@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 = {},
doi = {10.1101/2025.10.07.681036},
pmid = {41280004},
issn = {2692-8205},
abstract = {UNLABELLED: 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.

GRAPHICAL ABSTRACT: This schematic illustrates the proposed mechanism by which Riluzole enhances SDRT efficacy in osteosarcoma by targeting both tumor cells and VEGFA-mediated pro-survival signaling in endothelial cells. Riluzole increases radiation-induced ROS levels, induces G2/M cell cycle arrest, and inhibits DNA repair in osteosarcoma cells, thereby overcoming intrinsic tumor radioresistance. It also suppresses tumor cell VEGFA expression, which may contribute to reduced pro-survival signaling in the angiogenic endothelial cells within the tumor microenvironment. Together, these effects sensitize osteosarcoma tumors to SDRT, improving therapeutic outcomes (Illustration created using BioRender (BioRender.com, 2025)).},
}

@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 {pmid40721287,
year = {2025},
author = {Vyas, J and Johns, JR and Trivedi, A and Ali, FM and Ingram, JR and Salek, S and Finlay, AY},
title = {Systematic review of the use of the Dermatology Life Quality Index in routine clinical practice: evidence from 287 articles across 56 countries.},
journal = {Clinical and experimental dermatology},
volume = {50},
number = {12},
pages = {2456-2465},
doi = {10.1093/ced/llaf343},
pmid = {40721287},
issn = {1365-2230},
mesh = {Humans ; *Quality of Life ; *Skin Diseases/psychology ; *Dermatology ; },
abstract = {BACKGROUND: Although quality of life instruments are widely used in research, it is challenging to find evidence of their use in routine clinical use. The most widely used measure for skin disease burden is the Dermatology Life Quality Index (DLQI), and its scores have validated clinical meaning.

OBJECTIVES: To identify evidence of the use of the DLQI in routine clinical practice and explore the nature of its use.

METHODS: The study followed PRISMA guidelines, and the protocol was registered with PROSPERO. MEDLINE (Ovid), Embase, Scopus and CINAHL (EBSCO) databases were systematically searched for articles describing studies using the DLQI in routine clinical practice. Studies were excluded if participants were aged < 16 years and if there were predetermined treatment interventions, as in a clinical trial. Information was extracted on publications' authors' opinions on the use of the DLQI in their routine practice.

RESULTS: In total, 2178 publications were screened and 287 articles met the inclusion criteria, reporting on 112 diseases and describing 66 434 patients from 56 countries, using the DLQI in at least 29 languages. Of the studies, 121 (42.2%) were reported as retrospective and 63 (22.0%) as observational. Fifty-two (18.1%) stated DLQI data were retrieved from patient records, 29 (10.1%) as 'real life', 39 (13.6%) reported 'real-world data' and 47 (16.4%) used consecutive patient recruitment. In total, 264 (92.0%) studies were conducted in a single country; 96 (33.4%) were multicentred studies, whereas 171 (59.6%) were conducted at a single site. There were 93 (32.4%) that were conducted in hospitals, 66 (23.0%) specified outpatient clinics, 38 (13.2%) tertiary care, 33 (11.5%) clinics, 4 (1.4%) in the community, 18 (6.3%) in other settings and 35 (12.2%) were unspecified. The most common diseases in the study settings were psoriasis (106 studies, 36.9%), atopic dermatitis (32, 11.1%), urticaria (24, 8.4%), hidradenitis suppurativa (22, 7.7%) and vitiligo (17, 5.9%). Thirty studies (10.5%) used Hongbo et al.'s (J Invest Dermatol 2005; 125:659-64) DLQI score banding.

CONCLUSIONS: The DLQI was widely used in routine care locations internationally, informing clinical decisions and monitoring of treatment. The DLQI was embedded into some clinics' continuing routine practice.},
}

Humans
*Quality of Life
*Skin Diseases/psychology
*Dermatology

@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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

@article {pmid41228180,
year = {2025},
author = {Taubert, S and Collins, A and Henderson, R and McCombe, P and Tang, L and Kramer, K and Wishart, L and Burns, C},
title = {Co-Design and Non-Randomised Pilot Evaluation of Resources Developed to Optimise Saliva Management in People with Motor Neurone Disease.},
journal = {Healthcare (Basel, Switzerland)},
volume = {13},
number = {21},
pages = {},
pmid = {41228180},
issn = {2227-9032},
support = {EOGR-2022-01//Royal Brisbane and Women's Hospital Foundation/ ; },
abstract = {Background/Objectives: People living with MND (plwMND) commonly develop difficulty swallowing and subsequent difficulty clearing saliva from the airway. Medical saliva interventions include pharmacological agents, botulinum toxin injections, and radiation to salivary glands, with associated side effects. Non-invasive behavioural strategies and natural remedies are also recommended. Saliva symptom management is guided by the multidisciplinary MND team (typically through a three-monthly clinic) alongside community clinicians. Some plwMND report difficulty recalling and implementing treatments between clinics. This study aimed to enhance the content and method of providing recommendations for self-management of saliva symptoms by (i) developing MND-specific resources and (ii) evaluating resource use and preliminary clinical benefit. Methods: In Phase 1 plwMND, caregivers, and clinicians co-designed saliva management resources. Phase 2 examined the use of these resources via a hospital-based MND clinic with 28 plwMND, their caregivers, and community clinicians. In the clinic, plwMND were given a written treatment plan and relevant resources. During reviews at weeks 2, 6, and 12 saliva treatment was adjusted and clinical outcomes evaluated using the Clinical Saliva Scale for MND (CSS-MND). Community clinicians, plwMND, and caregivers were surveyed regarding the resource utility. Results: People living with MND reported the resources assisted saliva symptom self-management. Community clinicians found the resources informative and beneficial in supporting patient care. All plwMND required multiple treatment strategies and adjustments to manage symptoms. Of the treatments prescribed, 91% were non-invasive and 9% were medical interventions. For 54% (n = 15) of plwMND, improved CSS-MND scores were sustained over the three-month evaluation. Conclusions: Co-designed saliva resources and regular reviews assisted plwMND to implement their individualised saliva treatment, to self-manage saliva symptoms between clinics.},
}

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

@article {pmid41224202,
year = {2025},
author = {Metelmann, M and Heyne, S and Peuker, M and Claßen, J and Mehnert-Theuerkauf, A and Esser, P},
title = {[Experiences with the Application of Short-Term Psychotherapy in Patients with Amyotrophic Lateral Sclerosis: What Can We Learn from It?].},
journal = {Psychotherapie, Psychosomatik, medizinische Psychologie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2711-2085},
pmid = {41224202},
issn = {1439-1058},
abstract = {Amyotrophic lateral sclerosis (ALS) is associated with elevated distress, but evidence on psychosocial interventions is limited. We tested the feasibility of a psychotherapy for palliative cancer patients in ALS patients.We applied CALM (Managing Cancer and Living Meaningfully), an effective psychodynamic short-term therapy for advanced cancer patients, within a pre-post study among patients with ALS. We provided patient flow and formal treatment information. Based on the treatment protocols, the therapist reflected on the applicability of the treatment structure, specifics in the psychosocial work with ALS patients and suggestions for treatment modification.Among 15 eligible patients, five participated. Three patients completed the treatment, two patients provided complete study data. The trial was prematurely stopped due to issues in feasibility. Six (22%) sessions were conducted via telephone, 10 (37%) were attended by family caregivers. The structure showed limited applicability largely because fear-laden topics including suffering and death were extensively avoided. Compared to palliative cancer patients, ALS patients fluctuated more strongly in their psychological and physical symptom burden and were more strongly distressed by disease-related practical issues. Recommendations included a multi-professional team, booster sessions and a direct support for caregivers.A psychotherapy effective for cancer patients showed features that limit its applicability among ALS patients. Some of these limitations are treatment-inherent and thus hard to adapt. Rather than modifying the program, we suggest to develop a specific supportive psychotherapeutic intervention within a participatory approach.},
}

@article {pmid41222589,
year = {2025},
author = {Heyming, T and Knudsen-Robbins, C and Kain, A and Morphew, T and Ta-Perez, Z and Darabpour, A and Lee, H and Brukman, S and Shelton, SK},
title = {Prehospital PAT - Real World Data; EMS Use of the Pediatric Assessment Triangle in the Prehospital Environment.},
journal = {Prehospital emergency care},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/10903127.2025.2581753},
pmid = {41222589},
issn = {1545-0066},
abstract = {OBJECTIVES: Emergency medical services (EMS) clinicians report lack of training and experience with children, leading to discomfort and uncertainty regarding assessment and treatment. The Pediatric Assessment Triangle (PAT) was designed to provide a rapid and standardized approach. Despite widespread adoption, literature examining EMS implementation of PAT remains limited. We examined EMS use of PAT and assessment of clinical stability, and the association between EMS use of PAT and prehospital interventions, EMS transport decisions (ALS versus BLS), emergency department (ED) interventions, and ED disposition.

METHODS: This was a retrospective cohort study of pediatric patients 0 to <15 years transported to a quaternary care pediatric ED via EMS between October 2022 and November 2023. Data were abstracted from EMS and ED electronic health records (EHRs) including PAT evaluation, demographics, EMS and ED interventions, and ED disposition. Data were analyzed using counts and percentages, logistic regression, chi-square and McNemar's test.

RESULTS: A total of 2,929 patients were included. Most patients, 65.9%, had a PAT score of 0; for those with non-zero PATs, abnormalities in the appearance domain were most prevalent, 50.7%. A PAT score of 1 or higher was associated with transport via Advanced Life Support (OR 67.9; 95% CI 32.0, 144.1) compared to a PAT of 0. Most patients, 62.2%, received an EMS intervention; the most common was diagnostics (blood glucose or EKG). The EMS administered medications to 22% of patients. Pediatric Assessment Triangle scores of ≥2 were associated with double the odds of admission to the floor (OR 2.09; 95% CI 1.4, 3.0) and quadruple the odds of admission to ICU level of care/direct to surgery/expired (OR 4.9; 95% CI 2.9, 8.3); PATs abnormal for work of breathing only were associated with increased odds of admission to the floor (OR 2.5; 95% CI 1.8, 3.6).

CONCLUSIONS: This study suggests that EMS PAT assessment in the field appropriately reflects patient stability and may be associated with EMS intervention en-route. The EMS PAT scores demonstrate promise as an adjunct to ED assessment, alerting clinicians to increased likelihood of admission. The PAT has potential to serve as a practical mechanism for EMS feedback and quality improvement studies.},
}

@article {pmid41213077,
year = {2025},
author = {Cai, S and Liu, Y and Liu, B and Liao, H and Li, K},
title = {Hexokinase as a Central Hub in Neurodegeneration: From Metabolic Dysfunction to Therapeutic Innovation.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.0891},
pmid = {41213077},
issn = {2152-5250},
abstract = {Neurodegenerative diseases represent an escalating global health crisis affecting more than 55 million people worldwide; however, underlying mechanisms remain unclear, and therapeutic breakthroughs are elusive. Emerging evidence indicates that hexokinase (HK), the rate-limiting glycolytic enzyme, functions as a master regulator orchestrating neuronal survival through metabolic‒mitochondrial coupling. This review consolidates emerging paradigms revealing that HK maintains neuronal viability through its obligate interaction with mitochondrial VDAC1, forming a metabolic checkpoint that integrates energy status with survival signaling. Disease-specific HK dysfunction patterns precede clinical manifestations and drive pathological cascades across primary neurodegenerative conditions. Pathological proteins characteristic of neurodegeneration-amyloid-β in AD, α-synuclein in PD, mutant SOD1 in ALS, and huntingtin in HD-converge to disrupt the HK-VDAC1 axis through distinct molecular mechanisms, triggering mitochondrial permeabilization, bioenergetic collapse, and inflammatory activation. This uncoupling event promotes VDAC1 oligomerization, enabling the cytosolic release of mtDNA, which in turn activates the NLRP3 inflammasome while depleting antioxidant capacity, establishing self-perpetuating neuroinflammatory cycles. The literature reveals that HK functions as a molecular rheostat, determining neuronal fate through glucose-6-phosphate-mediated feedback control, modulation of growth factor signaling, and regulation of apoptosis/survival pathways. Therapeutic targeting of HK through peptide interventions, enzymatic modulation, and gene therapy demonstrates robust neuroprotective effects across multiple disease models. Meanwhile, combination strategies addressing metabolic-inflammatory networks show synergistic efficacy. These insights position HK as a convergent therapeutic nexus offering unprecedented opportunities for precision intervention in neurodegeneration, with potential for early diagnostic applications and preventive strategies that could transform treatment paradigms for conditions affecting millions worldwide.},
}

@article {pmid41210444,
year = {2025},
author = {Khan, S and Wennberg, B and Hooda, F and Witkowska, M},
title = {Delayed treatment and diagnostic challenges in differentiating multifocal acquired demyelinating sensory and motor neuropathy from lupus: a case report and literature review.},
journal = {AME case reports},
volume = {9},
number = {},
pages = {111},
pmid = {41210444},
issn = {2523-1995},
abstract = {BACKGROUND: Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) is a rare autoimmune-mediated inflammatory response with negative antibodies which causes demyelination of multiple peripheral nerves in an asymmetric distribution with both motor and sensory deficits. Diagnosis for MADSAM can be clinically challenging, relies on a combination of clinical and electrodiagnostic studies, and symptoms can overlap with other neurological conditions such as systemic lupus erythematosus (SLE). MADSAM is typically asymmetric, demyelinating, and limited to peripheral nerves, whereas SLE is systemic, more commonly axonal, and has vasculitic features. SLE is treated with steroids and immunosuppressants while MADSAM is treated with intravenous immunoglobulin (IVIG), steroids, or plasmapheresis. There is a good short-term prognosis for MADSAM with early treatment, but prognosis can worsen with delayed or inappropriate therapy.

CASE DESCRIPTION: We describe a case of a woman in her 50s who presented with progressive generalized weakness, weight loss, muscle atrophy, and numbness. She was initially diagnosed with SLE, but deteriorated despite treatment. A broad differential was considered which included SLE, paraneoplastic syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Guillain-Barré syndrome. Serological studies, neuroimaging studies, nerve conduction studies, and electromyography (EMG) were performed. She was ultimately diagnosed with Lewis-Sumner syndrome, or MADSAM, a variant of CIDP.

CONCLUSIONS: The case highlights the importance of understanding the various causes of weakness and neuropathy, particularly with an atypical presentation, to pursue the correct diagnostic tests and treatment. The case particularly focuses on the difference between MADSAM and SLE. There is significant clinical overlap between the two, and a misdiagnosis can delay effective treatment and worsen outcomes by allowing progression to more debilitating stages of the illness.},
}

@article {pmid41209384,
year = {2025},
author = {Han, K and Yan, SG and Liu, F and Li, L and Zhou, D and Li, L and Liu, N and Dong, J},
title = {The Alterations in the Osteoimmune Microenvironment of STZ-Induced Type 2 Diabetic Mice:A Single-Cell RNA Sequencing Analysis.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {15309-15327},
pmid = {41209384},
issn = {1178-7031},
abstract = {BACKGROUND: This study aimed to delineate the single-cell transcriptome of bone marrow (BM) cells from wild-type (WT) and type 2 diabetic (T2D) mice, revealing distinct immune microenvironment features.

METHODS: Single high-throughput single-cell RNA sequencing dataset (GSE212726) from BM cells of WT and streptozotocin (STZ)-induced T2DM mice were analyzed. Uniform manifold approximation and projection (UMAP), pseudo-time analysis, gene enrichment studies, and CellphoneDB were employed to identify immune cell interactions within the osteoimmune microenvironment. Key gene expression was validated by quantitative real-time polymerase chain reaction (qRT-PCR).

RESULTS: After filtering low-quality cells and doublets, 9,360 cells (WT) and 10,885 cells (T2DM) were retained and classified into 12 clusters. Proportional analysis revealed a significant decrease in BM-neutrophils (66.56% → 54.73%) and an increase in B cells (9.16% → 19.78%) in the DM group. The DM/WT ratio for BM-neutrophils/T cells, BM-neutrophils/DCs, and monocytes/T cells increased, while the ratio for BM-neutrophils/Naïve_B decreased. KEGG pathway analysis highlighted enrichment of neurodegeneration, protein processing in the endoplasmic reticulum, and amyotrophic lateral sclerosis pathways in BM-neutrophils. Intercellular communication analysis indicated reduced incoming and outgoing interaction strength for B cells and T cells, while the T2D group showed enhanced THBS, VISFATIN, CLEC, IL4, and IL6 signaling. Notably, CLEC was specific to outgoing signaling in T cells, and THBS was specific to both outgoing and incoming signaling in monocytes, MSCs, and BM-neutrophils.

CONCLUSION: Single-cell RNA sequencing provides a comprehensive profile of bone marrow immune cells in T2D mice and has highlighted their heterogeneity, population shifts, and intercellular interactions. These findings highlight critical alterations in immune cell functions that may contribute to T2D progression and suggest possible avenues for future therapeutic investigation. Future research should continue to leverage scRNA-seq technology to refine treatment strategies and enhance patient outcomes by addressing immune dysfunction and chronic inflammation.},
}

@article {pmid41206134,
year = {2025},
author = {Allel, K and Palmer, T and Abou Jaoude, GJ and Korotych, O and Yedilbayev, A and Vilc, V and Corloteanu, A and Macari, M and Evghenia, C and Laticevschi, D and Shakhimurat-Shaimovich, I and Anar-Saduakasovna, R and Gulzhan-Elbrusovna, T and Anatolievna-Ryazanet, D and Shahrizada-Yergalymovna, A and Yatskevich, N and Skrahina, A and Zhurkin, D and Avaliani, Z and Kiria, N and Lomtadze, N and Kiria, N and Avaliani, T and Khonelidze, I and Danelia, M and Maxim, C and Haghparast-Bidgoli, H and Skordis, J},
title = {Cost-effectiveness of modified fully oral 9-month treatment regimens for rifampicin-resistant tuberculosis in Belarus, Georgia, Kazakhstan and the Republic of Moldova.},
journal = {BMJ global health},
volume = {10},
number = {11},
pages = {},
pmid = {41206134},
issn = {2059-7908},
mesh = {Humans ; Cost-Benefit Analysis ; *Tuberculosis, Multidrug-Resistant/drug therapy/economics ; Moldova ; Kazakhstan ; Quality-Adjusted Life Years ; Male ; *Rifampin/therapeutic use/administration & dosage ; Republic of Belarus ; Female ; Adult ; *Antitubercular Agents/economics/administration & dosage/therapeutic use ; Administration, Oral ; Georgia (Republic) ; Middle Aged ; },
abstract = {INTRODUCTION: Prior to 2020, treatment options for multidrug-resistant tuberculosis (MDR-TB) were limited and typically involved long treatment durations and high financial burdens. In the eastern European and central Asian (EECA) region, traditional inpatient tuberculosis (TB) care models, alongside high MDR-TB rates, escalate nosocomial transmission risks and treatment costs. Modified, fully oral, shorter treatment regimens (mSTR) implemented in the WHO European Region under operational research conditions offered a potential reduction in the burden of MDR-TB treatment for both patients and health systems.

METHODS: We conducted the first regional evaluation of the cost-effectiveness of the novel mSTR treatment regimen compared with the standard of care (SOC) in Belarus, Georgia, Kazakhstan and Republic of Moldova. We used cohort data on mSTR efficacy and WHO data on SOC in patients with MDR-TB. We used a Markov model, with treatment costs calculated from the provider perspective. Outcomes were measured in quality-adjusted life years (QALYs), with incremental cost-effectiveness ratios (ICER) calculated per QALY gained in each country. An annual 3% discount rate was used for both costs and outcomes. We performed univariate and probabilistic sensitivity analysis (PSA) to assess the robustness of our cost-effectiveness calculations under varying assumptions. Finally, we estimated potential cost savings if mSTR was implemented nationally and we evaluated the incremental net monetary benefit (iNMB) and willingness-to-pay (WTP) thresholds based on Wood et al's country-level cost-effectiveness thresholds. All costs were reported in 2022 USD.

RESULTS: We estimated that mSTR can reduce TB treatment costs by between 23% and 47% and drug costs by 39% to 74%, compared with SOC in the countries studied. mSTR resulted in cost savings of between $3596 and $8174 per patient and offered additional health gains of between 0.56 to 2.69 QALYs per patient. mSTR remained cost-effective (iNMB>0) compared with SOC in 78%, 85%, 91% and 92% of PSA simulations in Belarus, Georgia, Kazakhstan and Republic of Moldova, respectively, when compared with their country-level WTP threshold. Implementing mSTR in up to 80% of MDR/rifampicin-resistant TB patients may result in cost savings of $20.5, 2.5, 0.7 and 0.2 million in Kazakhstan, Belarus, Republic of Moldova and Georgia; equivalent to 17%, 3%, 4% and 1% of their national TB budgets, respectively.

CONCLUSIONS: Compared with SOC, mSTR is a more cost-effective treatment option for MDR/RR-TB, which should be considered by policymakers in the EECA region. Using insights from current implementations to scale up, plan operational changes and reallocate savings from mSTR could greatly enhance TB services and patient care.},
}

Humans
Cost-Benefit Analysis
*Tuberculosis, Multidrug-Resistant/drug therapy/economics
Moldova
Kazakhstan
Quality-Adjusted Life Years
Male
*Rifampin/therapeutic use/administration & dosage
Republic of Belarus
Female
Adult
*Antitubercular Agents/economics/administration & dosage/therapeutic use
Administration, Oral
Georgia (Republic)
Middle Aged

@article {pmid41203507,
year = {2025},
author = {Zhang, YP and Kedia, S and Klenerman, D},
title = {Rethinking neurodegeneration through a co-proteinopathy lens.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2025.10.006},
pmid = {41203507},
issn = {1878-108X},
abstract = {Neurodegenerative diseases have long been considered distinct proteinopathies: amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, and TDP-43 in amyotrophic lateral sclerosis. This single-protein paradigm has guided therapeutic development for decades; yet clinical outcomes remain modest. Mounting evidence, however, reveals that protein aggregates rarely occur in isolation; instead, they coexist, colocalise, and modulate each other's pathogenicity. Here, we propose a co-proteinopathy framework that views neurodegeneration as an interactive network of misfolded proteins rather than as isolated disorders. Adopting this framework demands multiplexed quantification of protein aggregates and disease models that better reflect the biological complexity of human neurodegeneration. The co-proteinopathy perspective offers a more realistic foundation for next-generation approaches to neurodegeneration research and treatment.},
}

@article {pmid41202295,
year = {2025},
author = {Sales de Campos, P and Smith-Hublou, M and Olsen, WL and Souza Leite, W and Wymer, JP and Napoli, NJ and Vose, AK and Pulley, MT and Mitchell, GS and Smith, BK},
title = {Acute Adenosine Receptor Antagonism in Combination With Acute Intermittent Hypoxia to Promote Breathing Plasticity in Amyotrophic Lateral Sclerosis: Protocol for a Randomized, Double-Blinded, Placebo-Controlled Trial.},
journal = {JMIR research protocols},
volume = {14},
number = {},
pages = {e76105},
doi = {10.2196/76105},
pmid = {41202295},
issn = {1929-0748},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/drug therapy/therapy ; Double-Blind Method ; *Hypoxia/physiopathology ; Purines/therapeutic use/pharmacology ; *Respiration/drug effects ; *Neuronal Plasticity/drug effects ; *Purinergic P1 Receptor Antagonists/therapeutic use ; Randomized Controlled Trials as Topic ; Male ; Adult ; Middle Aged ; Female ; },
abstract = {BACKGROUND: Respiratory impairment is a major concern in amyotrophic lateral sclerosis (ALS), shortening survival and lowering quality of life. One therapy with promise to delay respiratory decline in ALS is acute intermittent hypoxia (AIH), consisting of alternating periods of breathing mildly hypoxic (9%-12% O2) and normoxic (21% O2) gas. AIH stimulates spinal, serotonin-dependent neuroplasticity in rodent models, conferring functional benefits in diverse physiological systems without detectable pathology. However, in rodent models, AIH-induced neuroplasticity is constrained by distinct signaling cascades initiated by spinal adenosine.

OBJECTIVE: We propose to investigate a therapeutic strategy to delay breathing compromise in those living with ALS by combining a selective adenosine 2A (A2A) receptor inhibitor (istradefylline) with AIH. The fundamental hypothesis guiding this proposal is that a single AIH trial after pretreatment with istradefylline enhances respiratory neuroplasticity versus AIH or sham intervention.

METHODS: We propose to evaluate resting breathing, respiratory strength, and participant-reported symptoms in adults living with ALS after combined istradefylline plus AIH. A mixed within- and between-participant study design incorporates 4 test sessions, separated by approximately 2 weeks (±5 days). Testing conditions include single sessions of AIH + istradefylline, AIH + placebo, sham AIH (ie, normoxia) + placebo, and sham AIH + istradefylline. Safety and feasibility will be characterized using the rate of adverse events, changes in vital signs, and participant-reported breathing sensations (Aim 1). Neuroplasticity of breathing and motor function will be evaluated as changes in resting breathing, voluntary respiratory strength, respiratory control, and maximal pinch force (Aim 2).

RESULTS: As of January 2025, with a target sample of 16 participants in each group, 10 participants with ALS and 5 control participants completed study procedures. Recruiting is ongoing, and the final participant will complete the study by December 2025. Publication of results is expected by the end of 2026.

CONCLUSIONS: These aims will provide crucial data regarding the preliminary safety and feasibility of this paired intervention and help optimize therapeutic AIH as a rehabilitation strategy, thereby guiding further research concerning this novel treatment for ALS.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05377424; https://clinicaltrials.gov/study/NCT05377424.

DERR1-10.2196/76105.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/drug therapy/therapy
Double-Blind Method
*Hypoxia/physiopathology
Purines/therapeutic use/pharmacology
*Respiration/drug effects
*Neuronal Plasticity/drug effects
*Purinergic P1 Receptor Antagonists/therapeutic use
Randomized Controlled Trials as Topic
Male
Adult
Middle Aged
Female

@article {pmid41202020,
year = {2025},
author = {Senior, E and Clarke, A and Wilson-Menzfeld, G},
title = {Living with a loved one's mental health issue: Recognizing the Lived Experiences of Military Spouses.},
journal = {PloS one},
volume = {20},
number = {11},
pages = {e0336295},
pmid = {41202020},
issn = {1932-6203},
mesh = {Humans ; *Spouses/psychology ; Female ; Male ; *Military Personnel/psychology ; *Mental Health ; Adult ; Middle Aged ; Qualitative Research ; *Mental Disorders/psychology ; },
abstract = {Limited evidence surrounds the lived experiences of military spouses whose partner has mental health issues. This lack of evidence may be due to factors such as global austerity, underfunding of armed forces, and inadequate healthcare systems. As a result, family members-especially spouses-often end up being the primary caregivers for their military partners with mental health issues. The study used a qualitative, biographical methodology, collecting data through life stories. Two face-to-face semi-structured interviews took place with nine military spouse recruited through military spouse networks and snowballing. Lieblich et al.'s (1998) framework provided analytical pluralism, which allowed for both narrative and thematic analysis. Stories are presented in the stages 'in the beginning', changing times' and 'this is me'. Thematic analysis identified six overarching categories; Living with disruption, living in the midst of it all, It isn't enough, seeking support, Diagnosis and treatment, Living alongside. Whilst the first of its kind in the UK, this biographical study advances both national and global understanding of military spouse experiences in the context of mental health. Both the stories and the categories indicate that living with a serving partner who has mental health issues is a complex journey marked by both struggle and growth. A uniqueness arising from this study highlights the period leading up to a mental health diagnosis, emphasising the prolonged emotional and psychological strain experienced by military spouses before any formal recognition of mental illness in their serving partner. The study adds a new dimension to understanding the emotional toll on military spouses and underscores the importance of early recognition and support. While participants faced emotional detachment and feelings of invisibility, they also identified gains in resilience and strengthened relationships. Through the convergence of the narrative and thematic analysis the participants experience throughout their partners mental health issue is conceptualised in a Relationship Trajectory model. It illustrates the positive, early relational strength, superseded by relationship decline followed with relationship reinvention.},
}

Humans
*Spouses/psychology
Female
Male
*Military Personnel/psychology
*Mental Health
Adult
Middle Aged
Qualitative Research
*Mental Disorders/psychology

@article {pmid41196032,
year = {2025},
author = {Mansoor, N and Heiman-Patterson, T and Feldman, EL and Wicks, P and Benatar, M and Vieira, F and Glass, J and Levine, T and Bertorini, T and Barkhaus, P and Mascias Cadavid, J and Jackson, C and Jhooty, S and Brown, A and Pattee, G and Sane, H and Mcdermott, CJ and Carter, G and Beauchamp, M and Wang, O and Ratner, D and Bedlack, R and Li, X},
title = {ALSUntangled #81: Pyridostigmine (mestinon[®]).},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/21678421.2025.2582830},
pmid = {41196032},
issn = {2167-9223},
abstract = {Pyridostigmine (Mestinon[®], Bausch Health, Canada Inc.) increases acetylcholine availability at the neuromuscular junction, enhancing transmission. Preclinical studies suggest that neuromuscular junction dysfunction develops early in ALS, and pyridostigmine may temporarily improve neuromuscular transmission. However, altered neuromuscular junction transmission has uncertain benefits in ALS progression. Pyridostigmine does not have other plausible mechanisms that truly modify ALS pathophysiology. People with ALS (PALS) who have positive acetylcholine receptor autoantibodies and no myasthenia symptoms are unlikely to respond to pyridostigmine treatment. Clinical trials on pyridostigmine in PALS are lacking, but two clinical trials of other similar anticholinesterase agents did not effectively slow ALS progression. Muscarinic cholinergic side effects, including gastrointestinal symptoms, are common. Given the lack of mechanistic plausibility and efficacy, we do not support the use of pyridostigmine for slowing ALS progression.},
}

@article {pmid41191158,
year = {2025},
author = {Pal, B and Panda, S and Bashir, B and Vishwas, S and Chaitanya, M and Hussain, MS and Gupta, G and Kumbhar, P and Gupta, S and Singh, SK},
title = {Nanomedicine-enabled neuroprotection: therapeutic role of berberine in neurodegenerative diseases.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {49},
pmid = {41191158},
issn = {1573-4978},
mesh = {Humans ; *Berberine/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nanomedicine/methods ; Animals ; *Neuroprotection/drug effects ; Nanoparticles/chemistry ; Oxidative Stress/drug effects ; Blood-Brain Barrier/metabolism/drug effects ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's, Amyotrophic lateral sclerosis, Huntington's, and Parkinson's, present an increasingly widespread health burden globally with limited curative or treatment modalities, mostly having symptomatic attenuation. Berberine (BBR) is an isoquinoline alkaloid that occurs naturally and has been proposed as a potential neuroprotectant, since it has been found to exert multiple effects to modulate most of the pathological hallmarks of NDs, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and protein aggregation. Although it shows promise, the practical utilization of BBR is marred by low oral bioavailability, high rate of oxidation, and low blood-brain barrier permeability. To combat these issues, recent developments in nanotechnology, especially in the use and creation of lipidic, inorganic, and polymeric nano-particles, have dramatically altered the pharmacokinetics and pharmacodynamics of BBR. This article summarizes recent advances in BBR-based nanoformulations and emphasizes the translational potential of BBR-based nanopreparations to improve treatment response in NDs. It also describes the molecular foundation of the neuroprotective effects of BBR and its possible place in clinical practice. Future nanocarrier development and investigation of BBR mechanisms will be essential to the development of the next generations of therapeutics in NDs.},
}

Humans
*Berberine/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
*Nanomedicine/methods
Animals
*Neuroprotection/drug effects
Nanoparticles/chemistry
Oxidative Stress/drug effects
Blood-Brain Barrier/metabolism/drug effects

@article {pmid41189652,
year = {2025},
author = {Guo, H and Yang, Z and Zhang, G and Lv, L and Zhao, X},
title = {Meta analysis of the diagnostic efficacy of transformer-based multimodal fusion deep learning models in early Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1641548},
pmid = {41189652},
issn = {1664-2295},
abstract = {INTRODUCTION: This study aims to systematically evaluate the diagnostic efficacy of Transformer-based multimodal fusion deep learning models in early Alzheimer's disease (AD) through a Meta-analysis, providing a scientific basis for clinical applications.

METHODS: Following PRISMA guidelines, databases such as PubMed and Web of Science were searched, and 20 eligible clinical studies (2022-2025) involving 12,897 participants were included. Study quality was assessed using the modified QUADAS-2 tool, statistical analyses were performed with Stata 16.0, effect sizes were pooled via random-effects models, and subgroup analyses, sensitivity analyses, and publication bias tests were conducted.

RESULTS: Results showed that Transformer-based multimodal fusion models exhibited excellent overall diagnostic performance, with a pooled AUC of 0.924 (95% CI: 0.912-0.936), sensitivity of 0.887 (0.865-0.904), specificity of 0.892 (0.871-0.910), and accuracy of 0.879 (0.858-0.897), significantly outperforming traditional single-modality methods. Subgroup analyses revealed that: Three or more modalities achieved a higher AUC (0.935 vs. 0.908 for two modalities, p =0.012). Intermediate fusion strategies (feature-level, AUC=0.931) significantly outperformed early (0.905) and late (0.912) fusion (p <0.05 for both). Multicenter data improved AUC (0.930 vs. 0.918 for single-center, p =0.046), while sample size stratification (<200 vs. ≥200 cases) showed no significant difference (p =0.113). Hybrid Transformer models (Transformer +CNN) trended toward higher AUC (0.928 vs. pure Transformer 0.917, p =0.068) but did not reach statistical significance.

DISCUSSION: Notable studies included Khan et al.'s (2024) Dual-3DM[3]AD model (AUC=0.945 for AD vs. MCI) and Gao et al.'s (2023) generative network (AUC=0.912 under data loss), validating model robustness and feature complementarity. Sensitivity analysis confirmed stable results (AUC range: 0.920-0.928), and Egger's test (p =0.217) and funnel plot symmetry indicated no significant publication bias. Limitations included a high proportion of single-center data and insufficient model interpretability. Future research should focus on multicenter data integration, interpretable module development, and lightweight design to facilitate clinical translation. Transformer-based multimodal fusion models demonstrate exceptional efficacy in early AD diagnosis, with multimodal integration, feature-level fusion, and multicenter data application as key advantages. They hold promise as core tools for AD "early diagnosis and treatment" but require further optimization for cross-cohort generalization and clinical interpretability.},
}

@article {pmid41184709,
year = {2025},
author = {Kiecka, A and Szczepanik, M},
title = {Dietary modulation of the gut microbiome as a supportive strategy in the treatment of amyotrophic lateral sclerosis - a narrative review.},
journal = {Pharmacological reports : PR},
volume = {},
number = {},
pages = {},
pmid = {41184709},
issn = {2299-5684},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease leading to permanent damage to the central and peripheral motor neurons. Currently, there is no effective treatment for ALS, and therapy focuses solely on slowing the progression of the disease. Recent studies show that gut microbiota plays an important role in the development of neurodegenerative diseases. Altered gut microbiota has also been found in ALS. These changes have prompted the search for alternative forms of ALS treatment, focusing on changing the microbial composition of the gut. It has been noted that diet, probiotics, prebiotics and vitamins can all influence the course of ALS. Another interesting issue is fecal microbiota transplantation, which is already used in the treatment of certain intestinal diseases and could potentially be useful in the treatment of ALS. This review summarizes current knowledge on the impact of gut microbiota on the neurodegenerative process in ALS, with particular emphasis on the role of diet and probiotics. It also discusses potential mechanisms and highlights future research directions in this emerging field.},
}

@article {pmid41182353,
year = {2025},
author = {Cai, Y and Huang, S and Dong, Y and Li, S and Jin, X},
title = {PIWI-Interacting RNAs in brain health and disease: biogenesis, mechanisms, and therapeutic horizons.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41182353},
issn = {1432-2072},
support = {81971083//National Natural Science Foundation of China/ ; 25JCLZJC00190//Tianjin Natural Science Foundation Project/ ; },
abstract = {PIWI-interacting RNAs (piRNAs), a class of small non-coding RNAs originally identified for their role in transposon silencing in germ cells, have recently been recognized as pivotal regulators of gene expression in the central nervous system. Beyond their canonical functions in genome defense, emerging evidence highlights piRNAs as key modulators of neuronal development, synaptic plasticity, axonal regeneration, and neuroimmune interactions-processes central to brain function and dysfunction. This review provides a comprehensive overview of piRNA biogenesis, molecular mechanisms, and regulatory pathways relevant to neurobiology. We focus on the growing body of evidence implicating piRNA dysregulation in major neurological and neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, glioma, autism spectrum disorder, and schizophrenia. Importantly, we discuss the neuropharmacological implications of piRNA pathways as novel targets for therapeutic intervention and their potential utility as biomarkers for early diagnosis and treatment stratification. By integrating mechanistic insights with emerging translational evidence, this review highlights piRNAs as promising molecular targets in the development of next-generation neurotherapeutics aimed at modifying disease progression and improving brain health.},
}

@article {pmid41181835,
year = {2025},
author = {Keritam, O and Erdler, M and Fasching, B and Zulehner, G and Rath, J and Krenn, M and Waldhör, T and Gruber, VA and Langweil, N and Kiss, C and Griedl, TA and Gold, V and Wanschitz, J and Hotter, A and Kleinveld, VEA and Horlings, CGC and Erber, A and Schernhammer, E and Troger, J and Grinzinger, S and Müller, P and Langenscheidt, D and Rappold, M and Wiesenhofer, A and Gosk-Tomek, M and Knipp, F and Mahal, S and Bernert, G and Baumann, M and Zimprich, F and Topakian, R and Eggers, C and Quasthoff, S and Löscher, W and Cetin, H},
title = {Efficacy and safety of risdiplam in adults with 5q-associated spinal muscular atrophy: a nationwide observational cohort study in Austria.},
journal = {EClinicalMedicine},
volume = {88},
number = {},
pages = {103536},
pmid = {41181835},
issn = {2589-5370},
abstract = {BACKGROUND: Spinal muscular atrophy (SMA) is a genetic motor neuron disease marked by the progressive decline of motor function. Risdiplam, an orally administered SMN2 splicing modifier, was approved for the treatment of 5q-associated SMA (5q-SMA) across all age groups. However, clinical trial data have primarily focused on paediatric populations, with limited evidence available for adult patients. This study aimed to evaluate the efficacy and safety of risdiplam in treatment-naïve adults with 5q-SMA in a real-world, multicentre setting.

METHODS: We conducted a nationwide, observational cohort study across eight neuromuscular centres in Austria. Patients aged ≥16 years at treatment initiation with genetically confirmed 5q-SMA, who were previously untreated and initiated risdiplam between December 2020 and September 2024 were eligible for inclusion if they had received risdiplam for ≥3 months and had functional motor assessments available at baseline (T0) and at least one follow-up. Functional outcomes were assessed at four predefined intervals after baseline: 3-<6 months (T1), 6-<12 months (T2), 12-<18 months (T3), and ≥18 months (T4). The primary outcome was the change from baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE). Secondary outcomes included changes in the Revised Upper Limb Module (RULM), Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), and 6-min walk test (6MWT). Adverse events were extracted from medical records.

FINDINGS: A total of 87 patients had received risdiplam, of whom 57 fulfilled the inclusion criteria and were included in this study. The median age at treatment initiation was 35.7 years (IQR 28.8-43.4), with a median disease duration of 29.6 years (IQR 24.2-36.3). Most individuals had SMA type II (40.4%) or III (47.4%). Mean HFMSE changes from baseline were +1.00 (95% CI 0.05-1.95, p = 0.0100) at T1, +0.97 (95% CI 0.22-1.72, p = 0.0132) at T2, +1.78 (0.66-2.89, p = 0.0008) at T3, and +1.73 (0.49-2.97, p = 0.0049) at T4. Clinically meaningful improvements in motor function (≥3 points in HFMSE and/or ≥2 in RULM) were observed in 63.9% of patients at T4. Improvements were more pronounced in patients with higher baseline function, ambulatory status, or without a history of spinal surgery. Risdiplam was generally well tolerated, with predominantly mild and non-specific adverse events reported in 14.0% of patients.

INTERPRETATION: In this nationwide observational study in a real-world setting, adult patients with 5q-SMA demonstrated consistent and clinically meaningful functional improvements with risdiplam over time, particularly by 18 months and beyond. These findings support the long-term use of risdiplam in adults with SMA and help close a critical evidence gap in this underrepresented population.

FUNDING: This study was financially supported by F. Hoffmann-La Roche Ltd.},
}

@article {pmid41175647,
year = {2025},
author = {Singh, A and Gupta, I and Saha, P and Hole, A and Anthony, F and Natu, A and Smoot, DT and Ashktorab, H and Chilakapati, MK and Gupta, S},
title = {Raman spectroscopy for detecting gastric and liver cancer cells that entered a tolerant persistence state to survive cisplatin chemotherapy.},
journal = {Biochemical and biophysical research communications},
volume = {790},
number = {},
pages = {152891},
doi = {10.1016/j.bbrc.2025.152891},
pmid = {41175647},
issn = {1090-2104},
abstract = {The persistence of minimal residual disease (MRD), a small population of tumor cells that survive therapy but remain below the limit of conventional detection methods, often leads to relapse. The residual disease is attributed to drug-tolerant persister (DTP) cells at the cellular level. In the present study, the differences in drug-tolerant persister cells, which represent a transient, reversible survival state, and drug-resistant cells, which reflect a stable, fixed phenotype of gastric and liver cancer cell lines, were investigated. The ultramicroscopic and confocal studies revealed a phenotypic shift in DTP cells induced upon drug treatment, characterized by cytoplasmic expansion, enhanced mitochondrial biogenesis, and active intercellular communication, potentially contributing to the survival of the drug-tolerant cells. The observed morphological alterations in a cell's physical characteristics are associated with underlying biochemical changes. Further, Raman spectroscopy provides a non-invasive method for studying biochemical alterations; Raman spectral analysis demonstrated precision in distinguishing with significant accuracy between DTP cells compared to resistant and parental cells. Multivariate Curve Resolution-alternating least squares (MCR-ALS) analysis showed alteration of lipid, nucleic acid, and protein-related features. The accumulation of lipid vacuoles inside the cytoplasm of DTP cells, and gene set enrichment analysis (GSEA) showed significant downregulation of metabolic pathways purine and pyrimidine, highlighting the potential metabolic shift in imparting a survival advantage to DTP cells. Thus, Raman analysis has confirmed the biochemical changes and provides proof of concept for identifying cisplatin-induced DTP and resistant tumor cells for a better therapeutic approach in resistant and relapse management.},
}

@article {pmid41171075,
year = {2025},
author = {Cazzola, J and Talpo, F and Faravelli, G and Donati, C and Maramai, S and Saletti, M and Giuliani, G and Paolino, M and Cappelli, A and Anzini, M and Sommi, P and Vitali, A and Sala, A and Trucco, A and Biella, GR and Spaiardi, P},
title = {Evaluation of a New Riluzole-Based Compound VA945 on Sodium and Potassium Conductances Expressed by SH-SY5Y- Derived Neurons.},
journal = {Journal of neurochemistry},
volume = {169},
number = {11},
pages = {e70280},
pmid = {41171075},
issn = {1471-4159},
mesh = {*Riluzole/pharmacology/analogs & derivatives ; Humans ; *Neurons/drug effects/metabolism ; *Neuroprotective Agents/pharmacology ; Cell Line, Tumor ; Potassium/metabolism ; *Potassium Channels ; Sodium/metabolism ; Membrane Potentials/drug effects ; Patch-Clamp Techniques ; *Sodium Channels ; Dose-Response Relationship, Drug ; },
abstract = {Riluzole (Rilutek), a derivative of benzothiazole, acts as a neuroprotective agent by inhibiting voltage-dependent sodium (Na[+]) and delaying rectifier potassium (K[+]) currents. By doing so, it helps reduce excitotoxicity, a key pathogenetic mechanism in various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although riluzole is a clinically approved treatment for ALS, it is not fully effective, particularly in advanced stages of the disease. In this study, we functionally characterized a newly synthetized riluzole-based compound, VA945, with potentially enhanced neuroprotective effects. By means of SH-SY5Y human neuroblastoma cells differentiated into neurons, we assessed using whole-cell patch-clamp techniques the effects of VA945 on voltage-dependent Na[+] and K[+] currents at extracellular concentrations of 5, 50, and 100 μM. The compound reduced maximal activation and inactivation of Na[+] conductance, as well as maximal activation of K[+] conductance, across all tested concentrations. We also observed shifts of the activation and inactivation curves to more hyperpolarized potentials along with changes in the slope factor (k), indicating an altered voltage sensitivity of voltage-dependent K[+] and Na[+] channels. While the activation kinetics of both channels remained unaffected, and the inactivation kinetics of Na[+] were unchanged, we noted a slowdown in the deactivation kinetics of the K[+] channels. Altogether, these findings suggest that VA945 exerts multi-target pharmacological effects on neuronal voltage-dependent ion currents critically involved in excitotoxicity and neurodegeneration, across a wide range of concentrations. This warrants further ex vivo and/or in vivo studies to explore its potential as a neuroprotective agent.},
}

*Riluzole/pharmacology/analogs & derivatives
Humans
*Neurons/drug effects/metabolism
*Neuroprotective Agents/pharmacology
Cell Line, Tumor
Potassium/metabolism
*Potassium Channels
Sodium/metabolism
Membrane Potentials/drug effects
Patch-Clamp Techniques
*Sodium Channels
Dose-Response Relationship, Drug

@article {pmid41169216,
year = {2025},
author = {Chisholm, CG and McAlary, L and Lum, JS},
title = {From translation to stabilization and degradation: A multifaceted approach for the treatment of superoxide dismutase 1-associated amyotrophic lateral sclerosis.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00778},
pmid = {41169216},
issn = {1673-5374},
}

@article {pmid41165282,
year = {2025},
author = {Roedl, K and Genbrugge, C},
title = {Managing cardiac arrest in the intensive care unit.},
journal = {Current opinion in critical care},
volume = {},
number = {},
pages = {},
doi = {10.1097/MCC.0000000000001319},
pmid = {41165282},
issn = {1531-7072},
abstract = {PURPOSE OF REVIEW: This review aims to explore the distinct clinical characteristics, epidemiology, treatment approaches, and research needs concerning cardiac arrest in the intensive care unit (ICU-CA), a specific subset of in-hospital cardiac arrest (IHCA). While IHCA remains a major cause of mortality, recent data indicate improved outcomes, with a notable variation in incidence and survival depending on the location, particularly within the ICU setting.

RECENT FINDINGS: Recent studies underscore that ICU-CA differs significantly from general IHCA in etiology, monitoring, and treatment environment. Although incidence rates vary widely (4-78 per 1000 ICU admissions), recent data suggest a stabilization. Causes of ICU-CA often involve noncardiac factors such as septic shock and respiratory failure. Treatment is typically guided by general advanced life support (ALS) protocols, but ICU-specific resources such as real-time monitoring, invasive pressure measurements, transesophageal echocardiography, and the potential for extracorporeal cardiopulmonary resuscitation offer unique advantages. The COVID-19 pandemic highlighted the vulnerability of ICU patients, with respiratory causes dominating and extremely poor outcomes reported.

SUMMARY: In summary, ICU-CA represents a distinct clinical entity requiring tailored research. Future directions should prioritize international registries, validation of predictive models using artificial intelligence, and clarification of do-not-resuscitate practices to improve outcomes and resource allocation in this critically ill population.},
}

@article {pmid41155541,
year = {2025},
author = {Perez, DM},
title = {α1A-Adrenergic Receptor as a Target for Neurocognition: Cautionary Tale from Nicergoline and Quinazoline Non-Selective Blockers.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {10},
pages = {},
pmid = {41155541},
issn = {1424-8247},
support = {R01 AG066627/AG/NIA NIH HHS/United States ; RO1AG066627/GF/NIH HHS/United States ; },
abstract = {Decades ago, previous studies that used non-selective ergot derivatives suggested that blockage of the α1A-adrenergic receptor mildly increased cognition through increased blood flow to the brain due to vasodilation and, thus, could be used as a treatment for dementia. However, further studies indicated that nicergoline was non-specific and hit many different targets. Today, a similar scenario is developing with the use of non-selective α1-AR antagonists of the quinazoline class, referred to as "osins", as potential treatments for COVID-19/SARS, post-traumatic stress disorder, cancer, and neurodegenerative disorders, such as Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis. While there is extensive evidence of neuroprotection from many clinical trials, the mechanism of action of quinazolines is often not α1-AR-mediated but keyed to its glycolysis-enhancing effects through activation of the enzyme phosphoglycerate kinase 1 (PGK1). These studies have incorrectly labeled the α1A-adrenergic receptor as an "old target" to treat Alzheimer's and other neurocognitive diseases, hampering drug development. This review will summarize these and other studies to indicate that activation, not blockage, of norepinephrine's actions, through α1A-AR, mediates cognitive, memory, and neuroprotective functions that may reverse the progression of neurocognitive diseases.},
}

@article {pmid41155480,
year = {2025},
author = {Turpo-Peqqueña, AG and Valencia-Arce, RJ and Del-Carpio-Carrazco, FL and Quispe-Ppacco, DJ and Carbajal-Llerena, PF and Loza-Chipa, HR and Vásquez-Macedo, AS and Gómez, B},
title = {Inhibition of Casein Kinase 1δ as a Novel Therapeutic Strategy for Amyotrophic Lateral Sclerosis: A Theoretical Study.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
pmid = {41155480},
issn = {1422-0067},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/enzymology ; *Casein Kinase Idelta/antagonists & inhibitors/chemistry/metabolism ; Molecular Docking Simulation ; Humans ; Molecular Dynamics Simulation ; *Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use ; Protein Binding ; },
abstract = {Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disease characterized by the degeneration of motor neurons and the pathological accumulation of phosphorylated TDP-43. Casein kinase one delta (CK1δ) has been identified as a key regulator of this aberrant phosphorylation, making it a promising therapeutic target. In this theoretical study, 26 structurally diverse compounds were evaluated against CK1δ using molecular docking, molecular dynamics simulations, and binding free energy calculations. Among them, BZH exhibited the most stable interaction with CK1δ (-46.53±1.94 kcal/mol). An inverse correlation was observed between theoretical affinity and experimental IC50 values, supporting the predictive validity of the computational approach. Pharmacokinetic analysis indicated that IMF and BIP show good oral absorption and the ability to cross the blood-brain barrier. At the same time, the toxicological profile classified all compounds in toxicity Class IV (moderate risk). Additionally, dynamic migration toward an alternative pocket was observed during simulation, highlighting the importance of considering protein flexibility in drug design. This study proposes BZH, IMF, and BIP as promising CK1δ inhibitors for future experimental validation in the treatment of ALS.},
}

*Amyotrophic Lateral Sclerosis/drug therapy/enzymology
*Casein Kinase Idelta/antagonists & inhibitors/chemistry/metabolism
Molecular Docking Simulation
Humans
Molecular Dynamics Simulation
*Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use
Protein Binding

@article {pmid41152189,
year = {2025},
author = {Snyder, A and Samra, K and Wu, T and Russell, LL and Farren, J and Crook, J and Haselhuhn, T and Porter, K and Szabo, M and Duckett, A and Lin, F and Danielian, L and Traynor, BJ and Scholz, SW and Boeve, BF and Rosen, HJ and Rohrer, JD and Kwan, JY},
title = {Integrating a motor domain enhances disease severity scales in an FTD-ALS spectrum cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70786},
pmid = {41152189},
issn = {1552-5279},
support = {U19 AG063911/AG/NIA NIH HHS/United States ; U19AG063911//The National Institute on Aging/ ; U01AG045390//The National Institute on Aging/ ; U54NS092089//The National Institute on Aging/ ; U01 AG045390/AG/NIA NIH HHS/United States ; //The Intramural Research Program of the National Institutes of Health/ ; U54 NS092089/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; Male ; *Severity of Illness Index ; Female ; *Frontotemporal Dementia/diagnosis/physiopathology ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Aged ; Longitudinal Studies ; Cohort Studies ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: The Genetic Frontotemporal Initiative (GENFI) and Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)-Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Longitudinal Frontotemporal Lobar Degeneration Study (ALLFTD) consortia developed Clinical Dementia Rating (CDR)-derived scales with a motor domain to overcome systematic underestimation of disease severity by the CDR. We calculated disease severity scores using these scales in a mixed neurodegenerative cohort and correlated them with objective motor measures.

METHODS: The CDR plus National Alzheimer's Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD), CDR + NACC FTLD-M (Motor), and Multidomain Impairment Rating (MIR) scores and motor measures were determined and correlated in 242 participants.

RESULTS: Both CDR + NACC FTLD-M and MIR showed increased disease severity scores and correlated with motor measures. These findings were held in 81 amyotrophic lateral sclerosis (ALS) participants and correlated with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Including a motor domain required fewer study participants in a simulated clinical trial sample size calculation.

DISCUSSION: With a motor domain, CDR + NACC FTLD-M and MIR improve disease severity classification and correlate with quantitative motor assessments. This addition more fully captures the extent of symptoms across the FTD-ALS spectrum and improves clinical trial efficiency.

HIGHLIGHTS: CDR + NACC FTLD-M and MIR strongly correlate with objective motor measures. The enhanced scales improve disease severity classification in FTD and ALS. Greater clinical trial efficiency is achieved using these enhanced scales.},
}

Humans
Male
*Severity of Illness Index
Female
*Frontotemporal Dementia/diagnosis/physiopathology
Middle Aged
*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology
Aged
Longitudinal Studies
Cohort Studies
Neuropsychological Tests

@article {pmid41149102,
year = {2025},
author = {Mauriello, L and Cuozzo, A and Pezzella, V and Isola, G and Spagnuolo, G and Iorio-Siciliano, V and Ramaglia, L and Blasi, A},
title = {Oral Health Status in Patients with Amyotrophic Lateral Sclerosis: A Scoping Review.},
journal = {Dentistry journal},
volume = {13},
number = {10},
pages = {},
pmid = {41149102},
issn = {2304-6767},
abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative syndrome which often leads to progressive muscular dysfunction and therefore oral health deterioration. The aim of this scoping review is to evaluate oral health status in ALS patients focusing on the importance of dental care in improving patient's quality of life. Methods: A comprehensive literature search was conducted on PubMed, Scopus, Web of Science, and Embase databases until June 2025 using a combination of keywords and MeSH terms related to ALS and oral health. Studies were screened and selected based on inclusion and exclusion criteria, focusing on human clinical data reporting oral health outcomes in ALS. Results: Eight studies met the inclusion criteria. The findings showed a high prevalence of oral complications in bulbar-onset ALS patients. Common issues included reduced tongue mobility, poor oral hygiene, sialorrhea, and decreased masticatory function were evaluated. Conclusions: Oral health impairment in ALS patients frequently contributes to systemic risks and reduced quality of life. A dental expert may play an important role in multidisciplinary care teams in terms of early diagnosis and conservative treatment of oral diseases ranging from periodontal disease to temporomandibular disorders (TMD). Personalized oral hygiene strategies and adjunctive therapies may serve as key elements in maintaining overall health and patient comfort in ALS. Therefore, the objective of the following review was to evaluate oral health complication in patients with ALS, highlighting the impact of oral care on patients' quality of life.},
}

@article {pmid41148458,
year = {2025},
author = {Goel, F and Kumar, D and Singh, P and Rai, SN and Yadav, DK},
title = {Molecular crosstalk between miRNAs and lncRNAs in neurodegenerative disease pathways.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {16},
pmid = {41148458},
issn = {1573-4978},
mesh = {Humans ; *RNA, Long Noncoding/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/therapy ; Gene Expression Regulation ; Animals ; Signal Transduction ; Gene Regulatory Networks ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal degeneration and dysfunction. Of recent interest, a series of studies have been targeting the role of non-coding RNAs, particularly miRNAs and lncRNAs, in regulating gene expression and influencing cellular pathways that may play a critical role in the pathogenesis of these diseases. miRNAs regulate many biological processes by degrading or repressing the translation of target mRNAs, whereas lncRNAs act as scaffolds, sponges, and guides to control gene expression and cellular activities. Both miRNAs and lncRNAs participate in neurodegenerative mechanisms such as protein aggregation, inflammation, oxidative stress, and neuroinflammation. While targeting miRNAs and lncRNAs holds promise for potential therapeutic benefits, problems persist with their efficient delivery, specificity, and off-target effects. New techniques like viral vectors, lipid nanoparticles, and CRISPR-based gene editing will further enhance the development of therapies based on miRNA and lncRNA. Moreover, their interaction with regulatory networks may present new avenues toward understanding disease mechanisms and guiding therapeutic design. This review covers the role of miRNAs and lncRNAs in neurodegenerative disorders, their therapeutic potential, challenges, and future directions in ncRNA-based treatment approaches.},
}

Humans
*RNA, Long Noncoding/genetics/metabolism
*MicroRNAs/genetics/metabolism
*Neurodegenerative Diseases/genetics/metabolism/therapy
Gene Expression Regulation
Animals
Signal Transduction
Gene Regulatory Networks

@article {pmid41146348,
year = {2025},
author = {Khizar, M and Alokozay, E and Junaid, M and Alokozay, N},
title = {Critical appraisal of progress and challenges in tuberculosis preventive treatment in the Western Pacific Region: a situational analysis of seven high tuberculosis burden countries.},
journal = {Tropical medicine and health},
volume = {53},
number = {1},
pages = {143},
pmid = {41146348},
issn = {1348-8945},
abstract = {We commend Oh et al.'s recent analysis of TB preventive treatment (TPT) in the Western Pacific Region, but note important gaps and ways forward. We first caution that reliance on routine program data may overestimate gains. For example, China's passive surveillance misses ≈20% of cases [1]. Prospective cohorts or integrated surveillance including clinical databases could validate coverage estimates. We also urge attention to overlooked risk groups beyond children and PLHIV (as highlighted by Oh et al. [2]), groups like healthcare workers, prisoners, and people with diabetes warrant targeted TPT pilots (e.g., occupational health or prison-based programs). In the Philippines, ~ 36% of TB patients first seek private care [3], so partnering with private clinics and pharmacies is essential to reach all contacts. Likewise, MDR-TB contacts were underemphasized; WHO now strongly recommends a 6-month levofloxacin regimen for MDR contacts [4]. We encourage pilot studies of this regimen (as in Mongolia [5]) and operational research on MDR-TPT. Finally, policy does not guarantee practice as Cambodia and Lao PDR have guidelines, yet stockouts and training gaps persist [6, 7]. Embedding TPT in universal health insurance and conducting cost effectiveness studies will support sustainable scale-up. In sum, by suggesting concrete examples and research strategies for each country, we aim to refine Oh et al.'s insights into actionable steps for TPT acceleration.},
}

@article {pmid41144002,
year = {2025},
author = {Vidovic, M and Lapp, HS and Dittes, I and Leuchten, N and Aringer, M and Günther, C and Günther, R},
title = {Methotrexate therapy as a promising long-term treatment approach for immune-mediated adverse reactions of tofersen in SOD1-ALS: a case report.},
journal = {Journal of neurology},
volume = {272},
number = {11},
pages = {732},
pmid = {41144002},
issn = {1432-1459},
}

@article {pmid41143669,
year = {2025},
author = {Morley, M and Aurora, M and Gustafson, K and Seals, CS and Feuer, A and Datar, S and Parvanta, S and Thakur, N and Dave, KD},
title = {Medicare expenditures in the first year of amyotrophic lateral sclerosis diagnosis.},
journal = {The American journal of managed care},
volume = {31},
number = {10},
pages = {e308-e312},
doi = {10.37765/ajmc.2025.89813},
pmid = {41143669},
issn = {1936-2692},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/economics/drug therapy/diagnosis ; United States ; *Health Expenditures/statistics & numerical data ; Aged ; Male ; Female ; *Medicare/economics/statistics & numerical data ; Aged, 80 and over ; Fee-for-Service Plans/economics/statistics & numerical data ; Cohort Studies ; },
abstract = {OBJECTIVES: To determine Medicare expenditures and potential beneficiary out-of-pocket liability for Medicare beneficiaries with amyotrophic lateral sclerosis (ALS), including costs related to drug treatments.

STUDY DESIGN: This cohort study utilized the 100% Medicare fee-for-service claims for 2017-2021, including Part A and Part B medical claims and Part D prescription drug event data.

METHODS: Eligible Medicare beneficiaries with ALS were identified based on 1 or more inpatient or 2 or more outpatient claims with an International Statistical Classification of Diseases, Tenth Revision diagnosis code for ALS (G12.21) between 2017 and 2020. Health care expenditures and beneficiary liability were assessed for the 12-month study period.

RESULTS: At 1 year post index, Medicare beneficiaries with ALS had more than 3 times the Medicare expenditures of beneficiaries without ALS ($47,450 vs $13,889, respectively). Similar patterns were observed for beneficiary liability. Approximately one-third of Medicare beneficiaries used either edaravone or riluzole in the first 12 months following ALS diagnosis. The cost of care for beneficiaries using these drugs was notably higher than for beneficiaries with ALS overall.

CONCLUSIONS: Approximately one-third of people with ALS on Medicare receive disease-modifying medication. ALS is a burdensome disease with significant financial implications for people with ALS and the Medicare program. Treatment for ALS presents affordability challenges, and policy makers must consider how current Medicare policy addresses the costs of care.},
}

Humans
*Amyotrophic Lateral Sclerosis/economics/drug therapy/diagnosis
United States
*Health Expenditures/statistics & numerical data
Aged
Male
Female
*Medicare/economics/statistics & numerical data
Aged, 80 and over
Fee-for-Service Plans/economics/statistics & numerical data
Cohort Studies

@article {pmid41141812,
year = {2025},
author = {Cobos, SN and Fisher, RMA and Bennett, SA and Janani, C and Dansu, DK and Cleere, MM and Yeasmin, A and Cruz, G and Qureshi, S and Villasi, W and Frederic, R and Chen, K and Mirzakandova, M and Angelakakis, G and Son, E and Elgendy, A and Torrente, MP},
title = {C9orf72 Dipeptide Repeat Proteinopathy Is Linked to Increased Histone H3 Phosphorylation on Serine 10.},
journal = {ACS omega},
volume = {10},
number = {41},
pages = {48395-48411},
pmid = {41141812},
issn = {2470-1343},
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal illnesses forming a neurodegenerative disease continuum. While most ALS/FTD cases are sporadic, a small proportion of cases are linked to mutations in many genes. Among these, hexanucleotide repeat expansions in the C9orf72 gene are the most common and lead to the formation of dipeptide repeat proteins (DPRs), including a proline-arginine dipeptide (PR), which aggregate in the cytoplasm of decaying neurons. As genetics alone fails to explain the etiology of ALS/FTD, it is possible that epigenetic mechanisms - such as histone post-translational modifications (PTMs) - are involved in disease processes. A Saccharomyces cerevisiae (PR)50 overexpression model displays overt growth suppression and aggregation. Here, we exploit this model as a discovery platform to comprehensively characterize changes in the levels of PTMs on Histones H3 and H4. We find that overexpression of (PR)50 is associated with increased levels of phosphorylation on Histone H3 at Serine 10 (H3S10ph). Furthermore, (PR)50 overexpression revealed modest increases in the levels of other marks associated with increased gene expression. Remarkably, decreased abundance of Ipl1, the kinase responsible for phosphorylating H3S10 in yeast, leads to amelioration of the growth suppression phenotype and restores H3S10ph levels even in the context of (PR)50 overexpression. Recapitulating our results in yeast, several c9orf72 ALS patient-derived fibroblasts and induced pluripotent stem cell (iPSCs) lines display similar increases in H3S10ph levels. Altogether, these findings reveal a previously undiscovered connection between H3S10ph and c9 ALS/FTD proteinopathy that could reveal novel targets for the treatment of this disease.},
}

@article {pmid41141079,
year = {2025},
author = {Jeong, E and Li, D},
title = {Antisense Oligonucleotide Therapy for Amyotrophic Lateral Sclerosis (ALS): An Umbrella Review.},
journal = {Cureus},
volume = {17},
number = {9},
pages = {e93140},
pmid = {41141079},
issn = {2168-8184},
abstract = {Amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease, is a fatal neurodegenerative disease prominent in the elderly population. To this point, no completely effective treatments have been procured; however, antisense oligonucleotide therapies, or ASOs, are a promising venue. In order to investigate the efficacy of ASOs in the treatment of ALS by targeting specific genetic mutations, we conducted an umbrella review utilizing keywords such as "ALS" and "ASO" in the PubMed database, excluding sources published more than 10 years ago for relevance. Results revealed that of multiple tentative ASO treatments, for multiple specific gene mutations, only one, Tofersen, was approved for the wider population. The main cause of failure was an inability to meet efficacy endpoints, resulting in the discontinuation of the product. Tofersen is able to treat mutations in the SOD1 gene, but not any others. While initially discouraging, the production of ASOs is a relatively new and advanced process, and slow progress is expected. However, there remains the problem of identifying and treating the much more prevalent sporadic ALS, which is much more common compared to familial ALS.},
}

@article {pmid41137739,
year = {2025},
author = {van Wijk, IF and Kraneburg, L and van Eijk, RPA and Veldink, JH and van Es, MA and Westeneng, HJ and van den Berg, LH},
title = {Prodromal symptoms in amyotrophic lateral sclerosis from the perspective of the patient and of the caregiver.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/21678421.2025.2574687},
pmid = {41137739},
issn = {2167-9223},
abstract = {OBJECTIVE: Clinically manifest ALS is preceded by a prodromal phase in gene mutation carriers, characterized by mild motor impairment. A well-defined prodromal phase could enable earlier diagnosis and treatment. We investigated the presence of a prodromal phase in sporadic ALS, from the perspective of patients and caregivers.

METHODS: A survey was conducted of symptom onset in 279 ALS patients from a population-based registry and 150 caregivers. 244 patients and 123 caregivers were included in the primary qualitative analysis, followed by quantitative analysis of identified themes. A prodromal phase was defined as symptoms, in response to open-ended questions, before onset of recorded weakness, bulbar complaints or shortness of breath. Mild motor symptoms were defined as fasciculations, cramps, stiffness, atrophy, reduced sports performance, or mobility issues.

RESULTS: 26.6% of patients and 17.5% of caregivers reported a prodromal phase, primarily with mild motor symptoms (patients 23.0%; caregivers 11.4%). Prodromal symptoms occurred a median of 6.0 months (IQR 2.8-11.8 months) before recorded disease onset. In closed-ended questions, 19.2% of patients and 22.2% of caregivers reported cognitive or behavioral symptoms before weakness onset, compared to only 0.6% and 1.8% in open-ended questions.

CONCLUSIONS: In sporadic ALS, approximately a quarter of patients report a prodromal phase characterized primarily by mild motor symptoms. However, mild motor symptoms alone are unlikely to contribute to earlier disease recognition. Cognitive or behavioral symptoms are often not recognized as part of the clinical spectrum. These findings emphasize the need for reliable biomarkers to detect ALS pathology at an early stage.},
}

@article {pmid41136425,
year = {2025},
author = {Vokali, E and Chevalier, E and Dreyfus, N and Charmey, D and Melly, T and Kocher, J and Ratnam, M and Serra, AM and Jaquier, T and Delgado, C and Ravache, M and Scialò, C and Cappelli, S and Kroth, H and Capotosti, F and Luthi-Carter, R and Afroz, T and Derouazi, M and Constantinescu, CC and Seelaar, H and Buratti, E and Nelson, PT and Polymenidou, M and Pfeifer, A and Kosco-Vilbois, M and Seredenina, T},
title = {Development of [[18]F]ACI-19626 as a first-in-class brain PET tracer for imaging TDP-43 pathology.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {9358},
pmid = {41136425},
issn = {2041-1723},
support = {P01 AG019724/AG/NIA NIH HHS/United States ; P30 AG028383/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; },
mesh = {*Positron-Emission Tomography/methods ; *Brain/diagnostic imaging/metabolism/pathology ; Humans ; *DNA-Binding Proteins/metabolism ; Animals ; *Radiopharmaceuticals/pharmacokinetics/chemistry ; Fluorine Radioisotopes ; *TDP-43 Proteinopathies/diagnostic imaging/metabolism/pathology ; Mice ; Male ; Frontotemporal Dementia/diagnostic imaging/metabolism/pathology ; Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism/pathology ; Female ; },
abstract = {Aggregated TDP-43 is a hallmark of frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and limbic-predominant age-related TDP-43 encephalopathy (LATE), and a common co-pathology in other neurodegenerative diseases. Currently, no specific biomarkers exist to assess TDP-43 pathology in vivo. We developed two small-molecule radiopharmaceuticals, [[18]F]ACI-19278 and [[18]F]ACI-19626, for visualizing TDP-43 inclusions by positron emission tomography (PET). Both ligands bind with high affinity to aggregated, but not soluble, TDP-43 in patient brain samples from diverse TDP-43 proteinopathies, including frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), ALS, and LATE, and in cell models. Both compounds display excellent selectivity for TDP-43 over Aβ, Tau, and α-synuclein aggregates. In non-human primates, [[18]F]ACI-19278 and [[18]F]ACI-19626 show a pharmacokinetic profile suitable for brain PET imaging (rapid brain uptake; fast and complete washout). ACI-19278 and ACI-19626 are promising first-in-class TDP-43 PET tracers with the potential to revolutionize the diagnosis and treatment of neurodegenerative proteinopathies, enabling a precision medicine approach.},
}

*Positron-Emission Tomography/methods
*Brain/diagnostic imaging/metabolism/pathology
Humans
*DNA-Binding Proteins/metabolism
Animals
*Radiopharmaceuticals/pharmacokinetics/chemistry
Fluorine Radioisotopes
*TDP-43 Proteinopathies/diagnostic imaging/metabolism/pathology
Mice
Male
Frontotemporal Dementia/diagnostic imaging/metabolism/pathology
Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism/pathology
Female

@article {pmid41135742,
year = {2025},
author = {Hu, T and Xi, J and Xie, N and Zhang, X and Huang, N and Cheng, Y},
title = {Multi-Omics Analysis Reveals the Protective Role of Transcriptional Enhancer Factor and the Pathogenic Mechanism of Monocytes in Parkinson's Disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111594},
doi = {10.1016/j.brainresbull.2025.111594},
pmid = {41135742},
issn = {1873-2747},
abstract = {Parkinson's disease (PD) is a multifactorial neurodegenerative disorder whose pathogenic mechanisms remain incompletely elucidated. This study aimed to systematically identify key regulatory factors involved in PD at the genetic, cellular, and molecular levels. Using univariate Mendelian randomization (UVMR), we identified plasma proteins and genes associated with Alzheimer's disease (AD), PD, and amyotrophic lateral sclerosis (ALS), and validated their causal relationships through colocalization analysis. Cross-validation across multi-omics datasets revealed transcriptional enhancer factor (TEF) as a protective factor for PD, whereas increased counts of CD14[+]CD16[+] monocytes were identified as a risk factor. Single-cell analysis and multivariate Mendelian randomization (MVMR) further suggested potential mediating roles of these factors in PD pathogenesis. In vitro experiments demonstrated that TEF overexpression significantly enhanced the resistance of neuroblastoma cells to rotenone-induced damage, inhibited apoptosis, and preserved tyrosine hydroxylase (TH) expression. In vivo, TEF notably improved motor coordination and exploratory behavior in PD mouse models. Collectively, these findings suggest that TEF may exert neuroprotective effects by modulating immune and neuronal pathways, offering a novel therapeutic target for the prevention and treatment of Parkinson's disease.},
}

@article {pmid41135686,
year = {2025},
author = {Columbro, SF and Tortarolo, M and Re Cecconi, AD and Piccirillo, R and Bendotti, C and Biasini, E and Pasetto, L and Bonetto, V},
title = {Beneficial effects of synthetic torpor in a fast-progressing mouse model of amyotrophic lateral sclerosis.},
journal = {Experimental neurology},
volume = {396},
number = {},
pages = {115521},
doi = {10.1016/j.expneurol.2025.115521},
pmid = {41135686},
issn = {1090-2430},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss, muscle atrophy, and progressive paralysis. Currently approved treatments provide only limited benefits. Due to the complex and multifactorial nature of ALS pathology, therapies targeting multiple pathways may prove more effective. Synthetic torpor, a state that mimics natural hibernation, has shown promise in promoting neuroprotection by modulating metabolism, reducing inflammation, and preserving both neurons and muscles. In this study, synthetic torpor was induced using 5'AMP combined with environmental cooling in the fast-progressing SOD1[G93A] ALS mouse model on the 129SvHsd genetic background, known for its aggressive disease course, early metabolic dysfunction and unresponsiveness to treatments. Synthetic torpor was highly effective in preserving motor neurons. The treatment significantly delayed disease onset and extended survival, although mildly, without altering overall disease duration. In the spinal cord, synthetic torpor increased glucose transporters, reduced markers of oxidative stress, decreased glial activation and sustained upregulation of neuroprotective proteins, such as RBM3 and PPIA. This occurred despite an increased SOD1 aggregation in a later phase of the disease. Muscles display clear protective effects across disease progression with preservation of mass, reduced atrogin-1, lower PDK4 and oxidative stress markers, associated with improvements in markers of axonal integrity and muscle denervation. This study provides proof-of-concept that activating multiple protective molecular pathways, particularly those involved in glucose metabolism and protein folding, can mitigate the pathological processes in ALS, especially in rapidly progressing forms of the disease.},
}

@article {pmid41132886,
year = {2025},
author = {Agüera-Morales, E and Fernández-Sánchez, VE and Navarro-Mascarell, G and Cabezas-Rodríguez, JA and Peña-Toledo, MÁ and Reyes-Rodríguez, V and Postigo-Pozo, MJ and Patrignani-Ochoa, G and Geniz-Clavijo, MÁ and Márquez-Infante, C and Tallon-Aguilar, L and Tinoco-González, J and Padillo-Ruiz, J and Valladares-Sánchez, A and Caballero-Eraso, C and López-Ramírez, C and Mata Alcázar-Caballero, R and Leyva-Fernández, L and Rodríguez-Acosta, A and Maldonado-Sánchez, R and García-Martín, ML and Somoza-Ramírez, M and Quijano-Ruiz, B and Macías-Sánchez, MDM and Carmona-Sánchez, G and Fernández-López, O and Fernández-Fernández, Ó},
title = {Adipose-derived mesenchymal stem cells for the treatment of Amyotrophic Lateral Sclerosis. A phase I/II safety and efficacy clinical trial.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1655124},
pmid = {41132886},
issn = {1664-2295},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with few treatments available. Mesenchymal stem cells have arisen as a potential treatment option for ALS due to their immune system modulation and their neuroprotective effects. This clinical trial aimed to evaluate the safety, efficacy and feasibility of three intravenous doses of autologous adipose-derived mesenchymal stem cells (AdMSC) in ALS patients.

METHODS: A multicentre, randomized, parallel group, placebo-controlled, double-blinded clinical trial (EudraCT: 2011-006254-85) was conducted in 40 patients with ALS in treatment with riluzole. Patients were randomized 1:1:1:1 into the following treatment groups: 1 × 10[6] cells/kg, 2 × 10[6] cells/kg, 4 × 10[6] cells/kg and placebo. After a 6 month follow-up, patients in the placebo group were randomized 1:1:1 to receive one of the three doses of AdMSC and they were followed up for another 6 months. Lastly, all patients were followed-up in a 36-month open-label extension. Safety was mainly assessed through the evaluation of adverse events and their relationship with the medicinal product. Several variables were measured to assess efficacy, such as ALS Functional Rating Scale, Ashworth spasticity scale, neurophysiological and neuropsychological parameters and overall survival. The feasibility of the procedure was assessed through the evaluation of the extraction and infusion of AdMSC.

RESULTS: Safety of AdMSC was observed through all follow-up periods, with similar percentages of adverse events between groups and no significant differences between groups in the rate of adverse events related to treatment. The administration procedure was feasible for all patients. Across all analyzed measures, we observed the expected progressive decline characteristic of ALS, with no statistically significant between-group differences in the rate of change.

DISCUSSION: The results obtained in this study are consistent with the ones obtained in other clinical trials using similar doses of MSC, where safety was demonstrated and efficacy results were inconclusive, due to not reaching statistical significance. Larger studies with an increased sample size, different doses and route of administration or combination of routes, repeated dosing or larger duration and comprehensive assessment of immunological effect would be needed to analyze the efficacy of AdMSC in the treatment of ALS.

CLINICAL TRIAL REGISTRATION: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2011-006254-85.},
}

@article {pmid41117572,
year = {2025},
author = {Soar, J and Böttiger, BW and Carli, P and Jiménez, FC and Cimpoesu, D and Cole, G and Couper, K and D'Arrigo, S and Deakin, CD and Ek, JE and Holmberg, MJ and Magliocca, A and Nikolaou, N and Paal, P and Pocock, H and Sandroni, C and Scquizzato, T and Skrifvars, MB and Verginella, F and Yeung, J and Nolan, JP},
title = {European Resuscitation Council Guidelines 2025 Adult Advanced Life Support.},
journal = {Resuscitation},
volume = {215 Suppl 1},
number = {},
pages = {110769},
doi = {10.1016/j.resuscitation.2025.110769},
pmid = {41117572},
issn = {1873-1570},
mesh = {Humans ; *Advanced Cardiac Life Support/standards/methods ; *Cardiopulmonary Resuscitation/standards/methods ; Adult ; Europe ; *Heart Arrest/therapy ; *Out-of-Hospital Cardiac Arrest/therapy ; },
abstract = {These European Resuscitation Council (ERC) Guidelines 2025 Adult Advanced Life Support (ALS) are based on the International Liaison Committee on Resuscitation (ILCOR) Consensus on Cardiopulmonary Resuscitation Science with Treatment Recommendations (CoSTR). The evidence informing the ALS Guidelines is also included. When ILCOR has not addressed a specific topic, the ERC ALS Writing Group has provided its own guidance and the evidence supporting it. This section provides recommendations for ALS for adults with in- or out-of-hospital cardiac arrest. The ERC Guidelines 2025 ALS emphasise providing early and effective ALS interventions to improve survival from cardiac arrest in adults.},
}

Humans
*Advanced Cardiac Life Support/standards/methods
*Cardiopulmonary Resuscitation/standards/methods
Adult
Europe
*Heart Arrest/therapy
*Out-of-Hospital Cardiac Arrest/therapy

@article {pmid41117139,
year = {2025},
author = {Pedro, KM and Alvi, MA and Goulart, GR and Fehlings, MG},
title = {Riluzole as a pharmacological therapy for spinal cord injury: where does this therapy stand?.},
journal = {Current opinion in neurology},
volume = {},
number = {},
pages = {},
doi = {10.1097/WCO.0000000000001434},
pmid = {41117139},
issn = {1473-6551},
abstract = {PURPOSE OF REVIEW: Spinal cord injury (SCI) remains a disabling condition associated with long term neurological impairment, functional disability, and reduced quality of life. Despite decades of research, pharmacological interventions with proven clinical efficacy remain limited. This review critically evaluates the current evidence supporting riluzole as a neuroprotective agent for acute traumatic and nontraumatic SCI. We synthesize findings from preclinical and clinical studies, assess the progress towards clinical translation, and outline key challenges and research opportunities for future implementation.

RECENT FINDINGS: Riluzole, an FDA-approved agent for amyotrophic lateral sclerosis (ALS), inhibits voltage-gated sodium channels and modulates glutaminergic transmission, two mechanisms central to the pathogenesis of secondary injury in SCI and in nerve cell degeneration in nontraumatic forms of SCI, including degenerative cervical myelopathy (DCM). Preclinical studies consistently demonstrate functional and histopathological improvements following riluzole administration. Phase I/II trials have provided evidence for its safety and tolerability in acute SCI patients, while the RISCIS and CSM-PROTECT trials, two landmark multicenter randomized controlled studies, along with their secondary analyses, revealed promising multidomain improvements in motor function, independence, and quality of life indices. Sub-studies have also established pharmacokinetic and pharmacodynamic frameworks for individualized dosing, and early biomarker analysis suggests potential for predictive stratification.

SUMMARY: Riluzole represents a promising candidate for neuroprotection in traumatic and nontraumatic SCI. The consistency of favorable trends across multiple domains and strong support from preclinical studies highlight riluzole's value in orphan diseases such as SCI. Future directions should focus on refining the therapeutic window, optimizing PK/PD modeling, and identifying patient subgroups most likely to benefit. Its implementation in a multimodal treatment paradigm for acute SCI will be crucial for optimizing management protocols in this highly disabling condition.},
}

@article {pmid41117127,
year = {2025},
author = {Kim, H and Uhm, JE and Park, J and Kim, YS and Sung, W and Lee, S and Kim, SH and Oh, KW},
title = {Monoclonal Gammopathy in Amyotrophic Lateral Sclerosis: No Impact on Clinical Progression and Immunotherapy Outcomes.},
journal = {European journal of neurology},
volume = {32},
number = {10},
pages = {e70376},
pmid = {41117127},
issn = {1468-1331},
support = {RS-2023-00265515//K-Brain Project of the National Research Foundation(NRF) Korean government (MSIT) (RS-2023-00265515)./ ; RS-2024-00348451//Korea Dementia Research Project through the Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea (RS-2024-00348451)./ ; },
mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/epidemiology/therapy/complications ; Female ; Disease Progression ; Aged ; *Immunotherapy/methods ; Middle Aged ; *Paraproteinemias/epidemiology/therapy/complications ; Republic of Korea/epidemiology ; Registries ; Prevalence ; Treatment Outcome ; Adult ; Aged, 80 and over ; },
abstract = {BACKGROUND: The association between amyotrophic lateral sclerosis (ALS) and monoclonal gammopathy has been proposed, but evidence on its prevalence, clinical relevance, and treatment response remains limited, especially in Asian populations. This study aimed to investigate the prevalence of monoclonal gammopathy in Korean patients with ALS and evaluate the impact of immunotherapy.

METHODS: This registry-based study analyzed Korean patients with ALS at a tertiary referral hospital (2005-2023). All patients underwent electrophoresis and immunofixation electrophoresis to detect monoclonal gammopathy. Clinical progression was assessed using ALSFRS-R scores, disease progression rate (ΔFS), survival analysis, and electrophysiological evaluations.

RESULTS: Among 2400 patients with ALS, monoclonal gammopathy was identified in 1.0% (25/2400). Prevalence increased with age, 1.9% in patients aged ≥ 65 years and 0.7% (13/1755) aged < 65 years. Patients with ALS and monoclonal gammopathy were older (63.2 vs. 57.1; p = 0.01) and predominantly male (7.3:1 vs. 1.5:1; p < 0.01). Immunotherapy targeting monoclonal gammopathy did not significantly affect disease progression (pre-treatment ΔFS 1.00 ± 1.23 vs. post-treatment ΔFS 0.94 ± 0.86; p = 0.46) or survival outcomes (median survival 55.0 vs. 57.0 months; log-rank p = 0.93). Nerve conduction study did not correlate with clinical outcomes. IgM monoclonal gammopathy demonstrated later slower disease progression (initial ΔFS, overall ΔFS; p < 0.05) compared to IgA and IgG subtypes.

CONCLUSION: Monoclonal gammopathy in Korean patients with ALS was not more prevalent than in the general population, and immunotherapy did not impact ALS progression or survival. Clinical features may vary by immunoglobulin subtype. This collectively suggests minimal clinical significance of monoclonal gammopathy in ALS.},
}

Humans
Male
*Amyotrophic Lateral Sclerosis/epidemiology/therapy/complications
Female
Disease Progression
Aged
*Immunotherapy/methods
Middle Aged
*Paraproteinemias/epidemiology/therapy/complications
Republic of Korea/epidemiology
Registries
Prevalence
Treatment Outcome
Adult
Aged, 80 and over

@article {pmid41114109,
year = {2025},
author = {Zhou, QQ and Ren, YM and Shi, SM and Liu, TF},
title = {Microenvironmental code of pancreatic ductal adenocarcinoma: The prognostic symphony of budding, matrix and lymphocytes.},
journal = {World journal of gastrointestinal oncology},
volume = {17},
number = {10},
pages = {110523},
pmid = {41114109},
issn = {1948-5204},
abstract = {This editorial discusses Alpsoy et al's significant study of prognosis of pancreatic ductal adenocarcinoma (PDAC), which lacks histopathological markers. This study evaluated the synergistic prognolymphocytes. Peritumoral budding is significantly correlated with tumor volume, while intratumoral budding is closely related to lymph node metastasis. Peritumoral budding and intratumoral budding are confirmed as independent adverse prognostic factors, and their high levels of expression are associated with immature stromal phenotypes, suggesting the key role of epithelial-mesenchymal transition. These breakthrough findings provide a new multidimensional biomarker system for the prognostic assessment of PDAC, and promote the clinical transformation process of incorporating tumor budding indicators into the pathological reporting process. However, the complexity and spatiotemporal heterogeneity of the tumor microenvironment require us to go beyond traditional morphological analysis and move towards multiomics integration and dynamic monitoring. Through standardized pathological assessment, innovative treatment strategies and interdisciplinary collaboration, it is expected to transform tumor microenvironment-related markers into clinically applicable indicators, ultimately improving the treatment predicament of PDAC. This editorial intended to summarize relevant studies and share some of our views, in order to offer perspectives for future research.},
}

@article {pmid41107100,
year = {2025},
author = {Palomeque, S and Loguercio, AD and Arrais, CAG and Sánchez, C and Pulido, C},
title = {Three-dimensionally printed and milled composite materials for definitive restorations. Part 2: Effect of surface treatment on the bond strength of light-polymerized resin cement and surface morphology.},
journal = {The Journal of prosthetic dentistry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.prosdent.2025.09.033},
pmid = {41107100},
issn = {1097-6841},
abstract = {STATEMENT OF PROBLEM: Evidence regarding the effect of surface treatment on the bond strength and surface morphology of 3-dimensionally (3D) printed and computer-aided design and computer-aided manufacturing (CAD-CAM) composite materials is sparse. Enhancing the bond strength to these materials and their surface modifications is essential for ensuring clinical success.

PURPOSE: The purpose of this in vitro study was to evaluate the microshear bond strength (µSBS) of light-polymerized resin cement and the surface morphology of composite materials for definitive indirect restorations after different pretreatments.

MATERIAL AND METHODS: Specimens (6×7×9 mm) from composite CAD-CAM materials were fabricated: 5 by 3D printing (Varseosmile Crown Plus - BEGO (VSC), Crowntec - Saremco Print (CWT), Biocrown - Prizma (BCN), Ceramic Crown - SprintRay (CCN), and Voxel Print - FGM (VXP) and 3 by milling: Cerasmart - GC (CSM), Brilliant Crios - Coltène (BCR), and Enamic - Vita (ENA). Thirteen specimens of each material were selected: 10 for μSBS and 3 for scanning electron microscopy (SEM). Two surface pretreatment protocols were applied: Airborne-particle abrasion with aluminum oxide followed by silane (AL+S), and 5% hydrofluoric acid followed by silane (HF+S). For µSBS testing, transparent cylindrical matrices were filled with light-polymerized resin cement. After 24-hour storage, the specimens were subjected to shear testing (crosshead speed of 1.0 mm/minute). The data were analyzed by 2-way variance analysis and the Bonferroni post hoc test (α=.05).

RESULTS: Within the HF+S groups, ENA exhibited the highest µSBS values (18.47 ±1.0 MPa), although no significant differences were found with VXP (16.12 ±1.4 MPa). The highest µSBS mean value was observed on the CCN surface after AL+S (19.49 ±2.8 MPa), followed by VSC (18.74 ±2.2 MPa) and CSM (18.45 ±1.1 MPa). The surface pattern with AL+S presented more evident irregularities on both printable and machinable materials.

CONCLUSIONS: Airborne-particle abrasion with aluminum oxide was found to be appropriate for both milled and printed materials. Hydrofluoric acid etching was not recommended for all types of CAD-CAM resin ceramics, even when followed by silane application.},
}

@article {pmid41103971,
year = {2025},
author = {Arachchige, ASPM},
title = {Rethinking ALS: Current understanding and emerging therapeutic strategies.},
journal = {AIMS neuroscience},
volume = {12},
number = {3},
pages = {391-405},
pmid = {41103971},
issn = {2373-7972},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of the upper and lower motor neurons, which leads to muscle atrophy, spasticity, and ultimately respiratory failure. The etiology of ALS remains unclear, though a combination of genetic and environmental factors is suspected. Advances in understanding ALS pathophysiology, including the role of RNA metabolism, mitochondrial dysfunction, and glutamate toxicity, have paved the way for new research directions. While Riluzole offers limited survival benefits, there is no cure, and treatment remains mostly supportive. This article summarizes the current understanding of ALS in terms of its pathophysiology, epidemiology, risk factors, clinical presentation, and treatment strategies.},
}

@article {pmid41101465,
year = {2025},
author = {Veenstra, J and Ozog, D and Stephens, A},
title = {Response to Bunick et al, "Response to Veenstra et al.'s 'Benzoyl Peroxide Acne Treatment Shows No Significant Association with Benzene-Related Cancers: A Multicenter Retrospective Analysis' on Statistical Design".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2025.09.104},
pmid = {41101465},
issn = {1097-6787},
}

@article {pmid41101301,
year = {2025},
author = {Sasidharan, A and Somayaji, Y and Fernandes, R},
title = {Shifting Microglial Phenotypes: Targeting Disease-Associated Microglia in Neurodegeneration.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00159},
pmid = {41101301},
issn = {1948-7193},
abstract = {Neurodegenerative disorders are marked by the gradual degeneration of neurons and deterioration of cognitive function. One key underlying factor in these diseases is neuroinflammation. An essential component of this process is microglia, which are the innate immune cells that maintain homeostasis in the brain. A common outcome of microglial dysregulation in neurodegenerative diseases is chronic neuroinflammation, which exacerbates neuronal damage and impairs synaptic function. This review focuses on the dual roles that disease-associated microglia (DAMs) play in neural inflammation and neuroprotection as well as their distinct transcriptional profile in neurodegenerative diseases. DAMs engage in phagocytosis to remove debris, in addition to releasing cytokines that promote inflammation. To create an effective medicine, it is imperative to comprehend these dual functions. The roles of DAMs in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are discussed, along with the mechanisms (such as the TREM2-APOE pathway) causing their activation. This review attempts to highlight the important aspects that could direct future investigations and treatment development by clarifying the interactions between DAMs and neurodegenerative diseases.},
}

@article {pmid41097004,
year = {2025},
author = {Daponte, A and Koros, C and Skarlis, C and Siozios, D and Rentzos, M and Papageorgiou, SG and Anagnostouli, M},
title = {Neurofilament Biomarkers in Neurology: From Neuroinflammation to Neurodegeneration, Bridging Established and Novel Analytical Advances with Clinical Practice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
pmid = {41097004},
issn = {1422-0067},
mesh = {Humans ; *Biomarkers/metabolism/blood ; *Neurofilament Proteins/metabolism/blood ; *Neurodegenerative Diseases/metabolism/diagnosis ; *Neuroinflammatory Diseases/metabolism/diagnosis ; Animals ; },
abstract = {Neuroaxonal damage underlies permanent disability in various neurological conditions, both neuroautoimmune and neurodegenerative. It is crucial to accurately quantify and monitor axonal injury using biomarkers to evaluate disease progression and treatment effectiveness and offer prognostic insights. Neurofilaments (NFs), and especially neurofilament light chain (NfL), show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. Recent advances in ultrasensitive immunoassays enable the reliable detection of NFs in blood, transforming them from research tools into clinically applicable measures. In multiple sclerosis (MS), serum NfL correlates with disease activity, treatment response, and long-term disability, and may complement MRI in monitoring subclinical progression. In MS, NfL is primarily emerging as a marker of disease activity and treatment response; in amyotrophic lateral sclerosis (ALS), it has progressed further, being integrated into clinical trials as a pharmacodynamic endpoint and considered by regulatory agencies as a drug development tool. Additionally, NFs are increasingly being investigated in Alzheimer's disease, frontotemporal dementia, and other neurodegenerative disorders, though their disease specificity is limited. Ongoing challenges include older and novel assay harmonization, normative range interpretation, biological and analytical variability, and integration with other molecular and imaging biomarkers. This critical narrative review synthesizes the existing literature on NFs as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers and discusses their role in therapeutic development and precision medicine in neuroautoimmune and neurodegenerative diseases.},
}

Humans
*Biomarkers/metabolism/blood
*Neurofilament Proteins/metabolism/blood
*Neurodegenerative Diseases/metabolism/diagnosis
*Neuroinflammatory Diseases/metabolism/diagnosis
Animals

@article {pmid41096667,
year = {2025},
author = {Skarlis, C and Angelopoulou, E and Rentzos, M and Papageorgiou, SG and Anagnostouli, M},
title = {Monoclonal Antibodies as Therapeutic Agents in Autoimmune and Neurodegenerative Diseases of the Central Nervous System: Current Evidence on Molecular Mechanisms and Future Directions.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
pmid = {41096667},
issn = {1422-0067},
mesh = {Humans ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/immunology ; Animals ; *Central Nervous System Diseases/drug therapy/immunology ; Neuromyelitis Optica/drug therapy ; Central Nervous System/drug effects/immunology ; Multiple Sclerosis/drug therapy ; },
abstract = {Monoclonal antibodies (mAbs) have revolutionized the treatment landscape for neurological diseases, providing targeted, mechanism-based therapies for conditions ranging from autoimmune demyelinating disorders to neurodegenerative diseases. In multiple sclerosis (MS), mAbs against CD20, CD52, and α4-integrins offer disease-modifying efficacy by altering immune responses, depleting B cells, or blocking leukocyte migration into the central nervous system (CNS). Similarly, novel agents under investigation, such as frexalimab and foralumab, modulate T and B cell interactions and regulatory immunity. In neuromyelitis optica spectrum disorder (NMOSD), mAbs targeting IL-6, the complement cascade, and B cell lineage have demonstrated significant clinical benefit in preventing relapses and disability. In Alzheimer's disease (AD), several anti-amyloid mAbs have gained regulatory approval. Anti-tau and anti-α-synuclein antibodies, though promising, have shown limited efficacy to date in AD and parkinson's disease (PD), respectively. The evolving armamentarium of mAbs reflects a paradigm shift toward personalized neuroimmunology and neurodegeneration-targeted treatments, based on ongoing clarification of molecular and neuroinflammatory mechanisms. In this context, the present review summarizes current evidence on mAbs used in CNS disorders, with an emphasis on their pathophysiological targets, molecular mechanisms, clinical efficacy, and safety.},
}

Humans
*Antibodies, Monoclonal/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy/immunology
Animals
*Central Nervous System Diseases/drug therapy/immunology
Neuromyelitis Optica/drug therapy
Central Nervous System/drug effects/immunology
Multiple Sclerosis/drug therapy

@article {pmid41096646,
year = {2025},
author = {García-Criado, F and Hurtado-García, L and Rojano, E and Esteban-Martos, Á and Pérez-García, J and Seoane, P and Ranea, JAG},
title = {Integrative Transcriptomic and Network-Based Analysis of Neuromuscular Diseases.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199376},
pmid = {41096646},
issn = {1422-0067},
support = {PID2019-108096RB-C21, PID2022-140047OB-C21, CPP2022-010108//Ministerio de Ciencia, Innovación y Universidades/ ; IMP/00019, ACCI-05-703, ACCI-02-770//Instituto de Salud Carlos III/ ; HORIZON-HLTH-2022-DISEASE-06, 101080580//European Union/ ; RH-0079-2021//Fundación Progreso y Salud/ ; PI RARE 24-03//Instituto de Investigación Biomédica de Málaga/ ; FPU21/01449, PRE2022/000510//Ministerio de Ciencia, Innovación y Universidades/ ; },
mesh = {Humans ; *Transcriptome ; *Neuromuscular Diseases/genetics/metabolism ; *Gene Regulatory Networks ; Protein Interaction Maps/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Gene Expression Profiling ; Muscular Dystrophy, Duchenne/genetics/metabolism ; Muscular Dystrophies, Limb-Girdle/genetics/metabolism ; Computational Biology/methods ; },
abstract = {Neuromuscular diseases (NMDs) like Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophy (LGMD), and amyotrophic lateral sclerosis (ALS) are rare, progressive disorders with complex molecular mechanisms. Traditional transcriptomic analyses often struggle to capture systems-level dysregulation, especially given the small sample sizes typical of rare disease studies. Our differential expression analysis of eight public RNA-seq datasets from various cell types in DMD, LGMD, and ALS revealed not only disease-relevant pathways but also unexpected enrichments, such as renal development, suggesting systemic impacts beyond muscle tissue. To address limitations in capturing broader molecular mechanisms, we applied an integrative systems biology approach combining differential expression data, protein-protein interaction (PPI) networks, and network embedding techniques. Comparative functional enrichment revealed shared pathways, including glycosaminoglycan binding in both DMD and FUS-related ALS, implicating extracellular matrix-protein interactions in FUS mutation effects. Mapping DEGs onto the human PPI network and assessing their proximity to causal genes uncovered dysregulated non-coding RNAs, such as PAX8-AS1, SBF2-AS1, and NEAT1, potentially indicating common regulatory roles. We also found candidate genes within disease-proximal clusters, like HS3ST3A1, which may contribute to pathogenesis. Overall, this integrative approach reveals shared transcriptional programs and novel targets, advancing our understanding and potential treatment strategies for NMDs.},
}

Humans
*Transcriptome
*Neuromuscular Diseases/genetics/metabolism
*Gene Regulatory Networks
Protein Interaction Maps/genetics
*Amyotrophic Lateral Sclerosis/genetics/metabolism
Gene Expression Profiling
Muscular Dystrophy, Duchenne/genetics/metabolism
Muscular Dystrophies, Limb-Girdle/genetics/metabolism
Computational Biology/methods

@article {pmid41095781,
year = {2025},
author = {Ferreira Laurentino, EK and Maldaner da Silva, VZ and Costa Meneses, WR and da Costa, LM and Otto-Yañez, M and Vera-Uribe, R and Torres-Castro, R and Carneiro de Sousa, BR and de Abreu Freitas, RP and Menezes Mateus, SR and Vasconcellos, IF and Fernandes Franco, HC and Pinto Nagem, DA and Medeiros Valentim, RA and Dourado Júnior, ME and Rodrigues Lindquist, AR and Santos Andrade, SMMD and Medeiros Fonseca, JD and Resqueti, VR and Freitas Fregonezi, G},
title = {High-Definition Transcranial Direct Current Stimulation (HD-tDCS) Therapy in Amyotrophic Lateral Sclerosis: Study Protocol for a Multicenter Randomized Controlled Clinical Trial.},
journal = {Journal of clinical medicine},
volume = {14},
number = {19},
pages = {},
doi = {10.3390/jcm14196701},
pmid = {41095781},
issn = {2077-0383},
support = {1748/22//Financiadora de Estudos e Projetos/ ; 88887.692599/2022-00 (JDMF)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 305960/2021-0 (VRR)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 316937/2021-5 (GF)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 001 (EKFL)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 001 (WRCM)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 001 (LMC)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 001 (BRCS)//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; },
abstract = {Background/Objectives: Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by motor neuron loss, muscle weakness, and respiratory dysfunction, often culminating in ventilatory failure. Evidence suggests that High-Definition Transcranial Direct Current Stimulation (HD-tDCS) may modulate motor cortical excitability and potentially influence motor and respiratory function in ALS. This study aims to evaluate the effects of home-based HD-tDCS applied over the primary diaphragmatic motor cortex on respiratory parameters and disease progression in individuals with ALS. Methods: This is a multicenter, randomized, controlled clinical trial. Eligible participants (aged 18-80, both sexes, diagnosed with ALS) will be randomized into an active HD-tDCS group (gTDCS) or a sham group (gSham). The intervention consists of 30 min daily HD-tDCS sessions (3 mA) applied for two weeks (5 days/week), using a 4 × 1 ring configuration targeting the diaphragmatic motor cortex. Sham stimulation includes an identical setup but only delivers ramp currents (30 s) with a minimal ongoing current (0.1 mA). Results: Pre-, intra-, and post-intervention evaluations will include measures of cortical excitability, cerebral and tissue perfusion, surface electromyography, respiratory and pulmonary function, fatigue, sleep quality, pain, motor performance, dyspnea, quality of life, and adverse effects. All procedures will be conducted at participants' homes with appropriate safety monitoring. Conclusions: This study will investigate the effects of HD-tDCS on respiratory and motor function in ALS and explore the feasibility of a home-based neuromodulation intervention. The outcomes may provide insight into non-pharmacological strategies for respiratory management in ALS.},
}

@article {pmid41095520,
year = {2025},
author = {Whelan, BM and Aldridge, D and Ruhle, J and Whitelock, P and Taubert, S and Collins, A and Kearney, E and Charania, S and Henderson, RD and Wallace, SJ and Mitchell, C and Stipancic, KL and Kuruvilla-Dugdale, M and Vogel, AP},
title = {To Treat or Not to Treat: A Scoping Review of Speech Treatment for Dysarthria in Amyotrophic Lateral Sclerosis (ALS).},
journal = {Healthcare (Basel, Switzerland)},
volume = {13},
number = {19},
pages = {},
doi = {10.3390/healthcare13192434},
pmid = {41095520},
issn = {2227-9032},
support = {N/A//University of Queensland, School of Health and Rehabilitation Sciences, New Staff Research Start-Up Fund/ ; },
abstract = {BACKGROUND: Speech loss is recognised as one of the most devastating outcomes for individuals with ALS, yet active speech intervention is rarely targeted in this population. Clinicians face significant challenges in managing dysarthria associated with ALS due to the rapidly progressive nature of the disease, historical concerns around intensive exercise accelerating decline, and an absence of direction on restorative and compensatory intervention strategies in current clinical care guidelines. This review evaluates the scope and quality of evidence for speech treatments in ALS to identify knowledge gaps and establish research priorities to guide clinical care.

METHODS: Studies were retrieved from six electronic databases (PubMed, CINAHL, Embase, Cochrane library, Web of Science, and PsycINFO).

RESULTS: Four studies met inclusion criteria. Treatment approaches included: music-based speech therapy; multisubsystem speech rehabilitation program, tongue strengthening and articulation training; and Lee Silverman Voice Treatment-LOUD[®] combined with additional voice and articulation therapy. Sample sizes were small, with all studies demonstrating notable methodological weaknesses. The limited evidence base, marked by conflicting results and methodological flaws, prevents any reliable conclusions about treatment effectiveness.

CONCLUSIONS: Despite the prevalence and impact of dysarthria in this population, evidence for speech treatment remains sparse, of generally low quality, and provides limited guidance for clinical practice. The changing perspective on exercise in ALS warrants rigorous investigation of tailored dysarthria interventions for this population that are minimally fatiguing and enhance speech by making use of residual physiologic support.},
}

@article {pmid41094045,
year = {2025},
author = {Li, A and Huang, S and Cao, SQ and Lin, J and Zhao, L and Yu, F and Huang, M and Yang, L and Xin, J and Wen, J and Yan, L and Zhang, K and Jiang, M and Le, W and Li, P and Liu, YU and Qin, D and Lu, J and Lu, G and Shen, H and Yao, X and Fang, EF and Su, H},
title = {Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy.},
journal = {EMBO molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {41094045},
issn = {1757-4684},
support = {0093/2024/AFJ//Macau University of Science and Technology (MUST)/ ; #81971327//MOST | National Natural Science Foundation of China (NSFC)/ ; #82271448//MOST | National Natural Science Foundation of China (NSFC)/ ; MYRGGRG2023-00152-ICMS-UMDF//MOST | National Natural Science Foundation of China (NSFC)/ ; #282952; #284930//Cure Alzheimer's Fund (CAF)/ ; #262175,#334361//research council of Norway/ ; 2020001,#2021021,#2023093//HELSE SOR-OST/ ; #282942//Molecule AG/VITADAO/ ; #119986//NordForsk/ ; 269901,#261973,#262960//Høgskolen i Oslo og Akershus (HiOA)/ ; #281931//civitan norges forskningsfond for Alzheimer skydom/ ; TO01000215//Ministerstvo Práce a Sociálních Věcí České Republiky (Ministry of Labour and Social Affairs of the Czech Republic)/ ; #101073251//horizon-TMA-MSCA-DN/ ; #104617//Burroughs Wellcome Fund (BWF)/ ; SKL-QRCM(UM)-2023-2025//Science and Technology Development Fund, MAR/ ; 001/2023/ALC//Science and Technology Development Fund, MAR/ ; },
abstract = {Damaged mitochondria initiate mitochondrial dysfunction-associated senescence, which is considered to be a critical cause for amyotrophic lateral sclerosis (ALS). Thus, mitophagic elimination of damaged mitochondria provides a promising strategy in ALS treatment. Here, through screening of a large natural compound library (n = 9555), we have identified isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba, as a robust and specific mitophagy inducer. ISO enhances PINK1-Parkin-dependent mitophagy via stabilization of the PINK1/TOM complex. In a translational perspective, ISO antagonizes ALS pathology in C. elegans and mouse models; intriguingly, ISO improves mitochondrial function and antagonizes motor neuron pathologies in three ALS patient-derived induced pluripotent stem cell systems (C9, SOD1, and TDP-43), highlighting a potential broad application to ALS patients of different genetic background. At the molecular level, ISO inhibits ALS pathologies in a PINK1-Parkin-dependent manner, as depletion or inhibition of PINK1 or Parkin blunts its benefits. These results support the hypothesis that mitochondrial dysfunction is a driver of ALS pathology and that defective mitophagy is a druggable therapeutic target for ALS.},
}

@article {pmid41093062,
year = {2025},
author = {Bunick, CG and Yang, K and Jafarian, F and Barbieri, JS},
title = {Response to Veenstra et al's "Benzoyl Peroxide Acne Treatment Shows No Significant Association with Benzene-Related Cancers: A Multicenter Retrospective Analysis" on Statistical Design.},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2025.10.042},
pmid = {41093062},
issn = {1097-6787},
}

@article {pmid41090678,
year = {2025},
author = {Jing, W and Shan, Y and Wu, H and Li, T and Tang, H and Sun, Y and Napattharin, V and Loong, S and Qin, B and Pan, W},
title = {Integrative treatment of the motor neuron disease amyotrophic lateral sclerosis, efficacy of pharmacotherapy, traditional Chinese medicine and importance of respiratory support, life-style, and gastrostomy-assisted nutrition: A review.},
journal = {International journal of clinical pharmacology and therapeutics},
volume = {63 (Suppl. 1)},
number = {},
pages = {S14-S25},
pmid = {41090678},
issn = {0946-1965},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/etiology/physiopathology ; *Gastrostomy ; *Medicine, Chinese Traditional ; *Life Style ; *Integrative Medicine/methods ; Treatment Outcome ; },
abstract = {Currently, there are no effective treatments for amyotrophic lateral sclerosis (ALS), a chronic progressive neurodegenerative disease. Although the etiology of ALS is unknown, it is thought that factors such as diet, the environment, and lifestyle habits play a role. The pathogenesis of ALS includes alterations in glutamate neurotransmission, oxidative stress, mitochondrial dysfunction. Drugs such as riluzole, edaravone, dextromethorphan/quinidine combinations, and the administration of tofersen by injection are approved treatment options for ALS although a number of other agents are being examined in clinical trials. Despite these developments, the availability of effective treatment options is limited. This review summarizes the etiology and pathogenesis of ALS and describes treatments in detail as an integrative medicine approach and including traditional Chinese medicine together with the importance of the timing for interventions, precautions necessary for noninvasive ventilator and gastrostomy surgery, and precautions for dealing with respiratory issues with the overall aim of providing state-of-the-art clinical recommendations for the care and therapy of ALS patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/etiology/physiopathology
*Gastrostomy
*Medicine, Chinese Traditional
*Life Style
*Integrative Medicine/methods
Treatment Outcome

@article {pmid41088992,
year = {2025},
author = {Essa, SM and Khosa, NA and Kakar, A and Öztürk, B and Ibrahim, IA and Haq, N},
title = {Unraveling the Potential of Stem Cell Therapy in Motor Neuron Disease: A Narrative Review.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273382519250918103218},
pmid = {41088992},
issn = {1996-3181},
abstract = {Motor neuron disorders (MNDs), including ALS, are deadly neurodegenerative conditions that cause progressive motor neuron degeneration. With neuroprotection and the potential for neuron regeneration employing MSCs, ESCs, iPSCs, and NSCs, stem cell treatment presents a viable alternative to current medicines, which only control a limited number of symptoms. Following PRISMA criteria, this narrative review methodically screened 1248 records from the Cochrane, Web of Science, PubMed, and Scopus databases. Following a thorough screening process, 22 studies, including preclinical models and 19 clinical trials, were analysed to assess the therapeutic mechanisms, safety, and efficacy of stem cell therapies for MNDs. Mesenchymal stem cell (MSC) therapy has shown a promising safety profile and possible therapeutic efficacy in ALS, with no substantial transplant-related toxicity noted. ALS functional rating scale-revised (ALSFRS-R) scores and forced vital capacity (FVC) assessments from clinical trials, such as those evaluating autologous bone marrow-derived MSCs, demonstrated stabilisation in ALS development. Studies have also emphasised as to how immunomodulation and neurotrophic factors play a part in MSC-based therapies. Recent data indicate that repeated intrathecal MSC injection could extend the duration of therapeutic advantages. Clinical trials have shown safety and early efficacy signals for motor neurons produced from embryonic stem cells (ESCs), especially using AstroRx®. This suggests that ESCs could be a viable option for regenerative medicine. Nonetheless, issues, like host integration and differentiation optimisation, still exist. Although clinical translation is still in its early stages, induced pluripotent stem cells (iPSCs) and their derivatives provide disease modelling and patient-specific therapeutic applications. Stem cell therapy holds promise for treating MND, with MSCs leading the way in current trials. It is necessary to enhance ESC- and iPSC-based techniques to tackle integration issues. To ensure long-term safety and efficacy, therapies must be developed using standardised protocols, patient stratification, optimised delivery, and large-scale studies.},
}

@article {pmid41086149,
year = {2025},
author = {Clackson, O and Hamid, MR and Wijesekera, A and Kulick, D and O'Neil, AL},
title = {Exposure to the organochlorine pesticide cis-chlordane induces ALS-like mitochondrial perturbations in stem cell-derived motor neurons.},
journal = {PloS one},
volume = {20},
number = {10},
pages = {e0332422},
pmid = {41086149},
issn = {1932-6203},
mesh = {*Motor Neurons/drug effects/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/chemically induced ; *Mitochondria/drug effects/metabolism/pathology ; Humans ; Reactive Oxygen Species/metabolism ; *Pesticides/toxicity ; *Chlordan/toxicity ; Membrane Potential, Mitochondrial/drug effects ; Animals ; Adenosine Triphosphate/metabolism ; Oxygen Consumption/drug effects ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a debilitating and incurable neurodegenerative disease with unsolved etiology. Due to the large proportion of patients lacking direct disease inheritance, understanding the environmental factors that contribute to ALS development is of high priority. Epidemiological studies have implicated pesticides and other environmental exposures as possible contributors to ALS pathogenesis. Recently, our group determined that the organochlorine pesticide cis-chlordane is toxic to human motor neurons in a dose-dependent manner, causing an ALS-like phenotype in culture and animals with a mode of action independent of its known GABAA antagonism. Here, we aimed to characterize downstream motor neuron phenotypes associated with cis-chlordane treatment. We performed bulk RNA sequencing, live imaging, immunofluorescent labeling, and real-time metabolic assays on stem cell-derived motor neurons to assess chlordane-associated phenotypes in vitro. We demonstrate that cis-chlordane treatment causes a highly altered mitochondrial phenotype in motor neurons, including increased production of reactive oxygen species, decreased oxygen consumption rate and ATP production, and loss of mitochondrial membrane potential. We further implicate cis-chlordane as a possible mediator of potent motor neuron damage, with exposure to the pesticide inducing mitochondrial phenotypes akin to those seen in ALS. Our findings contribute to the growing body of evidence that future studies of investigating the role of pesticides in ALS development should focus on organochlorine molecules.},
}

*Motor Neurons/drug effects/metabolism/pathology
*Amyotrophic Lateral Sclerosis/pathology/metabolism/chemically induced
*Mitochondria/drug effects/metabolism/pathology
Humans
Reactive Oxygen Species/metabolism
*Pesticides/toxicity
*Chlordan/toxicity
Membrane Potential, Mitochondrial/drug effects
Animals
Adenosine Triphosphate/metabolism
Oxygen Consumption/drug effects

@article {pmid41083392,
year = {2025},
author = {Guo, Y and Li, CJ and Wei, H and Ding, Y and Guo, LJ and Gao, YN},
title = {[Clinical analysis of a motor neuron disease-like phenotype associated with anti-IgLON5 disease].},
journal = {Zhonghua nei ke za zhi},
volume = {64},
number = {10},
pages = {977-983},
doi = {10.3760/cma.j.cn112138-20241018-00695},
pmid = {41083392},
issn = {0578-1426},
mesh = {Humans ; Aged ; Female ; *Autoantibodies/blood ; *Motor Neuron Disease/immunology/diagnosis ; Male ; Phenotype ; *Cell Adhesion Molecules, Neuronal/immunology ; Amyotrophic Lateral Sclerosis/immunology/diagnosis ; Electromyography ; },
abstract = {We report a case of anti-IgLON5 disease with a motor neuron disease-like presentation admitted to the Department of Neurology, Xuanwu Hospital, Capital Medical University in July 2021. The patient was a 71-year-old female who presented with the chief complaint of limb weakness persisting for 4 months. She showed progressive limb weakness accompanied by muscle atrophy. Electromyography (EMG) revealed extensive neurogenic damage. Initial serum evaluation for neural-specific autoantibodies was positive for IgLON5-Ab (1∶100). Repeat testing confirmed IgLON5-Ab positivity with a titer of 1∶1 000. The patient was diagnosed with anti-IgLON5 disease and treated with methylprednisolone and immunoglobulin, leading to clinical improvement. We found four relevant articles reporting a total of 11 similar cases. Thus, in this study, we analyzed a total of 12 cases, including our patient. Based on their clinical manifestations, these cases can be categorized into two types: amyotrophic lateral sclerosis(ALS)type and isolated bulbar type. Six cases-three males and three females-presented with the ALS type. Of these, three cases had diffuse limb weakness accompanied by muscle atrophy(two cases had diffuse hyperreflexia and one had a normal tendon reflex); one case presented with neck extensor weakness and bilateral asymmetric upper extremity weakness and was hyperreflexic at the bilateral patellar tendons; one case displayed asymmetric weakness in both lower limbs with normal deep reflexes, and one case exhibited neck weakness with hyperreflexia. EMG revealed diffuse lower motor neuron disease involving two or three regions. All patients tested positive for serum anti-IgLON5 antibodies. Four were also positive for anti-IgLON5 antibodies in cerebrospinal fluid, two were negative, and six were not tested. Among the 11 patients who received immunotherapy, 4 showed partial improvement in clinical symptoms, 2 exhibited transient improvement, 2 remained stable, and 3 showed no improvement. Testing for IgLON5-Ab should be considered among patients presenting with bulbar symptoms or ALS-like features, especially those with acute or subacute onset, rapid progression, autonomic dysfunction, vocal cord paralysis requiring tracheotomy, cognitive impairment, or involuntary movements. Early diagnosis and treatment may improve clinical symptoms and reduce adverse outcomes.},
}

Humans
Aged
Female
*Autoantibodies/blood
*Motor Neuron Disease/immunology/diagnosis
Male
Phenotype
*Cell Adhesion Molecules, Neuronal/immunology
Amyotrophic Lateral Sclerosis/immunology/diagnosis
Electromyography

@article {pmid41082679,
year = {2025},
author = {Tabor Gray, L and Sullivan, S and O'Brien, M and Costello, J and Plowman, E and Garand, KLF},
title = {International Survey of Practice Patterns of Speech-Language Pathologists Working With Patients With Amyotrophic Lateral Sclerosis.},
journal = {American journal of speech-language pathology},
volume = {},
number = {},
pages = {1-12},
doi = {10.1044/2025_AJSLP-25-00064},
pmid = {41082679},
issn = {1558-9110},
abstract = {BACKGROUND: Speech-language pathologists (SLPs) evaluate and treat swallowing and communication impairments in individuals with amyotrophic lateral sclerosis (ALS). Standardized clinical practice guidelines for the evaluation and management of bulbar dysfunction in ALS have not yet been established. This study aimed to describe current international practice patterns of SLPs evaluating and treating bulbar dysfunction in ALS.

HYPOTHESIS: Significant variability in practice patterns will exist across SLPs working in different clinical settings with varied resources.

METHOD: A 26-item Qualtrics survey was electronically distributed to SLPs via e-mail, social media, and professional discussion boards.

RESULTS: Data from 245 respondents across 20 countries and 32 states within the United States were collected, with the final analysis including 214 respondents. Most respondents practiced in metropolitan areas (69%) and worked in multidisciplinary ALS clinics (41%), outpatient clinics (16%), and home health settings (17%). Cranial nerve examination (91%), swallow trials (79%), speech intelligibility tasks (85%), and diadochokinetic speech rates (65%) were frequently included in evaluations. Although 81% of clinics had access to instrumental swallowing evaluations, 32% reported performing them in fewer than 25% of patients. Communication evaluations were offered directly by 58% of clinicians, while 26% referred to an outside SLP and 16% collaborated with device representatives. Most clinicians provided patient education on swallowing (87%) and oral health (83%). However, managed practice varied widely, revealing no standardized treatment that is routinely offered. Barriers to optimal ALS care included time constraints, relevant clinical training, timing of treatment, addressing psychosocial components of care, access to resources, interdisciplinary communication, and insurance coverage (United States only).

DISCUSSION: Findings reveal little consensus on symptomatic bulbar management and intervention timing. Results emphasize the urgent need for the development of a standardized minimal data set to best guide the evaluation and management of bulbar dysfunction in ALS.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.30249997.},
}

@article {pmid41076128,
year = {2025},
author = {Chen, CC and Chen, SC},
title = {Comments on Hong et al.'s "Radiotherapy Versus Imiquimod for Complex Lentigo Maligna: a Phase 3 Randomized Clinical Trial".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2025.08.128},
pmid = {41076128},
issn = {1097-6787},
}

@article {pmid41075758,
year = {2025},
author = {Gery, KL and Ramos, S and Lee, JC},
title = {Correlative Raman and immunofluorescence imaging reveals different protein abundance between stress granules induced by oxidative damage.},
journal = {Journal of inorganic biochemistry},
volume = {274},
number = {},
pages = {113091},
doi = {10.1016/j.jinorgbio.2025.113091},
pmid = {41075758},
issn = {1873-3344},
abstract = {Heavy metal toxicity generates reactive oxygen species (ROS) that can contribute to neurodegeneration. Oxidative damage from exposure to metals such as sodium arsenite will activate the integrated stress response and may result in the cytosolic formation of stress granules (SGs), which have been implicated in neurodegenerative disorders such as amyotrophic lateral sclerosis. Here, two different ROS sources, sodium arsenite and hydrogen peroxide, under acute (1 h) and chronic (24 h) conditions, were used to induce SG formation in human osteosarcoma (U-2 OS) cells and investigate if characteristics of SGs could depend on the induction. Specifically, correlative Raman and immunofluorescence imaging (CRIFI) was developed to evaluate the relative protein abundance found in SGs to ascertain their potential as loci for protein accumulation. Interestingly, while there are differences in the punctate-staining phenotypes for different stressors, two types of puncta visualized by CRIFI were common to all treatment conditions, where notably a subset exhibited protein concentration above cytosolic background, indicating that only some SGs are composed of protein-rich, dense phases. Differences in protein abundance between SGs were also observed within a single cell, suggesting that individual SGs can develop differently. These results demonstrate the versatility and the strength of pairing Raman spectroscopy, which allows for probe-free detection of different chemical functional groups, with specific protein localization granted by immunofluorescence, providing new cellular insights unattainable by either modality alone.},
}

@article {pmid41074071,
year = {2025},
author = {Cole, A and Chege, T and Aman, R and Githuka, G and Muga, R and Aspinall, A and Kokwaro, G},
title = {Health system challenges and facilitators associated with adaptive cycling deployment of multiple first-line treatment for uncomplicated malaria: a pilot study in a malaria-endemic region of Kenya.},
journal = {Malaria journal},
volume = {24},
number = {1},
pages = {328},
pmid = {41074071},
issn = {1475-2875},
support = {PO20/00538//Medicines for Malaria Venture/ ; },
mesh = {Kenya ; Pilot Projects ; *Antimalarials/therapeutic use/administration & dosage ; Humans ; Artemisinins/therapeutic use ; *Malaria/drug therapy ; Female ; Adult ; Male ; Drug Combinations ; Young Adult ; Drug Therapy, Combination ; Adolescent ; Middle Aged ; Artemether, Lumefantrine Drug Combination/therapeutic use ; Amodiaquine/therapeutic use ; },
abstract = {BACKGROUND: Artemisinin-based combination therapy (ACT) has been first-line treatment for uncomplicated malaria in sub-Saharan Africa for over two decades. However, emerging artemisinin partial resistance threatens efficacy. Multiple first-line treatments (MFTs) represent a proposed mitigation strategy, though associated health systems challenges remain unknown. This study evaluated health systems challenges and facilitators for MFT implementation in western Kenya.

METHODS: A 2 year pilot study (June 2020-June 2022) implemented adaptive cycling of four artemisinin-based combinations: Artemether-Lumefantrine (AL), Dihydroartemisin-Piperaquine (DHA-PIP), Amodiaquine-Artesunate (ASAQ), and Pyronaridine-Artesunate (PYR-ART) in western Kenya. Homa Bay (implementation) and Migori (control) counties were compared. Implementation involved 8 month drug cycling on mainland and 12 month cycling on Mfangano Island, while control county continued AL throughout. Adult patients diagnosed with uncomplicated malaria were included (pregnant women and children < 5 years excluded). Health systems assessment used semi-structured questionnaires, key informant interviews, and exit interviews. Outcome measures included diagnostic kit availability, procurement logistics, information system alignment, human resources, stakeholder acceptance, and side effects. Costs were tracked using ingredient approach, and malaria cases compared between counties.

RESULTS: MFT was accepted by key stakeholders. One minor adverse effect (vomiting) was reported. Patients preferred simple once-daily dosing of new drugs over AL's complicated regimen. Major challenges included logistics inefficiencies in drug quantification and stock management, human resource constraints, information system reconfiguration needs, and frequent diagnostic kit stock-outs. Start-up and implementation costs were roughly equal. Economic cost per patient treated was USD 3, lower than reported elsewhere in sub-Saharan Africa. Digital health tools (SMS/WhatsApp) facilitated implementation through improved communication and follow-up. Migori (control) showed 12.5 percentage points higher malaria positivity rates (23.3% vs 10.8%) with better directional consistency. Testing efficiency differed markedly (4.3 vs 9.2 tests per positive case) between counties.

CONCLUSION: Adaptive cycling MFT implementation is feasible in Kenya with adequate planning and addressing health systems challenges. Stakeholder engagement and continuous training were critical for success. Policy implications and regional cooperation potential warrant exploration in other sub-Saharan African countries with different deployment contexts.},
}

Kenya
Pilot Projects
*Antimalarials/therapeutic use/administration & dosage
Humans
Artemisinins/therapeutic use
*Malaria/drug therapy
Female
Adult
Male
Drug Combinations
Young Adult
Drug Therapy, Combination
Adolescent
Middle Aged
Artemether, Lumefantrine Drug Combination/therapeutic use
Amodiaquine/therapeutic use

@article {pmid41073493,
year = {2025},
author = {Montazeri, S and Bijani, S and Rashidzadeh, H and Ramazani, A and Andalib, S and Kalantari-Hesari, A and Cheraghi, G and Hosseini, MJ},
title = {Application of edaravone-loaded nanogel in alleviating behavioral deficits and oxidative stress in schizophrenia rat model.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {35468},
pmid = {41073493},
issn = {2045-2322},
support = {4000397//National Institute for Medical Research Development/ ; },
mesh = {Animals ; *Oxidative Stress/drug effects ; *Schizophrenia/drug therapy/metabolism ; *Edaravone/administration & dosage/pharmacology ; Rats ; Disease Models, Animal ; *Nanogels/chemistry ; Male ; Glutathione/chemistry ; *Behavior, Animal/drug effects ; Rats, Sprague-Dawley ; Prefrontal Cortex/drug effects/metabolism ; },
abstract = {Schizophrenia is considered as a main one of the public health issues, and imposes numerous burdens on patients and society. We previously reported, the pathophysiology of schizophrenia is influenced by inflammation and mitochondrial dysfunction. Edaravone (EDV) as a potent antioxidant with neuroprotective traits, has been approved for the treatment of amyotrophic lateral sclerosis (ALS), effecting through neutralizing soluble/insoluble peroxyl radicals. However, the main disadvantages of EDV are its low stability in aqueous media, poor water solubility, and un-optimized bioavailability. To effectively address these obstacles, nanogel was utilized as the drug vehicle. The decoration of nanogel surface with glutathione (GSH) was carried out to elevate edaravone's brain delivery. The probable improvement in drug delivery of edaravone loaded GSH-nanogel is the main hypothesis of this study. In order to mimic schizophrenia-like behaviors, we applied two month of post-weaning social isolation stress (PWSI) to rodent model. The choice of PWSI model was made due to the maturation and development of prefrontal cortex and hippocampus during adolescence. In addition to causing oxidative stress and upregulating genes linked to innate immunity in the prefrontal cortex (PFC), the data showed that PWSI triggered schizophrenia-like behaviors in rats. This study demonstrated that treatment with edaravone loaded GSH-nanogel decreased the impact of PWSI on behavioral dysfunctions and oxidative stress in the PFC of rats. Edaravone loaded GSH-nanogel (GSH-PMAA-EDV) down-regulated Toll-like receptor 4 (Tlr-4) and AMP-activated protein kinase (Ampk) gene expression which are involved in inflammation and cellular energy homeostasis, respectively. Increase immunoreactivity feedback and Brain-derived neurotrophic factor (Bdnf) as direct impact in neurogenesis and neural cell plasticity was observed in EDV loaded GSH-nanogel treated groups. edaravone loaded GSH-nanogel (100 µg/kg) in comparison to free form of edaravone (5 mg/kg) revealed more beneficial effects, which might be useful for future clinical use especially for the treatment of schizophrenia.},
}

Animals
*Oxidative Stress/drug effects
*Schizophrenia/drug therapy/metabolism
*Edaravone/administration & dosage/pharmacology
Rats
Disease Models, Animal
*Nanogels/chemistry
Male
Glutathione/chemistry
*Behavior, Animal/drug effects
Rats, Sprague-Dawley
Prefrontal Cortex/drug effects/metabolism

@article {pmid41072581,
year = {2025},
author = {Schundler, SF and Amber, KT},
title = {Response to Cao et al.'s "Efficacy, safety, and B-cell depletion capacity of three rituximab dosing regimens in the treatment of moderate-to-severe pemphigus vulgaris and pemphigus foliaceus: a 52-week clinical trial".},
journal = {Journal of the American Academy of Dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaad.2025.08.126},
pmid = {41072581},
issn = {1097-6787},
}

@article {pmid41066153,
year = {2025},
author = {Su, W and Zhang, C and Sun, L and Xu, H and Zhang, G and Xue, F and Leng, Q and Niu, Y and Wu, R},
title = {Multifaceted Mechanisms of Cyprosulfamide in Mitigating Mesosulfuron-Methyl Phytotoxicity in Maize Seedlings: GST Activation, Oxidative Stress Alleviation, and Target-Site Competition.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.5c07590},
pmid = {41066153},
issn = {1520-5118},
abstract = {Mesosulfuron-methyl (MS), a sulfonylurea herbicide used in wheat, poses significant residual phytotoxicity risks to subsequent maize (Zea mays L.) crops. This study evaluated the protective role of the safener cyprosulfamide (CSA) through physiological, biochemical, and molecular analyses. MS treatment drastically reduced maize shoot length and fresh weight by 80.74% and 74.24%, respectively, while CSA pretreatment significantly relieved these inhibitory effects, with the mitigation rates of shoot length and fresh weight reaching 66.3% and 63.57%, respectively. Physiologically, CSA alleviated MS-induced chlorophyll and carotenoid losses and reduced oxidative stress by lowering malondialdehyde (MDA) levels (23.39% at 6 days after sowing) while enhancing superoxide dismutase (SOD) and glutathione S-transferase (GST) activity. Molecularly, CSA upregulated nine GST genes, competitively bound to ZmALS1/2, increasing acetolactate synthase (ALS) activity by 70-146%, and reduced MS residues in shoots (4.02%) and roots (33.78%). These findings demonstrate CSA's multifunctional detoxification mechanism, combining gene activation, antioxidant regulation, and target-site competition, offering a viable strategy to mitigate herbicide carryover in crop rotations. CSA application could significantly reduce MS phytotoxicity, advancing sustainable herbicide management.},
}

@article {pmid41065069,
year = {2025},
author = {Shan, Y and Jing, W and Zhang, H and Liu, Y and Wei, S and Wu, F and Pan, W},
title = {Amyotrophic lateral sclerosis rehabilitation management and non-pharmacological symptomatic treatment: A review.},
journal = {International journal of clinical pharmacology and therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.5414/CP204744},
pmid = {41065069},
issn = {0946-1965},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that lacks effective treatment options for the prevention of progression. Relieving swallowing difficulties, reducing breathing difficulties, and alleviating muscle spasms are essential to improving the quality of life in patients with ALS. Many symptoms can be treated clinically with medication; however, the evidence level of related research is relatively low. Rehabilitation management can aid in improving various functional impairments and enhancing quality of life. This review introduces and describes the relevant evaluations of rehabilitation and nonpharmacological symptomatic treatment methods for functional disorders from the perspectives of motor and nonmotor symptoms. This review may promote the popularization of ALS rehabilitation management and provide an additional reference for ALS treatment.},
}

@article {pmid41061670,
year = {2025},
author = {James, RE and Bekier, M and Lee, PJ and Schroeder, FA and Evans, LT and Wagner, FF and Hickman, D and Richardson, T and Hatzipetros, T and Vieira, F and Callizot, N and Modi, S and Hooker, JM and Kranz, JE and Brown, RH and Barmada, SJ and Gilbert, TM},
title = {A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf380},
pmid = {41061670},
issn = {1460-2156},
abstract = {Dysregulated proteostasis and intracellular transport contribute to neurodegeneration. HDAC6, a therapeutic target of interest for neurodegenerative diseases, acts at a nexus modulating both proteostasis and intracellular transport. Inhibition of HDAC6 deacetylase activity promotes autophagic clearance of protein aggregates and increases ⍺-tubulin acetylation, thereby enhancing microtubule resiliency and motor protein-microtubule binding, which facilitates intracellular transport and, subsequently, proteostasis. Despite these benefits, advancement of HDAC6 inhibitor therapeutics for neurodegenerative disease has been hindered by inadequate selectivity and CNS-penetrance of first-generation compounds. Here we characterize a next-generation small molecule HDAC6 inhibitor, EKZ-438, in preclinical models of amyotrophic lateral sclerosis and frontotemporal dementia. We present the pharmacological properties of EKZ-438, which demonstrate high selectivity for HDAC6 (>8,500-fold selectivity for HDAC6 versus all other HDAC6 paralogs), low nanomolar potency (12 nM) for HDAC6, and, importantly, CNS-penetrance (Kp,uu,brain) ≥ 0.55 and high oral bioavailability (F% = 70). In complementary preclinical in vitro and in vivo immunolabeling and live imaging studies we tested the hypothesis that selective inhibition of HDAC6 deacetylase activity is sufficient to improve pathophysiological proteostasis and intracellular transport deficits in animal models of familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia. Notably, we extended these findings to human induced pluripotent stem cell-derived neuronal cellular models, supporting the relevance of our findings to human disease. EKZ-438 treatment fully rescued SOD1 (q < 0.0001) and TDP-43 (q < 0.001) proteostasis defects following an excitotoxic glutamate challenge, and increased survival of SOD1G93A and wildtype motor neurons by 59% (q < 0.0001) and 37% (q < 0.01), respectively, demonstrating in vitro neuroprotection. In SOD1G93A mice, EKZ-438 improved axonal transport by 16% (q < 0.05), motor performance by ∼40% (q < 0.05), and decreased plasma neurofilament light chain levels by 35% (q < 0.05), demonstrating in vivo neuroprotection. In a TDP-43 mouse model, EKZ-438 reduced TDP-43 pathology by ∼30% (q < 0.05) and neuroinflammation by ∼26% (q < 0.05) in the brain, supporting HDAC6 inhibition for sporadic amyotrophic lateral sclerosis and frontotemporal dementia. Furthermore, EKZ-438 treatment improved intracellular transport by 39% (q < 0.001), rescued cytoplasmic TDP-43 accumulation by 87% (q < 0.0001), and restored nuclear TDP-43 splicing activity (P < 0.05) in human TARDBP neurons. These mechanistic improvements aligned with nearly complete rescue of human TARDBP and C9orf72 mutant neuron survival (P < 0.0001). We conclude that selective HDAC6 inhibition represents a promising therapeutic approach for potential disease modification in amyotrophic lateral sclerosis and frontotemporal dementia.},
}

@article {pmid41058966,
year = {2024},
author = {Donohue, C and Perry, B and Focht Garand, KL},
title = {A Clinical Focus on Shared Decision Making in Clinical Practice When Providing Dysarthria and Dysphagia Services to Individuals With Amyotrophic Lateral Sclerosis.},
journal = {Perspectives of the ASHA special interest groups},
volume = {9},
number = {4},
pages = {1003-1015},
pmid = {41058966},
issn = {2381-4764},
support = {K23 NS123369/NS/NINDS NIH HHS/United States ; L30 NS123988/NS/NINDS NIH HHS/United States ; },
abstract = {PURPOSE: Traditional health care decision-making models center on clinicians making decisions for patients/caregivers based on the best available research evidence. However, this diminishes patient/caregiver involvement in their care and hinders the ability to align care plans with patient values and preferences. Shared decision making is a potentially beneficial process to implement with individuals with amyotrophic lateral sclerosis (ALS) to provide more holistic, patient-centered dysarthria and dysphagia treatment. Shared decision making promotes active involvement by patients/caregivers by informing them of potential treatment options, understanding their values and preferences, and aligning their desires with treatment options to determine the most optimal individualized care plan.

CONCLUSIONS: The benefits and barriers to incorporating shared decision making within ALS multidisciplinary clinics are discussed in this clinical focus article. Furthermore, a fictional case study example of how to apply shared decision making to dysarthria and dysphagia management of individuals with ALS is provided.},
}

@article {pmid41057909,
year = {2025},
author = {Hunter, E and Alshaker, H and Bundock, O and Weston, C and Bautista, S and Gebregzabhar, A and Virdi, A and Croxford, J and Dring, A and Powell, R and Vugrinec, D and Kingdon, C and Wilson, C and Dowrick, S and Green, J and Akoulitchev, A and Pchejetski, D},
title = {Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch[®] 3-dimensional genomic regulatory immuno-genetic profiling.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {1048},
pmid = {41057909},
issn = {1479-5876},
support = {6514//Oxford BioDynamics plc, Oxford UK/ ; },
abstract = {UNLABELLED: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating, multifactorial disorder characterised by profound fatigue, post-exertional malaise, cognitive impairments, and autonomic dysfunction. Despite its significant impact on quality of life, ME/CFS lacks definitive diagnostic biomarkers, complicating diagnosis and management. Recent evidence highlights potential blood tests for ME/CFS biomarkers in immunological, genetic, metabolic, and bioenergetic domains. Chromosome conformations (CCs) are potent epigenetic regulators of gene expression and cross-tissue exosome signalling. We have previously developed an epigenetic assay, EpiSwitch[®], that employs an algorithm-based CCs analysis. Using EpiSwitch[®] technology, we have shown the presence of disease-specific CCs in peripheral blood mononuclear cells (PBMCs) of patients with amyotrophic lateral sclerosis (ALS), rheumatoid arthritis (RA), prostate and colorectal cancers, diffuse Large B-cell lymphoma and severe COVID-19. In a recent paper, we have identified a profile of systemic chromosome conformations in cancer patients reflective of the predisposition to respond to immune checkpoint inhibitors, PD-1/PD-L1 antagonists, with 85% accuracy. In this Retrospective case/control study (EPI-ME, Epigenetic Profiling Investigation in Myalgic Encephalomyelitis), we used whole blood samples retrospectively collected from n = 47 patients with severe ME/CFS and n = 61 age-matched healthy control patients to perform whole-genome 3D DNA screening for CCs correlating to ME/CFS diagnosis. We identified a 200-marker model for ME/CFS diagnosis (Episwitch[®]CFS test). First testing on the retrospective independent validation cohort demonstrated a strong systemic ME/CFS signal with a sensitivity of 92% and a specificity of 98%.Pathways analysis revealed several likely contributors to the pathology of ME/CFS, including interleukins, TNFα, neuroinflammatory pathways, toll-like receptor signalling and JAK/STAT. Comparison with pathways involved in the action of Rituximab and glatiramer acetate (Copaxone) (therapies with potential in ME/CFS treatment) identified IL2 as a shared pathway with clear patient clustering, indicating a possibility of a potential responder group for targeted treatment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07203-w.},
}

@article {pmid41055678,
year = {2025},
author = {Byrne, SM and McClelland, J and Fursland, A},
title = {The Overlooked Burden of Atypical Anorexia Nervosa: Commentary on Melville et al. (2025).},
journal = {The International journal of eating disorders},
volume = {58},
number = {10},
pages = {1907-1910},
pmid = {41055678},
issn = {1098-108X},
mesh = {Humans ; *Anorexia Nervosa/diagnosis/epidemiology ; Body Mass Index ; *Obesity/epidemiology ; Adult ; },
abstract = {Obesity and eating disorders (EDs) have historically been viewed as distinct conditions; however, emerging evidence suggests a significant overlap, particularly among individuals seeking obesity treatment. While binge-eating disorder (BED) is commonly identified in this population, restrictive EDs such as atypical anorexia nervosa (atypical AN) can go largely undetected. This paper comments on findings from Melville et al.'s systematic review of 85 studies assessing ED prevalence in adults with high Body Mass Index (BMI) seeking obesity treatment. We highlight the striking absence of atypical AN diagnoses despite substantial evidence supporting its prevalence in broader populations. We explore several reasons for this under-recognition, including the definitional ambiguities of atypical AN in the DSM-5, limitations of assessment tools that emphasize binge eating, and weight stigma that tends to mask restrictive eating as "normal" dieting. The implications are significant: failure to identify atypical AN may lead to delayed or inappropriate care and reinforce harmful stereotypes that restrictive EDs only affect underweight individuals. We argue for greater clinical vigilance, the refinement and clarification of diagnostic criteria and the development of validated tools for detecting atypical AN, particularly in higher-weight individuals. Clinicians, particularly those providing weight loss interventions, should be trained to identify restrictive eating irrespective of BMI and prioritize behaviors and psychological impairment over weight status. Recognizing atypical AN as a serious, underdiagnosed condition is critical to ensuring ethical, equitable and effective care across the weight spectrum, in both ED and weight-loss treatment settings.},
}

Humans
*Anorexia Nervosa/diagnosis/epidemiology
Body Mass Index
*Obesity/epidemiology
Adult

@article {pmid41053519,
year = {2025},
author = {Amiri, M and Afshary, H and Bezaatpour, A and Hatamikia, S and Wei, J and Boukherroub, R and Szunerits, S},
title = {A critical review on neurodegenerative biomarker diagnostics: where is the field heading to?.},
journal = {Analytical and bioanalytical chemistry},
volume = {},
number = {},
pages = {},
pmid = {41053519},
issn = {1618-2650},
abstract = {Neurodegenerative diseases (NDD), a collection of disorders with different underlying causes and clinical presentations, are recognized as a major area of concern of our society today. The most common NDD are Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease, each one of them being characterized by the progressive degradation of nerve cells and accumulation of misfolded and aggregated proteins in the affected brain region. Diagnosing NDD is challenging, due to the heterogeneity of the disease and the overlap of symptoms. Yet, early detection and accurate diagnosis are crucial for effective NDD management. With the emergence of disease-modifying therapies for AD, monitoring disease progression and treatment success is becoming essential. The future of NND diagnostics is focusing on developing less invasive, cost-effective strategies that enable early NDD identification and detection with improved patient outcomes. The integration of biotechnology and nanotechnology is seen as crucial for advancing the analytical science aspect of NDD. The creation of these innovative tools and methodologies is on the verge of enabling new possibilities for clinical diagnostics, but is also faced with several hurdles that will be critically evaluated.},
}