krysiak, D and Ćwiertnia, M and Wójcik, M and Babik, P and Suchanek, Ł and Jaskiewicz, F and Trojak-Piętka, J and Szlagor, M and Pollok-Waksmańska, W and Kawecki, M and Ilczak, T},
title = {Analysis of Medical Response Team Interventions and the Impact of Certified Training on the Treatment of Patients with Hypoglycaemia-A Simulation Study.},
journal = {Journal of clinical medicine},
volume = {14},
number = {23},
pages = {},
pmid = {41375620},
issn = {2077-0383},
abstract = {Background/objectives: The effectiveness of emergency medical procedures administered to a patient in a life-threatening condition depends, to a large degree, on the knowledge and skills of medical response team personnel. Their competencies can be developed through participation in training and then verified during emergency medicine championships. Methods: The research was conducted on the basis of one of the tasks carried out during the '16th International Winter Championships in Emergency Medicine'. The task was completed by 28 Polish emergency response teams from ambulance stations across the country. The teams carried out a simulated scenario related to procedures with a patient with hypoglycaemia. The teams' interventions were assessed in accordance with European Resuscitation Council (ERC) guidelines by judges selected from among academic lecturers and ERC instructors. Results: The research showed that 86% of the teams obtained the maximum number of points for adhering to safety procedures. Further, 61% of the teams obtained the maximum of 6 points for the initial assessment, with the average number of points obtained by the teams being 5.54. The average number of points for the physical examination was 21.04, with only one team obtaining the maximum result of 26 points. Additionally, 57% of the teams obtained the maximum number of 6 points for the medical consultation, with the average obtained by the teams being 5.43. The teams obtained, on average, 8.18 points for the correct treatment of hypoglycaemia, with 68% of the teams obtaining the maximum of 9 points. The research demonstrated a positive correlation between the quality of patient examination and the collection of medical data, and the effectiveness of hypoglycaemia treatment. It was also shown that if the team leader had completed an ALS course, they obtained higher scores for the treatment of hypoglycaemia, although this finding is specific to this scenario. Conclusions: The teams demonstrated generally high performance in a simulated hypoglycaemia scenario. More complete assessment and history-taking were associated with higher treatment scores. Correct treatment was achieved in 79% of ALS-led teams versus 44% of non-ALS teams, although this observation is specific to this simulation and should not be generalised.},
}

@article {pmid41366746,
year = {2025},
author = {Huang, J and Liu, Y and Li, M and He, R and Tang, Z and Lei, Y and Zha, Y and Wei, J},
title = {Safety and efficacy of botulinum toxin injection for sialorrhea in amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {BMC neurology},
volume = {25},
number = {1},
pages = {496},
pmid = {41366746},
issn = {1471-2377},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, with 80% of ALS patients experiencing bulbar weakness at some stage of the disease. ALS patients with bulbar weakness often suffer from troublesome sialorrhea. Botulinum toxin injection, as a neuromuscular blocker, has been widely used in the treatment of sialorrhea. This paper evaluates the safety and efficacy of botulinum toxin injections for the treatment of sialorrhea in ALS patients through a systematic review and meta-analysis.

METHODS: A systematic review and meta-analysis was conducted by searching eight databases, including PubMed, EMBASE, and CNKI, up to April 13, 2025. Eligible randomized controlled trials and quasi-experimental studies were analyzed using Review Manager 5.4 and Stata software.

RESULTS: Thirteen studies (2 RCTs, 11 quasi-experimental studies) with 130 ALS patients were included. Botulinum toxin significantly reduced sialorrhea and improved quality of life (Z = 10.98, p < 0.00001; RD = 0.82, 95% CI: 0.67–0.97). The treatment effect was independent of toxin type (p = 0.48), injection site (p = 0.17), and ultrasound guidance use (p = 0.44).

CONCLUSION: Botulinum toxin appears to be a safe and effective option for managing sialorrhea in ALS patients, regardless of injection technique. However, given that most included studies were observational, further validation through high-quality RCTs is warranted.

TRIAL REGISTRATION: This meta-analysis has been registered with Prospero, and the registration number is CRD420251029441. The registration period is April 9, 2025.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12883-025-04515-8.},
}

@article {pmid41365015,
year = {2025},
author = {Svendsen, O and Stevens, MWR and Hamamura, T and Harpas, I and Radunz, M and King, DL},
title = {Reporting quality standards in gaming disorder treatment evidence: A systematic review.},
journal = {Acta psychologica},
volume = {262},
number = {},
pages = {106063},
doi = {10.1016/j.actpsy.2025.106063},
pmid = {41365015},
issn = {1873-6297},
abstract = {BACKGROUND: The treatment evidence base for gaming disorder (GD) has grown steadily over the past two decades. A systematic review by King et al. (2017) of 30 studies reported that GD treatment studies tended to favor psychotherapy approaches, but the research was limited by poor reporting standards as assessed by the Consolidated Standards of Reporting Trials (CONSORT) framework. This systematic review aimed to conduct a follow up evaluation of the reporting quality of subsequent GD treatment studies.

METHODS: A literature search of six databases yielded 51,056 records, which resulted in 31 eligible studies after screening. Each study's reporting quality was assessed using the CONSORT statement, and then these assessments were compared to King et al.'s (2017) review.

RESULTS: This review identified several methodological improvements since 2017: 61 % of studies were randomized controlled trials (vs. 40 % in 2017), 90 % included control groups (vs. 63 %), and follow-up duration increased to 6.1 months (vs. 3.5 months; p = .032). Reporting improved for participant flow (87.1 % vs. 43.3 %; p = .001) and group-level statistics (74.2 % vs. 36.7 %; p = .003), but some areas showed no improvement.

DISCUSSION: There have been several improvements in GD treatment study design and reporting, including controls, randomization and follow up, reflecting an increasing number of higher quality trials for the condition. Most of the studies with higher reporting quality (i.e., scoring ≥30/46 on the CONSORT framework) were psychotherapy-based. Future research should employ designs with longer follow-ups, broader assessment of outcomes, and standardized ICD-11-aligned tools. Pharmacological treatments, including novel pharmacotherapies for other addictions (e.g., Naltrexone), are underexplored and lack high quality evidence.},
}

@article {pmid41364388,
year = {2025},
author = {Levine, AA and Rucker, JA and Cockerham, A and Cartner, J and Chambers, JD},
title = {U.S. health plan coverage of Neuromuscular Disease Therapies: An assessment of policy availability and restrictions.},
journal = {Journal of neuromuscular diseases},
volume = {},
number = {},
pages = {22143602251405815},
doi = {10.1177/22143602251405815},
pmid = {41364388},
issn = {2214-3602},
abstract = {BACKGROUND: Health plan policies managing neuromuscular disease (NMD) therapies may impose burdensome requirements on patients and providers. While prior research has explored payer restrictions for rare NMD treatments, limited evidence exists on policies specifically governing therapy initiation and reauthorization.

OBJECTIVES: To examine initial and reauthorization coverage policies for therapies targeting five NMDs-Duchenne muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, generalized myasthenia gravis, and Lambert-Eaton myasthenic syndrome-across all U.S. state Medicaid programs and leading commercial health plans.

METHODS: We constructed a database of coverage decisions issued by 50 states and DC Medicaid programs and 35 major commercial insurers, including both fee-for-service and managed care organizations. We analyzed (1) policy availability and coverage frequency, (2) initial coverage requirements (e.g., subgroup restrictions, step therapy, prescriber type), (3) reauthorization criteria, and (4) approval durations.

RESULTS: Of 1204 potential decisions, 908 (75%) had publicly available policies. Of these, 558 (46%) included reauthorization criteria. Among covered therapies, 96% imposed restrictions beyond FDA label indications. Requirements varied by payer type, NMD, and therapy. Average approval durations were 6 months for initial coverage and 10 months for reauthorization.

CONCLUSIONS: Many plans lacked publicly accessible policies, and most covered therapies were subject to restrictive requirements. These barriers-such as step therapy, narrow prescriber criteria, and short approval periods-may delay treatment and disrupt care continuity. Findings underscore the need for greater transparency and reform in prior authorization and pharmacy benefit design to support timely access to NMD therapies.},
}

@article {pmid41355735,
year = {2025},
author = {Pal, P and Carrer, M and Weiss, L and Jaime, OG and Cheng, C and Shmara, A and Boock, V and Bosch, D and Youssef, M and Fazeli, Y and Afetian, M and Grossman, TR and Hicks, MR and Jafar-Nejad, P and Kimonis, V},
title = {Antisense oligonucleotides targeting valosin-containing protein ameliorate muscle pathology and molecular defects in cell and mouse models of multisystem proteinopathy.},
journal = {Clinical and translational medicine},
volume = {15},
number = {12},
pages = {e70530},
pmid = {41355735},
issn = {2001-1326},
support = {1297770//Muscular Dystrophy Association/ ; //Cure VCP Disease Inc. Ionis Pharmaceuticals, Inc./ ; },
mesh = {Animals ; *Valosin Containing Protein/genetics/metabolism/antagonists & inhibitors ; Mice ; *Oligonucleotides, Antisense/pharmacology/therapeutic use ; Disease Models, Animal ; Humans ; Muscle, Skeletal/pathology ; Muscular Dystrophies, Limb-Girdle/genetics ; Frontotemporal Dementia/genetics ; Myositis, Inclusion Body ; Osteitis Deformans/genetics ; },
abstract = {BACKGROUND: Valosin-containing protein (VCP) related disease, also known as multisystem proteinopathy 1 (MSP1), is an autosomal dominant disease caused by gain-of-function pathogenic variants of the VCP gene. The disease presents with variable combinations of inclusion body myopathy, early-onset Paget's disease of bone, frontotemporal dementia and may also overlap with familial amyotrophic lateral sclerosis. There is currently no treatment for this progressive disease associated with early demise resulting from proximal limb girdle and respiratory muscle weakness. We hypothesise that regulating VCP hyperactivity to normal levels can reduce the disease pathology.

MAIN TOPICS COVERED: In this study, we assessed the effect of antisense oligonucleotides (ASOs) specifically targeting the human VCP gene in the patient (R155H) iPSC-derived skeletal muscle progenitor cells (SMPCs). ASOs were well tolerated up to a concentration of 5 µM and significantly reduced VCP protein expression in the SMPCs by 48% (95% CI [39-56]). We also treated the transgenic mouse model of VCP disease with the overexpressed humanised VCP severe A232E pathogenic gene variant (VCP A232E mice) with weekly subcutaneous ASO injections starting from 6 months of age for 3 months. In the skeletal muscle of transgenic mice, ASOs resulted in 30% (95% CI [27-32]) knockdown of VCP protein compared with control ASO. The ASO-mediated reduction of VCP expression in muscle tissue was associated with improvement in autophagy flux and reduction in TAR DNA binding protein 43 (TDP-43) expression, hallmarks of VCP related MSP1. In addition, ASO-treated VCP A232E mice showed improvements in functional tests of muscle strength, such as rotarod and inverted screen test compared with mice treated with control ASO.

CONCLUSIONS: These results suggest that targeting VCP could be beneficial in preventing the progression of the VCP myopathy and hold promise for the treatment of patients with VCP related MSP1.

KEY POINTS: VCP multisystem proteinopathy 1 is caused by gain-of-function pathogenic variants of the VCP gene. VCP targeting ASOs were well tolerated and significantly reduced VCP, TAR DNA binding protein 43 (TDP 43), and autophagy protein expression in the (R155H) iPSC-derived skeletal muscle progenitor cells (SMPCs). The ASOs reduced VCP, TDP-43, and autophagy flux expression, and improved functional tests of muscle strength in the humanized VCP A232E mice.},
}

Animals
*Valosin Containing Protein/genetics/metabolism/antagonists & inhibitors
Mice
*Oligonucleotides, Antisense/pharmacology/therapeutic use
Disease Models, Animal
Humans
Muscle, Skeletal/pathology
Muscular Dystrophies, Limb-Girdle/genetics
Frontotemporal Dementia/genetics
Myositis, Inclusion Body
Osteitis Deformans/genetics

@article {pmid41354105,
year = {2025},
author = {Mendes Araújo, L and Chianca, T and Persaud, C and Hartung, P and Soares, Y and Almirón, G and João, R},
title = {Respiratory strength training for patients with amyotrophic lateral sclerosis: A meta-analysis of randomized controlled trials.},
journal = {Respiratory medicine},
volume = {251},
number = {},
pages = {108560},
doi = {10.1016/j.rmed.2025.108560},
pmid = {41354105},
issn = {1532-3064},
abstract = {INTRODUCTION: Respiratory strength training (RST) has been considered as a possible add-on treatment for amyotrophic lateral sclerosis (ALS). However, the benefits of RST are still controversial. We performed a meta-analysis of randomized controlled trials (RCTs) on the efficacy of RST in patients with ALS.

METHODS: PubMed, Embase and Cochrane Central were searched for RCTs comparing the use of RST with sham therapy or minimal device load in patients with ALS. The main outcomes were maximal expiratory pressure (MEP), maximal inspiratory pressure (MIP) and the ALS functioning rating scale (ALSFRS-R) score. Statistical analysis was performed using R software and heterogeneity was assessed with I[2] statistics.

RESULTS: Four RCTs were included with a total of 138 patients. RST was used to treat 69 (50 %) patients. The mean age was 60.2 ± 10.4 years, with 82 (62.3 %) male patients. Follow-up ranged from 2 to 8 months. Subgroup analysis of expiratory muscle training protocols showed a statistically significant improvement in MEP (MD 20.22 cmH2O; 95 % CI 2.66-37.77; p = 0.04). In overall analyses, there was no difference between groups regarding MEP (MD 9.40 cmH2O; 95 % CI -11.57-30.37; p = 0.25), MIP (MD 3.26 cmH2O; 95 % CI -9.23-15.75; p = 0.38), FVC (MD 4.05 %predicted; 95 % CI -0.91-9.01; p = 0.08) and ALSFRS-R score (MD 0.01 points; 95 % CI -0.29-0.32; p = 0.85).

CONCLUSION: In this meta-analysis of RCTs including patients with ALS, expiratory muscle training was associated with increased MEP compared with sham or minimal load. However, no statistically significant associations were found for overall RST in MIP, FVC, MEP, and ALSFRS-R.},
}

@article {pmid41352634,
year = {2025},
author = {Geleta, LA and Doyle, C and Garton, FC and Fowler, M and Carr, JM and Akkari, PA and McRae, AF and Rogers, ML and Madakkatel, I and Benyamin, B},
title = {The roles of human endogenous retrovirus in neurodegenerative diseases: A systematic review.},
journal = {Brain, behavior, and immunity},
volume = {132},
number = {},
pages = {106201},
doi = {10.1016/j.bbi.2025.106201},
pmid = {41352634},
issn = {1090-2139},
abstract = {BACKGROUND: Human endogenous retroviruses (HERVs) constitute ∼8 % of the human genome, far exceeding the 2 % occupied by protein-coding genes. Although most HERV sequences are inactive, some HERV elements can be reactivated under certain conditions and may contribute to neurodegenerative diseases (NDDs). However, the findings vary across different HERV families, disease models, and detection methods. Here, we systematically review and synthesize the available evidence on the role of HERVs in human NDDs and reconcile inconsistencies in the literature.

METHODS: We systematically searched MEDLINE, EMBASE, Cochrane Library, PsycINFO, Scopus, Web of Science, CINAHL, and Emcare to identify relevant studies. Two independent reviewers screened studies, assessed quality, and extracted data. Qualitative synthesis was conducted for all included NDDs, specifically Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson's disease (PD), and due to data availability, meta-analysis was used to assess the impact of HERVs antibodies on ALS only.

RESULTS: Twenty-six studies (N ranges: 6-485) met the inclusion criteria, with majority focusing on HERV-K and ALS. Across studies, the association between HERV expression and NDDs was inconsistent, particularly for ALS, PD, and FTD, whereas investigations in AD showed a more consistent upregulation of specific HERVs. Studies relying on polymerase chain reaction (PCR) (typically smaller) showed inconsistent associations (21 studies), while RNA sequencing studies reported consistent associations (9 studies). A preliminary meta-analysis revealed a fivefold increase [OR: 5.83; 95 % CI: 4.14, 8.18] in ALS risk among participants with positive HERV antibodies.

CONCLUSIONS: The inconsistencies in HERV involvement across NDDs highlight the need for further studies employing standardized methodologies. RNAseq findings on the association of HERVs expression and NDDs support the need for large-scale RNA sequencing studies (rather than small, PCR studies) and careful tissue selection to clarify HERVs' role in NDDs. The association of HERV-K antibodies with ALS risk and prognosis suggests a significant role in disease, which could help detect biomarkers and used as a target for treatment.},
}

@article {pmid41345272,
year = {2025},
author = {Duhayyim, MA},
title = {An efficient dimensionality reduction framework using metaheuristic optimization with deep learning models for amyotrophic lateral sclerosis disease progression prediction.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-30913-6},
pmid = {41345272},
issn = {2045-2322},
abstract = {Amyotrophic lateral sclerosis (ALS) is a disastrous neuro-degenerative infection which affects motor neuron inhabitants of the spinal cord, brainstem, and cerebral cortex, resulting in progressive disorder and demise from respiratory difficulty. ALS is considerably assorted disorder comprising symptoms such as muscle weakness, difficulty in swallowing, speaking, breathing, and changes in mental and emotional health. Hence, this disease requires more beneficial medication and also, successful treatment is affected by heterogeneous disease development, resulting in issues with patient stratification. Recently, many researches have been published by using deep learning (DL) and machine learning (ML) methods and, more commonly, artificial intelligence (AI). This paper presents a Dimensionality Reduction Framework Using Metaheuristic Optimization with Deep Learning Models for the Amyotrophic Lateral Sclerosis Disease Progression Prediction (DRMODL-ALSDP) method. The aim is to provide an effectual model for the progression prediction of ALS disease using advanced techniques. Initially, the data pre-processing stage applies min-mx normalization to transform raw data into a suitable format. Furthermore, SMOTE is employed to address class imbalance by upsampling the minority classes in disease progression stages. Furthermore, the binary swordfish movement optimization algorithm (BSMOA) technique is used for feature selection. Moreover, the hybrid of a temporal convolutional network and long short-term memory with attention mechanism (TCN-LSTM-AM) technique is employed for the classification process. Finally, the marine predator's algorithm (MPA) technique optimally fine-tunes the hyperparameter values and improves classification performance. A widespread simulation is performed to verify the performance of the DRMODL-ALSDP model. The comparison study of the DRMODL-ALSDP model accentuated the superior accuracy output of 98.17% over existing methods.},
}

@article {pmid41341510,
year = {2025},
author = {Yang, J and Yang, F and Chen, G and Liu, M and Yuan, S and Zhang, TE},
title = {Receptor-mediated mitophagy: a new target of neurodegenerative diseases.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1665315},
pmid = {41341510},
issn = {1664-2295},
abstract = {Neurodegenerative diseases are a category of neurological conditions with high prevalence that pose major treatment challenges. Common pathologies involve protein accumulation and mitochondrial damage. Mitophagy maintains cellular homeostasis by removing defective mitochondria, which are associated with the pathogenesis of neurodegenerative diseases. Although the ubiquitin-dependent mitophagy mediated by the PINK1-Parkin pathway has been extensively studied, growing evidence indicates that receptor-mediated mitophagy plays a crucial compensatory role in neurons, particularly when the PINK1-Parkin pathway is impaired. This review focuses on the emerging field of receptor-mediated mitophagy, systematically elaborating its role as a key homeostatic mechanism operating independently of the canonical PINK1/Parkin pathway. It provides a focused analysis of the specific functions and activation mechanisms of key receptors-including BNIP3, NIX, FUNDC1, and AMBRA1-in models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, this review explores the clinical potential of targeting these specific receptors for precise intervention, aiming to provide a new theoretical foundation and direction for developing therapeutic strategies against neurodegenerative diseases.},
}

@article {pmid41341242,
year = {2024},
author = {Gutman, B and Shmilovitch, AH and Aran, D and Shelly, S},
title = {Twenty-Five Years of AI in Neurology: The Journey of Predictive Medicine and Biological Breakthroughs.},
journal = {JMIR neurotechnology},
volume = {3},
number = {},
pages = {e59556},
pmid = {41341242},
issn = {2817-092X},
abstract = {Neurological disorders are the leading cause of physical and cognitive disability across the globe, currently affecting up to 15% of the world population, with the burden of chronic neurodegenerative diseases having doubled over the last 2 decades. Two decades ago, neurologists relying solely on clinical signs and basic imaging faced challenges in diagnosis and treatment. Today, the integration of artificial intelligence (AI) and bioinformatic methods is changing this landscape. This paper explores this transformative journey, emphasizing the critical role of AI in neurology, aiming to integrate a multitude of methods and thereby enhance the field of neurology. Over the past 25 years, integrating biomedical data science into medicine, particularly neurology, has fundamentally transformed how we understand, diagnose, and treat neurological diseases. Advances in genomics sequencing, the introduction of new imaging methods, the discovery of novel molecular biomarkers for nervous system function, a comprehensive understanding of immunology and neuroimmunology shaping disease subtypes, and the advent of advanced electrophysiological recording methods, alongside the digitalization of medical records and the rise of AI, all led to an unparalleled surge in data within neurology. In addition, telemedicine and web-based interactive health platforms, accelerated by the COVID-19 pandemic, have become integral to neurology practice. The real-world impact of these advancements is evident, with AI-driven analysis of imaging and genetic data leading to earlier and more accurate diagnoses of conditions such as multiple sclerosis, Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease, and more. Neuroinformatics is the key component connecting all these advances. By harnessing the power of IT and computational methods to efficiently organize, analyze, and interpret vast datasets, we can extract meaningful insights from complex neurological data, contributing to a deeper understanding of the intricate workings of the brain. In this paper, we describe the large-scale datasets that have emerged in neurology over the last 25 years and showcase the major advancements made by integrating these datasets with advanced neuroinformatic approaches for the diagnosis and treatment of neurological disorders. We further discuss challenges in integrating AI into neurology, including ethical considerations in data use, the need for further personalization of treatment, and embracing new emerging technologies like quantum computing. These developments are shaping a future where neurological care is more precise, accessible, and tailored to individual patient needs. We believe further advancements in AI will bridge traditional medical disciplines and cutting-edge technology, navigating the complexities of neurological data and steering medicine toward a future of more precise, accessible, and patient-centric health care.},
}

@article {pmid41329282,
year = {2025},
author = {Grigoryev, PN and Zefirov, AL and Mukhamedzyanov, RD and Salafutdinov, II and Islamov, RR and Mukhamedyarov, MA},
title = {Synaptic Vesicle Exocytosis and Endocytosis in Motor Nerve Endings of Transgenic Mice Modeling Amyotrophic Lateral Sclerosis upon Antioxidant Treatment and Gene-Cell Therapy.},
journal = {Doklady biological sciences : proceedings of the Academy of Sciences of the USSR, Biological sciences sections},
volume = {},
number = {},
pages = {},
pmid = {41329282},
issn = {1608-3105},
abstract = {Exocytosis and endocytosis of synaptic vesicles were studied in experiments with motor nerve endings of diaphragm neuromuscular preparations isolated from transgenic mice with a model of amyotrophic lateral sclerosis (ALS); treatment simulated antioxidant (edaravone) and gene-cell (umbilical cord blood mononuclear cells (UCB-MNCs) producing VEGF, GDNF, and NCAM) therapies. None of the treatments was found to significantly change the FM 1-43 fluorescent dye loading due to synaptic vesicle endocytosis. Gene-cell therapy increased the rate of dye unloading due to synaptic vesicle exocytosis, while antioxidant therapy did not change the FM 1-43 unloading rate. Based on the findings, gene-cell therapy was assumed to facilitate synaptic vesicle transport to release sites upon high-frequency stimulation in motor nerve endings of transgenic mice.},
}

@article {pmid41327179,
year = {2025},
author = {Eshak, D and Arumugam, M},
title = {Nanomaterials: an overview of current trends and future prospects in neurological disorder treatment.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {1366},
pmid = {41327179},
issn = {1479-5876},
mesh = {Humans ; *Nervous System Diseases/therapy/drug therapy ; *Nanostructures/therapeutic use/chemistry ; Animals ; Blood-Brain Barrier ; },
abstract = {The World Health Organization (WHO) has identified neurological disorders (NDs) as one of the major health concerns worldwide, resulting in high mortality rates. NDs are conditions affecting the central and peripheral nervous systems, including the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, neuromuscular junctions, and muscles. These neurological diseases include Alzheimer's disease, Parkinson's disease, glioma/brain cancer, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuroinfections, ischemic stroke, trauma, hypoxia/anoxia, and depression. Unfortunately, these disorders remain difficult to treat due to the limited ability of conventional drugs to cross the blood-brain barrier (BBB) and achieve significant pharmacological effects in the brain. There is an urgent need to develop methods that can enhance drug efficacy and bypass the BBB. The application of various nanomaterials represents a promising approach to address these neurological disorders. Drugs incorporated with nanomaterials help improve therapeutic outcomes, reduce toxicity, provide better stability, enable targeted delivery, and enhance drug loading capacity. Numerous types and morphologies of inorganic and organic nanomaterials are increasingly employed for treating NDs, including quantum dots, dendrimers, metal nanoparticles, polymeric nanoparticles, liposomes, carbon nanotubes, metal oxide nanoparticles, and micelles. Their exceptional properties such as sensitivity, selectivity, and potential to bypass the BBB make them suitable for both diagnosis and treatment of NDs. In this review article, we briefly summarize the etiology and pathophysiology of various NDs along with current literature highlighting the use of nanomaterials for treating neurological disorders.},
}

Humans
*Nervous System Diseases/therapy/drug therapy
*Nanostructures/therapeutic use/chemistry
Animals
Blood-Brain Barrier

@article {pmid41323796,
year = {2025},
author = {Kang, M and Lin, WH and Li, Y and Xu, F and Zhou, X and Si, C and Dai, J and He, J and Schacht, I and Gan, Z and Huang, V and Li, LC},
title = {SCAD: A modular platform for efficient delivery of duplex RNA to the CNS and beyond.},
journal = {Molecular therapy. Nucleic acids},
volume = {36},
number = {4},
pages = {102757},
pmid = {41323796},
issn = {2162-2531},
abstract = {Oligonucleotide therapeutics-including antisense oligonucleotides and duplex RNAs such as small interfering RNAs, small activating RNAs, and microRNAs-hold immense potential for treating both genetic and acquired diseases by modulating gene expression in a target-specific manner. However, effective delivery to extrahepatic tissues, particularly the central nervous system, remains a significant challenge. While N-Acetylgalactosamine conjugation has enabled liver-specific delivery of oligonucleotides leading to several approved siRNA drugs for hepatic indications, there remains a significant unmet need for effective treatment options in the CNS space. We have developed the smart chemistry-aided delivery platform that enables duplex RNA delivery by conjugating to an accessory oligonucleotide, which facilitates protein binding and promotes cellular uptake. Through extensive screening, we identified an optimal SCAD architecture that demonstrates enhanced cell-free protein binding and in vitro activity. In rodent models, local administration of SCAD-siRNA conjugates resulted in broad biodistribution throughout the CNS and sustained mRNA knockdown for over 5 months, with a favorable safety profile. The SCAD platform also exhibited efficient delivery to other extrahepatic tissues, including the eye, lung, and joint. The modular design of SCAD can be easily adapted to any duplex RNA, making it a powerful tool for advancing oligonucleotide therapeutics.},
}

@article {pmid41323448,
year = {2025},
author = {Tang, H and Jiang, P and Chen, J},
title = {Research Landscapes and Gaps in Neuropsychiatric Assessment for Neurodegenerative Diseases: A Bibliometric Study on Huntington's Disease, Amyotrophic Lateral Sclerosis, and Multiple System Atrophy.},
journal = {Dementia and geriatric cognitive disorders extra},
volume = {15},
number = {1},
pages = {174-191},
pmid = {41323448},
issn = {1664-5464},
abstract = {INTRODUCTION: The aim of the study was to provide a comprehensive overview of the current application of tools used for assessing neuropsychiatric symptoms (NPSs) in patients with Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple system atrophy (MSA) through bibliometric analysis.

METHODS: Publications published between 2014 and 2023 were searched using the Web of Science Core Collection database (WoSCC). Only articles and reviews published in the English language were included. CiteSpace was used to analyze the countries, keyword patterns, and reference co-citations. A detailed full-text analysis was further conducted across all studies to assess the usage of NPS assessment tools.

RESULTS: Our analysis included 530 publications demonstrating consistent annual growth, reflecting rising global interest in NPSs within neurodegenerative and neuroinflammatory diseases. However, these studies reveal research deficiency in current assessment methodologies that demands more attention. Research output remains predominantly concentrated in developed nations with aging populations, particularly the USA, which leads in both publication volume and quality. The primary focus of current research involves evaluating the validity of existing assessment tools, while emerging investigations explore next-generation assessment tools designed to enhance diagnostic precision and enable personalized treatment strategies. Despite these advances, widespread clinical adoption remains limited, and further validation studies are required to establish their reliability across diverse populations and disease stages.

CONCLUSION: This study highlights the growing importance of NPSs in neurodegenerative diseases, particularly in HD, ALS, and MSA. We identify hotspots and deficiencies in the research field of validating NPS assessment tools, integrating NPSs into the diagnostic framework and elucidating neurobiological mechanisms. These findings will contribute to enhanced diagnostic and therapeutic approaches for neurodegenerative diseases.},
}

@article {pmid41319477,
year = {2025},
author = {Benussi, A and Vucic, S},
title = {Emergent technologies and applications of TMS and TMS-EEG in clinical neurophysiology for early and differential diagnosis: IFCN handbook chapter.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {182},
number = {},
pages = {2111459},
doi = {10.1016/j.clinph.2025.2111459},
pmid = {41319477},
issn = {1872-8952},
abstract = {This chapter examines how emerging neurophysiological technologies are transforming the early and differential diagnosis of neurological disorders. While imaging and fluid biomarkers have greatly advanced the field, they remain limited by cost, invasiveness, and their inability to directly capture dynamic brain activity. Neurophysiological techniques, particularly transcranial magnetic stimulation (TMS) and TMS combined with EEG, offer a unique, non-invasive means of probing cortical excitability, connectivity, and plasticity with millisecond precision. Recent technological and analytical breakthroughs are moving these approaches from research laboratories into clinical practice. By detecting subtle network dysfunctions that precede structural degeneration, they open the possibility of identifying disease in its prodromal or even presymptomatic stages, when interventions may be most effective. This chapter outlines the principles of advanced TMS paradigms and TMS-EEG and explores their application across a range of conditions, including amyotrophic lateral sclerosis, dementias, and movement disorders. It also highlights how integrating neurophysiological measures with blood-based biomarkers and computational tools, such as machine learning, can enhance diagnostic accuracy and guide individualized treatment strategies. Together, these innovations establish neurophysiology as a cornerstone of precision neurology, linking mechanistic insights to clinical decision-making and enabling earlier diagnosis, improved patient stratification, and more targeted therapeutic interventions.},
}

@article {pmid41314745,
year = {2025},
author = {Fatima, S and Tiwari, S and Siddiqi, B and Quadri, SN and Abdin, MZ},
title = {Biomarkers: From early detection to treatment personalization.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {131-153},
doi = {10.1016/bs.pbr.2025.08.008},
pmid = {41314745},
issn = {1875-7855},
mesh = {Humans ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/diagnosis/therapy/metabolism ; *Precision Medicine/methods ; Early Diagnosis ; },
abstract = {Neurodegenerative disorders (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), present increasing issues associated with the unavoidable aging of the world's population. These challenges are further highlighted by the socioeconomic consequences of these diseases. The identification and use of biomarkers for prompt diagnosis, careful observation, and efficient treatment approaches is essential to overcoming these obstacles. The primary methods for diagnosing neurodegenerative illnesses are invasive procedures like lumbar punctures to measure CSF fluid or functional brain imaging methods. Biomarkers for underlying proteinopathy in blood serum and cerebral fluid have been the focus of recent biological research, particularly in vivo. With their ability to provide novel pathways for early detection, illness progression tracking, and individualized treatment plans, biomarkers have become essential instruments in precision medicine. The classification of biomarkers including fluid, digital imaging, and molecular biomarkers is examined in this chapter, with an emphasis on their function in neurodegenerative diseases. In neurodegenerative illnesses and the aging brain, tau, amyloid-β, α-synuclein, and TDP-43 are commonly seen to be deposited together rather than separately. These may be disregarded, and it might be challenging to determine their clinicopathological significance. An overview of illness pathophysiology, diagnostic implications, and the most recent molecular and ultrastructural categories for neurodegenerative disorders are given in this chapter. Addressing these issues through interdisciplinary research and technological advancements will be crucial for the future of biomarker-driven precision medicine. This chapter provides an in-depth overview of the evolving landscape of biomarkers and their transformative impact on the early detection and personalized treatment of neurodegenerative diseases.},
}

Humans
*Biomarkers/metabolism
*Neurodegenerative Diseases/diagnosis/therapy/metabolism
*Precision Medicine/methods
Early Diagnosis

@article {pmid41314744,
year = {2025},
author = {Gunasekaran, B and Arifin, AH and Yu, WH and Hanafi, S and Rao, KDK and Salvamani, S},
title = {Precision medicine in neurodegenerative diseases: From research to clinical practice.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {1-52},
doi = {10.1016/bs.pbr.2025.08.006},
pmid = {41314744},
issn = {1875-7855},
mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/therapy/genetics/diagnosis ; Biomarkers ; },
abstract = {The chapter outlines how precision medicine is reshaping the way neurodegenerative diseases (NDs) which includes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are understood, diagnosed, and treated. It discusses the limitations of current therapies, which mainly address symptoms without altering disease progression. Genetic and molecular factors that influence disease development are described, including distinctions between familial and sporadic forms. The chapter also covers the roles of epigenetic changes, gene expression, protein dysfunction, mitochondrial DNA, and non-coding RNAs in NDs. Biomarkers in blood and cerebrospinal fluid, along with imaging techniques and digital tools, are presented as key elements in early diagnosis and disease monitoring. Patient stratification based on clinical features, molecular profiles, and biomarkers helps guide treatment decisions and improve outcomes. The chapter reviews ongoing developments in genotype-based drug design, gene therapy, pharmacogenomics, and personalized lifestyle strategies. Clinical case studies show how these approaches are being used in practice. The chapter also discusses challenges in applying precision medicine, such as trial design, data integration, unequal access, and regulatory hurdles. Finally, it highlights the future tools like single-cell transcriptomics, digital twins, and global research collaborations that aim to bring precision approaches into everyday care.},
}

Humans
*Precision Medicine/methods
*Neurodegenerative Diseases/therapy/genetics/diagnosis
Biomarkers

@article {pmid41312566,
year = {2025},
author = {Kwinta, R and Morawiec, N and Bączyk, J and Kubicka-Bączyk, K and Adamczyk-Sowa, M},
title = {Aging immunity - the role of T and B cells in neurological disorders among older adults.},
journal = {Neurologia i neurochirurgia polska},
volume = {},
number = {},
pages = {},
doi = {10.5603/pjnns.106498},
pmid = {41312566},
issn = {0028-3843},
abstract = {INTRODUCTION: Immunosenescence is a natural process of immune system aging, which leads to significant changes in the functioning of both innate and adaptive immunity. Alterations in T and B lymphocytes can significantly impact the progression of neurological diseases including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

STATE OF THE ART: Immunosenescence affects T and B cell subsets, reducing their proliferative capacity and altering cytokine profiles. In MS, these changes promote disease progression and diminish responses to immunomodulatory therapies. In AD and PD, dysfunctional T and B cells contribute to sustained neuroinflammation, exacerbating neurodegeneration. ALS is similarly associated with altered adaptive immunity.

CLINICAL IMPLICATIONS: Recognizing how immunosenescent T and B cells contribute to disease in older adults is crucial for refining treatment strategies. These age-related immune changes may explain varied responses to therapies and highlight the need for novel approaches targeting the aged immune system in neurodegenerative diseases.

FUTURE DIRECTIONS: Future research should focus on identifying the mechanisms by which immunosenescent lymphocytes modulate neuroinflammation and neurodegeneration in aging populations. Novel biomarkers and immunomodulatory therapies tailored to older adults could significantly improve outcomes in patients with neurological diseases.},
}

@article {pmid41311831,
year = {2025},
author = {Guan, S and Wang, S and Shi, Y and Leng, Y and Ming, Y and Hou, Z and Yu, Y and Wang, Z and Liu, J},
title = {Comparative safety analysis of Riluzole, Edaravone and Tofersen in ALS management: insights from FAERS database.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1687698},
pmid = {41311831},
issn = {1663-9812},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. Riluzole, Edaravone, and Tofersen, three promising treatments, have distinct profiles that merit comparative analysis to guide clinical decision-making.

METHODS: This study utilizes a pharmacovigilance analysis of adverse events reported in the FDA Adverse Event Reporting System database from Q1 2004 to Q2 2024. Employing disproportionality, we assessed and compared the AE signals associated with Riluzole, Edaravone, and Tofersen to elucidate their safety profiles in ALS treatment. Finally, applying the Random Walk with Restart (RWR) algorithm to the protein-protein interaction (PPI) network for selecting drug target genes that have a strong correlation genes associated with severe adverse reactions. Finally, their interactions with the target were assessed through molecular docking and transcriptome analysis.

RESULTS: The analysis included 2106 AE reports for Riluzole, 2466 AE reports for Edaravone, and 136 for Tofersen. Highlights the higher incidence of adverse reactions associated with Riluzole, including abdominal discomfort, hypoaesthesia oral, and hepatic enzyme increased, as well as a significant correlation between Edaravone and falls, gait disturbance, and aphasia. Tofersen exhibits different adverse reactions compared to Riluzole and Edaravone, such as headaches, csf red blood cell count positive. Comparative analysis revealed that the three drugs shared a serious adverse reaction, which is thrombosis. RWR analysis identified seven targets related to thrombosis caused by the three drugs, including F10 and MMP9. Subsequently, molecular docking and transcriptome analysis indicate a favorable binding interaction between the drug candidate and the F10 molecule.

CONCLUSION: This comprehensive evaluation underscores the importance of understanding the distinct AE profiles of Riluzole, Edaravone, and Tofersen in clinical practice, providing valuable insights for personalized ALS management. Future research with rigorous prospective designs is recommended to validate these findings and explore the mechanisms underlying the reported adverse events.},
}

@article {pmid41307881,
year = {2025},
author = {Bazo Perez, M and de Carvalho, PHB and Frazier, LD},
title = {Examining the factor structure and measurement invariance of the online-administered Eating Disorder Examination-Questionnaire and the Eating Attitudes Test-26 in young and middle-aged women.},
journal = {Eating and weight disorders : EWD},
volume = {30},
number = {1},
pages = {95},
pmid = {41307881},
issn = {1590-1262},
support = {SEED Funds Award//FIU Psychology Department/ ; Dissertation Fellowship//FIU University Graduate School/ ; General Grant//Mental Research Institute/ ; },
mesh = {Humans ; Female ; *Feeding and Eating Disorders/diagnosis/psychology ; Adult ; Factor Analysis, Statistical ; Young Adult ; Psychometrics ; Middle Aged ; Surveys and Questionnaires ; Adolescent ; Reproducibility of Results ; Internet ; },
abstract = {PURPOSE: Widely used eating disorder (ED) measures, such as the Eating Disorder Examination-Questionnaire (EDE-Q) or the Eating Attitudes Test-26 (EAT-26), were originally developed and standardized in young White women, leading to poor performance, unclear factor structures, and inconsistent measurement invariance across diverse groups. As ED prevalence rises among middle-aged women, the need for age-appropriate and psychometrically sound assessment tools has become increasingly important. This study evaluated the factor structure, measurement invariance, and internal consistency of the EDE-Q and EAT-26 when administered online across two developmentally relevant age groups: emerging adults and middle-aged women.

METHOD: A sample of 829 women from across the U.S. (emerging adults: 419; middle-aged: 410) completed the EDE-Q and EAT-26 through an online survey platform. We tested the original factor structures and two alternative models for each measure through confirmatory factor analysis. Measurement invariance analyses were conducted on good-fitting models.

RESULTS: The original EDE-Q model failed to converge, while the original EAT-26 model demonstrated poor fit. The alternative factor models-Grilo et al.'s (2013) EDE-Q model, and Bazo Perez et al.'s (2023) EAT-26 model-demonstrated best fit and measurement invariance across both age groups. The EDE-Q subscales exhibited good internal consistency, while the EAT-26 showed acceptable to good internal consistency.

CONCLUSION: These findings emphasize the need for developmentally sensitive tools to improve diagnostic accuracy, early detection, and treatment of EDs across the lifespan. Because the factor structure and measurement invariance results reflect online administration, they should be interpreted within this context and motivate continued evaluation of these instruments across administration formats. Addressing a critical gap in ED research and clinical practice, this work underscores the need to refine ED assessment methods, to ensure equitable, accurate, and developmentally appropriate identification of ED risk in women beyond early adulthood.

LEVEL OF EVIDENCE: V, descriptive (cross-sectional) study.},
}

Humans
Female
*Feeding and Eating Disorders/diagnosis/psychology
Adult
Factor Analysis, Statistical
Young Adult
Psychometrics
Middle Aged
Surveys and Questionnaires
Adolescent
Reproducibility of Results
Internet

@article {pmid41300346,
year = {2025},
author = {Yeasmin, A and Torrente, MP},
title = {Histone Post-Translational Modifications and DNA Double-Strand Break Repair in Neurodegenerative Diseases: An Epigenetic Perspective.},
journal = {Biology},
volume = {14},
number = {11},
pages = {},
pmid = {41300346},
issn = {2079-7737},
support = {1R15NS125394-01/NH/NIH HHS/United States ; },
abstract = {DNA damage is a hallmark of the fatal process of neurodegeneration in the central nervous system (CNS). As neurons are terminally differentiated, they accumulate metabolic and oxidative burdens over their whole life span. Unrepaired DNA develops into DNA double-strand breaks (DSBs), which are repaired through homologous recombination (HR) or non-homologous end joining (NHEJ). Being post-mitotic and unable to normally undergo HR, damage and defective repair is especially burdensome to CNS neurons. Current research has not produced treatment to prevent and halt progression of neurodegeneration. Hence, novel targeting strategies are desperately needed. Recent investigations in histone post-translational modifications (PTMs) reveal new mechanistic insight and highlight unexplored targets to ameliorate neurodegeneration. As various histone PTMs dictate and facilitate DSB repair, they represent an underexploited area in investigating DNA damage and incorrect repair aiding neurodegeneration. Here, we review the histone PTM alterations in several neurodegenerative diseases: Amyotrophic Lateral Sclerosis/Frontotemporal Dementia, Parkinson's Disease, Alzheimer's Diseases, Multiple Sclerosis, and Huntington's Disease. These findings emphasize that histone PTM alterations can enable an aberrant DNA damage response (DDR) leading to neurodegeneration. Further research into the connections between histone PTMs and DNA damage in decaying neurons will illuminate novel targets to dampen the aberrant DDR and promote neuronal survival.},
}

@article {pmid41298223,
year = {2025},
author = {Lin, CY and Lee, BC and Zhang, PH and Lu, SC and Chang, WZ and Wang, CC and Tsai, HJ},
title = {A 16-amino acid peptide delays the progression of motor neuron degeneration and pathogenic symptoms in ALS models.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00806},
doi = {10.1016/j.neurot.2025.e00806},
pmid = {41298223},
issn = {1878-7479},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neurons (MNs) degenerative disease. Despite advancements in understanding ALS pathogenesis, drug development lags far behind. The reduced secretion of phosphoglycerate kinase 1 (Pgk1) by NogoA-overexpressing muscle cells inhibits neurite outgrowth of MNs (NOMNs). However, administration of extracellular Pgk1 (ePgk1) reduces phospho-Cofilin (p-Cofilin), a growth cone collapse marker, and mitigates MN degeneration. This improves NOMNs in NSC34 neural cells and locomotion in SOD1-G93A ALS-mice by suppressing the p-P38-T180/p-MK2-T334/p-Limk1-S323/p-Cofilin-S3 signaling pathway. Here, we identified two Pgk1-based 16-amino acid (aa) short peptides, FD-1 and FD-2, with neuroprotective effects equivalent to those of full-length ePgk1. Administration of FD-1 or FD-2 (FD-1/-2) reduced p-Cofilin and promoted NOMNs in NSC34 cells cultured in conditioned medium obtained from NogoA-overexpressing muscle cells. Furthermore, we found that exogenous addition of FD-1/-2 to the culture medium attenuated the accumulation of phospho-Tau-S396 and the cytoplasmic mislocalization of transactive response DNA binding protein of 43 kDa (TDP-43) in oxidative-stressed ALS-like SOD1-G93A NSC34 cells. In FD-1/-2-injected zebrafish embryos, we observed increased caudal primary MNs branching. In C9orf72-knockdown and hTDP-43-G348C mRNA overexpressing zebrafish embryos injected with FD-1/-2, axonal growth and motor function were rescued. Moreover, intravenous injection of FD-1/-2 in SOD1-G93A ALS-mice delayed denervation of neuromuscular junction, preserved cell bodies of MNs in the ventral horn of spinal cord, increased grip strength, improved locomotion and prolonged survival. Therefore, both 16-aa short FD peptides are functionally equivalent to full-length 417-aa ePgk1 and thus promising therapeutic short peptides for the treatment of ALS.},
}

@article {pmid41296103,
year = {2025},
author = {Ge, TQ and Ma, XY and Guan, PP and Wang, P},
title = {Aspirin Attenuates the Pathogenesis of Amyotrophic Lateral Sclerosis by Inhibiting the Activities of Microglia in a NF-κB-dependent Complement System-deactivating Mechanism.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {180},
pmid = {41296103},
issn = {1559-1182},
support = {JYTMS20230628//Liaoning Provincial Department of Education Funding/ ; D2402007//Shenzhen Medical Research Fund/ ; GDRC202404//Natural Science Foundation of Top Talent of SZTU/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/pathology/drug therapy/metabolism ; *NF-kappa B/metabolism ; *Microglia/drug effects/metabolism/pathology ; Animals ; *Aspirin/pharmacology/therapeutic use ; Mice ; *Complement System Proteins/metabolism ; Apoptosis/drug effects ; Cell Line ; Lipopolysaccharides/pharmacology ; Signal Transduction/drug effects ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which is pathologically characterized by impairing the motor neurons, leading to the disorders of motor function. Aspirin (ASP) has the ability to increase the survival time of SOD1[G93A] mice via concurrently reducing the activation of glial cells and restoring the number of neurons. Meanwhile, ASP treatment inhibited the activities of NF-κB pathway, which resulted in regulating the expression of complement system (CS), including C3, C1qb, and C4b in vivo. To reveal the inherent mechanisms, the in vitro experiments were carried out in SOD1[G93A] protein- and lipopolysaccharide (LPS)-treated BV2 cells. The results demonstrated that SOD1[G93A] protein or LPS induces the activation of NF-κB in BV2 cells, whose conditional medium induces the apoptosis of NSC34 cells. By blocking the activities of NF-κB by ASP, Bay 11-7082 or si NF-κB, the synthesis of CS molecules was suppressed, which results in alleviating the apoptosis of NSC34 cells. More importantly, Terminal complement complex (TCC) was identified to be the critical component of CS for mediating the effects of SOD1[G93A] protein or LPS on inducing the apoptosis of neurons, which was inhibited by the ASP or Bay 11-7082. On the basis of these observations, our findings novelly revealed that ASP delayed the progression of ALS via inhibiting the activities of microglia in a NF-κB-dependent CS-deactivating mechanisms.},
}

*Amyotrophic Lateral Sclerosis/pathology/drug therapy/metabolism
*NF-kappa B/metabolism
*Microglia/drug effects/metabolism/pathology
Animals
*Aspirin/pharmacology/therapeutic use
Mice
*Complement System Proteins/metabolism
Apoptosis/drug effects
Cell Line
Lipopolysaccharides/pharmacology
Signal Transduction/drug effects

@article {pmid41294911,
year = {2025},
author = {Abreu, MM and Hosseine-Farid, M and Silverman, DG},
title = {Total Reversal of ALS Confirmed by EMG Normalization, Structural Reconstitution, and Neuromuscular-Molecular Restoration Achieved Through Computerized Brain-Guided Reengineering of the 1927 Nobel Prize Fever Therapy: A Case Report.},
journal = {Diseases (Basel, Switzerland)},
volume = {13},
number = {11},
pages = {},
pmid = {41294911},
issn = {2079-9721},
abstract = {BACKGROUND: Neurological disorders are the leading cause of disability, affecting over three billion people worldwide. Amyotrophic lateral sclerosis (ALS) is among the most feared and uniformly fatal neurodegenerative diseases, with no therapy capable of restoring lost function.

METHODS: We report the first application of therapeutic fever to ALS using Computerized Brain-Guided Intelligent Thermofebrile Therapy (CBIT[2]). This fully noninvasive treatment, delivered through an FDA-approved computerized platform, digitally reengineers the 1927 Nobel Prize-recognized malarial fever therapy into a modern treatment guided by the Brain-Eyelid Thermoregulatory Tunnel. CBIT[2] induces therapeutic fever through synchronized hypothalamic feedback, activating heat shock proteins, which are known to restore proteostasis and neuronal function.

CASE PRESENTATION: A 56-year-old woman was diagnosed with progressive ALS at the Mayo Clinic, with electromyography (EMG) demonstrating fibrillation and fasciculation indicative of denervation corroborated by neurological and MRI findings; the patient was informed that she had an expected survival of three to five years. A neurologist from Northwestern University confirmed the diagnosis and thus maintained the patient on FDA-approved ALS drugs (riluzole and edaravone). Her condition rapidly worsened despite pharmacological treatment, and she underwent CBIT[2], resulting in (i) electrophysiological reversal with complete disappearance of denervation; (ii) biomarker correction, including reductions in neurofilament and homocysteine, IL-10 normalization (previously linked to mortality), and robust HSP70 induction; (iii) restoration of gait, swallowing, respiration, speech, and cognition; (iv) reconstitution of tongue structure; and (v) return to complex motor tasks, including golf, pickleball, and swimming.

DISCUSSION: This case provides the first documented evidence that ALS can be reversed through digitally reengineered fever therapy aligned with thermoregulation, which induces heat shock response and upregulates heat shock proteins, resulting in the patient no longer meeting diagnostic criteria for ALS and discontinuation of ALS-specific medications. Beyond ALS, shared protein-misfolding pathology suggests that CBIT[2] may extend to Alzheimer's, Parkinson's, and related disorders. By modernizing this Nobel Prize-recognized therapeutic principle with computerized precision, CBIT[2] establishes a framework for large-scale clinical trials. A century after fever therapy restored lost brain function and so decisively reversed dementia paralytica such that it earned the 1927 Nobel Prize in Medicine, CBIT[2] now safely harnesses the therapeutic power of fever through noninvasive, intelligent, brain-guided thermal modulation. Amid a global brain health crisis, fever-based therapies may offer a path to preserve thought, memory, movement, and independence for the more than one-third of humanity currently affected by neurological disorders.},
}

@article {pmid41294799,
year = {2025},
author = {Medigovic, G and Rachamala, HK and Dutta, SK and Pal, K},
title = {Structural and Functional Perspectives of Optineurin in Autophagy, Immune Signaling, and Cancer.},
journal = {Cells},
volume = {14},
number = {22},
pages = {},
pmid = {41294799},
issn = {2073-4409},
support = {R56 HL160545/HL/NHLBI NIH HHS/United States ; W81XWH-21-1-0678//Department of Defense Congressionally Directed Medical Research Program/ ; R56HL160545//The National Heart, Lung, and Blood Institute/ ; },
mesh = {Humans ; *Autophagy ; *Neoplasms/immunology/metabolism/pathology ; *Membrane Transport Proteins/chemistry/metabolism ; *Signal Transduction ; *Cell Cycle Proteins/chemistry/metabolism ; Animals ; *Transcription Factor TFIIIA/metabolism/chemistry/genetics ; },
abstract = {Optineurin (OPTN) is a multifunctional adaptor protein that regulates diverse cellular processes, including inflammatory signaling, autophagy, vesicular trafficking, and immune responses. This multifaceted role of OPTN is made possible by the presence of a complex structure comprising multiple domains that interact with different proteins to exert various functions important for modulating key signaling processes. Mutations in OPTN are linked with several human pathologies including glaucoma, Paget's disease of bone, Crohn's disease, and neurodegenerative diseases such as amyotrophic lateral sclerosis, and dementia. Emerging evidence suggests that OPTN has a complex and context-dependent role in cancer biology as well. It is upregulated in pancreatic ductal adenocarcinoma and hepatocellular carcinoma but downregulated in lung and colorectal cancers, indicating its dual role as a potential oncogene or tumor suppressor depending on the cellular environment. Additionally, OPTN plays a critical role in preventing immune evasion in colorectal cancer by maintaining interferon-gamma receptor 1 (IFNGR1) expression and supporting dendritic cell-mediated T-cell priming, thereby enhancing antitumor immune responses. Despite its significance in oncogenic pathways and immune regulation, the therapeutic potential of targeting OPTN in cancer remains largely unexplored. This review aims to provide a comprehensive understanding of OPTN's pleiotropic functions, highlighting its role in autophagy, inflammation, immune surveillance, and cancer progression. By elucidating its diverse regulatory mechanisms, we seek to encourage further research into the therapeutic implications of OPTN in cancer treatment and immunotherapy.},
}

Humans
*Autophagy
*Neoplasms/immunology/metabolism/pathology
*Membrane Transport Proteins/chemistry/metabolism
*Signal Transduction
*Cell Cycle Proteins/chemistry/metabolism
Animals
*Transcription Factor TFIIIA/metabolism/chemistry/genetics

@article {pmid41291238,
year = {2025},
author = {Li, H and Yu, C and Markovic, T and Nestler, EJ and Dong, Y},
title = {Chemical strategies for brain delivery of genomic therapy.},
journal = {Nature reviews. Chemistry},
volume = {9},
number = {12},
pages = {841-854},
pmid = {41291238},
issn = {2397-3358},
mesh = {Humans ; *Genetic Therapy/methods ; *Brain/metabolism ; Animals ; Nanoparticles/chemistry ; *Drug Delivery Systems/methods ; Lipids/chemistry ; Polymers/chemistry ; Oligonucleotides/chemistry ; *Gene Transfer Techniques ; },
abstract = {Genomic therapy has emerged as a transformative strategy for the prevention, diagnosis and treatment of a wide array of diseases, including Alzheimer's disease, amyotrophic lateral sclerosis and other CNS-related diseases. Recent developments in chemical strategies and delivery platforms have enhanced the potential of genomic therapies for brain disorders. In this Review, we summarize such strategies, focusing on advances in delivery platforms such as lipid nanoparticles, polymers and oligonucleotide conjugates to facilitate the brain delivery of DNA-based or RNA-based therapeutics into the CNS. We present an overview of the chemical structures and functional moieties of lipids, polymers and oligonucleotides used in these platforms. Lastly, we provide an outlook on future chemical directions to further improve the delivery of genomic medicines to the brain.},
}

Humans
*Genetic Therapy/methods
*Brain/metabolism
Animals
Nanoparticles/chemistry
*Drug Delivery Systems/methods
Lipids/chemistry
Polymers/chemistry
Oligonucleotides/chemistry
*Gene Transfer Techniques

@article {pmid41289739,
year = {2025},
author = {Dakroub, F and Awada, B and Abdelhady, S and Shaito, AA and Eid, AH and Walker, J and Mondello, S and Bondi, CO and Moro, F and Elgendy, B and Wang, KK and Zanier, ER and Mechref, Y and Kobeissy, F},
title = {Edaravone: Advances on cytoprotective effects, pharmacological properties, and mechanisms of action.},
journal = {Pharmacological reviews},
volume = {78},
number = {1},
pages = {100101},
doi = {10.1016/j.pharmr.2025.100101},
pmid = {41289739},
issn = {1521-0081},
abstract = {Neurological diseases often lead to life-altering consequences, underscoring the urgent need for therapies that can reverse or mitigate their effects. Effective management of neurological disorders necessitates a thorough understanding of the common pathological mechanisms driving their onset and progression. Mitochondrial dysfunction and oxidative stress stand out as critical contributors to neuronal damage, implicated in traumatic brain injury, stroke, and amyotrophic lateral sclerosis. Disruptions in energy metabolism lead to the accumulation of reactive oxygen species and elevate the level of neural injury. Moreover, these imbalances disrupt cellular homeostasis and activate apoptotic pathways, further exacerbating neuronal loss and ultimately worsening the clinical prognosis. In this context, edaravone (Eda), a Food and Drug Administration-approved free radical scavenger, has emerged as a compelling candidate for the treatment of neuropathologies. This review provides a comprehensive overview of Eda, detailing its chemical structure and pharmacokinetic profile, with a focus on strategies to enhance its delivery to the central nervous system by modulating blood-brain barrier permeability or employing delivery systems that facilitate central nervous system penetration. Moreover, the review examines Eda's pharmacodynamic properties, including the signaling pathways it influences. The neurotherapeutic potential of Eda is further examined through in vitro and in vivo models of neurological disease. Insights from clinical trials are discussed to bridge the gap between preclinical findings and patient outcomes. Finally, the review highlights the synergistic effects of combining Eda with other pharmacological agents or therapeutic interventions, underscoring its promise as a versatile and indispensable treatment for neurological disorders. SIGNIFICANCE STATEMENT: Edaravone, a Food and Drug Administration-approved free radical scavenger, shows broad neuroprotective potential by mitigating oxidative stress and mitochondrial dysfunction across diverse neurological disorders, including stroke, amyotrophic lateral sclerosis, and traumatic brain injury. By synthesizing preclinical and clinical evidence, this review highlights edaravone's pleiotropic therapeutic actions, identifies translational challenges, and underscores its promise as a versatile treatment strategy for neurodegenerative and acute and chronic brain conditions.},
}

@article {pmid41287286,
year = {2025},
author = {Prema, SS and Shanmugamprema, D},
title = {Empowering Parent-Focused Involvement in Early Detection and Treatment of Eating Disorders.},
journal = {European eating disorders review : the journal of the Eating Disorders Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/erv.70060},
pmid = {41287286},
issn = {1099-0968},
abstract = {OBJECTIVE: To critically appraise Sidari et al.'s pilot evaluation of the Strong Foundations programme - a 6-week pre-treatment, family-centred intervention that reconceptualises the waitlist as an active window for support, and to assess whether scalable caregiver interventions can improve clinical outcomes and treatment engagement.

METHOD: Critical synthesis of the pilot study's design, implementation, and outcomes. The programme delivered structured psychoeducation to parents alongside specialist medical oversight for adolescents during the pre-treatment period. We summarise reported process and clinical indicators, assess methodological strengths and limitations, and explore adaptations such as digital delivery, peer co-facilitation and primary care integration within stepped-care frameworks.

RESULTS: Participating parents reported increased caregiving confidence and understanding of treatment pathways. Adolescents demonstrated preliminary improvements in BMI, affective symptoms and eating-disorder psychopathology. Strengths included focus on an overlooked treatment interval and integrated medical support; limitations included small sample size, absence of a control condition, selection bias, and brief follow-up. Proposed adaptations may increase scalability while preserving family-centred elements.

CONCLUSIONS: Reframing waitlists as active therapeutic intervals via brief, caregiver-focused interventions are promising for improving early outcomes, uptake and retention. Larger, controlled trials of condensed and digitally enabled formats are needed to establish effectiveness, cost-effectiveness, implementation feasibility and generalisability.},
}

@article {pmid41285384,
year = {2025},
author = {Kılıç Çil, M and Telefon, AH and Afat Turgut, E and Kandemir Gülmez, T and Çelik, Ü},
title = {[Neutrophilen-Lymphozyten-Verhältnis, mittleres Thrombozytenvolumen und Breite der Erythrozytenverteilung als Biomarker für die Diagnose: Welches Verhältnis sollte für die Vorhersage der Diagnose].},
journal = {Klinische Padiatrie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2734-8740},
pmid = {41285384},
issn = {1439-3824},
abstract = {This study aims to evaluate the diagnostic and follow-up utility of complete blood count-derived biomarkers -neutrophil-to-lymphocyte ratio, mean platelet volume, and red cell distribution width - in pediatric tuberculosis. A total of 52 children diagnosed with tuberculosis and 55 healthy controls, followed between 2020 and 2023 at a tertiary pediatric infectious disease clinic, were retrospectively analyzed.Laboratory values were recorded at diagnosis, the second month of treatment, and at least 6 months post-treatment. Receiver operating characteristic analysis was performed to assess diagnostic performance. At diagnosis, the neutrophil-to-lymphocyte ratio and red cell distribution width levels were significantly higher in the tuberculosis group than in control group (p<0.001), while mean platelet volume showed no significant difference (p=0.096). During treatment, the neutrophil-to-lymphocyte ratio and red cell distribution width values progressively decreased. Receiver operating characteristic analysis demonstrated good diagnostic performance with optimal cut-off values of 1.7 for the neutrophil-to-lymphocyte ratio and 15.4 for the red cell distribution width. The neutrophil-to-lymphocyte ratio and red cell distribution width are accessible, cost-effective biomarkers that may support the diagnosis of tuberculosis and monitor treatment responses in children.While promising as supportive tools, the diagnostic specificity of these markers is subject to study limitations, including an age-unmatched control group. Therefore, they should be considered complementary to existing diagnostic methods, especially when microbiological confirmation is challenging in pediatric cases.},
}

@article {pmid41283860,
year = {2025},
author = {Varline, J and Enfinger, M and Kavanaugh, MS},
title = {Mental health treatment of persons with ALS & their families: implementing an intervention to support practitioners.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/21678421.2025.2593304},
pmid = {41283860},
issn = {2167-9223},
abstract = {Objective: Given the limited education available to practitioners who provide mental health care for persons with amyotrophic lateral sclerosis (ALS) and their family members, a partnership between Mental Health America, Global Neuro YCare, and the ALS Association developed a web-based education programme providing discussions addressing ALS background, lived experience, and impact of caregiving, to increase confidence in care and access to resources when serving persons living with ALS and their caregivers. Methods: A pre/post survey was utilized to assess the webinar's impact on provider confidence in their knowledge and experience of ALS, access to ALS information and resources, and the ability to refer persons with ALS to care. The percentage change from pretest to post-test, frequency of knowledge, and qualitative analyses were conducted. Results: The findings indicated a 24% increase in practitioners' confidence in working with people with ALS and their family members, a 19% increase in providing mental health care to a family member, and a 20% increase in assessing resource information about ALS. Qualitative data highlighted several categories of responses, including increases in knowledge from the workshop, the need for individuals to be treated as more than just ALS, and a continuing need for training, and additional emotional support for practitioners. Conclusion: The online training increased confidence in providing mental health care to people living with ALS and their family members, adding to this understudied area. Still, additional research is needed to increase confidence in referring people to care, accessing information, and growing knowledge about ALS.},
}

@article {pmid41283303,
year = {2025},
author = {Bartoshyk, P and O'Caoimh, R},
title = {Update on Disease-Modifying Pharmacological Treatments for Frontotemporal Dementia (FTD): A Scoping Review of Registered Trials.},
journal = {NeuroSci},
volume = {6},
number = {4},
pages = {},
pmid = {41283303},
issn = {2673-4087},
abstract = {Frontotemporal dementia (FTD) represents a cluster of adult-onset neurodegenerative diseases resulting from a combination of genetic and epigenetic factors. Currently, treatment is symptomatic and there are no licensed disease-modifying therapies available. The aim of this review was to provide an overview of ongoing or recently completed clinical studies targeting disease modification in FTD. A structured search of interventional trials of pharmacological compounds was conducted on three clinical trial registries (National Library of Medicine Clinical Trials, European Union Clinical Trials, and the Australian New Zealand Clinical Trials registries) up to September 2025. Twelve interventional trials were found. Half targeted autosomal-dominant progranulin (GRN) mutations (n = 6) and half examined therapies targeting neuroinflammatory-induced sporadic FTD (n = 6). The interim results of the early-phase (1/2) randomized controlled trials (RCTs), comprising three ongoing gene replacement studies (PROCLAIM, ASPIRE-FTD, upliFT-D) and one immune-modulating monoclonal antibody (INFRONT, now in phase 3)-all targeting the FTD-GRN mutation-show safety, tolerability, and effectiveness in restoring progranulin levels. Two recently completed phase 2 RCTs for sporadic FTD targeting neuroinflammation, the PEA-FTD and C9orf72 ALS/FTD trials, show disease-modifying potential. While interim results from six trials suggest clear mechanistic efficacy, prospective high-quality later-phase RCTs are required to ascertain long-term clinical efficacy. Since familial FTD encompasses less than half of the people with this disease, it is important to continue exploring the underlying pathophysiology, neuroimmunology, and treatment of epigenetic-induced sporadic FTD.},
}

@article {pmid41281507,
year = {2025},
author = {Lucke-Wold, B and Salam, HD and Karayi, G},
title = {Behavioral analysis of insomnia sufferers to acupuncture treatment.},
journal = {World journal of psychiatry},
volume = {15},
number = {11},
pages = {108630},
pmid = {41281507},
issn = {2220-3206},
abstract = {In this commentary, we respond to Zhao et al's recent paper which focuses on mechanisms underlying insomnia sufferers' engagement with acupuncture. Insomnia, a prevalent condition characterized by difficulty falling asleep and poor sleep quality, is associated with increased risk of cardiovascular disease, diabetes, and psychiatric illness. Acupuncture, a method involving the therapeutic placement of needles, has been widely accepted as a treatment for insomnia with minimal side effects. In fact, clinical trials suggest auricular acupuncture may improve sleep duration more than cognitive behavioral therapy. However, responses to acupuncture vary. Some patients find it extremely beneficial, while others view it as a routine treatment-or avoid it altogether due to needle phobia. Patient engagement is influenced by cultural beliefs, encouragement, motivation, prior experiences, and recommendations from peers or clinicians. Trust in the physician and testimonials from recovered patients are particularly important facilitators. Looking ahead, a holistic approach - integrating acupuncture with meditation, pranayama, yoga, and other restorative practices - may enhance treatment effectiveness and help patients achieve restorative sleep.},
}

@article {pmid41281478,
year = {2025},
author = {Kumar, S},
title = {Artificial intelligence powered radiomics model for the assessment of colorectal tumor immune microenvironment.},
journal = {World journal of gastrointestinal oncology},
volume = {17},
number = {11},
pages = {108576},
pmid = {41281478},
issn = {1948-5204},
abstract = {Zhou et al's investigation on the creation of a non-invasive deep learning (DL) method for colorectal tumor immune microenvironment evaluation using preoperative computed tomography (CT) radiomics published in the World Journal of Gastrointestinal Oncology is thorough and scientific. The study analyzed preoperative CT images of 315 confirmed colorectal cancer patients, using manual regions of interest to extract DL features. The study developed a DL model using CT images and histopathological images to predict immune-related indicators in colorectal cancer patients. Pathological (tumor-stroma ratio, tumor-infiltrating lymphocytes infiltration, immunohistochemistry, tumor immune microenvironment and immune score) parameters and radiomics (CT imaging and model construction) data were combined to generate artificial intelligence-powered models. Clinical benefit and goodness of fit of the models were assessed using receiver operating characteristic, area under curve and decision curve analysis. The developed DL-based radiomics prediction model for non-invasive evaluation of tumor markers demonstrated potential for personalized treatment planning and immunotherapy strategies in colorectal cancer patients. The study, involving a small group from a single medical center, lacks inclusion/exclusion criteria and should include clinicopathological features for valuable therapeutic practice insights in colorectal cancer patients.},
}

@article {pmid41280004,
year = {2025},
author = {Rao, PP and Herbert, C and Azeem, SM and Gary, E and Ho, G and Munira, R and Askarifirouzja, H and Haimovitz-Friedman, A and Mahajan, SS},
title = {Riluzole as a Dual-Targeted Radiosensitizer for Osteosarcoma: Targeting Tumor Cells and Angiogenic Vasculature to Enhance Single High Dose Radiotherapy Efficacy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {41280004},
issn = {2692-8205},
support = {SC1 GM131929/GM/NIGMS NIH HHS/United States ; },
abstract = {Osteosarcoma is a highly aggressive bone malignancy primarily affecting children and young adults. It presents significant treatment challenges due to its inherent resistance to conventional fractionated radiotherapy (CFRT). Single high dose radiation therapy (SDRT) has promise for the treatment of radioresistant sarcomas, especially those characterized with extensive vascularity. However, its clinical application is severely constrained by toxicity to adjacent critical tissues. Radiosensitizers can enhance tumor cell susceptibility to radiation-induced DNA damage, improving therapeutic efficacy and potentially reducing collateral toxicity. Monotherapies targeting tumor vasculature alone in solid tumors have shown limited success as radiosensitizers in clinical settings. This highlights the importance of compounds that can simultaneously target both tumor cells and its associated microvasculature to maximize the therapeutic outcome to SDRT. Riluzole, the FDA-approved drug for Amyotrophic Lateral Sclerosis, is currently under investigation as a therapeutic agent for osteosarcoma. Riluzole acts to inhibit glutamate release, reduce glutathione levels in cancer cells, and mitigate tumor angiogenesis, positioning it as a potent radiosensitizing agent for the treatment of osteosarcoma. We hypothesize that Riluzole enhances osteosarcoma radiosensitivity to SDRT by simultaneously targeting intrinsic tumor radioresistance and pro-angiogenic signaling. Our findings demonstrate that Riluzole radiosensitizes osteosarcoma cells in vitro by reducing clonogenic survival and enhancing apoptosis. Mechanistically, Riluzole potentiates irradiation-induced reactive oxygen species (ROS) production, induces G2/M phase cell cycle arrest, inhibits DNA repair, and thereby amplifies radiation-induced DNA damage. Additionally, Riluzole suppresses radiation-induced Vascular Endothelial growth factor A (VEGFA) expression indicating its ability to overcome endothelial cell mediated radioresistance. Collectively, these results establish Riluzole as a promising radiosensitizer for osteosarcoma, with the potential to improve SDRT efficacy by overcoming both tumor-intrinsic and microvasculature-mediated radioresistance.},
}

@article {pmid41278139,
year = {2025},
author = {Prodromos, CC and Del Villar, R and Jin, MY and Abd-Elsayed, A and Candido, K},
title = {Exosome-rich mesenchymal stem cell secretome improves strength in patients with amyotrophic lateral sclerosis, Kennedy disease, congenital myasthenic syndrome and Lewy body dementia.},
journal = {American journal of stem cells},
volume = {14},
number = {4},
pages = {217-229},
pmid = {41278139},
issn = {2160-4150},
abstract = {AIM: Amyotrophic lateral sclerosis (ALS), Lewy Body dementia (LBD), Kennedy disease (KD), and Congenital Myasthenic Syndrome (CMS) are progressive motor disorders for which no disease modifying treatment exists. ALS and LBD are uniformly, and often rapidly, fatal. No treatment of any kind has ever resulted in actual improvement for ALS patients; the best that has been achieved is minor slowing of their progression. Forty-one preclinical studies of intra-nasal instillation of mesenchymal stem cell exosomes have, however, demonstrated complete safety and efficacy for models of a variety of neurocognitive and motor disorders. We hypothesized that intranasal exosomes treatment in humans would be completely safe and also effective for the treatment of motor disorders such as ALS, LBD, KD and CMS.

METHODS: 18 patients with ALS, Kennedy Disease, Congenital Myasthenic Syndrome, or Lewy Body Dementia had 32 AlloEx Exosome[®] treatments to assess safety, attenuation of disease, and increase in strength and motor function. The study was conducted under the clinical trial NCT07105371 found at clinicaltrials.gov/study/NCT07105371.

RESULTS: There were no adverse events of any kind reported among these treatments. All patients, except for one, achieved some degree of clinical and strength improvement; the longest improvement was recorded at the 6-month follow-up.

CONCLUSION: Intranasally-instilled AlloEx Exosomes[®] are completely safe, attenuate progression, and improve strength in ALS, Kennedy Disease, CMS, and LBD.},
}

@article {pmid41272780,
year = {2025},
author = {Kumar, A and Shukla, S and Rai, A and Pathak, P and Narayan, KP},
title = {Concurrent nanotherapeutics and regulatory updates for the management of amyotrophic lateral sclerosis: a focused review for orphan drug (Tofersen).},
journal = {Orphanet journal of rare diseases},
volume = {20},
number = {1},
pages = {598},
pmid = {41272780},
issn = {1750-1172},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; Genetic Therapy/methods ; Orphan Drug Production ; *Oligonucleotides/therapeutic use ; United States Food and Drug Administration ; },
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting nerve cells in the brain and spinal cord. With a global incidence of 1.9 to 6 per 100,000 people, ALS is slightly more common in men and prevalent in individuals over 60. However, this review provides a concise update on the regulatory landscape and therapeutic advancements in managing ALS, focusing on the recent approval of Tofersen, the first gene therapy specifically targeting SOD1 mutation-related ALS.

RESULTS: It highlights Tofersen unique role as an orphan drug approved by the US FDA, emphasizing its mechanism of action, gene silencing and its impact on reducing neurodegeneration. Additionally, the review synthesizes data from ongoing clinical trials, pharmacovigilance reports, and case studies to comprehensively understand Tofersen's safety, efficacy and market exclusivity. Beyond this, it explores the emerging potential of nanotherapeutic approaches to ALS treatment, identifying critical research gaps and future directions.

CONCLUSION: Integrating regulatory updates, clinical evidence, and innovative therapeutic strategies, the review uniquely contributes to the ALS literature by bridging current treatment realities with potential future therapies, aiming to inform researchers, clinicians, and policymakers on optimizing ALS management.},
}

*Amyotrophic Lateral Sclerosis/drug therapy
Humans
Genetic Therapy/methods
Orphan Drug Production
*Oligonucleotides/therapeutic use
United States Food and Drug Administration

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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